Oncogenic KRAS plays a vital role in controlling tumor metabolism by enhancing aerobic glycolysis. Obesity driven by chronic consumption of high-fat diet (HFD) is a major risk factor for oncogenic KRAS-mediated pancreatic ductal adenocarcinoma (PDAC). However, the role of HFD in KRAS-mediated metabolic reprogramming has been obscure. Here, by using genetically engineered mouse models expressing an endogenous level of KRASG12D in pancreatic acinar cells, we demonstrate that hyperactivation of KRASG12D by obesogenic HFD, as compared to carbohydrate-rich diet, is responsible for enhanced aerobic glycolysis that associates with critical pathogenic responses in the path towards PDAC. Ablation of Cox-2 attenuates KRAS hyperactivation leading to the reversal of both aggravated aerobic glycolysis and high-grade dysplasia under HFD challenge. Our data highlight a pivotal role of the cooperative interaction between obesity-ensuing HFD and oncogenic KRAS in driving the heightened aerobic glycolysis during pancreatic tumorigenesis and suggest that in addition to directly targeting KRAS and aerobic glycolysis pathway, strategies to target the upstream of KRAS hyperactivation may bear important therapeutic value.

Authors

Wang, D; Bi, Y; Hu, L; Luo, Y; Ji, J; Mao, AZ; Logsdon, CD; Li, E; Abbruzzese, JL; Li, Z; Yang, VW; Lu, W

MLA Citation

Wang, D, Bi, Y, Hu, L, Luo, Y, Ji, J, Mao, AZ, Logsdon, CD, Li, E, Abbruzzese, JL, Li, Z, Yang, VW, and Lu, W. "Obesogenic high-fat diet heightens aerobic glycolysis through hyperactivation of oncogenic KRAS." Cell Communication and Signaling : Ccs 17.1 (February 28, 2019): 19-null.

PMID

30819189

Source

epmc

Published In

Cell Communication and Signaling : Ccs

Volume

17

Issue

1

Publish Date

2019

Start Page

19

DOI

10.1186/s12964-019-0333-7

Pancreatic cancer is a highly lethal disease and is projected to become the second leading cause of cancer-related death by 2020. Among the different subtypes, pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer. The genetic landscape of PDAC shows nearly ubiquitous mutations of KRAS. However, expression of KRAS somatic mutants alone is insufficient to drive PDAC. Redox deregulation may contribute significantly to KRAS-mediated PDAC. Thus, measurement of cellular reactive oxygen species (ROS) levels is essential to determine how oxidative stress affects mutant KRAS and modulates intracellular signaling pathways leading to the change of cellular functions and the development of PDAC. Here we describe the protocol for comparative measurement of several key forms of ROS, including intracellular and mitochondrial levels of superoxide as well as extracellular H2O2 and general cellular ROS, with oxidation-sensitive fluorescent probes using flow cytometry in pancreatic cancer cells or mutant KRAS transformed cells.

Authors

Luo, Y; Wang, D; Abbruzzese, JL; Lu, W

MLA Citation

Luo, Y, Wang, D, Abbruzzese, JL, and Lu, W. "Measurement of Reactive Oxygen Species by Fluorescent Probes in Pancreatic Cancer Cells." Methods in Molecular Biology (Clifton, N.J.) 1882 (January 2019): 207-219.

PMID

30378057

Source

epmc

Published In

Methods in Molecular Biology (Clifton, N.J.)

Volume

1882

Publish Date

2019

Start Page

207

End Page

219

DOI

10.1007/978-1-4939-8879-2_19

Authors

Stephens, SJ; Czito, B; Zhang, X; Duffy, E; Malicki, M; Pitcher, B; Niedzwiecki, D; Abbruzzese, J; Uronis, H; Blobe, G; Blazer, DG; Willett, CG; Palta, M

MLA Citation

Stephens, SJ, Czito, B, Zhang, X, Duffy, E, Malicki, M, Pitcher, B, Niedzwiecki, D, Abbruzzese, J, Uronis, H, Blobe, G, Blazer, DG, Willett, CG, and Palta, M. "Surgical and Pathologic Outcomes in Patients on a Phase II Trial of Neoadjuvant Chemotherapy and Hypofractionated Image-Guided Intensity Modulated Radiation Therapy (HIGRT) in Resectable and Borderline Resectable Pancreatic Cancer.": Elsevier BV, November 2018.

Source

crossref

Published In

International Journal of Radiation Oncology, Biology, Physics

Volume

102

Issue

3

Publish Date

2018

Start Page

S180

End Page

S180

DOI

10.1016/j.ijrobp.2018.07.056

Authors

Moschos, SJ; Eroglu, Z; Khushalani, NI; Kendra, KL; Ansstas, G; In, GK; Wang, P; Liu, G; Collichio, FA; Arrowood, CC; Reed, JE; Garrett-Mead, N; Thomas, NE; Ollila, DW; Ivy, SP; Ivanova, A; Dees, EC; Abbruzzese, JL

MLA Citation

Moschos, SJ, Eroglu, Z, Khushalani, NI, Kendra, KL, Ansstas, G, In, GK, Wang, P, Liu, G, Collichio, FA, Arrowood, CC, Reed, JE, Garrett-Mead, N, Thomas, NE, Ollila, DW, Ivy, SP, Ivanova, A, Dees, EC, and Abbruzzese, JL. "NCI 9922: Phase II study of ibrutinib in treatment-refractory distant metastatic cutaneous melanoma (DMCM)." 43rd ESMO Congress (ESMO). October 19, 2018 - October 23, 2018. Munich, GERMANY.: OXFORD UNIV PRESS, October 1, 2018.

Source

wos

Published In

Annals of Oncology

Volume

29

Publish Date

2018

Start Page

453

End Page

453

Authors

Turner, MC; Cerullo, M; Adam, M; Shah, KN; Blazer, DG; Abbruzzese, JL; Zani, S

MLA Citation

Turner, MC, Cerullo, M, Adam, M, Shah, KN, Blazer, DG, Abbruzzese, JL, and Zani, S. "Adjuvant Chemotherapy Should Follow Pancreaticoduodenectomy for Pancreatic Adenocarcinoma, Despite Delays.": Elsevier BV, October 2018.

Source

crossref

Published In

Journal of the American College of Surgeons

Volume

227

Issue

4

Publish Date

2018

Start Page

S169

End Page

S169

DOI

10.1016/j.jamcollsurg.2018.07.359

Specificity protein (Sp) transcription factors (TFs) such as Sp1 are critical for early development but their expression decreases with age and there is evidence that transformation of normal cells to cancer cells is associated with upregulation of Sp1, Sp3, and Sp4, which are highly expressed in cancer cells and tumors. Sp1 is a negative prognostic factor for pancreatic, colon, glioma, gastric, breast, prostate, and lung cancer patients. Functional studies also demonstrate that Sp TFs regulate genes responsible for cancer cell growth, survival, migration/invasion, inflammation and drug resistance, and Sp1, Sp3 and Sp4 are also nononcogene addiction (NOA) genes and important drug targets. The mechanisms of drug-induced downregulation of Sp TFs and pro-oncogenic Sp-regulated genes are complex and include ROS-dependent epigenetic pathways that initially decrease expression of the oncogene cMyc. Many compounds such as curcumin, aspirin, and metformin that are active in cancer prevention also exhibit chemotherapeutic activity and these compounds downregulate Sp TFs in cancer cell lines and tumors. The effects of these compounds on downregulation of Sp TFs in normal cells and the contribution of this response to their chemopreventive activity have not yet been determined. Cancer Prev Res; 11(7); 371-82. ©2018 AACR.

Authors

Safe, S; Abbruzzese, J; Abdelrahim, M; Hedrick, E

MLA Citation

Safe, S, Abbruzzese, J, Abdelrahim, M, and Hedrick, E. "Specificity Protein Transcription Factors and Cancer: Opportunities for Drug Development." Cancer Prevention Research (Philadelphia, Pa.) 11.7 (July 2018): 371-382. (Review)

PMID

29545399

Source

epmc

Published In

Cancer Prevention Research

Volume

11

Issue

7

Publish Date

2018

Start Page

371

End Page

382

DOI

10.1158/1940-6207.capr-17-0407

Authors

Palta, M; Czito, BG; Duffy, E; Malicki, M; Niedzwiecki, D; Abbruzzese, JL; Uronis, HE; Blobe, GC; Blazer, DG; Willett, C

MLA Citation

Palta, M, Czito, BG, Duffy, E, Malicki, M, Niedzwiecki, D, Abbruzzese, JL, Uronis, HE, Blobe, GC, Blazer, DG, and Willett, C. "A phase II trial of neoadjuvant gemcitabine/nab-paclitaxel and SBRT for potentially resectable pancreas cancer: An evaluation of acute toxicity.": American Society of Clinical Oncology (ASCO), May 20, 2018.

Source

crossref

Published In

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology

Volume

36

Issue

15_suppl

Publish Date

2018

Start Page

4121

End Page

4121

DOI

10.1200/jco.2018.36.15_suppl.4121

A workshop on "The Interface of Pancreatic Cancer with Diabetes, Obesity, and Inflammation: Research Gaps and Opportunities" was held by the National Institute of Diabetes and Digestive and Kidney Diseases on October 12, 2017. The purpose of the workshop was to explore the relationship and possible mechanisms of the increased risk of pancreatic ductal adenocarcinoma (PDAC) related to diabetes, the role of altered intracellular energy metabolism in PDAC, the mechanisms and biomarkers of diabetes caused by PDAC, the mechanisms of the increased risk of PDAC associated with obesity, and the role of inflammatory events and mediators as contributing causes of the development of PDAC. Workshop faculty reviewed the state of the current knowledge in these areas and made recommendations for future research efforts. Further knowledge is needed to elucidate the basic mechanisms contributing to the role of hyperinsulinemia, hyperglycemia, adipokines, and acute and chronic inflammatory events on the development of PDAC.

Authors

Abbruzzese, JL; Andersen, DK; Borrebaeck, CAK; Chari, ST; Costello, E; Cruz-Monserrate, Z; Eibl, G; Engleman, EG; Fisher, WE; Habtezion, A; Kim, SK; Korc, M; Logsdon, C; Lyssiotis, CA; Pandol, SJ; Rustgi, A; Wolfe, BM; Zheng, L; Powers, AC

MLA Citation

Abbruzzese, JL, Andersen, DK, Borrebaeck, CAK, Chari, ST, Costello, E, Cruz-Monserrate, Z, Eibl, G, Engleman, EG, Fisher, WE, Habtezion, A, Kim, SK, Korc, M, Logsdon, C, Lyssiotis, CA, Pandol, SJ, Rustgi, A, Wolfe, BM, Zheng, L, and Powers, AC. "The Interface of Pancreatic Cancer With Diabetes, Obesity, and Inflammation: Research Gaps and Opportunities: Summary of a National Institute of Diabetes and Digestive and Kidney Diseases Workshop." Pancreas 47.5 (May 2018): 516-525.

PMID

29702529

Source

epmc

Published In

Pancreas

Volume

47

Issue

5

Publish Date

2018

Start Page

516

End Page

525

DOI

10.1097/MPA.0000000000001037

© Springer Science+Business Media, LLC, part of Springer Nature 2018. Pancreatic adenocarcinoma is one of the most lethal cancers but has limited therapeutic options necessitating continued investigation of new therapeutic agents. Recently, improved overall survival has been achieved with cytotoxic drug combinations including 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) and gemcitabine/nab-paclitaxel, but the success has been modest at best. More targeted approaches focusing on EGFR and MAPK signaling have also enjoyed marginal success. Accumulating evidence suggests that pancreatic tumors have increased dependence on metabolic pathways through both KRAS and KRAS-independent mechanisms and are broadly resistant to drug therapy due to stromal remodeling. Genetic and epigenetic vulnerabilities, such as inactivating aberrations in DNA damage repair, chromatin remodeling, and microRNA dysregulation, may reveal exploitable weaknesses. Modern approaches to drug development tailored to molecularly defined subsets of patients likely to respond to targeted therapies are needed to achieve more substantial progress in this disease in an era of precision medicine.

Authors

Choe, JH; Abbruzzese, JL

MLA Citation

Choe, JH, and Abbruzzese, JL. "Emerging therapeutic targets in pancreatic adenocarcinoma." Pancreatic Cancer. April 11, 2018. 1613-1641.

Source

scopus

Publish Date

2018

Start Page

1613

End Page

1641

DOI

10.1007/978-1-4939-7193-0_92

Authors

Neoptolemos, JP; Urrutia, R; Abbruzzese, JL; Büchler, MW

MLA Citation

Neoptolemos, JP, Urrutia, R, Abbruzzese, JL, and Büchler, MW. Preface. April 11, 2018.

Source

scopus

Publish Date

2018

Start Page

ix

End Page

x

DOI

10.1007/978-1-4939-7193-0

The platelet-derived growth factor (PDGF) signaling pathway plays important roles in development and progression of human cancers. In our study, we aimed to identify genetic variants of the PDGF pathway genes associated with pancreatic cancer (PC) risk in European populations using three published genome-wide association study datasets, which consisted of 9,381 cases and 7,719 controls. The expression quantitative trait loci (eQTL) analysis was also performed using data from the 1000 Genomes, TCGA and GTEx projects. As a result, we identified two potential susceptibility loci (rs5757573 and rs6001516) of PDGFB associated with PC risk [odds ratio (OR) = 1.10, 95% confidence interval (CI) = 1.05-1.16, and p = 4.70 × 10-5 for the rs5757573 C allele and 1.21, 1.11-1.32, and 2.01 × 10-5 for the rs6001516 T allele]. Haplotype analysis revealed that the C-T haplotype carriers had a significantly increased risk of PC than those carrying the T-C haplotype (OR = 1.23, 95% CI = 1.12-1.34, p =5.00 × 10-6 ). The multivariate regression model incorporating the number of unfavorable genotypes (NUGs) with age and sex showed that carriers with 1-2 NUGs, particularly among 60-70 age group or males, had an increased risk of PC, compared to those without NUG. Furthermore, the eQTL analysis revealed that both loci were correlated with a decreased mRNA expression level of PDGFB in lymphoblastoid cell lines and pancreatic tumor tissues (p = 0.015 and 0.071, respectively). Our results suggest that genetic variants in PDGFB may play a role in susceptibility to PC. Further population and functional validations of our findings are warranted.

Authors

Duan, B; Hu, J; Liu, H; Wang, Y; Li, H; Liu, S; Xie, J; Owzar, K; Abbruzzese, J; Hurwitz, H; Gao, H; Wei, Q

MLA Citation

Duan, B, Hu, J, Liu, H, Wang, Y, Li, H, Liu, S, Xie, J, Owzar, K, Abbruzzese, J, Hurwitz, H, Gao, H, and Wei, Q. "Genetic variants in the platelet-derived growth factor subunit B gene associated with pancreatic cancer risk." International Journal of Cancer 142.7 (April 2018): 1322-1331.

PMID

29168174

Source

epmc

Published In

International Journal of Cancer

Volume

142

Issue

7

Publish Date

2018

Start Page

1322

End Page

1331

DOI

10.1002/ijc.31171

OBJECTIVES:Evaluate toxicity of two treatment arms, A (cetuximab) and B (bevacizumab), when combined with gemcitabine, and chemoradiation in patients with completely resected pancreatic carcinoma. Secondary objectives included overall survival (OS) and disease-free survival (DFS). METHODS:Patients with R0/R1 resection were randomized 1:1 to cetuximab or bevacizumab administered in combination with gemcitabine for two treatment cycles. Next three cycles included concurrent cetuximab/bevacizumab plus chemoradiation, followed by one cycle of cetuximab/bevacizumab. Cycles 7-12 included cetuximab/bevacizumab with gemcitabine. Cycles were 2 weeks. Frequency of specific toxicities was summarized for each treatment arm at two times during the study, after chemotherapy but prior to chemoradiation and after all therapy. RESULTS:A total of 127 patients were randomized (A, n = 65; B, n = 62). Prior to chemoradiation, the overall rate for toxicities of interest was 10% for arm A and 2% for arm B. After all therapy, the overall rates for toxicities of interest were 30 and 25% for arms A and B, respectively. Overall median OS and DFS were 17 and 11 months, respectively, which is not a significant improvement over expected survival rates for historical controls. CONCLUSIONS:Both treatments were tolerable with manageable toxicities, and were safe enough for a phase III trial had this been indicated.

Authors

Berlin, JD; Feng, Y; Catalano, P; Abbruzzese, JL; Philip, PA; McWilliams, RR; Lowy, AM; Benson, AB; Blackstock, AW

MLA Citation

Berlin, JD, Feng, Y, Catalano, P, Abbruzzese, JL, Philip, PA, McWilliams, RR, Lowy, AM, Benson, AB, and Blackstock, AW. "An Intergroup Randomized Phase II Study of Bevacizumab or Cetuximab in Combination with Gemcitabine and in Combination with Chemoradiation in Patients with Resected Pancreatic Carcinoma: A Trial of the ECOG-ACRIN Cancer Research Group (E2204)." Oncology 94.1 (January 2018): 39-46.

PMID

29040974

Source

epmc

Published In

Oncology

Volume

94

Issue

1

Publish Date

2018

Start Page

39

End Page

46

DOI

10.1159/000480295

The relationships between diabetes and pancreatic ductal adenocarcinoma (PDAC) are complex. Longstanding type 2 diabetes (T2DM) is a risk factor for pancreatic cancer, but increasing epidemiological data point to PDAC as also a cause of diabetes due to unknown mechanisms. New-onset diabetes is of particular interest to the oncology community as the differentiation of new-onset diabetes caused by PDAC as distinct from T2DM may allow for earlier diagnosis of PDAC. To address these relationships and raise awareness of the relationships between PDAC and diabetes, a symposium entitled Diabetes, Pancreatogenic Diabetes, and Pancreatic Cancer was held at the American Diabetes Association's 76th Scientific Sessions in June 2016. This article summarizes the data presented at that symposium, describing the current understanding of the interrelationships between diabetes, diabetes management, and pancreatic cancer, and identifies areas where additional research is needed.

Authors

Andersen, DK; Korc, M; Petersen, GM; Eibl, G; Li, D; Rickels, MR; Chari, ST; Abbruzzese, JL

MLA Citation

Andersen, DK, Korc, M, Petersen, GM, Eibl, G, Li, D, Rickels, MR, Chari, ST, and Abbruzzese, JL. "Diabetes, Pancreatogenic Diabetes, and Pancreatic Cancer." Diabetes 66.5 (May 2017): 1103-1110.

PMID

28507210

Source

epmc

Published In

Diabetes

Volume

66

Issue

5

Publish Date

2017

Start Page

1103

End Page

1110

DOI

10.2337/db16-1477

CA19-9, which is currently in clinical use as a pancreatic ductal adenocarcinoma (PDAC) biomarker, has limited performance in detecting early-stage disease. We and others have identified protein biomarker candidates that have the potential to complement CA19-9. We have carried out sequential validations starting with 17 protein biomarker candidates to determine which markers and marker combination would improve detection of early-stage disease compared with CA19-9 alone.Candidate biomarkers were subjected to enzyme-linked immunosorbent assay based sequential validation using independent multiple sample cohorts consisting of PDAC cases (n = 187), benign pancreatic disease (n = 93), and healthy controls (n = 169). A biomarker panel for early-stage PDAC was developed based on a logistic regression model. All statistical tests for the results presented below were one-sided.Six out of the 17 biomarker candidates and CA19-9 were validated in a sample set consisting of 75 PDAC patients, 27 healthy subjects, and 19 chronic pancreatitis patients. A second independent set of 73 early-stage PDAC patients, 60 healthy subjects, and 74 benign pancreatic disease patients (combined validation set) yielded a model that consisted of TIMP1, LRG1, and CA19-9. Additional blinded testing of the model was done using an independent set of plasma samples from 39 resectable PDAC patients and 82 matched healthy subjects (test set). The model yielded areas under the curve (AUCs) of 0.949 (95% confidence interval [CI] = 0.917 to 0.981) and 0.887 (95% CI = 0.817 to 0.957) with sensitivities of 0.849 and 0.667 at 95% specificity in discriminating early-stage PDAC vs healthy subjects in the combined validation and test sets, respectively. The performance of the biomarker panel was statistically significantly improved compared with CA19-9 alone (P < .001, combined validation set; P = .008, test set).The addition of TIMP1 and LRG1 immunoassays to CA19-9 statistically significantly improves the detection of early-stage PDAC.

Authors

Capello, M; Bantis, LE; Scelo, G; Zhao, Y; Li, P; Dhillon, DS; Patel, NJ; Kundnani, DL; Wang, H; Abbruzzese, JL; Maitra, A; Tempero, MA; Brand, R; Brennan, L; Feng, E; Taguchi, I; Janout, V; Firpo, MA; Mulvihill, SJ; Katz, MH; Hanash, SM

MLA Citation

Capello, M, Bantis, LE, Scelo, G, Zhao, Y, Li, P, Dhillon, DS, Patel, NJ, Kundnani, DL, Wang, H, Abbruzzese, JL, Maitra, A, Tempero, MA, Brand, R, Brennan, L, Feng, E, Taguchi, I, Janout, V, Firpo, MA, Mulvihill, SJ, Katz, MH, and Hanash, SM. "Sequential Validation of Blood-Based Protein Biomarker Candidates for Early-Stage Pancreatic Cancer." Journal of the National Cancer Institute 109.4 (April 2017).

PMID

27986802

Source

epmc

Published In

Journal of the National Cancer Institute

Volume

109

Issue

4

Publish Date

2017

Background:CA19-9, which is currently in clinical use as a pancreatic ductal adenocarcinoma (PDAC) biomarker, has limited performance in detecting early-stage disease. We and others have identified protein biomarker candidates that have the potential to complement CA19-9. We have carried out sequential validations starting with 17 protein biomarker candidates to determine which markers and marker combination would improve detection of early-stage disease compared with CA19-9 alone. Methods:Candidate biomarkers were subjected to enzyme-linked immunosorbent assay based sequential validation using independent multiple sample cohorts consisting of PDAC cases (n = 187), benign pancreatic disease (n = 93), and healthy controls (n = 169). A biomarker panel for early-stage PDAC was developed based on a logistic regression model. All statistical tests for the results presented below were one-sided. Results:Six out of the 17 biomarker candidates and CA19-9 were validated in a sample set consisting of 75 PDAC patients, 27 healthy subjects, and 19 chronic pancreatitis patients. A second independent set of 73 early-stage PDAC patients, 60 healthy subjects, and 74 benign pancreatic disease patients (combined validation set) yielded a model that consisted of TIMP1, LRG1, and CA19-9. Additional blinded testing of the model was done using an independent set of plasma samples from 39 resectable PDAC patients and 82 matched healthy subjects (test set). The model yielded areas under the curve (AUCs) of 0.949 (95% confidence interval [CI] = 0.917 to 0.981) and 0.887 (95% CI = 0.817 to 0.957) with sensitivities of 0.849 and 0.667 at 95% specificity in discriminating early-stage PDAC vs healthy subjects in the combined validation and test sets, respectively. The performance of the biomarker panel was statistically significantly improved compared with CA19-9 alone (P < .001, combined validation set; P = .008, test set). Conclusion:The addition of TIMP1 and LRG1 immunoassays to CA19-9 statistically significantly improves the detection of early-stage PDAC.

Authors

Capello, M; Bantis, LE; Scelo, G; Zhao, Y; Li, P; Dhillon, DS; Patel, NJ; Kundnani, DL; Wang, H; Abbruzzese, JL; Maitra, A; Tempero, MA; Brand, R; Firpo, MA; Mulvihill, SJ; Katz, MH; Brennan, P; Feng, Z; Taguchi, A; Hanash, SM

MLA Citation

Capello, M, Bantis, LE, Scelo, G, Zhao, Y, Li, P, Dhillon, DS, Patel, NJ, Kundnani, DL, Wang, H, Abbruzzese, JL, Maitra, A, Tempero, MA, Brand, R, Firpo, MA, Mulvihill, SJ, Katz, MH, Brennan, P, Feng, Z, Taguchi, A, and Hanash, SM. "Sequential Validation of Blood-Based Protein Biomarker Candidates for Early-Stage Pancreatic Cancer." Journal of the National Cancer Institute 109.4 (April 2017).

PMID

28376157

Source

epmc

Published In

Journal of the National Cancer Institute

Volume

109

Issue

4

Publish Date

2017

DOI

10.1093/jnci/djw266

The purpose of this study was to evaluate a single-institution experience with delivery of preoperative therapy to patients with pancreatic ductal adenocarcinoma (PDAC) prior to pancreatoduodenectomy (PD).Consecutive patients (622) with PDAC who underwent PD following chemotherapy and/or chemoradiation between 1990 and 2014 were retrospectively reviewed. Preoperative treatment regimens, clinicopathologic characteristics, operative details, and long-term outcomes in four successive time periods (1990-1999, 2000-2004, 2005-2009, 2010-2014) were evaluated and compared.The average number of patients per year who underwent PD following preoperative therapy as well as the proportion of operations performed for borderline resectable and locally advanced (BR/LA) tumors increased over time. The use of induction systemic chemotherapy, as well as postoperative adjuvant chemotherapy, also increased over time. Throughout the study period, the mean EBL decreased while R0 margin rates and vascular resection rates increased overall. Despite the increase in BR/LA resections, locoregional recurrence (LR) rates remained similar over time, and overall survival (OS) improved significantly (median 24.1, 28.1, 37.3, 43.4 months, respectively, p < 0.0001).Despite increases in case complexity, relatively low rates of LR have been maintained while significant improvements in OS have been observed. Further improvements in patient outcomes will likely require disruptive advances in systemic therapy.

Authors

Cloyd, JM; Katz, MHG; Prakash, L; Varadhachary, GR; Wolff, RA; Shroff, RT; Javle, M; Fogelman, D; Overman, M; Crane, CH; Koay, EJ; Das, P; Krishnan, S; Minsky, BD; Lee, JH; Bhutani, MS; Weston, B; Ross, W; Bhosale, P; Tamm, EP; Wang, H; Maitra, A; Kim, MP; Aloia, TA; Vauthey, J-N; Fleming, JB; Abbruzzese, JL; Pisters, PWT; Evans, DB; Lee, JE

MLA Citation

Cloyd, JM, Katz, MHG, Prakash, L, Varadhachary, GR, Wolff, RA, Shroff, RT, Javle, M, Fogelman, D, Overman, M, Crane, CH, Koay, EJ, Das, P, Krishnan, S, Minsky, BD, Lee, JH, Bhutani, MS, Weston, B, Ross, W, Bhosale, P, Tamm, EP, Wang, H, Maitra, A, Kim, MP, Aloia, TA, Vauthey, J-N, Fleming, JB, Abbruzzese, JL, Pisters, PWT, Evans, DB, and Lee, JE. "Preoperative Therapy and Pancreatoduodenectomy for Pancreatic Ductal Adenocarcinoma: a 25-Year Single-Institution Experience." Journal of Gastrointestinal Surgery : Official Journal of the Society for Surgery of the Alimentary Tract 21.1 (January 2017): 164-174.

PMID

27778257

Source

epmc

Published In

Journal of Gastrointestinal Surgery : Official Journal of the Society for Surgery of the Alimentary Tract

Volume

21

Issue

1

Publish Date

2017

Start Page

164

End Page

174

DOI

10.1007/s11605-016-3265-1

The antiobese and antidiabetic fibroblast growth factor 21 (FGF21) regulates lipid metabolism and energy homeostasis by targeting the βKlotho-FGFR1 (fibroblast growth factor receptor 1) binary complex in adipose tissue adipocytes. Because lipid droplet is the organelle responsible for storing lipid energy in adipocytes, it is the plausible target of FGF21 action. However, the impact of the FGF21-βKlotho-FGFR1 signaling pathway on the functions of the lipid droplet is not clearly understood. Using our mouse models of adipocyte-specific FGFR1 ablation and hepatic overexpression of FGF21 with diet-induced obesity established previously, we analyzed the alterations of the pathways involved in energy and substrate metabolism that is attributable to the dynamic functions of the lipid droplet. In addition to the previous reports showing that FGFR1 deficiency abrogated lipolysis, fatty acid oxidation, and energy expenditure promoted by the elevated FGF21 signal, we observed that the deficiency up-regulated the biosynthesis and remodeling of membrane phospholipids that are important for the biogenesis and expansion of the droplet, whereas the enhanced FGF21 signal constrained the biosynthesis of phospholipids. As a result, the loss of adipose FGFR1 led to a sustained droplet expansion and endoplasmic reticulum (ER) stress, whereas the enhanced FGF21 signal suppressed them in obesogenesis. These new findings reveal that the FGF21-βKlotho-FGFR1 signaling axis plays roles in maintaining phospholipid homeostasis and the dynamic functions of the lipid droplet, whereas protecting against ER stress, and suggest a potential link of phospholipid biosynthesis, lipid droplet dynamics, ER stress, and energy homeostasis in adipose tissue coordinated by this signaling axis.

Authors

Ye, M; Lu, W; Wang, X; Wang, C; Abbruzzese, JL; Liang, G; Li, X; Luo, Y

MLA Citation

Ye, M, Lu, W, Wang, X, Wang, C, Abbruzzese, JL, Liang, G, Li, X, and Luo, Y. "FGF21-FGFR1 Coordinates Phospholipid Homeostasis, Lipid Droplet Function, and ER Stress in Obesity." Endocrinology 157.12 (December 2016): 4754-4769.

PMID

27690692

Source

epmc

Published In

Endocrinology

Volume

157

Issue

12

Publish Date

2016

Start Page

4754

End Page

4769

DOI

10.1210/en.2016-1710

Authors

Palta, M; Czito, B; Abbruzzese, J; Uronis, H; Duffy, EA; Blazer, DT; Willett, CG

MLA Citation

Palta, M, Czito, B, Abbruzzese, J, Uronis, H, Duffy, EA, Blazer, DT, and Willett, CG. "Interim Acute Toxicity Analysis and Surgical Outcomes of Neoadjuvant Gemcitabine/nab-Paclitaxel and Hypofractionated Image Guided Intensity Modulated Radiation Therapy in Resectable and Borderline Resectable Pancreatic Cancer (ANCHOR) Study." October 1, 2016.

Source

wos-lite

Published In

International Journal of Radiation Oncology, Biology, Physics

Volume

96

Issue

2

Publish Date

2016

Start Page

S204

End Page

S205

DOI

10.1016/j.ijrobp.2016.06.509

Authors

Palta, M; Czito, B; Abbruzzese, J; Uronis, H; Duffy, EA; Blazer, DT; Willett, CG

MLA Citation

Palta, M, Czito, B, Abbruzzese, J, Uronis, H, Duffy, EA, Blazer, DT, and Willett, CG. "Interim Acute Toxicity Analysis and Surgical Outcomes of Neoadjuvant Gemcitabine/nab-Paclitaxel and Hypofractionated Image Guided Intensity Modulated Radiation Therapy in Resectable and Borderline Resectable Pancreatic Cancer (ANCHOR) Study." October 1, 2016.

Source

wos-lite

Published In

International Journal of Radiation Oncology, Biology, Physics

Volume

96

Issue

2

Publish Date

2016

Start Page

S204

End Page

S205

Authors

Palta, M; Czito, B; Abbruzzese, J; Uronis, H; Duffy, EA; Blazer, DT; Willett, CG

MLA Citation

Palta, M, Czito, B, Abbruzzese, J, Uronis, H, Duffy, EA, Blazer, DT, and Willett, CG. "Interim Acute Toxicity Analysis and Surgical Outcomes of Neoadjuvant Gemcitabine/nab-Paclitaxel and Hypofractionated Image Guided Intensity Modulated Radiation Therapy in Resectable and Borderline Resectable Pancreatic Cancer (ANCHOR) Study." International journal of radiation oncology, biology, physics 96.2S (October 2016): S204-S205.

PMID

27675789

Source

epmc

Published In

International Journal of Radiation Oncology, Biology, Physics

Volume

96

Issue

2S

Publish Date

2016

Start Page

S204

End Page

S205

DOI

10.1016/j.ijrobp.2016.06.509

UNLABELLED: Amplification of the MET oncogene is associated with poor prognosis, metastatic dissemination, and drug resistance in many malignancies. We developed a method to capture and characterize circulating tumor cells (CTC) expressing c-MET using a ferromagnetic antibody. Immunofluorescence was used to characterize cells for c-MET, DAPI, and pan-CK, excluding CD45(+) leukocytes. The assay was validated using appropriate cell line controls spiked into peripheral blood collected from healthy volunteers (HV). In addition, peripheral blood was analyzed from patients with metastatic gastric, pancreatic, colorectal, bladder, renal, or prostate cancers. CTCs captured by c-MET were enumerated, and DNA FISH for MET amplification was performed. The approach was highly sensitive (80%) for MET-amplified cells, sensitive (40%-80%) for c-MET-overexpressed cells, and specific (100%) for both c-MET-negative cells and in 20 HVs. Of 52 patients with metastatic carcinomas tested, c-MET CTCs were captured in replicate samples from 3 patients [gastric, colorectal, and renal cell carcinoma (RCC)] with 6% prevalence. CTC FISH demonstrated that MET amplification in both gastric and colorectal cancer patients and trisomy 7 with gain of MET gene copies in the RCC patient. The c-MET CTC assay is a rapid, noninvasive, sensitive, and specific method for detecting MET-amplified tumor cells. CTCs with MET amplification can be detected in patients with gastric, colorectal, and renal cancers. IMPLICATIONS: This study developed a novel c-MET CTC assay for detecting c-MET CTCs in patients with MET amplification and warrants further investigation to determine its clinical applicability. Mol Cancer Res; 14(6); 539-47. ©2016 AACR.

Authors

Zhang, T; Boominathan, R; Foulk, B; Rao, C; Kemeny, G; Strickler, JH; Abbruzzese, JL; Harrison, MR; Hsu, DS; Healy, P; Li, J; Pi, C; Prendergast, KM; Hobbs, C; Gemberling, S; George, DJ; Hurwitz, HI; Connelly, M; Garcia-Blanco, MA; Armstrong, AJ

MLA Citation

Zhang, T, Boominathan, R, Foulk, B, Rao, C, Kemeny, G, Strickler, JH, Abbruzzese, JL, Harrison, MR, Hsu, DS, Healy, P, Li, J, Pi, C, Prendergast, KM, Hobbs, C, Gemberling, S, George, DJ, Hurwitz, HI, Connelly, M, Garcia-Blanco, MA, and Armstrong, AJ. "Development of a Novel c-MET-Based CTC Detection Platform." Mol Cancer Res 14.6 (June 2016): 539-547.

Website

http://hdl.handle.net/10161/11944

PMID

26951228

Source

pubmed

Published In

Mol Cancer Res

Volume

14

Issue

6

Publish Date

2016

Start Page

539

End Page

547

DOI

10.1158/1541-7786.MCR-16-0011

Incorporation of multiple enrichment biomarkers into prospective clinical trials is an active area of investigation, but the factors that determine clinical trial enrollment following a molecular prescreening program have not been assessed.Patients with 5-fluorouracil-refractory metastatic colorectal cancer at the MD Anderson Cancer Center were offered screening in the Assessment of Targeted Therapies Against Colorectal Cancer (ATTACC) program to identify eligibility for companion phase I or II clinical trials with a therapy targeted to an aberration detected in the patient, based on testing by immunohistochemistry, targeted gene sequencing panels, and CpG island methylation phenotype assays.Between August 2010 and December 2013, 484 patients were enrolled, 458 (95%) had a biomarker result, and 157 (32%) were enrolled on a clinical trial (92 on biomarker-selected and 65 on nonbiomarker selected). Of the 458 patients with a biomarker result, enrollment on biomarker-selected clinical trials was ninefold higher for predefined ATTACC-companion clinical trials as opposed to nonpredefined biomarker-selected clinical trials, 17.9% versus 2%, P < 0.001. Factors that correlated positively with trial enrollment in multivariate analysis were higher performance status, older age, lack of standard of care therapy, established patient at MD Anderson, and the presence of an eligible biomarker for an ATTACC-companion study. Early molecular screening did result in a higher rate of patients with remaining standard of care therapy enrolling on ATTACC-companion clinical trials, 45.1%, in contrast to nonpredefined clinical trials, 22.7%; odds ratio 3.1, P = 0.002.Though early molecular prescreening for predefined clinical trials resulted in an increase rate of trial enrollment of nonrefractory patients, the majority of patients enrolled on clinical trials were refractory to standard of care therapy. Within molecular prescreening programs, tailoring screening for preidentified and open clinical trials, temporally linking screening to treatment and optimizing both patient and physician engagement are efforts likely to improve enrollment on biomarker-selected clinical trials.The study NCT number is NCT01196130.

Authors

Overman, MJ; Morris, V; Kee, B; Fogelman, D; Xiao, L; Eng, C; Dasari, A; Shroff, R; Mazard, T; Shaw, K; Vilar, E; Raghav, K; Shureiqi, I; Liang, L; Mills, GB; Wolff, RA; Hamilton, S; Meric-Bernstam, F; Abbruzzese, J; Morris, J; Maru, D; Kopetz, S

MLA Citation

Overman, MJ, Morris, V, Kee, B, Fogelman, D, Xiao, L, Eng, C, Dasari, A, Shroff, R, Mazard, T, Shaw, K, Vilar, E, Raghav, K, Shureiqi, I, Liang, L, Mills, GB, Wolff, RA, Hamilton, S, Meric-Bernstam, F, Abbruzzese, J, Morris, J, Maru, D, and Kopetz, S. "Utility of a molecular prescreening program in advanced colorectal cancer for enrollment on biomarker-selected clinical trials." Annals of Oncology : Official Journal of the European Society for Medical Oncology 27.6 (June 2016): 1068-1074.

Website

http://hdl.handle.net/10161/11946

PMID

27045102

Source

epmc

Published In

Annals of Oncology

Volume

27

Issue

6

Publish Date

2016

Start Page

1068

End Page

1074

DOI

10.1093/annonc/mdw073

Curcumin is a natural product that is often explored by patients with cancer. Weight loss due to fat and muscle depletion is a hallmark of pancreatic cancer and is associated with worse outcomes. Studies of curcumin's effects on muscularity show conflicting results in animal models.Retrospective matched 1:2 case-control study to evaluate the effects of curcumin on body composition (determined by computerized tomography) of 66 patients with advanced pancreatic cancer (22 treated,44 controls). Average age (SEM) was 63(1.8) years, 30/66(45%) women, median number of prior therapies was 2, median (IQR) time from advanced pancreatic cancer diagnosis to baseline image was 7(2-13.5) months (p>0.2, all variables). All patients lost weight (3.3% and 1.3%, treated vs. control, p=0.13). Treated patients lost more muscle (median [IQR] percent change -4.8[-9.1,-0.1] vs. -0.05%[-4.2, 2.6] in controls,p<0.001) and fat (median [IQR] percent change -6.8%[-15,-0.6] vs. -4.0%[-7.6, 1.3] in controls,p=0.04). Subcutaneous fat was more affected in the treated patients. Sarcopenic patients treated with curcumin(n=15) had survival of 169(115-223) days vs. 299(229-369) sarcopenic controls(p=0.024). No survival difference was found amongst non-sarcopenic patients.Patients with advanced pancreatic cancer treated with curcumin showed significantly greater loss of subcutaneous fat and muscle than matched untreated controls.

Authors

Parsons, HA; Baracos, VE; Hong, DS; Abbruzzese, J; Bruera, E; Kurzrock, R

MLA Citation

Parsons, HA, Baracos, VE, Hong, DS, Abbruzzese, J, Bruera, E, and Kurzrock, R. "The effects of curcumin (diferuloylmethane) on body composition of patients with advanced pancreatic cancer." Oncotarget 7.15 (April 2016): 20293-20304.

Website

http://hdl.handle.net/10161/11945

PMID

26934122

Source

epmc

Published In

Oncotarget

Volume

7

Issue

15

Publish Date

2016

Start Page

20293

End Page

20304

DOI

10.18632/oncotarget.7773

PURPOSE:To confirm whether a previously observed association between RECQ1 A159C variant and clinical outcome of resectable pancreatic cancer patients treated with preoperative chemoradiation is reproducible in another patient population prospectively treated with postoperative chemoradiation. METHODS AND MATERIALS:Patients were selected, according to tissue availability, from eligible patients with resected pancreatic cancer who were enrolled on the NRG Oncology Radiation Therapy Oncology Group 9704 trial of 5-fluorouacil (5-FU)-based chemoradiation preceded and followed by 5-FU or gemcitabine. Deoxyribonucleic acid was extracted from paraffin-embedded tissue sections, and genotype was determined using the Taqman method. The correlation between genotype and overall survival was analyzed using a Kaplan-Meier plot, log-rank test, and multivariate Cox proportional hazards models. RESULTS:In the 154 of the study's 451 eligible patients with evaluable tissue, genotype distribution followed Hardy-Weinberg equilibrium (ie, 37% had genotype AA, 43% AC, and 20% CC). The RECQ1 variant AC/CC genotype carriers were associated with being node positive compared with the AA carrier (P=.03). The median survival times (95% confidence interval [CI]) for AA, AC, and CC carriers were 20.6 (16.3-26.1), 18.8 (14.2-21.6), and 14.2 (10.3-21.0) months, respectively. On multivariate analysis, patients with the AC/CC genotypes were associated with worse survival than patients with the AA genotype (hazard ratio [HR] 1.54, 95% CI 1.07-2.23, P=.022). This result seemed slightly stronger for patients on the 5-FU arm (n=82) (HR 1.64, 95% CI 0.99-2.70, P=.055) than for patients on the gemcitabine arm (n=72, HR 1.46, 95% CI 0.81-2.63, P=.21). CONCLUSIONS:Results of this study suggest that the RECQ1 A159C genotype may be a prognostic or predictive factor for resectable pancreatic cancer patients who are treated with adjuvant 5-FU before and after 5-FU-based chemoradiation. Further study is needed in patients treated with gemcitabine to determine whether an association exists.

Authors

Li, D; Moughan, J; Crane, C; Hoffman, JP; Regine, WF; Abrams, RA; Safran, H; Liu, C; Chang, P; Freedman, GM; Winter, KA; Guha, C; Abbruzzese, JL

MLA Citation

Li, D, Moughan, J, Crane, C, Hoffman, JP, Regine, WF, Abrams, RA, Safran, H, Liu, C, Chang, P, Freedman, GM, Winter, KA, Guha, C, and Abbruzzese, JL. "RECQ1 A159C Polymorphism Is Associated With Overall Survival of Patients With Resected Pancreatic Cancer: A Replication Study in NRG Oncology Radiation Therapy Oncology Group 9704." International Journal of Radiation Oncology, Biology, Physics 94.3 (March 2016): 554-560.

PMID

26725729

Source

epmc

Published In

International Journal of Radiation Oncology, Biology, Physics

Volume

94

Issue

3

Publish Date

2016

Start Page

554

End Page

560

DOI

10.1016/j.ijrobp.2015.10.062

Pancreatic cancer is a devastating disease with a universally poor prognosis. In 2015, it is estimated that there will be 48,960 new cases of pancreatic cancer and that 40,560 people will die of the disease. The 5-year survival rate is 7.2% for all patients with pancreatic cancer; however, survival depends greatly on the stage at diagnosis. Unfortunately, 53% of patients already have metastatic disease at diagnosis, which corresponds to a 5-year survival rate of 2.4%. Even for the 9% of patients with localized disease confined to the pancreas, the 5-year survival is still modest at only 27.1%. These grim statistics highlight the need for ways to identify cohorts of individuals at highest risk, methods to screen those at highest risk to identify preinvasive pathologic precursors, and development of effective systemic therapies. Recent clinical and translational progress has emphasized the relationship with diabetes, the role of the stroma, and the interplay of each of these with inflammation in the pathobiology of pancreatic cancer. In this article, we will discuss these relationships and how they might translate into novel management strategies for the treatment of this disease.

Authors

Mettu, NB; Abbruzzese, JL

MLA Citation

Mettu, NB, and Abbruzzese, JL. "Clinical Insights Into the Biology and Treatment of Pancreatic Cancer." Journal of Oncology Practice 12.1 (January 2016): 17-23. (Review)

Website

http://hdl.handle.net/10161/11572

PMID

26759461

Source

epmc

Published In

Journal of Oncology Practice

Volume

12

Issue

1

Publish Date

2016

Start Page

17

End Page

23

DOI

10.1200/jop.2015.009092

The decision by journals to append protocols to published reports of randomized trials was a landmark event in clinical trial reporting. However, limited information is available on how this initiative effected transparency and selective reporting of clinical trial data.We analyzed 74 oncology-based randomized trials published in Journal of Clinical Oncology, the New England Journal of Medicine, and The Lancet in 2012. To ascertain integrity of reporting, we compared published reports with their respective appended protocols with regard to primary end points, nonprimary end points, unplanned end points, and unplanned analyses.A total of 86 primary end points were reported in 74 randomized trials; nine trials had greater than one primary end point. Nine trials (12.2%) had some discrepancy between their planned and published primary end points. A total of 579 nonprimary end points (median, seven per trial) were planned, of which 373 (64.4%; median, five per trial) were reported. A significant positive correlation was found between the number of planned and nonreported nonprimary end points (Spearman r = 0.66; P < .001). Twenty-eight studies (37.8%) reported a total of 65 unplanned end points; 52 (80.0%) of which were not identified as unplanned. Thirty-one (41.9%) and 19 (25.7%) of 74 trials reported a total of 52 unplanned analyses involving primary end points and 33 unplanned analyses involving nonprimary end points, respectively. Studies reported positive unplanned end points and unplanned analyses more frequently than negative outcomes in abstracts (unplanned end points odds ratio, 6.8; P = .002; unplanned analyses odd ratio, 8.4; P = .007).Despite public and reviewer access to protocols, selective outcome reporting persists and is a major concern in the reporting of randomized clinical trials. To foster credible evidence-based medicine, additional initiatives are needed to minimize selective reporting.

Authors

Raghav, KPS; Mahajan, S; Yao, JC; Hobbs, BP; Berry, DA; Pentz, RD; Tam, A; Hong, WK; Ellis, LM; Abbruzzese, J; Overman, MJ

MLA Citation

Raghav, KPS, Mahajan, S, Yao, JC, Hobbs, BP, Berry, DA, Pentz, RD, Tam, A, Hong, WK, Ellis, LM, Abbruzzese, J, and Overman, MJ. "From Protocols to Publications: A Study in Selective Reporting of Outcomes in Randomized Trials in Oncology." Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology 33.31 (November 2015): 3583-3590. (Review)

PMID

26304898

Source

epmc

Published In

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology

Volume

33

Issue

31

Publish Date

2015

Start Page

3583

End Page

3590

DOI

10.1200/JCO.2015.62.4148

Authors

Lu, W; Yang, Y; Luo, Y; Liu, Y; Wang, X; Liu, M; Wolff, RA; Abbruzzese, JL; Logsdon, CD

MLA Citation

Lu, W, Yang, Y, Luo, Y, Liu, Y, Wang, X, Liu, M, Wolff, RA, Abbruzzese, JL, and Logsdon, CD. "FGF21 Delays Pancreatic Cancer Formation and Prevents Liver Metastasis in Oncogenic Kras Expressing Mice Fed on High-Fat Diet." PANCREAS 44.8 (November 2015): 1393-1393.

Source

wos-lite

Published In

Pancreas

Volume

44

Issue

8

Publish Date

2015

Start Page

1393

End Page

1393

ABO blood type has previously been identified as a risk factor for thrombosis and pancreatic cancer (PC). The aim of the study is to demonstrate the associations between ABO blood type and other clinical factors with the risk of thromboembolism (TE) in patients with PC. We conducted a retrospective study in 670 patients with pathologically confirmed pancreatic adenocarcinoma at the University of Texas MD Anderson Cancer Center. Clinical information was retrieved from medical records. ABO blood type was determined serologically and/or genetically. Logistic regression models, Kaplan-Meier plot, log-rank test, and Cox proportional hazard regression models were employed in data analysis. The incidence of TE was 35.2% in 670 patients who did not have TE prior to cancer diagnosis. Pulmonary embolism (PE) and deep vein thrombosis (DVT) consisted 44.1% of the TE events. Non-O blood type, pancreatic body/tail tumors, previous use of antithrombotic medication, and obesity (body mass index >30 kg/m(2) ) were significant predictors for TE in general. Blood type A and AB, low hemoglobin level (≤ 10 g/dL), obesity, metastatic tumor, and pancreatic body/tail tumors were significant predictors for PE and DVT. Patients with metastatic tumor or pancreatic body/tail tumors had a much higher frequency of early TE events (≤ 3 months after cancer diagnosis); and early TE occurrence was a significant independent predictor for increased risk of death. These observations suggest that ABO non-O blood type is an independent predictor for TE in PC. A better understanding of the risk factors for TE in PC may help to identify patients who are most likely to benefit from prophylactic anticoagulation therapy.

Authors

Li, D; Pise, MN; Overman, MJ; Liu, C; Tang, H; Vadhan-Raj, S; Abbruzzese, JL

MLA Citation

Li, D, Pise, MN, Overman, MJ, Liu, C, Tang, H, Vadhan-Raj, S, and Abbruzzese, JL. "ABO non-O type as a risk factor for thrombosis in patients with pancreatic cancer." Cancer medicine 4.11 (November 2015): 1651-1658.

PMID

26275671

Source

epmc

Published In

Cancer Medicine

Volume

4

Issue

11

Publish Date

2015

Start Page

1651

End Page

1658

DOI

10.1002/cam4.513

© 2016 by John Wiley & Sons, Inc. All rights reserved. As we learn more about the molecular underpinnings of pancreatic cancer, we are discovering new growth pathways that present opportunities for treatment. KRAS represents one such target. Activating mutations, found in the majority of pancreatic cancer, activate downstream activators including RAF, MEK, and ERK, and the hedgehog pathway. The PI3 kinase pathway is also frequently activated through the disruption of the PTEN tumor pathway, in turn activating NF-kB and C-MYC. Likewise, the TGF-β pathway acts through SMAD dependent and independent pathways to control MYC expression, affect epithelial-mesenchymal transition, and modify the immune response. Activation of the Notch pathway receptors has also been shown to regulate cell cycle effectors. DNA repair abnormalities may play a role in the rise of pancreatic cancer; these also have implications for treatment. Finally, immunotherapeutic agents are now being developed for use in pancreatic cancer and other treatments. In this chapter, we review each of these molecular pathways and discuss their applicability to pancreatic cancer treatment.

Authors

Fogelman, D; Javle, M; Abbruzzese, J

MLA Citation

Fogelman, D, Javle, M, and Abbruzzese, J. "Molecular Therapeutics: Pancreatic Cancer." Targeted Therapy in Translational Cancer Research. October 30, 2015. 255-262.

Source

scopus

Publish Date

2015

Start Page

255

End Page

262

DOI

10.1002/9781118468678.ch26

Metastatic pancreatic adenocarcinoma is considered a uniformly fatal disease with a median survival of 1 year with modern chemotherapy. While a subset of patients achieve prolonged survival, few of the factors that define this group of patients are known.For the determination of overall survival (OS), 549 patients with histologically confirmed metastatic pancreatic adenocarcinoma were evaluated. Emphasis was placed on treatment history and family history of breast, ovarian, and pancreatic cancers. To ensure a uniform metastatic population, patients treated with prior locoregional therapies (i.e., surgery or radiotherapy) were excluded as were patients with a prior history of stage I-III disease.Patients with family history or pedigree history of cancer had superior OS. This was especially true in patients with three or more relatives with either breast, ovarian, or pancreatic cancers [hazard ratio (HR) 0.49, 95 % confidence interval (CI) 0.30-0.80, p = 0.003]. First-line platinum chemotherapy was associated with a poor survival (hazard ratio for death 1.74, 95% CI 1.12-2.71, p = 0.01) for patients without a family history of these cancers but not for those without such a history (p = 0.31). In fact, as the number of relatives with these cancers increased, the OS survival improved for individuals receiving first-line platinum therapy (HR 0.76, 95 % CI 0.65-0.89, p = 0.0004), which was not the case for those receiving other therapies (p = 0.98).Treatment with platinum chemotherapy in patients with a family history of breast, ovarian, or pancreatic cancers was associated with a longer survival, whereas platinum use in patients without such a family history of cancer was associated with poor survival. These findings suggest that family history may serve as a predictive marker for platinum use in patients with metastatic pancreatic adenocarcinoma.

Authors

Fogelman, D; Sugar, EA; Oliver, G; Shah, N; Klein, A; Alewine, C; Wang, H; Javle, M; Shroff, R; Wolff, RA; Abbruzzese, JL; Laheru, D; Diaz, LA

MLA Citation

Fogelman, D, Sugar, EA, Oliver, G, Shah, N, Klein, A, Alewine, C, Wang, H, Javle, M, Shroff, R, Wolff, RA, Abbruzzese, JL, Laheru, D, and Diaz, LA. "Family history as a marker of platinum sensitivity in pancreatic adenocarcinoma." Cancer Chemotherapy and Pharmacology 76.3 (September 2015): 489-498.

PMID

26126726

Source

epmc

Published In

Cancer Chemotherapy and Pharmacology

Volume

76

Issue

3

Publish Date

2015

Start Page

489

End Page

498

DOI

10.1007/s00280-015-2788-6

Authors

Lu, W; Yang, Y; Wang, X; Liu, Y; Luo, Y; Wolff, RA; Abbruzzese, JL; Logsdon, CD

MLA Citation

Lu, W, Yang, Y, Wang, X, Liu, Y, Luo, Y, Wolff, RA, Abbruzzese, JL, and Logsdon, CD. "Abstract 891: FGF21 prevents high fat diet-induced pancreatic cancer in mice expressing oncogenic Kras.": American Association for Cancer Research (AACR), August 1, 2015.

Source

crossref

Published In

Cancer Research

Volume

75

Issue

15 Supplement

Publish Date

2015

Start Page

891

End Page

891

DOI

10.1158/1538-7445.am2015-891

Src has a critical role in tumor cell migration and invasion. Increased Src activity has been shown to correlate with disease progression and poor prognosis, suggesting Src could serve as a therapeutic target for kinase inhibition. Saracatinib (AZD0530) is a novel selective oral Src kinase inhibitor.Metastatic colorectal cancer patients who had received one prior treatment and had measurable disease were enrolled in this phase 2 study. Saracatinib was administered at 175 mg by mouth daily for 28 day cycles until dose-limiting toxicity or progression as determined by staging every 2 cycles. The primary endpoint was improvement in 4 month progression-free survival. Design of Thall, Simon, and Estey was used to monitor proportion of patients that were progression free at 4 months. The trial was opened with plan to enroll maximum of 35 patients, with futility assessment every 10 patients.A total of 10 patients were enrolled between January and November 2007. Further enrollment was stopped due to futility. Median progression-free survival was 7.9 weeks, with all 10 patients showing disease progression following radiographic imaging. Median overall survival was 13.5 months. All patients were deceased by time of analysis. Observed adverse events were notable for a higher than expected number of patients with grade 3 hypophosphatemia (n = 5).Saracatinib is a novel oral Src kinase inhibitor that was well tolerated but failed to meet its primary endpoint of improvement in 4 month progression-free survival as a single agent in previously treated metastatic colorectal cancer patients.

Authors

Reddy, SM; Kopetz, S; Morris, J; Parikh, N; Qiao, W; Overman, MJ; Fogelman, D; Shureiqi, I; Jacobs, C; Malik, Z; Jimenez, CA; Wolff, RA; Abbruzzese, JL; Gallick, G; Eng, C

MLA Citation

Reddy, SM, Kopetz, S, Morris, J, Parikh, N, Qiao, W, Overman, MJ, Fogelman, D, Shureiqi, I, Jacobs, C, Malik, Z, Jimenez, CA, Wolff, RA, Abbruzzese, JL, Gallick, G, and Eng, C. "Phase II study of saracatinib (AZD0530) in patients with previously treated metastatic colorectal cancer." Investigational New Drugs 33.4 (August 2015): 977-984.

PMID

26062928

Source

epmc

Published In

Investigational New Drugs

Volume

33

Issue

4

Publish Date

2015

Start Page

977

End Page

984

DOI

10.1007/s10637-015-0257-z

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers. Cyclopamine (CPA), a potent inhibitor for sonic hedgehog pathway (SHH), shows great promises in PDAC treatment, including the disruption of tumor-associated stroma, and enhancement of radiation therapy. However, CPA is insoluble in water and therefore requires a nanometric delivery platform to achieve satisfactory performance. We herein encapsulated CPA in a core-cross-linked polymeric micelle system (M-CPA). M-CPA was combined with Cs-137 radiation and evaluated in vitro in PDAC cell lines and a human pancreatic stellate cell line. The results showed that M-CPA had higher cytotoxicity than CPA, abolished Gli-1 expression (a key component of SHH), and enhanced the radiation therapy of Cs-137. M-CPA radiosensitization correlated with its ability to disrupt the repair of radiation-induced DNA damage. These findings indicate that the combination therapy of M-CPA and radiation is an effective strategy to simultaneously treat pancreatic tumors and tumor-associated stroma.

Authors

Zhao, J; Wu, C; Abbruzzese, J; Hwang, RF; Li, C

MLA Citation

Zhao, J, Wu, C, Abbruzzese, J, Hwang, RF, and Li, C. "Cyclopamine-loaded core-cross-linked polymeric micelles enhance radiation response in pancreatic cancer and pancreatic stellate cells." Molecular Pharmaceutics 12.6 (June 2015): 2093-2100.

PMID

25936695

Source

epmc

Published In

Molecular Pharmaceutics

Volume

12

Issue

6

Publish Date

2015

Start Page

2093

End Page

2100

DOI

10.1021/mp500875f

Authors

Zhang, T; Boominathan, R; Foulk, B; Connelly, MC; Rao, C; Kemeny, G; Strickler, JH; Abbruzzese, JL; Harrison, MR; George, DJ; Hurwitz, H; Garcia-Blanco, MA; Armstrong, AJ

MLA Citation

Zhang, T, Boominathan, R, Foulk, B, Connelly, MC, Rao, C, Kemeny, G, Strickler, JH, Abbruzzese, JL, Harrison, MR, George, DJ, Hurwitz, H, Garcia-Blanco, MA, and Armstrong, AJ. "Evaluation of a novel c-MET based circulating tumor cell (CTC) biomarker in patients with gastrointestinal (GI) and genitourinary (GU) malignancies." May 20, 2015.

Source

wos-lite

Published In

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology

Volume

33

Issue

15

Publish Date

2015

Patients with pancreatic cancer have a high frequency of concurrent diabetes. This study is aimed to demonstrate the impact of diabetes on clinical outcome of pancreatic cancer. Clinical and epidemiological information was collected from medical records or by personal interview in 1328 patients with pancreatic ductal adenocarcinoma. Diabetes was defined by a known medical history, or abnormal fasting blood glucose (FBG) and HbA1c levels within three months of the cancer diagnosis. Duration of ≤3 years was used as the cutoff to arbitrarily define the new-onset and long-term diabetes. Logistic regression, Kaplan-Meier plot, log-rank test and Cox regression models were employed in the data analysis. Elevated level of FBG or HbA1c was observed in 24.7% and 11.5% of the patients without a known diabetes history, respectively. The prevalence of DM was 44.4% and was comparable by strata of tumor stage. New-onset diabetes was a significant independent predictor for risk of death in metastatic patients (HR=1.35, 95% CI=1.11-1.63, P=0.002) and in all patients (HR=1.23, 95% CI=1.09-1.40, P=0.001). Both new-onset and long term diabetes were significantly associated with older age, obesity, hypertension and coronary artery disease as well as weight loss. New-onset diabetes was also significantly related to larger tumors and elevated level of CA19-9 but not to tumor site and presence of biliary obstruction. Diabetes in general and new-onset diabetes in particular, is associated with poor outcome of pancreatic cancer. New-onset and long-term diabetes share common risk factors for type 2 diabetes.

Authors

Li, D; Mao, Y; Chang, P; Liu, C; Hassan, MM; Yeung, SJ; Abbruzzese, JL

MLA Citation

Li, D, Mao, Y, Chang, P, Liu, C, Hassan, MM, Yeung, SJ, and Abbruzzese, JL. "Impacts of new-onset and long-term diabetes on clinical outcome of pancreatic cancer." American Journal of Cancer Research 5.10 (January 1, 2015): 3260-3269.

Source

scopus

Published In

American Journal of Cancer Research

Volume

5

Issue

10

Publish Date

2015

Start Page

3260

End Page

3269

There is substantial heterogeneity in the clinical behavior of pancreatic cancer and in its response to therapy. Some of this variation may be due to differences in delivery of cytotoxic therapies between patients and within individual tumors. Indeed, in 12 patients with resectable pancreatic cancer, we previously demonstrated wide inter-patient variability in the delivery of gemcitabine as well as in the mass transport properties of tumors as measured by computed tomography (CT) scans. However, the variability of drug delivery and transport properties within pancreatic tumors is currently unknown. Here, we analyzed regional measurements of gemcitabine DNA incorporation in the tumors of the same 12 patients to understand the degree of intra-tumoral heterogeneity of drug delivery. We also developed a volumetric segmentation approach to measure mass transport properties from the CT scans of these patients and tested inter-observer agreement with this new methodology. Our results demonstrate significant heterogeneity of gemcitabine delivery within individual pancreatic tumors and across the patient cohort, with gemcitabine DNA incorporation in the inner portion of the tumors ranging from 38 to 74% of the total. Similarly, the CT-derived mass transport properties of the tumors had a high degree of heterogeneity, ranging from minimal difference to almost 200% difference between inner and outer portions of the tumor. Our quantitative method to derive transport properties from CT scans demonstrated less than 5% difference in gemcitabine prediction at the average CT-derived transport value across observers. These data illustrate significant inter-patient and intra-tumoral heterogeneity in the delivery of gemcitabine, and highlight how this variability can be reproducibly accounted for using principles of mass transport. With further validation as a biophysical marker, transport properties of tumors may be useful in patient selection for therapy and prediction of therapeutic outcome.

Authors

Koay, EJ; Baio, FE; Ondari, A; Truty, MJ; Cristini, V; Thomas, RM; Chen, R; Chatterjee, D; Kang, Y; Zhang, J; Court, L; Bhosale, PR; Tamm, EP; Qayyum, A; Crane, CH; Javle, M; Katz, MH; Gottumukkala, VN; Rozner, MA; Shen, H; Lee, JE; Wang, H; Chen, Y; Plunkett, W; Abbruzzese, JL; Wolff, RA; Maitra, A; Ferrari, M; Varadhachary, GR; Fleming, JB

MLA Citation

Koay, EJ, Baio, FE, Ondari, A, Truty, MJ, Cristini, V, Thomas, RM, Chen, R, Chatterjee, D, Kang, Y, Zhang, J, Court, L, Bhosale, PR, Tamm, EP, Qayyum, A, Crane, CH, Javle, M, Katz, MH, Gottumukkala, VN, Rozner, MA, Shen, H, Lee, JE, Wang, H, Chen, Y, Plunkett, W, Abbruzzese, JL, Wolff, RA, Maitra, A, Ferrari, M, Varadhachary, GR, and Fleming, JB. "Intra-tumoral heterogeneity of gemcitabine delivery and mass transport in human pancreatic cancer." Physical Biology 11.6 (November 26, 2014): 065002-null.

PMID

25427073

Source

epmc

Published In

Physical Biology

Volume

11

Issue

6

Publish Date

2014

Start Page

065002

DOI

10.1088/1478-3975/11/6/065002

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human malignancies with less than 5% five-year survival rate. Despite significant improvements in medical and surgical oncology and postoperative mortality rate, the overall survival for patients with pancreatic cancer has not changed significantly in the last four decades. Neoadjuvant chemoradiation therapy (NCT) is increasingly used to treat patients with potentially resectable PDAC, especially for patients with borderline resectable disease. However, analysis of prognostic factors is limited for patients with PDAC treated with NCT and pancreaticoduodenectomy. We systemically examined the pancreaticoduodenectomy specimens from 240 consecutive patients with PDAC who received NCT and pancreaticoduodenectomy between 1999 and 2007 at our institution. We found that posttreatment pathologic stage, pathologic tumor response grading, tumor involvement of the superior mesenteric/portal vein, tumor invasion into the muscular vessels, and perineural invasion are significant prognostic factors in our patient population. Therefore careful pathologic evaluation of the pancreatectomy specimens plays a key role in predicting prognosis of patients with PDAC who received NCT and pancreaticoduodenectomy.

Authors

Wang, H; Estrella, JS; Chatterjee, D; Katz, MH; Rashid, A; Wang, H; Wolff, RA; Varadhachary, GR; Lee, JE; Pisters, PW; Abbruzzese, JL; Fleming, JB

MLA Citation

Wang, H, Estrella, JS, Chatterjee, D, Katz, MH, Rashid, A, Wang, H, Wolff, RA, Varadhachary, GR, Lee, JE, Pisters, PW, Abbruzzese, JL, and Fleming, JB. "Hepatobiliary/Pancreas Pathology: SY11-3 PANCREATIC DUCTAL ADENOCARCINOMA: NEOADJUVANT THERAPIES AND PATHOLOGY." Pathology 46 Suppl 2 (October 2014): S25-.

PMID

25188109

Source

epmc

Published In

Pathology

Volume

46 Suppl 2

Publish Date

2014

Start Page

S25

DOI

10.1097/01.pat.0000454135.19954.47

Authors

Abbruzzese, JL; Hess, KR

MLA Citation

Abbruzzese, JL, and Hess, KR. "New option for the initial management of metastatic pancreatic cancer?." Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology 32.23 (August 2014): 2405-2407.

PMID

24982449

Source

epmc

Published In

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology

Volume

32

Issue

23

Publish Date

2014

Start Page

2405

End Page

2407

DOI

10.1200/JCO.2013.54.4155

Child-Turcotte-Pugh (CTP) score is the standard tool to assess hepatic reserve in hepatocellular carcinoma (HCC), and CTP-A is the classic group for active therapy. However, CTP stratification accuracy has been questioned. We hypothesized that plasma insulin-like growth factor 1 (IGF-1) is a valid surrogate for hepatic reserve to replace the subjective parameters in CTP score to improve its prognostic accuracy.We retrospectively tested plasma IGF-1 levels in the training set (n = 310) from MD Anderson Cancer Center. Recursive partitioning identified three optimal IGF-1 ranges that correlated with overall survival (OS): greater than 50 ng/mL = 1 point; 26 to 50 ng/mL = 2 points; and less than 26 ng/mL = 3 points. We modified the CTP score by replacing ascites and encephalopathy grading with plasma IGF-1 value (IGF-CTP) and subjected both scores to log-rank analysis. Harrell's C-index and U-statistics were used to compare the prognostic performance of both scores in both the training and validation cohorts (n = 155). All statistical tests were two-sided.Patients' stratification was statistically significantly stronger for IGF-CTP than CTP score for the training (P = .003) and the validation cohort (P = .005). Patients reclassified by IGF-CTP relative to their original CTP score were better stratified by their new risk groups. Most important, patients classified as A by CTP but B by IGF-CTP had statistically significantly worse OS than those who remained under class A by IGF-CTP in both cohorts (P = .03 and P < .001, respectively, from Cox regression models). AB patients had a worse OS than AA patients in both the training and validation set (hazard ratio [HR] = 1.45, 95% confidence interval [CI] = 1.03 to 2.04, P = .03; HR = 2.83, 95% CI = 1.65 to 4.85, P < .001, respectively).The IGF-CTP score is simple, blood-based, and cost-effective, stratified HCC better than CTP score, and validated well on two independent cohorts. International validation studies are warranted.

Authors

Kaseb, AO; Xiao, L; Hassan, MM; Chae, YK; Lee, J-S; Vauthey, J-N; Krishnan, S; Cheung, S; Hassabo, HM; Aloia, T; Conrad, C; Curley, SA; Vierling, JM; Jalal, P; Raghav, K; Wallace, M; Rashid, A; Abbruzzese, JL; Wolff, RA; Morris, JS

MLA Citation

Kaseb, AO, Xiao, L, Hassan, MM, Chae, YK, Lee, J-S, Vauthey, J-N, Krishnan, S, Cheung, S, Hassabo, HM, Aloia, T, Conrad, C, Curley, SA, Vierling, JM, Jalal, P, Raghav, K, Wallace, M, Rashid, A, Abbruzzese, JL, Wolff, RA, and Morris, JS. "Development and validation of insulin-like growth factor-1 score to assess hepatic reserve in hepatocellular carcinoma." Journal of the National Cancer Institute 106.5 (May 9, 2014).

PMID

24815863

Source

epmc

Published In

Journal of the National Cancer Institute

Volume

106

Issue

5

Publish Date

2014

DOI

10.1093/jnci/dju088

Previous studies on the molecular alterations in ampullary adenocarcinoma (AA) are limited, and little is known about their clinical implications. The objective of this study is to examine the expression of p53, p21, cyclin D1, and Bcl2 and their clinical significance in patients with AA. Tissue microarrays were constructed using archival tissue from 92 patients with AA who underwent pancreaticoduodenectomy at our institution. Each tumor was sampled in triplicate with a 1.0-mm punch from representative areas. The expression of p53, p21, cyclin D1, and Bcl2 was evaluated by immunohistochemistry, and the staining results were correlated with clinicopathological features and survival. Among 92 cases studied, overexpression of p53, p21, cyclin D1, and Bcl2 was observed in 58.7%, 39.2%, 71.7%, and 5.4% of tumors, respectively. Patients whose tumor showed high level of cyclin D1 expression had higher risk of disease recurrence (P = .02) and worse recurrence-free and overall survivals after pancreaticoduodenectomy than did those with no or low cyclin D1 expression (P = .027 and P = .02, respectively). In multivariate analysis, cyclin D1 expression was an independent prognostic factor for both recurrence-free and overall survival (P < .05). However, there was no significant correlation between p53, p21, or Bcl2 expression and survival (P > .05). Our study showed that p53, p21, and cyclin D1, but not Bcl2, are frequently overexpressed in AAs. Cyclin D1 overexpression is associated with increased risk of disease recurrence and worse survival in patients with AA after resection.

Authors

Guo, R; Overman, M; Chatterjee, D; Rashid, A; Shroff, S; Wang, H; Katz, MH; Fleming, JB; Varadhachary, GR; Abbruzzese, JL; Wang, H

MLA Citation

Guo, R, Overman, M, Chatterjee, D, Rashid, A, Shroff, S, Wang, H, Katz, MH, Fleming, JB, Varadhachary, GR, Abbruzzese, JL, and Wang, H. "Aberrant expression of p53, p21, cyclin D1, and Bcl2 and their clinicopathological correlation in ampullary adenocarcinoma." Human pathology 45.5 (May 2014): 1015-1023.

PMID

24746206

Source

epmc

Published In

Human Pathology

Volume

45

Issue

5

Publish Date

2014

Start Page

1015

End Page

1023

DOI

10.1016/j.humpath.2013.12.016

The therapeutic resistance of pancreatic ductal adenocarcinoma (PDAC) is partly ascribed to ineffective delivery of chemotherapy to cancer cells. We hypothesized that physical properties at vascular, extracellular, and cellular scales influence delivery of and response to gemcitabine-based therapy.We developed a method to measure mass transport properties during routine contrast-enhanced CT scans of individual human PDAC tumors. Additionally, we evaluated gemcitabine infusion during PDAC resection in 12 patients, measuring gemcitabine incorporation into tumor DNA and correlating its uptake with human equilibrative nucleoside transporter (hENT1) levels, stromal reaction, and CT-derived mass transport properties. We also studied associations between CT-derived transport properties and clinical outcomes in patients who received preoperative gemcitabine-based chemoradiotherapy for resectable PDAC.Transport modeling of 176 CT scans illustrated striking differences in transport properties between normal pancreas and tumor, with a wide array of enhancement profiles. Reflecting the interpatient differences in contrast enhancement, resected tumors exhibited dramatic differences in gemcitabine DNA incorporation, despite similar intravascular pharmacokinetics. Gemcitabine incorporation into tumor DNA was inversely related to CT-derived transport parameters and PDAC stromal score, after accounting for hENT1 levels. Moreover, stromal score directly correlated with CT-derived parameters. Among 110 patients who received preoperative gemcitabine-based chemoradiotherapy, CT-derived parameters correlated with pathological response and survival.Gemcitabine incorporation into tumor DNA is highly variable and correlates with multiscale transport properties that can be derived from routine CT scans. Furthermore, pretherapy CT-derived properties correlate with clinically relevant endpoints.Clinicaltrials.gov NCT01276613.Lustgarten Foundation (989161), Department of Defense (W81XWH-09-1-0212), NIH (U54CA151668, KCA088084).

Authors

Koay, EJ; Truty, MJ; Cristini, V; Thomas, RM; Chen, R; Chatterjee, D; Kang, Y; Bhosale, PR; Tamm, EP; Crane, CH; Javle, M; Katz, MH; Gottumukkala, VN; Rozner, MA; Shen, H; Lee, JE; Wang, H; Chen, Y; Plunkett, W; Abbruzzese, JL; Wolff, RA; Varadhachary, GR; Ferrari, M; Fleming, JB

MLA Citation

Koay, EJ, Truty, MJ, Cristini, V, Thomas, RM, Chen, R, Chatterjee, D, Kang, Y, Bhosale, PR, Tamm, EP, Crane, CH, Javle, M, Katz, MH, Gottumukkala, VN, Rozner, MA, Shen, H, Lee, JE, Wang, H, Chen, Y, Plunkett, W, Abbruzzese, JL, Wolff, RA, Varadhachary, GR, Ferrari, M, and Fleming, JB. "Transport properties of pancreatic cancer describe gemcitabine delivery and response." The Journal of Clinical Investigation 124.4 (April 2014): 1525-1536.

PMID

24614108

Source

epmc

Published In

The Journal of Clinical Investigation

Volume

124

Issue

4

Publish Date

2014

Start Page

1525

End Page

1536

DOI

10.1172/JCI73455

Authors

Shroff, RT; Abbruzzese, JL

MLA Citation

Shroff, RT, and Abbruzzese, JL. "Molecular Pathogenesis of Pancreatic Adenocarcinoma." The Molecular Basis of Cancer: Fourth Edition. March 1, 2014.

Source

scopus

Publish Date

2014

DOI

10.1016/B978-1-4557-4066-6.00035-4

Previous studies showed that SOX9 plays a critical role in pancreatic ductal development. The aim of this study was to evaluate SOX9 as a marker for pancreatic ductal lineage. SOX9 expression was evaluated by immunohistochemistry in 146 benign pancreas (BP), 136 pancreatic ductal adenocarcinomas, 47 pancreatic intraepithelial neoplasia (PanIN), 21 intraductal papillary mucinous neoplasms (IPMNs), 14 mucinous cystic neoplasms, 10 serous cystadenomas, 39 pancreatic neuroendocrine tumors, 9 acinar cell carcinomas, and 23 solid pseudopapillary neoplasms. Nuclear expression of SOX9 was detected in the centroacinar cells and ductal cells, but not in acinar or endocrine cells in 100% BP. Focal or diffuse SOX9 expression was detected in 100% PanINs, 100% IPMNs, 100% mucinous cystic neoplasms, 100% serous cystadenomas, 89.0% pancreatic ductal adenocarcinomas, 2.6% pancreatic neuroendocrine tumors, 11.1% acinar cell carcinomas, and 0% solid pseudopapillary neoplasms. SOX9 expression was lower in PanIN2 and PanIN3 than in PanIN1 lesions (P < .01). Compared with BP, IPMN had lower SOX9 expression (P < .05). No correlation between SOX9 expression and other clinicopathologic parameters was identified. Our study showed that SOX9 is expressed in centroacinar and ductal epithelial cells of BP and is a useful marker for pancreatic ductal lineage of pancreatic neoplasms.

Authors

Shroff, S; Rashid, A; Wang, H; Katz, MH; Abbruzzese, JL; Fleming, JB; Wang, H

MLA Citation

Shroff, S, Rashid, A, Wang, H, Katz, MH, Abbruzzese, JL, Fleming, JB, and Wang, H. "SOX9: a useful marker for pancreatic ductal lineage of pancreatic neoplasms." Human pathology 45.3 (March 2014): 456-463.

PMID

24418153

Source

epmc

Published In

Human Pathology

Volume

45

Issue

3

Publish Date

2014

Start Page

456

End Page

463

DOI

10.1016/j.humpath.2013.10.008

Although solid pseudopapillary neoplasms (SPNs) are considered tumors of low malignant potential, patients may present with aggressive disease (ie, liver metastasis/invasion into adjacent organs) and, rarely, die from disease. Although the clinicopathologic features associated with aggressive SPNs have been reported, important prognostic factors of survival remain unclear. We systematically reviewed 64 cases of SPN resected at our institution for tumor size, extent of invasion, margin status, presence of lymphovascular, muscular vessel, and perineural invasion, and lymph node and distant metastases. Clinicopathologic characteristics were correlated with the presence of metastasis/recurrence and disease-specific survival. Five (8%) patients presented with stage IV disease. During follow-up, 5 (13%) of 39 patients with stage I-II disease had recurrences. Patients with metastatic/recurrent SPNs had significantly larger tumor size (P<0.001) and more frequent tumor invasion into muscular vessels (P=0.02). In a median follow-up of 76 months, only 2 died of disease (1 who presented with extensive peritoneal tumor involvement who died 2.5 mo after surgery, and 1 unusual case who presented with multiple liver metastasis and peritoneal seeding who died 19 mo after surgery), and 5 were alive with disease. The 10-year disease-specific survival rate was 96%. Muscular vessel invasion (P=0.001), tumor (T) stage by European Neuroendocrine Tumors Society (ENETS) classification (P<0.001), ENETS stage grouping (P<0.001), and stage grouping by the American Joint Committee on Cancer (AJCC stage, P<0.001) were important predictors of disease-specific survival in patients with SPN. Our study highlights the importance of pathologic evaluation in risk assessment in patients with SPNs.

Authors

Estrella, JS; Li, L; Rashid, A; Wang, H; Katz, MH; Fleming, JB; Abbruzzese, JL; Wang, H

MLA Citation

Estrella, JS, Li, L, Rashid, A, Wang, H, Katz, MH, Fleming, JB, Abbruzzese, JL, and Wang, H. "Solid pseudopapillary neoplasm of the pancreas: clinicopathologic and survival analyses of 64 cases from a single institution." The American Journal of Surgical Pathology 38.2 (February 2014): 147-157.

PMID

24418850

Source

epmc

Published In

The American Journal of Surgical Pathology

Volume

38

Issue

2

Publish Date

2014

Start Page

147

End Page

157

DOI

10.1097/pas.0000000000000141

HPK1, a member of mammalian Ste20-like serine/threonine kinases, is lost in >95% pancreatic cancer through proteasome-mediated degradation. However, the mechanism of HPK1 loss has not been defined. The aims of this study are to identify the ubiquitin ligase and to examine the mechanisms that targets HPK1 degradation. We found that the CUL7/Fbxw8 ubiquitin ligase targeted HPK1 for degradation via the 26 S proteasome. The ubiquitination of HPK1 required its kinase activity and autophosphorylation. Wild-type protein phosphatase 4 (PP4), but not the phosphatase-dead PP4 mutant, PP4-RL, inhibits the interaction of Fbxw8 with HPK1 and Fbxw8-mediated ubiquitination of HPK1. In addition, we showed that Thr-355 of HPK1 is a key PP4 dephosphorylation site, through which CUL7/Fbxw8 ubiquitin ligase and PP4 regulates HPK1 stability. Knockdown of Fbxw8 restores endogenous HPK1 protein expression and inhibits cell proliferation of pancreatic cancer cells. Our study demonstrated that targeted degradation of HPK1 by the CUL7/Fbxw8 ubiquitin ligase constitutes a negative-feedback loop to restrain the activity of HPK1 and that CUL7/Fbxw8 ubiquitin ligase promotes pancreatic cancer cell proliferation. CUL7/Fbxw8 ubiquitin ligase-mediated HPK1 degradation revealed a direct link and novel role of CUL7/Fbxw8 ubiquitin ligase in the MAPK pathway, which plays a critical role in cell proliferation and differentiation.

Authors

Wang, H; Chen, Y; Lin, P; Li, L; Zhou, G; Liu, G; Logsdon, C; Jin, J; Abbruzzese, JL; Tan, T-H; Wang, H

MLA Citation

Wang, H, Chen, Y, Lin, P, Li, L, Zhou, G, Liu, G, Logsdon, C, Jin, J, Abbruzzese, JL, Tan, T-H, and Wang, H. "The CUL7/F-box and WD repeat domain containing 8 (CUL7/Fbxw8) ubiquitin ligase promotes degradation of hematopoietic progenitor kinase 1." The Journal of Biological Chemistry 289.7 (February 2014): 4009-4017.

PMID

24362026

Source

epmc

Published In

The Journal of Biological Chemistry

Volume

289

Issue

7

Publish Date

2014

Start Page

4009

End Page

4017

DOI

10.1074/jbc.M113.520106

Authors

Estrella, J; Li, L; Rashid, A; Wang, H; Katz, MH; Fleming, JB; Abbruzzese, JL; Wang, H

MLA Citation

Estrella, J, Li, L, Rashid, A, Wang, H, Katz, MH, Fleming, JB, Abbruzzese, JL, and Wang, H. "Solid Pseudopapillary Neoplasm of the Pancreas: Clinicopathologic and Survival Analyses of 64 Cases from a Single Institution." February 2014.

Source

wos-lite

Published In

Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc

Volume

27

Publish Date

2014

Start Page

448A

End Page

449A

Hepatocellular carcinoma (HCC) staging systems were developed using data predominantly from patients who had hepatitis and cirrhosis. Given the recent change in prevalence of viral hepatitis and cirrhosis at oncology centers, which has altered the natural history of HCC, we aimed at comparing the accuracy of HCC staging systems in patients with or without hepatitis and cirrhosis.A total of 438 patients were enrolled. Baseline clinicopathologic parameters, Barcelona Clinic Liver Cancer stage, Cancer of the Liver Italian Program score, TNM (6th edition) stage, Okuda stage, and Chinese University Prognostic Index score were prospectively obtained for all patients, and retrospectively analyzed. Kaplan-Meier analysis was used to determine overall survival (OS), Cox regression analyses were performed, and Harrell's Correspondence Index compared the staging systems' ability to predict OS duration. Subgroup analyses of patients with or without hepatitis or cirrhosis were performed.Median patient OS was 13.9 months; 165 patients (37.7%) had no cirrhosis and 256 patients (58.4%) had no hepatitis. Overall, all staging systems were significantly less predictive of OS in patients who did not have cirrhosis or hepatitis.Our results advocate the need to further stratify HCC based on cirrhosis and hepatitis status, which may change patient risk-stratification and, ultimately, treatment decisions.

Authors

Kaseb, AO; Shah, NN; Hassabo, HM; Morris, JS; Xiao, L; Abaza, YM; Soliman, K; Lee, J-S; Vauthey, J-N; Wallace, M; Aloia, TA; Curley, S; Abbruzzese, JL; Hassan, MM

MLA Citation

Kaseb, AO, Shah, NN, Hassabo, HM, Morris, JS, Xiao, L, Abaza, YM, Soliman, K, Lee, J-S, Vauthey, J-N, Wallace, M, Aloia, TA, Curley, S, Abbruzzese, JL, and Hassan, MM. "Reassessing hepatocellular carcinoma staging in a changing patient population." Oncology 86.2 (January 8, 2014): 63-71.

PMID

24401634

Source

epmc

Published In

Oncology

Volume

86

Issue

2

Publish Date

2014

Start Page

63

End Page

71

DOI

10.1159/000356573

Child-Turcotte-Pugh (CTP) score is the standard tool to assess hepatic reserve in hepatocellular carcinoma (HCC), and CTP-A is the classic group for active therapy. However, CTP stratification accuracy has been questioned. We hypothesized that plasma insulin-like growth factor 1 (IGF-1) is a valid surrogate for hepatic reserve to replace the subjective parameters in CTP score to improve its prognostic accuracy. We retrospectively tested plasma IGF-1 levels in the training set (n = 310) from MD Anderson Cancer Center. Recursive partitioning identified three optimal IGF-1 ranges that correlated with overall survival (OS): greater than 50 ng/mL = 1 point; 26 to 50 ng/mL = 2 points; and less than 26 ng/mL = 3 points. We modified the CTP score by replacing ascites and encephalopathy grading with plasma IGF-1 value (IGF-CTP) and subjected both scores to log-rank analysis. Harrell's C-index and U-statistics were used to compare the prognostic performance of both scores in both the training and validation cohorts (n = 155). All statistical tests were two-sided. Patients' stratification was statistically significantly stronger for IGF-CTP than CTP score for the training (P = .003) and the validation cohort (P = .005). Patients reclassified by IGF-CTP relative to their original CTP score were better stratified by their new risk groups. Most important, patients classified as A by CTP but B by IGF-CTP had statistically significantly worse OS than those who remained under class A by IGF-CTP in both cohorts (P = .03 and P < .001, respectively, from Cox regression models). AB patients had a worse OS than AA patients in both the training and validation set (hazard ratio [HR] = 1.45, 95% confidence interval [CI] = 1.03 to 2.04, P = .03; HR = 2.83, 95% CI = 1.65 to 4.85, P < .001, respectively). The IGF-CTP score is simple, blood-based, and cost-effective, stratified HCC better than CTP score, and validated well on two independent cohorts. International validation studies are warranted. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Authors

Kaseb, AO; Xiao, L; Hassan, MM; Chae, YK; Lee, JS; Vauthey, JN; Krishnan, S; Cheung, S; Hassabo, HM; Aloia, T; Conrad, C; Curley, SA; Vierling, JM; Jalal, P; Raghav, K; Wallace, M; Rashid, A; Abbruzzese, JL; Wolff, RA; Morris, JS

MLA Citation

Kaseb, AO, Xiao, L, Hassan, MM, Chae, YK, Lee, JS, Vauthey, JN, Krishnan, S, Cheung, S, Hassabo, HM, Aloia, T, Conrad, C, Curley, SA, Vierling, JM, Jalal, P, Raghav, K, Wallace, M, Rashid, A, Abbruzzese, JL, Wolff, RA, and Morris, JS. "Development and validation of insulin-like growth factor-1 score to assess hepatic reserve in hepatocellular carcinoma." Journal of the National Cancer Institute 106.5 (January 1, 2014).

Source

scopus

Published In

J Natl Cancer Inst

Volume

106

Issue

5

Publish Date

2014

Authors

Fisch, MJ; Abbruzzese, JL; Hong, WK

MLA Citation

Fisch, MJ, Abbruzzese, JL, and Hong, WK. "Evaluating physician performance in oncology: moneyball becomes impactball." Journal of oncology practice 10.1 (January 2014): 79-81.

PMID

24443736

Source

epmc

Published In

Journal of Oncology Practice

Volume

10

Issue

1

Publish Date

2014

Start Page

79

End Page

81

DOI

10.1200/jop.2013.001218

Barriers to multimodality therapy (MMT) completion among patients with resectable pancreatic adenocarcinoma include early cancer progression and postoperative major complications (PMC). We sought to evaluate the influence of these factors on MMT completion rates of patients treated with neoadjuvant therapy (NT) and surgery-first (SF) approaches. We evaluated all operable patients treated for clinically resectable pancreatic head adenocarcinoma at our institution from 2002 to 2007. Rates of MMT completion, 90-day PMC, and overall survival (OS) were evaluated. Ninety-five of 115 (83 %) NT and 29/50 (58 %) SF patients completed MMT. Patients who completed MMT lived longer than those who did not (36 vs. 11 months, p < 0.001). The most common reason that NT (11 %) and SF (26 %) patients failed to complete MMT was early disease progression. The rates of PMC among NT and SF patients were similar. Among SF patients, 69 % with no PMC completed MMT versus 29 % after PMC (p = 0.040). PMC were associated with decreased OS in SF patients but not in NT patients. The impact of early cancer progression and PMC upon completion of MMT is reduced by delivery of nonoperative therapies prior to pancreaticoduodenectomy. NT sequencing is a practical treatment strategy, particularly for patients at high biological or perioperative risk.

Authors

Tzeng, C-WD; Tran Cao, HS; Lee, JE; Pisters, PWT; Varadhachary, GR; Wolff, RA; Abbruzzese, JL; Crane, CH; Evans, DB; Wang, H; Abbott, DE; Vauthey, J-N; Aloia, TA; Fleming, JB; Katz, MHG

MLA Citation

Tzeng, C-WD, Tran Cao, HS, Lee, JE, Pisters, PWT, Varadhachary, GR, Wolff, RA, Abbruzzese, JL, Crane, CH, Evans, DB, Wang, H, Abbott, DE, Vauthey, J-N, Aloia, TA, Fleming, JB, and Katz, MHG. "Treatment sequencing for resectable pancreatic cancer: influence of early metastases and surgical complications on multimodality therapy completion and survival." Journal of Gastrointestinal Surgery : Official Journal of the Society for Surgery of the Alimentary Tract 18.1 (January 2014): 16-24.

PMID

24241967

Source

epmc

Published In

Journal of Gastrointestinal Surgery : Official Journal of the Society for Surgery of the Alimentary Tract

Volume

18

Issue

1

Publish Date

2014

Start Page

16

End Page

24

DOI

10.1007/s11605-013-2412-1

We previously described the clinical classification of patients with resectable pancreatic tumor anatomy but marginal performance status (PS) or reversible comorbidities as "borderline resectable type C" (BR-C). This study was designed to analyze the incidence and risk factors for post-pancreaticoduodenectomy (PD) morbidity/mortality in a multi-institutional cohort of BR-C patients.Elective PDs were evaluated from the 2005-10 ACS-NSQIP database. BR-C was defined as age ≥ 80, poor PS, weight loss > 10 %, pulmonary disease, recent myocardial infarction/angina, stroke history, and/or preoperative sepsis. Variables associated with 30-day postoperative major complications (PMC) and mortality were analyzed.A total of 3,033/8,266 (36.7 %) patients were BR-C. BR-C patients were more likely to suffer PMC (31.3 vs. 26.2 %) and mortality (4.1 vs. 2.3 %). BR-C patients with PMC suffered 50 % higher mortality versus non-BR-C patients with PMC (11.5 vs. 7.7 %) (all p < 0.001). For BR-C patients, multivariate analysis identified the following risk factors for PMC or mortality: albumin < 3.5 g/dL, dyspnea, preoperative sepsis, age ≥ 80, poor PS, anesthesia score ≥ 4, and intraoperative transfusion ≥ 4 units.Nationwide, one third of patients undergoing PD are medically borderline. These BR-C patients are at higher risk for and less able to be rescued from PMC. Surgeons should identify and optimize comorbidities and utilize prehabilitation to address functional deficits before elective PD.

Authors

Tzeng, C-WD; Katz, MHG; Fleming, JB; Lee, JE; Pisters, PWT; Holmes, HM; Varadhachary, GR; Wolff, RA; Abbruzzese, JL; Vauthey, J-N; Aloia, TA

MLA Citation

Tzeng, C-WD, Katz, MHG, Fleming, JB, Lee, JE, Pisters, PWT, Holmes, HM, Varadhachary, GR, Wolff, RA, Abbruzzese, JL, Vauthey, J-N, and Aloia, TA. "Morbidity and mortality after pancreaticoduodenectomy in patients with borderline resectable type C clinical classification." Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract 18.1 (January 2014): 146-155.

PMID

24129825

Source

epmc

Published In

Journal of Gastrointestinal Surgery : Official Journal of the Society for Surgery of the Alimentary Tract

Volume

18

Issue

1

Publish Date

2014

Start Page

146

End Page

155

DOI

10.1007/s11605-013-2371-6

Because of the rarity of duodenal adenocarcinoma (DAC), the clinicopathologic features and prognostication data for DAC are limited. There are no published studies directly comparing the prognosis of DAC to that of ampullary adenocarcinoma (AA) and of pancreatic ductal adenocarcinoma (PDA) after resection. In this study, we examined the clinicopathologic features of 68 patients with DAC, 92 patients with AA, and 126 patients with PDA who underwent resection. Patient clinicopathologic and survival information were extracted from medical records. Statistical analysis was performed using Statistical Package for the Social Sciences with 2-sided significance level of .05. Patients with DAC had higher American Joint Committee on Cancer (AJCC) stage than AA patients (P = .001). Lymph node metastasis (P = .013) and AJCC stage (P = .02) correlated with overall survival in DAC patients. Patients with DAC or AA had lower frequencies of lymph node metastasis and positive margin and better survival than those with PDA (P < .05). However, no differences in nodal metastasis, margin status, or survival were observed between DAC patients and those with AA. Our study showed that lymph node metastasis and AJCC stage are important prognostic factors for overall survival in DAC patients. Patients with DAC had less frequent nodal metastasis and better prognosis than those with PDA. There was no significant difference in prognosis between DAC and AA.

Authors

Zenali, M; Overman, MJ; Rashid, A; Broaddus, RB; Wang, H; Katz, MH; Fleming, JB; Abbruzzese, JL; Wang, H

MLA Citation

Zenali, M, Overman, MJ, Rashid, A, Broaddus, RB, Wang, H, Katz, MH, Fleming, JB, Abbruzzese, JL, and Wang, H. "Clinicopathologic features and prognosis of duodenal adenocarcinoma and comparison with ampullary and pancreatic ductal adenocarcinoma." Human Pathology 44.12 (December 2013): 2792-2798.

PMID

24139211

Source

epmc

Published In

Human Pathology

Volume

44

Issue

12

Publish Date

2013

Start Page

2792

End Page

2798

DOI

10.1016/j.humpath.2013.07.030

To study the histological changes in non-neoplastic pancreas and the effects on pancreatic intraepithelial neoplasia (PanIN) after neoadjuvant chemoradiation therapy (NCRT) for pancreatic ductal adenocarcinoma (PDAC).We reviewed the archival H&E slides from 218 patients with PDAC who completed NCRT and pancreaticoduodenectomy. Sixty-five patients who underwent pancreaticoduodenectomy for PDAC without NCRT were used as controls. Various histological features were reviewed and correlated with NCRT and survival. The NCRT group had lower densities of PanIN2 (P = 0.004) and PanIN3 (P = 0.02) than the control group. The extent of fibrosis, the frequency of neuroma-like nerve proliferation and the frequency of islet cell aggregation were significantly higher in the NCRT group than in the control group (P < 0.05). The intensity of inflammation was less in the NCRT group than in the control group (P = 0.02). In the NCRT group, patents with moderate to severe fibrosis or grade 2 inflammation had poorer survival than those with mild fibrosis (P = 0.04) or those with grade 0 or grade 1 inflammation (P = 0.003), respectively.Non-neoplastic pancreatic tissue from patients who received NCRT had a reduced density of high-grade PanIN lesions, more pancreatic fibrosis, and higher frequencies of neuroma-like nerve proliferation and islet cell aggregation, but less inflammation, compared to tissue from those who did not receive NCRT.

Authors

Chatterjee, D; Katz, MH; Rashid, A; Estrella, JS; Wang, H; Varadhachary, GR; Wolff, RA; Lee, JE; Pisters, PW; Abbruzzese, JL; Fleming, JB; Wang, H

MLA Citation

Chatterjee, D, Katz, MH, Rashid, A, Estrella, JS, Wang, H, Varadhachary, GR, Wolff, RA, Lee, JE, Pisters, PW, Abbruzzese, JL, Fleming, JB, and Wang, H. "Pancreatic intraepithelial neoplasia and histological changes in non-neoplastic pancreas associated with neoadjuvant therapy in patients with pancreatic ductal adenocarcinoma." Histopathology 63.6 (December 2013): 841-851.

PMID

24111684

Source

epmc

Published In

Histopathology

Volume

63

Issue

6

Publish Date

2013

Start Page

841

End Page

851

DOI

10.1111/his.12234

In treating pancreatic cancer, there is no clearly defined optimal sequence of chemotherapy, radiation therapy and surgery. Therefore, cost-effectiveness should be considered. The objective of this study was to compare cost and outcomes between a surgery-first approach versus neoadjuvant chemoradiation followed by surgery for resectable pancreatic head cancer.A decision analytic model was constructed to compare the 2 approaches. Data from the National Cancer Database, National Surgical Quality Improvement Program, and literature populated the surgery-first arm. Data from our prospectively maintained institutional pancreatic cancer database populated the neoadjuvant arm. Costs were estimated by Medicare payment (2011 U.S. dollars). Survival was reported in quality-adjusted life-months (QALMs).The neoadjuvant chemoradiation arm consisted of 164 patients who completed preoperative therapy. Of these, 36 (22 %) did not proceed to surgery; 12 (7 %) underwent laparotomy but had unresectable disease; and 116 (71 %) underwent definitive resection. The surgery-first approach cost $46,830 and yielded survival of 8.7 QALMs; the neoadjuvant chemoradiation approach cost $36,583 and yielded survival of 18.8 QALMs. In the neoadjuvant arm, costs and survival times for patients not undergoing surgery, those with unresectable disease at laparotomy, and those completing surgery were $12,401 and 7.7 QALMs, $20,380 and 7.1 QALMs, and $45,673 and 23.4 QALMs, respectively.Neoadjuvant chemoradiation for pancreatic cancer identifies patients with early metastases or poor performance status, who can be spared an ineffective or prohibitively morbid operation, and is associated with improved survival at significantly lower cost than a surgery-first approach. Neoadjuvant chemoradiation followed by surgery is a strategy that provides more cost-effective care than a surgery-first approach.

Authors

Abbott, DE; Tzeng, C-WD; Merkow, RP; Cantor, SB; Chang, GJ; Katz, MH; Bentrem, DJ; Bilimoria, KY; Crane, CH; Varadhachary, GR; Abbruzzese, JL; Wolff, RA; Lee, JE; Evans, DB; Fleming, JB

MLA Citation

Abbott, DE, Tzeng, C-WD, Merkow, RP, Cantor, SB, Chang, GJ, Katz, MH, Bentrem, DJ, Bilimoria, KY, Crane, CH, Varadhachary, GR, Abbruzzese, JL, Wolff, RA, Lee, JE, Evans, DB, and Fleming, JB. "The cost-effectiveness of neoadjuvant chemoradiation is superior to a surgery-first approach in the treatment of pancreatic head adenocarcinoma." Annals of Surgical Oncology 20 Suppl 3 (December 2013): S500-S508.

PMID

23397153

Source

epmc

Published In

Annals of Surgical Oncology

Volume

20 Suppl 3

Publish Date

2013

Start Page

S500

End Page

S508

DOI

10.1245/s10434-013-2882-0

Context.- Phosphatase and tensin homolog (PTEN) is one of the most frequently inactivated tumor suppressor genes in sporadic cancers. Somatic mutations of PTEN occur in many tumors including those of the gastrointestinal and hepatobiliary tracts. Loss of PTEN expression is associated with poor prognosis in patients with metastatic colonic adenocarcinoma, gastroesophageal junction adenocarcinoma, gastric adenocarcinoma, and pancreatic ductal adenocarcinoma. Objective.- To study the expression of PTEN and its significance in ampullary adenocarcinoma (AA). Design.- We constructed tissue microarrays by using archival tissue from 92 patients (55 males, 37 females; median age, 63 years; age range, 37 to 87 years) with previously untreated AA who underwent pancreaticoduodenectomy at our institution. PTEN expression was evaluated by immunohistochemistry, scored semiquantitatively (based on staining intensity and percentage positive tumor cells), and correlated with clinicopathologic features and survival. Results.- Of 92 cases, 23 (25.0%) were PTEN negative. Loss of PTEN expression correlated with lymph node metastasis (P=.004), advanced American Joint Committee on Cancer (AJCC) stage (P = .02), and higher frequency of recurrence (P = .03). Patients with PTEN-negative tumors had shorter disease-free survival (DFS, mean: 89.0 ± 20.8 months) and overall survival (OS, mean: 93.1 ± 19.1 months) than those with PTEN-positive tumors (DFS, mean: 161.4 ± 11.7 months, P = .01; OS, mean: 175.4 ± 11.0 months, P = .001). In multivariate analyses, PTEN expression was a prognostic factor for both DFS and OS, independent of AJCC stage, lymph node status, pathologic tumor (pT) stage, and differentiation. Conclusions.- Loss of PTEN expression is associated with poor DFS and OS in patients with AA after curative surgery. PTEN expression may be used as a prognostic marker for patients with resected AA.

Authors

Stuti, S; Shroff, S; Overman, MJ; Rashid, A; Shroff, RT; Wang, H; Chatterjee, D; Katz, MH; Lee, JE; Wolff, RA; Abbruzzese, JL; Fleming, JB

MLA Citation

Stuti, S, Shroff, S, Overman, MJ, Rashid, A, Shroff, RT, Wang, H, Chatterjee, D, Katz, MH, Lee, JE, Wolff, RA, Abbruzzese, JL, and Fleming, JB. "The expression of pten is associated with improved prognosis in patients with ampullary adenocarcinoma after pancreaticoduodenectomy." Archives of Pathology and Laboratory Medicine 137.11 (November 1, 2013): 1619-1626.

Source

scopus

Published In

Archives of Pathology & Laboratory Medicine

Volume

137

Issue

11

Publish Date

2013

Start Page

1619

End Page

1626

DOI

10.5858/arpa.2012-0418-OA)

Phosphatase and tensin homolog (PTEN) is one of the most frequently inactivated tumor suppressor genes in sporadic cancers. Somatic mutations of PTEN occur in many tumors including those of the gastrointestinal and hepatobiliary tracts. Loss of PTEN expression is associated with poor prognosis in patients with metastatic colonic adenocarcinoma, gastroesophageal junction adenocarcinoma, gastric adenocarcinoma, and pancreatic ductal adenocarcinoma.To study the expression of PTEN and its significance in ampullary adenocarcinoma (AA).We constructed tissue microarrays by using archival tissue from 92 patients (55 males, 37 females; median age, 63 years; age range, 37 to 87 years) with previously untreated AA who underwent pancreaticoduodenectomy at our institution. PTEN expression was evaluated by immunohistochemistry, scored semiquantitatively (based on staining intensity and percentage positive tumor cells), and correlated with clinicopathologic features and survival.Of 92 cases, 23 (25.0%) were PTEN negative. Loss of PTEN expression correlated with lymph node metastasis (P = .004), advanced American Joint Committee on Cancer (AJCC) stage (P = .02), and higher frequency of recurrence (P = .03). Patients with PTEN-negative tumors had shorter disease-free survival (DFS, mean: 89.0 ± 20.8 months) and overall survival (OS, mean: 93.1 ± 19.1 months) than those with PTEN-positive tumors (DFS, mean: 161.4 ± 11.7 months, P = .01; OS, mean: 175.4 ± 11.0 months, P = .001). In multivariate analyses, PTEN expression was a prognostic factor for both DFS and OS, independent of AJCC stage, lymph node status, pathologic tumor (pT) stage, and differentiation.Loss of PTEN expression is associated with poor DFS and OS in patients with AA after curative surgery. PTEN expression may be used as a prognostic marker for patients with resected AA.

Authors

Shroff, S; Overman, MJ; Rashid, A; Shroff, RT; Wang, H; Chatterjee, D; Katz, MH; Lee, JE; Wolff, RA; Abbruzzese, JL; Fleming, JB; Wang, H

MLA Citation

Shroff, S, Overman, MJ, Rashid, A, Shroff, RT, Wang, H, Chatterjee, D, Katz, MH, Lee, JE, Wolff, RA, Abbruzzese, JL, Fleming, JB, and Wang, H. "The expression of PTEN is associated with improved prognosis in patients with ampullary adenocarcinoma after pancreaticoduodenectomy." Archives of Pathology & Laboratory Medicine 137.11 (November 2013): 1619-1626.

PMID

24168499

Source

epmc

Published In

Archives of Pathology & Laboratory Medicine

Volume

137

Issue

11

Publish Date

2013

Start Page

1619

End Page

1626

DOI

10.5858/arpa.2012-0418-OA

Nonalcoholic fatty liver disease (NAFLD) is an emerging epidemic with high prevalence in Western countries. Genome-wide association studies had reported that a variation in the patatin-like phospholipase domain containing 3 (PNPLA3) gene is associated with high susceptibility to NAFLD. However, the relationship between this variation and hepatocellular carcinoma (HCC) has not been well established. We investigated the impact of PNPLA3 genetic variation (rs738409: C>G) on HCC risk and prognosis in the United States by conducting a case-control study that included 257 newly diagnosed and pathologically confirmed Caucasian patients with HCC (cases) and 494 healthy controls. Multivariate logistics and Cox regression models were used to control for the confounding effects of HCC risk and prognostic factors. We observed higher risk of HCC for subjects with a homozygous GG genotype than for those with CC or CG genotypes, the adjusted odds ratio (OR) was 3.21 (95% confidence interval [CI], 1.68-6.41). We observed risk modification among individuals with diabetes mellitus (OR = 19.11; 95% CI, 5.13-71.20). The PNPLA3 GG genotype was significantly associated with underlying cirrhosis in HCC patients (OR = 2.48; 95% CI, 1.05-5.87). Moreover, GG allele represents an independent risk factor for death. The adjusted hazard ratio of the GG genotype was 2.11 (95% CI, 1.26-3.52) compared with CC and CG genotypes. PNPLA3 genetic variation (rs738409: C>G) may determine individual susceptibility to HCC development and poor prognosis. Further experimental investigations are necessary for thorough assessment of the hepatocarcinogenic role of PNPLA3.

Authors

Hassan, MM; Kaseb, A; Etzel, CJ; El-Serag, H; Spitz, MR; Chang, P; Hale, KS; Liu, M; Rashid, A; Shama, M; Abbruzzese, JL; Loyer, EM; Kaur, H; Hassabo, HM; Vauthey, J-N; Wray, CJ; Hassan, BS; Patt, YZ; Hawk, E; Soliman, KM; Li, D

MLA Citation

Hassan, MM, Kaseb, A, Etzel, CJ, El-Serag, H, Spitz, MR, Chang, P, Hale, KS, Liu, M, Rashid, A, Shama, M, Abbruzzese, JL, Loyer, EM, Kaur, H, Hassabo, HM, Vauthey, J-N, Wray, CJ, Hassan, BS, Patt, YZ, Hawk, E, Soliman, KM, and Li, D. "Genetic variation in the PNPLA3 gene and hepatocellular carcinoma in USA: risk and prognosis prediction." Molecular Carcinogenesis 52 Suppl 1 (November 2013): E139-E147.

PMID

23776098

Source

epmc

Published In

Molecular Carcinogenesis

Volume

52 Suppl 1

Publish Date

2013

Start Page

E139

End Page

E147

DOI

10.1002/mc.22057

Authors

Varadhachary, GR; Lenzi, R; Raber, MN; Abbruzzese, JL

MLA Citation

Varadhachary, GR, Lenzi, R, Raber, MN, and Abbruzzese, JL. "Carcinoma of Unknown Primary." Abeloff's Clinical Oncology: Fifth Edition. October 22, 2013. 1792-1803.e2.

Source

scopus

Publish Date

2013

Start Page

1792

End Page

1803.e2

DOI

10.1016/B978-1-4557-2865-7.00094-1

Metastatic pancreatic cancer carries a poor prognosis, with median survival on the order of several months. There is evidence that combining gemcitabine with either erlotinib or cisplatin may be superior to single agent gemcitabine in patients with good performance (PS 0-1). We retrospectively compared outcomes of patients treated with either the three drug regimen of gemcitabine, cisplatin, and erlotinib (GCE) or the doublet of gemcitabine and cisplatin (GC) in order to assess the potential benefit of erlotinib. We also evaluated the role of erlotinib among smokers and non-smokers. We retrospectively analyzed 145 patients who presented between 2006 and 2009 with previously untreated metastatic pancreatic cancer initially treated at the M.D. Anderson cancer center with either GC or GCE. Information on tumor characteristics and overall survival time (OS) was collected by medical record review. Kaplan-Meier curves were used to estimate OS. Log rank tests were used to compare OS between groups. The Cox proportional hazards regression model was used to evaluate the ability of patient prognostic variables or treatment group to predict OS. A total of 71 patients were treated with GC, while 74 were treated with GCE. Cox analyses found no significant difference in overall survival (median 5.5 vs. 8.0 months, respectively, p-value=0.1). Small sampling numbers may have contributed to this result. One year survival was 23 % in the GCE group and 13 % in the GC group. Patients with poor performance status (PS=2-3) had worse survival as compared to patients with better performance status (PS=0-1, p=0.001). As in earlier studies, patients treated with more lines of therapy tended to have better survival (p <0.0001), and CA19-9 was found to be a significant predictor for OS (p=0.001). No statistical evidence of a survival difference was found between smokers and non-smokers in both treatment groups (p=0.72). In conclusion, though there was a trend towards improved survival with the addition of erlotinib to gemcitabine and cisplatin, this does not reach statistical significance.

Authors

Khalil, MA; Qiao, W; Carlson, P; George, B; Javle, M; Overman, M; Varadhachary, G; Wolff, RA; Abbruzzese, JL; Fogelman, DR

MLA Citation

Khalil, MA, Qiao, W, Carlson, P, George, B, Javle, M, Overman, M, Varadhachary, G, Wolff, RA, Abbruzzese, JL, and Fogelman, DR. "The addition of erlotinib to gemcitabine and cisplatin does not appear to improve median survival in metastatic pancreatic cancer." Investigational new drugs 31.5 (October 2013): 1375-1383.

PMID

23645398

Source

epmc

Published In

Investigational New Drugs

Volume

31

Issue

5

Publish Date

2013

Start Page

1375

End Page

1383

DOI

10.1007/s10637-013-9967-2

The purpose of this study was to evaluate the factors associated with response rate, resectability, and survival after cisplatin/interferon α-2b/doxorubicin/5-fluorouracil (PIAF) combination therapy in patients with initially unresectable hepatocellular carcinoma.The study included 2 groups of patients treated with conventional high-dose PIAF (n = 84) between 1994 and 2003 and those without hepatitis or cirrhosis treated with modified PIAF (n = 33) between 2003 and 2012. Tolerance of chemotherapy, best radiographic response, rate of conversion to curative surgery, and overall survival were analyzed and compared between the 2 groups, and multivariate and logistic regression analyses were applied to identify predictors of response and survival.The modified PIAF group had a higher median number of PIAF cycles (4 versus 2, P = .049), higher objective response rate (36% versus 15%, P = .013), higher rate of conversion to curative surgery (33% versus 10%, P = .004), and longer median overall survival (21.3 versus 10.6 months, P = .002). Multivariate analyses confirmed that positive hepatitis B serology (hazard ratio [HR] = 1.68; 95% confidence interval [CI] = 1.08-2.59) and Eastern Cooperative Oncology Group performance status ≥ 2 (HR = 1.75; 95% CI = 1.04-2.93) were associated with worse survival whereas curative surgical resection after PIAF treatment (HR = 0.15; 95% CI = 0.07-0.35) was associated with improved survival.In patients with initially unresectable hepatocellular carcinoma, the modified PIAF regimen in patients with no hepatitis or cirrhosis is associated with improved response, resectability, and survival.

Authors

Kaseb, AO; Shindoh, J; Patt, YZ; Roses, RE; Zimmitti, G; Lozano, RD; Hassan, MM; Hassabo, HM; Curley, SA; Aloia, TA; Abbruzzese, JL; Vauthey, J-N

MLA Citation

Kaseb, AO, Shindoh, J, Patt, YZ, Roses, RE, Zimmitti, G, Lozano, RD, Hassan, MM, Hassabo, HM, Curley, SA, Aloia, TA, Abbruzzese, JL, and Vauthey, J-N. "Modified cisplatin/interferon α-2b/doxorubicin/5-fluorouracil (PIAF) chemotherapy in patients with no hepatitis or cirrhosis is associated with improved response rate, resectability, and survival of initially unresectable hepatocellular carcinoma." Cancer 119.18 (September 2013): 3334-3342.

PMID

23821538

Source

epmc

Published In

Cancer

Volume

119

Issue

18

Publish Date

2013

Start Page

3334

End Page

3342

DOI

10.1002/cncr.28209

Authors

Overman, MJ; Zhang, J; Kopetz, S; Davies, M; Jiang, ZQ; Stemke-Hale, K; Rümmele, P; Pilarsky, C; Grützmann, R; Hamilton, S; Hwang, R; Abbruzzese, JL; Varadhachary, G; Broom, B; Wang, H

MLA Citation

Overman, MJ, Zhang, J, Kopetz, S, Davies, M, Jiang, ZQ, Stemke-Hale, K, Rümmele, P, Pilarsky, C, Grützmann, R, Hamilton, S, Hwang, R, Abbruzzese, JL, Varadhachary, G, Broom, B, and Wang, H. "Erratum: Gene expression profiling of ampullary carcinomas classifies ampullary carcinomas into biliary-like and intestinal-like subtypes that are prognostic of outcome (PLoS ONE (2013) 8:7 DOI: 10.1371/annotation/6afdd046- e1a7-4421-b7ec-0c9492ce2544)." Plos One 8.7 (July 3, 2013).

Source

scopus

Published In

Plos One

Volume

8

Issue

7

Publish Date

2013

DOI

10.1371/annotation/6afdd046-e1a7-4421-b7ec-0c9492ce2544

Few data exist to guide oncologic surveillance following curative treatment of pancreatic cancer. We sought to identify a rational, cost-effective postoperative surveillance strategy.We constructed a Markov model to compare the cost-effectiveness of 5 postoperative surveillance strategies. No scheduled surveillance served as the baseline strategy. Clinical evaluation and carbohydrate antigen (CA) 19-9 testing without/with routine computed tomography and chest X-ray at either 6- or 3-month intervals served as the 4 comparison strategies of increasing intensity. We populated the model with symptom, recurrence, treatment, and survival data from patients who had received intensive surveillance after multimodality treatment at our institution between 1998 and 2008. Costs were based on Medicare payments (2011 US dollars).The baseline strategy of no scheduled surveillance was associated with a postoperative overall survival (OS) of 24.6 months and a cost of $3837/patient. Clinical evaluation and CA 19-9 assay every 6 months until recurrence was associated with a 32.8-month OS and a cost of $7496/patient, with an incremental cost-effectiveness ratio (ICER) of $5364/life-year (LY). Additional routine imaging every 6 months incrementally increased total cost by $3465 without increasing OS. ICERs associated with clinic visits every 3 months without/with routine imaging were $127,680 and $294,696/LY, respectively. Sensitivity analyses changed the strategies' absolute costs but not the relative ranks of their ICERs.Increasing the frequency and intensity of postoperative surveillance of patients after curative therapy for pancreatic cancer beyond clinical evaluation and CA 19-9 testing every 6 months increases cost but confers no clinically significant survival benefit.

Authors

Tzeng, C-WD; Abbott, DE; Cantor, SB; Fleming, JB; Lee, JE; Pisters, PWT; Varadhachary, GR; Abbruzzese, JL; Wolff, RA; Ahmad, SA; Katz, MHG

MLA Citation

Tzeng, C-WD, Abbott, DE, Cantor, SB, Fleming, JB, Lee, JE, Pisters, PWT, Varadhachary, GR, Abbruzzese, JL, Wolff, RA, Ahmad, SA, and Katz, MHG. "Frequency and intensity of postoperative surveillance after curative treatment of pancreatic cancer: a cost-effectiveness analysis." Annals of surgical oncology 20.7 (July 2013): 2197-2203.

PMID

23408126

Source

epmc

Published In

Annals of Surgical Oncology

Volume

20

Issue

7

Publish Date

2013

Start Page

2197

End Page

2203

DOI

10.1245/s10434-013-2889-6

Phosphatase and tensin homolog (PTEN) is a tumor suppressor in the AKT/mTOR pathway. Animal model studies have shown that loss of PTEN function is involved in the progression of pancreatic cancer. However, the prognostic significance of loss of PTEN expression in pancreatic cancer is unclear. PTEN expression was evaluated by immunohistochemistry on tissue microarrays consisting of multiple cores of 133 resected stage II pancreatic ductal adenocarcinomas. A PTEN expression score was calculated as the product of the percentage of positive tumor cells and the intensity of PTEN staining. We categorized PTEN expression for each tumor as retained (PTEN score >5) or lost (PTEN score ≤5). Thirty-four (25.6%) patients had tumors with loss of PTEN expression, and 99 (74.4%) had tumors with retained PTEN expression. Recurrence/Metastasis was observed in 88.2% (30/34) of patients whose tumors showed loss of PTEN compared with 68.7% (68/99) of patients whose tumors showed retained PTEN (P = .03). Patients whose tumors showed loss of PTEN had a shorter overall survival (median, 19.9 ± 3.6 months) than did patients whose tumors had retained PTEN (32.7 ± 5.0 months, P = .03). In a multivariate analysis, loss of PTEN expression was an independent prognostic factor for poor overall survival in patients with stage II pancreatic ductal adenocarcinoma. No significant correlations between loss of PTEN expression and other clinicopathologic parameters were observed (P > .05). Assessment of PTEN expression may be used as a prognostic marker for patients with resected pancreatic ductal adenocarcinoma.

Authors

Foo, WC; Rashid, A; Wang, H; Katz, MH; Lee, JE; Pisters, PW; Wolff, RA; Abbruzzese, JL; Fleming, JB; Wang, H

MLA Citation

Foo, WC, Rashid, A, Wang, H, Katz, MH, Lee, JE, Pisters, PW, Wolff, RA, Abbruzzese, JL, Fleming, JB, and Wang, H. "Loss of phosphatase and tensin homolog expression is associated with recurrence and poor prognosis in patients with pancreatic ductal adenocarcinoma." Human pathology 44.6 (June 2013): 1024-1030.

PMID

23260327

Source

epmc

Published In

Human Pathology

Volume

44

Issue

6

Publish Date

2013

Start Page

1024

End Page

1030

DOI

10.1016/j.humpath.2012.09.001

The most common genetic lesions in pancreatic ductal adenocarcinoma (PDAC) have been identified. However, significant gaps still exist in our understanding of how such genetic alterations act in concert to induce PDAC development. In this study, we investigated the mechanism of tumorigenic transformation in the immortalized human pancreatic ductal epithelial (HPDE) cell line by sequentially introducing PDAC signature alterations into this cell line.The phenotype for stable expression of mutant K-ras, Her2, p16/p14shRNA, and Smad4shRNA in HPDE cells was examined by assays for cell proliferation, migration, invasion, soft agar, and orthotopic tumorigenesis. The mechanisms of tumorigenic transformation were further explored by gene expression profiling and pathway analyses.The transformed cells exhibited enhanced proliferation, migration, and invasion, displayed anchorage-independent growth in soft agar, and grew orthotopic tumors with some histopathologic features of PDAC. We found that Smad4 played key roles in the tumorigenic transformation of HPDE cells. We further found that MDM2 and Bmi-1 were overexpressed in the tumorigenic HPDE cells and that Bmi-1 overexpression was regulated by Smad4. Ingenuity Pathway Analysis software analysis of microarray data revealed that dysregulation of integrin-linked kinase signaling and the cell cycle were the most significant changes involved in tumorigenic transformation. Altogether, this cell culture model closely recapitulated human pancreatic carcinogenesis from gene lesions, activation of specific signaling pathways, and some histopathologic features.The combination of activated K-ras and Her2 with inactivated p16/p14 and Smad4 was sufficient and essential to transform HPDE cells, thus revealing the potential tumorigenic mechanism.

Authors

Chang, Z; Li, Z; Wang, X; Kang, Y; Yuan, Y; Niu, J; Wang, H; Chatterjee, D; Fleming, JB; Li, M; Abbruzzese, JL; Chiao, PJ

MLA Citation

Chang, Z, Li, Z, Wang, X, Kang, Y, Yuan, Y, Niu, J, Wang, H, Chatterjee, D, Fleming, JB, Li, M, Abbruzzese, JL, and Chiao, PJ. "Deciphering the mechanisms of tumorigenesis in human pancreatic ductal epithelial cells." Clinical cancer research : an official journal of the American Association for Cancer Research 19.3 (February 2013): 549-559.

PMID

23340292

Source

epmc

Published In

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research

Volume

19

Issue

3

Publish Date

2013

Start Page

549

End Page

559

DOI

10.1158/1078-0432.ccr-12-0032

Solid pseudopapillary neoplasm of the pancreas (SPN) is a rare low-grade malignant neoplasm. To our knowledge, SPN with prominent atypical multinucleated giant tumour cells (MNGTCs) has not yet been reported.We identified four cases of SPN with prominent atypical MNGTCs in a cohort of 62 cases of SPN (6.5%). The MNGTCs contained multiple enlarged, hyperchromatic, irregular nuclei with ample eosinophilic cytoplasm, typically present in the solid area of the tumour. The MNGTCs had an immunohistochemical profile typical of the conventional SPN and were positive for vimentin, β-catenin, CD10 and progesterone receptor, but negative for pan-cytokeratin, chromogranin, synaptophysin, trypsin, Ki-67 and CD68 in all four cases. Patients of SPN with prominent MNGTCs were older than those with conventional SPN (P = 0.01); tumours were discovered incidentally by imaging studies for an unrelated disease in all four cases, and with a female to male ratio of 1:1. The proliferation index (Ki-67) was <1% in all four cases. None of the three patients for whom information was available developed recurrence during follow-up of 2.7, 3.8 and 5.0 years.The presence of MNGTCs in SPN most probably represents degenerative change of the tumour cells and does not seem to affect the prognosis.

Authors

Li, L; Othman, M; Rashid, A; Wang, H; Li, Z; Katz, MH; Lee, JE; Pisters, PW; Abbruzzese, JL; Fleming, JB; Wang, H

MLA Citation

Li, L, Othman, M, Rashid, A, Wang, H, Li, Z, Katz, MH, Lee, JE, Pisters, PW, Abbruzzese, JL, Fleming, JB, and Wang, H. "Solid pseudopapillary neoplasm of the pancreas with prominent atypical multinucleated giant tumour cells." Histopathology 62.3 (February 2013): 465-471.

PMID

23134473

Source

epmc

Published In

Histopathology

Volume

62

Issue

3

Publish Date

2013

Start Page

465

End Page

471

DOI

10.1111/his.12023

Phosphorylation and activation of Akt1 is a crucial signaling event that promotes adipogenesis. However, neither the complex multistep process that leads to activation of Akt1 through phosphorylation at Thr³⁰⁸ and Ser⁴⁷³ nor the mechanism by which Akt1 stimulates adipogenesis is fully understood. We found that the BSD domain-containing signal transducer and Akt interactor (BSTA) promoted phosphorylation of Akt1 at Ser⁴⁷³ in various human and murine cells, and we uncovered a function for the BSD domain in BSTA-Akt1 complex formation. The mammalian target of rapamycin complex 2 (mTORC2) facilitated the phosphorylation of BSTA and its association with Akt1, and the BSTA-Akt1 interaction promoted the association of mTORC2 with Akt1 and phosphorylation of Akt1 at Ser⁴⁷³ in response to growth factor stimulation. Furthermore, analyses of bsta gene-trap murine embryonic stem cells revealed an essential function for BSTA and phosphorylation of Akt1 at Ser⁴⁷³ in promoting adipocyte differentiation, which required suppression of the expression of the gene encoding the transcription factor FoxC2. These findings indicate that BSTA is a molecular switch that promotes phosphorylation of Akt1 at Ser⁴⁷³ and reveal an mTORC2-BSTA-Akt1-FoxC2-mediated signaling mechanism that is critical for adipocyte differentiation.

Authors

Yao, Y; Suraokar, M; Darnay, BG; Hollier, BG; Shaiken, TE; Asano, T; Chen, C-H; Chang, BH-J; Lu, Y; Mills, GB; Sarbassov, D; Mani, SA; Abbruzzese, JL; Reddy, SAG

MLA Citation

Yao, Y, Suraokar, M, Darnay, BG, Hollier, BG, Shaiken, TE, Asano, T, Chen, C-H, Chang, BH-J, Lu, Y, Mills, GB, Sarbassov, D, Mani, SA, Abbruzzese, JL, and Reddy, SAG. "BSTA promotes mTORC2-mediated phosphorylation of Akt1 to suppress expression of FoxC2 and stimulate adipocyte differentiation." Science Signaling 6.257 (January 8, 2013): ra2-null.

PMID

23300339

Source

epmc

Published In

Science Signaling

Volume

6

Issue

257

Publish Date

2013

Start Page

ra2

DOI

10.1126/scisignal.2003295

BACKGROUND: Endocrine FGF21 and FGF19 target adipocytes and hepatocytes through betaKlotho (KLB) and FGFR tyrosine kinases effecting glucose, lipid and energy metabolism. Both factors alleviate obesity and metabolic abnormalities which are contributing factors to breast tumor progression. Genomic manipulation of hepatic FGFR4 has uncovered roles of endocrine FGF signaling in both metabolic and cellular homeostasis. Here we determined whether systemic and microenvironmental metabolic alterations caused by the FGFR4 deficiency affect tumorigenesis in breast where FGFR4 is negligible. Breast tumors were induced in the bigenic mice with ablation of FGFR4 and overexpression of TGFα that activates Her2 in the ductal and lobular epithelium surrounded by adipocytes. Mammary tumorigenesis and alterations in systemic and breast microenvironmental metabolic parameters and regulatory pathways were analyzed. RESULTS: Ablation of FGFR4 had no effect on cellular homeostasis and Her2 activity of normal breast tissue. However, the absence of FGFR4 reduced TGFα-driven breast tumor incidence and progression and improved host survival. Notable increases in hepatic and serum FGF21, ileal FGF15/19, adiponectin and adipsin, and decreases in systemic Fetuin A, IGF-1, IGFBP-1, RBP4 and TIMP1 were observed. The ablation affected adipogenesis and secretory function of adipocytes as well as lipogenesis, glycolysis and energy homeostasis associated with the functions of mitochondria, ER and peroxisomes in the breast and tumor foci. Treatment with a chemical inhibitor of NAMPT involved in the pathways inhibited the growth and survival of breast tumor cells and tumor-initiating cell-containing spheres. The FGFR4 ablation also caused elevation of inflammatory factors in the breast. CONCLUSIONS: Although the primary role of FGFR4 in metabolism occurs in hepatocytes, its ablation results in a net inhibitory effect on mammary tumor progression. We suggest that the tumor-delaying effect of FGFR4 deficiency may be in large part due to elevated anti-obesogenic FGF21 that triggers tumor-suppressing signals from both peripheral and breast adipocytes. The predominant changes in metabolic pathways suggested roles of metabolic effects from both peripheral and breast adipocytes on metabolic reprogramming in breast epithelial cells that contribute to the suppression of tumor progression. These results provide new insights into the contribution of systemic and microenvironmental metabolic effects controlled by endocrine FGF signaling to breast carcinogenesis.

Authors

Luo, Y; Yang, C; Ye, M; Jin, C; Abbruzzese, JL; Lee, M-H; Yeung, S-CJ; McKeehan, WL

MLA Citation

Luo, Y, Yang, C, Ye, M, Jin, C, Abbruzzese, JL, Lee, M-H, Yeung, S-CJ, and McKeehan, WL. "Deficiency of metabolic regulator FGFR4 delays breast cancer progression through systemic and microenvironmental metabolic alterations." Cancer & metabolism 1.1 (January 2013): 21-.

PMID

24279986

Source

epmc

Published In

Cancer & Metabolism

Volume

1

Issue

1

Publish Date

2013

Start Page

21

DOI

10.1186/2049-3002-1-21

Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare variant of HCC. We report an analysis of the clinicopathologic features, treatment outcomes, and prognostic indicators of 94 cases.We retrospectively collected clinicopathologic and treatment outcome data from 94 FLHCC patients (48 males and 46 females). Median overall survival (OS) and recurrence-free survival (RFS) were calculated using Kaplan-Meier curves, and survival rates were compared by the log-rank test. The Cox proportional hazard model was used for univariate and multivariate estimation of hazard risk ratios and 95% confidence intervals (CI) for factors that correlated with survival and disease recurrence after resection.Median age was 23 years (14-75); median OS was 57.2 months (95% CI, 36.4-77.9), and median RFS was 13.9 months (95% CI, 8.8-18.9). White race, female gender, early tumor stage, and tumor resection including metastasectomy were positively associated with longer OS, while female gender was the only significant positive predictor of longer RFS. Finally, the 5-fluorouracil-interferon combination was the most frequently used systemic therapy.Our analyses indicate that surgical approaches including metastasectomy as the first-line treatment in FLHCC correlated with better outcome. Multimodality approaches, including neoadjuvant and adjuvant therapies, prolonged patient survival.

Authors

Kaseb, AO; Shama, M; Sahin, IH; Nooka, A; Hassabo, HM; Vauthey, J-N; Aloia, T; Abbruzzese, JL; Subbiah, IM; Janku, F; Curley, S; Hassan, MM

MLA Citation

Kaseb, AO, Shama, M, Sahin, IH, Nooka, A, Hassabo, HM, Vauthey, J-N, Aloia, T, Abbruzzese, JL, Subbiah, IM, Janku, F, Curley, S, and Hassan, MM. "Prognostic indicators and treatment outcome in 94 cases of fibrolamellar hepatocellular carcinoma." Oncology 85.4 (January 2013): 197-203.

PMID

24051705

Source

epmc

Published In

Oncology

Volume

85

Issue

4

Publish Date

2013

Start Page

197

End Page

203

DOI

10.1159/000354698

Adenocarcinomas of the ampulla of Vater are classified as biliary cancers, though the exact epithelium of origin for these cancers is not known. We sought to molecularly classify ampullary adenocarcinomas in comparison to known adenocarcinomas of the pancreas, bile duct, and duodenum by gene expression analysis.We analyzed 32 fresh-frozen resected, untreated periampullary adenocarcinomas (8 pancreatic, 2 extrahepatic biliary, 8 duodenal, and 14 ampullary) using the Affymetrix U133 Plus 2.0 genome array. Unsupervised and supervised hierarchical clustering identified two subtypes of ampullary carcinomas that were molecularly and histologically characterized.Hierarchical clustering of periampullary carcinomas segregated ampullary carcinomas into two subgroups, which were distinctly different from pancreatic carcinomas. Non-pancreatic periampullary adenocarcinomas were segregated into two subgroups with differing prognoses: 5 year RFS (77% vs. 0%, p = 0.007) and 5 year OS (100% vs. 35%, p = 0.005). Unsupervised clustering analysis of the 14 ampullary samples also identified two subgroups: a good prognosis intestinal-like subgroup and a poor prognosis biliary-like subgroup with 5 year OS of 70% vs. 28%, P = 0.09. Expression of CK7+/CK20- but not CDX-2 correlated with these two subgroups. Activation of the AKT and MAPK pathways were both increased in the poor prognostic biliary-like subgroup. In an independent 80 patient ampullary validation dataset only histological subtype (intestinal vs. pancreaticobiliary) was significantly associated with OS in both univariate (p = 0.006) and multivariate analysis (P = 0.04).Gene expression analysis discriminated pancreatic adenocarcinomas from other periampullary carcinomas and identified two prognostically relevant subgroups of ampullary adenocarcinomas. Histological subtype was an independent prognostic factor in ampullary adenocarcinomas.

Authors

Overman, MJ; Zhang, J; Kopetz, S; Davies, M; Jiang, Z-Q; Stemke-Hale, K; Rümmele, P; Pilarsky, C; Grützmann, R; Hamilton, S; Hwang, R; Abbruzzese, JL; Varadhachary, G; Broom, B; Wang, H

MLA Citation

Overman, MJ, Zhang, J, Kopetz, S, Davies, M, Jiang, Z-Q, Stemke-Hale, K, Rümmele, P, Pilarsky, C, Grützmann, R, Hamilton, S, Hwang, R, Abbruzzese, JL, Varadhachary, G, Broom, B, and Wang, H. "Gene expression profiling of ampullary carcinomas classifies ampullary carcinomas into biliary-like and intestinal-like subtypes that are prognostic of outcome." PloS one 8.6 (January 2013): e65144-.

PMID

23776447

Source

epmc

Published In

Plos One

Volume

8

Issue

6

Publish Date

2013

Start Page

e65144

DOI

10.1371/journal.pone.0065144

Although the incorporation of research biopsies into clinical trials is increasing, limited information is available about how study protocols and informed consents integrate and describe their use.All therapeutic clinical trials in which image-guided research biopsies were performed from January 1, 2005, to October 1, 2010, were identified from an interventional radiology database. Data from study protocols and informed consents were extracted and analyzed. Procedural complications were recorded.A total of 57 clinical trials were identified, of which 38 (67%) contained at least one mandatory biopsy. The analysis of the research biopsy tumor tissue was a study end point in 95% of trials. The primary indication for a research biopsy was for integral biomarker analysis in 32% and for correlative science in 68% of trials. A statistical analytic plan for the correlative science research biopsy tumor tissue was mentioned in 26%, described as exploratory in 51%, and not mentioned in 23% of trials. For studies with mandatory biopsies, biopsy was an eligibility criterion in 71% of trials, and a statistical justification for the research biopsy sample size was present in 50% of trials. A total of 745 research biopsies were performed on 576 patients. Overall and major complication rates were 5.2% (39 of 745 biopsies) and 0.8% (six of 745 biopsies), respectively. Complication rates for intrathoracic and abdominal/pelvic solid organ biopsies were 17.1% (36 of 211 biopsies) and 1.6% (three of 189 biopsies), respectively. Site-stratified research biopsy-related risks were discussed in five consents.A better representation of the risks and benefits of research biopsies in study protocols and informed consents is needed.

Authors

Overman, MJ; Modak, J; Kopetz, S; Murthy, R; Yao, JC; Hicks, ME; Abbruzzese, JL; Tam, AL

MLA Citation

Overman, MJ, Modak, J, Kopetz, S, Murthy, R, Yao, JC, Hicks, ME, Abbruzzese, JL, and Tam, AL. "Use of research biopsies in clinical trials: are risks and benefits adequately discussed?." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 31.1 (January 2013): 17-22.

PMID

23129736

Source

epmc

Published In

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology

Volume

31

Issue

1

Publish Date

2013

Start Page

17

End Page

22

DOI

10.1200/jco.2012.43.1718

Experience with preoperative therapy for other cancers has led to an assumption that borderline resectable pancreatic cancers can be converted to resectable cancers with preoperative therapy. In this study, the authors sought to determine the rate at which neoadjuvant therapy is associated with a reduction in the size or stage of borderline resectable tumors.Patients who had borderline resectable pancreatic cancer and received neoadjuvant therapy before potentially undergoing surgery at the authors' institution between 2005 and 2010 were identified. The patients' pretreatment and post-treatment pancreatic protocol computed tomography images were rereviewed to determine changes in tumor size or stage using modified Response Evaluation Criteria in Solid Tumors (RECIST) (version 1.1) and standardized anatomic criteria.The authors identified 129 patients who met inclusion criteria. Of the 122 patients who had their disease restaged after receiving preoperative therapy, 84 patients (69%) had stable disease, 15 patients (12%) had a partial response to therapy, and 23 patients (19%) had progressive disease. Although only 1 patient (0.8%) had their disease downstaged to resectable status after receiving neoadjuvant therapy, 85 patients (66%) underwent pancreatectomy. The median overall survival duration for all 129 patients was 22 months (95% confidence interval, 14-30 months). The median overall survival duration for the patients who underwent pancreatectomy was 33 months (95% confidence interval, 25-41 months) and was not associated with RECIST response (P = .78).Radiographic downstaging was rare after neoadjuvant therapy, and RECIST response was not an effective treatment endpoint for patients with borderline resectable pancreatic cancer. The authors concluded that these patients should undergo pancreatectomy after initial therapy in the absence of metastases.

Authors

Katz, MHG; Fleming, JB; Bhosale, P; Varadhachary, G; Lee, JE; Wolff, R; Wang, H; Abbruzzese, J; Pisters, PWT; Vauthey, J-N; Charnsangavej, C; Tamm, E; Crane, CH; Balachandran, A

MLA Citation

Katz, MHG, Fleming, JB, Bhosale, P, Varadhachary, G, Lee, JE, Wolff, R, Wang, H, Abbruzzese, J, Pisters, PWT, Vauthey, J-N, Charnsangavej, C, Tamm, E, Crane, CH, and Balachandran, A. "Response of borderline resectable pancreatic cancer to neoadjuvant therapy is not reflected by radiographic indicators." Cancer 118.23 (December 2012): 5749-5756.

PMID

22605518

Source

epmc

Published In

Cancer

Volume

118

Issue

23

Publish Date

2012

Start Page

5749

End Page

5756

DOI

10.1002/cncr.27636

Protein phosphatase 4 (PP4) has been reported to be overexpressed in breast and lung cancers. PP4 plays an important role in the regulation of centrosome maturation, DNA repair, NF-κB, and c-jun-NH(2)-kinase (JNK) signaling pathways. However, the expression and functions of PP4 in pancreatic cancer have not been studied.We examined the expression of PP4 catalytic subunit (PP4C) protein in 133 patients with stage II pancreatic ductal adenocarcinoma (PDAC) and their paired benign pancreatic samples (N = 113) by immunohistochemistry. To confirm the immunohistochemical results, we measured PP4C protein and mRNA levels by Western blotting and real-time reverse transcriptase PCR. Using univariate and multivariate analysis, we correlated PP4C expression with survival and other clinicopathologic features.PP4C was overexpressed in 75 of 133 (56.4%) stage II PDAC samples, which was significantly higher than the paired benign pancreatic tissue (15%, 17 of 113). PP4C mRNA expression levels were also higher in PDAC samples than the paired benign pancreatic tissue. Overexpression of PP4C in PDAC samples was associated with higher frequencies of distant metastasis (P = 0.02) and poor disease-free and overall survivals in patients with stage II PDAC (P = 0.006 and 0.02) independent of tumor size, margin status, and lymph node status (stage).Our study showed that PP4C is overexpressed in PDAC. Overexpression of PP4C in PDAC samples is associated with poor prognosis in patients with stage II PDAC. Therefore, targeting PP4 signaling pathway may represent a new approach for the treatment of PDAC.Our study showed that PP4C is an independent prognostic factor in patients with stage II PDAC.

Authors

Weng, S; Wang, H; Chen, W; Katz, MH; Chatterjee, D; Lee, JE; Pisters, PW; Gomez, HF; Abbruzzese, JL; Fleming, JB; Wang, H

MLA Citation

Weng, S, Wang, H, Chen, W, Katz, MH, Chatterjee, D, Lee, JE, Pisters, PW, Gomez, HF, Abbruzzese, JL, Fleming, JB, and Wang, H. "Overexpression of protein phosphatase 4 correlates with poor prognosis in patients with stage II pancreatic ductal adenocarcinoma." Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 21.8 (August 2012): 1336-1343.

PMID

22665577

Source

epmc

Published In

Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology

Volume

21

Issue

8

Publish Date

2012

Start Page

1336

End Page

1343

DOI

10.1158/1055-9965.epi-12-0223

Studies have shown that superior mesenteric vein (SMV)/portal vein (PV) resection with pancreaticoduodenectomy (PD) is safe and feasible for patient with pancreatic adenocarcinoma (PAC). However, the prognostic significance of tumor involvement of the resected vein in patients who received neoadjuvant therapy is unclear.The authors evaluated 225 consecutive patients with stage II PAC who received neoadjuvant therapy and PD with or without SMV/PV resection. The resected SMV/PV was entirely submitted for histologic assessment and reviewed in all cases. Tumor involvement of the SMV/PV was correlated with clinicopathologic features and survival.Among the 225 patients, SMV/PV resection was performed in 85 patients. Histologic tumor involvement of the resected SMV/PV was identified in 57 patients. Histologic tumor involvement of the SMV/PV was associated with larger tumor size, higher rates of positive margin, and local/distant recurrence. By multivariate analysis, tumor involvement of the SMV/PV was an independent predictor of both disease-free survival (DFS) and overall survival (OS). However, addition of venous resection to PD itself had no impact on either DFS or OS compared with those with PD alone.Histologic tumor involvement of the SMV/PV is an independent predictor of both DFS and OS in patients with stage II PAC treated with neoadjuvant therapy and PD. Complete histologic evaluation of the resected SMV/PV is important for the prognosis in patients with PAC who received neoadjuvant therapy and PD.

Authors

Wang, J; Estrella, JS; Peng, L; Rashid, A; Varadhachary, GR; Wang, H; Lee, JE; Pisters, PWT; Vauthey, J-N; Katz, MH; Gomez, HF; Evans, DB; Abbruzzese, JL; Fleming, JB; Wang, H

MLA Citation

Wang, J, Estrella, JS, Peng, L, Rashid, A, Varadhachary, GR, Wang, H, Lee, JE, Pisters, PWT, Vauthey, J-N, Katz, MH, Gomez, HF, Evans, DB, Abbruzzese, JL, Fleming, JB, and Wang, H. "Histologic tumor involvement of superior mesenteric vein/portal vein predicts poor prognosis in patients with stage II pancreatic adenocarcinoma treated with neoadjuvant chemoradiation." Cancer 118.15 (August 2012): 3801-3811.

PMID

22180096

Source

epmc

Published In

Cancer

Volume

118

Issue

15

Publish Date

2012

Start Page

3801

End Page

3811

DOI

10.1002/cncr.26717

Patients identified at surgical exploration with unresectable pancreatic ductal adenocarcinoma receive palliative, noncurative therapy. We hypothesized that accurate radiographic restaging, multimodality treatment, and advanced surgical technique can offer patients deemed unresectable at previous exploration the possibility for curative salvage pancreatectomy.Review of a prospectively maintained pancreatic ductal adenocarcinoma database identified all patients (1990 to 2010) evaluated after being deemed unresectable at first exploration elsewhere. Referring hospitals were categorized per National Cancer Data Base criteria as academic, community, or international. Patients were restaged using objective imaging (CT) criteria and classified based on anatomic resectability. Clinicopathologic factors and cancer-related outcomes were assessed.We evaluated 88 patients who underwent previously unsuccessful resection attempts at academic (n = 50), community (n = 25), and international (n = 13) centers. Radiographic restaging confirmed that 7 (8%) patient tumors were locally advanced and unresectable, but 81 (92%) were resectable (n = 61) or borderline resectable (n = 20). Using a surgery first (9%) or preoperative chemoradiation (91%) approach, successful reoperative pancreatectomy was performed in 66 (81%) patients, with 94% receiving R0 resections. Vascular resection/reconstruction was required in 30 (46%) patients and 50 (76%) required complex revision of previously created biliary/gastrointestinal bypass. The major complication rate was 20% and 3 (4.5%) patients died perioperatively. Median overall survival was 29.6 months for successfully resected patients vs 10.6 and 5.1 months (p < 0.0001) for those patients with locally advanced unresectable disease at initial referral or in whom metastatic disease developed before resection, respectively.In this very selected cohort of high-risk patients, the majority had anatomically resectable tumors on restaging. Accurate radiographic restaging, a multimodality treatment strategy, and advanced surgical techniques can provide an opportunity for cure in a substantial proportion of select patients who were deemed unresectable at exploration.

Authors

Truty, MJ; Thomas, RM; Katz, MH; Vauthey, J-N; Crane, C; Varadhachary, GR; Wolff, RA; Abbruzzese, JL; Lee, JE; Fleming, JB

MLA Citation

Truty, MJ, Thomas, RM, Katz, MH, Vauthey, J-N, Crane, C, Varadhachary, GR, Wolff, RA, Abbruzzese, JL, Lee, JE, and Fleming, JB. "Multimodality therapy offers a chance for cure in patients with pancreatic adenocarcinoma deemed unresectable at first operative exploration." Journal of the American College of Surgeons 215.1 (July 2012): 41-51.

PMID

22608401

Source

epmc

Published In

Journal of the American College of Surgeons

Volume

215

Issue

1

Publish Date

2012

Start Page

41

End Page

51

DOI

10.1016/j.jamcollsurg.2012.03.024

Several grading schemes for the extent of residual tumor in posttreatment pancreaticoduodenectomy (PD) specimens have been proposed. However, the prognostic significance of these grading schemes is unknown.Histopathologic slides of 223 cases who received neoadjuvant chemoradiation and PD were reviewed. The extent of residual tumor was graded using both the College of American Pathologists (CAP) and the Evans grading systems. The grading results were correlated with clinicopathological parameters and survival.Among the 223 patients, 6 patients (2.7%) showed pathologic complete response (pCR; CAP grade 0 or Evans grade IV), 36 cases (16.1%) had minimal residual tumor (CAP grade 1 or Evans grade III), 124 cases (55.6%) had moderate response (CAP grade 2 or Evans grade IIb), and 57 cases (25.6%) had poor response (CAP grade 3, where 18 had Evans grade I and 39 had Evans grade IIa response). Patients with pCR or minimal residual tumor (response group 1) had better survival rates than those with moderate and poor response (response group 2). Response group 1 patients had lower posttherapy tumor and American Joint Committee on Cancer stages and lower rates of lymph node metastasis, positive resection margin, and recurrence and/or metastasis. Grading the extent of residual tumor is an independent prognostic factor for overall survival in multivariate analysis.pCR or minimal residual tumor in posttreatment PD specimens correlate with better survival in patients with pancreatic ductal adenocarcinoma who received neoadjuvant therapy and PD. Histologic grading of the extent of residual tumor in PD specimen is an important prognostic factor in patients with pancreatic ductal adenocarcinoma who received neoadjuvant therapies.

Authors

Chatterjee, D; Katz, MH; Rashid, A; Varadhachary, GR; Wolff, RA; Wang, H; Lee, JE; Pisters, PWT; Vauthey, J-N; Crane, C; Gomez, HF; Abbruzzese, JL; Fleming, JB; Wang, H

MLA Citation

Chatterjee, D, Katz, MH, Rashid, A, Varadhachary, GR, Wolff, RA, Wang, H, Lee, JE, Pisters, PWT, Vauthey, J-N, Crane, C, Gomez, HF, Abbruzzese, JL, Fleming, JB, and Wang, H. "Histologic grading of the extent of residual carcinoma following neoadjuvant chemoradiation in pancreatic ductal adenocarcinoma: a predictor for patient outcome." Cancer 118.12 (June 2012): 3182-3190.

PMID

22028089

Source

epmc

Published In

Cancer

Volume

118

Issue

12

Publish Date

2012

Start Page

3182

End Page

3190

DOI

10.1002/cncr.26651

DNA repair plays a critical role in human cancers. We hypothesized that DNA mismatch repair gene variants are associated with risk of pancreatic cancer. We retrospectively genotyped 102 single-nucleotide polymorphisms (SNPs) of 13 mismatch repair related genes in 706 patients with pancreatic cancer and 706 cancer-free controls using the mass spectroscopy-based MassArray method. Association of genotype with pancreatic cancer risk was tested by multivariate logistic regression models. A significance level of P ≤ 0.0015 was set at the false discovery rate (FDR) <1% using the Beta-Uniform Mixture method. We found 28 SNPs related to altered pancreatic cancer risk (P < 0.05). Adjusting for multiple comparisons, MGMT I143V AG/GG, PMS2 IVS1-1121C > T TC/TT, and PMS2L3 Ex1 + 118C > T CT/TT genotypes showed significant main effects on pancreatic cancer risk at FDR <1% with OR (95% CI) of 0.60 (0.46-0.80), 1.44 (1.14-1.81), and 5.54 (2.10-14.61), respectively (P ≤ 0.0015). To demonstrate genotype-phenotype association, we measured O(6)-ethylguanosine (O(6)-EtGua) adduct levels in vitro by immunoslot blot assay in lymphocytes treated with N-ethyl-N-nitrosourea (ENU) in 297 case/control subjects. MGMT I143V GG, MGMT K178R GG, MSH6 G39E AG/AA, PMS2L3 IVS3 + 9A > G GA and TP73 IVS1-7449G > C CG/CC genotypes correlated with a higher level of ENU-induced DNA adducts. Haplotypes of MGMT, MSH6, PMS2, PMS2L3, and TP73 were significantly associated with pancreatic cancer risk (P ≤ 0.0015). Our findings suggest that mismatch repair gene variants may affect susceptibility to pancreatic cancer.

Authors

Dong, X; Li, Y; Chang, P; Hess, KR; Abbruzzese, JL; Li, D

MLA Citation

Dong, X, Li, Y, Chang, P, Hess, KR, Abbruzzese, JL, and Li, D. "DNA mismatch repair network gene polymorphism as a susceptibility factor for pancreatic cancer." Molecular carcinogenesis 51.6 (June 2012): 491-499.

PMID

21681824

Source

epmc

Published In

Molecular Carcinogenesis

Volume

51

Issue

6

Publish Date

2012

Start Page

491

End Page

499

DOI

10.1002/mc.20817

Because of its rarity, adenocarcinoma of the small intestine is frequently compared to adenocarcinoma of the colon, although the validity of this comparison is not known.Patients with small and large bowel adenocarcinoma (SBA and LBA) diagnosed between 1988 and 2007 were identified from the Surveillance, Epidemiology, and End Results registry. Age-standardized incidence and mortality rates were determined. Cancer-specific survival (CSS) stratified by stage and by number of assessed lymph nodes was calculated.A total of 4518 and 261,521 patients with SBA and LBA, respectively, were identified. In comparison to LBA, patients with SBA were younger and presented with disease of higher stage and histologic grade. The age-standardized incidence rates decreased for LBA (-1.24% per year) but increased for SBA (+1.47% per year). Although age-standardized mortality rates decreased for both LBA and SBA, the decreases were more pronounced for LBA. Five-year CSS was worse for resected SBA compared with resected LBA, although this difference diminished when comparing cases having eight or more lymph nodes assessed. The relative reduction in CSS when selecting eight or more lymph nodes was much greater for duodenal as opposed to jejunal/ileal subsite of the small bowel. With nodal selection the absolute difference in CSS between LBA and SBA for stages I, II, and III was 13, 15.9, and 18.5%, respectively.Adequate nodal assessment is much less common in SBA than LBA; and it appears that SBA, in particular duodenal adenocarcinoma, is understaged. Even after corrections to minimize the effect of stage migration and inadequate lymph node evaluation, SBA demonstrated distinctly worse CSS than LBA.

Authors

Overman, MJ; Hu, C-Y; Kopetz, S; Abbruzzese, JL; Wolff, RA; Chang, GJ

MLA Citation

Overman, MJ, Hu, C-Y, Kopetz, S, Abbruzzese, JL, Wolff, RA, and Chang, GJ. "A population-based comparison of adenocarcinoma of the large and small intestine: insights into a rare disease." Annals of surgical oncology 19.5 (May 2012): 1439-1445.

PMID

22187121

Source

epmc

Published In

Annals of Surgical Oncology

Volume

19

Issue

5

Publish Date

2012

Start Page

1439

End Page

1445

DOI

10.1245/s10434-011-2173-6

The specific aims of the study were to evaluate the 2-year overall survival (OS) and progression-free survival (PFS), toxicity profile, and best objective response rate in patients with locally advanced, clinically unresectable esophageal cancer receiving cetuximab, cisplatin, irinotecan, and thoracic radiotherapy (TRT) within a multi-institutional cooperative-group setting.Eligible patients (cT4 M0 or medically unresectable, biopsy proven, and noncervical esophageal cancer) were to receive four 21-day cycles of cetuximab 400 mg/m (day 1, cycle 1), cetuximab 250 mg/m (day 8, 15, cycle 1; then days 1, 8, and 15 for subsequent cycles), cisplatin 30 mg/m (days 1 and 8, all cycles), and irinotecan 65 mg/m (days 1 and 8, all cycles). TRT was administered at 1.8 Gy in 28 daily fractions to a total dose of 50.4 Gy, to begin with on day 1 of cycle 3. The primary endpoint was 2-year OS, with an accrual goal of 75 patients with adenocarcinoma.The study was closed because of slow accrual, with 21 eligible patients (11 squamous, 10 adenocarcinoma) enrolled from May 2005 to September 2007. Two-year OS and PFS (95% confidence interval [CI]) were 33.3% (14.6-57.0%) and 23.8% (8.2-47.2%), respectively. Kaplan-Meier estimates of median (95% CI) OS and PFS were 11.2 (6.4-43.6) and 6.4 (3.7-12.0) months, respectively. The overall response rate (95% CI) among 17 evaluable patients was 17.6% (3.8-43.4%), including 6% confirmed complete responders and 12% unconfirmed partial responders. Two deaths resulted from protocol treatment (sudden death and gastrointestinal necrosis). Ten (47.6%) and 6 (28.6%) patients had grade-3 or -4 toxicity, respectively: 52.4% were hematologic, 23.8% had fatigue, 19.0% had nausea, 19.0% had dehydration, and 19.0% had anorexia.Concomitant cetuximab, cisplatin, irinotecan, and TRT were poorly tolerated in the first North American cooperative group trial testing this regimen for locally advanced esophageal cancer as treatment-related mortality approached 10%. Single-institution phase-II cetuximab-based combined modality trials have yielded encouraging results in preliminary analyses. The SWOG GI Committee endorses enrollment to open clinical trials to clarify the therapeutic ratio of cetuximab-based combined modality approaches for esophageal cancer.

Authors

Tomblyn, MB; Goldman, BH; Thomas, CR; Benedetti, JK; Lenz, H-J; Mehta, V; Beeker, T; Gold, PJ; Abbruzzese, JL; Blanke, CD; SWOG GI Committee,

MLA Citation

Tomblyn, MB, Goldman, BH, Thomas, CR, Benedetti, JK, Lenz, H-J, Mehta, V, Beeker, T, Gold, PJ, Abbruzzese, JL, Blanke, CD, and SWOG GI Committee, . "Cetuximab plus cisplatin, irinotecan, and thoracic radiotherapy as definitive treatment for locally advanced, unresectable esophageal cancer: a phase-II study of the SWOG (S0414)." Journal of Thoracic Oncology : Official Publication of the International Association for the Study of Lung Cancer 7.5 (May 2012): 906-912.

PMID

22481235

Source

epmc

Published In

Journal of Thoracic Oncology

Volume

7

Issue

5

Publish Date

2012

Start Page

906

End Page

912

DOI

10.1097/JTO.0b013e31824c7bed

BACKGROUND: The nucleoside 3'-c-ethynylcytidine (TAS-106) was designed to inhibit RNA synthesis which occurs throughout the cell cycle except for the M phase. TAS-106 is incorporated into cells, is rapidly phosphorylated to a monophosphate form, and is preferentially distributed into malignant cells. Preclinical studies showed that TAS-106 has a wide antitumor spectrum against human cancer xenografts. This phase I study was conducted in order to determine the recommended phase II dose of TAS-106 administered once per week for three consecutive weeks, every 28 days in patients with solid tumors. PATIENTS AND METHODS: Patients were enrolled in cohorts of three, starting at 0.22 mg/m(2)/dose. Patients received at least two doses in order to be evaluable in each dose cohort. Dose escalation was stopped if two or more patients experienced dose limiting toxicity at any dose level. RESULTS: In 20 evaluable patients, TAS-106 was given at the following dose levels (mg/m(2)/dose): 0.22 (3 pts), 0.33 (3 pts), 0.66 (3 pts), 0.99 (1 pt), 1.32 (3 pts), 2.64 (3 pts) and 3.96 (1 pt). Three additional patients were evaluated at 2.64 mg/m(2)/dose for further characterization of toxicity and safety. A total of 16 patients completed courses 1 and 2. All 21 patients enrolled experienced at least one adverse event. The AE attributed to the study drug was grade 2 peripheral neuropathy characterized by peripheral sensory neuropathy, numbness, tremor, pain, and hyperesthesia involving the fingers, hands, toes, and feet. CONCLUSION: Due to neurotoxicity the MTD was the 2.64 mg/m(2)/dose for the study schedule. No suggested phase II dose was determined. However, at the 1.32 mg/m(2)/dose level, no patients experienced DLTs during course 1 or 2. This could be further studied to determine its viability as a potential phase II dosage.

Authors

Friday, B; Lassere, Y; Meyers, CA; Mita, A; Abbruzzese, JL; Thomas, MB

MLA Citation

Friday, B, Lassere, Y, Meyers, CA, Mita, A, Abbruzzese, JL, and Thomas, MB. "A phase I study to determine the safety and pharmacokinetics of intravenous administration of TAS-106 once per week for three consecutive weeks every 28 days in patients with solid tumors." Anticancer research 32.5 (May 2012): 1689-1696.

PMID

22593447

Source

epmc

Published In

Anticancer Research

Volume

32

Issue

5

Publish Date

2012

Start Page

1689

End Page

1696

Accumulating evidence suggests that metformin has antitumor activity. The aim of this study was to determine whether metformin use has a survival benefit in patients with pancreatic cancer.We conducted a retrospective study of patients with diabetes and pancreatic cancer treated at The University of Texas MD Anderson Cancer Center (Houston, TX). Information on diabetes history, including treatment modalities and clinical outcome of pancreatic cancer, was collected using personal interviews and medical record review. Survival analysis was carried out using a Kaplan-Meier plot, log-rank test, and Cox proportional hazards regression models.Among the 302 patients identified, there were no significant differences in demographic or major clinical characteristics between the patients who had received metformin (n = 117) and those who had not (n = 185). The 2-year survival rate was 30.1% for the metformin group and 15.4% for the non-metformin group (P = 0.004; χ(2) test). The median overall survival time was 15.2 months for the metformin group, and 11.1 months for the non-metformin group (P = 0.004, log-rank test). Metformin users had a 32% lower risk of death; the HR (95% confidence interval) was 0.68 (0.52-0.89) in a univariate model (P = 0.004), 0.64 (0.48-0.86) after adjusting for other clinical predictors (P = 0.003), and 0.62 (0.44-0.87) after excluding insulin users (P = 0.006). Metformin use was significantly associated with longer survival in patients with nonmetastatic disease only.Our finding that metformin use was associated with improved outcome of patients with diabetes and pancreatic cancer should be confirmed in independent studies. Future research should prospectively evaluate metformin as a supplemental therapy in this population.

Authors

Sadeghi, N; Abbruzzese, JL; Yeung, S-CJ; Hassan, M; Li, D

MLA Citation

Sadeghi, N, Abbruzzese, JL, Yeung, S-CJ, Hassan, M, and Li, D. "Metformin use is associated with better survival of diabetic patients with pancreatic cancer." Clinical Cancer Research : an Official Journal of the American Association for Cancer Research 18.10 (May 2012): 2905-2912.

PMID

22465831

Source

epmc

Published In

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research

Volume

18

Issue

10

Publish Date

2012

Start Page

2905

End Page

2912

DOI

10.1158/1078-0432.CCR-11-2994

Cell division cycle 20 (CDC20) homolog is an anaphase-promoting complex activator that is essential for cell division, but whether its expression in pancreatic ductal adenocarcinoma (PDAC) is significant is unknown. In this retrospective study, we determined whether aberrant CDC20 expression can be used as a biomarker in pancreatic ductal adenocarcinoma (PDAC) tumorigenesis and whether its expression reflects clinical progression.We compared CDC20 expression levels in normal, cancerous, and inflamed pancreatic tissues from stage II PDAC patients with clinical outcomes and determined CDC20 levels in seven PDAC cell lines. CDC20 was identified using a cDNA microarray database containing gene expression profiles for PDAC tissues and cell lines and chronic pancreatitis and normal pancreas tissues. Its expression was confirmed by real-time quantitative reverse-transcriptase-polymerase chain reaction (qRT-PCR). An immunohistochemical analysis of tissue microarrays from resected PDAC tumors and paired benign pancreatic tissues was done and CDC20 levels were correlated with clinical outcome.Fifty-six patients were included in this study. A microarray analysis revealed 5-fold higher CDC20 expression in PDAC tissue than in chronic pancreatitis tissue. A qRT-PCR analysis confirmed a mean 20-fold higher CDC20 level in PDAC tissue than in normal pancreas and pancreatitis tissue. RNA and protein CDC20 expression was detected in several PDAC cell lines. An immunohistochemical analysis revealed higher CDC20 protein expression levels in PDAC tissue than in normal pancreas tissue, and high CDC20 expression was associated with poor differentiation (P = 0.020) and a significantly lower 5-year recurrence-free survival rate (P = 0.039); we also found a trend toward a shorter overall survival duration.Aberrant CDC20 expression may play an important role in PDAC tumorigenesis and progression and may thus be useful as a marker of disease progression and prognosis and as a therapeutic target.

Authors

Chang, DZ; Ma, Y; Ji, B; Liu, Y; Hwu, P; Abbruzzese, JL; Logsdon, C; Wang, H

MLA Citation

Chang, DZ, Ma, Y, Ji, B, Liu, Y, Hwu, P, Abbruzzese, JL, Logsdon, C, and Wang, H. "Increased CDC20 expression is associated with pancreatic ductal adenocarcinoma differentiation and progression." Journal of Hematology & Oncology 5 (April 4, 2012): 15-null.

PMID

22475564

Source

epmc

Published In

Journal of Hematology & Oncology

Volume

5

Publish Date

2012

Start Page

15

DOI

10.1186/1756-8722-5-15

Lymphovascular invasion (LVI) is a prognostic factor in many types of human malignancies, including pancreatic ductal adenocarcinoma (PDAC). However, the prognostic significance of LVI in patients with PDAC who have received neoadjuvant therapy and pancreaticoduodenectomy is unclear. In this study, we analyzed LVI in 212 patients who had received neoadjuvant chemoradiation and subsequent pancreaticoduodenectomy at our institution between January 1999 and December 2007. LVI was present in 61.8% (131/212) of the patients. Of the 131 patients who were positive for LVI, 67 (31.6%) had tumor invasion into lymphovascular spaces without muscle layer (nonmuscular lymphovascular spaces), and 64 (30.2%) had tumor invasion into muscular vessels. Tumor invasion into muscular vessels correlated with higher frequencies of positive resection margin, lymph node metastasis, and locoregional/distant recurrence. Patients with tumor invasion into muscular vessels had significantly shorter disease-free survival and overall survival than did patients who had no LVI or who had tumor invasion of nonmuscular lymphovascular spaces (P<0.01). Tumor invasion into muscular vessels is an independent prognostic factor in patients with PDAC who have received neoadjuvant therapies. Our results showed that tumor invasion into muscular vessels plays an important role in the progression of PDAC and in predicting prognosis in this group of patients.

Authors

Chatterjee, D; Rashid, A; Wang, H; Katz, MH; Wolff, RA; Varadhachary, GR; Lee, JE; Pisters, PW; Gomez, HF; Abbruzzese, JL; Fleming, JB; Wang, H

MLA Citation

Chatterjee, D, Rashid, A, Wang, H, Katz, MH, Wolff, RA, Varadhachary, GR, Lee, JE, Pisters, PW, Gomez, HF, Abbruzzese, JL, Fleming, JB, and Wang, H. "Tumor invasion of muscular vessels predicts poor prognosis in patients with pancreatic ductal adenocarcinoma who have received neoadjuvant therapy and pancreaticoduodenectomy." The American journal of surgical pathology 36.4 (April 2012): 552-559.

PMID

22301496

Source

epmc

Published In

The American Journal of Surgical Pathology

Volume

36

Issue

4

Publish Date

2012

Start Page

552

End Page

559

DOI

10.1097/pas.0b013e318240c1c0

Insulin-like growth factor (IGF)-axis genes plays a critical role in cancer development and progression via their impact on the RAS/MAPK/ERK and PI3K/AKT/mTOR signaling pathways. We hypothesized that IGF-axis genetic variants modify individual susceptibility to pancreatic cancer.We retrospectively genotyped 41 single-nucleotide polymorphisms of 10 IGF-axis genes (IGF1, IGF2, IGF1R, IGF2R, IGFBP1, IGFBP3, IGFBP5, IRS1, IRS2, and IRS4) in 706 pancreatic cancer patients and 706 cancer-free controls using Sequenom and TaqMan technology. The association between genotype and pancreatic cancer risk was evaluated using multivariate logistic regression. A P value ≤.007 at a false discovery rate of 10% was set as the significance level.We observed that the IGF1 *10212C>A and Ex4+2776G>A and IGF1R IVS2-70184A>G and IVS2+46329T>C variant genotypes were significantly associated with decreased pancreatic cancer risk (odds ratio [OR] range, 0.60-0.75) and that IGFBP1 Ex4+111A>G (I253M) was significantly associated with increased pancreatic cancer risk (OR=1.46) after adjusted for other risk factors and multiple comparisons (P≤.007). IGF2R and IGFBP3 variant haplotypes were associated with increased and decreased pancreatic cancer risk, respectively (P<.001). We also observed a weak interaction of the IGF1R IVS2+46329T>C and IGF2R Ex45+11C>T (L2222L) genotypes with diabetes (P(interaction)=.05) and interaction of IGF2R and IRS1 genotypes with alcohol consumption (P(interaction)=.03 and .019, respectively) on increased pancreatic cancer risk.These findings support our hypothesis that polymorphic variants of IGF-axis genes act alone or jointly with other risk factors to affect susceptibility to pancreatic cancer.

Authors

Dong, X; Li, Y; Tang, H; Chang, P; Hess, KR; Abbruzzese, JL; Li, D

MLA Citation

Dong, X, Li, Y, Tang, H, Chang, P, Hess, KR, Abbruzzese, JL, and Li, D. "Insulin-like growth factor axis gene polymorphisms modify risk of pancreatic cancer." Cancer Epidemiology 36.2 (April 2012): 206-211.

PMID

21852217

Source

epmc

Published In

Cancer Epidemiology

Volume

36

Issue

2

Publish Date

2012

Start Page

206

End Page

211

DOI

10.1016/j.canep.2011.05.013

Authors

Kaseb, AO; Morris, JS; Hassan, MM; Abbruzzese, JL

MLA Citation

Kaseb, AO, Morris, JS, Hassan, MM, and Abbruzzese, JL. "Reply to A. Goyal et al." Journal of Clinical Oncology 30.9 (March 20, 2012): 1019-1020. (Letter)

Source

scopus

Published In

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology

Volume

30

Issue

9

Publish Date

2012

Start Page

1019

End Page

1020

DOI

10.1200/JCO.2011.40.9375

Perineural invasion (PNI) is one of the established prognostic factors in pancreatic ductal adenocarcinoma (PDAC). However, the prognostic significance of PNI in patients with PDAC who received neoadjuvant therapy and pancreaticoduodenectomy is not clear. In this study, we performed a detailed examination of neural invasion in pancreaticoduodenectomy specimens from 212 patients with PDAC who received neoadjuvant chemoradiation (treated group) and in 60 untreated patients at our institution between January 1999 and December 2007. The frequency of PNI was higher in the untreated group (80%, 48/60) than in the treated group (58%, 123/212). For the 123 treated cases that were positive for PNI, extratumoral PNI, intratumoral PNI, intrapancreatic PNI only, extrapancreatic PNI, and intraneural invasion were identified in 86 (69.9%), 37 (30.1%), 11 (8.9%), 112 (91.1%), and 35 cases (28.5%), respectively. The presence of PNI correlated with tumor size, margin status, lymph node metastasis, pathologic tumor, and American Joint Committee on Cancer stages in the treated group. Tumor involvement of nerves >0.8 mm correlated with higher frequency of positive margin compared with tumors with PNI involving nerves ≤0.8 mm but not with other clinicopathologic parameters and survival. In the treated group, the presence of PNI or intraneural invasion correlated significantly with shorter disease-free survival and overall survival compared with no PNI or PNI only, respectively. PNI was an independent prognostic factor for both disease-free survival and overall survival in multivariate analysis. Our results showed that PNI plays an important role in the progression of PDAC and in predicting prognosis in this group of patients.

Authors

Chatterjee, D; Katz, MH; Rashid, A; Wang, H; Iuga, AC; Varadhachary, GR; Wolff, RA; Lee, JE; Pisters, PW; Crane, CH; Gomez, HF; Abbruzzese, JL; Fleming, JB; Wang, H

MLA Citation

Chatterjee, D, Katz, MH, Rashid, A, Wang, H, Iuga, AC, Varadhachary, GR, Wolff, RA, Lee, JE, Pisters, PW, Crane, CH, Gomez, HF, Abbruzzese, JL, Fleming, JB, and Wang, H. "Perineural and intraneural invasion in posttherapy pancreaticoduodenectomy specimens predicts poor prognosis in patients with pancreatic ductal adenocarcinoma." The American journal of surgical pathology 36.3 (March 2012): 409-417.

PMID

22301497

Source

epmc

Published In

The American Journal of Surgical Pathology

Volume

36

Issue

3

Publish Date

2012

Start Page

409

End Page

417

DOI

10.1097/pas.0b013e31824104c5

There are limited data regarding the role of second-line treatment for metastatic pancreatic cancer (mPC) after the failure of initial chemotherapy. No data exist on the use of GTX after the failure of first-line therapy.We identified patients who were given GTX chemotherapy for a diagnosis of mPC after the failure of initial therapy. Demographic features, progression-free (PFS) and overall survival (OS), response to treatment, and toxicities were recorded.The 59 evaluable patients received a median of 2 prior therapies. Three had no prior gemcitabine. Median PS was 1. Median survival was 22 weeks; progression-free survival was 9.9 weeks. Survival did not correlate with the number of prior regimens but trended with PS. There were no radiologic responses; those with stable disease (n = 21) had a better survival than those with progression (n = 29) or unevaluable patients (n = 9). Median survival was 38.3, 15.0, and 7.4 weeks, respectively. Grade 3 and 4 toxicities included leucopenia (n = 14), anemia (n = 7), and thrombocytopenia (n = 6). Hospitalizations were required in 21 patients, for febrile neutropenia (n = 7), non-neutropenic infection (n = 3), pulmonary embolus (n = 2), anemia or failure to thrive (n = 9). A 75% drop or more in CA 19-9 correlated with improved survival.GTX is an active regimen in patients previously treated with gemcitabine for mPC. Better performance status and >75% drop in pretreatment CA 19-9 were associated with longer survival. The number of prior regimens did not predict for survival duration.

Authors

Dakik, HK; Moskovic, DJ; Carlson, PJ; Tamm, EP; Qiao, W; Wolff, RA; Abbruzzese, JL; Fogelman, DR

MLA Citation

Dakik, HK, Moskovic, DJ, Carlson, PJ, Tamm, EP, Qiao, W, Wolff, RA, Abbruzzese, JL, and Fogelman, DR. "The use of GTX as second-line and later chemotherapy for metastatic pancreatic cancer: a retrospective analysis." Cancer Chemotherapy and Pharmacology 69.2 (February 2012): 425-430.

PMID

21850466

Source

epmc

Published In

Cancer Chemotherapy and Pharmacology

Volume

69

Issue

2

Publish Date

2012

Start Page

425

End Page

430

DOI

10.1007/s00280-011-1705-x

TAS-106 is a novel nucleoside analog that inhibits RNA polymerases I, II and II and has demonstrated robust antitumor activity in a wide range of models of human cancer in preclinical studies. This study was performed to principally evaluate the feasibility of administering TAS-106 as a bolus intravenous (IV) infusion every 3 weeks.Patients with advanced solid malignancies were treated with escalating doses of TAS-106 as a single bolus IV infusion every 3 weeks. Plasma and urine sampling were performed during the first course to characterize the pharmacokinetic profile of TAS-106 and assess pharmacodynamic relationships.Thirty patients were treated with 66 courses of TAS-106 at eight dose levels ranging from 0.67-9.46 mg/m(2). A cumulative sensory peripheral neuropathy was the principal dose-limiting toxicity (DLT) of TAS-106 at the 6.31 mg/m(2) dose level, which was determined to be the maximum tolerated dose (MTD). Other mild-moderate drug-related toxicities include asthenia, anorexia, nausea, vomiting, myelosuppression, and dermatologic effects. Major objective antitumor responses were not observed. The pharmacokinetics of TAS-106 were dose-proportional. The terminal elimination half-life (t(1/2)) averaged 11.3 ± 3.3 h. Approximately 71% of TAS-106 was excreted in the urine as unchanged drug. Pharmacodynamic relationships were observed between neuropathy and: C(5min;) AUC(0-inf;) and dermatologic toxicity.The recommended phase II dose of TAS-106 is 4.21 mg/m(2). However, due to a cumulative drug-related peripheral sensory neuropathy that proved to be dose-limiting, further evaluation of this bolus every 21 day infusion schedule will not be pursued and instead, an alternate dosing schedule of TAS-106 administered as a continuous 24-hour infusion will be explored to decrease C(max) in efforts to minimize peripheral neuropathy and maximize antitumor activity.

Authors

Hammond-Thelin, LA; Thomas, MB; Iwasaki, M; Abbruzzese, JL; Lassere, Y; Meyers, CA; Hoff, P; de Bono, J; Norris, J; Matsushita, H; Mita, A; Rowinsky, EK

MLA Citation

Hammond-Thelin, LA, Thomas, MB, Iwasaki, M, Abbruzzese, JL, Lassere, Y, Meyers, CA, Hoff, P, de Bono, J, Norris, J, Matsushita, H, Mita, A, and Rowinsky, EK. "Phase I and pharmacokinetic study of 3'-C-ethynylcytidine (TAS-106), an inhibitor of RNA polymerase I, II and III,in patients with advanced solid malignancies." Investigational new drugs 30.1 (February 2012): 316-326.

PMID

20839029

Source

epmc

Published In

Investigational New Drugs

Volume

30

Issue

1

Publish Date

2012

Start Page

316

End Page

326

DOI

10.1007/s10637-010-9535-y

OBJECTIVE: A phase II study was performed to evaluate the efficacy and tolerability of bevacizumab and erlotinib in advanced hepatocellular carcinoma (HCC) patients, and to investigate clinical and molecular predictors of outcome. METHODS: 59 patients with advanced HCC received 10 mg/kg i.v. of bevacizumab every 14 days and 150 mg p.o. of erlotinib daily. The primary endpoint was progression-free survival (PFS) at 16 weeks. Clinical characteristics and plasma biomarkers expression levels were analyzed. RESULTS: PFS at 16 weeks was 64% (95% CI 51-76): 14 patients achieved partial response (24%), 33 had stable disease (56%), 6 progressed (10%), and 6 were not evaluable (10%). Median overall survival was 13.7 months (95% CI 9.6-19.7), and median PFS was 7.2 months (95% CI 5.6-8.3). Grade 3-4 adverse events included fatigue (30%), diarrhea (17%), hypertension (14%), elevated transaminases (12%), and gastrointestinal hemorrhage (10%). High plasma angiopoietin-2, epidermal growth factor receptor, and endothelin-1, and lack of acneiform rash were associated with poor outcome. CONCLUSIONS: The combination of bevacizumab with erlotinib achieved encouraging results in patients with advanced HCC. Current correlatives may help to guide future HCC studies.

Authors

Kaseb, AO; Garrett-Mayer, E; Morris, JS; Xiao, L; Lin, E; Onicescu, G; Hassan, MM; Hassabo, HM; Iwasaki, M; Deaton, FL; Abbruzzese, JL; Thomas, MB

MLA Citation

Kaseb, AO, Garrett-Mayer, E, Morris, JS, Xiao, L, Lin, E, Onicescu, G, Hassan, MM, Hassabo, HM, Iwasaki, M, Deaton, FL, Abbruzzese, JL, and Thomas, MB. "Efficacy of bevacizumab plus erlotinib for advanced hepatocellular carcinoma and predictors of outcome: final results of a phase II trial." Oncology 82.2 (January 2012): 67-74.

PMID

22327795

Source

epmc

Published In

Oncology

Volume

82

Issue

2

Publish Date

2012

Start Page

67

End Page

74

DOI

10.1159/000335963

In patients with pancreatic ductal adenocarcinoma (PDA) who received neoadjuvant therapy and pancreatectomy, pathologic complete response (pCR) is rarely observed and the prognostic significance of pCR is not clear. In this study, we identified 11 patients with pCR (2.5%) from 442 patients with PDA who received neoadjuvant treatment and pancreatectomy from 1995 to 2010. There were 6 men and 5 women, with a median age of 61 years. Four patients had either synchronous or history of extrapancreatic cancer. Five patients received neoadjuvant chemotherapy followed by chemoradiation, and 6 received chemoradiation alone. Ten patients had pancreaticoduodenectomy, and 1 had distal pancreatectomy. Scar and chronic pancreatitis consistent with therapy effect were present in all cases (100%). Pancreatic intraepithelial neoplasia (PanIN) 3/carcinoma in situ was present in 5 cases, and PanIN1 and PanIN2 in 5 cases. However, no residual invasive carcinoma or lymph node metastasis was identified in all cases. Follow-up information was available in 10 patients. Follow-up time ranges from 6 to 194 months (median, 63 months). During the follow-up, 3 patients died of other causes, and 1 developed a second primary PDA in the tail of the pancreas at 84 months after the initial pancreaticoduodenectomy and died at 105 months after the initial diagnosis of PDA. The other 6 patients were alive with no evidence of disease. Patients with pCR had a better survival than did those who had posttherapy stage I or IIA disease (P < .001). Patients with PDA who received neoadjuvant therapy and had pCR in pancreatectomy are rare but have a better prognosis.

Authors

Zhao, Q; Rashid, A; Gong, Y; Katz, MH; Lee, JE; Wolf, R; Balachandran, A; Varadhachary, GR; Pisters, PW; Wang, H; Gomez, HF; Abbruzzese, JL; Fleming, JB; Wang, H

MLA Citation

Zhao, Q, Rashid, A, Gong, Y, Katz, MH, Lee, JE, Wolf, R, Balachandran, A, Varadhachary, GR, Pisters, PW, Wang, H, Gomez, HF, Abbruzzese, JL, Fleming, JB, and Wang, H. "Pathologic complete response to neoadjuvant therapy in patients with pancreatic ductal adenocarcinoma is associated with a better prognosis." Annals of diagnostic pathology 16.1 (January 2012): 29-37.

PMID

22050964

Source

epmc

Published In

Annals of Diagnostic Pathology

Volume

16

Issue

1

Publish Date

2012

Start Page

29

End Page

37

DOI

10.1016/j.anndiagpath.2011.08.005

To determine the influence of neoadjuvant chemoradiation and standardized dissection of the superior mesenteric artery upon the oncologic outcome of patients with localized pancreatic adenocarcinoma.One hundred ninety-four patients with pancreatic adenocarcinoma who underwent pancreaticoduodenectomy between 2004 and 2008 were evaluated. The retroperitoneal dissection was performed directly along the superior mesenteric artery in all cases. A standard histopathologic protocol that measured the "superior mesenteric artery (SMA) margin distance" between cancer cells and the superior mesenteric artery was employed.Seventy-six percent of patients received neoadjuvant chemoradiation. The SMA margin was positive in 4% of patients but an additional 22% of patients with a negative margin had a SMA margin distance of ≤1 mm. Preoperative CT images overestimated the SMA margin distance in 73% of cases. Patients who received chemoradiation had longer SMA margin distances than those who did not. Patients who received chemoradiation and had a SMA margin of >1 mm had the lowest recurrence rates. Administration of neoadjuvant chemoradiation and lower estimated blood loss were independently associated with longer progression-free survival on multivariate analysis.Preoperative chemoradiation and meticulous dissection of the superior mesenteric artery maximize the distance between cancer cells and the SMA margin and may influence locoregional control.

Authors

Katz, MHG; Wang, H; Balachandran, A; Bhosale, P; Crane, CH; Wang, X; Pisters, PWT; Lee, JE; Vauthey, J-N; Abdalla, EK; Wolff, R; Abbruzzese, J; Varadhachary, G; Chopin-Laly, X; Charnsangavej, C; Fleming, JB

MLA Citation

Katz, MHG, Wang, H, Balachandran, A, Bhosale, P, Crane, CH, Wang, X, Pisters, PWT, Lee, JE, Vauthey, J-N, Abdalla, EK, Wolff, R, Abbruzzese, J, Varadhachary, G, Chopin-Laly, X, Charnsangavej, C, and Fleming, JB. "Effect of neoadjuvant chemoradiation and surgical technique on recurrence of localized pancreatic cancer." Journal of Gastrointestinal Surgery : Official Journal of the Society for Surgery of the Alimentary Tract 16.1 (January 2012): 68-78.

PMID

22065318

Source

epmc

Published In

Journal of Gastrointestinal Surgery : Official Journal of the Society for Surgery of the Alimentary Tract

Volume

16

Issue

1

Publish Date

2012

Start Page

68

End Page

78

DOI

10.1007/s11605-011-1748-7

Neoadjuvant chemoradiation before surgery is an emerging treatment modality for pancreatic ductal adenocarcinoma (PDAC). However, analysis of prognostic factors is limited for patients with PDAC treated with neoadjuvant chemoradiation and pancreaticoduodenectomy (PD).The study population was comprised of 240 consecutive patients with PDAC who received neoadjuvant chemoradiation and PD and was compared with 60 patients who had no neoadjuvant therapy between 1999 and 2007. Clinicopathologic features were correlated with disease-free survival (DFS) and overall survival (OS).Among the 240 treated patients, the 1-year and 3-year DFS rates were 52% and 32%, with a median DFS of 15.1 months. The 1-year and 3-year OS rates were 95% and 47%, with a median OS of 33.5 months. By univariate analysis, DFS was associated with age, post-therapy tumor stage (ypT), lymph node status (ypN), number of positive lymph nodes, and American Joint Committee on Cancer (AJCC) stage, whereas OS was associated with intraoperative blood loss, margin status, ypT, ypN, number of positive lymph nodes, and AJCC stage. By multivariate analysis, DFS was independently associated with age, number of positive lymph nodes, and AJCC stage, and OS was independently associated with differentiation, margin status, number of positive lymph nodes, and AJCC stage. In addition, the treated patients had better OS and lower frequency of lymph node metastasis than those who had no neoadjuvant therapy.In patients with PDAC who received neoadjuvant chemoradiation and subsequent PD, post-therapy pathologic AJCC stage and number of positive lymph nodes are independent prognostic factors.

Authors

Estrella, JS; Rashid, A; Fleming, JB; Katz, MH; Lee, JE; Wolf, RA; Varadhachary, GR; Pisters, PWT; Abdalla, EK; Vauthey, J-N; Wang, H; Gomez, HF; Evans, DB; Abbruzzese, JL; Wang, H

MLA Citation

Estrella, JS, Rashid, A, Fleming, JB, Katz, MH, Lee, JE, Wolf, RA, Varadhachary, GR, Pisters, PWT, Abdalla, EK, Vauthey, J-N, Wang, H, Gomez, HF, Evans, DB, Abbruzzese, JL, and Wang, H. "Post-therapy pathologic stage and survival in patients with pancreatic ductal adenocarcinoma treated with neoadjuvant chemoradiation." Cancer 118.1 (January 2012): 268-277.

PMID

21735446

Source

epmc

Published In

Cancer

Volume

118

Issue

1

Publish Date

2012

Start Page

268

End Page

277

DOI

10.1002/cncr.26243

PURPOSE: The gemcitabine and oxaliplatin (GEMOX) has yielded among the longest progression-free survival durations in patients with advanced pancreatic cancer (APC). We postulated that adding bevacizumab would increase the effectiveness of GEMOX. METHODS: Eligible patients had stage III or IV pancreatic cancer, ECOG PS 0-2, and no prior gemcitabine. Treatment included 1,000 mg/m(2) intravenous gemcitabine over 100 min on day 1, 10 mg/kg intravenous bevacizumab on day 1, and 100 mg/m(2) oxaliplatin given on day 2. Cycles were repeated every 2 weeks. CT imaging was performed every 6 weeks. RESULTS: Fifty patients were enrolled: 14 had stage III disease, the remainder stage IV. Median age was 59 years. Fourty-five patients were ECOG 0-1. The grade 3-4 toxicity rate was 94%; fatigue (47%) and nausea (40%) were frequent. One patient died after a bowel perforation; a second died of a CVA. The median PFS was 4.9 months; median survival was 11.9 months; 1 year survival was 42%. Locally advanced patients lived 12.8 months; metastatic patients lived 10.2 months. Patients developing grade 3 hypertension were more likely to have a radiologic response (P = .012); survival among the top and bottom quintiles of hypertension was 14.7 and 6.2 months, respectively. Survival correlated with baseline CA 19-9 (P = .004) and radiologic response. The overall response rate was 36%; 34% demonstrated stable disease. CONCLUSIONS: The GEMOX/bevacizumab regimen demonstrated an excellent median overall survival but did not meet our objective of a 14 month median survival. Toxicity was significant. We do not recommend further evaluation of this regimen.

Authors

Fogelman, D; Jafari, M; Varadhachary, GR; Xiong, H; Bullock, S; Ozer, H; Lin, E; Morris, J; Cunningham, P; Bennett, B; Abbruzzese, JL; Wolff, RA

MLA Citation

Fogelman, D, Jafari, M, Varadhachary, GR, Xiong, H, Bullock, S, Ozer, H, Lin, E, Morris, J, Cunningham, P, Bennett, B, Abbruzzese, JL, and Wolff, RA. "Bevacizumab plus gemcitabine and oxaliplatin as first-line therapy for metastatic or locally advanced pancreatic cancer: a phase II trial." Cancer Chemotherapy and Pharmacology 68.6 (December 2011): 1431-1438.

PMID

21479635

Source

epmc

Published In

Cancer Chemotherapy and Pharmacology

Volume

68

Issue

6

Publish Date

2011

Start Page

1431

End Page

1438

DOI

10.1007/s00280-011-1601-4

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer death. No effective therapy is currently available for PDAC because of the lack of understanding of the mechanisms leading to its growth and development. Inflammatory cells, particularly mast cells, have been shown to play key roles in some cancers. We carried out this study to test the hypothesis that mast cells in the tumor microenvironment are essential for PDAC tumorigenesis.The presence of inflammatory cells at various stages of PDAC development was determined in a spontaneous mouse model of PDAC (K-ras(G12V)). The importance of mast cells was determined using orthotopically implanted PDAC cells in mast cell-deficient Kit(w-sh/w-sh) mice and further confirmed by reconstitution of wild-type bone marrow-derived mast cells. Clinical relevance was assessed by correlating the presence of mast cells with clinical outcome in patients with PDAC.In the spontaneous mouse model of PDAC (K-ras(G12V)), there was an early influx of mast cells to the tumor microenvironment. PDAC tumor growth was suppressed in mast cell-deficient Kit(w-sh/w-sh) mice, but aggressive PDAC growth was restored when PDAC cells were injected into mast cell-deficient mice reconstituted with wild-type bone marrow-derived mast cells. Mast cell infiltration into the tumor microenvironment was predictive of poor prognosis in patients with PDAC.Mast cells play an important role in PDAC growth and development in mouse models and are indicative of poor prognosis in humans, which makes them a potential novel therapeutic target.

Authors

Chang, DZ; Ma, Y; Ji, B; Wang, H; Deng, D; Liu, Y; Abbruzzese, JL; Liu, Y-J; Logsdon, CD; Hwu, P

MLA Citation

Chang, DZ, Ma, Y, Ji, B, Wang, H, Deng, D, Liu, Y, Abbruzzese, JL, Liu, Y-J, Logsdon, CD, and Hwu, P. "Mast cells in tumor microenvironment promotes the in vivo growth of pancreatic ductal adenocarcinoma." Clinical cancer research : an official journal of the American Association for Cancer Research 17.22 (November 2011): 7015-7023.

PMID

21976550

Source

epmc

Published In

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research

Volume

17

Issue

22

Publish Date

2011

Start Page

7015

End Page

7023

DOI

10.1158/1078-0432.ccr-11-0607

Cirrhosis and hepatocellular carcinoma (HCC) together form a two-disease state that affects survival of patients with HCC and dictates treatment decisions and prognostic stratification of patients in clinical trials. The study objective was to improve prognostic stratification of patients with HCC.We prospectively collected plasma samples and baseline clinicopathologic features from 288 new patients with HCC, and plasma insulin-like growth factor-1 (IGF-1) and vascular endothelial growth factor (VEGF) levels were tested. We applied Cox regression and log-rank tests to assess association of IGF-1 and VEGF with overall survival (OS), Kaplan-Meier curves to estimate OS, and recursive partitioning to determine optimal cutoff points for IGF-1 and VEGF. Prognostic ability of conventional and molecular Barcelona Clinic Liver Cancer classifications was compared using the c-index.Lower plasma IGF-1 and higher plasma VEGF levels significantly correlated with advanced clinicopathologic parameters and poor OS, with optimal cut points of 26 ng/mL and 450 pg/mL, respectively. The combination of low IGF-1 and high VEGF predicted median OS of 2.7 months compared with 19 months for patients with high IGF-1 and low VEGF (P < .001), further refining the prognostic ability of conventional HCC staging (P < .001).Baseline levels of plasma IGF-1 and VEGF correlated significantly with survival in patients with HCC. Integrating IGF-1 and VEGF into HCC staging significantly enhanced prognostic stratification of patients. If validated, these results may prove to be useful in designing strategies to personalize management approaches among these patients.

Authors

Kaseb, AO; Morris, JS; Hassan, MM; Siddiqui, AM; Lin, E; Xiao, L; Abdalla, EK; Vauthey, J-N; Aloia, TA; Krishnan, S; Abbruzzese, JL

MLA Citation

Kaseb, AO, Morris, JS, Hassan, MM, Siddiqui, AM, Lin, E, Xiao, L, Abdalla, EK, Vauthey, J-N, Aloia, TA, Krishnan, S, and Abbruzzese, JL. "Clinical and prognostic implications of plasma insulin-like growth factor-1 and vascular endothelial growth factor in patients with hepatocellular carcinoma." Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology 29.29 (October 2011): 3892-3899.

PMID

21911725

Source

epmc

Published In

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology

Volume

29

Issue

29

Publish Date

2011

Start Page

3892

End Page

3899

DOI

10.1200/JCO.2011.36.0636

The resistance of tumors to antiangiogenic therapies is becoming increasingly relevant. There are currently no validated predictive biomarkers for selecting which cancer patients will benefit from antiangiogenic therapy. Also lacking are resistance biomarkers that can identify which escape pathways should be targeted after tumors develop resistance to VEGF treatment. Recent studies showed that anti-VEGF treatment can make tumor cells more aggressive and metastatic. However, the mechanisms and mediators of this are unidentified. Therefore, we aimed this study at directly identifying the tumor cell-initiated mechanisms responsible for the resistance of pancreatic cancer to anti-VEGF treatment.We established and validated two murine models of human pancreatic cancer resistant to the VEGF-specific antibody bevacizumab in vivo. We used a genome-wide analysis to directly identify which tumor-secreted factors were overexpressed by pancreatic cancer cells that were resistant to anti-VEGF treatment.Rather than direct proangiogenic factors, we identified several proinflammatory factors that were expressed at higher levels in cells resistant to anti-VEGF treatment than in treatment-sensitive control cells. These proinflammatory factors acted in a paracrine manner to stimulate the recruitment of CD11b(+) proangiogenic myeloid cells. Also, we found that secreted factors overexpressed by anti-VEGF treatment-resistant pancreatic cancer cells acted in an autocrine manner to induce epithelial-to-mesenchymal transition (EMT) and were thus responsible for increased aggressiveness of bevacizumab-resistant pancreatic tumors.Our results identified proinflammatory factors and EMT markers as potential biomarkers for selecting patients with pancreatic cancer for antiangiogenic therapy.

Authors

Carbone, C; Moccia, T; Zhu, C; Paradiso, G; Budillon, A; Chiao, PJ; Abbruzzese, JL; Melisi, D

MLA Citation

Carbone, C, Moccia, T, Zhu, C, Paradiso, G, Budillon, A, Chiao, PJ, Abbruzzese, JL, and Melisi, D. "Anti-VEGF treatment-resistant pancreatic cancers secrete proinflammatory factors that contribute to malignant progression by inducing an EMT cell phenotype." Clinical cancer research : an official journal of the American Association for Cancer Research 17.17 (September 2011): 5822-5832.

PMID

21737511

Source

epmc

Published In

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research

Volume

17

Issue

17

Publish Date

2011

Start Page

5822

End Page

5832

DOI

10.1158/1078-0432.ccr-11-1185

Authors

Abbruzzese, JL

MLA Citation

Abbruzzese, JL. "Introducing CCR perspectives in drug approval." Clinical cancer research : an official journal of the American Association for Cancer Research 17.15 (August 2011): 4929-.

PMID

21791634

Source

epmc

Published In

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research

Volume

17

Issue

15

Publish Date

2011

Start Page

4929

DOI

10.1158/1078-0432.ccr-11-1479

TGF-β-activated kinase-1 (TAK1), a mitogen-activated protein kinase kinase kinase, functions in the activation of nuclear factor κB (NF-κB) and activator protein-1, which can suppress proapoptotic signaling pathways and thus promote resistance to chemotherapeutic drugs. However, it is not known if inhibition of TAK1 is effective in reducing chemoresistance to therapeutic drugs against pancreatic cancer.NF-κB activity was measured by luciferase reporter assay in human pancreatic cancer cell lines AsPc-1, PANC-1, and MDAPanc-28, in which TAK1 expression was silenced by small hairpin RNA. TAK1 kinase activity was targeted in AsPc-1, PANC-1, MDAPanc-28, and Colo357FG cells with exposure to increasing doses of a selective small-molecule inhibitor, LYTAK1, for 24 hours. To test the effect of LYTAK1 in combination with chemotherapeutic agents, AsPc-1, PANC-1, MDAPanc-28 cells, and control cells were treated with increasing doses of oxaliplatin, SN-38, or gemcitabine in combination with LYTAK1. In vivo activity of oral LYTAK1 was evaluated in an orthotopic nude mouse model (n = 40, 5 per group) with luciferase-expressing AsPc-1 pancreatic cancer cells. The results of in vitro proliferation were analyzed for statistical significance of differences by nonlinear regression analysis; differences in mouse survival were determined using a log-rank test. All statistical tests were two-sided.AsPc-1 and MDAPanc-28 TAK1 knockdown cells had a statistically significantly lower NF-κB activity than did their respective control cell lines (relative luciferase activity: AsPc-1, mean = 0.18, 95% confidence interval [CI] = 0.10 to 0.27; control, mean = 3.06, 95% CI = 2.31 to 3.80; MDAPanc-28, mean = 0.30, 95% CI = 0.13 to 0.46; control, mean = 4.53, 95% CI = 3.43 to 5.63; both P < .001). TAK1 inhibitor LYTAK1 had potent in vitro cytotoxic activity in AsPc-1, PANC-1, MDAPanc-28, and Colo357FG cells, with IC(50) between 5 and 40 nM. LYTAK1 also potentiated the cytotoxicity of chemotherapeutic agents oxaliplatin, SN-38, and gemcitabine in AsPc-1, PANC-1, and MDAPanc-28 cells compared with control cells (P < .001). In nude mice, oral administration of LYTAK1 plus gemcitabine statistically significantly reduced tumor burden (gemcitabine vs gemcitabine plus LYTAK1, P = .03) and prolonged survival duration (median survival: gemcitabine, 82 days vs gemcitabine plus LYTAK1, 122 days; hazard ratio = 0.334, 95% CI = 0.027 to 0.826, P = .029).The results of this study suggest that genetic silencing or inhibition of TAK1 kinase activity in vivo is a potential therapeutic approach to reversal of the intrinsic chemoresistance of pancreatic cancer.

Authors

Melisi, D; Xia, Q; Paradiso, G; Ling, J; Moccia, T; Carbone, C; Budillon, A; Abbruzzese, JL; Chiao, PJ

MLA Citation

Melisi, D, Xia, Q, Paradiso, G, Ling, J, Moccia, T, Carbone, C, Budillon, A, Abbruzzese, JL, and Chiao, PJ. "Modulation of pancreatic cancer chemoresistance by inhibition of TAK1." Journal of the National Cancer Institute 103.15 (August 2011): 1190-1204.

PMID

21743023

Source

epmc

Published In

Journal of the National Cancer Institute

Volume

103

Issue

15

Publish Date

2011

Start Page

1190

End Page

1204

DOI

10.1093/jnci/djr243

BACKGROUND: The EGFR/Akt/NF-κB signalling pathway is frequently deregulated in pancreatic cancer and contributes to cell growth, metastasis and chemoresistance. An isoflavone, genistein, inactivates Akt and NF-κB and enhances the anti-tumor activity of erlotinib and gemcitabine in experimental systems of pancreas cancer. This phase II study was undertaken to determine the effects of adding isoflavone to a regimen of gemcitabine and erlotinib on survival in patients with advanced pancreatic cancer. METHODS: Eligibility included previously untreated patients with advanced pancreatic adenocarcinoma. Patients received gemcitabine 1,000 mg/m² on days 1, 8, and 15, and erlotinib 150 mg once daily P.O. on day 1 to day 28. Soy isoflavones (Novasoy®) were administered at a dose of 531 mg twice daily P.O. starting day -7 until the end of study participation. RESULTS: Twenty patients with advanced pancreas cancer were enrolled (median age 57.9 years). Sixteen patients had stage IV disease. The median number of cycles was 2 per patient. The median survival time was 5.2 months (95% CI, 4.6-N/A months). The probability of survival at 6 months was 50% (95% CI, 32-78%). CONCLUSIONS: The addition of soy isoflavones to gemcitabine and erlotinib did not appear to increase the survival of patients with advanced pancreatic cancer.

Authors

El-Rayes, BF; Philip, PA; Sarkar, FH; Shields, AF; Ferris, AM; Hess, K; Kaseb, AO; Javle, MM; Varadhachary, GR; Wolff, RA; Abbruzzese, JL

MLA Citation

El-Rayes, BF, Philip, PA, Sarkar, FH, Shields, AF, Ferris, AM, Hess, K, Kaseb, AO, Javle, MM, Varadhachary, GR, Wolff, RA, and Abbruzzese, JL. "A phase II study of isoflavones, erlotinib, and gemcitabine in advanced pancreatic cancer." Investigational new drugs 29.4 (August 2011): 694-699.

PMID

20107864

Source

epmc

Published In

Investigational New Drugs

Volume

29

Issue

4

Publish Date

2011

Start Page

694

End Page

699

DOI

10.1007/s10637-010-9386-6

This phase II trial was designed to assess the efficacy and safety of cetuximab, gemcitabine, and oxaliplatin followed by cetuximab, capecitabine, and radiation therapy in locally advanced pancreatic cancer (LAPC).Treatment-naive eligible patients (n = 69) received intravenous gemcitabine (1,000 mg/m(2)) and oxaliplatin (100 mg/m(2)) every 2 weeks for four doses, followed by radiation (50.4 Gy to the gross tumor only) with concurrent capecitabine (825 mg/m(2) twice daily on radiation treatment days). Cetuximab (500 mg/m(2)) was started on day 1 of chemotherapy and was continued every 2 weeks during chemotherapy and chemoradiotherapy. Diagnostic cytology specimens were immunostained for Smad4(Dpc4) expression.Median overall survival time was 19.2 months (95% CI, 14.2 to 24.2 months), and 1-year, 2-year, and 4-year actuarial overall survival rates were 66.0%, 25.02%, and 11.3%, respectively. Acneiform rash correlated with improved survival (P = .001), but initial CA19-9, borderline resectable initial stage, and surgical resection (n = 7) did not. The 1-year and 2-year radiographic local progression rates were 22.8% and 61.0%, respectively. The worst acute toxic effects were GI toxicity (32% and 10% for grades 2 and 3, respectively); fatigue (26% and 6% for grades 2 and 3, respectively); sensory neuropathy (9% and 1% for grades 2 and 3, respectively); and acneiform rash (54% and 3% for grades 2 and 3, respectively). Smad4(Dpc4) expression correlated with a local rather than a distant dominant pattern of disease progression (P = .016).This regimen appears effective and has acceptable toxicity. The primary end point (1-year overall survival rate > 45%) was met, with encouraging survival duration. Smad4(Dpc4) immunostaining correlated with the pattern of disease progression. Prospective validation of Smad4(Dpc4) expression in cytology specimens as a predictive biomarker is warranted and may lead to personalized treatment strategies for patients with localized pancreatic cancer.

Authors

Crane, CH; Varadhachary, GR; Yordy, JS; Staerkel, GA; Javle, MM; Safran, H; Haque, W; Hobbs, BD; Krishnan, S; Fleming, JB; Das, P; Lee, JE; Abbruzzese, JL; Wolff, RA

MLA Citation

Crane, CH, Varadhachary, GR, Yordy, JS, Staerkel, GA, Javle, MM, Safran, H, Haque, W, Hobbs, BD, Krishnan, S, Fleming, JB, Das, P, Lee, JE, Abbruzzese, JL, and Wolff, RA. "Phase II trial of cetuximab, gemcitabine, and oxaliplatin followed by chemoradiation with cetuximab for locally advanced (T4) pancreatic adenocarcinoma: correlation of Smad4(Dpc4) immunostaining with pattern of disease progression." Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology 29.22 (August 2011): 3037-3043.

PMID

21709185

Source

epmc

Published In

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology

Volume

29

Issue

22

Publish Date

2011

Start Page

3037

End Page

3043

DOI

10.1200/JCO.2010.33.8038

This study was designed to determine whether DNA methylation biomarkers are associated with recurrence and survival in colon cancer patients.A retrospective analysis of 82 patients who received curative surgical resection for American Joint Committee on Cancer (AJCC) high-risk stage II or III colon cancer (1999-2007) was conducted. DNA methylation status was quantitatively evaluated by the pyrosequencing method. We preselected three tumor suppressor genes and one locus of interest; CHFR, ID4, RECK, and MINT1. Mean methylation levels of multiple CpG sites in the promoter regions were used for analysis; 15% or more was defined as methylation positive. The association of recurrence-free survival (RFS) and overall survival (OS) with methylation status was analyzed by the log-rank test, Kaplan-Meier method, and Cox proportional hazards model.Methylation levels of ID4, MINT1, and RECK did not correlate with RFS or OS. CHFR was methylation positive in 63% patients. When methylation status was dichotomized (negative or low: <30%, high: ≥30%), patients with CHFR methylation-high (44%) had worse RFS (P = 0.006) and reduced OS (P = 0.069). When stratified by stage, CHFR methylation-high was associated with reduced RFS (P = 0.004) and OS (P = 0.010) in stage III patients. CHFR methylation-high was commonly associated with N2 disease (P = 0.04) and proximal tumors (P = 0.002). Multivariate analysis indicated AJCC T4 disease and CHFR methylation-high (P = 0.001 and P = 0.015, respectively) were independent predictors for recurrence.The extent of CHFR promoter methylation correlates with RFS, indicating it is a promising epigenetic marker for recurrence.

Authors

Tanaka, M; Chang, P; Li, Y; Li, D; Overman, M; Maru, DM; Sethi, S; Phillips, J; Bland, GL; Abbruzzese, JL; Eng, C

MLA Citation

Tanaka, M, Chang, P, Li, Y, Li, D, Overman, M, Maru, DM, Sethi, S, Phillips, J, Bland, GL, Abbruzzese, JL, and Eng, C. "Association of CHFR promoter methylation with disease recurrence in locally advanced colon cancer." Clinical cancer research : an official journal of the American Association for Cancer Research 17.13 (July 2011): 4531-4540.

PMID

21551253

Source

epmc

Published In

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research

Volume

17

Issue

13

Publish Date

2011

Start Page

4531

End Page

4540

DOI

10.1158/1078-0432.ccr-10-0763

Several staging systems have been proposed for hepatocellular carcinoma (HCC); however, none has incorporated circulating angiogenic biomarkers. The purpose of this study was to determine whether vascular endothelial growth factor (VEGF) could independently predict overall survival in patients with HCC, and whether adding VEGF level into the Cancer of the Liver Italian Program (CLIP) score could improve patient stratification and prediction of overall survival.Between 2001 and 2008, baseline plasma VEGF levels were available from 288 patients, and multivariate Cox regression models and median survival (95% confidence intervals) were calculated. Recursive partitioning was used to determine the optimal cutpoint for VEGF, using 10 repeated training/validation samples, each using two-thirds of the data to determine the best cutpoint and the remaining one-third to validate it. Prognostic ability of CLIP and V-CLIP was compared using the concordence index.Plasma VEGF was a significant independent predictor of overall survival, with an optimal VEGF cutpoint of 450 pg/mL. After CLIP validation in our patients, we added VEGF to the CLIP score and found that the new V-CLIP score better separates patients into homogenous prognostic groups (P = .005).The assessment of baseline plasma VEGF levels increases the precision of the CLIP scoring system for predicting HCC prognosis, which may assist in equally randomizing patients with HCC in clinical trials. Prospective validation of the V-CLIP scoring system is warranted.

Authors

Kaseb, AO; Hassan, MM; Lin, E; Xiao, L; Kumar, V; Pathak, P; Lozano, R; Rashid, A; Abbruzzese, JL; Morris, JS

MLA Citation

Kaseb, AO, Hassan, MM, Lin, E, Xiao, L, Kumar, V, Pathak, P, Lozano, R, Rashid, A, Abbruzzese, JL, and Morris, JS. "V-CLIP: Integrating plasma vascular endothelial growth factor into a new scoring system to stratify patients with advanced hepatocellular carcinoma for clinical trials." Cancer 117.11 (June 2011): 2478-2488.

PMID

24048796

Source

epmc

Published In

Cancer

Volume

117

Issue

11

Publish Date

2011

Start Page

2478

End Page

2488

DOI

10.1002/cncr.25791

PURPOSE: Accurate identification of tissue of origin (ToO) for patients with carcinoma of unknown primary (CUP) may help customize therapy to the putative primary and thereby improve the clinical outcome. We prospectively studied the performance of a microRNA-based assay to identify the ToO in CUP patients. EXPERIMENTAL DESIGN: Formalin-fixed paraffin-embedded (FFPE) metastatic tissue from 104 patients was reviewed and 87 of these contained sufficient tumor for testing. The assay quantitates 48 microRNAs and assigns one of 25 tumor diagnoses by using a biologically motivated binary decision tree and a K-nearest neighbors (KNN). The assay predictions were compared with clinicopathologic features and, where suitable, to therapeutic response. RESULTS: Seventy-four of the 87 cases were processed successfully. The assay result was consistent or compatible with the clinicopathologic features in 84% of cases processed successfully (71% of all samples attempted). In 65 patients, pathology and immunohistochemistry (IHC) suggested a diagnosis or (more often) a differential diagnosis. Out of those, the assay was consistent or compatible with the clinicopathologic presentation in 55 (85%) cases. Of the 9 patients with noncontributory IHC, the assay provided a ToO prediction that was compatible with the clinical presentation in 7 cases. CONCLUSIONS: In this prospective study, the microRNA diagnosis was compatible with the clinicopathologic picture in the majority of cases. Comparative effectiveness research trials evaluating the added benefit of molecular profiling in appropriate CUP subsets are warranted. MicroRNA profiling may be particularly helpful in patients in whom the IHC profile of the metastasis is nondiagnostic or leaves a large differential diagnosis.

Authors

Varadhachary, GR; Spector, Y; Abbruzzese, JL; Rosenwald, S; Wang, H; Aharonov, R; Carlson, HR; Cohen, D; Karanth, S; Macinskas, J; Lenzi, R; Chajut, A; Edmonston, TB; Raber, MN

MLA Citation

Varadhachary, GR, Spector, Y, Abbruzzese, JL, Rosenwald, S, Wang, H, Aharonov, R, Carlson, HR, Cohen, D, Karanth, S, Macinskas, J, Lenzi, R, Chajut, A, Edmonston, TB, and Raber, MN. "Prospective gene signature study using microRNA to identify the tissue of origin in patients with carcinoma of unknown primary." Clinical Cancer Research : an Official Journal of the American Association for Cancer Research 17.12 (June 2011): 4063-4070.

PMID

21531815

Source

epmc

Published In

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research

Volume

17

Issue

12

Publish Date

2011

Start Page

4063

End Page

4070

DOI

10.1158/1078-0432.ccr-10-2599

Long-term type 2 diabetes is a known risk factor for pancreatic cancer (PC). We hypothesized that genetic variants in glucose metabolism modify individual susceptibility to PC, especially those associated with diabetes. We retrospectively genotyped 26 single-nucleotide polymorphisms of 5 glucose metabolism genes: glucokinase (GCK), glutamine-fructose-6-phosphate transaminase 1 (GFPT1), glucose phosphate isomerase (GPI), hexokinase 2 (HK2), and O-linked N-acetylglucosamine transferase (OGT) in a case-control study of PC conducted at MD Anderson during 2004 to 2010. Initial genotyping was conducted in 706 patients with PC and 706 cancer-free controls by using the Sequenom method. A HK2 genotype (R844K) with low frequency of homozygous variant was further examined in additional 948 patients and 476 controls. In the combined set of 1,654 cases and 1,182 controls, we showed a significant association of the HK2 R844K GA/AA genotype with reduced PC risk (OR = 0.78; 95% CI, 0.64-0.94; P = 0.009) and a significant interaction with diabetes (P(interaction) < 0.001). The HK2 R844K GA/AA genotype was associated with a reduced risk of PC among nondiabetic individuals (OR = 0.68; 95% CI, 0.56-0.83) but with increased risk among diabetic patients (OR = 3.69; 95% CI, 2.34-5.82). These risk associations remained statistically significant when the analysis was restricted to whites or after exclusion of recent onset diabetes. No significant main effect of other genes or significant interaction of genotype with other risk factors was observed. The findings show a potential role of HK2 gene, alone or in interaction with diabetes, in modifying the risk of PC.

Authors

Dong, X; Li, Y; Chang, P; Tang, H; Hess, KR; Abbruzzese, JL; Li, D

MLA Citation

Dong, X, Li, Y, Chang, P, Tang, H, Hess, KR, Abbruzzese, JL, and Li, D. "Glucose metabolism gene variants modulate the risk of pancreatic cancer." Cancer prevention research (Philadelphia, Pa.) 4.5 (May 2011): 758-766.

PMID

21411499

Source

epmc

Published In

Cancer Prevention Research

Volume

4

Issue

5

Publish Date

2011

Start Page

758

End Page

766

DOI

10.1158/1940-6207.capr-10-0247

The genetic factors predisposing individuals with obesity or diabetes to pancreatic cancer have not been identified.To investigate the hypothesis that obesity- and diabetes-related genes modify the risk of pancreatic cancer.We genotyped 15 single nucleotide polymorphisms of fat mass and obesity-associated (FTO), peroxisome proliferators-activated receptor gamma (PPARγ), nuclear receptor family 5 member 2 (NR5A2), AMPK, and ADIPOQ genes in 1,070 patients with pancreatic cancer and 1,175 cancer-free controls. Information on risk factors was collected by personal interview. Adjusted ORs (AOR) and 95% CIs were calculated using unconditional logistic regression.The PPARγ P12A GG genotype was inversely associated with risk of pancreatic cancer (AOR, 0.21; 95% CI, 0.07-0.62). Three NR5A2 variants that were previously identified in a genome-wide association study were significantly associated with reduced risk of pancreatic cancer, AORs ranging from 0.57 to 0.79. Two FTO gene variants and one ADIPOQ variant were differentially associated with pancreatic cancer according to levels of body mass index (BMI; P(interaction) = 0.0001, 0.0015, and 0.03). For example, the AOR (95% CI) for FTO IVS1-2777AC/AA genotype was 0.72 (0.55-0.96) and 1.54 (1.14-2.09) in participants with a BMI of less than 25 or 25 kg/m(2) or more, respectively. We observed no significant association between AMPK genotype and pancreatic cancer and no genotype interactions with diabetes or smoking.Our findings suggest the PPARγ P12A GG genotype and NR5A2 variants may reduce the risk for pancreatic cancer. A positive association of FTO and ADIPOQ gene variants with pancreatic cancer may be limited to persons who are overweight.The discovery of genetic factors modifying the risk of pancreatic cancer may help to identify high-risk individuals for prevention efforts.

Authors

Tang, H; Dong, X; Hassan, M; Abbruzzese, JL; Li, D

MLA Citation

Tang, H, Dong, X, Hassan, M, Abbruzzese, JL, and Li, D. "Body mass index and obesity- and diabetes-associated genotypes and risk for pancreatic cancer." Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology 20.5 (May 2011): 779-792.

PMID

21357378

Source

epmc

Published In

Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology

Volume

20

Issue

5

Publish Date

2011

Start Page

779

End Page

792

DOI

10.1158/1055-9965.EPI-10-0845

Survivin is a universal tumor antigen that is being currently targeted in vaccine approaches against cancer. Our study here examined the immunogenicity of a novel variant of an HLA-A0201-binding decamer peptide from region 95 to 104 of Survivin (ELMLGEFLKL) with a T→M modification at position 3 in the peptide. We found that this new modified 10-mer peptide had enhanced HLA-A0201 binding and induced a stronger T-cell response over its wild type counterpart peptide (ELTLGEFLKL) in select HLA-A0201(+) normal donors. In addition, when compared to the previously characterized altered 96-104 peptide (LMLGEFLKL) from the same region of Survivin currently used in vaccine trials, we found that both peptides had similar immunogenicity, but donor T cells preferentially reacted strongly to either one or the other, but not strongly to both. These results suggest that these two closely related Survivin peptides yield distinct T-cell responses and that most individuals dominantly respond to one or the other altered peptide. We also found a novel association between positive reactivity to the new altered decamer Survivin peptide in some individuals and their expression of the HLA-C0701 allele along with HLA-A0201. Thus, vaccinating with both the 10-mer and 9-mer peptides would be required to immunize a maximum number of individuals in the HLA-A0201(+) population and could lead to more consistent T-cell responses against this region of Survivin.

Authors

Bernatchez, C; Zhu, K; Li, Y; Andersson, H; Ionnides, C; Fernandez-Vina, M; Cano, P; Cooper, L; Abbruzzese, J; Hwu, P; Chang, DZ; Radvanyi, LG

MLA Citation

Bernatchez, C, Zhu, K, Li, Y, Andersson, H, Ionnides, C, Fernandez-Vina, M, Cano, P, Cooper, L, Abbruzzese, J, Hwu, P, Chang, DZ, and Radvanyi, LG. "Altered decamer and nonamer from an HLA-A0201-restricted epitope of Survivin differentially stimulate T-cell responses in different individuals." Vaccine 29.16 (April 2011): 3021-3030.

PMID

21320548

Source

epmc

Published In

Vaccine

Volume

29

Issue

16

Publish Date

2011

Start Page

3021

End Page

3030

DOI

10.1016/j.vaccine.2011.01.115

Pancreatic cancer is an aggressive, frequently fatal malignancy that strikes 37,000 patients annually in the U.S.A. It is poorly responsive to standard chemotherapies such as gemcitabine. Approximately 5-10% of pancreatic cancer occurs in the setting of a BRCA2 mutation. Breast and ovarian carcinomas that harbor BRCA2 mutations are susceptible to the effects of an emerging class of targeted agents, namely, poly(ADP-ribose) polymerase (PARP) inhibitors. This report describes the case of a patient with a germline BRCA2 mutation and an associated pancreatic cancer treated with iniparib (BSI-201), a PARP inhibitor, who demonstrated a complete pathologic response to this agent. This case highlights the potential benefit for PARP inhibition in BRCA2-related pancreatic cancer.

Authors

Fogelman, DR; Wolff, RA; Kopetz, S; Javle, M; Bradley, C; Mok, I; Cabanillas, F; Abbruzzese, JL

MLA Citation

Fogelman, DR, Wolff, RA, Kopetz, S, Javle, M, Bradley, C, Mok, I, Cabanillas, F, and Abbruzzese, JL. "Evidence for the efficacy of Iniparib, a PARP-1 inhibitor, in BRCA2-associated pancreatic cancer." Anticancer research 31.4 (April 2011): 1417-1420.

PMID

21508395

Source

epmc

Published In

Anticancer Research

Volume

31

Issue

4

Publish Date

2011

Start Page

1417

End Page

1420

PURPOSE:This study evaluated PX-12, a novel small molecule inhibitor of the proto-oncogene (Trx-1), in patients with previously treated advanced pancreatic cancer (APC). METHODS:PX-12 (54 or 128 mg/m²) was administered by 3-hour IV infusion daily × 5 days every 21 days (n = 17). Patients were randomized to either 54 or 128 mg/m² and then stratified based on CA 19-9 level (≥ 1,000 vs. < 1,000 U/ml) and SUV values on PET scans (≥ 7.0 vs. <7.0). The primary endpoint was based on a progression-free survival (PFS) at 4 months in ≥ 40% of patients, and required 40 patients in each arm. An amendment required elevated Trx-1 levels (> 18 ng/ml) as an entry criteria after the first 17 patients were accrued. RESULTS:Plasma Trx-1 levels were elevated in 3/28 (11%) patients screened for study. The grade of the expired metabolite odor was higher in the 128 mg/m² arm. Therapy was well tolerated, and Grade ≥ 3 adverse events were uncommon. The best response was stable disease in 2 patients. There was no consistent decrease in SUV, Trx-1 levels or CA 19-9 levels with therapy. No patients had a PFS of >4 months. Median PFS and survival were 0.9 months (95% CI 0.5-1.2) and 3.2 months (95% CI 2.4-4.2), respectively. CONCLUSIONS:Due to the lack of significant antitumor activity and unexpectedly low baseline Trx-1 levels, the study was terminated early. PX-12 does not appear to be active in unselected patients with previously treated APC.

Authors

Ramanathan, RK; Abbruzzese, J; Dragovich, T; Kirkpatrick, L; Guillen, JM; Baker, AF; Pestano, LA; Green, S; Von Hoff, DD

MLA Citation

Ramanathan, RK, Abbruzzese, J, Dragovich, T, Kirkpatrick, L, Guillen, JM, Baker, AF, Pestano, LA, Green, S, and Von Hoff, DD. "A randomized phase II study of PX-12, an inhibitor of thioredoxin in patients with advanced cancer of the pancreas following progression after a gemcitabine-containing combination." Cancer Chemotherapy and Pharmacology 67.3 (March 2011): 503-509.

PMID

20461382

Source

epmc

Published In

Cancer Chemotherapy and Pharmacology

Volume

67

Issue

3

Publish Date

2011

Start Page

503

End Page

509

DOI

10.1007/s00280-010-1343-8

Altered glucose metabolism is the most common metabolic hallmark of malignancies. The authors tested the hypothesis that glucose metabolism gene variations affect clinical outcome in pancreatic cancer.The authors retrospectively genotyped 26 single nucleotide polymorphisms from 5 glucose metabolism genes in 154 patients with localized disease and validated the findings in 552 patients with different stages of pancreatic adenocarcinoma. Association between genotypes and overall survival (OS) was evaluated using multivariate Cox proportional hazard regression models with adjustment for clinical predictors.Glucokinase (GCK) IVS1 + 9652C > T and hexokinase 2 (HK2) N692N homozygous variants were significantly associated with reduced OS in the training set of 154 patients (P < .001). These associations were confirmed in the validation set of 552 patients and in the combined dataset of all 706 patients (P ≤ .001). In addition, HK2 R844K variant K allele was associated with a better survival in the validation set and the combined dataset (P ≤ .001). When data were further analyzed by disease stage, glutamine-fructose-6-phosphate transaminase (GFPT1) IVS14-3094T>C, HK2 N692N and R844K in patients with localized disease and GCK IVS1 + 9652C>T in patients with advanced disease were significant independent predictors for OS (P ≤ .001). Haplotype CGG of GPI and GCTATGG of HK2 were associated with better OS, respectively, with P values of .004 and .007.The authors demonstrated that glucose metabolism gene polymorphisms affect clinical outcome in pancreatic cancer. These observations support a role of abnormal glucose metabolism in pancreatic carcinogenesis.

Authors

Dong, X; Tang, H; Hess, KR; Abbruzzese, JL; Li, D

MLA Citation

Dong, X, Tang, H, Hess, KR, Abbruzzese, JL, and Li, D. "Glucose metabolism gene polymorphisms and clinical outcome in pancreatic cancer." Cancer 117.3 (February 2011): 480-491.

PMID

20845477

Source

epmc

Published In

Cancer

Volume

117

Issue

3

Publish Date

2011

Start Page

480

End Page

491

DOI

10.1002/cncr.25612

The receptor tyrosine kinase Axl has been reported to be overexpressed in a variety of human cancers. Although previous studies have identified the role of Axl in the transformation, proliferation, survival, and invasion in cancers, the expression and functions of Axl in pancreatic cancer have not been studied in detail.The expression of Axl protein in 12 pancreatic cancer cell lines and 54 patient samples of stage II pancreatic ductal adenocarcinoma (PDA) and their paired non-neoplastic pancreatic tissue samples were examined. Using univariate and multivariate analysis, Axl expression was correlated with survival and other clinicopathologic features. To examine Axl functions in PDA, the effects of Axl knockdown on the invasion ability and radiation-induced apoptosis in PDA cell lines were measured.Axl was overexpressed in 38 of 54 (70%) stage II PDA samples and 9 of 12 (75%) PDA cell lines. Axl overexpression was associated with higher frequencies of distant metastasis and poor overall and recurrence-free survivals (P = .03 and P = .04, respectively) independent of tumor size and stage or lymph node status in patients with stage II PDA. Knockdown of Axl expression in PDA cells abolished Gas6-mediated Akt activation, decreased invasion, and increased radiation-induced PARP cleavage and the percentage of apoptosis.This study showed that Gas6 and Axl are frequently overexpressed in PDA cells and are associated with a poor prognosis in patients with stage II PDA. Axl promotes the invasion and survival of PDA cells. Therefore, targeting the Axl signaling pathway may represent a new approach to the treatment of PDA.

Authors

Song, X; Wang, H; Logsdon, CD; Rashid, A; Fleming, JB; Abbruzzese, JL; Gomez, HF; Evans, DB; Wang, H

MLA Citation

Song, X, Wang, H, Logsdon, CD, Rashid, A, Fleming, JB, Abbruzzese, JL, Gomez, HF, Evans, DB, and Wang, H. "Overexpression of receptor tyrosine kinase Axl promotes tumor cell invasion and survival in pancreatic ductal adenocarcinoma." Cancer 117.4 (February 2011): 734-743.

PMID

20922806

Source

epmc

Published In

Cancer

Volume

117

Issue

4

Publish Date

2011

Start Page

734

End Page

743

DOI

10.1002/cncr.25483

The purpose of this study was to identify single nucleotide polymorphisms (SNPs) of multidrug resistance genes that are associated with clinical outcome in patients with potentially resectable pancreatic adenocarcinoma who were treated with preoperative gemcitabine-based chemoradiotherapy at M. D. Anderson Cancer Center.We selected 8 SNPs of 7 drug resistance genes, including MDR1 (ABCB1), MRP1-5 (ABCC1-5), and BCRP (ABCG2), reported to be important in mediating drug resistance. Genotype was determined by the Taqman method. The associations of genotype with tumor response to therapy and overall survival (OS) were evaluated using log-rank test, Cox regression, and logistic regression models.MRP5 A-2G AA genotype showed significant association with OS (log-rank P = .010). The hazard ratio (95% confidence interval) was 1.65 (1.11-2.45) after adjusting for clinical predictors. The MRP2 G40A GG genotype had a weak association with reduced OS (log-rank P = .097). A combined effect of the two genotypes on OS was observed. Patients with none of the adverse genotypes had a median survival time (MST) of 34.0 months, and those with 1-2 deleterious alleles had a significantly lower MST of 20.7 months (log-rank P = .006). MRP2 G40A GG genotype was also significantly associated with poor histological response to chemoradiotherapy (P = .028).These observations suggest a potential role of polymorphic variants of drug resistance genes in predicting therapeutic efficacy and survival of patients with potentially resectable pancreatic cancer.

Authors

Tanaka, M; Okazaki, T; Suzuki, H; Abbruzzese, JL; Li, D

MLA Citation

Tanaka, M, Okazaki, T, Suzuki, H, Abbruzzese, JL, and Li, D. "Association of multi-drug resistance gene polymorphisms with pancreatic cancer outcome." Cancer 117.4 (February 2011): 744-751.

PMID

20922799

Source

epmc

Published In

Cancer

Volume

117

Issue

4

Publish Date

2011

Start Page

744

End Page

751

DOI

10.1002/cncr.25510

DNA mismatch repair (MMR) maintains genomic stability and mediates cellular response to DNA damage. We aim to demonstrate whether MMR genetic variants affect overall survival (OS) in pancreatic cancer.Using the Sequenom method in genomic DNA, we retrospectively genotyped 102 single-nucleotide polymorphisms (SNPs) of 13 MMR genes from 706 patients with pancreatic adenocarcinoma seen at The University of Texas MD Anderson Cancer Center. Association between genotype and OS was evaluated using multivariable Cox proportional hazard regression models.At a false discovery rate of 1% (p ≤ .0015), 15 SNPs of EXO1, MLH1, MSH2, MSH3, MSH6, PMS2, PMS2L3, TP73, and TREX1 in patients with localized disease (n = 333) and 6 SNPs of MSH3, MSH6, and TP73 in patients with locally advanced or metastatic disease (n = 373) were significantly associated with OS. In multivariable Cox proportional hazard regression models, SNPs of EXO1, MSH2, MSH3, PMS2L3, and TP73 in patients with localized disease, MSH2, MSH3, MSH6, and TP73 in patients with locally advanced or metastatic disease, and EXO1, MGMT, MSH2, MSH3, MSH6, PMS2L3, and TP73 in all patients remained significant predictors for OS (p ≤ .0015) after adjusting for all clinical predictors and all SNPs with p ≤ .0015 in single-locus analysis. Sixteen haplotypes of EXO1, MLH1, MSH2, MSH3, MSH6, PMS2, PMS2L3, RECQL, TP73, and TREX1 significantly correlated with OS in all patients (p ≤ .001).MMR gene variants may have potential value as prognostic markers for OS in pancreatic cancer patients.

Authors

Dong, X; Li, Y; Hess, KR; Abbruzzese, JL; Li, D

MLA Citation

Dong, X, Li, Y, Hess, KR, Abbruzzese, JL, and Li, D. "DNA mismatch repair gene polymorphisms affect survival in pancreatic cancer." The oncologist 16.1 (January 6, 2011): 61-70.

PMID

21212431

Source

epmc

Published In

The Oncologist

Volume

16

Issue

1

Publish Date

2011

Start Page

61

End Page

70

DOI

10.1634/theoncologist.2010-0127

Non-steroidal anti-inflammatory drugs (NSAIDs) are primarily used for the treatment of acute or chronic conditions with pain and inflammation. Evidence from a wide range of sources suggested that chronic administration of NSAIDs reduced the risk of cancer incidences. Both the epidemiological and animal studies showed an inverse association between the incidence of various cancers and the use of aspirin or other NSAIDs. The chemopreventive and therapeutic interventions of NSAIDs in cancer are obvious; however, the instigation of drug and treatment period depends on the study objective. Typically, prevention involves initiating the medication before the appearance of clinical symptoms and lasts long-term; while treatment could be short-term and contingent to the response of patient to the medication. Recent studies from our laboratories provided substantial evidence on the anti-cancer activity of tolfenamic acid, a NSAID for the potential applications in pancreatic, esophageal and lung cancers. In this review, we provide a summary on the potential benefits of NSAIDs in a variety of human cancers with more emphasis on tolfenamic acid.

Authors

Basha, R; Baker, CH; Sankpal, UT; Ahmad, S; Safe, S; Abbruzzese, JL; Abdelrahim, M

MLA Citation

Basha, R, Baker, CH, Sankpal, UT, Ahmad, S, Safe, S, Abbruzzese, JL, and Abdelrahim, M. "Therapeutic applications of NSAIDS in cancer: special emphasis on tolfenamic acid." Frontiers in bioscience (Scholar edition) 3 (January 2011): 797-805. (Review)

PMID

21196413

Source

epmc

Published In

Frontiers in Bioscience (Scholar Edition)

Volume

3

Publish Date

2011

Start Page

797

End Page

805

DOI

10.2741/s188

Improving the prognostic stratification of unresectable hepatocellular carcinoma (HCC) patients is critically needed. Since patients' survival is closely linked to the severity of the underlying liver disease, and insulin-like growth factor-1 (IGF-1) is produced predominantly in the liver, we hypothesized that IGF-1 may correlate with patients' survival and hence improve the prognostic ability of the Cancer of the Liver Italian Program (CLIP) score.Baseline plasma IGF-1 and clinicopathologic parameters were available from 288 patients. Multivariate Cox regression models, Kaplan-Meier curves, and the log-rank test were applied. Recursive partitioning was used to determine the optimal cut point for IGF-1 using training/validation samples. Prognostic ability of the I-CLIP (I = IGF) was compared to CLIP using C-index.IGF-1 significantly correlated with the clinicopathologic features. With an optimal IGF-1 cut point of 26 ng/ml, the overall survival of patients with IGF-1 >26 was 17.7 months (95% CI 13.6-22.8), and with IGF-1 ≤26 was 5.8 months (95% CI 4.0-12.5), p < 0.0001. The concordance probabilities for CLIP and I-CLIP were 0.7037 and 0.7096, respectively (p < 0.0001).Our preliminary results indicate that I-CLIP significantly improved prognostic stratification of patients with advanced HCC. However, independent validation of our study is warranted.

Authors

Kaseb, AO; Abbruzzese, JL; Vauthey, J-N; Aloia, TA; Abdalla, EK; Hassan, MM; Lin, E; Xiao, L; El-Deeb, AS; Rashid, A; Morris, JS

MLA Citation

Kaseb, AO, Abbruzzese, JL, Vauthey, J-N, Aloia, TA, Abdalla, EK, Hassan, MM, Lin, E, Xiao, L, El-Deeb, AS, Rashid, A, and Morris, JS. "I-CLIP: improved stratification of advanced hepatocellular carcinoma patients by integrating plasma IGF-1 into CLIP score." Oncology 80.5-6 (January 2011): 373-381.

PMID

21822028

Source

epmc

Published In

Oncology

Volume

80

Issue

5-6

Publish Date

2011

Start Page

373

End Page

381

DOI

10.1159/000329040

Multiple studies in recent years have identified highly tumorigenic populations of cells that drive tumor formation. These cancer stem cells (CSCs), or tumor-initiating cells (TICs), exhibit properties of normal stem cells and are associated with resistance to current therapies. As pancreatic adenocarcinoma is among the most resistant human cancers to chemo-radiation therapy, we sought to evaluate the presence of cell populations with tumor-initiating capacities in human pancreatic tumors. Understanding which pancreatic cancer cell populations possess tumor-initiating capabilities is critical to characterizing and understanding the biology of pancreatic CSCs towards therapeutic ends.We have isolated populations of cells with high ALDH activity (ALDH(high)) and/or CD133 cell surface expression from human xenograft tumors established from multiple patient tumors with pancreatic adenocarcinoma (direct xenograft tumors) and from the pancreatic cancer cell line L3.6pl. Through fluorescent activated cell sorting (FACs)-mediated enrichment and depletion of selected pancreatic cancer cell populations, we sought to discriminate the relative tumorigenicity of cell populations that express the pancreatic CSC markers CD133 and aldehyde dehydrogenase (ALDH). ALDH(high) and ALDH(low) cell populations were further examined for co-expression of CD44 and/or CD24. We demonstrate that unlike cell populations demonstrating low ALDH activity, as few as 100 cells enriched for high ALDH activity were capable of tumor formation, irrespective of CD133 expression. In direct xenograft tumors, the proportions of total tumor cells expressing ALDH and/or CD133 in xenograft tumors were unchanged through a minimum of two passages. We further demonstrate that ALDH expression among patients with pancreatic adenocarcinoma is heterogeneous, but the expression is constant in serial generations of individual direct xenograft tumors established from bulk human pancreatic tumors in NOD/SCID mice.We conclude that, in contrast to some previous studies, cell populations enriched for high ALDH activity alone are sufficient for efficient tumor-initiation with enhanced tumorigenic potential relative to CD133(+) and ALDH(low) cell populations in some direct xenograft tumors. Although cell populations enriched for CD133 expression may alone possess tumorigenic potential, they are significantly less tumorigenic than ALDH(high) cell populations. ALDH(high)/CD44(+)/CD24(+) or ALDH(low)/CD44(+)/CD24(+) phenotypes do not appear to significantly contribute to tumor formation at low numbers of inoculated tumor cells. ALDH expression broadly varies among patients with pancreatic adenocarcinoma and the apparent expression is recapitulated in serial generations of direct xenograft tumors in NOD/SCID. We have thus identified a distinct population of TICs that should lead to identification of novel targets for pancreatic cancer therapy.

Authors

Kim, MP; Fleming, JB; Wang, H; Abbruzzese, JL; Choi, W; Kopetz, S; McConkey, DJ; Evans, DB; Gallick, GE

MLA Citation

Kim, MP, Fleming, JB, Wang, H, Abbruzzese, JL, Choi, W, Kopetz, S, McConkey, DJ, Evans, DB, and Gallick, GE. "ALDH activity selectively defines an enhanced tumor-initiating cell population relative to CD133 expression in human pancreatic adenocarcinoma." Plos One 6.6 (January 2011): e20636-null.

PMID

21695188

Source

epmc

Published In

Plos One

Volume

6

Issue

6

Publish Date

2011

Start Page

e20636

DOI

10.1371/journal.pone.0020636

Non-steroidal anti-inflammatory drugs (NSAIDs) are primarily used for the treatment of acute or chronic conditions with pain and inflammation. Evidence from a wide range of sources suggested that chronic administration of NSAIDs reduced the risk of cancer incidences. Both the epidemiological and animal studies showed an inverse association between the incidence of various cancers and the use of aspirin or other NSAIDs. The chemopreventive and therapeutic interventions of NSAIDs in cancer are obvious; however, the instigation of drug and treatment period depends on the study objective. Typically, prevention involves initiating the medication before the appearance of clinical symptoms and lasts longterm; while treatment could be short-term and contingent to the response of patient to the medication. Recent studies from our laboratories provided substantial evidence on the anti-cancer activity of tolfenamic acid, a NSAID for the potential applications in pancreatic, esophageal and lung cancers. In this review, we provide a summary on the potential benefits of NSAIDs in a variety of human cancers with more emphasis on tolfenamic acid.

Authors

Basha, R; Baker, CT; Sankpal, UT; Ahmad, S; Safe, S; Abbruzzese, JL; Abdelrahim, M

MLA Citation

Basha, R, Baker, CT, Sankpal, UT, Ahmad, S, Safe, S, Abbruzzese, JL, and Abdelrahim, M. "Therapeutic applications of NSAIDS in cancer: Special emphasis on tolfenamic acid." Frontiers in Bioscience - Scholar 3 S.2 (2011): 797-805.

Source

scival

Published In

Frontiers in Bioscience (Scholar Edition)

Volume

3 S

Issue

2

Publish Date

2011

Start Page

797

End Page

805

It has not been well established whether genetic variations can be biomarkers for clinical outcome of gemcitabine therapy. The purpose of this study was to identify single nucleotide polymorphisms (SNPs) of gemcitabine metabolic and transporter genes that are associated with toxicity and efficacy of gemcitabine-based therapy in patients with locally advanced pancreatic cancer.The authors evaluated 17 SNPs of the CDA,dCK, DCTD, RRM1, hCNT1-3, and hENT1 genes in 149 patients with locally advanced pancreatic cancer who underwent gemcitabine-based chemoradiotherapy. The association of genotypes with neutropenia, tumor response to therapy, overall survival, and progression-free survival (PFS) was analyzed by logistic regression, log-rank test, Kaplan-Meier plot, and Cox proportional hazards regression.The CDA A-76C, dCK C-1205T, RRM1 A33G, and hENT1 C913T genotypes were significantly associated with grade 3 to 4 neutropenia (P = .020, .015, .003, and .017, respectively).The CDA A-76C and hENT1 A-201G genotypes were significantly associated with tumor response to therapy (P = .017 and P = .019). A combined genotype effect of CDA A-76C, RRM1 A33G, RRM1 C-27A, and hENT1 A-201G on PFS was observed. Patients carrying 0 to 1 (n = 64), 2 (n = 50), or 3 to 4 (n = 17) at-risk genotypes had median PFS times of 8.3, 6.0, and 4.2 months, respectively (P = .002).The results indicated that some polymorphic variations of drug metabolic and transporter genes may be potential biomarkers for clinical outcome of gemcitabine-based therapy in patients with locally advanced pancreatic cancer.

Authors

Tanaka, M; Javle, M; Dong, X; Eng, C; Abbruzzese, JL; Li, D

MLA Citation

Tanaka, M, Javle, M, Dong, X, Eng, C, Abbruzzese, JL, and Li, D. "Gemcitabine metabolic and transporter gene polymorphisms are associated with drug toxicity and efficacy in patients with locally advanced pancreatic cancer." Cancer 116.22 (November 2010): 5325-5335.

PMID

20665488

Source

epmc

Published In

Cancer

Volume

116

Issue

22

Publish Date

2010

Start Page

5325

End Page

5335

DOI

10.1002/cncr.25282

Advances in our molecular, clinical, and epidemiologic understanding of the risk and development of pancreatic cancer offer hope for preventing this disease, which is largely intractable once developed. This perspective on provocative, genetically engineered mouse model work reported by Mohammed et al. (beginning on page 1417 in this issue of the journal) examines the prospects for pancreatic cancer chemoprevention with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI). Despite having limited value in advanced pancreatic cancer, EGFR TKIs show promise in the setting of early pancreatic carcinogenesis.

Authors

Logsdon, CD; Abbruzzese, JL

MLA Citation

Logsdon, CD, and Abbruzzese, JL. "Chemoprevention of pancreatic cancer: ready for the clinic?." Cancer Prevention Research (Philadelphia, Pa.) 3.11 (November 2010): 1375-1378.

PMID

21084259

Source

epmc

Published In

Cancer Prevention Research

Volume

3

Issue

11

Publish Date

2010

Start Page

1375

End Page

1378

DOI

10.1158/1940-6207.CAPR-10-0216

Pancreatic cancer (PC) is a highly lethal disease with complex etiology involving both environmental and genetic factors. Although cigarette smoking is known to explain 25% of cases, data from recent studies suggest that obesity and long-term type II diabetes are two major modifiable risk factors for PC. Furthermore, obesity and diabetes seem to affect the clinical outcome of patients with PC. Understanding the mechanistic effects of obesity and diabetes on the pancreas may identify new strategies for prevention or therapy. Experimental and epidemiologic evidence suggests that the antidiabetic drug metformin has protective antitumor activity in PC. In addition to insulin resistance and inflammation as mechanisms of carcinogenesis, obesity and diabetes are linked to impairments in endothelial function and coagulation status, which increase the risks of thrombosis and angiogenesis and, in turn, the risk of PC development and progression. The associations of the ABO blood group gene and NR5A2 gene variants with PC discovered by recent genome-wide association studies may link insulin resistance, inflammation, and thrombosis to pancreatic carcinogenesis. These exciting findings open new avenues for understanding the etiology of PC and provide opportunities for developing novel strategies for prevention and treatment of this disease.

Authors

Li, D; Abbruzzese, JL

MLA Citation

Li, D, and Abbruzzese, JL. "New strategies in pancreatic cancer: emerging epidemiologic and therapeutic concepts." Clinical cancer research : an official journal of the American Association for Cancer Research 16.17 (September 2010): 4313-4318.

PMID

20647474

Source

epmc

Published In

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research

Volume

16

Issue

17

Publish Date

2010

Start Page

4313

End Page

4318

DOI

10.1158/1078-0432.ccr-09-1942

Because of the inflammatory nature and extensive stromal compartment in pancreatic tumors, we investigated the role of mesenchymal stromal cells (MSC) to engraft selectively in pancreatic carcinomas and serve as anti-tumor drug delivery vehicles to control pancreatic cancer progression.Human pancreatic carcinoma cells, PANC-1, expressing renilla luciferase were orthotopically implanted into SCID mice and allowed to develop for 10 days. Firefly luciferase-transduced MSC or MSC expressing interferon (IFN)-beta were then injected intraperitoneally weekly for 3 weeks. Mice were monitored by bioluminescent imaging for expression of renilla (PANC-1) and firefly (MSC) luciferase.MSC selectively homed to sites of primary and metastatic pancreatic tumors and inhibited tumor growth (P=0.032). The production of IFN-beta within the tumor site by MSC-IFN-beta further suppressed tumor growth (P=0.0000083). Prior studies indicated that MSC home to sites of inflammation; therefore, we sought to alter the tumor microenvironment through treatment with a potent anti-inflammatory agent. After treatment, inflammation-associated mediators were effectively down-regulated, including NFkappaB, vascular endothelial growth factor (VEGF) and interleukin (IL)-6 as well as chemokines involved in MSC migration (CCL3 and CCL25). Treatment with the anti-inflammatory agent CDDO-Me before and after MSC-IFN-beta injections resulted in reduction of MSC in the tumors and reversed the positive effect of tumor inhibition by MSC-IFN-beta alone (P=0.041).These results suggest that MSC exhibit innate anti-tumor effects against PANC-1 cells and can serve as delivery vehicles for IFN-beta for the treatment of pancreatic cancer. However, these beneficial effects may be lost in therapies combining MSC with anti-inflammatory agents.

Authors

Kidd, S; Caldwell, L; Dietrich, M; Samudio, I; Spaeth, EL; Watson, K; Shi, Y; Abbruzzese, J; Konopleva, M; Andreeff, M; Marini, FC

MLA Citation

Kidd, S, Caldwell, L, Dietrich, M, Samudio, I, Spaeth, EL, Watson, K, Shi, Y, Abbruzzese, J, Konopleva, M, Andreeff, M, and Marini, FC. "Mesenchymal stromal cells alone or expressing interferon-beta suppress pancreatic tumors in vivo, an effect countered by anti-inflammatory treatment." Cytotherapy 12.5 (September 2010): 615-625.

PMID

20230221

Source

epmc

Published In

Cytotherapy

Volume

12

Issue

5

Publish Date

2010

Start Page

615

End Page

625

DOI

10.3109/14653241003631815

Patients with advanced pancreas cancer present with disease that is poorly responsive to conventional therapies. Preclinical and early clinical evidence has supported targeting the epidermal growth factor receptor (EGFR) signaling pathway in patients with pancreas cancer. This trial was conducted to evaluate the contribution of an EGFR-targeted agent to standard gemcitabine therapy. Cetuximab is a monoclonal antibody against the ligand-binding domain of the receptor.Patients with unresectable locally advanced or metastatic pancreatic adenocarcinoma were randomly assigned to receive gemcitabine alone or gemcitabine plus cetuximab. The primary end point was overall survival. Secondary end points included progression-free survival, time to treatment failure, objective response, and toxicity.A total of 745 eligible patients were accrued. No significant difference was seen between the two arms of the study with respect to the median survival time (6.3 months for the gemcitabine plus cetuximab arm v 5.9 months for the gemcitabine alone arm; hazard ratio = 1.06; 95% CI, 0.91 to 1.23; P = .23, one-sided). Objective responses and progression-free survival were similar in both arms of the study. Although time to treatment failure was longer in patients on gemcitabine plus cetuximab (P = .006), the difference in length of treatment was only 2 weeks longer in the combination arm. Among patients who were studied for tumoral EGFR expression, 90% were positive, with no treatment benefit detected in this patient subset.In patients with advanced pancreas cancer, the anti-EGFR monoclonal antibody cetuximab did not improve the outcome compared with patients treated with gemcitabine alone. Alternate targets other than EGFR should be evaluated for new drug development.

Authors

Philip, PA; Benedetti, J; Corless, CL; Wong, R; O'Reilly, EM; Flynn, PJ; Rowland, KM; Atkins, JN; Mirtsching, BC; Rivkin, SE; Khorana, AA; Goldman, B; Fenoglio-Preiser, CM; Abbruzzese, JL; Blanke, CD

MLA Citation

Philip, PA, Benedetti, J, Corless, CL, Wong, R, O'Reilly, EM, Flynn, PJ, Rowland, KM, Atkins, JN, Mirtsching, BC, Rivkin, SE, Khorana, AA, Goldman, B, Fenoglio-Preiser, CM, Abbruzzese, JL, and Blanke, CD. "Phase III study comparing gemcitabine plus cetuximab versus gemcitabine in patients with advanced pancreatic adenocarcinoma: Southwest Oncology Group-directed intergroup trial S0205." Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology 28.22 (August 2010): 3605-3610.

PMID

20606093

Source

epmc

Published In

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology

Volume

28

Issue

22

Publish Date

2010

Start Page

3605

End Page

3610

DOI

10.1200/JCO.2009.25.7550

Insulin-like growth factor (IGF)-axis mediated signaling pathways play an important role in pancreatic cancer development and progression. We examined whether IGF-axis gene variants are associated with clinical outcomes in pancreatic cancer.We retrospectively genotyped 41 single-nucleotide polymorphisms from 10 IGF-axis genes in 333 patients with localized pancreatic adenocarcinoma and validated the findings in 373 patients with advanced disease. Associations between genotype and overall survival (OS) were evaluated using multivariable Cox proportional hazard regression models.IGF1 *8470T>C, IGF1R IVS2+46329T>C, IGFBP3 A32G, IRS1 G972R in patients with localized disease; IGF1R IVS20-3431A>G, IGF1R T766T, IGFBP3-202A>C, IRS1 IVS1+4315C>G, IRS1 G972R in patients with advanced disease; and IGF1R T766T, IGF2R L252V, IGFBP3 -202A>C, IRS1 IVS1+4315C>G, IRS1 G972R, IRS2 IVS1+5687T>C in all patients were significantly associated with OS (PA, and an IRS2 haplotype predicted worse OS (P

Authors

Dong, X; Javle, M; Hess, KR; Shroff, R; Abbruzzese, JL; Li, D

MLA Citation

Dong, X, Javle, M, Hess, KR, Shroff, R, Abbruzzese, JL, and Li, D. "Insulin-like growth factor axis gene polymorphisms and clinical outcomes in pancreatic cancer." Gastroenterology 139.2 (August 2010): 464-473.e3.

PMID

20416304

Source

epmc

Published In

Gastroenterology

Volume

139

Issue

2

Publish Date

2010

Start Page

464

End Page

473.e3

DOI

10.1053/j.gastro.2010.04.042

The phosphoinositide 3-kinase (PI3K)/Akt pathway is constitutively activated in pancreatic cancer and the mammalian target of rapamycin (mTOR) kinase is an important mediator for its signaling. Our recent in vitro studies suggest that prolonged exposure of pancreatic cancer cells to mTOR inhibitors can promote insulin receptor substrate-PI3K interactions and paradoxically increase Akt phosphorylation and cyclin D1 expression in pancreatic cancer cells (negative feedback loop). The addition of erlotinib to rapamycin can down-regulate rapamycin-stimulated Akt and results in synergistic antitumor activity with erlotinib in preclinical tumor models.Two studies prospectively enrolled adult patients with advanced pancreatic cancer, Eastern Cooperative Oncology Group performance status 0-1, adequate hematologic, hepatic and renal parameters and measurable disease. In Study A, temsirolimus was administered intravenously at 25 mg weekly. In Study B, everolimus was administered orally at 30 mg weekly and erlotinib was administered at 150 mg daily. The primary endpoint in both studies was overall survival at 6 months. Secondary endpoints included time to progression, progression-free survival, overall survival, response rate, safety and toxicity. Pretreatment tumor biopsies were analyzed by immunofluorescence and laser scanning cytometry for the expression of pmTOR/mTOR, pAkt/Akt, pErk/Erk, pS6, p4EBP-1 and PTEN.Five patients enrolled in Study A; Two patients died within a month (rapid disease progression and hemorrhagic stroke, respectively). One patient developed dehydration and another developed asthenia. Sixteen patients enrolled in Study B.: 12 males, all ECOG PS = 1. Median cycles = 1 (range 1-2). Grade 4 toxicity: hyponatremia (n = 1), Grade 3: diarrhea (n = 1), cholangitis (n = 3), hyperglycemia (n = 1), fatigue (n = 1). Grade 2: pneumonia (n = 2), dehydration (n = 2), nausea (n = 2), neutropenia (n = 1), mucositis (n = 2) & rash (n = 2). Four patients were hospitalized. Progressive disease occurred in 15 and 1 was non-evaluable. Pretreatment biopsies revealed a higher pAkt/Akt ratio in tumor specimens that in nonmalignant pancreatic tissue. No such trends were noted for the other biomarkers.Neither study with mTOR inhibitors demonstrated objective responses or disease stability. The negative feedback loop resulting from mTOR inhibition may account for the disease progression and toxicity noted in these studies. Future strategies should aim for a broader targeting of the PI3K pathway in pancreatic cancer.NCT 0075647.NCT00640978.

Authors

Javle, MM; Shroff, RT; Xiong, H; Varadhachary, GA; Fogelman, D; Reddy, SA; Davis, D; Zhang, Y; Wolff, RA; Abbruzzese, JL

MLA Citation

Javle, MM, Shroff, RT, Xiong, H, Varadhachary, GA, Fogelman, D, Reddy, SA, Davis, D, Zhang, Y, Wolff, RA, and Abbruzzese, JL. "Inhibition of the mammalian target of rapamycin (mTOR) in advanced pancreatic cancer: results of two phase II studies." Bmc Cancer 10 (July 14, 2010): 368-null.

PMID

20630061

Source

epmc

Published In

Bmc Cancer

Volume

10

Publish Date

2010

Start Page

368

DOI

10.1186/1471-2407-10-368

Nucleolin is a major nucleolar protein that has been shown to be overexpressed in rapidly dividing cells and plays an essential role in cell proliferation and survival. However, the expression and significance of nucleolin in pancreatic ductal adenocarcinoma (PDA) have not been studied.We used a tissue microarray consisting of 1.0-mm cores of tumor and paired nonneoplastic pancreatic tissue from 69 pancreaticoduodenectomy specimens with stage II PDA. Nucleolin expression was evaluated by immunohistochemistry and scored quantitatively by image analysis. Nucleolin expression was classified as nucleolin-high or nucleolin-low using the median nucleolin labeling index of 3.5% as cutoff. Staining results were correlated with clinicopathologic features and survival.Both PDAs and PDA cell lines showed nucleolar staining for nucleolin. Nucleolin expression was higher in PDAs and PDA cell lines than in nonneoplastic ductal epithelial cells. Among the 69 stage II PDAs, 34 (49%) were nucleolin-high. The median overall survival was 65.2 +/- 16.3 months for patients who had nucleolin-high PDAs compared with 19.5 +/- 3.3 months for patients whose tumors were nucleolin-low (P = 0.03, log-rank method). No significant correlation between nucleolin expression and other clinicopathologic parameters was found. In multivariate analysis, nucleolin expression was a prognostic factor for overall survival in patients with stage II PDA independent of patient's age, gender, tumor size, differentiation, and lymph node status.Nucleolin was overexpressed in PDAs and PDA cell lines. A high level of nucleolar expression of nucleolin was an independent prognostic marker for better survival for patients with stage II PDAs.

Authors

Peng, L; Liang, J; Wang, H; Song, X; Rashid, A; Gomez, HF; Corley, LJ; Abbruzzese, JL; Fleming, JB; Evans, DB; Wang, H

MLA Citation

Peng, L, Liang, J, Wang, H, Song, X, Rashid, A, Gomez, HF, Corley, LJ, Abbruzzese, JL, Fleming, JB, Evans, DB, and Wang, H. "High levels of nucleolar expression of nucleolin are associated with better prognosis in patients with stage II pancreatic ductal adenocarcinoma." Clinical cancer research : an official journal of the American Association for Cancer Research 16.14 (July 13, 2010): 3734-3742.

PMID

20628027

Source

epmc

Published In

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research

Volume

16

Issue

14

Publish Date

2010

Start Page

3734

End Page

3742

DOI

10.1158/1078-0432.ccr-09-3411

The role of carbohydrate antigen (CA) 19-9 in the evaluation of patients with resectable pancreatic cancer treated with neoadjuvant therapy prior to planned surgical resection is unknown. We evaluated CA 19-9 as a marker of therapeutic response, completion of therapy, and survival in patients enrolled on two recently reported clinical trials.We analyzed patients with radiographically resectable adenocarcinoma of the head/uncinate process treated on two phase II trials of neoadjuvant chemoradiation. Patients without evidence of disease progression following chemoradiation underwent pancreaticoduodenectomy (PD). CA 19-9 was evaluated in patients with a normal bilirubin level.We enrolled 174 patients, and 119 (68%) completed all therapy including PD. Pretreatment CA 19-9 <37 U/ml had a positive predictive value (PPV) for completing PD of 86% but a negative predictive value (NPV) of 33%. Among patients without evidence of disease at last follow-up, the highest pretreatment CA 19-9 was 1,125 U/ml. Restaging CA 19-9 <61 U/ml had a PPV of 93% and a NPV of 28% for completing PD among resectable patients. The area under the receiver-operating characteristics curve of pretreatment and restaging CA 19-9 levels for completing PD was 0.59 and 0.74, respectively. We identified no association between change in CA 19-9 and histopathologic response (P = 0.74).Although the PPV of CA 19-9 for completing neoadjuvant therapy and undergoing PD was high, its clinical utility was compromised by a low NPV. Decision-making for patients with resectable PC should remain based on clinical assessment and radiographic staging.

Authors

Katz, MHG; Varadhachary, GR; Fleming, JB; Wolff, RA; Lee, JE; Pisters, PWT; Vauthey, J-N; Abdalla, EK; Sun, CC; Wang, H; Crane, CH; Lee, JH; Tamm, EP; Abbruzzese, JL; Evans, DB

MLA Citation

Katz, MHG, Varadhachary, GR, Fleming, JB, Wolff, RA, Lee, JE, Pisters, PWT, Vauthey, J-N, Abdalla, EK, Sun, CC, Wang, H, Crane, CH, Lee, JH, Tamm, EP, Abbruzzese, JL, and Evans, DB. "Serum CA 19-9 as a marker of resectability and survival in patients with potentially resectable pancreatic cancer treated with neoadjuvant chemoradiation." Annals of surgical oncology 17.7 (July 2010): 1794-1801.

PMID

20162463

Source

epmc

Published In

Annals of Surgical Oncology

Volume

17

Issue

7

Publish Date

2010

Start Page

1794

End Page

1801

DOI

10.1245/s10434-010-0943-1

BACKGROUND: The benefit of adjuvant therapy for resected small bowel adenocarcinoma has not been proven. We undertook a retrospective analysis to evaluate the benefit of adjuvant therapy in a clearly defined patient population with curatively resected small bowel adenocarcinoma. MATERIAL AND METHODS: We identified 54 patients with small bowel adenocarcinoma who underwent margin-negative surgical resection and were evaluated after surgery at the University of Texas, M. D. Anderson Cancer Center between 1990 and 2008. Disease-free survival (DFS) and overall survival (OS) were estimated. RESULTS: Median age was 55 years and primary tumor site was duodenum in 67%, jejunum in 20%, and ileum in 13%. Thirty patients (56%) received adjuvant therapy consisting of systemic chemotherapy with or without radiation in 28 and radiation alone in two. Patients who received adjuvant therapy had significantly higher tumor stage and rate of lymph node involvement. Five-year DFS and OS did not differ between treatment groups. In multivariate analysis, the use of adjuvant therapy was associated with improved DFS (HR 0.27; 95% CI 0.07-0.98, P = 0.05) but not OS (HR 0.47; 95% CI 0.13-1.62, P = 0.23). In patients with a high risk of relapse (defined as a lymph node ratio >or=10%), adjuvant therapy appeared to improve OS, P = 0.04, but not DFS, P = 0.15. DISCUSSION: The use of adjuvant therapy for curatively resected small bowel adenocarcinoma was associated with an improvement in DFS. This finding strongly supports further investigation of adjuvant chemotherapy in this tumor type.

Authors

Overman, MJ; Kopetz, S; Lin, E; Abbruzzese, JL; Wolff, RA

MLA Citation

Overman, MJ, Kopetz, S, Lin, E, Abbruzzese, JL, and Wolff, RA. "Is there a role for adjuvant therapy in resected adenocarcinoma of the small intestine." Acta Oncologica (Stockholm, Sweden) 49.4 (May 2010): 474-479.

PMID

20397775

Source

epmc

Published In

Acta Oncologica (Stockholm, Sweden)

Volume

49

Issue

4

Publish Date

2010

Start Page

474

End Page

479

DOI

10.3109/02841860903490051

The primary objective of this trial was to evaluate the response rate for trimetrexate in conjunction with 5-FU and leucovorin (LV) (= TFL) in the treatment of advanced gastric cancer in a phase II, cooperative group setting.Patients with locally advanced, unresectable, or metastatic adenocarcinoma of the stomach received trimetrexate 110 mg/m IV over 60 minutes day 1, followed by 5-FU 500 mg/m IV bolus and LV 200 mg/m IV over 60 minutes day 2, followed by oral LV 15 mg every 6 hours x 7 doses, all weekly for 6 weeks followed by 2 weeks of rest, continued until progression.Characteristics for 37 eligible patients: median age 63 (range: 23-83); male/female: 69% of 31%; performance status 0/1/2 15/20/1. The confirmed response rate was 19%, and median overall survival was 6 months. Two patients died as a result of therapy, 1 because of infection without significant neutropenia, and 1 due to perforation of a responding gastric lesion. Seventy-two percent experienced grades 3 and 4 toxicity, most commonly diarrhea, fatigue, and lymphopenia.This regimen achieves response rates comparable to other 5-FU-based regimens, when used in treatment of incurable gastric cancer. Toxicity appears manageable.

Authors

Blanke, CD; Chansky, K; Christman, KL; Hundahl, SA; Issell, BF; Van Veldhuizen, PJ; Budd, GT; Abbruzzese, JL; Macdonald, JS

MLA Citation

Blanke, CD, Chansky, K, Christman, KL, Hundahl, SA, Issell, BF, Van Veldhuizen, PJ, Budd, GT, Abbruzzese, JL, and Macdonald, JS. "S9511: a Southwest Oncology Group phase II study of trimetrexate, 5-fluorouracil, and leucovorin in unresectable or metastatic adenocarcinoma of the stomach." American Journal of Clinical Oncology 33.2 (April 2010): 117-120.

PMID

19770625

Source

epmc

Published In

American Journal of Clinical Oncology

Volume

33

Issue

2

Publish Date

2010

Start Page

117

End Page

120

DOI

10.1097/COC.0b013e318199fb84

Despite the observed association between diabetes mellitus and hepatocellular carcinoma (HCC), little is known about the effect of diabetes duration before HCC diagnosis and whether some diabetes medications reduced the risk of HCC development. This objective of the current study was to determine the association between HCC risk and diabetes duration and type of diabetes treatment.A total of 420 patients with HCC and 1104 healthy controls were enrolled in an ongoing hospital-based case-control study. Multivariate logistic regression models were used to adjust for HCC risk factors.The prevalence of diabetes mellitus was 33.3% in patients with HCC and 10.4% in the control group, yielding an adjusted odds ratio (AOR) of 4.2 (95% confidence interval [95% CI], 3.0-5.9). In 87% of cases, diabetes was present before the diagnosis of HCC, yielding an AOR of 4.4 (95% CI, 3.0-6.3). Compared with patients with a diabetes duration of 2 to 5 years, the estimated AORs for those with a diabetes duration of 6 to 10 years and those with a diabetes duration >10 years were 1.8 (95% CI, 0.8-4.1) and 2.2 (95% CI, 1.2-4.8), respectively. With respect to diabetes treatment, the AORs were 0.3 (95% CI, 0.2-0.6), 0.3 (95% CI, 0.1-0.7), 7.1 (95% CI, 2.9-16.9), 1.9 (95% CI, 0.8-4.6), and 7.8 (95% CI, 1.5-40.0) for those treated with biguanides, thiazolidinediones, sulfonylureas, insulin, and dietary control, respectively.Diabetes appears to increase the risk of HCC, and such risk is correlated with a long duration of diabetes. Relying on dietary control and treatment with sulfonylureas or insulin were found to confer the highest magnitude of HCC risk, whereas treatment with biguanides or thiazolidinediones was associated with a 70% HCC risk reduction among diabetics.

Authors

Hassan, MM; Curley, SA; Li, D; Kaseb, A; Davila, M; Abdalla, EK; Javle, M; Moghazy, DM; Lozano, RD; Abbruzzese, JL; Vauthey, J-N

MLA Citation

Hassan, MM, Curley, SA, Li, D, Kaseb, A, Davila, M, Abdalla, EK, Javle, M, Moghazy, DM, Lozano, RD, Abbruzzese, JL, and Vauthey, J-N. "Association of diabetes duration and diabetes treatment with the risk of hepatocellular carcinoma." Cancer 116.8 (April 2010): 1938-1946.

PMID

20166205

Source

epmc

Published In

Cancer

Volume

116

Issue

8

Publish Date

2010

Start Page

1938

End Page

1946

DOI

10.1002/cncr.24982

Authors

Abbruzzese, JL; Eggermont, AMM; Rubin, EH

MLA Citation

Abbruzzese, JL, Eggermont, AMM, and Rubin, EH. "Introducing new strategies in.." Clinical cancer research : an official journal of the American Association for Cancer Research 16.5 (March 2010): 1347-.

PMID

20179221

Source

epmc

Published In

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research

Volume

16

Issue

5

Publish Date

2010

Start Page

1347

DOI

10.1158/1078-0432.ccr-10-0236

BACKGROUND: Docetaxel, cisplatin, and 5-flurouracil (DCF) administered every 3 weeks produces a high rate of treatment-related adverse events. The objective of the current study was to evaluate the efficacy and tolerability of a weekly formulation of DCF. METHODS: Data from 117 patients treated at The University of Texas M. D. Anderson Cancer Center from 2002 to 2006 with a weekly formulation of DCF were retrospectively collected. A total of 95 patients received front-line therapy with 20 mg/m(2) of cisplatin, 350 mg/m(2) of 5-fluorouracil, and 20 mg/m(2) of docetaxel administered once weekly for 6 consecutive weeks followed by a 2-week break. RESULTS: Ninety-five patients (median age, 62 years [range, 33 to 87 years], with an Eastern Cooperative Oncology Group performance status of 1 or 2 in 67%) received a median of 10 weeks of DCF treatment (range, 3-41 weeks). Grade 3 or 4 hematologic toxicity (assessed according to National Cancer Institute Common Toxicity Criteria [version 3.0]) included granulocytopenia (4 patients) and anemia (9 patients). None of the patients developed a febrile neutropenic infection, but grade 3 or 4 non-neutropenic infections occurred in 8 patients. Eighty patients had measurable disease with an objective response rate determined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria of 34% (95% confidence interval [95% CI], 24-45%). The median follow-up was 9 months, with a median time to disease progression of 4.1 months (95% CI, 3.6-5.7 months) and a median overall survival of 8.9 months (95% CI, 7.7-10.8 months). CONCLUSIONS: In patients with advanced gastric and esophageal cancer who were not candidates for every-3-week DCF, a weekly formulation of DCF demonstrated modest activity with minimal hematologic toxicity, suggesting that weekly DCF is a reasonable treatment option for such patients.

Authors

Overman, MJ; Kazmi, SM; Jhamb, J; Lin, E; Yao, JC; Abbruzzese, JL; Ho, L; Ajani, J; Phan, A

MLA Citation

Overman, MJ, Kazmi, SM, Jhamb, J, Lin, E, Yao, JC, Abbruzzese, JL, Ho, L, Ajani, J, and Phan, A. "Weekly docetaxel, cisplatin, and 5-fluorouracil as initial therapy for patients with advanced gastric and esophageal cancer." Cancer 116.6 (March 2010): 1446-1453.

PMID

20108336

Source

epmc

Published In

Cancer

Volume

116

Issue

6

Publish Date

2010

Start Page

1446

End Page

1453

DOI

10.1002/cncr.24925

Authors

Pino, MS; Shrader, M; Baker, CH; Cognetti, F; Xiong, HQ; Abbruzzese, JL; McConkey, DJ

MLA Citation

Pino, MS, Shrader, M, Baker, CH, Cognetti, F, Xiong, HQ, Abbruzzese, JL, and McConkey, DJ. "Correction: Transforming growth factor α expression drives constitutive epidermal growth factor receptor pathway activation and sensitivity to gefitinib (Iressa) in human pancreatic cancer cell lines (Cancer Research (2006) 66, 7, (3802-3812))." Cancer Research 70.2 (January 15, 2010): 852-853.

Source

scopus

Published In

Cancer Research

Volume

70

Issue

2

Publish Date

2010

Start Page

852

End Page

853

DOI

10.1158/0008-5472.CAN-09-4221

To show whether single nucleotide polymorphisms (SNP) of drug metabolic genes were associated with toxicity of 2',2'-difluoro 2'-deoxycytidine (gemcitabine)-based chemoradiotherapy and overall survival (OS) of patients with pancreatic cancer.We evaluated 17 SNPs of the CDA, dCK, DCTD, RRM1, hCNT1, hCNT2, hCNT3, and hENT1 genes in 154 patients with potentially resectable pancreatic adenocarcinoma who were enrolled in clinical trials at The University of Texas M.D. Anderson Cancer Center (Houston, TX) from February 1999 to January 2006, with follow-up until April 2009. Patients received neoadjuvant concurrent gemcitabine and radiation therapy with or without gemcitabine-cisplatin induction therapy. The association of genotypes with toxicity or OS was tested, respectively, by logistic regression and Cox regression analysis.None of the 17 SNPs, individually, had a significant association with OS. A combined genotype effect of CDA A-76C, dCK C-1205T, DCTD T-47C, hCNT3 C-69T, hENT1 T-549C, and hENT1 C913T on OS was observed. Patients carrying 0 to 1 (n = 43), 2 to 3 (n = 77), or 4 to 6 (n = 30) variant alleles had median survival time of 31.5, 21.4, and 17.5 months, respectively. The hazard ratio of dying was 1.71 (95% confidence interval, 1.06-2.76) and 3.16 (95% confidence interval, 1.77-5.63) for patients carrying two to three or four to six at-risk genotypes (P = 0.028 and P < 0.001), respectively, after adjusting for clinical predictors. CDA C111T, dCK C-1205T, dCK A9846G, and hCNT3 A25G, individually and jointly, had a significant association with neutropenia toxicity.These observations suggest that polymorphic variations of drug metabolic genes were associated with toxicity of gemcitabine-based therapy and OS of patients with resectable pancreatic cancer.

Authors

Okazaki, T; Javle, M; Tanaka, M; Abbruzzese, JL; Li, D

MLA Citation

Okazaki, T, Javle, M, Tanaka, M, Abbruzzese, JL, and Li, D. "Single nucleotide polymorphisms of gemcitabine metabolic genes and pancreatic cancer survival and drug toxicity." Clinical cancer research : an official journal of the American Association for Cancer Research 16.1 (January 2010): 320-329.

PMID

20028759

Source

epmc

Published In

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research

Volume

16

Issue

1

Publish Date

2010

Start Page

320

End Page

329

DOI

10.1158/1078-0432.ccr-09-1555

Despite having a dramatically larger surface area than the large intestine, the small intestine is an infrequent site for the development of adenocarcinoma. To better understand the molecular abnormalities in small bowel adenocarcinoma (SBA), we characterised a number of candidate oncogenic pathways and the immunophenotype of this rare cancer.Tissue microarrays were constructed from tumour samples from 54 patients with all stages of the disease. Immunohistochemistry and microsatellite instability (MSI) testing were conducted.The profile of cytokeratin 20 and 7 coexpression was variable, but expression of caudal type homeobox transcription factor 2 (CDX2) was present in 70% of cases. In this young population (median age 54 years), loss of mismatch repair (MMR) proteins occurred in 35% of patients, with confirmed MSI in 100% of tested cases. Expression of vascular endothelial growth factor-A (VEGF-A) and epidermal growth factor receptor (EGFR) was common, occurring in 96 and 71% of patients, respectively. Only one case showed HER2 expression and none showed loss of phosphatase and tensin homologue mutated on chromosome 10 (PTEN).These results suggest that alterations in DNA MMR pathways are common in SBAs, similar to what is observed in large bowel adenocarcinomas. Furthermore, the high percentage of tumours expressing both EGFR and VEGF suggests that patients with this rare cancer may benefit from therapeutic strategies targeting EGFR and VEGF receptor (VEGFR).

Authors

Overman, MJ; Pozadzides, J; Kopetz, S; Wen, S; Abbruzzese, JL; Wolff, RA; Wang, H

MLA Citation

Overman, MJ, Pozadzides, J, Kopetz, S, Wen, S, Abbruzzese, JL, Wolff, RA, and Wang, H. "Immunophenotype and molecular characterisation of adenocarcinoma of the small intestine." British Journal of Cancer 102.1 (January 2010): 144-150.

PMID

19935793

Source

epmc

Published In

British Journal of Cancer

Volume

102

Issue

1

Publish Date

2010

Start Page

144

End Page

150

DOI

10.1038/sj.bjc.6605449

We investigated the efficacy of fluorouracil (FU), leucovorin, irinotecan, and bevacizumab (FOLFIRI + B) in a phase II trial in patients previously untreated for metastatic colorectal cancer (mCRC), and changes during treatment in plasma cytokines and angiogenic factors (CAFs) as potential markers of treatment response and therapeutic resistance.We conducted a phase II, two-institution trial of FOLFIRI + B. Each 14-day cycle consisted of bevacizumab (5 mg/kg), irinotecan (180 mg/m(2)), bolus FU (400 mg/m(2)), and leucovorin (400 mg/m(2)) followed by a 46-hour infusion of FU (2,400 mg/m(2)). Levels of 37 CAFs were assessed using multiplex-bead assays and enzyme-linked immunosorbent assay at baseline, during treatment, and at the time of progressive disease (PD).Forty-three patients were enrolled. Median progression-free survival (PFS), the primary end point of the study, was 12.8 months. Median overall survival was 31.3 months, with a response rate of 65%. Elevated interleukin-8 at baseline was associated with a shorter PFS (11 v 15.1 months, P = .03). Before the radiographic development of PD, several CAFs associated with angiogenesis and myeloid recruitment increased compared to baseline, including basic fibroblast growth factor (P = .046), hepatocyte growth factor (P = .046), placental growth factor (P < .001), stromal-derived factor-1 (P = .04), and macrophage chemoattractant protein-3 (P < .001).Efficacy and tolerability of FOLFIRI + B appeared favorable to historical controls in this single arm study. Before radiographic progression, there was a shift in balance of CAFs, with a rise in alternate pro-angiogenic cytokines and myeloid recruitment factors in subsets of patients that may represent mechanisms of resistance.

Authors

Kopetz, S; Hoff, PM; Morris, JS; Wolff, RA; Eng, C; Glover, KY; Adinin, R; Overman, MJ; Valero, V; Wen, S; Lieu, C; Yan, S; Tran, HT; Ellis, LM; Abbruzzese, JL; Heymach, JV

MLA Citation

Kopetz, S, Hoff, PM, Morris, JS, Wolff, RA, Eng, C, Glover, KY, Adinin, R, Overman, MJ, Valero, V, Wen, S, Lieu, C, Yan, S, Tran, HT, Ellis, LM, Abbruzzese, JL, and Heymach, JV. "Phase II trial of infusional fluorouracil, irinotecan, and bevacizumab for metastatic colorectal cancer: efficacy and circulating angiogenic biomarkers associated with therapeutic resistance." Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology 28.3 (January 2010): 453-459.

PMID

20008624

Source

epmc

Published In

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology

Volume

28

Issue

3

Publish Date

2010

Start Page

453

End Page

459

DOI

10.1200/JCO.2009.24.8252

The identification of high-risk subsets of colon cancers has undergone extensive study over the years, and multidimensional gene signatures have shown promise for colon cancer. However, several hurdles need to be overcome in order to show the benefit of this approach and successfully apply them to the clinic. © 2009 American Association for Cancer Research.

Authors

Kopetz, S; Abbruzzese, JL

MLA Citation

Kopetz, S, and Abbruzzese, JL. "Barriers to integrating gene profiling for stage II colon cancer." Clinical Cancer Research 15.24 (December 15, 2009): 7451-7452.

Source

scopus

Published In

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research

Volume

15

Issue

24

Publish Date

2009

Start Page

7451

End Page

7452

DOI

10.1158/1078-0432.CCR-09-2523

We previously demonstrated that select cytokine gene polymorphisms in interleukin (IL)-8 are a significant predictor of pain and analgesia in patients with lung cancer. This study explores the role of 13 potentially functional polymorphisms in cytokine genes, including IL-1beta, IL-6, IL-8, IL-10, IL-18, tumor necrosis factor-alpha, and nuclear factor kappa-B subunit 1, in pain severity in patients with pancreatic cancer. We evaluated a series of patients with histologically confirmed adenocarcinoma of the pancreas (n=484), who had completed a self-administered survey of pain before initiating any cancer treatment. DNA (n=156) available for a subset of white patients was assayed and assessed for association with pain severity. Results showed that 26% (128 of 484) reported experiencing severe pain (score of >7 on a 0-10 scale). Severe pain varied by the stage of disease (odds ratio [OR] Stage II=4.02, 95% confidence interval (CI)=1.07, 15.07; Stage III=5.02, 95% CI=1.28, 19.61; Stage IV=6.90, 95% CI=1.96, 24.29), ethnicity (OR non-Hispanic blacks=3.67; 95% CI=1.44, 9.38), reports of depressed mood (OR=1.94; 95% CI=1.09, 3.43), and female sex (OR=1.78; 95% CI=1.04, 3.05). Controlling for these covariates, IL8-251T/A (OR=2.43, 95% CI=1.3, 4.7, P<0.009) significantly predicted severe pain in a subset of white patients. When we adjusted for reported analgesic use, we found that IL8-251T/A persisted as a predictor for severe pain, with carriers of TT and AT genotypes having more than a threefold risk (OR=3.23, 95% CI=1.4, 4.7) for severe pain relative to the AA genotypes. We provide preliminary evidence of the role of IL-8 in the severity of pain in pancreatic cancer patients. Additional studies are needed in larger cohorts of patients.

Authors

Reyes-Gibby, CC; Shete, S; Yennurajalingam, S; Frazier, M; Bruera, E; Kurzrock, R; Crane, CH; Abbruzzese, J; Evans, D; Spitz, MR

MLA Citation

Reyes-Gibby, CC, Shete, S, Yennurajalingam, S, Frazier, M, Bruera, E, Kurzrock, R, Crane, CH, Abbruzzese, J, Evans, D, and Spitz, MR. "Genetic and nongenetic covariates of pain severity in patients with adenocarcinoma of the pancreas: assessing the influence of cytokine genes." Journal of pain and symptom management 38.6 (December 2009): 894-902.

PMID

19692203

Source

epmc

Published In

Journal of Pain and Symptom Management

Volume

38

Issue

6

Publish Date

2009

Start Page

894

End Page

902

DOI

10.1016/j.jpainsymman.2009.04.019

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer mortality, despite significant improvements in diagnostic imaging and operative mortality rates. The 5-year survival rate remains less than 5% because of microscopic or gross metastatic disease at time of diagnosis. The Clinical Trials Planning Meeting in pancreatic cancer was convened by the National Cancer Institute's Gastrointestinal Cancer Steering Committee to discuss the integration of basic and clinical knowledge in the design of clinical trials in PDAC. Major emphasis was placed on the enhancement of research to identify and validate the relevant targets and molecular pathways in PDAC, cancer stem cells, and the microenvironment. Emphasis was also placed on developing rational combinations of targeted agents and the development of predictive biomarkers to assist selection of patient subsets. The development of preclinical tumor models that are better predictive of human PDAC must be supported with wider availability to the research community. Phase III clinical trials should be implemented only if there is a meaningful clinical signal of efficacy and safety in the phase II setting. The emphasis must therefore be on performing well-designed phase II studies with uniform sets of basic entry and evaluation criteria with survival as a primary endpoint. Patients with either metastatic or locally advanced PDAC must be studied separately.

Authors

Philip, PA; Mooney, M; Jaffe, D; Eckhardt, G; Moore, M; Meropol, N; Emens, L; O'Reilly, E; Korc, M; Ellis, L; Benedetti, J; Rothenberg, M; Willett, C; Tempero, M; Lowy, A; Abbruzzese, J; Simeone, D; Hingorani, S; Berlin, J; Tepper, J

MLA Citation

Philip, PA, Mooney, M, Jaffe, D, Eckhardt, G, Moore, M, Meropol, N, Emens, L, O'Reilly, E, Korc, M, Ellis, L, Benedetti, J, Rothenberg, M, Willett, C, Tempero, M, Lowy, A, Abbruzzese, J, Simeone, D, Hingorani, S, Berlin, J, and Tepper, J. "Consensus report of the national cancer institute clinical trials planning meeting on pancreas cancer treatment." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 27.33 (November 2009): 5660-5669. (Review)

PMID

19858397

Source

epmc

Published In

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology

Volume

27

Issue

33

Publish Date

2009

Start Page

5660

End Page

5669

DOI

10.1200/jco.2009.21.9022

Development of novel agents and drug combinations are urgently needed for treatment of pancreatic cancer. Oxaliplatin belongs to an important class of DNA-damaging organoplatinum agents, useful in pancreatic cancer therapy. However, increased ability of cancer cells to recognize and repair DNA damage enables resistance to these agents. Poly (ADP ribose) polymerase-1 is a sensor of DNA damage with key roles in DNA repair. Here, we report the therapeutic activity of the poly (ADP ribose) polymerase-1 inhibitor BSI-401, as a single agent and in combination with oxaliplatin in orthotopic nude mouse models of pancreatic cancer, and its effect on oxaliplatin-induced acute neurotoxicity.We determined in vitro the effect of BSI-401 and its synergism with oxaliplatin on the growth of pancreatic cancer cells. Activity of different dosages of parenteral and oral BSI-401, alone and in combination with oxaliplatin, was evaluated in orthotopic nude mouse models with luciferase-expressing pancreatic cancer cells. The effect of BSI-401 in preventing oxaliplatin-induced acute cold allodynia was measured in rats using a temperature-controlled plate.BSI-401 alone and in synergism with oxaliplatin significantly inhibited the growth of pancreatic cancer cells in vitro. In nude mice, i.p. [200 mg/kg once a week (QW) x 4] and oral [400 mg/kg days 1-5 of each week (QD5 + R2) x 4] administration of BSI-401 significantly reduced tumor burden and prolonged survival (46 versus 144 days, P = 0.0018; 73 versus 194 days, P = 0.0017) compared with no treatment. BSI-401 combined with oxaliplatin had potent synergistic antitumor activity (46 versus 132 days, P = 0.0063), and significantly (P = 0.0148) prevented acute oxaliplatin-induced neurotoxicity.BSI-401, alone or in combination with oxaliplatin, is a promising new therapeutic agent that warrants further evaluation for treatment of pancreatic cancer.

Authors

Melisi, D; Ossovskaya, V; Zhu, C; Rosa, R; Ling, J; Dougherty, PM; Sherman, BM; Abbruzzese, JL; Chiao, PJ

MLA Citation

Melisi, D, Ossovskaya, V, Zhu, C, Rosa, R, Ling, J, Dougherty, PM, Sherman, BM, Abbruzzese, JL, and Chiao, PJ. "Oral poly(ADP-ribose) polymerase-1 inhibitor BSI-401 has antitumor activity and synergizes with oxaliplatin against pancreatic cancer, preventing acute neurotoxicity." Clinical Cancer Research : an Official Journal of the American Association for Cancer Research 15.20 (October 6, 2009): 6367-6377.

PMID

19808866

Source

epmc

Published In

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research

Volume

15

Issue

20

Publish Date

2009

Start Page

6367

End Page

6377

DOI

10.1158/1078-0432.CCR-09-0910

Patients with metastatic colorectal cancer who progress on standard chemotherapy have limited treatment options. New and effective drugs are needed for these patients. Romidepsin is a histone deacetylase inhibitor that can alter chromatin structure and gene transcription leading to multiple changes in cellular protein production. This may result in cell cycle arrest and tumor growth inhibition. Romidepsin has shown anti-proliferative activity in vitro against multiple mouse and human tumor cell lines and in vivo in human tumor xenograft models.Patients were required to have pathologically verified, measurable, metastatic or locally advanced colorectal cancer that was surgically unresectable. They must have failed either one or two prior chemotherapy regimens, had performance status of 0-1, adequate bone marrow, renal and hepatic function, and no significant cardiac disease. Patients were treated with romidepsin at a dose of 13 mg/m(2) as a 4-h iv infusion on days 1, 8, and 15 of a 28-day cycle. The study had a two stage design. The primary objective of the study was to determine the confirmed response probability in this group of patients treated with romidepsin.Twenty-eight patients were registered to the study, two of whom were ineligible. One eligible patient refused all treatment and was not analyzed. For the 25 remaining patients, performance status was 0 in 16 patients and 1 in nine patients. Ten patients had received one prior chemotherapy regimen and fifteen 2 prior regimens. Out of the 25 eligible and analyzable patients accrued in the first stage of the protocol, no objective responses were observed and the study was permanently closed. Four patients had stable disease as the best response. Twenty-five patients were assessed for toxicity. No grade 4 or greater toxicities were seen. Fourteen of the 25 patients experienced grade 3 toxicities the most common of which were fatigue or anorexia.Romidepsin at this dose and schedule is ineffective in the treatment of patients with metastatic colorectal cancer after prior chemotherapy. Future trials might evaluate combinations of romidepsin with chemotherapeutic or other agents.

Authors

Whitehead, RP; Rankin, C; Hoff, PMG; Gold, PJ; Billingsley, KG; Chapman, RA; Wong, L; Ward, JH; Abbruzzese, JL; Blanke, CD

MLA Citation

Whitehead, RP, Rankin, C, Hoff, PMG, Gold, PJ, Billingsley, KG, Chapman, RA, Wong, L, Ward, JH, Abbruzzese, JL, and Blanke, CD. "Phase II trial of romidepsin (NSC-630176) in previously treated colorectal cancer patients with advanced disease: a Southwest Oncology Group study (S0336)." Investigational new drugs 27.5 (October 2009): 469-475.

PMID

18941712

Source

epmc

Published In

Investigational New Drugs

Volume

27

Issue

5

Publish Date

2009

Start Page

469

End Page

475

DOI

10.1007/s10637-008-9190-8

Authors

Hassan, MM; Abbruzzese, JL

MLA Citation

Hassan, MM, and Abbruzzese, JL. "Reply:." Hepatology 50.3 (September 2009): 994-994.

Source

crossref

Published In

Hepatology (Baltimore, Md.)

Volume

50

Issue

3

Publish Date

2009

Start Page

994

End Page

994

DOI

10.1002/hep.23172

Authors

Hassan, MM; Abbruzzese, JL

MLA Citation

Hassan, MM, and Abbruzzese, JL. "Reply:." Hepatology 50.3 (September 2009): 994-994.

Source

crossref

Published In

Hepatology (Baltimore, Md.)

Volume

50

Issue

3

Publish Date

2009

Start Page

994

End Page

994

DOI

10.1002/hep.23172

Antidiabetic drugs have been found to have various effects on cancer in experimental systems and in epidemiologic studies, although the association between these therapeutics and the risk of human pancreatic cancer has not been explored. We investigated the effect of antidiabetic therapies on the risk of pancreatic cancer.A hospital-based case-control study was conducted at M. D. Anderson Cancer Center from 2004 to 2008 involving 973 patients with pancreatic adenocarcinoma (including 259 diabetic patients) and 863 controls (including 109 diabetic patients). Information on diabetes history and other risk factors was collected by personal interview. The frequencies of use of insulin, insulin secretagogues, metformin, and other antidiabetic medications among diabetic patients were compared between cases and controls. The risk of pancreatic cancer was estimated using unconditional logistic regression analysis.Diabetic patients who had taken metformin had a significantly lower risk of pancreatic cancer compared with those who had not taken metformin (odds ratio, 0.38; 95% confidence interval, 0.22-0.69; P = .001), with adjustments for potential confounders. This difference remained statistically significant when the analysis was restricted to patients with a duration of diabetes >2 years or those who never used insulin. In contrast, diabetic patients who had taken insulin or insulin secretagogues had a significantly higher risk of pancreatic cancer compared with diabetic patients who had not taken these drugs.Metformin use was associated with reduced risk, and insulin or insulin secretagogue use was associated with increased risk of pancreatic cancer in diabetic patients.

Authors

Li, D; Yeung, S-CJ; Hassan, MM; Konopleva, M; Abbruzzese, JL

MLA Citation

Li, D, Yeung, S-CJ, Hassan, MM, Konopleva, M, and Abbruzzese, JL. "Antidiabetic therapies affect risk of pancreatic cancer." Gastroenterology 137.2 (August 2009): 482-488.

PMID

19375425

Source

epmc

Published In

Gastroenterology

Volume

137

Issue

2

Publish Date

2009

Start Page

482

End Page

488

DOI

10.1053/j.gastro.2009.04.013

A better understanding of drug resistance mechanisms is required to improve outcomes in patients with pancreatic cancer. Here, we characterized patterns of sensitivity and resistance to three conventional chemotherapeutic agents with divergent mechanisms of action [gemcitabine, 5-fluorouracil (5-FU), and cisplatin] in pancreatic cancer cells. Four (L3.6pl, BxPC-3, CFPAC-1, and SU86.86) were sensitive and five (PANC-1, Hs766T, AsPC-1, MIAPaCa-2, and MPanc96) were resistant to all three agents based on GI(50) (50% growth inhibition). Gene expression profiling and unsupervised hierarchical clustering revealed that the sensitive and resistant cells formed two distinct groups and differed in expression of specific genes, including several features of "epithelial to mesenchymal transition" (EMT). Interestingly, an inverse correlation between E-cadherin and its transcriptional suppressor, Zeb-1, was observed in the gene expression data and was confirmed by real-time PCR. Independent validation experiment using five new pancreatic cancer cell lines confirmed that an inverse correlation between E-cadherin and Zeb-1 correlated closely with resistance to gemcitabine, 5-FU, and cisplatin. Silencing Zeb-1 in the mesenchymal lines not only increased the expression of E-cadherin but also other epithelial markers, such as EVA1 and MAL2, and restored drug sensitivity. Importantly, immunohistochemical analysis of E-cadherin and Zeb-1 in primary tumors confirmed that expression of the two proteins was mutually exclusive (P = 0.012). Therefore, our results suggest that Zeb-1 and other regulators of EMT may maintain drug resistance in human pancreatic cancer cells, and therapeutic strategies to inhibit Zeb-1 and reverse EMT should be evaluated.

Authors

Arumugam, T; Ramachandran, V; Fournier, KF; Wang, H; Marquis, L; Abbruzzese, JL; Gallick, GE; Logsdon, CD; McConkey, DJ; Choi, W

MLA Citation

Arumugam, T, Ramachandran, V, Fournier, KF, Wang, H, Marquis, L, Abbruzzese, JL, Gallick, GE, Logsdon, CD, McConkey, DJ, and Choi, W. "Epithelial to mesenchymal transition contributes to drug resistance in pancreatic cancer." Cancer Research 69.14 (July 7, 2009): 5820-5828.

PMID

19584296

Source

epmc

Published In

Cancer Research

Volume

69

Issue

14

Publish Date

2009

Start Page

5820

End Page

5828

DOI

10.1158/0008-5472.CAN-08-2819

PURPOSE: Adenocarcinomas of the small bowel and ampulla of Vater represent rare cancers that have limited data regarding first-line therapy. We conducted a phase II trial to evaluate the benefit of capecitabine in combination with oxaliplatin (CAPOX) in patients with advanced adenocarcinoma of small bowel or ampullary origin. PATIENTS AND METHODS: Eligible patients with metastatic or unresectable tumors and no prior systemic chemotherapy for advanced disease participated in this phase II trial. CAPOX was administered as a 21-day cycle with oxaliplatin 130 mg/m(2) on day 1 and capecitabine 750 mg/m(2) twice a day on days 1 through 14. The primary end point was overall response rate as assessed by Response Evaluation Criteria in Solid Tumors. RESULTS: Thirty-one patients were enrolled onto the study, and 30 patients received study treatment. The confirmed overall response rate was 50%; three patients with metastatic disease achieved complete responses. The median time to progression (TTP) was 11.3 months, and the median overall survival (OS) was 20.4 months. Subset analysis of patients with metastatic disease only (n = 25) revealed a median TTP of 9.4 months and median OS of 15.5 months. The most common grades 3 or 4 toxicities included fatigue (30%), peripheral neuropathy (10%), vomiting (10%), diarrhea (10%), and neutropenia (10%). CONCLUSION: When administered to patients with good performance status, CAPOX is well tolerated and produces a superior response rate and longer OS compared with other regimens in the literature. CAPOX should be considered a new standard regimen for advanced small bowel and ampullary adenocarcinomas.

Authors

Overman, MJ; Varadhachary, GR; Kopetz, S; Adinin, R; Lin, E; Morris, JS; Eng, C; Abbruzzese, JL; Wolff, RA

MLA Citation

Overman, MJ, Varadhachary, GR, Kopetz, S, Adinin, R, Lin, E, Morris, JS, Eng, C, Abbruzzese, JL, and Wolff, RA. "Phase II study of capecitabine and oxaliplatin for advanced adenocarcinoma of the small bowel and ampulla of Vater." Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology 27.16 (June 2009): 2598-2603.

PMID

19164203

Source

epmc

Published In

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology

Volume

27

Issue

16

Publish Date

2009

Start Page

2598

End Page

2603

DOI

10.1200/jco.2008.19.7145

Obesity has been implicated as a risk factor for pancreatic cancer.To demonstrate the association of excess body weight across an age cohort and the risk, age of onset, and overall survival of patients with pancreatic cancer.A case-control study of 841 patients with pancreatic adenocarcinoma and 754 healthy individuals frequency matched by age, race, and sex. The study was conducted at a university cancer center in the United States from 2004 to 2008. Height and body weight histories were collected by personal interview starting at ages 14 to 19 years and over 10-year intervals progressing to the year prior to recruitment in the study.The associations between patients' body mass index (BMI) and risk of pancreatic cancer, age at onset, and overall survival were examined by unconditional logistic regression, linear regression, and Cox proportional hazard regression models, respectively.Individuals who were overweight (a BMI of 25-29.9) from the ages of 14 to 39 years (highest odds ratio [OR], 1.67; 95% confidence interval [CI], 1.20-2.34) or obese (a BMI > or = 30) from the ages of 20 to 49 years (highest OR, 2.58; 95% CI, 1.70-3.90) had an associated increased risk of pancreatic cancer, independent of diabetes status. The association was stronger in men (adjusted OR, 1.80; 95% CI, 1.45-2.23) by mean BMI from the ages of 14 to 59 years than in women (adjusted OR, 1.32; 95% CI, 1.02-1.70) and in ever smokers (adjusted OR, 1.75; 95% CI, 1.37-2.22) than in never smokers (adjusted OR, 1.46; 95% CI, 1.16-1.84). The population-attributable risk percentage of pancreatic cancer based on the mean BMI from the ages of 14 to 59 years was 10.3% for never smokers and 21.3% for ever smokers. Individuals who were overweight or obese from the ages of 20 to 49 years had an earlier onset of pancreatic cancer by 2 to 6 years (median age of onset was 64 years for patients with normal weight, 61 years for overweight patients [P = .02], and 59 years for obese patients [P < .001]). Compared with those with normal body weight and after adjusting for all clinical factors, individuals who were overweight or obese from the ages of 30 to 79 years or in the year prior to recruitment had reduced overall survival of pancreatic cancer regardless of disease stage and tumor resection status (overweight patients: hazard ratio, 1.26 [95% CI, 0.94-1.69], P = .04; obese patients: hazard ratio, 1.86 [95% CI, 1.35-2.56], P < .001).Overweight or obesity during early adulthood was associated with a greater risk of pancreatic cancer and a younger age of disease onset. Obesity at an older age was associated with a lower overall survival in patients with pancreatic cancer.

Authors

Li, D; Morris, JS; Liu, J; Hassan, MM; Day, RS; Bondy, ML; Abbruzzese, JL

MLA Citation

Li, D, Morris, JS, Liu, J, Hassan, MM, Day, RS, Bondy, ML, and Abbruzzese, JL. "Body mass index and risk, age of onset, and survival in patients with pancreatic cancer." Jama 301.24 (June 2009): 2553-2562.

PMID

19549972

Source

epmc

Published In

Jama

Volume

301

Issue

24

Publish Date

2009

Start Page

2553

End Page

2562

DOI

10.1001/jama.2009.886

Activator protein-1 (AP-1) regulates the expression of several genes involved in human tumorigenesis. However, there is little known about this transcription factor in pancreatic ductal adenocarcinoma. We recently found high levels of AP-1-binding activities and multiple AP-1/DNA complexes containing c-Jun, JunD, Fra1, and Fra2 in pancreatic cancer cells. Transient transfection assays indicated that AP-1 was functional and capable of transactivating its gene targets. Furthermore, a c-Jun transactivation mutant inhibited anchorage-dependent and anchorage-independent proliferation, suggesting that AP-1 had an essential role in pancreatic cancer cells. Our study also uncovered a novel mechanism by which protein kinase Akt controls c-Jun activity in pancreatic cancer cells. Indeed, distinct from its known ability to induce c-fos and fra1 and to stabilize c-Jun, Akt appeared to directly regulate the transcriptional activity of c-Jun independently of the phosphorylation sites targeted by c-Jun NH(2)-terminal kinase (Ser(63)/Ser(73)) and glycogen synthase kinase-3 (Thr(239)). Our data also suggest that growth factors might use this Akt-regulated mechanism to potently induce c-Jun targets such as cyclin D1. Collectively, our findings indicate that AP-1 has an important function in pancreatic cancer cells and provide evidence for a previously unknown Akt-mediated mechanism of c-Jun activation.

Authors

Shin, S; Asano, T; Yao, Y; Zhang, R; Claret, F-X; Korc, M; Sabapathy, K; Menter, DG; Abbruzzese, JL; Reddy, SAG

MLA Citation

Shin, S, Asano, T, Yao, Y, Zhang, R, Claret, F-X, Korc, M, Sabapathy, K, Menter, DG, Abbruzzese, JL, and Reddy, SAG. "Activator protein-1 has an essential role in pancreatic cancer cells and is regulated by a novel Akt-mediated mechanism." Molecular cancer research : MCR 7.5 (May 12, 2009): 745-754.

PMID

19435822

Source

epmc

Published In

Molecular Cancer Research : Mcr

Volume

7

Issue

5

Publish Date

2009

Start Page

745

End Page

754

DOI

10.1158/1541-7786.mcr-08-0462

OBJECTIVES: To compare blood flow measurements of tumors assessed by perfusion computed tomography (pCT) and the clinical gold standard of 15O-labeled water positron emission tomography (15O-PET). METHODS: Blood flows were estimated by pCT (4-row multidetector, CT Perfusion 3.1) and 15O-PET (Posicam, first-pass model) in 14 patients with solid tumors, totaling 22 index tumors and 57 matched pairs of examinations. Blood flow estimates were compared using t test, Bland-Altman, and linear mixed regression analyses. RESULTS: There was no significant difference between the mean (SD) blood flow values measured by pCT and 15O-PET: 25.9 +/- 15.4 and 27.8 +/- 14.0 mL/min per 100 g, respectively. CONCLUSIONS: The demonstration of a good correlation between pCT and 15O-PET potentially enables the use of pCT, which is more widely available than 15O-PET, when tumor blood flow estimates are required, particularly in the context of clinical studies.

Authors

Ng, CS; Kodama, Y; Mullani, NA; Barron, BJ; Wei, W; Herbst, RS; Abbruzzese, JL; Charnsangavej, C

MLA Citation

Ng, CS, Kodama, Y, Mullani, NA, Barron, BJ, Wei, W, Herbst, RS, Abbruzzese, JL, and Charnsangavej, C. "Tumor blood flow measured by perfusion computed tomography and 15O-labeled water positron emission tomography: a comparison study." Journal of Computer Assisted Tomography 33.3 (May 2009): 460-465.

PMID

19478644

Source

epmc

Published In

Journal of Computer Assisted Tomography

Volume

33

Issue

3

Publish Date

2009

Start Page

460

End Page

465

DOI

10.1097/rct.0b013e318182d2e0

Thyroid hormones play an essential role in lipid mobilization, lipid degradation, and fatty acid oxidation. Hypothyroidism has been associated with nonalcoholic steatohepatitis; however, the association between thyroid diseases and hepatocellular carcinoma (HCC) in men and women has not been well established. We investigated the association between hypothyroidism and HCC risk in men and women in a case-control study, which included 420 eligible patients with HCC and 1104 healthy controls. We used multivariate unconditional logistic regression models to control for the confounding effects of established HCC risk factors. A long-term history of hypothyroidism (>10 years) was associated with a statistically significant high risk of HCC in women; after adjusting for demographic factors, diabetes, hepatitis, alcohol consumption, cigarette smoking, and family history of cancer, the odds ratio (OR) was 2.9 (95% confidence interval [CI], 1.3-6.3). Restricted analyses among hepatitis virus-negative subjects, nondrinkers, nondiabetics, nonsmokers, and nonobese individuals indicated a significant association between hypothyroidism and HCC, with an approximate two-fold to three-fold increased risk of HCC development. We observed risk modification among women with diabetes mellitus (OR = 9.4; 95% CI = 2.7-32.7) and chronic hepatitis virus infection (OR = 31.2; 95% CI = 6.3-153.2). A history of hyperthyroidism was not significantly related to HCC (OR = 1.7; CI = 0.6-5.1). We noted significant elevated risk association between hypothyroidism and HCC in women that was independent of established HCC risk factors. Experimental investigations are necessary for thorough assessment of the relationship between thyroid disorders and HCC.

Authors

Hassan, MM; Kaseb, A; Li, D; Patt, YZ; Vauthey, J-N; Thomas, MB; Curley, SA; Spitz, MR; Sherman, SI; Abdalla, EK; Davila, M; Lozano, RD; Hassan, DM; Chan, W; Brown, TD; Abbruzzese, JL

MLA Citation

Hassan, MM, Kaseb, A, Li, D, Patt, YZ, Vauthey, J-N, Thomas, MB, Curley, SA, Spitz, MR, Sherman, SI, Abdalla, EK, Davila, M, Lozano, RD, Hassan, DM, Chan, W, Brown, TD, and Abbruzzese, JL. "Association between hypothyroidism and hepatocellular carcinoma: a case-control study in the United States." Hepatology 49.5 (May 2009): 1563-1570.

PMID

19399911

Source

pubmed

Published In

Hepatology

Volume

49

Issue

5

Publish Date

2009

Start Page

1563

End Page

1570

DOI

10.1002/hep.22793

Chemotherapeutic regimens for the treatment of colorectal cancer generally include oxaliplatin, although inherent and acquired resistance is common. One potential mediator of oxaliplatin sensitivity is the nonreceptor protein tyrosine kinase, Src, the activity of which correlates with disease stage and patient survival. Therefore, we investigated the effects of Src inhibition using the tyrosine kinase inhibitor dasatinib on oxaliplatin sensitivity. We show that oxaliplatin acutely activates Src and that combination treatment with dasatinib is synergistic in a cell-line dependent manner, with the level of Src activation correlating with extent of synergy in a panel of six cell lines. Intracellular reactive oxygen species (ROS) are generated after oxaliplatin treatment, and ROS potently activates Src. Pretreatment with antioxidants inhibits oxaliplatin-induced Src activation. In oxaliplatin-resistant cell lines, Src activity is constitutively increased. In a mouse model of colorectal liver metastases, treatment with oxaliplatin also results in chronic Src activation. The combination of dasatinib and oxaliplatin results in significantly smaller tumors compared with single-agent treatment, corresponding with reduced proliferation and angiogenesis. Therefore, we conclude that oxaliplatin activates Src through a ROS-dependent mechanism. Src inhibition increases oxaliplatin activity both in vitro and in vivo. These results suggest that Src inhibitors combined with oxaliplatin may have efficacy in metastatic colon cancer and may provide the first indication of a molecular phenotype that might be susceptible to such combinations.

Authors

Kopetz, S; Lesslie, DP; Dallas, NA; Park, SI; Johnson, M; Parikh, NU; Kim, MP; Abbruzzese, JL; Ellis, LM; Chandra, J; Gallick, GE

MLA Citation

Kopetz, S, Lesslie, DP, Dallas, NA, Park, SI, Johnson, M, Parikh, NU, Kim, MP, Abbruzzese, JL, Ellis, LM, Chandra, J, and Gallick, GE. "Synergistic activity of the SRC family kinase inhibitor dasatinib and oxaliplatin in colon carcinoma cells is mediated by oxidative stress." Cancer Research 69.9 (May 2009): 3842-3849.

PMID

19383922

Source

epmc

Published In

Cancer Research

Volume

69

Issue

9

Publish Date

2009

Start Page

3842

End Page

3849

DOI

10.1158/0008-5472.CAN-08-2246

Actual 5-year survival rates of 10-18% have been reported for patients with resected pancreatic adenocarcinoma (PC), but the use of multimodality therapy was uncommon in these series. We evaluated long-term survival and patterns of recurrence in patients treated for PC with contemporary staging and multimodality therapy.We analyzed 329 consecutive patients with PC evaluated between 1990 and 2002 who underwent resection. Each received a multidisciplinary evaluation and a standard operative approach. Pre- or postoperative chemotherapy and/or chemoradiation were routine. Surgical specimens of 5-year survivors were re-reviewed. A multivariate model of factors associated with long-term survival was constructed.Patients underwent pancreaticoduodenectomy (n = 302; 92%), distal (n = 20; 6%), or total pancreatectomy (n = 7; 2%). A total of 108 patients (33%) underwent vascular reconstruction, 301 patients (91%) received neoadjuvant or adjuvant therapy, 157 specimens (48%) were node positive, and margins were microscopically positive in 52 patients (16%). Median overall survival and disease-specific survival was 23.9 and 26.5 months. Eighty-eight patients (27%) survived a minimum of 5 years and had a median overall survival of 11 years. Of these, 21 (24%) experienced recurrence, 7 (8%) after 5 years. Late recurrences occurred most frequently in the lungs, the latest at 6.7 years. Multivariate analysis identified disease-negative lymph nodes (P = .02) and no prior attempt at resection (P = 0.01) as associated with 5-year survival.Our 27% actual 5-year survival rate for patients with resected PC is superior to that previously reported, and it is influenced by our emphasis on detailed staging and patient selection, a standardized operative approach, and routine use of multimodality therapy.

Authors

Katz, MHG; Wang, H; Fleming, JB; Sun, CC; Hwang, RF; Wolff, RA; Varadhachary, G; Abbruzzese, JL; Crane, CH; Krishnan, S; Vauthey, J-N; Abdalla, EK; Lee, JE; Pisters, PWT; Evans, DB

MLA Citation

Katz, MHG, Wang, H, Fleming, JB, Sun, CC, Hwang, RF, Wolff, RA, Varadhachary, G, Abbruzzese, JL, Crane, CH, Krishnan, S, Vauthey, J-N, Abdalla, EK, Lee, JE, Pisters, PWT, and Evans, DB. "Long-term survival after multidisciplinary management of resected pancreatic adenocarcinoma." April 2009.

PMID

19194760

Source

epmc

Published In

Annals of Surgical Oncology

Volume

16

Issue

4

Publish Date

2009

Start Page

836

End Page

847

DOI

10.1245/s10434-008-0295-2

DNA mismatch repair (MMR) is critical in maintaining genomic stability and may modulate the cellular response to gemcitabine. We hypothesized that genetic variations in MMR may affect the clinical outcome of patients with pancreatic cancer.We evaluated 15 single-nucleotide polymorphisms (SNPs) of eight MMR genes in 154 patients with potentially resectable pancreatic adenocarcinoma who were enrolled onto phase II clinical trials for preoperative gemcitabine-based chemoradiotherapy from 1999 to 2006. Associations of genotypes with tumor response to therapy (change of tumor size by radiologic evaluation at restaging), margin-negative tumor resection, and overall survival were evaluated using logistic regression and Cox proportional regression models.Five, six, and 10 genotypes were significantly associated with tumor response to preoperative chemoradiotherapy, tumor resectability, and overall survival, respectively, in univariable analysis. TREX1 EX14-460C>T and TP73 Ex2+4G>A genotypes remained as significant predictors for tumor response, MLH1 IVS12-169C>T and TP73 remained as significant predictors for tumor resectability, and EXO1 R354H, TREX1, and TP73 remained as significant predictors for overall survival in multivariable models that included all clinical factors and genotypes examined. A strong combined genotype effect on each clinical end point was observed. For example, 20 of the 25 patients with zero to one adverse genotypes were alive, those with two, three, four, five, and six to seven adverse genotypes had median survival times of 36.2, 23.9, 16.3, 13.0, and 8.3 months, respectively (P < .001).SNPs of MMR genes have a potential value as predictors for clinical response to chemoradiotherapy and as prognostic markers for tumor resectability and overall survival of patients with resectable pancreatic cancer.

Authors

Dong, X; Jiao, L; Li, Y; Evans, DB; Wang, H; Hess, KR; Abbruzzese, JL; Li, D

MLA Citation

Dong, X, Jiao, L, Li, Y, Evans, DB, Wang, H, Hess, KR, Abbruzzese, JL, and Li, D. "Significant associations of mismatch repair gene polymorphisms with clinical outcome of pancreatic cancer." Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology 27.10 (April 2009): 1592-1599.

PMID

19237629

Source

epmc

Published In

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology

Volume

27

Issue

10

Publish Date

2009

Start Page

1592

End Page

1599

DOI

10.1200/JCO.2008.20.1111

Authors

Kopetz, S; Abbruzzese, JL

MLA Citation

Kopetz, S, and Abbruzzese, JL. "Hidden biases in an observational study of bevacizumab beyond progression." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 27.10 (April 2009): 1732-1733. (Letter)

PMID

19255299

Source

epmc

Published In

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology

Volume

27

Issue

10

Publish Date

2009

Start Page

1732

End Page

1733

DOI

10.1200/jco.2009.21.2084

Despite rapid advances in many fronts, pancreatic cancer (PC) remains one of the most difficult human malignancies to treat due, in part, to de novo and acquired chemoresistance and radioresistance. Gemcitabine alone or in combination with other conventional therapeutics is the standard of care for the treatment of advanced PC without any significant improvement in the overall survival of patients diagnosed with this deadly disease. Previous studies have shown that PC cells that are gemcitabine-resistant (GR) acquired epithelial-mesenchymal transition (EMT) phenotype, which is reminiscent of "cancer stem-like cells"; however, the molecular mechanism that led to EMT phenotype has not been fully investigated. The present study shows that Notch-2 and its ligand, Jagged-1, are highly up-regulated in GR cells, which is consistent with the role of the Notch signaling pathway in the acquisition of EMT and cancer stem-like cell phenotype. We also found that the down-regulation of Notch signaling was associated with decreased invasive behavior of GR cells. Moreover, down-regulation of Notch signaling by siRNA approach led to partial reversal of the EMT phenotype, resulting in the mesenchymal-epithelial transition, which was associated with decreased expression of vimentin, ZEB1, Slug, Snail, and nuclear factor-kappaB. These results provide molecular evidence showing that the activation of Notch signaling is mechanistically linked with chemoresistance phenotype (EMT phenotype) of PC cells, suggesting that the inactivation of Notch signaling by novel strategies could be a potential targeted therapeutic approach for overcoming chemoresistance toward the prevention of tumor progression and/or treatment of metastatic PC.

Authors

Wang, Z; Li, Y; Kong, D; Banerjee, S; Ahmad, A; Azmi, AS; Ali, S; Abbruzzese, JL; Gallick, GE; Sarkar, FH

MLA Citation

Wang, Z, Li, Y, Kong, D, Banerjee, S, Ahmad, A, Azmi, AS, Ali, S, Abbruzzese, JL, Gallick, GE, and Sarkar, FH. "Acquisition of epithelial-mesenchymal transition phenotype of gemcitabine-resistant pancreatic cancer cells is linked with activation of the notch signaling pathway." Cancer Research 69.6 (March 10, 2009): 2400-2407.

PMID

19276344

Source

epmc

Published In

Cancer Research

Volume

69

Issue

6

Publish Date

2009

Start Page

2400

End Page

2407

DOI

10.1158/0008-5472.CAN-08-4312

Survivin is overexpressed in most human cancers, including pancreatic adenocarcinoma. Expression of survivin is regulated by specificity protein (Sp) proteins and related to resistance to radiation therapy. Tolfenamic acid induces Sp protein degradation in several cancer cell lines. The purpose of this study is to investigate whether tolfenamic acid inhibits survivin expression and sensitizes pancreatic cancer cells/tumor to radiotherapy. Panc1 and L3.6pl cells have been used to study the effect of radiation on survivin expression and to investigate the efficacy of tolfenamic acid in enhancing the response to radiation therapy. In addition, an orthotopic model for human pancreatic cancer has been used to confirm the efficacy of tolfenamic acid to enhance tumor response to radiation in vivo. Pancreatic cancer cell lines express variable levels of survivin mRNA/protein, which correlate with their radiosensitivity. Radiation increased survivin promoter activity and protein expression in Panc1 and L3.6pl cells and tolfenamic acid inhibited both constitutive and radiation-induced survivin protein expression and enhanced the response of pancreatic cancer cells to radiation therapy. In vivo studies show that tolfenamic acid enhanced the radiation-induced apoptosis associated with decreased survivin expression in tumors and this correlates with the enhanced response of these tumors to the radiation. Thus, tolfenamic acid significantly enhances pancreatic cancer cells/tumor response to radiation therapy. The underlying mechanism includes tolfenamic acid-induced degradation of Sp proteins, which in tumor decreases expression of the Sp-dependent antiapoptotic protein survivin. These preclinical data suggest that tolfenamic acid has the potential to increase the response of pancreatic adenocarcinoma to radiation therapy.

Authors

Konduri, S; Colon, J; Baker, CH; Safe, S; Abbruzzese, JL; Abudayyeh, A; Basha, MR; Abdelrahim, M

MLA Citation

Konduri, S, Colon, J, Baker, CH, Safe, S, Abbruzzese, JL, Abudayyeh, A, Basha, MR, and Abdelrahim, M. "Tolfenamic acid enhances pancreatic cancer cell and tumor response to radiation therapy by inhibiting survivin protein expression." Molecular Cancer Therapeutics 8.3 (March 3, 2009): 533-542.

PMID

19258429

Source

epmc

Published In

Molecular Cancer Therapeutics

Volume

8

Issue

3

Publish Date

2009

Start Page

533

End Page

542

DOI

10.1158/1535-7163.mct-08-0405

Authors

Hassan, MM; Li, D; Abbruzzese, JL

MLA Citation

Hassan, MM, Li, D, and Abbruzzese, JL. "In reply." Journal of Clinical Oncology 27.4 (February 1, 2009): 648-649. (Letter)

Source

scopus

Published In

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology

Volume

27

Issue

4

Publish Date

2009

Start Page

648

End Page

649

DOI

10.1200/JCO.2008.20.8587

Hematopoietic progenitor kinase 1 (HPK1) regulates stress responses, proliferation, and apoptosis in hematopoietic cells. In this study, we examined the expression, regulation, and functions of HPK1 in pancreatic ductal adenocarcinomas (PDA). We found that loss of HPK1 protein expression correlated significantly with the progression of pancreatic intraepithelial neoplasias (P = 0.001) and development of invasive PDA. Similarly, HPK1 protein was not expressed in any of eight PDA cell lines examined but was expressed in immortalized human pancreatic duct epithelial (HPDE) cells. There was no difference in HPK1 mRNA levels in PDA cell lines or primary PDA compared with those in HPDE cells or ductal epithelium in chronic pancreatitis and normal pancreas, respectively. Treatment of Panc-1 cells with a proteasome inhibitor, MG132, increased the HPK1 protein levels in a dose-dependent manner, suggesting that alteration in proteasome activity contributes to the loss of HPK1 protein expression in pancreatic cancer. Like the endogenous HPK1, both wild-type HPK1 and its kinase-dead mutant, HPK1-M46, overexpressed in Panc-1 cells, were also targeted by proteasome-mediated degradation. After MG132 withdrawal, wild-type HPK1 protein expression was markedly decreased within 24 hours, but kinase-dead HPK1 mutant protein expression was sustained for up to 96 hours. Therefore, HPK1 kinase activities were required for the loss of HPK1 protein in PDAs. Furthermore, restoring wild-type HPK1 protein in PDA cells led to the increase in p21 and p27 protein expression and cell cycle arrest. Thus, HPK1 may function as a novel tumor suppressor and its loss plays a critical role in pancreatic cancer.

Authors

Wang, H; Song, X; Logsdon, C; Zhou, G; Evans, DB; Abbruzzese, JL; Hamilton, SR; Tan, T-H; Wang, H

MLA Citation

Wang, H, Song, X, Logsdon, C, Zhou, G, Evans, DB, Abbruzzese, JL, Hamilton, SR, Tan, T-H, and Wang, H. "Proteasome-mediated degradation and functions of hematopoietic progenitor kinase 1 in pancreatic cancer." Cancer Research 69.3 (February 2009): 1063-1070.

PMID

19141650

Source

epmc

Published In

Cancer Research

Volume

69

Issue

3

Publish Date

2009

Start Page

1063

End Page

1070

DOI

10.1158/0008-5472.CAN-08-1751

PURPOSE: The study objective was to determine the proportion of patients with hepatocellular carcinoma (HCC) treated with the combination of bevacizumab (B) and erlotinib (E) who were alive and progression free at 16 weeks (16-week progression-free survival [PFS16]) of continuous therapy. Secondary objectives included response rate, median PFS, survival, and toxicity. PATIENTS AND METHODS: Patients who had advanced HCC that was not amenable to surgical or regional therapies, up to one prior systemic treatment; Childs-Pugh score A or B liver function; Eastern Cooperative Oncology Group performance status 0, 1, or 2 received B 10 mg/kg every 14 days and E 150 mg orally daily, continuously, for 28-day cycles. Tumor response was evaluated every 2 cycles by using Response Evaluation Criteria in Solid Tumors Group criteria. A total of 40 patients were treated. RESULTS: The primary end point of PFS16 was 62.5%. Ten patients achieved a partial response for a confirmed overall response rate (intent-to-treat) of 25%. The median PFSevent was 39 weeks (95% CI, 26 to 45 weeks; 9.0 months), and the median overall survival was 68 weeks (95% CI, 48 to 78 weeks; 15.65 months). Grades 3 to 4 drug-related toxicity included fatigue (n = 8; 20%), hypertension (n = 6; 15%), diarrhea (n = 4; 10%) elevated transaminases (n = 4; 10%), gastrointestinal hemorrhage (n = 5; 12.5%), wound infection (n = 2; 5%) thrombocytopenia (n = 1; 2.5%), and proteinuria, hyperbilirubinemia, back pain, hyperkalemia, and anorexia (n = 1 each). CONCLUSION: The combination of B + E in patients who had advanced HCC showed significant, clinically meaningful antitumor activity. B + E warrant additional evaluation in randomized controlled trials.

Authors

Thomas, MB; Morris, JS; Chadha, R; Iwasaki, M; Kaur, H; Lin, E; Kaseb, A; Glover, K; Davila, M; Abbruzzese, J

MLA Citation

Thomas, MB, Morris, JS, Chadha, R, Iwasaki, M, Kaur, H, Lin, E, Kaseb, A, Glover, K, Davila, M, and Abbruzzese, J. "Phase II trial of the combination of bevacizumab and erlotinib in patients who have advanced hepatocellular carcinoma." Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology 27.6 (February 2009): 843-850.

PMID

19139433

Source

epmc

Published In

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology

Volume

27

Issue

6

Publish Date

2009

Start Page

843

End Page

850

DOI

10.1200/jco.2008.18.3301

Genetic polymorphisms play an important role in clinical response to cytotoxic therapies. We hypothesized that polymorphisms in cell cycle genes may modulate response to preoperative chemoradiation and survival of pancreatic cancer patients. We evaluated 12 single-nucleotide polymorphisms (SNPs) of ten cell cycle genes in 88 patients with resectable adenocarcinoma of the pancreatic head who were treated with neoadjuvant concurrent gemcitabine and radiotherapy. Response was assessed by computerized tomography obtained before and 4-6 weeks after preoperative treatment. Time to tumor progression and survival after treatment were measured. Patients underwent pancreaticoduodenectomy (PD) if no disease progression was found at restaging after preoperative therapy. MDM2 T309G and p16 C580T genotype distributions were significantly different in the patients who underwent PD and those who did not (P = 0.025 for MDM2; P = 0.016 for p16). The MDM2 and p27 genotypes had a significant effect on survival times after treatment (log-rank test, P = 0.010 and P = 0.050, respectively). A strong joint effect of these two genes was observed (log-rank test, P = 0.010). The p73 and p16 polymorphic genotypes were significantly associated with shorter time to tumor progression (log-rank test, P = 0.021 and P = 0.039, respectively). A gene-dosage effect on time to tumor progression was observed for polymorphisms in the p73, p16, and MDM2 genes. The hazard ratios for patients with one, two, or three adverse genotypes were 2.13 (1.04-4.36), 3.18 (1.37-7.39), and 10.09 (3.17-32.05), respectively. These findings suggest these polymorphisms in the cell cycle genes are promising prognostic markers for patients with pancreatic cancer.

Authors

Chen, J; Li, D; Killary, AM; Sen, S; Amos, CI; Evans, DB; Abbruzzese, JL; Frazier, ML

MLA Citation

Chen, J, Li, D, Killary, AM, Sen, S, Amos, CI, Evans, DB, Abbruzzese, JL, and Frazier, ML. "Polymorphisms of p16, p27, p73, and MDM2 modulate response and survival of pancreatic cancer patients treated with preoperative chemoradiation." Annals of surgical oncology 16.2 (February 2009): 431-439.

PMID

19020940

Source

epmc

Published In

Annals of Surgical Oncology

Volume

16

Issue

2

Publish Date

2009

Start Page

431

End Page

439

DOI

10.1245/s10434-008-0220-8

There is emerging evidence that the oncogenic potential of hdm2 (human and/or murine double minute-2 protein) stems not only from its ability to counteract tumor suppressor p53 but also from its less understood p53-independent functions. Surprisingly, little is known about the role and regulation of hdm2 in pancreatic tumors, a large proportion (50-75%) of which contain mutant p53. In this study, we determined that hdm2 was expressed in a Ras-signaling-dependent manner in various pancreatic cancer cell lines. As p53 was mutated and inactive in these cells, the expression of hdm2 was seemingly redundant. Indeed, the proliferation and survival of cell lines such as Panc-1 and Panc-28 could be inhibited by PRIMA-1 (mutant p53 activator) but not by Nutlin-3 (inhibitor of the hdm2-p53 interaction). Unexpectedly, however, the proliferation of both cell lines was strongly inhibited by hdm2-specific RNAi. Our data also revealed cyclin D1, c-Jun and c-Myc to be novel targets of hdm2 and suggested that they might mediate hdm2's role in cellular proliferation and/or survival. We conclude from our results that hdm2 is expressed in pancreatic cancer cells as a result of activated Ras signaling, and that it regulates cellular proliferation and the expression of three novel target genes by p53-independent mechanisms.

Authors

Sui, X; Shin, S; Zhang, R; Firozi, PF; Yang, L; Abbruzzese, JL; Reddy, SAG

MLA Citation

Sui, X, Shin, S, Zhang, R, Firozi, PF, Yang, L, Abbruzzese, JL, and Reddy, SAG. "Hdm2 is regulated by K-Ras and mediates p53-independent functions in pancreatic cancer cells." Oncogene 28.5 (February 2009): 709-720.

PMID

19029954

Source

epmc

Published In

Oncogene

Volume

28

Issue

5

Publish Date

2009

Start Page

709

End Page

720

DOI

10.1038/onc.2008.423

The study aimed at addressing the connection between positive family history of liver cancer and hepatocellular carcinoma (HCC) development in the USA.At The University of Texas M.D. Anderson Cancer Center, 347 patients with pathologically confirmed HCC and 1075 healthy controls were studied. All subjects were interviewed for their family history of cancer, including the number of relatives with cancer, the type of cancer, the individual's relationship with the relative, and the age at which the relative was diagnosed.Independently of hepatitis B virus (HBV) and hepatitis C virus (HCV), a history of liver cancer in first degree relatives was significantly associated with HCC development (AOR=4.1 [95% CI, 1.3-12.9]). Multiple relatives with liver cancer were only observed among HCC patients with chronic HBV/HCV infection. Affected siblings with liver cancer is significantly associated with HCC development with and without HBV/HCV infection; (AOR=5.7 [95% CI, 1.2-27.3]) and (AOR=4.3 [95% CI, 1.01-20.9]), respectively. Individuals with HBV/HCV and a family history of liver cancer were at higher risk for HCC (AOR=61.9 [95% CI, 6.6-579.7]).First degree family history of liver cancer is associated with HCC development in the USA. Further research exploring the genetic-environment interactions associated with risk of HCC is warranted.

Authors

Hassan, MM; Spitz, MR; Thomas, MB; Curley, SA; Patt, YZ; Vauthey, J-N; Glover, KY; Kaseb, A; Lozano, RD; El-Deeb, AS; Nguyen, NT; Wei, SH; Chan, W; Abbruzzese, JL; Li, D

MLA Citation

Hassan, MM, Spitz, MR, Thomas, MB, Curley, SA, Patt, YZ, Vauthey, J-N, Glover, KY, Kaseb, A, Lozano, RD, El-Deeb, AS, Nguyen, NT, Wei, SH, Chan, W, Abbruzzese, JL, and Li, D. "The association of family history of liver cancer with hepatocellular carcinoma: a case-control study in the United States." Journal of Hepatology 50.2 (February 2009): 334-341.

PMID

19070394

Source

epmc

Published In

Journal of Hepatology

Volume

50

Issue

2

Publish Date

2009

Start Page

334

End Page

341

DOI

10.1016/j.jhep.2008.08.016

The current research was undertaken to examine the association between genetic variations in DNA repair and pancreatic cancer risk.We analyzed 9 single nucleotide polymorphisms of 7 DNA repair genes (LIG3, LIG4, OGG1, ATM, POLB, RAD54L, and RECQL) in 734 patients with pancreatic adenocarcinoma and 780 healthy controls using the Taqman method. Information on cigarette smoking, alcohol consumption, medical history, and other risk factors was collected by personal interview.The homozygous mutant genotype of LIG3 G-39A [odds ratio (OR), 0.23; 95% confidence interval (CI), 0.06-0.82; P = 0.027] and ATM D1853N (OR, 2.55; 95% CI, 1.08-6.00; P = 0.032) was significantly associated with altered risk for pancreatic cancer. A statistically significant interaction of ATM D1853N and LIG4 C54T genotype with diabetes on the risk of pancreatic cancer was also detected. Compared with nondiabetics with the ATM D1853N GG genotype, nondiabetics with the GA/AA, diabetics with the GG, and diabetics with the GA/AA genotypes, respectively, had ORs (95% CI) of 0.96 (0.74-1.24), 1.32 (0.89-1.95), and 3.23 (1.47-7.12; P(interaction) = 0.032, likelihood ratio test). The OR (95% CI) was 0.91 (0.71-1.17), 1.11 (0.73-1.69), and 2.44 (1.34-4.46) for nondiabetics carrying the LIG4 CT/TT genotype, diabetics with the CC genotype, and diabetics carrying the CT/TT genotype, respectively, compared with nondiabetics carrying the CC genotype (P(interaction) = 0.02).These observations suggest that genetic variations in DNA repair may act alone or in concert with other risk factors on modifying a patient's risk for pancreatic cancer.

Authors

Li, D; Suzuki, H; Liu, B; Morris, J; Liu, J; Okazaki, T; Li, Y; Chang, P; Abbruzzese, JL

MLA Citation

Li, D, Suzuki, H, Liu, B, Morris, J, Liu, J, Okazaki, T, Li, Y, Chang, P, and Abbruzzese, JL. "DNA repair gene polymorphisms and risk of pancreatic cancer." Clinical Cancer Research : an Official Journal of the American Association for Cancer Research 15.2 (January 2009): 740-746.

PMID

19147782

Source

epmc

Published In

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research

Volume

15

Issue

2

Publish Date

2009

Start Page

740

End Page

746

DOI

10.1158/1078-0432.CCR-08-1607

For decades, xenografts using well-established human tumor cell lines have been the most commonly used models to study human cancers in mice. More recently, human tumors implanted directly into immunodeficient mice have become increasingly popular as evidence accrues that they more accurately recapitulate features of patient tumors. Here we describe our protocols for the orthotopic and heterotopic implantation of pancreatic cancer cell lines and freshly isolated patient tumors into immunodeficient mice. We also describe procedures for the digestion of tumors into single-cell suspensions for the isolation of subpopulations of tumor cells. Orthotopic or heterotopic implantation of established cell lines requires 1-2 h, with 1-cm tumors arising after 2-5 weeks. Engraftment of patient tumor samples takes approximately 2 h and growth of palpable tumor requires approximately 14 weeks. Once established, direct xenograft tumors require 2 and 5 h for heterotopic and orthotopic implantation, respectively, and 5-6 weeks for palpable tumor growth.

Authors

Kim, MP; Evans, DB; Wang, H; Abbruzzese, JL; Fleming, JB; Gallick, GE

MLA Citation

Kim, MP, Evans, DB, Wang, H, Abbruzzese, JL, Fleming, JB, and Gallick, GE. "Generation of orthotopic and heterotopic human pancreatic cancer xenografts in immunodeficient mice." Nature Protocols 4.11 (January 2009): 1670-1680.

PMID

19876027

Source

epmc

Published In

Nature Protocols

Volume

4

Issue

11

Publish Date

2009

Start Page

1670

End Page

1680

DOI

10.1038/nprot.2009.171

Authors

Abbruzzese, JL

MLA Citation

Abbruzzese, JL. "Highlights of the 2008 San Antonio Breast Cancer Symposium." January 2009.

PMID

19274039

Source

epmc

Published In

Clinical Advances in Hematology & Oncology : H&O

Volume

7

Issue

1

Publish Date

2009

Start Page

39

End Page

41

Pancreatic cancer is a systemic disease for most patients, and two-thirds of patients have locally advanced or metastatic disease at the time of diagnosis. For the subset of patients (20%) who present with potentially resectable tumors, the 5-year survival rate for those whose tumors are successfully resected is approximately 15-20% and lower for those with positive nodes or margins [1]. Patients usually succumb to metastatic disease or locoregional failure. As with other cancers, the rationale for postoperative therapy is to treat micrometastatic disease and improve survival in patients with resected cancer; unfortunately, despite more than two decades of research, there is no consensus on the best postoperative therapy for pancreatic adenocarcinoma. In a study reported in 1999, trends in disease stage, treatment patterns, and outcomes were analyzed for patients diagnosed with pancreatic adenocarcinoma between 1985 and 1995 [2]. Data were available for 100,313 patients. For the 9,044 patients who underwent pancreatectomy, the overall 5-year survival rate was 23.4%. Adjuvant treatment was used in 40% of cases and consisted of radiation therapy, chemotherapy, or both in 6.5%, 5.1%, and 28.3% of patients, respectively. The approach to adjuvant therapy also differs between high-volume centers in the USA and Europe. Some of the barriers to determining the best postoperative therapy include poor surgical recovery that complicates the use of chemotherapy and chemoradiation therapy, poor patient selection and inadequate staging studies for patients in postoperative trials, lack of standardized criteria for evaluating resection margins, and lack of chemotherapy with significant activity in pancreatic adenocarcinoma. More recently, preoperative or neoadjuvant treatments have been explored as an alternative to adjuvant therapy. In this chapter, we review the data for adjuvant and neoadjuvant strategies for the treatment of pancreatic cancer. © Springer-Verlag Berlin Heidelberg 2008.

Authors

Varadhachary, GR; Abbruzzese, JL

MLA Citation

Varadhachary, GR, and Abbruzzese, JL. "Resected pancreatic cancer." Diseases of the Pancreas: Current Surgical Therapy. December 1, 2008. 675-687.

Source

scopus

Publish Date

2008

Start Page

675

End Page

687

DOI

10.1007/978-3-540-28656-1_65

Authors

Xiong, HQ; Abbruzzese, JL

MLA Citation

Xiong, HQ, and Abbruzzese, JL. "Molecular Pathogenesis of Pancreatic Adenocarcinoma." The Molecular Basis of Cancer. December 1, 2008. 455-461.

Source

scopus

Publish Date

2008

Start Page

455

End Page

461

DOI

10.1016/B978-141603703-3.10035-4

p21 and p27, members of the kinase inhibitor protein (KIP) family, bind to cyclin-CDK complexes to inhibit their catalytic activity and induce cell cycle arrest. The purpose of our study was to identify whether the p21 (C-to-A), and p27 (T-to-G) polymorphisms were associated with age at diagnosis of pancreatic cancer, either independently or jointly. Two hundred and five patients with a diagnosis of pancreatic cancer were genotyped for the p21 and p27 polymorphisms. We found patients with the p21 variant genotype (CA/AA) had an earlier age at diagnosis than those with the wild-type genotype (CC) (log-rank, P=0.001; HR=1.89; 95%CI, 1.28-2.78). The p21 and p27 polymorphisms combined had a joint effect on age-associated risk for early diagnosis of pancreatic cancer (log-rank, P=0.004; HR=2.91; 95%CI, 1.49-5.67). Our findings suggest that the p21 polymorphism independently and p21 and p27 polymorphisms jointly contribute to a significantly earlier age at diagnosis of pancreatic cancer.

Authors

Chen, J; Killary, AM; Sen, S; Amos, CI; Evans, DB; Abbruzzese, JL; Frazier, ML

MLA Citation

Chen, J, Killary, AM, Sen, S, Amos, CI, Evans, DB, Abbruzzese, JL, and Frazier, ML. "Polymorphisms of p21 and p27 jointly contribute to an earlier age at diagnosis of pancreatic cancer." Cancer letters 272.1 (December 2008): 32-39.

PMID

18694622

Source

epmc

Published In

Cancer Letters

Volume

272

Issue

1

Publish Date

2008

Start Page

32

End Page

39

DOI

10.1016/j.canlet.2008.06.022

Insulin-like growth factors (IGF) have been associated with risk of common human cancers, but the association between IGFs and pancreatic cancer risk is unclear. To determine whether genetic variations of IGF modify pancreatic cancer risk, we compared the frequency of six single nucleotide polymorphisms of IGF1 and IGF2 in a large-scale case control study. Single nucleotide polymorphisms were investigated using the TaqMan method in 892 patients with pancreatic ductal adenocarcinoma and 783 healthy controls who were recruited from The University of Texas M. D. Anderson Cancer Center from 2000 to 2007. Cases and controls were frequency matched by age (+/-5 years), race, and sex. Risk factor information was collected using direct interviews. We estimated odds ratios (OR) and 95% confidence intervals (95% CI) using unconditional multivariate logistic regression models. A haplotype of IGF1 gene containing the 3'-UTR Ex4 -177 G>C G allele had a significantly lower frequency in cases (0.027) than in controls (0.041; P = 0.039). A statistically significant joint effect of the IGF1 3'-UTR Ex4 -177 G>C C allele and diabetes on pancreatic cancer risk was observed. The OR (95% CI) were 1.07 (0.81-1.42), 2.12 (1.53-2.93), and 5.69 (2.63-12.3) for individuals who had the CC/CG genotype alone, diabetes alone, or both factors, respectively, compared with subjects without either of the two factors with adjustment for other risk factors. The IGF2 3'-UTR Ex4 -233C>T TT genotype was significantly associated with a reduced risk of pancreatic cancer (OR = 0.07; 95% CI = 0.01-0.57; P = 0.013). The polymorphic variants of the IGF genes may serve as a susceptibility factor for pancreatic cancer.

Authors

Suzuki, H; Li, Y; Dong, X; Hassan, MM; Abbruzzese, JL; Li, D

MLA Citation

Suzuki, H, Li, Y, Dong, X, Hassan, MM, Abbruzzese, JL, and Li, D. "Effect of insulin-like growth factor gene polymorphisms alone or in interaction with diabetes on the risk of pancreatic cancer." Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology 17.12 (December 2008): 3467-3473.

PMID

19064563

Source

epmc

Published In

Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology

Volume

17

Issue

12

Publish Date

2008

Start Page

3467

End Page

3473

DOI

10.1158/1055-9965.EPI-08-0514

Preclinical models showed TAC-101 (4-[3,5-bis(trimethylsilyl) benzamide] benzoic acid), an oral synthetic retinoid, has anti-tumor activity in hepatocellular carcinoma (HCC). A phase I/II study was performed in advanced HCC patients (pts).Thirty-three patients were enrolled. During Phase I, pts received 40 mg daily for 14 days q3 weeks; 2 of 5 patients developed DLT so dose was reduced to 20 mg/day. Twenty-eight patients received 20 mg/day.No pt had a CR or PR, but 12 of 21 (57%) had SD. Two pts (9.5%) had late PR after discontinuing TAC-101. Median survival (MS) for all 28 pts treated with 20 mg/day was 12.7 months (95% CI 8.8-22.7); MS for 21 evaluable pts was 19.2 months (95% CI 10.4-27.6).20 mg of TAC- was well tolerated. Significant disease stabilization (12/21 pts, 57%), 2 late PRs, and prolonged MS (19.2 months) suggest that TAC-101 provides meaningful patient benefit.

Authors

Higginbotham, KB; Lozano, R; Brown, T; Patt, YZ; Arima, T; Abbruzzese, JL; Thomas, MB

MLA Citation

Higginbotham, KB, Lozano, R, Brown, T, Patt, YZ, Arima, T, Abbruzzese, JL, and Thomas, MB. "A phase I/II trial of TAC-101, an oral synthetic retinoid, in patients with advanced hepatocellular carcinoma." Journal of cancer research and clinical oncology 134.12 (December 2008): 1325-1335.

PMID

18504614

Source

epmc

Published In

Journal of Cancer Research and Clinical Oncology

Volume

134

Issue

12

Publish Date

2008

Start Page

1325

End Page

1335

DOI

10.1007/s00432-008-0406-2

Authors

Varadhachary, GR; Abbruzzese, JL

MLA Citation

Varadhachary, GR, and Abbruzzese, JL. "Novel approaches to 'borderline resectable' pancreatic tumors." Oncology (Williston Park, N.Y.) 22.13 (November 2008): 1529-1530.

PMID

19227575

Source

epmc

Published In

Oncology (Williston Park, N.Y.)

Volume

22

Issue

13

Publish Date

2008

Start Page

1529

End Page

1530

PURPOSE: Mitogen-activated protein 4 kinase 4 (MAP4K4) is a serine/threonine kinase and belongs to the mammalian STE20/MAP4K family. Recent studies have shown that MAP4K4 is overexpressed in many types of human cancer and cancer cell lines. MAP4K4 plays an important role in transformation, invasiveness, adhesion, and cell migration. However, the expression of MAP4K4 and its significance in pancreatic ductal adenocarcinoma (PDA) has not been studied. EXPERIMENTAL DESIGN: We examined the expression of MAP4K4 by immunohistochemistry using tissue microarrays consisting of 66 stage II PDA and their paired benign pancreatic tissue. The staining results were categorized as MAP4K4-H or MAP4K4-L. The results were correlated with clinicopathologic features and patient survival. RESULTS: MAP4K4 was overexpressed (MAP4K4-H) in 30 of 66 (46%) PDAs and was higher than the paired benign pancreatic tissue samples (19%; P=0.002). The median overall and recurrence-free survival for patients with MAP4K4-H PDAs were 19.5 and 9.3 months, respectively, compared with 65.2 and 28.8 months for patients with MAP4K4-L tumor (P=0.02 and 0.0005, log-rank test). MAP4K4 expression was associated with poor overall and recurrence-free survival in univariate analysis (P=0.02 and 0.001). In multivariate analysis, MAP4K4 expression significantly correlated with overall and recurrence-free survival (P=0.025 and 0.004) independent of age, tumor size, differentiation, and stage. MAP4K4 expression was also associated with higher frequency of recurrence/metastasis, larger tumor size, and increased number of positive lymph nodes (P<0.05). CONCLUSION: MAP4K4 was overexpressed in about half of PDAs. Overexpression of MAP4K4 was associated with worse prognosis and is a prognostic marker for stage II PDAs.

Authors

Liang, JJ; Wang, H; Rashid, A; Tan, T-H; Hwang, RF; Hamilton, SR; Abbruzzese, JL; Evans, DB; Wang, H

MLA Citation

Liang, JJ, Wang, H, Rashid, A, Tan, T-H, Hwang, RF, Hamilton, SR, Abbruzzese, JL, Evans, DB, and Wang, H. "Expression of MAP4K4 is associated with worse prognosis in patients with stage II pancreatic ductal adenocarcinoma." Clinical Cancer Research : an Official Journal of the American Association for Cancer Research 14.21 (November 2008): 7043-7049.

PMID

18981001

Source

epmc

Published In

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research

Volume

14

Issue

21

Publish Date

2008

Start Page

7043

End Page

7049

DOI

10.1158/1078-0432.ccr-08-0381

Metastatic small bowel adenocarcinoma (SBA) has a poor prognosis. Because of the rarity of SBA, only a few studies have evaluated the role of chemotherapy in the treatment of metastatic SBA; thus, the benefit, if any, of adding a platinum compound to fluorouracil (5-FU) is unknown. The objective of this retrospective study was to determine whether the addition of a platinum compound to 5-FU provided any benefit in the treatment of patients with metastatic SBA.The authors identified 80 patients with metastatic SBA who were treated with chemotherapy at the University of Texas M. D. Anderson Cancer Center between 1978 and 2005. Response rates, progression-free survival (PFS), and overall survival (OS) were compared between patients who received 5-FU and a platinum compound and patients who received other chemotherapy combinations.The median patient age was 53 years. The primary tumor site was the jejunum in 35 patients (43%), duodenum in 30 patients (38%), ileum in 6 patients (8%), and nonspecified small bowel in 9 patients (11%). Of all 80 patients, 29 patients (36%) received 5-FU and a platinum compound, 41 patients (51%) received 5-FU without a platinum compound, and 10 patients (13%) received non-5-FU-based treatment. Compared with other chemotherapy regimens, treatment with 5-FU and a platinum agent resulted in a higher response rate (46% vs 16% with other regimens; P = .01) and longer median PFS (8.7 months vs 3.9 months; P < or = .01) but not better OS (14.8 months vs 12 months; P = .1). In multivariate analysis, treatment with 5-FU and a platinum compound was a significant predictor of response (odds ratio, 4.5; 95% confidence interval [CI], 1.3-15.8; P = .02) and PFS (hazard ratio. 0.49; 95% CI, 0.29-0.84; P = .01) but only reached borderline significance for OS (hazard ratio, 0.63; 95% CI, 0.37-1.07; P = .08).To the authors' knowledge, the current analysis represents the largest number of patients with metastatic SBA treated with chemotherapy in the literature, and the results suggested that the combination of 5-FU and a platinum compound leads to a higher response rate and PFS compared with other chemotherapy regimes. The authors concluded that prospective investigation of platinum analogues in the treatment of SBA is warranted.

Authors

Overman, MJ; Kopetz, S; Wen, S; Hoff, PM; Fogelman, D; Morris, J; Abbruzzese, JL; Ajani, JA; Wolff, RA

MLA Citation

Overman, MJ, Kopetz, S, Wen, S, Hoff, PM, Fogelman, D, Morris, J, Abbruzzese, JL, Ajani, JA, and Wolff, RA. "Chemotherapy with 5-fluorouracil and a platinum compound improves outcomes in metastatic small bowel adenocarcinoma." Cancer 113.8 (October 2008): 2038-2045.

PMID

18759326

Source

epmc

Published In

Cancer

Volume

113

Issue

8

Publish Date

2008

Start Page

2038

End Page

2045

DOI

10.1002/cncr.23822

Hepatitis B virus (HBV) and hepatitis C virus (HCV) are considered to be hepatotropic and are a major cause of hepatocellular carcinoma. However, little is known about the role of HBV and HCV infection in other malignancies. This study aimed to determine whether HBV and HCV infections increase the risk for pancreatic cancer development.At The University of Texas M. D. Anderson Cancer Center, Houston, TX, we recruited 476 patients with pathologically confirmed adenocarcinoma of the pancreas and 879 age-, sex-, and race-matched healthy controls. Blood samples were tested for the presence of HCV antibodies (anti-HCV), HBV surface antigen (HBsAg), antibodies against HBV core antigen (anti-HBc), and antibodies against HBsAg (anti-HBs). The positive samples were retested by two confirmatory tests. An unconditional multivariable logistic regression analysis was used to estimate adjusted odds ratios (AORs).Anti-HCV was positive in seven cases (1.5%) and nine controls (1%). Anti-HBc was positive in 36 cases (7.6%) and 28 controls (3.2%). The estimated AORs and 95% CIs were as follows: anti-HCV-positive, 0.9 (95% CI, 0.3 to 2.8), anti-HBc-positive, 2.5 (95% CI, 1.5 to 4.2), anti-HBc-positive/anti-HBs-positive, 2.3 (95% CI, 1.2 to 4.2), and anti-HBc-positive/anti-HBs-negative, 4 (95% CI, 1.4 to 11.1). Risk modification by past exposure to HBV was observed among diabetics (AOR, 7.1; 95% CI, 1.7 to 28.7).Past exposure to HBV may be associated with pancreatic cancer development. Should such findings be confirmed by other studies, it may offer important insights into the etiology of pancreatic cancer and may suggest the need to consider prevention of HBV reactivation among patients with HBV-related pancreatic cancer during chemotherapy.

Authors

Hassan, MM; Li, D; El-Deeb, AS; Wolff, RA; Bondy, ML; Davila, M; Abbruzzese, JL

MLA Citation

Hassan, MM, Li, D, El-Deeb, AS, Wolff, RA, Bondy, ML, Davila, M, and Abbruzzese, JL. "Association between hepatitis B virus and pancreatic cancer." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 26.28 (October 2008): 4557-4562.

PMID

18824707

Source

epmc

Published In

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology

Volume

26

Issue

28

Publish Date

2008

Start Page

4557

End Page

4562

DOI

10.1200/jco.2008.17.3526

TAS-102 is a novel formulation of the fluorinated pyrimidine analogue trifluorothymidine (FTD) with an inhibitor of thymidine phosphorylase. The purpose of this study was to determine the MTD and DLT for TAS-102 administered three times a day on days 1-5 and 8-12 every 4 weeks. Fifteen patients were enrolled with two patients experiencing dose-limiting fatigue and granulocytopenia at the first dose level (80 mg/m2/day). Granulocytopenia was the primary toxicity: 7 patients experienced grade 3 or 4 granulocytopenia with the first course. No responses were noted, but nine patients demonstrated prolonged stable disease in this heavily pretreated 5-FU refractory population.

Authors

Overman, MJ; Kopetz, S; Varadhachary, G; Fukushima, M; Kuwata, K; Mita, A; Wolff, RA; Hoff, P; Xiong, H; Abbruzzese, JL

MLA Citation

Overman, MJ, Kopetz, S, Varadhachary, G, Fukushima, M, Kuwata, K, Mita, A, Wolff, RA, Hoff, P, Xiong, H, and Abbruzzese, JL. "Phase I clinical study of three times a day oral administration of TAS-102 in patients with solid tumors." Cancer investigation 26.8 (October 2008): 794-799.

PMID

18798063

Source

epmc

Published In

Cancer Investigation

Volume

26

Issue

8

Publish Date

2008

Start Page

794

End Page

799

DOI

10.1080/07357900802087242

This study was designed to determine the safety and optimal dosing of TAS-102, a novel oral combination of alphaalphaalpha-trifluorothymidine (FTD) and an inhibitor of thymidine phoshorylase, in patients with solid tumors. Patients who met the eligibility criteria were treated with one of two different TAS-102 regimens: once per day on either days 1-5 and 8-12 every 4 weeks (schedule A) or days 1-5 every 3 weeks (schedule B). The primary objectives were the determination of the maximum tolerated dose, dose-limiting toxicities (DLTs), and recommended phase II dose. Pharmacokinetic analysis was conducted during courses 1 and 2. Sixty-three patients received a total of 172 courses of therapy with the median number of courses delivered on both schedules being 2. DLTs were observed in three patients on schedule A, 70 mg/m(2)/day (1) and 110 mg/m(2)/day (2); and in five patients on schedule B, 120 mg/m(2)/day (1), 170 mg/m(2)/day (2), 180 mg/m(2)/day (2). Granulocytopenia was the DLT in seven of the eight cases. The most frequent toxicities were nausea, fatigue, granulocytopenia, anemia, diarrhea, and abdominal pain. Twelve patients, 6 on schedule A and 6 on schedule B, were treated at the recommended phase II dose, with good tolerance. No objective responses were seen in this heavily pretreated, 5-FU-refractory population. The pharmacokinetic parameters of FTD are a T (max) of 0.53 to 3.15 h, t (1/2) of 1.46 to 4.20 h, volume of distribution of 0.0526 to 0.483 l/kg, and clearance of 0.0194 to 0.197 1/h/kg. The recommended phase II doses for TAS-102 are 100 mg/m(2)/day on schedule A and 160 mg/m(2)/day on schedule B. Future development of TAS-102 should focus upon multiple daily dosing schedules.

Authors

Overman, MJ; Varadhachary, G; Kopetz, S; Thomas, MB; Fukushima, M; Kuwata, K; Mita, A; Wolff, RA; Hoff, PM; Xiong, H; Abbruzzese, JL

MLA Citation

Overman, MJ, Varadhachary, G, Kopetz, S, Thomas, MB, Fukushima, M, Kuwata, K, Mita, A, Wolff, RA, Hoff, PM, Xiong, H, and Abbruzzese, JL. "Phase 1 study of TAS-102 administered once daily on a 5-day-per-week schedule in patients with solid tumors." Investigational New Drugs 26.5 (October 2008): 445-454.

PMID

18528634

Source

epmc

Published In

Investigational New Drugs

Volume

26

Issue

5

Publish Date

2008

Start Page

445

End Page

454

DOI

10.1007/s10637-008-9142-3

BACKGROUND: To the authors' knowledge, there is no established second-line chemotherapy for patients with pancreatic cancer who have received gemcitabine-based therapy. A phase 2 trial was conducted to explore the efficacy of capecitabine and oxaliplatin (XELOX) in patients with advanced pancreatic cancer previously who were treated with gemcitabine. METHODS: Patients aged < or = 65 years who had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 1 received oxaliplatin at a dose of 130 mg/m(2) given on Day 1 and capecitabine at a dose of 1000 mg/m(2) twice daily for 14 days. For patients aged >65 years or with an ECOG PS of 2, the oxaliplatin dose was 110 mg/m(2) on Day 1 and the capecitabine dose was 750 mg/m(2) twice daily for 14 days. The treatment was repeated every 3 weeks. Tumor measurements were performed every 9 weeks and the primary study objective was 6-month overall survival. RESULTS: The study enrolled 41 patients. Of the 39 evaluable patients, 1 patient had a partial response and 10 patients demonstrated stable disease. The Kaplan-Meier estimate of the overall median survival was 23 weeks (95% confidence interval [95% CI], 17.0-31.0 weeks). Progression-free survival was 9.9 weeks (95% CI, 9.6-14.5 weeks). The 6-month and 1-year survival rates were 44% (95% CI, 31%-62%) and 21% (95% CI, 11%-38%), respectively. The most common grade 3-4 nonhematologic toxicity was fatigue (toxicity was graded using the National Cancer Institute Common Toxicity Criteria [version 2.0]). CONCLUSIONS: The combination of capecitabine and oxaliplatin is active in gemcitabine-pretreated patients with advanced pancreatic cancer, especially in patients with a good PS and those who have responded to first-line chemotherapy.

Authors

Xiong, HQ; Varadhachary, GR; Blais, JC; Hess, KR; Abbruzzese, JL; Wolff, RA

MLA Citation

Xiong, HQ, Varadhachary, GR, Blais, JC, Hess, KR, Abbruzzese, JL, and Wolff, RA. "Phase 2 trial of oxaliplatin plus capecitabine (XELOX) as second-line therapy for patients with advanced pancreatic cancer." Cancer 113.8 (October 2008): 2046-2052.

PMID

18756532

Source

epmc

Published In

Cancer

Volume

113

Issue

8

Publish Date

2008

Start Page

2046

End Page

2052

DOI

10.1002/cncr.23810

The International Agency for Research on Cancer has declared smoking to be a risk factor for hepatocellular carcinoma (HCC). However, passive exposure to cigarette smoke and use of noncigarette tobacco products on the risk of HCC has not been examined. Therefore, we evaluated the independent effects of different types of smoking exposure along with multiple risk factors for HCC and determined whether the magnitude of smoking was modified by other risk factors in men and women. We conducted a case-control study at The University of Texas M. D. Anderson Cancer Center where 319 HCC patients and 1,061 healthy control subjects were personally interviewed for several HCC risk factors. Multivariate logistic regression analysis was performed to estimate the adjusted odds ratio (AOR) and 95% confidence interval (CI) for each potential risk factor. Use of smokeless tobacco (chewing tobacco and snuff), cigars, pipes and passive smoking exposure were not related to HCC among noncigarette smokers. However, regular cigarette smoking was associated with HCC in men: AOR, 1.9 (95% CI, 1.1-3.1). Heavy alcohol consumption was associated with HCC in women: AOR, 7.7 (95% CI, 2.3-25.1). Cigarette smoking interacted synergistically with chronic infection of hepatitis C virus in men: AOR, 136.3 (95% CI, 43.2-429.6) and with heavy alcohol consumption in women: AOR, 13.7 (95% CI, 3.2-57.9). We conclude that sex differences were observed in HCC relationship with cigarette smoking and alcohol consumption. Controlling for smoking exposure might be a prudent approach to the prevention of HCC, especially in patients with chronic viral hepatitis infections.

Authors

Hassan, MM; Spitz, MR; Thomas, MB; El-Deeb, AS; Glover, KY; Nguyen, NT; Chan, W; Kaseb, A; Curley, SA; Vauthey, J-N; Ellis, LM; Abdalla, E; Lozano, RD; Patt, YZ; Brown, TD; Abbruzzese, JL; Li, D

MLA Citation

Hassan, MM, Spitz, MR, Thomas, MB, El-Deeb, AS, Glover, KY, Nguyen, NT, Chan, W, Kaseb, A, Curley, SA, Vauthey, J-N, Ellis, LM, Abdalla, E, Lozano, RD, Patt, YZ, Brown, TD, Abbruzzese, JL, and Li, D. "Effect of different types of smoking and synergism with hepatitis C virus on risk of hepatocellular carcinoma in American men and women: case-control study." International Journal of Cancer 123.8 (October 2008): 1883-1891.

PMID

18688864

Source

epmc

Published In

International Journal of Cancer

Volume

123

Issue

8

Publish Date

2008

Start Page

1883

End Page

1891

DOI

10.1002/ijc.23730

Prolonged infusions have been shown to be safer and potentially more effective than bolus regimens of 5-fluorouracil (5-FU) as treatment for metastatic colorectal cancer (mCRC). However, infusional 5-FU requires central venous access and costly infusion pumps. Oral fluoropyrimidines enable longer exposures to 5-FU with increased convenience. Tegafur-uracil (UFT) with leucovorin (LV) given thrice daily has improved safety plus comparable survival and response rates to bolus 5-FU/LV. We conducted a phase II clinical study in 98 patients with mCRC to evaluate if UFT with LV given twice daily provided comparable time to progression (TTP), efficacy and tolerability to that reported for thrice daily in two phase III clinical studies. Secondary objectives included overall response rate (ORR) and overall survival (OS). Median TTP was 3.8 months, when compared with 3.5 months for thrice daily. The ORR (11%) and median OS (12.8 months) with twice daily administration were similar to that of thrice daily administration (12% and 12.4 months). The incidence of grade 3/4 treatment-related diarrhoea was 30% on the twice daily and 21% on the thrice daily schedule. These results suggest that twice daily administration has similar efficacy and tolerability to thrice daily administration and is an acceptable alternative for patients who would benefit from UFT with LV therapy.

Authors

Hoff, PM; Kopetz, S; Thomas, MB; Langleben, A; Rinaldi, D; Anthony, L; Wolff, RA; Lassere, Y; Abbruzzese, JL

MLA Citation

Hoff, PM, Kopetz, S, Thomas, MB, Langleben, A, Rinaldi, D, Anthony, L, Wolff, RA, Lassere, Y, and Abbruzzese, JL. "A phase II study of UFT with leucovorin administered as a twice daily schedule in the treatment of patients with metastatic colorectal cancer." British Journal of Cancer 99.5 (September 2008): 722-726.

PMID

18728662

Source

epmc

Published In

British Journal of Cancer

Volume

99

Issue

5

Publish Date

2008

Start Page

722

End Page

726

DOI

10.1038/sj.bjc.6604541

BACKGROUND: Since its advent, endoscopic ultrasonography (EUS) has emerged as an invaluable tool in the diagnosis and management of gastrointestinal and adjacent cancers. Yet, it remains unclear how non-gastroenterologists who manage these malignancies use EUS in their practices. METHODS: A link to a self-administered questionnaire, hosted on our university website, was emailed to 650 practicing medical, radiation, and surgical oncologists in the United States. RESULTS: Data were analyzed from 100 responses. When available, the overall utilization of EUS for staging nonsmall cell lung cancer (NSCLC) was significantly low (19.0%), although available. When EUS was unavailable, majority of the patients with pancreatobiliary cancer (79%; P<0.01) were not referred for staging, unlike those with esophageal (57.9%) and rectal cancer (73.7%) were. EUS availability did not impact its use in staging gastric cancer. Majority of the respondents thought EUS made an impact in managing patients with rectal (89.5%), esophageal (84.5%), and pancreatobiliary cancers (58.5%) but not gastric (54.7%) or NSCLC (61.5%). In staging NSCLC, endoscopic ultrasound-guided fine-needle aspirate (35.7%) and mediastinoscopy (34.7%) were noted as the most accurate for tissue sampling of lymph nodes in levels 5, 7, and 8. EUS was deemed better than computerized tomography or magnetic resonance imaging by 42% in detecting small pancreatic tumors. Majority have not referred patients for EUS-guided celiac plexus neurolysis for palliation of pain in unresectable pancreatic cancer. CONCLUSIONS: These data highlight the utilization of EUS that did not necessarily follow established guidelines. Further research is essential to evaluate obstacles to utilization of endoscopic ultrasound-guided fine-needle aspirate.

Authors

Reddy, NK; Markowitz, AB; Abbruzzese, JL; Bhutani, MS

MLA Citation

Reddy, NK, Markowitz, AB, Abbruzzese, JL, and Bhutani, MS. "Knowledge of indications and utilization of EUS: a survey of oncologists in the United States." Journal of clinical gastroenterology 42.8 (September 2008): 892-896.

PMID

18645535

Source

epmc

Published In

Journal of Clinical Gastroenterology

Volume

42

Issue

8

Publish Date

2008

Start Page

892

End Page

896

DOI

10.1097/mcg.0b013e3180cab11a

To evaluate the feasibility of a 10-gene reverse transcriptase polymerase chain reaction assay to identify the tissue of origin in patients with carcinoma of unknown primary (CUP) site.Diagnostic biopsy formalin-fixed, paraffin-embedded (FFPE) specimens from 120 patients with CUP were collected retrospectively from Sarah Cannon Research Institute, Nashville, TN, and prospectively from The University of Texas M. D. Anderson Cancer Center, Houston, TX. Tissue of origin assignments by the assay were correlated with clinical and pathologic features and with response to therapy.The assay was successfully performed in 104 patients (87%), and a tissue of origin was assigned in 63 patients (61%). In the remaining 41 patients (39%), the molecular profiles were not specific for the six tumor types detectable by this assay. The tissues of origin most commonly identified were lung, pancreas, and colon; most of these patients had clinical and pathologic features consistent with these diagnoses. Patients with lung and pancreas profiles had poor response to treatment. Patients with colon cancer profiles had better response to colon cancer-specific therapies than they did to empiric CUP therapy with taxane/platinum regimens. Patients with ovarian cancer profiles were atypical, with widespread visceral metastases and a paucity of overt peritoneal involvement.This gene expression profiling assay was feasible using FFPE biopsy specimens and identified a putative tissue of origin in 61% of patients with CUP. In most patients, the assigned tissue of origin was compatible with clinicopathologic features and response to treatment. Prospective studies in which assay results are used to direct therapy are indicated.

Authors

Varadhachary, GR; Talantov, D; Raber, MN; Meng, C; Hess, KR; Jatkoe, T; Lenzi, R; Spigel, DR; Wang, Y; Greco, FA; Abbruzzese, JL; Hainsworth, JD

MLA Citation

Varadhachary, GR, Talantov, D, Raber, MN, Meng, C, Hess, KR, Jatkoe, T, Lenzi, R, Spigel, DR, Wang, Y, Greco, FA, Abbruzzese, JL, and Hainsworth, JD. "Molecular profiling of carcinoma of unknown primary and correlation with clinical evaluation." Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology 26.27 (September 2008): 4442-4448.

PMID

18802157

Source

epmc

Published In

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology

Volume

26

Issue

27

Publish Date

2008

Start Page

4442

End Page

4448

DOI

10.1200/jco.2007.14.4378

Methylation of lysine 27 on histone H3 (H3K27) by the EZH2 complex is an epigenetic mark that mediates gene silencing. EZH2 is overexpressed in many cancers and correlates with poor prognosis in both breast and prostate cancers. However, the status of H3K27 methylation and its clinical implication in cancer patients have not been reported. We thus examined trimethylation of H3K27 (H3K27me3) by immunohistochemistry and its association with clinical variables and prognosis in breast, ovarian, and pancreatic cancers. We found that H3K27me3 expression was significantly lower in breast, ovarian and pancreatic cancers than in normal tissues (62% in breast cancer vs. 88% in normal breast tissue, P = 0.001; 38.4% in ovarian cancer vs. 83.3% in normal ovarian tissue, P < 0.05; and 26% in pancreatic cancer vs. 89% in normal pancreatic tissue, P < 0.001). H3K27me3 expression showed significant prognostic impact in breast, ovarian and pancreatic cancers in univariate survival analyses. In all three cancer types, patients with low expression of H3K27me3 had significantly shorter overall survival time when compared with those with high H3K27me3 expression. In a multivariate model, H3K27me3 expression was an independent prognostic value for overall survival in all three cancer types. These results suggest that H3K27me3 expression is a prognostic indicator for clinical outcome in patients with breast, ovarian, and pancreatic cancers.

Authors

Wei, Y; Xia, W; Zhang, Z; Liu, J; Wang, H; Adsay, NV; Albarracin, C; Yu, D; Abbruzzese, JL; Mills, GB; Bast, RC; Hortobagyi, GN; Hung, M-C

MLA Citation

Wei, Y, Xia, W, Zhang, Z, Liu, J, Wang, H, Adsay, NV, Albarracin, C, Yu, D, Abbruzzese, JL, Mills, GB, Bast, RC, Hortobagyi, GN, and Hung, M-C. "Loss of trimethylation at lysine 27 of histone H3 is a predictor of poor outcome in breast, ovarian, and pancreatic cancers." Molecular Carcinogenesis 47.9 (September 2008): 701-706.

PMID

18176935

Source

epmc

Published In

Molecular Carcinogenesis

Volume

47

Issue

9

Publish Date

2008

Start Page

701

End Page

706

DOI

10.1002/mc.20413

Pancreatic cancer (PC) remains the fourth most common cause of cancer related death in the United States. Therefore, novel strategies for the prevention and treatment are urgently needed. Numerous dietary and pharmacological agents have been proposed as alternative strategies for the prevention and/or treatment of PC. Isoflavone is a prominent flavonoid found in soy products and has been proposed to be responsible for lowering the incidence of PC in Asians. Similarly, curcumin, an active ingredient of turmeric, that inhibits growth of malignant neoplasms, has a promising role in the prevention and/or treatment of PC. Here we examined whether isoflavone together with curcumin could elicit a greater inhibition of growth of PC cells than either agent alone, and also sought to determine the molecular mechanism of action. We found that the inhibition of cell growth and induction of apoptosis was significantly greater in the combination group than that could be achieved by either agent alone. These changes were associated with decreased Notch-1 expression and DNA binding activity of NF-kappaB and its target genes such as Cyclin D1, Bcl-2, and Bcl-xL. Moreover, we found that the combination of four natural agents at lower concentration was much more effective. Collectively, our results suggest that diet containing multiple natural products should be preferable over single agents for the prevention and/or treatment of PC. The superior effects of the combinatorial treatment could partly be attributed to the inhibition of constitutive activation of Notch-1 and NF-kappaB signaling pathways.

Authors

Wang, Z; Desmoulin, S; Banerjee, S; Kong, D; Li, Y; Deraniyagala, RL; Abbruzzese, J; Sarkar, FH

MLA Citation

Wang, Z, Desmoulin, S, Banerjee, S, Kong, D, Li, Y, Deraniyagala, RL, Abbruzzese, J, and Sarkar, FH. "Synergistic effects of multiple natural products in pancreatic cancer cells." Life sciences 83.7-8 (August 2008): 293-300.

PMID

18640131

Source

epmc

Published In

Life Sciences

Volume

83

Issue

7-8

Publish Date

2008

Start Page

293

End Page

300

DOI

10.1016/j.lfs.2008.06.017

PURPOSE: Pancreatic cancer is almost always lethal, and the only U.S. Food and Drug Administration-approved therapies for it, gemcitabine and erlotinib, produce objective responses in <10% of patients. We evaluated the clinical biological effects of curcumin (diferuloylmethane), a plant-derived dietary ingredient with potent nuclear factor-kappaB (NF-kappaB) and tumor inhibitory properties, against advanced pancreatic cancer. EXPERIMENTAL DESIGN: Patients received 8 g curcumin by mouth daily until disease progression, with restaging every 2 months. Serum cytokine levels for interleukin (IL)-6, IL-8, IL-10, and IL-1 receptor antagonists and peripheral blood mononuclear cell expression of NF-kappaB and cyclooxygenase-2 were monitored. RESULTS: Twenty-five patients were enrolled, with 21 evaluable for response. Circulating curcumin was detectable as drug in glucuronide and sulfate conjugate forms, albeit at low steady-state levels, suggesting poor oral bioavailability. Two patients showed clinical biological activity. One had ongoing stable disease for >18 months; interestingly, one additional patient had a brief, but marked, tumor regression (73%) accompanied by significant increases (4- to 35-fold) in serum cytokine levels (IL-6, IL-8, IL-10, and IL-1 receptor antagonists). No toxicities were observed. Curcumin down-regulated expression of NF-kappaB, cyclooxygenase-2, and phosphorylated signal transducer and activator of transcription 3 in peripheral blood mononuclear cells from patients (most of whom had baseline levels considerably higher than those found in healthy volunteers). Whereas there was considerable interpatient variation in plasma curcumin levels, drug levels peaked at 22 to 41 ng/mL and remained relatively constant over the first 4 weeks. CONCLUSIONS: Oral curcumin is well tolerated and, despite its limited absorption, has biological activity in some patients with pancreatic cancer.

Authors

Dhillon, N; Aggarwal, BB; Newman, RA; Wolff, RA; Kunnumakkara, AB; Abbruzzese, JL; Ng, CS; Badmaev, V; Kurzrock, R

MLA Citation

Dhillon, N, Aggarwal, BB, Newman, RA, Wolff, RA, Kunnumakkara, AB, Abbruzzese, JL, Ng, CS, Badmaev, V, and Kurzrock, R. "Phase II trial of curcumin in patients with advanced pancreatic cancer." Clinical Cancer Research : an Official Journal of the American Association for Cancer Research 14.14 (July 2008): 4491-4499.

PMID

18628464

Source

epmc

Published In

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research

Volume

14

Issue

14

Publish Date

2008

Start Page

4491

End Page

4499

DOI

10.1158/1078-0432.ccr-08-0024

We conducted a phase II trial of preoperative gemcitabine and cisplatin chemotherapy in addition to chemoradiation (Gem-Cis-XRT) and pancreaticoduodenectomy (PD) for patients with stage I/II pancreatic adenocarcinoma.Chemotherapy consisted of gemcitabine (750 mg/m(2)) and cisplatin (30 mg/m(2)) given every 2 weeks for four doses. Chemoradiation consisted of four weekly infusions of gemcitabine (400 mg/m(2)) combined with radiation therapy (30 Gy in 10 fractions administered over 2 weeks) delivered 5 days per week. Patients underwent restaging 4 to 6 weeks after completion of chemoradiation and, in the absence of disease progression, were taken to surgery.The study enrolled 90 patients; 79 patients (88%) completed chemo-chemoradiation. Sixty-two (78%) of 79 patients were taken to surgery and 52 (66%) of 79 underwent PD. The median overall survival of all 90 patients was 17.4 months. Median survival for the 79 patients who completed chemo-chemoradiation was 18.7 months, with a median survival of 31 months for the 52 patients who underwent PD and 10.5 months for the 27 patients who did not undergo surgical resection of their primary tumor (P < .001).Preoperative Gem-Cis-XRT did not improve survival beyond that achieved with preoperative gemcitabine-based chemoradiation (Gem-XRT) alone. The longer preoperative interval required more durable biliary decompression (metal stents) but was not associated with local tumor progression. The gemcitabine-based chemoradiation platform is a reasonable foundation on which to build future phase II multimodality trials for stage I/II pancreatic cancer incorporating emerging systemic therapies.

Authors

Varadhachary, GR; Wolff, RA; Crane, CH; Sun, CC; Lee, JE; Pisters, PWT; Vauthey, J-N; Abdalla, E; Wang, H; Staerkel, GA; Lee, JH; Ross, WA; Tamm, EP; Bhosale, PR; Krishnan, S; Das, P; Ho, L; Xiong, H; Abbruzzese, JL; Evans, DB

MLA Citation

Varadhachary, GR, Wolff, RA, Crane, CH, Sun, CC, Lee, JE, Pisters, PWT, Vauthey, J-N, Abdalla, E, Wang, H, Staerkel, GA, Lee, JH, Ross, WA, Tamm, EP, Bhosale, PR, Krishnan, S, Das, P, Ho, L, Xiong, H, Abbruzzese, JL, and Evans, DB. "Preoperative gemcitabine and cisplatin followed by gemcitabine-based chemoradiation for resectable adenocarcinoma of the pancreatic head." Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology 26.21 (July 2008): 3487-3495.

PMID

18640929

Source

epmc

Published In

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology

Volume

26

Issue

21

Publish Date

2008

Start Page

3487

End Page

3495

DOI

10.1200/jco.2007.15.8642

We conducted a phase II trial to assess the outcomes of patients who received preoperative gemcitabine-based chemoradiation and pancreaticoduodenectomy (PD) for stage I/II pancreatic adenocarcinoma.Eligible patients with pancreatic head/uncinate process adenocarcinoma and radiographically defined potentially resectable disease received chemoradiation with 7 weekly intravenous (IV) infusions of gemcitabine (400 mg/m(2) IV over 30 minutes) plus radiation therapy (30 Gy in 10 fractions over 2 weeks). Patients underwent restaging 4 to 6 weeks after completion of chemoradiation and, in the absence of disease progression, were taken to surgery.The study enrolled 86 patients. At the time of restaging, disease progression or a decline in performance status precluded 13 patients from surgery. Seventy-three (85%) of 86 patients were taken to surgery, extrapancreatic disease was found in nine, and 64 (74%) of 86 underwent a successful PD. Median overall survival (86 patients) was 22.7 months with a 27% 5-year survival. Median survival was 34 months for the 64 patients who underwent PD and 7 months for the 22 unresected patients (P < .001). The 5-year survival for those who did and did not undergo PD was 36% and 0%, respectively.Preoperative gemcitabine-based chemoradiation followed by restaging and evaluation for surgery separated the study population into two different subsets: patients likely to benefit from PD (n = 64) and those in whom surgery would be unlikely to provide clinical benefit (n = 22). Furthermore, the encouraging overall survival observed in this large trial supports the continued investigation of gemcitabine-based preoperative therapy in resectable pancreatic cancer.

Authors

Evans, DB; Varadhachary, GR; Crane, CH; Sun, CC; Lee, JE; Pisters, PWT; Vauthey, J-N; Wang, H; Cleary, KR; Staerkel, GA; Charnsangavej, C; Lano, EA; Ho, L; Lenzi, R; Abbruzzese, JL; Wolff, RA

MLA Citation

Evans, DB, Varadhachary, GR, Crane, CH, Sun, CC, Lee, JE, Pisters, PWT, Vauthey, J-N, Wang, H, Cleary, KR, Staerkel, GA, Charnsangavej, C, Lano, EA, Ho, L, Lenzi, R, Abbruzzese, JL, and Wolff, RA. "Preoperative gemcitabine-based chemoradiation for patients with resectable adenocarcinoma of the pancreatic head." Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology 26.21 (July 2008): 3496-3502.

PMID

18640930

Source

epmc

Published In

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology

Volume

26

Issue

21

Publish Date

2008

Start Page

3496

End Page

3502

DOI

10.1200/jco.2007.15.8634

Carcinoma of unknown primary (CUP), which accounts for about 3-5% of all new cancers, is a challenging heterogeneous entity with an unmet research need. Traditionally, CUP has been managed with broad-spectrum chemotherapy, but with the increasing availability of sophisticated diagnostic techniques and the emergence of new treatments that have been shown to be effective in specific cancers the one-treatment-fits-all approach to CUP might eventually no longer be valid. CUP in association with a colon-cancer profile (CCP-CUP) is an example of an emerging, specific CUP subset that seems to benefit from a tailored approach. CCP-CUP is identified by CK20 and CDX2-positive and CK7-negative immunohistochemistry and a clinical course consistent with that of patients known to have metastatic colon cancer. Our findings suggest that patients with CCP-CUP derive substantial benefit from the use of specific treatments developed for colon cancer and larger clinical trials are warranted to more definitely test this finding. In the era of molecular profiling, we expect that additional work with CCP-CUP and other CUP subsets will provide attractive tailored treatment alternatives, with efficacies that exceed the current one-treatment-fits-all approach.

Authors

Varadhachary, GR; Raber, MN; Matamoros, A; Abbruzzese, JL

MLA Citation

Varadhachary, GR, Raber, MN, Matamoros, A, and Abbruzzese, JL. "Carcinoma of unknown primary with a colon-cancer profile-changing paradigm and emerging definitions." The Lancet. Oncology 9.6 (June 2008): 596-599.

PMID

18510991

Source

epmc

Published In

The Lancet. Oncology

Volume

9

Issue

6

Publish Date

2008

Start Page

596

End Page

599

DOI

10.1016/s1470-2045(08)70151-7

Aromatic amines, N-nitroso compounds and heterocyclic amines are suspected human pancreatic carcinogens. Cytochrome P450 (CYP) 1A2, N-acetyltransferase (NAT) 1, NAT2 and sulfotransferase (SULT) are enzymes involved in the metabolism of these carcinogens. To test the hypothesis that genetic variations in carcinogen metabolism modify the risk of pancreatic cancer (PC), we investigated the effect of single-nucleotide polymorphisms (SNPs) of the CYP1A2, NAT1, NAT2 and SULT1A1 gene on modification of the risk of PC in a hospital-based study of 755 patients with pancreatic adenocarcinoma and 636 healthy frequency-matched controls. Smoking and dietary mutagen exposure information was collected by personal interviews. Genotypes were determined using the polymerase chain reaction-restriction fragment length polymorphism and Taqman methods. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional multivariate logistic regression analysis. We observed no significant main effects of any of these genes on the risk of PC. The CYP1A2 and NAT1 but not SULT1A1 and NAT2 genotypes showed significant interactions with heavy smoking in women not men. In contrast, a significant interaction between NAT1 genotype and dietary mutagen intake on modifying the risk of PC were observed among men but not women. The OR (95% CI) of PC was 2.23 (1.33-3.72) and 2.54 (1.51-4.25) for men having the NAT1*10 and a higher intake of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and benzo[a]pyrene, respectively, compared with individuals having no NAT1*10 or a lower intake of these dietary mutagens. These data suggest the existence of gender-specific susceptibility to tobacco carcinogen and dietary mutagen exposure in PC.

Authors

Suzuki, H; Morris, JS; Li, Y; Doll, MA; Hein, DW; Liu, J; Jiao, L; Hassan, MM; Day, RS; Bondy, ML; Abbruzzese, JL; Li, D

MLA Citation

Suzuki, H, Morris, JS, Li, Y, Doll, MA, Hein, DW, Liu, J, Jiao, L, Hassan, MM, Day, RS, Bondy, ML, Abbruzzese, JL, and Li, D. "Interaction of the cytochrome P4501A2, SULT1A1 and NAT gene polymorphisms with smoking and dietary mutagen intake in modification of the risk of pancreatic cancer." Carcinogenesis 29.6 (June 2008): 1184-1191.

PMID

18499698

Source

epmc

Published In

Carcinogenesis

Volume

29

Issue

6

Publish Date

2008

Start Page

1184

End Page

1191

DOI

10.1093/carcin/bgn085

The integration of biospecimens with reliable clinical data is critical to advance molecular findings from the laboratory to the clinic. We describe the development of an integrated pancreatic tissue bank (PTB) and clinical database for patients with pancreatic cancer and other pancreatic disorders.A clinical database and PTB were created in 1990 and 2000, respectively, to collect clinical information and biospecimens from patients with suspected or confirmed pancreatic cancer, other pancreatic diseases, and tumors of the duodenum, ampulla of Vater, and distal bile duct. Standard procedures for biospecimen collection and data entry were developed.From 2000 through 2006, the PTB collected 8,061 pancreatic tissue specimens from 620 patients. The most common histologies of pancreatic tumors were pancreatic ductal adenocarcinoma (55.3%) and neuroendocrine carcinoma (16.3%). The biospecimen collection also includes 431 plasma samples, 40 fine-needle aspiration samples, and a tissue microarray containing 85 pancreatic adenocarcinomas and matched normal tissue specimens. The clinical database contains information for 7,647 patients with pancreatic cancer, other pancreatic disorders, and duodenal, ampullary, or bile duct neoplasms. The data are arranged into nine modules: patient, presentation, risk factors, diagnostic imaging, treatment plan, surgery, pathology, postoperative complications, and follow-up.We have established a pancreatic cancer tissue bank with standardized procedures for collection of biospecimens along with a comprehensive multidisciplinary clinical database. The integrated biospecimen bank and clinical database for pancreatic cancer described here can serve as a model from which other groups may develop similar systems.

Authors

Hwang, RF; Wang, H; Lara, A; Gomez, H; Chang, T; Sieffert, N; Moon, Y; Ram, S; Zimmerman, S; Lee, JH; Pisters, PWT; Tamm, EP; Fleming, JB; Abbruzzese, JL; Evans, DB

MLA Citation

Hwang, RF, Wang, H, Lara, A, Gomez, H, Chang, T, Sieffert, N, Moon, Y, Ram, S, Zimmerman, S, Lee, JH, Pisters, PWT, Tamm, EP, Fleming, JB, Abbruzzese, JL, and Evans, DB. "Development of an integrated biospecimen bank and multidisciplinary clinical database for pancreatic cancer." Annals of surgical oncology 15.5 (May 2008): 1356-1366.

PMID

18256882

Source

epmc

Published In

Annals of Surgical Oncology

Volume

15

Issue

5

Publish Date

2008

Start Page

1356

End Page

1366

DOI

10.1245/s10434-008-9833-1

PURPOSE: The current strategy of drug development has been criticized as being highly inefficient. In 2004, the US Food and Drug Administration (FDA) released recommendations to improve this process, including a push for increased use of enrichment trials. It is unclear to what extent aspects of this "Critical Path Initiative" have been adopted in trial designs in metastatic colorectal cancer. METHODS: A systematic review was conducted of actively enrolling treatment trials in metastatic colorectal cancer. Trials were identified from the National Cancer Institute's clinicaltrials.gov and Investigative Drug Branch databases. Trials were categorized based on the number of prior treatments allowed, phase of the trial, agent mechanism of action, and FDA approval status of agents under investigation. RESULTS: One hundred two trials are enrolling, with a combined enrollment goal of more than 20,000 patients. Thirteen percent of trials investigated an agent not yet FDA-approved for any oncology indication. The most common study design was a phase II study limited to previously untreated patients; compared with the remaining trials, these phase II trials were more than 10 times more likely to only use agents FDA-approved for colorectal cancer. Three percent of patients were enrolled onto trials enriched for tumor characteristics that were hypothesized to improve clinical benefit. CONCLUSION: Current clinical trials for metastatic colorectal cancer are deficient in the investigation of agents directed at a novel therapeutic target, overuse phase II studies of FDA-approved agents, and fail to incorporate enrichment trial designs as encouraged by the FDA initiative.

Authors

Kopetz, S; Overman, M; Chang, DZ; Glover, KY; Shureiqi, I; Wolff, RA; Abbruzzese, JL; Eng, C

MLA Citation

Kopetz, S, Overman, M, Chang, DZ, Glover, KY, Shureiqi, I, Wolff, RA, Abbruzzese, JL, and Eng, C. "Systematic survey of therapeutic trials for metastatic colorectal cancer: room for improvement in the critical pathway." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 26.12 (April 2008): 2000-2005.

PMID

18421052

Source

epmc

Published In

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology

Volume

26

Issue

12

Publish Date

2008

Start Page

2000

End Page

2005

DOI

10.1200/jco.2007.13.2407

Pancreatic ductal adenocarcinoma (PDAC) progresses rapidly and exhibits profound resistance to treatment. We recently reported that a great majority of PDAC tumors and tumor cell lines express elevated levels of tissue transglutaminase (TG2). Here, we provide first evidence that TG2 expression in PDAC cells results in constitutive activation of focal adhesion kinase/AKT by modulating the expression of the tumor suppressor phosphatase PTEN.Using PDAC cell lines, we determined the effect of TG2 overexpression on PTEN stability and functions. We confirmed the correlation between TG2 expression and PTEN levels in a few (n=51) PDAC tumor samples.We observed that expression of TG2 is inversely correlated with PTEN expression in PDAC cells. Ectopic expression of TG2 inhibited PTEN phosphorylation and promoted its degradation by ubiquitin-proteasomal pathway. Conversely, down-regulation of TG2 by small interfering RNA up-regulated PTEN expression. Clinical relevance of these results was evident in an athymic nude mouse model where down-regulation of endogenous TG2 caused a significant retardation in PDAC xenograft growth. Importantly, the analysis of 51 tumor samples from patients with stage II PDAC revealed that overexpression of TG2 was associated with loss of PTEN expression (P=0.023; odds ratio, 4.1). In multivariate analysis, TG2-mediated loss of PTEN was a prognostic factor for overall survival in patients with stage II pancreatic ductal carcinoma independent of tumor stage/lymph node status and tumor differentiation (P=0.01).TG2 expression in PDAC promotes degradation of PTEN by ubiquitin-proteasomal pathway and results in constitutive activation of focal adhesion kinase/AKT cell survival signaling.

Authors

Verma, A; Guha, S; Wang, H; Fok, JY; Koul, D; Abbruzzese, J; Mehta, K

MLA Citation

Verma, A, Guha, S, Wang, H, Fok, JY, Koul, D, Abbruzzese, J, and Mehta, K. "Tissue transglutaminase regulates focal adhesion kinase/AKT activation by modulating PTEN expression in pancreatic cancer cells." Clinical cancer research : an official journal of the American Association for Cancer Research 14.7 (April 2008): 1997-2005.

PMID

18381937

Source

epmc

Published In

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research

Volume

14

Issue

7

Publish Date

2008

Start Page

1997

End Page

2005

DOI

10.1158/1078-0432.ccr-07-1533

UNLABELLED: PET molecular imaging of 15O-labeled water is the gold standard for measuring blood flow in humans. However, this requires an on-site cyclotron to produce the short-lived 15O tracer, which is cost-prohibitive for most clinical PET centers. The purpose of this study was to determine if the early uptake of 18F-FDG could be used to measure regional blood flow in tumors in the absence of 15O-water. METHODS: PET scans were obtained in patients being evaluated for tumor perfusion and glucose metabolism in a phase I dose-escalating protocol for endostatin, a novel antiangiogenic agent. A 2-min perfusion scan was performed with a bolus injection of 2,220 MBq (60 mCi) of 15O-water, which was followed by a 370-MBq (10 mCi) dose of 18F-FDG. Four sequential scans of 18F-FDG uptake were acquired, consisting of an early 2-min uptake scan-or first-pass scan-and 3 sequential 15-min late 18F-FDG uptake scans. Regions of interest (ROIs) were drawn on 2 or more tumor sites and on back muscle, as a control ROI, for each patient. Arterial blood concentration was derived from the PET scans by drawing an ROI over a large artery in the field of view. Blood flow was computed with a simple 1-compartment blood flow model using the first 2 min of data after injection. RESULTS: Blood flow estimated from the early uptake of 18F-FDG was linearly correlated with 15O-measured blood flow, with an intercept of 0.01, a slope of 0.86, and an R2 regression coefficient of 0.74 (r = 0.86). The 18F-FDG tumor extraction fraction relative to 15O-water averaged 0.86. A preliminary case study of a patient with prostate cancer confirms the utility of the first-pass 18F-FDG blood flow analysis in tumor diagnosis. CONCLUSION: These results suggest that the first-pass uptake of 18F-FDG may provide an estimate of perfusion in a tumor within the limitations of incomplete extraction of 18F-FDG compared with 15O-water.

Authors

Mullani, NA; Herbst, RS; O'Neil, RG; Gould, KL; Barron, BJ; Abbruzzese, JL

MLA Citation

Mullani, NA, Herbst, RS, O'Neil, RG, Gould, KL, Barron, BJ, and Abbruzzese, JL. "Tumor blood flow measured by PET dynamic imaging of first-pass 18F-FDG uptake: a comparison with 15O-labeled water-measured blood flow." Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine 49.4 (April 2008): 517-523.

PMID

18344436

Source

epmc

Published In

Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine

Volume

49

Issue

4

Publish Date

2008

Start Page

517

End Page

523

DOI

10.2967/jnumed.107.048504

The goals of this study were to determine if single-nucleotide polymorphisms in DNA damage repair genes and cell cycle regulating genes affect clinical response to combined gemcitabine radiation therapy and the overall survival (OS) of patients with pancreatic cancer.We evaluated six single-nucleotide polymorphisms of the ATM, ATM and Rad3-related (ATR), CHEK1, and CHEK2 genes in 119 patients with potentially resectable pancreatic cancer who were enrolled in clinical trials at The University of Texas M. D. Anderson Cancer Center from February 1999 to January 2006, with follow-up until February 2007. Patients received neoadjuvant concurrent gemcitabine and radiation therapy with or without gemcitabine-cisplatin induction therapy. Genotypes were determined and tested for associations with OS by Kaplan-Meier estimation, the log-rank test, and Cox regression analysis. P values of

Authors

Okazaki, T; Jiao, L; Chang, P; Evans, DB; Abbruzzese, JL; Li, D

MLA Citation

Okazaki, T, Jiao, L, Chang, P, Evans, DB, Abbruzzese, JL, and Li, D. "Single-nucleotide polymorphisms of DNA damage response genes are associated with overall survival in patients with pancreatic cancer." Clinical cancer research : an official journal of the American Association for Cancer Research 14.7 (April 2008): 2042-2048.

PMID

18381943

Source

epmc

Published In

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research

Volume

14

Issue

7

Publish Date

2008

Start Page

2042

End Page

2048

DOI

10.1158/1078-0432.ccr-07-1520

Most pancreatic cancer patients present with inoperable disease or develop metastases after surgery. Conventional therapies are usually ineffective in treating metastatic disease. It is evident that novel therapies remain to be developed. Transforming growth factor beta (TGF-beta) plays a key role in cancer metastasis, signaling through the TGF-beta type I/II receptors (TbetaRI/II). We hypothesized that targeting TbetaRI/II kinase activity with the novel inhibitor LY2109761 would suppress pancreatic cancer metastatic processes. The effect of LY2109761 has been evaluated on soft agar growth, migration, invasion using a fibroblast coculture model, and detachment-induced apoptosis (anoikis) by Annexin V flow cytometric analysis. The efficacy of LY2109761 on tumor growth, survival, and reduction of spontaneous metastasis have been evaluated in an orthotopic murine model of metastatic pancreatic cancer expressing both luciferase and green fluorescence proteins (L3.6pl/GLT). To determine whether pancreatic cancer cells or the cells in the liver microenvironment were involved in LY2109761-mediated reduction of liver metastasis, we used a model of experimental liver metastasis. LY2109761 significantly inhibited the L3.6pl/GLT soft agar growth, suppressed both basal and TGF-beta1-induced cell migration and invasion, and induced anoikis. In vivo, LY2109761, in combination with gemcitabine, significantly reduced the tumor burden, prolonged survival, and reduced spontaneous abdominal metastases. Results from the experimental liver metastasis models indicate an important role for targeting TbetaRI/II kinase activity on tumor and liver microenvironment cells in suppressing liver metastasis. Targeting TbetaRI/II kinase activity on pancreatic cancer cells or the cells of the liver microenvironment represents a novel therapeutic approach to prevent pancreatic cancer metastasis.

Authors

Melisi, D; Ishiyama, S; Sclabas, GM; Fleming, JB; Xia, Q; Tortora, G; Abbruzzese, JL; Chiao, PJ

MLA Citation

Melisi, D, Ishiyama, S, Sclabas, GM, Fleming, JB, Xia, Q, Tortora, G, Abbruzzese, JL, and Chiao, PJ. "LY2109761, a novel transforming growth factor beta receptor type I and type II dual inhibitor, as a therapeutic approach to suppressing pancreatic cancer metastasis." Molecular Cancer Therapeutics 7.4 (April 2008): 829-840.

PMID

18413796

Source

epmc

Published In

Molecular Cancer Therapeutics

Volume

7

Issue

4

Publish Date

2008

Start Page

829

End Page

840

DOI

10.1158/1535-7163.MCT-07-0337

Effective systemic therapy for advanced carcinoid is lacking. The combination of bevacizumab (BEV) and pegylated (PEG) interferon alpha-2b was evaluated among patients with metastatic or unresectable carcinoid tumors.Forty-four patients on stable doses of octreotide were randomly assigned to 18 weeks of treatment with bevacizumab or PEG interferon alpha-2b. At disease progression (PD) or at the end of 18 weeks (whichever occurred earlier), patients received bevacizumab plus PEG interferon until progression. Functional computer tomography (CT) scans were performed to measure effect on tumor blood flow.In the bevacizumab arm, four patients (18%) achieved confirmed partial response (PR), 17 patients (77%) had stable disease (SD), and one patient (5%) had PD. In the PEG interferon arm, 15 patients (68%) had SD and six patients (27%) had PD. Progression-free survival (PFS) rates after 18 weeks of monotherapy were 95% in bevacizumab versus 68% on the PEG interferon arm. The overall median PFS for all 44 patients is 63 weeks. Compared with paired baseline measurements on functional CT scans, we observed a 49% (P < .01) and 28% (P < .01) decrease in tumor blood flow at day 2 and week 18 among patients treated with bevacizumab. No significant changes in tumor blood flow were observed following PEG interferon. PEG interferon alpha-2b treatment was associated with decrease in plasma basic fibroblast growth factor (bFGF; P = .04) and increase in plasma interleukin-18 (IL-18; P < .01). No significant changes in bFGF or IL-18 following treatment with bevacizumab were observed.Bevacizumab therapy resulted in objective responses, reduction of tumor blood flow, and longer PFS in patients with carcinoid than PEG interferon treatment.

Authors

Yao, JC; Phan, A; Hoff, PM; Chen, HX; Charnsangavej, C; Yeung, S-CJ; Hess, K; Ng, C; Abbruzzese, JL; Ajani, JA

MLA Citation

Yao, JC, Phan, A, Hoff, PM, Chen, HX, Charnsangavej, C, Yeung, S-CJ, Hess, K, Ng, C, Abbruzzese, JL, and Ajani, JA. "Targeting vascular endothelial growth factor in advanced carcinoid tumor: a random assignment phase II study of depot octreotide with bevacizumab and pegylated interferon alpha-2b." Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology 26.8 (March 2008): 1316-1323.

PMID

18323556

Source

epmc

Published In

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology

Volume

26

Issue

8

Publish Date

2008

Start Page

1316

End Page

1323

DOI

10.1200/jco.2007.13.6374

Authors

Abbruzzese, JL

MLA Citation

Abbruzzese, JL. "Adjuvant therapy for surgically resected pancreatic adenocarcinoma." JAMA 299.9 (March 2008): 1066-1067.

PMID

18319419

Source

epmc

Published In

Jama

Volume

299

Issue

9

Publish Date

2008

Start Page

1066

End Page

1067

DOI

10.1001/jama.299.9.1066

XRCC2 and XRCC3 are key components of the homologous recombination (HR) machinery that repairs DNA double-strand breaks. We hypothesized that the altered HR repair capacity conferred by single nucleotide polymorphisms (SNPs) would modify individual susceptibility to sporadic pancreatic cancer.In a hospital-based case-control study, genomic DNA and exposure information was obtained from 468 patients with pathologically confirmed pancreatic adenocarcinoma and 498 frequency-matched healthy controls at M.D. Anderson Cancer Center during January 2000 to September 2006. Genotypes of XRCC2 31479 G>A (Arg188His) and XRCC3 17893 A>G and 18067 C>T (Thr241Met) were determined using the Masscode technology. Unconditional logistic regression models were used to estimate the odds ratio (OR) and its 95% confidence interval (CI) in non-Hispanic whites (408 cases and 449 controls).The distribution of genotype frequencies was not different between cases and controls. We observed a significant effect modification between XRCC2 polymorphism and smoking status and pack-year of smoking in modifying pancreatic cancer risk (P value for interaction 0.02 and 0.05, respectively). Compared with never-smokers carrying the XRCC2 Arg188Arg genotype, the OR (95% CI) for individuals carrying the (188)His allele was 2.32 (1.25-4.31) among ever-smokers, 1.43 (0.59-3.48) among light smokers (< or = 22 pack-years), and 3.42 (1.47-7.96) among heavy smokers (> or =22 pack-years). The two XRCC3 SNPs are in strong linkage disequilibrium, but there was no suggestive association between XRCC3 genotype and the risk of pancreatic cancer.XRCC2 Arg188His polymorphism may be one of the genetic modifiers for smoking-related pancreatic cancer.

Authors

Jiao, L; Hassan, MM; Bondy, ML; Wolff, RA; Evans, DB; Abbruzzese, JL; Li, D

MLA Citation

Jiao, L, Hassan, MM, Bondy, ML, Wolff, RA, Evans, DB, Abbruzzese, JL, and Li, D. "XRCC2 and XRCC3 gene polymorphism and risk of pancreatic cancer." The American Journal of Gastroenterology 103.2 (February 2008): 360-367.

PMID

17986315

Source

epmc

Published In

American Journal of Gastroenterology

Volume

103

Issue

2

Publish Date

2008

Start Page

360

End Page

367

DOI

10.1111/j.1572-0241.2007.01615.x

Background: Improved survival of patients with metastatic colorectal cancer (CRC) has been shown to correlate with increased utilization of the 3 active cytotoxic chemotherapeutic agents: 5-fluorouracil (5-FU), irinotecan, and oxaliplatin, usually administered in 2 lines of therapy. However, it is unclear which patient, disease, and treatment characteristics are associated with the utilization of a second-line regimen. Patients and Methods: We performed a retrospective chart review. Patients with metastatic CRC treated with bevacizumab outside of a clinical trial and any infusional 5-FU/leucovorin (LV) regimen off-protocol (ie, 5-FU/LV/irinotecan [FOLFIRI]/bevacizumab or 5-FU/LV/oxaliplatin [FOLFOX]/bevacizumab) at the University of Texas M. D.Anderson Cancer Center between February 2004 and September 2005 were included. Prespecified characteristics of age, tumor burden, severe toxicity, and front-line regimen efficacy were compared with exploratory analyses of additional patient, disease, and treatment characteristics. Results: Eighty-seven sequential patients treated with the specified front-line regimens were identified. Seventy-six percent of the eligible patients were treated with a second-line regimen. Despite equal treatment durations, patients with a better response of stable disease were significantly less likely to receive a third cytotoxic agent than patients with a partial response (68% vs. 95%; odds ratio, 8.2; P = .02) due to declining performance status (86%) or patient preference (14%). This was associated with a decreased 2-year overall survival (86% vs. 55%). Neither age, tumor burden, nor development of toxicities were associated with a different utilization of a second-line regimen. Conclusion: Failure to obtain a response to initial chemotherapy for metastatic disease appears to be associated with decreased utilization of a second-line regimen.

Authors

Politano, S; Overman, M; Pathak, P; Chadha, R; Glover, K; Chang, DZ; Wolff, RA; Hoff, PM; Abbruzzese, J; Eng, C; Kopetz, S

MLA Citation

Politano, S, Overman, M, Pathak, P, Chadha, R, Glover, K, Chang, DZ, Wolff, RA, Hoff, PM, Abbruzzese, J, Eng, C, and Kopetz, S. "Second-line chemotherapy use in metastatic colon cancer varies by disease responsiveness." Clinical Colorectal Cancer 7.1 (January 1, 2008): 55-59.

Source

scopus

Published In

Clinical Colorectal Cancer

Volume

7

Issue

1

Publish Date

2008

Start Page

55

End Page

59

DOI

10.3816/CCC.2008.n.008

Authors

Thomas, MB; Davila, M; Abbruzzese, JL

MLA Citation

Thomas, MB, Davila, M, and Abbruzzese, JL. "Stemming the tide of hepatitis B virus related hepatocellular carcinoma?." Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology 26.2 (January 2008): 172-174.

PMID

18182657

Source

epmc

Published In

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology

Volume

26

Issue

2

Publish Date

2008

Start Page

172

End Page

174

DOI

10.1200/jco.2007.14.4337

Platelet-derived growth factor-D (PDGF-D) signaling plays critical roles in the pathogenesis and progression of human malignancies; however, the precise mechanism by which PDGF-D causes tumor cell invasion and angiogenesis remain unclear. Because Notch-1, nuclear factor-kappaB (NF-kappaB), vascular endothelial growth factor (VEGF), and matrix metalloproteinases (MMP) are critically involved in the processes of tumor cell invasion and metastasis, we investigated whether PDGF-D down-regulation could be mechanistically associated with the down-regulation of Notch-1, NF-kappaB, VEGF, and MMP-9, resulting in the inhibition of tumor cell invasion and angiogenesis. Our data showed that down-regulation of PDGF-D leads to the inactivation of Notch-1 and NF-kappaB DNA-binding activity and, in turn, down regulates the expression of its target genes, such as VEGF and MMP-9. We also found that the down-regulation of PDGF-D by small interfering RNA (siRNA) decreased tumor cell invasion, whereas PDGF-D overexpression by cDNA transfection led to increased cell invasion. Consistent with these results, we also found that the down-regulation of PDGF-D not only decreased MMP-9 mRNA and its protein expression but also inhibited the processing of pro-MMP-9 protein to its active form. Moreover, conditioned medium from PDGF-D siRNA-transfected cells showed reduced levels of VEGF and, in turn, inhibited the tube formation of human umbilical vascular endothelial cells, suggesting that down-regulation of PDGF-D leads to the inhibition of angiogenesis. Taken together, we conclude that the down-regulation of PDGF-D by novel approaches could lead to the down-regulation of Notch-1 and, in turn, inactivate NF-kappaB and its target genes (i.e., MMP-9 and VEGF), resulting in the inhibition of invasion and angiogenesis.

Authors

Wang, Z; Kong, D; Banerjee, S; Li, Y; Adsay, NV; Abbruzzese, J; Sarkar, FH

MLA Citation

Wang, Z, Kong, D, Banerjee, S, Li, Y, Adsay, NV, Abbruzzese, J, and Sarkar, FH. "Down-regulation of platelet-derived growth factor-D inhibits cell growth and angiogenesis through inactivation of Notch-1 and nuclear factor-kappaB signaling." Cancer Research 67.23 (December 2007): 11377-11385.

PMID

18056465

Source

epmc

Published In

Cancer Research

Volume

67

Issue

23

Publish Date

2007

Start Page

11377

End Page

11385

DOI

10.1158/0008-5472.can-07-2803

Although cigarette smoking is the most well-established environmental risk factor for pancreatic cancer, the interaction between smoking and other risk factors has not been assessed. We evaluated the independent effects of multiple risk factors for pancreatic cancer and determined whether the magnitude of cigarette smoking was modified by other risk factors in men and women.We conducted a hospital-based case-control study involving 808 patients with pathologically diagnosed pancreatic cancer and 808 healthy frequency-matched controls. Information on risk factors was collected by personal interview, and unconditional logistic regression was used to determine adjusted odds ratios (AORs) by the maximum-likelihood method.Cigarette smoking, family history of pancreatic cancer, heavy alcohol consumption (>60 mL ethanol/day), diabetes mellitus, and history of pancreatitis were significant risk factors for pancreatic cancer. We found synergistic interactions between cigarette smoking and family history of pancreatic cancer (AOR 12.8, 95% confidence interval [CI] 1.6-108.9) and diabetes mellitus (AOR 9.3, 95% CI 2.0-44.1) in women, according to an additive model. Approximately 23%, 9%, 3%, and 5% of pancreatic cancer cases in this study were related to cigarette smoking, diabetes mellitus, heavy alcohol consumption, and family history of pancreatic cancer, respectively.The significant synergy between these risk factors suggests a common pathway for carcinogenesis of the pancreas. Determining the underlying mechanisms for such synergies may lead to the development of pancreatic cancer prevention strategies for high-risk individuals.

Authors

Hassan, MM; Bondy, ML; Wolff, RA; Abbruzzese, JL; Vauthey, J-N; Pisters, PW; Evans, DB; Khan, R; Chou, T-H; Lenzi, R; Jiao, L; Li, D

MLA Citation

Hassan, MM, Bondy, ML, Wolff, RA, Abbruzzese, JL, Vauthey, J-N, Pisters, PW, Evans, DB, Khan, R, Chou, T-H, Lenzi, R, Jiao, L, and Li, D. "Risk factors for pancreatic cancer: case-control study." The American Journal of Gastroenterology 102.12 (December 2007): 2696-2707.

PMID

17764494

Source

epmc

Published In

American Journal of Gastroenterology

Volume

102

Issue

12

Publish Date

2007

Start Page

2696

End Page

2707

DOI

10.1111/j.1572-0241.2007.01510.x

Authors

Javle, MM; Xie, X; Xia, W; Li, Z; Kuo, H; Liu, Y; Ding, Q; Zhang, S; Spohn, B; Yang, Y; Wei, Y; Lang, Y; Abbruzzese, JL; Hung, MC

MLA Citation

Javle, MM, Xie, X, Xia, W, Li, Z, Kuo, H, Liu, Y, Ding, Q, Zhang, S, Spohn, B, Yang, Y, Wei, Y, Lang, Y, Abbruzzese, JL, and Hung, MC. "Pancreatic cancer targeted C-VISA-BikDD: DNA-liposome complex results in minimal toxicity in vivo." December 2007.

Source

wos-lite

Published In

Molecular Cancer Therapeutics

Volume

6

Issue

12

Publish Date

2007

Start Page

3482S

End Page

3482S

Authors

Fogelman, DR; Abbruzzese, JL

MLA Citation

Fogelman, DR, and Abbruzzese, JL. "'Unresectable' pancreatic cancer: Conceptual challenges." Oncology 21.13 (November 1, 2007): 1571-1572. (Review)

Source

scopus

Published In

Oncology (Williston Park, N.Y.)

Volume

21

Issue

13

Publish Date

2007

Start Page

1571

End Page

1572

We investigated the antitumor effect of survivin DNA vaccine in murine pancreatic and lymphoma models, and if xenogenic survivin can generate stronger immune response. We found that mice vaccinated with either human or mouse survivin DNA have significantly slower tumor growth and longer survival than those vaccinated with vector DNA. There was no significant difference between groups that received human and mouse survivin DNA. Lymphocyte infiltration was greater in tumors of mice immunized with survivin DNA than in tumors of control mice. We conclude that survivin DNA vaccine generated specific antitumor effects with increased lymphocyte infiltration at the tumor sites.

Authors

Zhu, K; Qin, H; Cha, S-C; Neelapu, SS; Overwijk, W; Lizee, GA; Abbruzzese, JL; Hwu, P; Radvanyi, L; Kwak, LW; Chang, DZ

MLA Citation

Zhu, K, Qin, H, Cha, S-C, Neelapu, SS, Overwijk, W, Lizee, GA, Abbruzzese, JL, Hwu, P, Radvanyi, L, Kwak, LW, and Chang, DZ. "Survivin DNA vaccine generated specific antitumor effects in pancreatic carcinoma and lymphoma mouse models." Vaccine 25.46 (November 2007): 7955-7961.

PMID

17933439

Source

epmc

Published In

Vaccine

Volume

25

Issue

46

Publish Date

2007

Start Page

7955

End Page

7961

DOI

10.1016/j.vaccine.2007.08.050

We examined the association between N-acetyltransferase 1 and 2 (NAT1 and NAT2) haplotype and risk of pancreatic cancer by genotyping eight NAT1 and seven NAT2 single nucleotide polymorphisms in 532 patients and in 581 healthy controls (all non-Hispanic white) who were recruited at M. D. Anderson Cancer Center from January 2000 to December 2006. Haplotypes were reconstructed by using an expectation-maximization algorithm. Odds ratios and 95% confidence intervals were estimated by using unconditional logistic regression models. Covariates included age (continuous variable), sex, pack-year of smoking (categorical), and history of diabetes when appropriate. NAT1 and NAT2 genotype was mutually adjusted. The prevalence of haplotype NAT1*10-NAT2*6A was 4.3% versus 2.7% (P=0.06) and NAT1*11-NAT2*6A was 1.2% versus 0.4% (P=0.05) in patients and controls, respectively. The diplotype NAT1*10/*10 or NAT1*10/*11 and NAT2*6A/any slow allele was associated with a higher risk of pancreatic cancer compared with other diplotypes (multivariate odds ratio, 4.15; 95% confidence interval, 1.15-15.00; P=0.03). NAT2 slow genotype were associated with increased risk of pancreatic cancer among heavy smokers and among individuals with a history of diabetes. We for the first time found that rare NAT1*10 or NAT1*11-NAT2*6A diplotype may be an "at-risk" genetic variant for pancreatic cancer. The NAT2*6A/any slow acetylation genotype may be a predisposing factor for pancreatic cancer among diabetics with smoking exposure. Our observations must be confirmed in larger independent studies.

Authors

Jiao, L; Doll, MA; Hein, DW; Bondy, ML; Hassan, MM; Hixson, JE; Abbruzzese, JL; Li, D

MLA Citation

Jiao, L, Doll, MA, Hein, DW, Bondy, ML, Hassan, MM, Hixson, JE, Abbruzzese, JL, and Li, D. "Haplotype of N-acetyltransferase 1 and 2 and risk of pancreatic cancer." Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 16.11 (November 2007): 2379-2386.

PMID

18006927

Source

epmc

Published In

Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology

Volume

16

Issue

11

Publish Date

2007

Start Page

2379

End Page

2386

DOI

10.1158/1055-9965.epi-06-0992

Aberrant epidermal growth factor receptor (EGFR) signaling is a major cause of tumor progression and metastasis; the underlying mechanisms, however, are not well understood. In particular, it remains elusive whether deregulated EGFR pathway is involved in epithelial-mesenchymal transition (EMT), an early event that occurs during metastasis of cancers of an epithelial origin. Here, we show that EGF induces EGFR-expressing cancer cells to undergo a transition from the epithelial to the spindle-like mesenchymal morphology. EGF reduced E-cadherin expression and increased that of mesenchymal proteins. In search of a downstream mediator that may account for EGF-induced EMT, we focused on transcription repressors of E-cadherin, TWIST, SLUG, and Snail and found that cancer cells express high levels of TWIST and that EGF enhances its expression. EGF significantly increases TWIST transcripts and protein in EGFR-expressing lines. Forced expression of EGFR reactivates TWIST expression in EGFR-null cells. TWIST expression is suppressed by EGFR and Janus-activated kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) inhibitors, but not significantly by those targeting phosphoinositide-3 kinase and MEK/ERK. Furthermore, constitutively active STAT3 significantly activates the TWIST promoter, whereas the JAK/STAT3 inhibitor and dominant-negative STAT3 suppressed TWIST promoter. Deletion/mutation studies further show that a 26-bp promoter region contains putative STAT3 elements required for the EGF-responsiveness of the TWIST promoter. Chromatin immunoprecipitation assays further show that EGF induces binding of nuclear STAT3 to the TWIST promoter. Immunohistochemical analysis of 130 primary breast carcinomas indicates positive correlations between non-nuclear EGFR and TWIST and between phosphorylated STAT3 and TWIST. Together, we report here that EGF/EGFR signaling pathways induce cancer cell EMT via STAT3-mediated TWIST gene expression.

Authors

Lo, H-W; Hsu, S-C; Xia, W; Cao, X; Shih, J-Y; Wei, Y; Abbruzzese, JL; Hortobagyi, GN; Hung, M-C

MLA Citation

Lo, H-W, Hsu, S-C, Xia, W, Cao, X, Shih, J-Y, Wei, Y, Abbruzzese, JL, Hortobagyi, GN, and Hung, M-C. "Epidermal growth factor receptor cooperates with signal transducer and activator of transcription 3 to induce epithelial-mesenchymal transition in cancer cells via up-regulation of TWIST gene expression." Cancer Research 67.19 (October 2007): 9066-9076.

PMID

17909010

Source

epmc

Published In

Cancer Research

Volume

67

Issue

19

Publish Date

2007

Start Page

9066

End Page

9076

DOI

10.1158/0008-5472.CAN-07-0575

BACKGROUND: Growth factor overexpression, including epidermal growth factor receptor (EGFR) expression, is common in hepatocellular cancers. Erlotinib is a receptor tyrosine kinase inhibitor with specificity for EGFR. The primary objective of this study was to determine the proportion of hepatocellular carcinoma (HCC) patients treated with erlotinib who were alive and progression-free (PFS) at 16 weeks of continuous treatment. METHODS: Patients with unresectable HCC, no prior systemic therapy, performance status (PS) of 0, 1, or 2, and Childs-Pugh (CP) cirrhosis A or B received oral erlotinib 150 mg daily for 28-day cycles. Tumor response was assessed every 2 cycles by using Response Evaluation Criteria in Solid Tumors (RECIST; National Cancer Institute Cancer Therapy Evaluation Program, Bethesda, Md) criteria. Patients accrued to either "low" or "high" EGFR expression cohorts; each cohort had stopping rules applied when there was a lack of efficacy. RESULTS: Forty HCC patients were enrolled. Median age was 64 years (range, 33-83 years), sex distribution was 32 males and 8 females, performance scores were 40% PS 0, 55% PS 1, Childs-Pugh distribution was 75% A and 20% B. There were no complete or partial responses; however, 17 of 40 patients achieved stable disease at 16 weeks of continuous therapy. The PFS at 16 weeks was 43%, and the median overall survival (OS) was 43 weeks (10.75 months). No patients required dose reductions of erlotinib. No correlation between EGFR expression and outcome was found. CONCLUSIONS: Results of this study indicated that single-agent erlotinib is well tolerated and has modest disease-control benefit in HCC, manifested as modestly prolonged PFS and OS when compared with historical controls.

Authors

Thomas, MB; Chadha, R; Glover, K; Wang, X; Morris, J; Brown, T; Rashid, A; Dancey, J; Abbruzzese, JL

MLA Citation

Thomas, MB, Chadha, R, Glover, K, Wang, X, Morris, J, Brown, T, Rashid, A, Dancey, J, and Abbruzzese, JL. "Phase 2 study of erlotinib in patients with unresectable hepatocellular carcinoma." Cancer 110.5 (September 2007): 1059-1067.

PMID

17623837

Source

epmc

Published In

Cancer

Volume

110

Issue

5

Publish Date

2007

Start Page

1059

End Page

1067

DOI

10.1002/cncr.22886

Pancreatic cancer is a lethal disease characterized by multiple disease-related symptoms. Chemoradiation therapy is a standard of treatment for locally advanced pancreatic cancer. Although shown to prolong survival, there is little information about treatment-related symptoms or the palliative benefits of chemoradiation. We assessed symptoms of patients with locally advanced pancreatic cancer receiving chemoradiation to determine the prevalence, and co-occurrence, of symptoms and to identify the extent to which symptoms interfered with function. Forty-eight patients were treated with chemoradiation on a Phase I protocol. Patients received radiotherapy (50.4 Gy in 28 fractions), capecitabine (median dose 825 mg/m(2) twice daily), and bevacizumab (2.5-10 mg/kg). Symptom severity and its interference with function were prospectively assessed (at presentation, during, and after chemoradiation) in 43 consenting patients using the M.D. Anderson Symptom Inventory. Results showed that 95% of patients reported at least one of the 13 symptoms assessed at presentation. The most commonly reported symptoms of moderate to severe (>or=5 on a 0-10 scale) intensity at presentation were lack of appetite (24%), pain (19%), fatigue (19%), and sleep disturbance (10%). We observed an increase in patients reporting moderate to severe fatigue, nausea, and sleep disturbance during chemoradiation. McNemar tests for paired binary observations showed the proportion of patients reporting moderate to severe symptoms significantly (P<0.001) decreased after chemoradiation at 94 days follow-up (lack of appetite=7%, pain=7%, fatigue=13%, sleep disturbance=7%). This study demonstrates the feasibility and usefulness of symptom assessment in chemoradiation protocols. Future studies with larger cohorts are needed to further characterize multiple symptoms associated with chemoradiation.

Authors

Reyes-Gibby, CC; Chan, W; Abbruzzese, JL; Xiong, HQ; Ho, L; Evans, DB; Varadhachary, G; Bhat, S; Wolff, RA; Crane, C

MLA Citation

Reyes-Gibby, CC, Chan, W, Abbruzzese, JL, Xiong, HQ, Ho, L, Evans, DB, Varadhachary, G, Bhat, S, Wolff, RA, and Crane, C. "Patterns of self-reported symptoms in pancreatic cancer patients receiving chemoradiation." Journal of pain and symptom management 34.3 (September 2007): 244-252.

PMID

17513082

Source

epmc

Published In

Journal of Pain and Symptom Management

Volume

34

Issue

3

Publish Date

2007

Start Page

244

End Page

252

DOI

10.1016/j.jpainsymman.2006.11.007

BACKGROUND: Variations in genetic mutations in pancreatic carcinoma between different geographical regions have not been studied extensively, especially in developing countries where pancreatic cancer is relatively rare. METHODS: We studied the molecular pathology of 54 pancreatic adenocarcinomas from Egyptian patients residing in a heavily polluted region of the eastern Nile River delta and compared the findings with 45 tumors from patients residing in low-pollution regions. RESULTS: Rates of K-ras mutation in codon 12 and of p53 mutation in exons 5-8 were higher in tumors of patients from the high-pollution region as compared with the low-pollution regions (61.5 versus 34.2%, respectively, for K-ras, P = 0.01; 25.9 versus 11.6%, respectively, for p53, P = 0.08). There were also distinct differences in the specific types of K-ras and p53 mutations between the two regions. The ratio of G-to-T k-ras transversion mutation (codon 12) relative to wild-type was significantly higher in tumors from the high-pollution region (0.90) than tumors from the non-pollution site (0.28) (P = 0.03). Relative to tumors with wild-type, the ratio of p53 mutations in exons 5, 7 or 8 to wild-type in tumors from the high-pollution region was significantly higher than the ratio from the non-pollution site (0.28 versus 0.03, P = 0.01). Logistic regression showed that G-to-T transversion mutation in K-ras was predicted by the region of residence of the patients. CONCLUSIONS: Our study reveals that there are differences in the frequencies and types of K-ras and p53 mutations found in pancreatic adenocarcinomas of patients in high-pollution and low-pollution regions in Egypt and suggests that environmental factors may explain these differences. We speculate that gene-environment interactions in pancreatic carcinogenesis also occur in other populations.

Authors

Soliman, AS; Lo, A-C; Banerjee, M; El-Ghawalby, N; Khaled, HM; Bayoumi, S; Seifeldin, IA; Abdel-Aziz, A; Abbruzzese, JL; Greenson, JK; Hamilton, SR

MLA Citation

Soliman, AS, Lo, A-C, Banerjee, M, El-Ghawalby, N, Khaled, HM, Bayoumi, S, Seifeldin, IA, Abdel-Aziz, A, Abbruzzese, JL, Greenson, JK, and Hamilton, SR. "Differences in K-ras and p53 gene mutations among pancreatic adenocarcinomas associated with regional environmental pollution." Carcinogenesis 28.8 (August 2007): 1794-1799.

PMID

17575320

Source

epmc

Published In

Carcinogenesis

Volume

28

Issue

8

Publish Date

2007

Start Page

1794

End Page

1799

DOI

10.1093/carcin/bgm138

OBJECTIVES: This study examined the epidemiology of pancreatic cancer in Egypt. METHODS: We obtained detailed information on smoking, occupational, medical, and reproductive histories from 194 pancreatic cancer cases and 194 controls. RESULTS: Compared with not smoking, smoking cigarettes alone or in conjunction with other smoking methods (eg, water pipe, cigar) was associated with an increased risk (odds ratio [OR], 4.5 and 7.8; 95% confidence interval [95% CI], 1.9-10.7 and 3.0-20.6, respectively). Passive smoking was also a significant risk factor (OR, 6.0; 95% CI, 2.4-14.8). The risk of pancreatic cancer was elevated among subjects exposed to pesticides (OR, 2.6; 95% CI, 0.97-7.2). A prior diagnosis of diabetes mellitus for a period of 10 years was associated with higher risk (OR, 5.4; 95% CI, 1.5-19.9). For women, having 7 or more live births and lactating for 144 months or longer were associated with a reduced risk (OR, 0.5 and 0.2; 95% CI, 0.2-1.3 and 0.1-0.9, respectively). No association was found between family history, allergy, or obesity and pancreatic cancer in Egypt. CONCLUSIONS: Multiple tobacco consumption methods, passive smoking, pesticide exposures, and diabetes are associated with an increased risk for pancreatic cancer. Prolonged lactation and increased parity are associated with a reduced risk for pancreatic cancer.

Authors

Lo, A-C; Soliman, AS; El-Ghawalby, N; Abdel-Wahab, M; Fathy, O; Khaled, HM; Omar, S; Hamilton, SR; Greenson, JK; Abbruzzese, JL

MLA Citation

Lo, A-C, Soliman, AS, El-Ghawalby, N, Abdel-Wahab, M, Fathy, O, Khaled, HM, Omar, S, Hamilton, SR, Greenson, JK, and Abbruzzese, JL. "Lifestyle, occupational, and reproductive factors in relation to pancreatic cancer risk." Pancreas 35.2 (August 2007): 120-129.

PMID

17632317

Source

epmc

Published In

Pancreas

Volume

35

Issue

2

Publish Date

2007

Start Page

120

End Page

129

DOI

10.1097/mpa.0b013e318053e7d3

Authors

Pentz, RD; Flamm, AL; Sugarman, J; Cohen, MZ; Xu, Z; Herbst, RS; Abbruzzese, JL

MLA Citation

Pentz, RD, Flamm, AL, Sugarman, J, Cohen, MZ, Xu, Z, Herbst, RS, and Abbruzzese, JL. "Who should go first in trials with scarce agents? The views of potential participants." Irb 29.4 (July 2007): 1-6.

PMID

17847620

Source

epmc

Published In

Irb

Volume

29

Issue

4

Publish Date

2007

Start Page

1

End Page

6

BACKGROUND: The current study was conducted to determine whether there were differences in outcome for patients with unresectable locally advanced pancreatic cancer (LAPC) who received treatment with chemoradiation therapy (CR) versus induction chemotherapy followed by CR (CCR). METHODS: Between December 1993 and July 2005, 323 consecutive patients with LAPC were treated at the authors' institution with radiotherapy and concurrent gemcitabine or fluoropyrimidine chemotherapy. Two hundred forty-seven patients received CR as initial treatment, and 76 patients received a median of 2.5 months of gemcitabine-based induction chemotherapy prior to CR. Most patients received a radiation dose of 30 grays in 10 fractions (85%) concurrently with infusional 5-fluorouracil (41%), gemcitabine (39%), or capecitabine (20%). RESULTS: The median follow-up was 5.5 months (range, 1-63 months). For all patients, the median overall survival (OS) and progression-free survival (PFS) were 9 months and 5 months, respectively, and the 2-year estimated OS and PFS rates were 9% and 5%, respectively. The median OS and PFS were 8.5 months and 4.2 months, respectively, in the CR group and 11.9 months and 6.4 months, respectively, in the CCR group (both P < .001). The median times to local and distant progression were 6.0 months and 5.6 months, respectively, in the CR group and 8.9 and 9.5 months, respectively, in the CCR group (P = .003 and P = .007, respectively). There was no significant difference in the patterns of failure with the use of induction chemotherapy. CONCLUSIONS: The results from this analysis indicated that, by excluding patients with rapid distant progression, induction chemotherapy may select patients with LAPC for optimal benefit from consolidative CR. The authors believe that this strategy of enriching the population of patients who receive a locoregional treatment modality merits prospective randomized evaluation.

Authors

Krishnan, S; Rana, V; Janjan, NA; Varadhachary, GR; Abbruzzese, JL; Das, P; Delclos, ME; Gould, MS; Evans, DB; Wolff, RA; Crane, CH

MLA Citation

Krishnan, S, Rana, V, Janjan, NA, Varadhachary, GR, Abbruzzese, JL, Das, P, Delclos, ME, Gould, MS, Evans, DB, Wolff, RA, and Crane, CH. "Induction chemotherapy selects patients with locally advanced, unresectable pancreatic cancer for optimal benefit from consolidative chemoradiation therapy." Cancer 110.1 (July 2007): 47-55.

PMID

17538975

Source

epmc

Published In

Cancer

Volume

110

Issue

1

Publish Date

2007

Start Page

47

End Page

55

DOI

10.1002/cncr.22735

Participants' perception of quality of life (QOL) and respondent burden have significant implications for investigators' ethical responsibilities to their subjects in phase I cancer trials. To address these responsibilities, analysis was conducted on participants' views of their experiences of a phase I trial, including the associated burdens and what constitutes QOL.One hundred potential participants of the endostatin trial were surveyed. Sixteen of the 18 trial participants were interviewed extensively about their experiences on the trial.Participants described 'normality' as a baseline ability to function, be productive, and be free from symptoms of disease and side effects of treatment. Reflecting the relative nontoxicity of the study drug, participants contrasted their current QOL with their negative experience of previous cancer treatments and viewed their QOL as fairly good. However, participants emphasized that indirect and procedural burdens of trial participation had a significant impact on their current QOL.Candid descriptions of a trial's practical demands, in addition to potential physical complications in a trial, could improve the quality of informed consent.

Authors

Cohen, MZ; Slomka, J; Pentz, RD; Flamm, AL; Gold, D; Herbst, RS; Abbruzzese, JL

MLA Citation

Cohen, MZ, Slomka, J, Pentz, RD, Flamm, AL, Gold, D, Herbst, RS, and Abbruzzese, JL. "Phase I participants' views of quality of life and trial participation burdens." Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer 15.7 (July 2007): 885-890.

PMID

17252219

Source

epmc

Published In

Supportive Care in Cancer : Official Journal of the Multinational Association of Supportive Care in Cancer

Volume

15

Issue

7

Publish Date

2007

Start Page

885

End Page

890

DOI

10.1007/s00520-007-0216-0

Three-dimensional (3D) cultures of epithelial cells offer singular advantages for studies of morphogenesis or the role of cancer genes in oncogenesis. In this study, as part of establishing a 3D culture system of pancreatic duct epithelial cells, we compared human pancreatic duct epithelial cells (HPDE-E6E7) with pancreatic cancer cell lines. Our results show, that in contrast to cancer cells, HPDE-E6E7 organized into spheroids with what appeared to be apical and basal membranes and a luminal space. Immunostaining experiments indicated that protein kinase Akt was phosphorylated (Ser473) and CTMP, a negative Akt regulator, was expressed in both HPDE-E6E7 and cancer cells. However, a nuclear pool of CTMP was detectable in HPDE-E6E7 cells that showed a dynamic concentrated expression pattern, a feature that further distinguished HPDE-E637 cells from cancer cells. Collectively, these data suggest that 3D cultures of HPDE-E6E7 cells are useful for investigating signaling and morphological abnormalities in pancreatic cancer cells.

Authors

Gutierrez-Barrera, AM; Menter, DG; Abbruzzese, JL; Reddy, SAG

MLA Citation

Gutierrez-Barrera, AM, Menter, DG, Abbruzzese, JL, and Reddy, SAG. "Establishment of three-dimensional cultures of human pancreatic duct epithelial cells." Biochemical and biophysical research communications 358.3 (July 2007): 698-703.

PMID

17512909

Source

epmc

Published In

Biochemical and Biophysical Research Communications

Volume

358

Issue

3

Publish Date

2007

Start Page

698

End Page

703

DOI

10.1016/j.bbrc.2007.04.166

Pancreatic cancer is an aggressive malignancy with morbidity rates almost equal to mortality rates because of the current lack of effective treatment options. Here, we describe a targeted approach to treating pancreatic cancer with effective therapeutic efficacy and safety in noninvasive imaging models. We developed a versatile expression vector "VISA" (VP16-GAL4-WPRE integrated systemic amplifier) and a CCKAR (cholecystokinin type A receptor) gene-based, pancreatic-cancer-specific promoter VISA (CCKAR-VISA) composite to target transgene expression in pancreatic tumors in vivo. Targeted expression of BikDD, a potent proapoptotic gene driven by CCKAR-VISA, exhibited significant antitumor effects on pancreatic cancer and prolonged survival in multiple xenograft and syngeneic orthotopic mouse models of pancreatic tumors with virtually no toxicity.

Authors

Xie, X; Xia, W; Li, Z; Kuo, H-P; Liu, Y; Li, Z; Ding, Q; Zhang, S; Spohn, B; Yang, Y; Wei, Y; Lang, J-Y; Evans, DB; Chiao, PJ; Abbruzzese, JL; Hung, M-C

MLA Citation

Xie, X, Xia, W, Li, Z, Kuo, H-P, Liu, Y, Li, Z, Ding, Q, Zhang, S, Spohn, B, Yang, Y, Wei, Y, Lang, J-Y, Evans, DB, Chiao, PJ, Abbruzzese, JL, and Hung, M-C. "Targeted expression of BikDD eradicates pancreatic tumors in noninvasive imaging models." Cancer Cell 12.1 (July 2007): 52-65.

PMID

17613436

Source

epmc

Published In

Cancer Cell

Volume

12

Issue

1

Publish Date

2007

Start Page

52

End Page

65

DOI

10.1016/j.ccr.2007.05.009

The associations between passive smoking and the use of noncigarette tobacco products with pancreatic cancer are not clear.In this case-control study, the authors collected information on passive smoking and the use of noncigarette tobacco products in 808 patients with pancreatic adenocarcinoma and 808 healthy controls by personal interview. Multivariable logistic regression was performed to estimate the adjusted odds ratio (AOR) and 95% confidence interval (95% CI).The results confirmed the previously reported association between active smoking and increased risk for pancreatic cancer. The AOR was 1.7 (95% CI, 1.4-2.2) for regular smokers, 1.8 (95% CI, 1.4-2.4) for long-term smokers, and 3.1 (95% CI, 2.2-4.3) for former smokers. Although passive smoking showed a nonsignificantly elevated risk for pancreatic cancer in the entire study population (AOR, 1.3; 95% CI, 0.9-1.7), the association was present among ever smokers (AOR, 1.7; 95% CI, 1.03-2.6) but was absent among never smokers (AOR, 1.1; 95% CI, 0.8-1.6). Neither intensity nor duration of passive smoking modified the risk of pancreatic cancer among never smokers. The use of chewing tobacco, snuff, and pipes showed no significant risk elevation for pancreatic cancer after controlling for the confounding effects of demographics and other known risk factors. The use of cigars in never smokers showed a borderline significant increase of risk for pancreatic cancer (AOR, 2.2; 95% CI, 1.0-4.7; P = .05).The current observations did not support a role for passive smoking or the use of noncigarette tobacco products in the etiology of pancreatic cancer. The association between cigar use and the risk of pancreatic cancer needs to be confirmed in other study populations.

Authors

Hassan, MM; Abbruzzese, JL; Bondy, ML; Wolff, RA; Vauthey, J-N; Pisters, PW; Evans, DB; Khan, R; Lenzi, R; Jiao, L; Li, D

MLA Citation

Hassan, MM, Abbruzzese, JL, Bondy, ML, Wolff, RA, Vauthey, J-N, Pisters, PW, Evans, DB, Khan, R, Lenzi, R, Jiao, L, and Li, D. "Passive smoking and the use of noncigarette tobacco products in association with risk for pancreatic cancer: a case-control study." Cancer 109.12 (June 2007): 2547-2556.

PMID

17492688

Source

epmc

Published In

Cancer

Volume

109

Issue

12

Publish Date

2007

Start Page

2547

End Page

2556

DOI

10.1002/cncr.22724

BACKGROUND: Constitutive activation of nuclear factor-kappaB (NF-kappaB) is a frequent molecular alteration in pancreatic cancer and a number of studies have suggested that constitutive NF-kappaB activity plays a key role in the aggressive behavior of this disease. In an attempt to identify an effective therapeutic agent for pancreatic cancer, the authors studied the role of FUT-175, a synthetic serine protease inhibitor, in the inhibition of NF-kappaB activation and the induction of apoptotic responses. METHODS: To examine the effect of FUT-175 on the inhibition of NF-kappaB and the induction of apoptosis in pancreatic cancer cell lines, Western and Northern blot analyses, electromobility shift (EMSA), luciferase reporter gene, DNA fragmentation, immunoprecipitation, in vitro kinase, small interfering RNA (siRNA), and chromatin immunoprecipitation (ChIP) assays were performed. RESULTS: In a time-dependent and dose-dependent manner, FUT-175 inhibited IkappaBalpha phosphorylation and NF-kappaB activation, thereby inhibiting the antiapoptotic activity of NF-kappaB. Simultaneously, FUT-175 up-regulated the expression of tumor necrosis factor receptor-1 (TNFR1), which in turn activated the proapoptotic caspase-8 and Bid pathways and induced apoptosis in pancreatic cancer cells. FUT-175-induced activation of Fas-associated death domain (FADD) and caspase-8 was suppressed by RNA interference-mediated inhibition of TNFR1 expression. Furthermore, expression of the transcription factor PEA3 was up-regulated by FUT-175 and was involved in FUT-175-mediated TNFR1 expression. CONCLUSIONS: These results suggested a possible mechanism by which FUT-175 may disrupt interconnected signaling pathways by both suppressing the NF-kappaB antiapoptotic activity and inducing TNFR-mediated apoptosis. Supported by this unique function as a NF-kappaB inhibitor and apoptosis inducer, this well-established synthetic serine protease inhibitor with as-of-yet poorly understood mechanisms of actions appears to be a potentially therapeutic agent for pancreatic cancer.

Authors

Uwagawa, T; Li, Z; Chang, Z; Xia, Q; Peng, B; Sclabas, GM; Ishiyama, S; Hung, M-C; Evans, DB; Abbruzzese, JL; Chiao, PJ

MLA Citation

Uwagawa, T, Li, Z, Chang, Z, Xia, Q, Peng, B, Sclabas, GM, Ishiyama, S, Hung, M-C, Evans, DB, Abbruzzese, JL, and Chiao, PJ. "Mechanisms of synthetic serine protease inhibitor (FUT-175)-mediated cell death." Cancer 109.10 (May 2007): 2142-2153.

PMID

17410536

Source

epmc

Published In

Cancer

Volume

109

Issue

10

Publish Date

2007

Start Page

2142

End Page

2153

DOI

10.1002/cncr.22658

Maspin (SERPINB5), a serine proteinase inhibitor, was first identified as a potential tumor suppressor on the basis of its differential expression between normal mammary epithelial cells and human breast carcinoma cell lines. Recent studies have shown that maspin might be a prognostic tumor marker. Pancreatic ductal adenocarcinoma acquires maspin expression through hypomethylation of the maspin promoter. However, no study has investigated the prognostic significance of maspin expression in pancreatic ductal adenocarcinomas. In this study, we investigated maspin protein expression in a large series of 223 surgically resected pancreatic ductal adenocarcinomas using immunohistochemical staining and high throughput tissue microarrays. Maspin expression was correlated with postoperative survival and other clinicopathologic factors. Maspin was detected in 209 of these 223 (94% cases) pancreatic ductal adenocarcinomas including 39 (18% cases) focal (5-50% tumor cells) and 170 (76% cases) diffuse (>50% tumor cells). Fourteen (or 6% cases) pancreatic ductal adenocarcinomas did not show maspin expression by immunohistochemical staining (<5% tumor cells). Normal ductal epithelium is not labeled with maspin. Overexpression of maspin in pancreatic ductal adenocarcinoma is associated with worse postoperative survival especially in patients whose tumors exhibit diffuse expression of maspin. After adjusting other clinicopathologic factors, maspin expression remains to be an independent adverse prognosticator for postoperative survival. Maspin expression is not associated with patient age, gender, tumor size, tumor pathologic stage, lymph node status, and vascular invasion or perineural invasion. Nuclear labeling of maspin is associated with better tumor differentiation although this staining pattern is not associated with a better prognosis. In addition, maspin overexpression is also observed in 48% low-grade (grades 1a and 1b) pancreatic intraepithelial neoplasias (PanINs) and 78% high-grade (grades 2 and 3) PanINs, suggesting that maspin upregulation occurs early during the multi-step progression model of pancreatic ductal adenocarcinoma.

Authors

Cao, D; Zhang, Q; Wu, LS-F; Salaria, SN; Winter, JW; Hruban, RH; Goggins, MS; Abbruzzese, JL; Maitra, A; Ho, L

MLA Citation

Cao, D, Zhang, Q, Wu, LS-F, Salaria, SN, Winter, JW, Hruban, RH, Goggins, MS, Abbruzzese, JL, Maitra, A, and Ho, L. "Prognostic significance of maspin in pancreatic ductal adenocarcinoma: tissue microarray analysis of 223 surgically resected cases." Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 20.5 (May 2007): 570-578.

PMID

17396143

Source

epmc

Published In

Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc

Volume

20

Issue

5

Publish Date

2007

Start Page

570

End Page

578

DOI

10.1038/modpathol.3800772

Pancreatic cancer is being pursued as an immunotherapy target using antigen-specific vaccine approaches activating CD8(+) CTL and CD4(+) T-helper cells. CD8(+) CTL exert their anti-tumor effects in an HLA-restricted manner and only tumor cells carrying a matched HLA class I sub-type are targets for antigen-specific CTL. In the process of characterizing CD8(+) T cell responses against pancreatic cancer, we screened a number of human pancreatic tumor cell lines for HLA-A0201 positive (HLA-A2(+)) cell lines to be used in the evaluation of CTL function. This analysis revealed some new findings and discrepancies in the literature on the HLA sub-type of some commonly used pancreatic cell lines. We found that Capan-1 cells, originally reported to be HLA-A0201(+), actually only express HLA-A010101 and HLA-A300101 and were targets for HLA-A0201-restricted CTL only after transduction with an HLA-A0201-expressing lentivirus. Panc-1 cells were found to be HLA-A0201 positive, in agreement with published reports, while CF-Pac-1 cells were found to express both HLA-A020101 and HLA-A030101. We also found a normal human pancreatic ductal epithelial cell line, HPDE, to be HLA-A0201 positive. Our findings were verified with two different sequence-based typing methods, antibody staining followed by flow cytometry analysis, and functional analysis using an HLA-A0201-restricted peptide-specific T cell response.

Authors

Zhu, K; Lizee, G; Cano, P; Fernando-Vina, M; Ji, B; Abbruzzese, JL; Hwu, P; Radvanyi, L; Chang, DZ

MLA Citation

Zhu, K, Lizee, G, Cano, P, Fernando-Vina, M, Ji, B, Abbruzzese, JL, Hwu, P, Radvanyi, L, and Chang, DZ. "HLA-A0201 positive pancreatic cell lines: new findings and discrepancies." Cancer immunology, immunotherapy : CII 56.5 (May 2007): 719-724.

PMID

16947023

Source

epmc

Published In

Cancer Immunology, Immunotherapy

Volume

56

Issue

5

Publish Date

2007

Start Page

719

End Page

724

DOI

10.1007/s00262-006-0217-8

Aurora-A and p16 play a major role in cell cycle checkpoint regulation. Both of them are important in the maintenance of centrosome duplication. Therefore, we hypothesized that polymorphisms in the two genes may interact or work together to influence the finely tuned mechanisms of cell cycle regulation that these proteins regulate. The purpose of this study was to investigate the association of the Aurora-A (T91A), and p16 (C540G and C580T) polymorphisms with age at diagnosis of pancreatic cancer.We genotyped 148 Caucasian patients with a diagnosis of pancreatic cancer for the Aurora-A and p16 polymorphisms using pyrosequencing. We tested the association between age at diagnosis and the Aurora-A and p16 genotypes by comparing Kaplan-Meier curves, evaluating the homogeneity of the curves using the log-rank test. We used Cox proportional hazard regression analysis to estimate the association between time to diagnosis and genotype, adjusting for gender.Patients with the Aurora-A polymorphic genotypes had a median age at diagnosis with pancreatic cancer that was 2.8 years earlier than those with the wild-type genotype [log-rank, P=0.015; hazard ratio (HR), 1.55; 95% confidence intervals (95% CI), 1.09-2.20]. There was no significant association between the p16 genotypes and age at diagnosis. However, the Aurora-A and p16 C580T polymorphisms combined had a synergistic effect on age-associated risk for early diagnosis of pancreatic cancer. Compared with patients with wild-type genotypes for both genes, the median age at diagnosis for patients with one or two polymorphic alleles for both genes was 12.6 years earlier (log-rank, P=0.0002; HR, 3.88; 95% CI, 1.94-7.76). No significant associations between the polymorphisms and the cancer metastatic status or survival after diagnosis were found.Our findings suggest that the Aurora-A polymorphism contributes to a significantly earlier age at diagnosis of pancreatic cancer, and that Aurora-A and p16 C580T polymorphisms synergistically contribute to an earlier age at diagnosis of pancreatic cancer.

Authors

Chen, J; Li, D; Wei, C; Sen, S; Killary, AM; Amos, CI; Evans, DB; Abbruzzese, JL; Frazier, ML

MLA Citation

Chen, J, Li, D, Wei, C, Sen, S, Killary, AM, Amos, CI, Evans, DB, Abbruzzese, JL, and Frazier, ML. "Aurora-A and p16 polymorphisms contribute to an earlier age at diagnosis of pancreatic cancer in Caucasians." Clinical cancer research : an official journal of the American Association for Cancer Research 13.10 (May 2007): 3100-3104.

PMID

17505013

Source

epmc

Published In

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research

Volume

13

Issue

10

Publish Date

2007

Start Page

3100

End Page

3104

DOI

10.1158/1078-0432.ccr-06-2319

Vascular endothelial growth factor receptor-1 (VEGFR1) is expressed in cancer cell lines and tumors and, in pancreatic and colon cancer cells, activation of VEGFR1 is linked to increased tumor migration and invasiveness. Tolfenamic acid, a nonsteroidal anti-inflammatory drug, decreases Sp protein expression in Panc-1 and L3.6pl pancreatic cancer cells, and this was accompanied by decreased VEGFR1 protein and mRNA and decreased luciferase activity on cells transfected with constructs (pVEGFR1) containing VEGFR1 promoter inserts. Comparable results were obtained in pancreatic cancer cells transfected with small inhibitory RNAs for Sp1, Sp3, and Sp4 and all three proteins bound to GC-rich elements in the VEGFR1 promoter. These results show that VEGFR1 is regulated by Sp proteins and that treatment with tolfenamic acid decreases expression of this critical angiogenic factor. Moreover, in vitro studies in Panc-1 cells show that activation of VEGFR1 by VEGFB to increase mitogen-activated protein kinase 1/2 phosphorylation and cell migration on collagen-coated plates is also inhibited by tolfenamic acid. Thus, targeted degradation of Sp proteins is highly effective for inhibiting VEGFR1 and associated angiogenic responses in pancreatic cancer.

Authors

Abdelrahim, M; Baker, CH; Abbruzzese, JL; Sheikh-Hamad, D; Liu, S; Cho, SD; Yoon, K; Safe, S

MLA Citation

Abdelrahim, M, Baker, CH, Abbruzzese, JL, Sheikh-Hamad, D, Liu, S, Cho, SD, Yoon, K, and Safe, S. "Regulation of vascular endothelial growth factor receptor-1 expression by specificity proteins 1, 3, and 4 in pancreatic cancer cells." Cancer Research 67.7 (April 2007): 3286-3294.

PMID

17409437

Source

epmc

Published In

Cancer Research

Volume

67

Issue

7

Publish Date

2007

Start Page

3286

End Page

3294

DOI

10.1158/0008-5472.can-06-3831

To explore the association between single nucleotide polymorphisms of DNA repair genes and overall survival of patients with pancreatic cancer, we conducted a study in 378 cases of pancreatic adenocarcinoma who were treated at The University of Texas M. D. Anderson Cancer Center between February 1999 and October 2004 and were followed up to April 2006. Genotypes were determined using genomic DNA and the MassCode method. Overall survival was analyzed using the Kaplan-Meier plot, log-rank test and Cox regression. We observed a strong effect of the POLB A165G and T2133C genotypes on overall survival. The median survival time (MST) was 35.7 months for patients carrying at least 1 of the 2 homozygous variant POLB GG or CC genotypes, compared with 14.8 months for those carrying the AA/AG or TT/TC genotypes (p = 0.02, log rank test). The homozygous variants of hOGG1 G2657A, APEX1 D148E and XRCC1 R194W polymorphisms all showed a weak but significant effect on overall survival as demonstrated by either log rank test or multivariate COX regression after adjusting for other potential confounders. In combined genotype analysis, a predominant effect of the POLB homozygous variants on survival was observed. When POLB was not included in the model, a slightly better survival was observed among those carrying none of the adverse genotypes than those carrying at least one of the adverse genotypes. These observations suggest that polymorphisms of base excision repair genes significantly affect the clinical outcome of patients with pancreatic cancer. These observations need to be confirmed in a larger study of homogenous patient population.

Authors

Li, D; Li, Y; Jiao, L; Chang, DZ; Beinart, G; Wolff, RA; Evans, DB; Hassan, MM; Abbruzzese, JL

MLA Citation

Li, D, Li, Y, Jiao, L, Chang, DZ, Beinart, G, Wolff, RA, Evans, DB, Hassan, MM, and Abbruzzese, JL. "Effects of base excision repair gene polymorphisms on pancreatic cancer survival." International journal of cancer 120.8 (April 2007): 1748-1754.

PMID

17230526

Source

epmc

Published In

International Journal of Cancer

Volume

120

Issue

8

Publish Date

2007

Start Page

1748

End Page

1754

DOI

10.1002/ijc.22301

To investigate the association between dietary exposure to food mutagens and risk of pancreatic cancer, we conducted a hospital-based case-control study at the University of Texas M. D. Anderson Cancer Center during June 2002 to May 2006. A total of 626 cases and 530 noncancer controls were frequency matched for race, sex and age (+/-5 years). Dietary exposure information was collected via personal interview using a meat preparation questionnaire. A significantly greater portion of the cases than controls showed a preference to well-done pork, bacon, grilled chicken, and pan-fried chicken, but not to hamburger and steak. Cases had a higher daily intake of food mutagens and mutagenicity activity (revertants per gram of daily meat intake) than controls did. The daily intakes of 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx) and benzo(a)pyrene (BaP), as well as the mutagenic activity, were significant predictors for pancreatic cancer (P = 0.008, 0.031, and 0.029, respectively) with adjustment of other confounders. A significant trend of elevated cancer risk with increasing DiMeIQx intake was observed in quintile analysis (P(trend) = 0.024). A higher intake of dietary mutagens (those in the two top quintiles) was associated with a 2-fold increased risk of pancreatic cancer among those without a family history of cancer but not among those with a family history of cancer. A possible synergistic effect of dietary mutagen exposure and smoking was observed among individuals with the highest level of exposure (top 10%) to PhIP and BaP, P(interaction) = 0.09 and 0.099, respectively. These data support the hypothesis that dietary mutagen exposure alone and in interaction with other factors contribute to the development of pancreatic cancer.

Authors

Li, D; Day, RS; Bondy, ML; Sinha, R; Nguyen, NT; Evans, DB; Abbruzzese, JL; Hassan, MM

MLA Citation

Li, D, Day, RS, Bondy, ML, Sinha, R, Nguyen, NT, Evans, DB, Abbruzzese, JL, and Hassan, MM. "Dietary mutagen exposure and risk of pancreatic cancer." Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology 16.4 (April 2007): 655-661.

PMID

17416754

Source

epmc

Published In

Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology

Volume

16

Issue

4

Publish Date

2007

Start Page

655

End Page

661

DOI

10.1158/1055-9965.EPI-06-0993

This study tested the hypothesis that genetic variants of phase II detoxification enzymes and DNA repair proteins affect individual response to DNA damage from alkylating agents. In 171 healthy individuals, an immunoslot blot assay was used to measure O6-ethylguanosine (O6-EtGua) adduct levels in peripheral blood lymphocytes treated with N-ethyl-N-nitrosourea (ENU) in vitro. The genotypes of GSTM1, GSTT1, GSTP1 I(105)V and A(114)V, MGMT L(84)F and I(143)V, XPD D(312)N and K(751)Q, and XRCC3 T(241)M were determined. Demographic and exposure information was collected by in-person interview. Student's t-test, analysis of (co)variance, and multiple linear regression models were used in statistical analyses. The mean and median (range) O6-EtGua levels were 94.6 and 84.8 (3.2-508.1)fmol/g DNA, respectively. The adduct level was significantly lower in people who smoked >or=25 years than that in never-smokers (square-root transformed mean values 8.20 versus 9.37, P=0.03). Multiple linear regression models revealed that GSTT1 (beta=-2.36, P=0.009) polymorphism was a significant predictor of the level of adducts in 82 never-smokers, whereas the number of years smoked (beta=-0.08, P=0.005) and XRCC3 T(241)M (beta=2.22, P=0.007) in 89 ever-smokers. The association between GSTP1 I(105)V, MGMT I(143)V, and XPD D(312)N with the level of adducts was not conclusive. Each polymorphism could explain 2-10% of the variation of the adduct level. These observations suggest that GSTT1 null and XRCC3 T(241)M polymorphism may have some functional significance in modulating the level of ENU-induced DNA damage and these effects are smoking-dependent. Results from this exploratory study need to be confirmed in other experimental systems.

Authors

Jiao, L; Chang, P; Firozi, PF; Lai, D; Abbruzzese, JL; Li, D

MLA Citation

Jiao, L, Chang, P, Firozi, PF, Lai, D, Abbruzzese, JL, and Li, D. "Polymorphisms of phase II xenobiotic-metabolizing and DNA repair genes and in vitro N-ethyl-N-nitrosourea-induced O6-ethylguanine levels in human lymphocytes." Mutation research 627.2 (March 2007): 146-157.

PMID

17158087

Source

epmc

Published In

Mutation Research

Volume

627

Issue

2

Publish Date

2007

Start Page

146

End Page

157

DOI

10.1016/j.mrgentox.2006.11.001

BACKGROUND: Delayed recovery after pancreaticoduodenectomy (PD) is believed to preclude adjuvant therapy for approximately 30% of patients who undergo elective PD as initial treatment for pancreatic adenocarcinoma. This study reexamined the frequency of delayed recovery and assessed other factors associated with adjuvant therapy administration after PD at a high-volume center. STUDY DESIGN: Preoperative and perioperative variables were reviewed in a consecutive series of 85 patients with pancreatic adenocarcinoma undergoing PD without preoperative chemotherapy or radiotherapy from 1990 to 2004. RESULTS: Study groups included patients undergoing emergency PD (group 1, n=13); elective PD with good preoperative Eastern Cooperative Oncology Group (ECOG) performance status (PS) (group 2, ECOG PS: 0 to 1, n=63); and elective PD with marginal preoperative PS (group 3, ECOG PS: 2 to 3, n=9). Delayed recovery of PS precluded adjuvant therapy in 23% of patients in group 1, 6% of patients in group 2, and 44% of patients in group 3 (p=0.0001). CONCLUSIONS: The impact of delayed recovery after PD on the delivery of adjuvant therapy depends on the urgency of surgery and the preoperative PS. For patients with good preoperative PS who undergo elective PD at a high-volume center, it is uncommon for delayed recovery to preclude delivery of adjuvant therapy.

Authors

Aloia, TA; Lee, JE; Vauthey, J-N; Abdalla, EK; Wolff, RA; Varadhachary, GR; Abbruzzese, JL; Crane, CH; Evans, DB; Pisters, PWT

MLA Citation

Aloia, TA, Lee, JE, Vauthey, J-N, Abdalla, EK, Wolff, RA, Varadhachary, GR, Abbruzzese, JL, Crane, CH, Evans, DB, and Pisters, PWT. "Delayed recovery after pancreaticoduodenectomy: a major factor impairing the delivery of adjuvant therapy?." Journal of the American College of Surgeons 204.3 (March 2007): 347-355.

PMID

17324767

Source

epmc

Published In

Journal of the American College of Surgeons

Volume

204

Issue

3

Publish Date

2007

Start Page

347

End Page

355

DOI

10.1016/j.jamcollsurg.2006.12.011

Pancreatic cancer is a multifactorial disease with metastasis-prone and therapy-resistant nature. The authors hypothesized that genetic variants of glutathione S-transferase (GST) affect detoxification of carcinogens and anticancer agents in the human pancreas and, thus, the risk and survival of pancreatic cancer.Genotypes of GSTM1, GSTT1, and GSTP1 were determined in 352 patients with pancreatic ductal adenocarcinoma and in a control group of 315 healthy, non-Hispanic whites (frequency-matched by age and sex). Survival analysis was performed in a subset of 290 patients. Epidemiological and clinical information was obtained. A multiple unconditional logistic regression model, a Cox proportional hazards model, and log-rank tests were used for statistical analysis.No significant main effects of any of 3 GST genes on the risk of pancreatic cancer were observed. Subgroup analysis showed that older individuals (aged >or=62 years) who carried the GSTP1*C ((105)Val-(114)Val) containing genotype tended to have a reduced risk compared with younger individuals who carried the non-*C genotype (for sex and pack-years of smoking, the adjusted odd ratio was 0.54; 95% confidence interval [95% CI], 0.29-1.02). In a survival analysis of 138 patients who received 5-flurorouracil, patients who carried the GSTP1*C containing genotype had a significantly longer survival than patients who carried the non-*C genotype (multivariate hazard ratio, 0.45; 95% CI, 0.22-0.94).The GSTP1*C variant conferred a possible protective effect against pancreatic cancer in older individuals and a significant survival advantage in patients who received 5-florouracil. The current findings must be confirmed before further inferences can be made.

Authors

Jiao, L; Bondy, ML; Hassan, MM; Chang, DZ; Abbruzzese, JL; Evans, DB; Smolensky, MH; Li, D

MLA Citation

Jiao, L, Bondy, ML, Hassan, MM, Chang, DZ, Abbruzzese, JL, Evans, DB, Smolensky, MH, and Li, D. "Glutathione S-transferase gene polymorphisms and risk and survival of pancreatic cancer." Cancer 109.5 (March 2007): 840-848.

PMID

17265526

Source

epmc

Published In

Cancer

Volume

109

Issue

5

Publish Date

2007

Start Page

840

End Page

848

DOI

10.1002/cncr.22468

We recently reported the potential of genistein in augmenting gemcitabine-induced killing of pancreatic cancer (Banerjee, S. et al., Cancer Research 2005;65:9064-72). Since cis-diaminedichloroplatinum (II) (cisplatin) is widely used against solid tumors, we further investigated whether genistein pretreatment could be used as a novel strategy for cisplatin-induced killing of pancreatic cancer cells in vitro and enhanced antitumor activity in vivo. Our in vitro results showed that pretreatment of cells with genistein followed by cisplatin resulted in significant loss of cell viability and potentiated apoptosis irrespective of the metastatic ability of cells. Mechanistically, genistein augmented cisplatin induced killing by down regulating transcription factor-NF-kappaB and anti-apoptotic Akt expression. NF-kappaB was found upregulated when pancreatic cancer cells were exposed to cisplatin, suggesting the potential mechanism of acquired chemo-resistance. In addition, we also showed, for the first time, that genistein in combination with cisplatin is more effective antitumor agent in our orthotopic tumor model. But most importantly, our data also showed that a specific target, such as NF-kappaB, was inactivated in animal tumors treated with genistein and cisplatin. Immunohistochemical data showed reduced staining for phospho-p65, Bcl-xL and MMP-9 in treated tumors compared to control tumors, but the lowest activity was seen in the combination group. These results provide strong molecular in vivo evidence in support of our hypothesis that inactivation of the NF-kappaB signaling pathway by genistein results in the chemo-sensitization of pancreatic tumors to cisplatin, which is likely to be an important and novel strategy for the treatment of pancreatic cancer.

Authors

Banerjee, S; Zhang, Y; Wang, Z; Che, M; Chiao, PJ; Abbruzzese, JL; Sarkar, FH

MLA Citation

Banerjee, S, Zhang, Y, Wang, Z, Che, M, Chiao, PJ, Abbruzzese, JL, and Sarkar, FH. "In vitro and in vivo molecular evidence of genistein action in augmenting the efficacy of cisplatin in pancreatic cancer." International journal of cancer 120.4 (February 2007): 906-917.

PMID

17131310

Source

epmc

Published In

International Journal of Cancer

Volume

120

Issue

4

Publish Date

2007

Start Page

906

End Page

917

DOI

10.1002/ijc.22332

© 2008 by Taylor & Francis Group, LLC. The targeting of tumor angiogenesis has evolved into one of the most widely pursued therapeutic strategies. However, as of yet, no antiangiogenic agent used as a monotherapy has demonstrated a survival benefit in a randomized Phase III trial. The combination of bevacizumab, the first FDA approved angiogenesis inhibitor, with cytotoxic regimens has led to survival benefits in cancer patients. This has raised important questions about the complexities inherent in the clinical application of angiogenesis inhibitors. Compiles the results of four decades of progress Integrating fundamental concepts with therapeutic strategies, Anti-Angiogenic Cancer Therapy promotes the idea that an understanding of the molecular and cellular regulation of angiogenesis leads to optimal therapeutic strategies and positive clinical results. It brings together contributions from leading researchers to provide the most authoritative and encyclopedic volume available on this subject. •Examines the role of angiogenesis in cancer, including strategies to prolong the nonangiogenic dormant state of human tumors, molecular mechanisms and cellular regulation of angiogenesis in solid tumors and hematologic malignancies, and the regulation of angiogenesis by the tumor microenvironment. • Covers specific molecular targets for inhibiting angiogenesis in cancer therapy. • Discusses clinical trial design and translational research approaches essential for identifying and developing effective angiogenesis inhibitors. • Outlines current understanding of the molecular biology of each cancer type followed by discussions that examine strategies for targeting angiogenesis in specific cancers. This volume celebrates progress made in four decades, and more importantly, it provides a clear indication of the complex biology that needs further investigation to realize the possibilities envisioned for this beneficial therapeutic modality.

Authors

Davis, DW; Herbst, RS; Abbruzzese, JM

MLA Citation

Davis, DW, Herbst, RS, and Abbruzzese, JM. "Antiangiogenic cancer therapy." January 1, 2007. 1-859.

Source

scopus

Publish Date

2007

Start Page

1

End Page

859

DOI

10.1201/9781420004298

PURPOSE: Effective systemic therapy options for carcinoid tumors are lacking. We conducted in vitro studies and a phase II clinical trial to explore the activity of imatinib in carcinoid tumors. EXPERIMENTAL DESIGN: Cells of the human bronchial carcinoid cell line NCI-H727 and the human pancreatic carcinoid cell line BON-1 were treated with increasing concentrations of imatinib using standard procedures to assess in vitro growth-inhibitory activity. A clinical trial using a two-stage phase II design to assess the response rate and safety profile of imatinib at a dose of 400 mg given twice daily in patients with advanced carcinoid tumors was completed. RESULTS: In both cell lines, there was a dose- and time-dependent cytotoxic effect. The clinical trial enrolled 27 evaluable patients. Median duration on trial was 16 weeks. One patient had a partial response, 17 had stable disease, and 9 had progressive disease by the Response Evaluation Criteria in Solid Tumors criteria. Median progression-free survival time was 24 weeks. Median overall survival is 36 months. Seven patients who achieved a biochemical response had a superior progression-free survival time compared with patients without biochemical response (115 weeks compared with 24 weeks; P = 0.003). An increase in plasma basic fibroblast growth factor was associated with a shorter progression-free survival duration (P = 0.02). CONCLUSIONS: Our data suggest that imatinib is active in vitro and has a modest clinical activity in carcinoid patients. Changes in tumor markers may help select patients who are likely to benefit from therapy.

Authors

Yao, JC; Zhang, JX; Rashid, A; Yeung, S-CJ; Szklaruk, J; Hess, K; Xie, K; Ellis, L; Abbruzzese, JL; Ajani, JA

MLA Citation

Yao, JC, Zhang, JX, Rashid, A, Yeung, S-CJ, Szklaruk, J, Hess, K, Xie, K, Ellis, L, Abbruzzese, JL, and Ajani, JA. "Clinical and in vitro studies of imatinib in advanced carcinoid tumors." Clinical cancer research : an official journal of the American Association for Cancer Research 13.1 (January 2007): 234-240.

PMID

17200360

Source

epmc

Published In

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research

Volume

13

Issue

1

Publish Date

2007

Start Page

234

End Page

240

DOI

10.1158/1078-0432.ccr-06-1618

To examine the profiles of K-ras mutations and p16 and preproenkephalin (ppENK) promoter hypermethylation and their associations with cigarette smoking in pancreatic cancer patients.In plasma DNA of 83 patients with untreated primary pancreatic ductal adenocarcinoma, DNA hypermethylation was determined by methylation-specific polymerase chain reaction and K-ras codon 12 mutations by enriched-nested polymerase chain reaction followed by direct sequencing. Information on smoking exposure was collected by in-person interview. Pearson chi test and Fisher exact test were used in statistical analysis.K-ras mutations, ppENK, and p16 promoter hypermethylation were detected in 32.5%, 29.3%, and 24.6% of the patients, respectively. Sixty-three percent (52/83) of patients exhibited at least one of the alterations. Smoking was associated with the presence of K-ras mutations (P = 0.003). A codon 12 G-to-A mutation was predominantly observed in regular smokers and in heavy smokers (pack-year of smoking > or =36). Smoking was not associated with p16 or ppENK hypermethylation.These preliminary observations suggest that plasma DNA might be a useful surrogate in detecting genetic and epigenetic alterations of pancreatic cancer. The findings on the association between K-ras mutation and smoking were in consistency with previous studies. Further studies on environmental modulators of epigenetic changes in pancreatic cancer are warranted.

Authors

Jiao, L; Zhu, J; Hassan, MM; Evans, DB; Abbruzzese, JL; Li, D

MLA Citation

Jiao, L, Zhu, J, Hassan, MM, Evans, DB, Abbruzzese, JL, and Li, D. "K-ras mutation and p16 and preproenkephalin promoter hypermethylation in plasma DNA of pancreatic cancer patients: in relation to cigarette smoking." Pancreas 34.1 (January 2007): 55-62.

PMID

17198183

Source

epmc

Published In

Pancreas

Volume

34

Issue

1

Publish Date

2007

Start Page

55

End Page

62

DOI

10.1097/01.mpa.0000246665.68869.d4

We evaluated the association between the XPD exon 10 Asp(312)Asn and exon 23 Lys(751)Gln polymorphisms and the risk of pancreatic cancer in a hospital-based study of 344 patients and 386 controls frequency matched by age, gender, and race. Stratified analyses showed ever smokers carrying the Asn(312)Asn genotype had a significantly reduced risk when compared with those carrying the (312)Asp allele (OR=0.46, 95% confidence interval 0.24-0.88) (P for interaction=0.03). The (312)Asp-(751)Gln was identified as the putative at risk haplotype. Our study shows that the XPD gene polymorphism could be a genetic risk modifier for smoking-related pancreatic cancer.

Authors

Jiao, L; Hassan, MM; Bondy, ML; Abbruzzese, JL; Evans, DB; Li, D

MLA Citation

Jiao, L, Hassan, MM, Bondy, ML, Abbruzzese, JL, Evans, DB, and Li, D. "The XPD Asp312Asn and Lys751Gln polymorphisms, corresponding haplotype, and pancreatic cancer risk." Cancer letters 245.1-2 (January 2007): 61-68.

PMID

16458430

Source

epmc

Published In

Cancer Letters

Volume

245

Issue

1-2

Publish Date

2007

Start Page

61

End Page

68

DOI

10.1016/j.canlet.2005.12.026

BACKGROUND: Although patients with locally advanced pancreatic cancer (LAPC) have an extremely poor prognosis, they are a heterogeneous group. Prognostic factors are inadequately defined for disease-free survival and overall survival in patients with LAPC who are receiving chemoradiation, so more definitive prognostic factors would be very useful for designing clinical trials. METHODS: Between December 1993 and July 2005, 247 patients with nonmetastatic LAPC were treated at M. D. Anderson Cancer Center (Houston, Tex) with concurrent chemoradiation (CRT). Median radiation dose was 30 Gy (range, 15-52.2 Gy). Radiosensitizers included 5-fluorouracil (54%), gemcitabine (33%), and capecitabine (13%). Actuarial univariate and multivariate statistical methods were used to determine significant prognostic factors for disease-free survival and overall survival. RESULTS: Median follow-up was 4.3 months (range, 1-63 months). Median disease-free survival and overall survival were 4.2 months and 8.5 months, respectively. On univariate analysis, prognostic factors for improved disease-free survival were a Karnofsky performance scale (KPS) status of >80 (P < .01) and a hemoglobin (Hgb)level at presentation of >/=12 (P = .03). On multivariate analysis, KPS was the only independent prognostic factor for disease-free survival. Median disease-free survival was 4.9 months among patients with a KPS score of >80 and was 3.9 months among those with a KPS score of /=12 (P = .02), KPS>80 (P < .001), and <5% weight loss (P = .03). On multivariate analysis, Hgb and KPS were independent prognostic factors for overall survival. CONCLUSIONS: In the current study, KPS score was an independent prognostic factor for disease-free and overall survival among patients treated with chemoradiation for LAPC. The pretreatment Hgb level was an additional independent prognostic factor for overall survival.

Authors

Krishnan, S; Rana, V; Janjan, NA; Abbruzzese, JL; Gould, MS; Das, P; Delclos, ME; Palla, S; Guha, S; Varadhachary, G; Evans, DB; Wolff, RA; Crane, CH

MLA Citation

Krishnan, S, Rana, V, Janjan, NA, Abbruzzese, JL, Gould, MS, Das, P, Delclos, ME, Palla, S, Guha, S, Varadhachary, G, Evans, DB, Wolff, RA, and Crane, CH. "Prognostic factors in patients with unresectable locally advanced pancreatic adenocarcinoma treated with chemoradiation." Cancer 107.11 (December 2006): 2589-2596.

PMID

17083124

Source

epmc

Published In

Cancer

Volume

107

Issue

11

Publish Date

2006

Start Page

2589

End Page

2596

DOI

10.1002/cncr.22328

From February, 2001 to September, 2002, the Southwest Oncology Group (SWOG) accrued 65 patients with advanced gastric adenocarcinoma to a phase II trial of weekly 5-FU, leucovorin, and the orally-administered uridine analog PN401. Of these 65 patients, 57 were assessable for survival and toxicity, which were the endpoints for the study. Treatment consisted of the administration of 1200 mg/m(2) of 5-FU, 500 mg/m(2) of leucovorin, and 6 grams of PN401 every 8 h, beginning 8 h after the completion of the 5-FU infusion, and continuing for a total of 8 doses (48 grams) during each weekly chemotherapy session. Therapy was delivered for six weeks out of every 8-week treatment cycle. The gastrointestinal toxicity of this regimen was mild with 2 patients experiencing grade 3 stomatitis, and 6 patients having grade 3 diarrhea; and the hematologic toxicity was acceptable with 6 of 57 patients found to have had grade 3 or 4 leukopenia, and 14 of 57 patients experiencing grade 3 or 4 neutropenia. There were two deaths judged possibly related to treatment; one in a patient who experienced a variety of Grade 2 gastrointestinal toxicities and died at home with an unknown cause of death; and a second patient who also died at home, and for whom treatment-related sepsis could not be ruled out. The overall median survival was 7.2 months. The ability to safely deliver twice the usual dose of 5-FU with leucovorin on a weekly schedule suggests that oral uridine analog supplementation with PN401 may enhance the therapeutic index of the fluoropyrimidines.

Authors

Doroshow, JH; McCoy, S; Macdonald, JS; Issell, BF; Patel, T; Cobb, PW; Yost, KJ; Abbruzzese, JL

MLA Citation

Doroshow, JH, McCoy, S, Macdonald, JS, Issell, BF, Patel, T, Cobb, PW, Yost, KJ, and Abbruzzese, JL. "Phase II trial of PN401, 5-FU, and leucovorin in unresectable or metastatic adenocarcinoma of the stomach: a Southwest Oncology Group study." Investigational new drugs 24.6 (November 2006): 537-542.

PMID

16832602

Source

epmc

Published In

Investigational New Drugs

Volume

24

Issue

6

Publish Date

2006

Start Page

537

End Page

542

DOI

10.1007/s10637-006-9244-8

To determine whether the synthetic microRNAs (miRNA) could effectively target tumor cells we designed several miRNA complementary to glioma-associated antigen-1 (Gli-1) mRNA and investigated their ability to inhibit tumor cell proliferation. The sonic hedgehog pathway is an early and late mediator of tumorigenesis in epithelial cancers. Activation of sonic hedgehog signaling seems to precede transformation of tissue stem cells to cancerous stem cells, with the Gli-1 transcription factor functioning as a mediator of environmental signals. Inhibiting cancer cell proliferation by targeting the Gli-1 effector pathway is difficult to achieve by chemotherapeutic agents or short interfering RNA.We hypothesized that targeting the 3'-untranslated region of Gli-1 mRNA would effectively inhibit tumor cell proliferation. To test this hypothesis, we used synthetic miRNAs of our own design and corresponding duplex/small temporal RNAs by introducing three-nucleotide loops in the 3'-untranslated region Gli-1 sequence of high GU content.We found that miRNA (Gli-1-miRNA-3548) and its corresponding duplex (Duplex-3548) significantly inhibited proliferation of Gli-1+ ovarian (SK-OV-3) and pancreatic (MiaPaCa-2) tumor cells. The miRNAs mediated delayed cell division and activation of late apoptosis in MiaPaCa-2 cells. This is the first demonstration of inhibition of pancreatic tumor cell division by designed miRNA.Gli-1 miRNAs should significantly add to the general understanding of the mechanisms of metastasis and contribute toward the design of better treatments for epithelial cancers.

Authors

Tsuda, N; Ishiyama, S; Li, Y; Ioannides, CG; Abbruzzese, JL; Chang, DZ

MLA Citation

Tsuda, N, Ishiyama, S, Li, Y, Ioannides, CG, Abbruzzese, JL, and Chang, DZ. "Synthetic microRNA designed to target glioma-associated antigen 1 transcription factor inhibits division and induces late apoptosis in pancreatic tumor cells." Clinical Cancer Research : an Official Journal of the American Association for Cancer Research 12.21 (November 2006): 6557-6564.

PMID

17085671

Source

epmc

Published In

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research

Volume

12

Issue

21

Publish Date

2006

Start Page

6557

End Page

6564

DOI

10.1158/1078-0432.ccr-06-0588

The epidermal growth factor receptor (EGFR) is a target of new therapies in most nonhematologic cancers. EGFR blockade alone may not be sufficient for the control of growth and invasion of human pancreas cancer because of the independent activation of Akt and nuclear factor-kappaB (NF-kappaB). The expression of EGFR, Akt, and NF-kappaB was determined in six human pancreatic cancer cell lines. Selected cells for specific expression were treated with erlotinib, genistein, gemcitabine, or the combination. Growth inhibition was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and apoptosis was assayed by ELISA. EGFR, phosphorylated EGFR, phosphorylated Akt, and survivin expressions were determined by immunoblotting. Electrophoretic mobility shift assay was used to evaluate the DNA binding activity of NF-kappaB. Genistein significantly increased (P < 0.05) erlotinib-induced growth inhibition and apoptosis in BxPC-3, CAPAN-2, and AsPC-1 cells. In the BxPC-3 cell line, significant down-regulation of EGFR, phosphorylated Akt, NF-kappaB activation, and survivin was observed in the cells treated with the combination compared with the erlotinib-treated cells. In the HPAC and MIAPaCa cell line, no potentiation of the effects of erlotinib by genistein on cell growth or inhibition of the EGFR/Akt/NF-kappaB was observed. Genistein potentiated growth inhibition and apoptosis of the gemcitabine and erlotinib combination in COLO-357 cell line. Genistein potentiates the growth inhibition and apoptosis induced by erlotinib and gemcitabine in certain pancreatic cancer cells. Akt and NF-kappaB inhibition represents one of the mechanisms for the potentiation of erlotinib- and gemcitabine-induced cell death by genistein.

Authors

El-Rayes, BF; Ali, S; Ali, IF; Philip, PA; Abbruzzese, J; Sarkar, FH

MLA Citation

El-Rayes, BF, Ali, S, Ali, IF, Philip, PA, Abbruzzese, J, and Sarkar, FH. "Potentiation of the effect of erlotinib by genistein in pancreatic cancer: the role of Akt and nuclear factor-kappaB." Cancer Research 66.21 (November 2006): 10553-10559.

PMID

17079479

Source

epmc

Published In

Cancer Research

Volume

66

Issue

21

Publish Date

2006

Start Page

10553

End Page

10559

DOI

10.1158/0008-5472.can-06-2333

PURPOSE: The purpose of this Phase II multi-institutional study was to define the efficacy and toxicity of ixabepilone in patients with advance pancreatic adenocarcinoma. PATIENTS AND METHODS: Patients were required to have pancreatic adenocarcinoma and metastatic or recurrent disease that was not amenable to curative resection. Performance status was 0-1, and patients could not have had prior chemotherapy, or chemoradiation therapy for their advanced disease although prior local palliative radiation was allowed. Ixabepilone was administered iv as a 3 hour infusion every 21 days. Initially, the dose was 50 mg/m(2) but this was lowered to 40 mg/m(2) shortly after the trial opened because of concerns about neurotoxicity. RESULTS: Sixty-two patients were registered however 2 were ineligible because they did not have recurrent or metastatic disease. For the 60 eligible patients, 22 had performance status of 0 and 38 performance status of 1. The estimated 6-month survival was 60% (95% CI 48%-72%) with a median survival of 7.2 months and an estimated time to treatment failure of 2.3 months. Out of 56 patients with measurable disease there were 5 confirmed partial responses for a confirmed response probability of 9% (95% CI 3%-20%) and 7 unconfirmed partial responses for an overall response probability of 21% (95% CI 12%-34%). Common toxicities were neutropenia/granulocytopenia, nausea and vomiting and neuropathy. There was one death, cause not determined but judged "possibly" related to treatment. CONCLUSION: Ixabepilone shows encouraging activity in patients with advanced pancreatic cancer and should be investigated further in this disease.

Authors

Whitehead, RP; McCoy, S; Rivkin, SE; Gross, HM; Conrad, ME; Doolittle, GC; Wolff, RA; Goodwin, JW; Dakhil, SR; Abbruzzese, JL

MLA Citation

Whitehead, RP, McCoy, S, Rivkin, SE, Gross, HM, Conrad, ME, Doolittle, GC, Wolff, RA, Goodwin, JW, Dakhil, SR, and Abbruzzese, JL. "A Phase II trial of epothilone B analogue BMS-247550 (NSC #710428) ixabepilone, in patients with advanced pancreas cancer: a Southwest Oncology Group study." Investigational new drugs 24.6 (November 2006): 515-520.

PMID

16699973

Source

epmc

Published In

Investigational New Drugs

Volume

24

Issue

6

Publish Date

2006

Start Page

515

End Page

520

DOI

10.1007/s10637-006-8440-x

BACKGROUND: Imatinib has demonstrated marked clinical efficacy against gastrointestinal stromal tumor (GIST). Microarray technology, real-time polymerase chain reaction (PCR) validation, and fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging were used to study the early molecular effects of imatinib antitumor activity in GIST. METHODS: After exposure of sensitive and resistant sarcoma cell lines to imatinib for 24 to 48 hours, the changes in gene expression were evaluated using a 1146 unique pathway array with Western blot validation. Real-time PCR was used to confirm changes in gene expression in human GIST samples (preimatinib biopsy and postimatinib surgical specimen after 3-7 days of therapy). FDG-PET was performed to correlate radiographic findings with the effects of imatinib on gene expression in GIST. RESULTS: In all, 55 genes demonstrated a > or = 2-fold change after imatinib treatment of the GIST882 cells. Among these genes there was up-regulation of insulin-like growth factor binding protein-3 (IGFBP-3), a protein that modulates proliferation and apoptosis. Western blot analysis confirmed the increase of IGFBP-3 only in imatinib-sensitive GIST882 cells. Up to a 7-fold induction (49% mean increase; P = .08) of IGFBP-3 mRNA was found in tumor samples from patients with low residual FDG uptake, whereas there was an up to 12-fold reduction (-102% mean decrease; P = .03) in IGFBP-3 in those patients with high residual FDG uptake after imatinib therapy. CONCLUSIONS: In the current study, imatinib appears to regulate numerous genes and specifically induces IGFBP-3 in GIST cells and tumor samples. IGFBP-3 levels also were found to be inversely correlated with residual FDG uptake in GIST patients early in imatinib therapy. These initial observations suggest that IGFBP-3 is an important early marker of antitumor activity of imatinib in GIST.

Authors

Trent, JC; Ramdas, L; Dupart, J; Hunt, K; Macapinlac, H; Taylor, E; Hu, L; Salvado, A; Abbruzzese, JL; Pollock, R; Benjamin, RS; Zhang, W

MLA Citation

Trent, JC, Ramdas, L, Dupart, J, Hunt, K, Macapinlac, H, Taylor, E, Hu, L, Salvado, A, Abbruzzese, JL, Pollock, R, Benjamin, RS, and Zhang, W. "Early effects of imatinib mesylate on the expression of insulin-like growth factor binding protein-3 and positron emission tomography in patients with gastrointestinal stromal tumor." Cancer 107.8 (October 2006): 1898-1908.

PMID

16986125

Source

epmc

Published In

Cancer

Volume

107

Issue

8

Publish Date

2006

Start Page

1898

End Page

1908

DOI

10.1002/cncr.22214

PURPOSE: A phase II trial of the oral epidermal growth factor receptor (EGFR) inhibitor erlotinib in patients with gastroesophageal adenocarcinomas stratified according to primary tumor location into two groups: gastroesophageal junction (GEJ)/cardia and distal gastric adenocarcinomas. PATIENTS AND METHODS: Patients with a histologically proven diagnosis of adenocarcinoma of the GEJ or stomach (ST) that was unresectable or metastatic; presence of measurable disease; no prior chemotherapy for advanced or metastatic cancer; Zubrod performance status (PS) of 0 to 1; and adequate renal, hepatic, and hematologic function were treated with erlotinib 150 mg/d orally. Patient characteristics were median age, GEJ-63 years, ST-64 years; sex, GEJ-84% male and 16% female, ST-60 male and 40 female; Zubrod PS, GEJ-25 had a PS of 0 and 18 had a PS 1, ST-13 had a PS of 0 and 12 had a PS of 1. RESULTS: Percentage of common toxicities were skin rash, 86% and 72%; fatigue, 51% and 44%; and AST/ALT elevation, 28% and 28%, respectively for GEJ and ST. There has been one confirmed complete response, three confirmed partial responses (PRs) and one unconfirmed PR for an overall response probability of 9% confirmed (95% CI, 3% to 22%), all occurring in GEJ stratum. No responses were observed in ST stratum. The median survival was 6.7 months in GEJ and 3.5 months in ST stratum. Neither intratumoral EGFR, transforming growth factor-alpha or phosphorylated Akt kinase expression nor plasma proteomic analyses were predictive of clinical outcome. No somatic mutations of the EGFR exons 18, 19, or 21 were detected and there was no gross amplification of EGFR by fluorescence in situ hybridization. CONCLUSION: Erlotinib is active in patients with GEJ adenocarcinomas, but appears inactive in gastric cancers. The molecular correlates examined were not predictive of the patient therapeutic response.

Authors

Dragovich, T; McCoy, S; Fenoglio-Preiser, CM; Wang, J; Benedetti, JK; Baker, AF; Hackett, CB; Urba, SG; Zaner, KS; Blanke, CD; Abbruzzese, JL

MLA Citation

Dragovich, T, McCoy, S, Fenoglio-Preiser, CM, Wang, J, Benedetti, JK, Baker, AF, Hackett, CB, Urba, SG, Zaner, KS, Blanke, CD, and Abbruzzese, JL. "Phase II trial of erlotinib in gastroesophageal junction and gastric adenocarcinomas: SWOG 0127." Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology 24.30 (October 2006): 4922-4927.

PMID

17050876

Source

epmc

Published In

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology

Volume

24

Issue

30

Publish Date

2006

Start Page

4922

End Page

4927

DOI

10.1200/jco.2006.07.1316

Although it displays promising activity in other tumor models, the effects of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on human pancreatic cancer cells have not been comprehensively explored. We report that a majority of human pancreatic cancer cell lines (seven of nine) underwent apoptosis when they were exposed to recombinant human TRAIL in vitro. Characterization of surface TRAIL receptors by fluorescence-activated cell sorting showed that TRAIL-resistant cells (Panc-1 and HS766T) expressed lower levels of DR4 and DR5 than did TRAIL-sensitive cells. The proteasome inhibitor bortezomib (PS-341, Velcade) further increased TRAIL responsiveness in the TRAIL-sensitive cells and synergized with TRAIL to reverse resistance in Panc-1 and HS776T cells. The effects of bortezomib were mimicked by transfection with a small interfering RNA construct specific for the p65 subunit of nuclear factor-kappaB (NF-kappaB) or exposure to a selective chemical inhibitor of IKK (PS-1145). Silencing IkappaBalpha prevented TRAIL sensitization by PS-1145, confirming that IkappaBalpha mediated the effects of PS-1145. NF-kappaB inhibition resulted in down-regulation of BCL-XL and XIAP, and silencing either restored TRAIL sensitivity in TRAIL-resistant cells. Finally, therapy with TRAIL plus PS-1145 reversed TRAIL resistance in vivo to produce synergistic growth inhibition in orthotopic Panc-1 tumors. Together, our results show that NF-kappaB inhibits TRAIL-induced apoptosis in human pancreatic cancer cells and suggest that combination therapy with TRAIL and NF-kappaB inhibitors, such as bortezomib, PS-1145, or curcumin, should be considered as a possible treatment strategy in patients with pancreatic cancer.

Authors

Khanbolooki, S; Nawrocki, ST; Arumugam, T; Andtbacka, R; Pino, MS; Kurzrock, R; Logsdon, CD; Abbruzzese, JL; McConkey, DJ

MLA Citation

Khanbolooki, S, Nawrocki, ST, Arumugam, T, Andtbacka, R, Pino, MS, Kurzrock, R, Logsdon, CD, Abbruzzese, JL, and McConkey, DJ. "Nuclear factor-kappaB maintains TRAIL resistance in human pancreatic cancer cells." Molecular cancer therapeutics 5.9 (September 2006): 2251-2260.

PMID

16985059

Source

epmc

Published In

Molecular Cancer Therapeutics

Volume

5

Issue

9

Publish Date

2006

Start Page

2251

End Page

2260

DOI

10.1158/1535-7163.mct-06-0075

BACKGROUND: The purpose of the current study was to determine the maximum tolerated dose, dose-limiting toxicities, pharmacokinetic profile, and recommended Phase II dose of oral administration of TAS-102, a novel nucleoside formed by the combination of alpha,alpha,alpha-trifluorothymidine (FTD) and a thymidine phosphorylase inhibitor (TPI: 5-chloro-6-(2-iminopyrrolidin-1-yl)methyl-2,4(1H,3H)-pyrimidinedione). METHODS: Eligible patients had advanced solid tumors, adequate organ function, and had not received anticancer therapy in the preceding 4 weeks. TAS-102 was administered orally once daily for 14 days, followed by a 1-week rest, repeated every 3 weeks. The initial dose of TAS-102 administered was 100 mg/m2/day. The first 2 patients treated at that dose experienced substantial toxicity and, therefore, lower dose levels of TAS-102 were subsequently explored. RESULTS: Fourteen patients were enrolled; all patients were evaluable for toxicity assessment and 12 were evaluable for response. The initial dose explored was 100 mg/m2/day, based on a preclinical monkey model. However, the first 2 patients experienced bone marrow suppression of Grade 3 or 4 in course 1. The protocol was amended to study the next cohort of patients at 50 mg/m2/day. At this dose level no Grade 3 or 4 toxicities were observed in course 1. In the subsequent dose level (60 mg/m2/day), 3 of 6 patients experienced Grade 3 or 4 granulocytopenia as dose-limiting toxicity. Three additional patients for a total of 6 were enrolled at 50 mg/m2/day without occurrence of dose-limiting toxicity. Thus, 50 mg/m2/day was declared the maximum tolerated dose for this schedule. CONCLUSIONS: The authors' study showed that 50 mg/m2/day was a tolerable dose of the novel antimetabolite FTD in combination with an inhibitor of its inactivating enzyme TP, and this is the recommended Phase II dose. Evaluation of this daily dose in malignancies for which fluoropyrimidines have failed is needed.

Authors

Hong, DS; Abbruzzese, JL; Bogaard, K; Lassere, Y; Fukushima, M; Mita, A; Kuwata, K; Hoff, PM

MLA Citation

Hong, DS, Abbruzzese, JL, Bogaard, K, Lassere, Y, Fukushima, M, Mita, A, Kuwata, K, and Hoff, PM. "Phase I study to determine the safety and pharmacokinetics of oral administration of TAS-102 in patients with solid tumors." Cancer 107.6 (September 2006): 1383-1390.

PMID

16902987

Source

epmc

Published In

Cancer

Volume

107

Issue

6

Publish Date

2006

Start Page

1383

End Page

1390

DOI

10.1002/cncr.22125

Variations in genetic mutations in pancreatic carcinoma between different populations have not been studied extensively, especially in developing countries where pancreatic cancer is rare. We studied the molecular pathology of 44 pancreatic carcinomas from patients residing in a heavily polluted region in the Nile River delta and compared the findings with tumors from 44 United States (US) patients. We evaluated K-ras mutations in codon 12, p53 mutations in exons 5-8, and Gadd45a mutations in exons 1 and 4. Overall, rates of K-ras, p53 and Gadd45 mutations were not statistically different in tumors of patients from Egypt and the US (67.4 vs. 63.4%; 27.3 vs. 36.4% and 9.1 vs. 4.5%, respectively). However, there were distinct differences in the specific types of K-ras and p53 mutations between the 2 groups. In K-ras, G --> T transversion mutation was more frequent in the tumors from Egypt than from the US (58.6 vs. 26.9%), whereas G --> C transversion was detected in 26.9% of US tumors but none from Egypt (p = 0.003). We also found a trend toward differences in the p53 exons in which mutations occurred, with higher frequency of exon 5 mutation and lower frequency of exon 6 mutation in Egyptian tumors. Logistic regression showed that K-ras G --> T transversion mutations and p53 exon 6 mutations were predicted by the country of residence of the patients. Our study identifies that there are differences in the types of mutations found in tumors from pancreatic carcinoma patients in Egypt and the US, and suggests that environmental factors may explain these differences.

Authors

Soliman, AS; Bondy, M; Webb, CR; Schottenfeld, D; Bonner, J; El-Ghawalby, N; Soultan, A; Abdel-Wahab, M; Fathy, O; Ebidi, G; Zhang, Q; Greenson, JK; Abbruzzese, JL; Hamilton, SR

MLA Citation

Soliman, AS, Bondy, M, Webb, CR, Schottenfeld, D, Bonner, J, El-Ghawalby, N, Soultan, A, Abdel-Wahab, M, Fathy, O, Ebidi, G, Zhang, Q, Greenson, JK, Abbruzzese, JL, and Hamilton, SR. "Differing molecular pathology of pancreatic adenocarcinoma in Egyptian and United States patients." International journal of cancer 119.6 (September 2006): 1455-1461.

PMID

16619252

Source

epmc

Published In

International Journal of Cancer

Volume

119

Issue

6

Publish Date

2006

Start Page

1455

End Page

1461

DOI

10.1002/ijc.21986

The epidermal growth factor receptor (EGFR) signaling network plays critical roles in human cancers, including pancreatic cancer, suggesting that the discovery of specific agents targeting EGFR would be extremely valuable for pancreatic cancer therapy. EGFR-related protein (ERRP), a recently identified pan-erbB inhibitor, has been shown to inhibit growth and induce apoptosis of pancreatic cancer cells in vitro and tumor growth in a xenograft model. However, the precise molecular mechanism(s) by which ERRP exerts its antitumor activity remains unclear. The current investigation was undertaken to delineate the tumor growth inhibitory mechanism(s) of ERRP in pancreatic cancer cells. Using multiple molecular assays, such as 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, apoptosis, gene transfection, real-time reverse transcription-PCR, Western blotting, invasion, and electrophoretic mobility shift assay for measuring DNA-binding activity of nuclear factor-kappaB (NF-kappaB), we found that ERRP caused marked inhibition of pancreatic cancer cell growth. This was accompanied by increased apoptosis and concomitant attenuation of Notch-1 and NF-kappaB and down-regulation of NF-kappaB downstream genes, such as matrix metalloproteinase-9 and vascular endothelial growth factor, resulting in the inhibition of pancreatic cancer cell invasion through the Matrigel. We also found that down-regulation of Notch-1 by small interfering RNA before ERRP treatment resulted in enhanced cell growth inhibition and apoptosis. Our data suggest that the ERRP-mediated inactivation of EGFR, Notch-1, NF-kappaB, and its downstream target genes contributed to the inhibition of cell growth and invasion. We conclude that ERRP could be an effective agent for inhibiting tumor growth and invasion for the treatment of pancreatic cancer.

Authors

Wang, Z; Sengupta, R; Banerjee, S; Li, Y; Zhang, Y; Rahman, KMW; Aboukameel, A; Mohammad, R; Majumdar, APN; Abbruzzese, JL; Sarkar, FH

MLA Citation

Wang, Z, Sengupta, R, Banerjee, S, Li, Y, Zhang, Y, Rahman, KMW, Aboukameel, A, Mohammad, R, Majumdar, APN, Abbruzzese, JL, and Sarkar, FH. "Epidermal growth factor receptor-related protein inhibits cell growth and invasion in pancreatic cancer." Cancer research 66.15 (August 2006): 7653-7660.

PMID

16885366

Source

epmc

Published In

Cancer Research

Volume

66

Issue

15

Publish Date

2006

Start Page

7653

End Page

7660

DOI

10.1158/0008-5472.can-06-1019

With recent advances in pancreatic imaging and surgical techniques, a distinct subset of pancreatic tumors is emerging that blurs the distinction between resectable and locally advanced disease: tumors of "borderline resectability." In our practice, patients with borderline-resectable pancreatic cancer include those whose tumors exhibit encasement of a short segment of the hepatic artery, without evidence of tumor extension to the celiac axis, that is amenable to resection and reconstruction; tumor abutment of the superior mesenteric artery involving <180 degrees of the circumference of the artery; or short-segment occlusion of the superior mesenteric vein, portal vein, or their confluence with a suitable option available for vascular reconstruction because the veins are normal above and below the area of tumor involvement. With currently available surgical techniques, patients with borderline-resectable pancreatic head cancer are at high risk for a margin-positive resection. Therefore, our approach to these patients is to use preoperative systemic therapy and local-regional chemoradiation to maximize the potential for an R0 resection and to avoid R2 resections. In our experience, patients with favorable responses to preoperative therapy (radiographical evidence of tumor regression and improvement in serum tumor marker levels) are the subset of patients who have the best chance for an R0 resection and a favorable long-term outcome.

Authors

Varadhachary, GR; Tamm, EP; Abbruzzese, JL; Xiong, HQ; Crane, CH; Wang, H; Lee, JE; Pisters, PWT; Evans, DB; Wolff, RA

MLA Citation

Varadhachary, GR, Tamm, EP, Abbruzzese, JL, Xiong, HQ, Crane, CH, Wang, H, Lee, JE, Pisters, PWT, Evans, DB, and Wolff, RA. "Borderline resectable pancreatic cancer: definitions, management, and role of preoperative therapy." Annals of Surgical Oncology 13.8 (August 2006): 1035-1046. (Review)

PMID

16865597

Source

epmc

Published In

Annals of Surgical Oncology

Volume

13

Issue

8

Publish Date

2006

Start Page

1035

End Page

1046

DOI

10.1245/aso.2006.08.011

The purpose of this Phase II multi-institutional trial was to determine the efficacy and toxicity of R115777 in previously untreated patients with metastatic colorectal carcinoma.Patients were required to have histologically confirmed colorectal cancer with distant metastatic disease that was not surgically curable. They could not have received prior chemotherapy for metastatic disease. R115777 was given at a dose of 300 mg p.o. twice a day for 21 days every 28 days until tumor progression or toxicity or other reason for discontinuation occurred. The primary endpoint was to determine the confirmed response probability with this treatment.There were 55 eligible patients accrued to the study. There were no complete responses, but one confirmed partial response for a confirmed response probability of 2% (95%CI 0-10%). Three additional patients had an unconfirmed partial response for an overall response probability of 7%. The time to treatment failure was 1.7 months and the estimated median survival was 8.1 months. One patient died of treatment related infection and there were 7 other patients with grade 4 toxicities consisting of neutropenia, leukopenia, febrile neutropenia and thrombocytopenia, depression, increased bilirubin, anemia, and pneumonitis/infiltrates.R115777 given as a single agent by this dose and schedule is ineffective in patients with metastatic colorectal cancer.

Authors

Whitehead, RP; McCoy, S; Macdonald, JS; Rivkin, SE; Neubauer, MA; Dakhil, SR; Lenz, H-J; Tanaka, MS; Abbruzzese, JL; Southwest Oncology Group,

MLA Citation

Whitehead, RP, McCoy, S, Macdonald, JS, Rivkin, SE, Neubauer, MA, Dakhil, SR, Lenz, H-J, Tanaka, MS, Abbruzzese, JL, and Southwest Oncology Group, . "Phase II trial of R115777 (NSC #70818) in patients with advanced colorectal cancer: a Southwest Oncology Group study." Investigational new drugs 24.4 (July 2006): 335-341.

PMID

16683076

Source

epmc

Published In

Investigational New Drugs

Volume

24

Issue

4

Publish Date

2006

Start Page

335

End Page

341

DOI

10.1007/s10637-005-4345-3

The northeast Nile Delta, Egypt's most polluted region, appears to have a high incidence of pancreatic cancer. We sought to determine whether there is any geographic clustering of pancreatic cancers there and, if so, whether such clustering might be associated with environmental pollution. Using data from the medical records of the Gastrointestinal Surgical Center of Mansoura University in the Dakahleia Province of Egypt and detailed geographical maps of the northeast Nile Delta region, we plotted the residences of all 373 patients who had pancreatic cancer diagnosed between 1995 and 2000. The study region has 15 administrative districts, whose centroid coordinates, population, and number of pancreatic cancer patients were determined for this study. Monte Carlo simulation identified statistically significant clustering of pancreatic cancer in five subdivisions located near the Nile River and Delta plains. This clustering was independent of population size and formed two larger clusters. When data were analyzed by sex, clustering of pancreatic cancer was observed in the same five subdivisions for men but only two subdivisions showed clustering for women. Together, our data suggest that there is clustering of pancreatic cancer cases in the northeast Nile delta region and that this clustering may be related to water pollution. Our data also warrant future studies of the association between water pollution and pancreatic cancer in the region.

Authors

Soliman, AS; Wang, X; Stanley, J-D; El-Ghawalby, N; Bondy, ML; Ezzat, F; Soultan, A; Abdel-Wahab, M; Fathy, O; Ebidi, G; Abdel-Karim, N; Do, K-A; Levin, B; Hamilton, SR; Abbruzzese, JL

MLA Citation

Soliman, AS, Wang, X, Stanley, J-D, El-Ghawalby, N, Bondy, ML, Ezzat, F, Soultan, A, Abdel-Wahab, M, Fathy, O, Ebidi, G, Abdel-Karim, N, Do, K-A, Levin, B, Hamilton, SR, and Abbruzzese, JL. "Geographical clustering of pancreatic cancers in the Northeast Nile Delta region of Egypt." Archives of environmental contamination and toxicology 51.1 (July 2006): 142-148.

PMID

16453066

Source

epmc

Published In

Archives of Environmental Contamination and Toxicology

Volume

51

Issue

1

Publish Date

2006

Start Page

142

End Page

148

DOI

10.1007/s00244-005-0154-0

Recent epidemiological investigations have observed an association between the consumption of grilled or barbecued meat and an increased risk of pancreatic cancer, suggesting that dietary exposure to heterocyclic aromatic amines (HCA) may contribute to the development of this disease. 2-Amino-1-methyl-6-phenylimidazo [4,5-b]-pyridine (PhIP) is the most abundant HCA found in well-done and grilled meats. To determine whether HCA-induced DNA damage is present in the human pancreas, immunohistochemistry and computer-assisted image analysis were used to measure PhIP-DNA adducts in 54 normal pancreatic tissues (N) from persons without pancreatic cancer and in 38 normal adjacent pancreatic tissues (A) and in 39 cancer tissues (T) from 68 patients with pancreatic adenocarcinoma. PhIP-DNA adducts were detected in 53 N, 34 A and 39 T samples. Mean values (+/-SD) of the absorbency for PhIP staining were 0.22+/-0.04, 0.24+/-0.04, and 0.24+/-0.03 for N, A, and T samples, respectively (p=0.004). Using the median absorbency (0.21) of the samples from normal controls as the cut-off, 71% of A and 77% of T tissues, compared with 48% of N tissues, were distributed in the higher range (p=0.009). The odds ratio of pancreatic cancer was 3.4 (95% confidence interval 1.5-7.5, p=0.002) for individuals with a higher level of PhIP-DNA adducts. This is the first report of the detection of PhIP-DNA adducts in human pancreatic tissue samples obtained from patients with unknown exposure to HCA. Although limited by the small sample size, these preliminary results suggest that PhIP exposure may contribute to human pancreatic cancer development.

Authors

Zhu, J; Rashid, A; Cleary, K; Abbruzzese, JL; Friess, H; Takahashi, S; Shirai, T; Li, D

MLA Citation

Zhu, J, Rashid, A, Cleary, K, Abbruzzese, JL, Friess, H, Takahashi, S, Shirai, T, and Li, D. "Detection of 2-amino-1-methyl-6-phenylimidazo [4,5-b]-pyridine (PhIP)-DNA adducts in human pancreatic tissues." Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals 11.4 (July 2006): 319-328.

PMID

16908439

Source

epmc

Published In

Biomarkers

Volume

11

Issue

4

Publish Date

2006

Start Page

319

End Page

328

DOI

10.1080/13547500600667911

PURPOSE: This phase II randomized discontinuation trial evaluated the effects of sorafenib (BAY 43-9006), an oral multikinase inhibitor targeting the tumor and vasculature, on tumor growth in patients with metastatic renal cell carcinoma. PATIENTS AND METHODS: Patients initially received oral sorafenib 400 mg twice daily during the initial run-in period. After 12 weeks, patients with changes in bidimensional tumor measurements that were less than 25% from baseline were randomly assigned to sorafenib or placebo for an additional 12 weeks; patients with > or = 25% tumor shrinkage continued open-label sorafenib; patients with > or = 25% tumor growth discontinued treatment. The primary end point was the percentage of randomly assigned patients remaining progression free at 24 weeks after the initiation of sorafenib. RESULTS: Of 202 patients treated during the run-in period, 73 patients had tumor shrinkage of > or = 25%. Sixty-five patients with stable disease at 12 weeks were randomly assigned to sorafenib (n = 32) or placebo (n = 33). At 24 weeks, 50% of the sorafenib-treated patients were progression free versus 18% of the placebo-treated patients (P = .0077). Median progression-free survival (PFS) from randomization was significantly longer with sorafenib (24 weeks) than placebo (6 weeks; P = .0087). Median overall PFS was 29 weeks for the entire renal cell carcinoma population (n = 202). Sorafenib was readministered in 28 patients whose disease progressed on placebo; these patients continued on sorafenib until further progression, for a median of 24 weeks. Common adverse events were skin rash/desquamation, hand-foot skin reaction, and fatigue; 9% of patients discontinued therapy, and no patients died from toxicity. CONCLUSION: Sorafenib has significant disease-stabilizing activity in metastatic renal cell carcinoma and is tolerable with chronic daily therapy.

Authors

Ratain, MJ; Eisen, T; Stadler, WM; Flaherty, KT; Kaye, SB; Rosner, GL; Gore, M; Desai, AA; Patnaik, A; Xiong, HQ; Rowinsky, E; Abbruzzese, JL; Xia, C; Simantov, R; Schwartz, B; O'Dwyer, PJ

MLA Citation

Ratain, MJ, Eisen, T, Stadler, WM, Flaherty, KT, Kaye, SB, Rosner, GL, Gore, M, Desai, AA, Patnaik, A, Xiong, HQ, Rowinsky, E, Abbruzzese, JL, Xia, C, Simantov, R, Schwartz, B, and O'Dwyer, PJ. "Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma." Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology 24.16 (June 2006): 2505-2512.

PMID

16636341

Source

epmc

Published In

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology

Volume

24

Issue

16

Publish Date

2006

Start Page

2505

End Page

2512

DOI

10.1200/jco.2005.03.6723

BACKGROUND: Sp1, Sp3, and Sp4 are transcription factors that regulate cell proliferation and vascular endothelial growth factor (VEGF) expression and are overexpressed in many cancer cell lines. For some cancers, Sp1 overexpression is associated with poor survival. Cyclooxygenase inhibitors decrease Sp1 expression in cancer cells, and therefore different structural classes of nonsteroidal anti-inflammatory drugs (NSAIDs) were screened for their ability to decrease levels of Sp1, Sp3, and Sp4 and to decrease pancreatic tumor growth and metastasis in an in vivo model. METHODS: Levels of Sp1, Sp3, Sp4, and VEGF proteins in pancreatic cancer cell lines were assessed by immunoblot analysis. mRNA was assessed by reverse transcription-polymerase chain reaction. Panc-1 pancreatic cancer cells transfected with VEGF promoter constructs were used to assess VEGF promoter activation. Pancreatic tumor weight and size and liver metastasis were assessed in an orthotopic mouse model of pancreatic cancer (groups of 10 mice). Protein expression in tumors was assessed immunohistochemically. RESULTS: Tolfenamic acid and structurally related biaryl derivatives induced degradation of Sp1, Sp3, and Sp4 in pancreatic cancer cells. Tolfenamic acid also inhibited VEGF mRNA and protein expression in pancreatic cancer cells; this inhibition was associated with the decreased Sp-dependent activation of the VEGF promoter. In the mouse model for pancreatic cancer, treatment with tolfenamic acid (50 mg/kg of body weight), compared with control treatment, statistically significantly decreased tumor growth and weight (P = .005), liver metastasis (P = .027), and levels of Sp3 and VEGF (P = .009) and Sp1 and Sp4 (P = .006) proteins in tumors. For example, tumors from mice treated with tolfenamic acid (50 mg/kg) had statistically significantly lower VEGF levels (45%, 95% confidence interval = 39% to 51%; P = .009) than tumors from control mice. CONCLUSIONS: Tolfenamic acid is a new antipancreatic cancer NSAID that activates degradation of transcription factors Sp1, Sp3, and Sp4; reduces VEGF expression; and decreases tumor growth and metastasis.

Authors

Abdelrahim, M; Baker, CH; Abbruzzese, JL; Safe, S

MLA Citation

Abdelrahim, M, Baker, CH, Abbruzzese, JL, and Safe, S. "Tolfenamic acid and pancreatic cancer growth, angiogenesis, and Sp protein degradation." Journal of the National Cancer Institute 98.12 (June 2006): 855-868.

PMID

16788159

Source

epmc

Published In

Journal of the National Cancer Institute

Volume

98

Issue

12

Publish Date

2006

Start Page

855

End Page

868

DOI

10.1093/jnci/djj232

Pancreatic cancer is highly aggressive with extremely poor prognosis. Developing a pancreatic cancer specific promoter (PCSP) is one approach for pancreatic cancer gene therapy. We have modified the promoter of cholecystokinin type A receptor (CCKAR), named CCK/Mpd, which possesses a relatively high activity in pancreatic cancer cells as compared with normal cells. The CCK/Mpd promoter-driven luciferase exhibits a better tumor specific tissue distribution than the CMV promoter-driven luciferase when systemically administered in vivo. Notably, we demonstrate a treatment efficacy by using CCK/Mpd-Bik-DD/liposome in a nude mice xenograft model, suggesting the feasibility of PCSP-based gene therapy in pancreatic cancer treatment.

Authors

Li, Z; Ding, Q; Li, Y; Miller, SA; Abbruzzese, JL; Hung, M-C

MLA Citation

Li, Z, Ding, Q, Li, Y, Miller, SA, Abbruzzese, JL, and Hung, M-C. "Suppression of pancreatic tumor progression by systemic delivery of a pancreatic-cancer-specific promoter driven Bik mutant." Cancer Letters 236.1 (May 2006): 58-63.

PMID

15953675

Source

epmc

Published In

Cancer Letters

Volume

236

Issue

1

Publish Date

2006

Start Page

58

End Page

63

DOI

10.1016/j.canlet.2005.05.001

BACKGROUND: Unique metastatic patterns cited in the literature often arise from anecdotal clinical observations and autopsy reports. The authors analyzed clinical data from a large number of patients with histologically confirmed, distant-stage adenocarcinoma to evaluate metastatic patterns. METHODS: Tumor registry data were collected between 1994-1996 on 11 primary tumor sites and 15 metastatic sites from 4399 patients. The primary and metastatic sites were cross-tabulated in various ways to identify patterns, and the authors developed algorithms by using multinomial logistic regression analysis to predict the locations of primary tumors based on metastatic patterns. RESULTS: Three primary tumors had single, dominant metastatic sites: ovary to abdominal cavity (91%), prostate to bone (90%), and pancreas to liver (85%). The liver was the dominant metastatic site for gastrointestinal (GI) primary tumors (71% of patients), whereas bone and lung metastases were noted most frequently in non-GI primary tumors (43% and 29%, respectively). In a study of combinations of liver, abdominal cavity, and bone metastases, 86% of prostate primary tumors had only bone metastases, 80% of ovarian primary tumors had only abdominal cavity metastases, and 74% of pancreas primary tumors had only liver metastases. A single organ was the dominant source of metastases in 7 sites: axillary lymph node from the breast (97%), intestinal lymph node from the colon (84%), thoracic lymph node from the lung (66%), brain from the lung (64%), mediastinal lymph node from the lung (62%), supraclavicular lymph node from the breast (51%), and adrenal gland from the lung (51%). CONCLUSIONS: The algorithms that the authors developed achieved a cross-validated accuracy of 64% and an accuracy of 64% on an 1851-patient independent test set, compared with 9% accuracy when a random classifier was used.

Authors

Hess, KR; Varadhachary, GR; Taylor, SH; Wei, W; Raber, MN; Lenzi, R; Abbruzzese, JL

MLA Citation

Hess, KR, Varadhachary, GR, Taylor, SH, Wei, W, Raber, MN, Lenzi, R, and Abbruzzese, JL. "Metastatic patterns in adenocarcinoma." Cancer 106.7 (April 2006): 1624-1633.

PMID

16518827

Source

epmc

Published In

Cancer

Volume

106

Issue

7

Publish Date

2006

Start Page

1624

End Page

1633

DOI

10.1002/cncr.21778

Metastatic esophageal carcinoma is an incurable disease with median survival duration of 6 to 8 months. Based on preclinical data suggesting a dose-dependent synergy between gemcitabine and irinotecan we have conducted a phase II trial in patients with advanced or metastatic esophageal carcinoma.Patient eligibility included a diagnosis of squamous cell or adenocarcinoma of the esophagus/gastroesophageal (GE) junction, metastatic or recurrent disease, no CNS metastasis, no prior chemotherapy, prior adjuvant/neoadjuvant chemotherapy was allowed, no prior gemcitabine or irinotecan, performance status of 0 to 2 and adequate organ function. Patients received gemcitabine 1000 mg/m2 and irinotecan 100 mg/m2 given day 1 and day 8, every 3 weeks. The primary end point was the 6-month survival rate. The secondary end point was to assess qualitative and quantitative toxicities.Fifty-seven eligible patients were accrued. There were 4 treatment-related deaths. The primary grade 3 to 4 toxic events were diarrhea, dehydration, neutropenia, thrombocytopenia, anemia, and anorexia; and 4 episodes of grade 3 to 5 febrile neutropenia, 1 fatal. The study was designed to detect a difference between the null hypothesis of 30% 6-month survival and the alternative hypothesis of 50% 6-month survival. The Kaplan-Meier estimate of 6-month survival is 56% (95% CI: 43-69%), with a median of 6.3 months. The median time to progression was 3.7 months. The 6-month progression-free survival estimate is 25% (95% CI: 13-36%).The length of survival suggests that this combination has benefit similar to platinum containing regimens, however, the toxicity is substantial and is unlikely to prove superior to platinum containing regimens.

Authors

Williamson, SK; McCoy, SA; Gandara, DR; Dakhil, SR; Yost, KJ; Paradelo, JC; Atkins, JN; Blanke, CD; Abbruzzese, JL; Southwest Oncology Group (SWOG),

MLA Citation

Williamson, SK, McCoy, SA, Gandara, DR, Dakhil, SR, Yost, KJ, Paradelo, JC, Atkins, JN, Blanke, CD, Abbruzzese, JL, and Southwest Oncology Group (SWOG), . "Phase II trial of gemcitabine plus irinotecan in patients with esophageal cancer: a Southwest Oncology Group (SWOG) trial." American Journal of Clinical Oncology 29.2 (April 2006): 116-122.

PMID

16601427

Source

epmc

Published In

American Journal of Clinical Oncology

Volume

29

Issue

2

Publish Date

2006

Start Page

116

End Page

122

DOI

10.1097/01.coc.0000199883.10685.2b

The epidermal growth factor receptor (EGFR) is considered an important therapeutic target in pancreatic cancer, but it is currently impossible to identify those patients who are most likely to benefit from EGFR-directed therapy. We examined the biological effects of the EGFR tyrosine kinase inhibitor gefitinib (ZD1839, Iressa) in a panel of nine human pancreatic cancer cell lines. The drug strongly inhibited DNA synthesis and induced low levels of apoptosis at clinically relevant concentrations in a subset of three of the lines (L3.6pl, BxPC3, and Cfpac1). Sensitivity to gefitinib correlated directly with ligand [transforming growth factor-alpha (TGF-alpha)] expression (r(2) = 0.71, P = 0.004) but not with surface EGFR expression. The gefitinib-sensitive cells displayed constitutive baseline EGFR phosphorylation, whereas the gefitinib-resistant cells did not. Exposure to gefitinib or a small interfering RNA construct specific for TGF-alpha reversed the constitutive EGFR phosphorylation and downstream target [extracellular signal-regulated kinases (ERK), AKT] phosphorylation in the gefitinib-sensitive cells but had no effects on ERK or AKT phosphorylation in gefitinib-resistant cells. Baseline EGFR phosphorylation was lower in a subclone of L3.6pl selected for low TGF-alpha expression, and these cells were also resistant to gefitinib-mediated growth inhibition. Gefitinib blocked the growth of tumor xenografts derived from L3.6pl cells but had no effect on the growth of tumors derived from EGFR-independent MiaPaCa-2 cells. Together, our data show that TGF-alpha expression identifies a subset of human pancreatic cancer cells that is dependent on EGFR signaling in vitro and in vivo. Quantification of TGF-alpha expression may therefore represent an effective means of identifying EGFR-responsive primary tumors.

Authors

Pino, MS; Shrader, M; Baker, CH; Cognetti, F; Xiong, HQ; Abbruzzese, JL; McConkey, DJ

MLA Citation

Pino, MS, Shrader, M, Baker, CH, Cognetti, F, Xiong, HQ, Abbruzzese, JL, and McConkey, DJ. "Transforming growth factor alpha expression drives constitutive epidermal growth factor receptor pathway activation and sensitivity to gefitinib (Iressa) in human pancreatic cancer cell lines." Cancer Research 66.7 (April 2006): 3802-3812.

PMID

16585207

Source

epmc

Published In

Cancer Research

Volume

66

Issue

7

Publish Date

2006

Start Page

3802

End Page

3812

DOI

10.1158/0008-5472.can-05-3753

BACKGROUND: The natural history and prognosis for patients with intraductal papillary mucinous neoplasms (IPMN) with and without invasion remain poorly defined. This study evaluated the outcome after pancreatectomy for IPMN according to the pancreatic transection margin status and the presence or absence of invasive carcinoma. METHODS: Data from a prospective pancreatic tumor database and medical records were reviewed for all patients who underwent pancreatic resection for IPMN at our institution between July 1990 and July 2003. Surgical specimens were re-reviewed by a single pathologist. RESULTS: IPMN was diagnosed in 35 (26%) of 137 patients who underwent pancreatic resection for cystic neoplasms. Invasive IPMN was confirmed in 13 (37%) of 35 patients. Noninvasive IPMN was found in 22 (63%) of 35 patients; pathology re-review changed the original diagnosis from invasive to noninvasive IPMN in 6 patients. Noninvasive IPMN was found at the final pancreatic margin in eight patients; none developed recurrent disease at a median follow-up of 34 months. Recurrent disease was identified in 7 (58%) of 13 patients with invasive IPMN and in none with noninvasive IPMN. The median overall survival was 22.9 and 84.9 months in patients with invasive and noninvasive IPMN, respectively (P=.0009). CONCLUSIONS: Distinction between invasive and noninvasive IPMN is essential in estimating prognosis and determining the need for adjuvant therapy and the frequency of follow-up surveillance. Noninvasive IPMN, even if present at the pancreatic margin, was not associated with recurrent disease. In contrast, invasive IPMN was associated with early recurrence and short survival.

Authors

Raut, CP; Cleary, KR; Staerkel, GA; Abbruzzese, JL; Wolff, RA; Lee, JH; Vauthey, J-N; Lee, JE; Pisters, PWT; Evans, DB

MLA Citation

Raut, CP, Cleary, KR, Staerkel, GA, Abbruzzese, JL, Wolff, RA, Lee, JH, Vauthey, J-N, Lee, JE, Pisters, PWT, and Evans, DB. "Intraductal papillary mucinous neoplasms of the pancreas: effect of invasion and pancreatic margin status on recurrence and survival." Annals of surgical oncology 13.4 (April 2006): 582-594.

PMID

16523362

Source

epmc

Published In

Annals of Surgical Oncology

Volume

13

Issue

4

Publish Date

2006

Start Page

582

End Page

594

DOI

10.1245/aso.2006.05.002

The proteasome inhibitor bortezomib (formerly known as PS-341) recently received Food and Drug Administration approval for the treatment of multiple myeloma, and its activity is currently being evaluated in solid tumors. Bortezomib triggers apoptosis in pancreatic cancer cells, but the mechanisms involved have not been fully elucidated. Here, we show that pancreatic cancer cells exposed to bortezomib formed aggregates of ubiquitin-conjugated proteins ("aggresomes") in vitro and in vivo. Bortezomib-induced aggresome formation was determined to be cytoprotective and could be disrupted using histone deacetylase (HDAC) 6 small interfering RNA or chemical HDAC inhibitors, which resulted in endoplasmic reticulum stress and synergistic levels of apoptosis in vitro and in an orthotopic pancreatic cancer xenograft model in vivo. Interestingly, bortezomib did not induce aggresome formation in immortalized normal human pancreatic epithelial cells in vitro or in murine pancreatic epithelial cells in vivo. In addition, these cells did not undergo apoptosis following treatment with bortezomib, suberoylanilide hydroxamic acid, or the combination, showing tumor selectivity. Taken together, our study shows that inhibition of aggresome formation can strongly potentiate the efficacy of bortezomib and provides the foundation for clinical trials of bortezomib in combination with HDAC inhibitors for the treatment of pancreatic cancer.

Authors

Nawrocki, ST; Carew, JS; Pino, MS; Highshaw, RA; Andtbacka, RHI; Dunner, K; Pal, A; Bornmann, WG; Chiao, PJ; Huang, P; Xiong, H; Abbruzzese, JL; McConkey, DJ

MLA Citation

Nawrocki, ST, Carew, JS, Pino, MS, Highshaw, RA, Andtbacka, RHI, Dunner, K, Pal, A, Bornmann, WG, Chiao, PJ, Huang, P, Xiong, H, Abbruzzese, JL, and McConkey, DJ. "Aggresome disruption: a novel strategy to enhance bortezomib-induced apoptosis in pancreatic cancer cells." Cancer Research 66.7 (April 2006): 3773-3781.

PMID

16585204

Source

epmc

Published In

Cancer Research

Volume

66

Issue

7

Publish Date

2006

Start Page

3773

End Page

3781

DOI

10.1158/0008-5472.can-05-2961

We previously reported a protein expression profiling experiment conducted on human pancreatic tissues using 2D gel electrophoresis and mass spectrometry. Here, 18 spots that were identified in the gel at molecular weights more than 10 kDa lower than database values are characterized. The matrix-assisted laser desorption/ionization mass spectrometry coverage is sufficient to identify the protein region present in each spot. Most of the fragments correspond to processed chains and known structural or functional domains, which may result from limited proteolysis.

Authors

Person, MD; Shen, J; Traner, A; Hensley, SC; Lo, H-H; Abbruzzese, JL; Li, D

MLA Citation

Person, MD, Shen, J, Traner, A, Hensley, SC, Lo, H-H, Abbruzzese, JL, and Li, D. "Protein fragment domains identified using 2D gel electrophoresis/MALDI-TOF." Journal of biomolecular techniques : JBT 17.2 (April 2006): 145-156.

PMID

16741242

Source

epmc

Published In

Journal of Biomolecular Techniques : Jbt

Volume

17

Issue

2

Publish Date

2006

Start Page

145

End Page

156

Our goal was to determine whether single nucleotide polymorphisms (SNPs) in DNA repair genes influence the clinical outcome of pancreatic cancer.We evaluated 13 SNPs of eight DNA damage response and repair genes in 92 patients with potentially resectable pancreatic adenocarcinoma. All patients were treated with neoadjuvant concurrent gemcitabine and radiotherapy with or without a component of induction gemcitabine/cisplatin at The University of Texas M.D. Anderson Cancer Center (Houston, TX) from February 1999 to August 2004 and observed through August 2005. Response to the pretreatment was assessed by evaluating time to tumor progression and overall survival. Kaplan-Meier plot, log-rank test, and Cox regression were used to compare survival of patients according to genotype.The RecQ1 A159C, RAD54L C157T, XRCC1 R194W, and ATM T77C genotypes had a significant effect on the overall survival with log-rank P values of .001, .004, .001, and .02, respectively. A strong combined effect of the four genotypes was observed. Patients with none of the adverse genotypes had a mean survival time of 62.1 months, and those with one, two, or three or more at-risk alleles had median survival times of 27.5, 14.4, and 9.9 months, respectively (log-rank P < .001). There is a significant interaction between the RecQ1 gene and other genotypes. All four genes except XRCC1 remained as independent predictors of survival in multivariate Cox regression models adjusted for other clinical predictors.These observations support the hypothesis that polymorphic variants of DNA repair genes affect clinical prognosis of patients with pancreatic cancer.

Authors

Li, D; Frazier, M; Evans, DB; Hess, KR; Crane, CH; Jiao, L; Abbruzzese, JL

MLA Citation

Li, D, Frazier, M, Evans, DB, Hess, KR, Crane, CH, Jiao, L, and Abbruzzese, JL. "Single nucleotide polymorphisms of RecQ1, RAD54L, and ATM genes are associated with reduced survival of pancreatic cancer." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 24.11 (April 2006): 1720-1728.

PMID

16520463

Source

epmc

Published In

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology

Volume

24

Issue

11

Publish Date

2006

Start Page

1720

End Page

1728

DOI

10.1200/jco.2005.04.4206

Authors

Abbruzzese, JL

MLA Citation

Abbruzzese, JL. "Introducing CCR practice of translational oncology." Clinical Cancer Research 12.6 (March 15, 2006): 1657-null.

Source

scopus

Published In

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research

Volume

12

Issue

6

Publish Date

2006

Start Page

1657

DOI

10.1158/1078-0432.CCR-06-0403

Genetic variation in DNA repair may affect the clinical response to cytotoxic therapies. We investigated the effect of six single nucleotide polymorphisms of the RecQ1, RAD54L, XRCC2, and XRCC3 genes on overall survival of 378 patients with pancreatic adenocarcinoma who were treated at University of Texas M.D. Anderson Cancer Center during February 1999 to October 2004 and were followed up to October 2005. Genotypes were determined using the MassCode method. Survival was determined from pathologic diagnosis to death. Patients who were alive at the last follow-up evaluation were censored at that time. Kaplan-Meier plot, log-rank test, and Cox regression were used to compare overall survival by genotypes. A significant effect on survival of all patients was observed for RecQ1 and RAD54L genes. The median survival time was 19.2, 14.7, and 13.2 months for the RecQ1 159 AA, AC, and CC genotypes, and 16.4, 13.3, and 10.3 months for RAD54L 157 CC, CT, and TT genotypes, respectively. A significantly reduced survival was associated with the variant alleles of XRCC2 R188H and XRCC3 A17893G in subgroup analysis. When the four genes were analyzed in combination, an increasing number of adverse alleles were associated with a significantly decreased survival. Subgroup analyses have shown that the genotype effect on survival was present among patients without metastatic disease or among patients who receive radiotherapy. These observations suggest that polymorphisms of genes involved in the repair of DNA double-strand breaks significantly affect the clinical outcome of patients with pancreatic cancer.

Authors

Li, D; Liu, H; Jiao, L; Chang, DZ; Beinart, G; Wolff, RA; Evans, DB; Hassan, MM; Abbruzzese, JL

MLA Citation

Li, D, Liu, H, Jiao, L, Chang, DZ, Beinart, G, Wolff, RA, Evans, DB, Hassan, MM, and Abbruzzese, JL. "Significant effect of homologous recombination DNA repair gene polymorphisms on pancreatic cancer survival." Cancer research 66.6 (March 2006): 3323-3330.

PMID

16540687

Source

epmc

Published In

Cancer Research

Volume

66

Issue

6

Publish Date

2006

Start Page

3323

End Page

3330

DOI

10.1158/0008-5472.can-05-3032

The nonreceptor protein tyrosine kinase Src is overexpressed in 70% of pancreatic adenocarcinomas. Here, we describe the effect of molecular and pharmacological down-regulation of Src on incidence, growth, and metastasis of pancreatic tumor cells in an orthotopic model. Src expression in L3.6pl human pancreatic tumor cells was reduced by stable expression of a plasmid encoding small interfering RNA (siRNA) to c-src. In stable siRNA clones, Src expression was reduced >80%, with no change in expression of the related kinases c-Yes and c-Lyn, and proliferation rates were similar in all clones. Phosphorylation of Akt and p44/42 Erk mitogen-activated protein kinase and production of VEGF and IL-8 in culture supernatants were also reduced (P < 0.005). On orthotopic implantation of varying cell numbers into nude mice, tumor incidence was unchanged; however, in the siRNA clones, large tumors failed to develop, and incidence of metastasis was significantly reduced, suggesting that c-Src activity is critical to tumor progression. To examine this possibility further, animals bearing established wild-type tumors were treated with the Src/Abl-selective inhibitor BMS-354825 (dasatinib). Tumor size was decreased, and incidence of metastases was significantly reduced in treated mice compared with controls. These results demonstrate that Src activation contributes to pancreatic tumor progression in this model, offering Src as a candidate for targeted therapy.

Authors

Trevino, JG; Summy, JM; Lesslie, DP; Parikh, NU; Hong, DS; Lee, FY; Donato, NJ; Abbruzzese, JL; Baker, CH; Gallick, GE

MLA Citation

Trevino, JG, Summy, JM, Lesslie, DP, Parikh, NU, Hong, DS, Lee, FY, Donato, NJ, Abbruzzese, JL, Baker, CH, and Gallick, GE. "Inhibition of SRC expression and activity inhibits tumor progression and metastasis of human pancreatic adenocarcinoma cells in an orthotopic nude mouse model." The American Journal of Pathology 168.3 (March 2006): 962-972.

PMID

16507911

Source

epmc

Published In

The American Journal of Pathology

Volume

168

Issue

3

Publish Date

2006

Start Page

962

End Page

972

DOI

10.2353/ajpath.2006.050570

PURPOSE: To study the safety of bevacizumab with capecitabine-based chemoradiotherapy. PATIENTS AND METHODS: Patients with inoperable pancreatic adenocarcinoma received bevacizumab 2 weeks before radiotherapy (50.4 Gy treating the primary tumor and gross adenopathy), every 2 weeks during radiotherapy (12 patients each at 2.5, 5.0, 7.5, and 10 mg/kg), and after radiotherapy until disease progression. Capecitabine was administered on days 14 through 52 (650 mg/m2 orally twice daily for the first six patients; 825 mg/m2 for the remaining patients). RESULTS: Significant acute gastrointestinal (43% grade 2; 4% grade 3), hand and foot syndrome (21% grade 2), and transient hematologic (8% grade 3 or greater) events were uncommon with protocol mandated dose reductions of capecitabine grade 2 toxicity (43% of patients). Among the first 30 patients treated, three patients had tumor-associated bleeding duodenal ulcers, and one had a contained duodenal perforation. No additional bleeding events occurred among the final 18 patients after patients with duodenal involvement by tumor were excluded. Nine (20%) of 46 assessable patients had confirmed partial responses until distant progression for a median of 6.2 months. Four patients have undergone pancreaticoduodenectomy without perioperative complication. The median survival was 11.6 months (95% CI, 9.6 to 13.6), from the start of protocol therapy. CONCLUSION: Concurrent bevacizumab did not significantly increase the acute toxicity of a relatively well-tolerated chemoradiotherapy regimen. However, ulceration and bleeding in the radiation field possibly related to bevacizumab occurred when tumor involved the duodenal mucosa. The encouraging efficacy end points suggest that the further study of bevacizumab with chemoradiotherapy is warranted.

Authors

Crane, CH; Ellis, LM; Abbruzzese, JL; Amos, C; Xiong, HQ; Ho, L; Evans, DB; Tamm, EP; Ng, C; Pisters, PWT; Charnsangavej, C; Delclos, ME; O'Reilly, M; Lee, JE; Wolff, RA

MLA Citation

Crane, CH, Ellis, LM, Abbruzzese, JL, Amos, C, Xiong, HQ, Ho, L, Evans, DB, Tamm, EP, Ng, C, Pisters, PWT, Charnsangavej, C, Delclos, ME, O'Reilly, M, Lee, JE, and Wolff, RA. "Phase I trial evaluating the safety of bevacizumab with concurrent radiotherapy and capecitabine in locally advanced pancreatic cancer." Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology 24.7 (March 2006): 1145-1151.

PMID

16505434

Source

epmc

Published In

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology

Volume

24

Issue

7

Publish Date

2006

Start Page

1145

End Page

1151

DOI

10.1200/jco.2005.03.6780

One of the most studied pro-angiogenic factors involved in the development of colorectal cancer is the vascular endothelial growth factor (VEGF). The small molecule tyrosine kinase inhibitor semaxanib (SU5416) is one of the several agents targeting the VEGF signaling pathway, and its development centered mostly in the treatment of colorectal cancer.We designed and conducted an NCI-sponsored trial to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of semaxanib given twice weekly in combination with weekly irinotecan in patients with advanced colorectal cancer who had failed at least one prior treatment. The irinotecan dose was fixed at 125 mg/m(2) given weekly for 4 weeks followed by 2 weeks of rest. Patients with prior pelvic irradiation received a reduced dose of 100 mg/m(2). The semaxanib dose was escalated, going from 85 to 110 mg/m(2) and finally to 145 mg/m(2).Ten patients were treated in our study and all were evaluable for toxicity. There were no drug-related Grade 4 toxicities. There was one episode of Grade 3 headache and one episode of Grade 3 vomiting. The most common Grades 1 and 2 toxicities included diarrhea, abdominal cramping, anemia and nausea. Nine patients completed at least one 6 week cycle of treatment and were considered evaluable for response. Among those nine, two had a partial response, three had stable disease and four had progressive disease after the first cycle.Both irinotecan and semaxanib could be given at their full single-agent recommended doses without significant toxicity, and the combination showed signs of clinical activity. However, owing to discouraging results from Phase III trials, it is unlikely that this combination will be further explored.

Authors

Hoff, PM; Wolff, RA; Bogaard, K; Waldrum, S; Abbruzzese, JL

MLA Citation

Hoff, PM, Wolff, RA, Bogaard, K, Waldrum, S, and Abbruzzese, JL. "A Phase I study of escalating doses of the tyrosine kinase inhibitor semaxanib (SU5416) in combination with irinotecan in patients with advanced colorectal carcinoma." Japanese Journal of Clinical Oncology 36.2 (February 2006): 100-103.

PMID

16449240

Source

epmc

Published In

Japanese Journal of Clinical Oncology

Volume

36

Issue

2

Publish Date

2006

Start Page

100

End Page

103

DOI

10.1093/jjco/hyi229

Genetic variants of DNA repair genes may contribute to pancreatic carcinogenesis. O(6)-methylguanine-DNA methyltransferase (MGMT) is the major protein that removes alkylating DNA adducts, and apurinic/apyrimidinic endonuclease 1 (APE1) and X-ray repair cross-complementing group 1 (XRCC1) play important roles in the base excision repair pathway.We investigated the association between polymorphisms of MGMT (Leu(84)Phe and Ile(143)Val), APE1 (Asp(148)Glu), and XRCC1 (Arg(194)Trp and Arg(399)Gln) and risk of pancreatic cancer in a case-control study. Exposure information from 384 patients with primary pancreatic ductal adenocarcinoma and 357 cancer-free healthy controls were collected and genomic DNAs were genotyped for five markers. Controls were frequency matched to patients by age at enrollment (+/-5 years), gender, and race. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) by using unconditional logistic regression models.There was no significant main effect or interaction with smoking of these genetic variants on the risk of pancreatic cancer. However, the XRCC1(194) polymorphism had a significant interaction with the APE1(148) (p=0.005) or MGMT(84) polymorphism (p=0.02) in modifying the risk of pancreatic cancer.This study suggests that polymorphisms of genes involved in the repair of alkylating DNA adduct and DNA base damage may play a role in modulating the risk of pancreatic cancer. Larger studies are required to validate these preliminary findings. The mechanism of the combined genotype effects remains to be elucidated.

Authors

Jiao, L; Bondy, ML; Hassan, MM; Wolff, RA; Evans, DB; Abbruzzese, JL; Li, D

MLA Citation

Jiao, L, Bondy, ML, Hassan, MM, Wolff, RA, Evans, DB, Abbruzzese, JL, and Li, D. "Selected polymorphisms of DNA repair genes and risk of pancreatic cancer." Cancer detection and prevention 30.3 (January 2006): 284-291.

PMID

16844323

Source

epmc

Published In

Cancer Detection and Prevention

Volume

30

Issue

3

Publish Date

2006

Start Page

284

End Page

291

DOI

10.1016/j.cdp.2006.05.002

The erbB family of receptor tyrosine kinases plays critical roles in human cancers, including pancreatic cancer. Discovering a specific agent, which targets multiple members of the erbB family, would be important in pancreatic cancer therapy. Recently, we isolated a novel negative regulator of epidermal growth factor receptor (EGFR), termed EGFR-related protein (ERRP), whose expression attenuates EGFR activation. In the current study, we examined the effects of recombinant ERRP on the growth and ligand-induced activation of multiple members of erbB family in three pancreatic cancer cell lines that express varying levels of EGFR and other member(s) of its family, specifically HER-2. Additionally, we compared the growth inhibitory effect of ERRP with that of Erbitux or Herceptin. Our results showed that ERRP is most effective in inhibiting proliferation of BxPC-3, HPAC, and PANC-1 pancreatic cancer cells. ERRP also inhibited ligand-induced activation of EGFR, HER-2, and HER-3 (ErbB3). In contrast, Erbitux and Herceptin only partially or modestly inhibited activation of EGFR, HER-2, and HER-3. Most importantly, ERRP was found to inhibit pancreatic tumor growth in a severe combined immunodeficient mouse xenograft model. The antitumor activity of ERRP correlates well with tumor differentiation and down-regulation of nuclear factor-kappaB activity. In summary, our results suggest that ERRP is an effective pan-erbB inhibitor, which could be a potential therapeutic agent for pancreatic cancers expressing different levels and subclasses of erbB family of proteins.

Authors

Zhang, Y; Banerjee, S; Wang, Z; Xu, H; Zhang, L; Mohammad, R; Aboukameel, A; Adsay, NV; Che, M; Abbruzzese, JL; Majumdar, APN; Sarkar, FH

MLA Citation

Zhang, Y, Banerjee, S, Wang, Z, Xu, H, Zhang, L, Mohammad, R, Aboukameel, A, Adsay, NV, Che, M, Abbruzzese, JL, Majumdar, APN, and Sarkar, FH. "Antitumor activity of epidermal growth factor receptor-related protein is mediated by inactivation of ErbB receptors and nuclear factor-kappaB in pancreatic cancer." Cancer Research 66.2 (January 2006): 1025-1032.

PMID

16424038

Source

epmc

Published In

Cancer Research

Volume

66

Issue

2

Publish Date

2006

Start Page

1025

End Page

1032

DOI

10.1158/0008-5472.can-05-2968

We retrospectively evaluated acute toxicity in 88 patients that were treated with capecitabine and concurrent radiotherapy to the upper abdomen. These patients included 28 (32%) with pancreatic adenocarcinoma, 18 (20%) with cholangiocarcinoma, 11 (13%) with ampullary carcinoma, 11 (13%) with other primary tumors, 14 (16%) with liver metastases, and 6 (7%) with metastases at other sites. The median dose of radiotherapy was 45 Gy (range 30-72 Gy). The median dose of capecitabine was 850 mg/m(2) twice daily, with 77% receiving 800-900 mg/m(2) twice daily. The highest grade of acute toxicity was Common Terminology Criteria (CTC) grade 0 in 5 (6%), grade 1 in 60 (68%), grade 2 in 18 (20%), and grade 3 in 5 (6%) patients. No patient had CTC grade 4 toxicity. The most common grade 2 toxicities were nausea, hand-foot syndrome, fatigue, anorexia and diarrhea. The grade 3 toxicities included nausea, vomiting and fatigue. Three patients (3%) required hospitalization due to grade 3 acute toxicity. Capecitabine was interrupted, discontinued or given at an adjusted dose in 13 (15%) patients because of acute toxicity. Therefore, capecitabine and concurrent radiotherapy to the upper abdomen appears to be well tolerated. Capecitabine may serve as an alternative to bolus or infusional 5-FU during chemoradiation for upper gastrointestinal malignancies.

Authors

Das, P; Wolff, RA; Abbruzzese, JL; Varadhachary, GR; Evans, DB; Vauthey, JN; Baschnagel, A; Delclos, ME; Krishnan, S; Janjan, NA; Crane, CH

MLA Citation

Das, P, Wolff, RA, Abbruzzese, JL, Varadhachary, GR, Evans, DB, Vauthey, JN, Baschnagel, A, Delclos, ME, Krishnan, S, Janjan, NA, and Crane, CH. "Concurrent capecitabine and upper abdominal radiation therapy is well tolerated." Radiation oncology (London, England) 1 (January 2006): 41-.

PMID

17062148

Source

epmc

Published In

Radiation Oncology

Volume

1

Publish Date

2006

Start Page

41

DOI

10.1186/1748-717x-1-41

The northeast Nile Delta region exhibits a high incidence of early-onset pancreatic cancer. It is well documented that this region has one of the highest levels of pollution in Egypt. Epidemiologic studies have suggested that cadmium, a prevalent pollutant in the northeast Nile Delta region, plays a role in the development of pancreatic cancer.We aimed to assess serum cadmium levels as markers of exposure in pancreatic cancer patients and noncancer comparison subjects from the same region in Egypt.We assessed serum cadmium levels of 31 newly diagnosed pancreatic cancer patients and 52 hospital comparison subjects from Mansoura, Egypt. EVALUATION/MEASUREMENTS: Serum cadmium levels were measured using a novel immunoassay procedure.We found a significant difference between the mean serum cadmium levels in patients versus comparison subjects (mean+/-SD, 11.1+/-7.7 ng/mL vs. 7.1+/-5.0 ng/mL, respectively; p=0.012) but not in age, sex, residence, occupation, or smoking status. The odds ratio (OR) for pancreatic cancer risk was significant for serum cadmium level [OR=1.12; 95% confidence interval (CI), 1.04-1.23; p=0.0089] and farming (OR=3.25; 95% CI, 1.03-11.64; p=0.0475) but not for age, sex, residence, or smoking status.The results from this pilot study suggest that pancreatic cancer in the East Nile Delta region is significantly associated with high levels of serum cadmium and farming. RELEVANCE TO CLINICAL PRACTICE/PUBLIC HEALTH: Future studies should further investigate the etiologic relationship between cadmium exposure and pancreatic carcinogenesis in cadmium-exposed populations.

Authors

Kriegel, AM; Soliman, AS; Zhang, Q; El-Ghawalby, N; Ezzat, F; Soultan, A; Abdel-Wahab, M; Fathy, O; Ebidi, G; Bassiouni, N; Hamilton, SR; Abbruzzese, JL; Lacey, MR; Blake, DA

MLA Citation

Kriegel, AM, Soliman, AS, Zhang, Q, El-Ghawalby, N, Ezzat, F, Soultan, A, Abdel-Wahab, M, Fathy, O, Ebidi, G, Bassiouni, N, Hamilton, SR, Abbruzzese, JL, Lacey, MR, and Blake, DA. "Serum cadmium levels in pancreatic cancer patients from the East Nile Delta region of Egypt." Environmental Health Perspectives 114.1 (January 2006): 113-119.

PMID

16393667

Source

epmc

Published In

Environmental Health Perspectives

Volume

114

Issue

1

Publish Date

2006

Start Page

113

End Page

119

DOI

10.1289/ehp.8035

OBJECTIVES: Little is known about the descriptive epidemiology of pancreatic cancer in many developing countries, such as Egypt. It is believed to be rare in developing countries, but this may reflect lack of systematic cancer registration. Mortality may serve as a surrogate for incidence, since the disease is lethal. Because of availability of reliable mortality registration in Egypt, we used the national mortality data to estimate pancreatic cancer mortality in 2765 deaths from 2000 to 2004, and to gain insights into the disease incidence. METHODS: Mortality data in Egypt was obtained from the electronic national mortality records of the Ministry of Health. We calculated population-based age-specific and age-standardized pancreatic cancer mortality rates for Egypt, and compared them with the Surveillance, Epidemiology, and End Results (SEER) mortality data of the United States. RESULTS: Comparisons of age-specific mortality demonstrated higher rates in Egypt compared to the United States for subjects under age 20 years (relative risks (RR) of 7.7 and 4.2, for the age groups 0-15 and 15-20, respectively), and significantly higher rates in the United States compared to Egypt for subjects 40 years and older (RR 1.8-80.5 for the age groups of 40-45 to 75+). For the majority of age groups in Egypt and the United States, mortality in males was higher than in females. Analysis of regional distribution of pancreatic cancer mortality in Egypt showed significant variations in rates among provinces (p<0.0001) with Northern provinces having average rate that is 2.85 times the rate of Southern provinces. The highest mortality rates were observed in the Nile Delta compared to southern Egypt and the oasis. CONCLUSIONS: The findings of this study demonstrate both international and regional variation in pancreatic cancer mortality, and highlight the importance of further investigation to explore the possible factors that may contribute to the observed epidemiological patterns.

Authors

Soliman, AS; Zhang, Q; Saleh, T; Zarzour, A; Selim, M; Abdel-Fattah, M; Abbruzzese, JL

MLA Citation

Soliman, AS, Zhang, Q, Saleh, T, Zarzour, A, Selim, M, Abdel-Fattah, M, and Abbruzzese, JL. "Pancreatic cancer mortality in Egypt: comparison to the United States pancreatic cancer mortality rates." Cancer detection and prevention 30.5 (January 2006): 473-479.

PMID

17067749

Source

epmc

Published In

Cancer Detection and Prevention

Volume

30

Issue

5

Publish Date

2006

Start Page

473

End Page

479

DOI

10.1016/j.cdp.2006.06.006

Chemotherapy remains the mainstay of treatment for pancreatic cancer as most patients present with advanced disease, which precludes locoregional treatment. However, the efficacy of chemotherapy is limited. Gemcitabine is the only agent that improves symptoms and confers a modest survival advantage. Many combination therapy regimens have been studied in phase II settings. Eleven randomised phase III trials have been conducted to compare gemcitabine-containing regimens with gemcitabine monotherapy since gemcitabine became available clinically. The combination of gemcitabine plus capecitabine has demonstrated a survival advantage over gemcitabine, whereas gemcitabine plus oxaliplatin and gemcitabine plus cisplatin have shown improved progression-free survival or time to tumour progression but failed to demonstrate a survival advantage over gemcitabine. The search for effective therapy for advanced pancreatic cancer continues. Gemcitabine in combination with cytotoxic agents or molecular targeted agents hold promise.

Authors

Xiong, HQ; Carr, K; Abbruzzese, JL

MLA Citation

Xiong, HQ, Carr, K, and Abbruzzese, JL. "Cytotoxic chemotherapy for pancreatic cancer: Advances to date and future directions." Drugs 66.8 (January 2006): 1059-1072. (Review)

PMID

16789792

Source

epmc

Published In

Drugs

Volume

66

Issue

8

Publish Date

2006

Start Page

1059

End Page

1072

DOI

10.2165/00003495-200666080-00003

To test the hypothesis that genetic variation in the metabolism of tobacco carcinogens, such as aromatic amines (AA) and heterocyclic amines (HCA), contributes to pancreatic cancer, we have examined genetic polymorphisms of three key enzymes, i.e. cytochrome P450 1A2 (CYP1A2) and N-acetyltransferase 1 and 2 (NAT1 and NAT2), in a hospital-based case-control study of 365 patients with pancreatic adenocarcinoma and 379 frequency-matched healthy controls. Genotypes were determined using PCR-restriction fragment length polymorphism (RFLP) and Taqman methods. Smoking information was collected by personal interview. Adjusted odds ratio (AOR) and 95% confidence interval (CI) was estimated by unconditional multivariate logistic regression analysis. We found that the NAT1 'rapid' alleles were associated with a 1.5-fold increased risk of pancreatic cancer (95% CI: 1.0-2.1) with adjustment of potential confounders. This effect was more prominent among never smokers (AOR: 2.4, 95% CI: 1.4-4.3) and females (AOR: 1.8, 95% CI: 1.0-3.1). Some genotypes were significantly associated with increased risk for pancreatic cancer among smokers, especially heavy smokers (<20 pack years). For example, heavy smokers with the CYP1A2*1D (T-2467delT) delT, CYP1A2*1F(A-163C) C allele, NAT1 'rapid' or NAT2 'slow' alleles had an AOR (95% CI) of 1.4 (0.7-2.3), 1.9 (1.1-3.4), 3.0 (1.6-5.4) and 1.5 (0.8-2.6), respectively, compared with never smokers carrying the non-at-risk alleles. These effects were more prominent in females than in males. The corresponding AOR (95% CI) was 3.1 (1.0-8.0), 3.8 (1.5-10.1), 4.5 (1.6-12.7) and 2.0 (0.8-5.1) for females versus 1.0 (0.4-1.9), 1.1 (0.5-2.4), 2.1 (1.0-4.6) and 1.1 (0.5-2.6) for males. A significant synergistic effect of CYP1A2*1F C allele and NAT1"rapid" alleles on the risk for pancreatic cancer was also detected among never smokers (AOR: 2.9, 95% CI: 1.2-6.9) and among females (AOR: 2.5, 95% CI: 1.1-5.7). These data suggest that polymorphisms of the CYP1A2 and NAT1 genes modify the risk of pancreatic cancer.

Authors

Li, D; Jiao, L; Li, Y; Doll, MA; Hein, DW; Bondy, ML; Evans, DB; Wolff, RA; Lenzi, R; Pisters, PW; Abbruzzese, JL; Hassan, MM

MLA Citation

Li, D, Jiao, L, Li, Y, Doll, MA, Hein, DW, Bondy, ML, Evans, DB, Wolff, RA, Lenzi, R, Pisters, PW, Abbruzzese, JL, and Hassan, MM. "Polymorphisms of cytochrome P4501A2 and N-acetyltransferase genes, smoking, and risk of pancreatic cancer." Carcinogenesis 27.1 (January 2006): 103-111.

PMID

15987714

Source

epmc

Published In

Carcinogenesis

Volume

27

Issue

1

Publish Date

2006

Start Page

103

End Page

111

DOI

10.1093/carcin/bgi171

Bortezomib (Velcade, formerly known as PS-341) is a boronic acid dipeptide derivative that is a selective and potent inhibitor of the proteasome. We hypothesized that proteasome inhibition would lead to an accumulation of misfolded proteins in the cell resulting in endoplasmic reticulum (ER) stress. The ability of bortezomib to induce ER stress and the unfolded protein response was investigated in a human pancreatic cancer cell line, L3.6pl. Bortezomib increased expression of ER stress markers, CHOP and BiP, but inhibited PKR-like ER kinase and subsequent phosphorylation of eukaryotic initiation factor 2alpha (eif2alpha), both of which are key events in translational suppression. These effects resulted in an accumulation of ubiquitylated proteins leading to protein aggregation and proteotoxicity. Peptide inhibitor or small interfering RNA targeting ER-resident caspase-4 blocked DNA fragmentation, establishing a central role for caspase-4 in bortezomib-induced cell death. The translation inhibitor cycloheximide abrogated bortezomib-induced protein aggregation, caspase-4 processing, and all other characteristics of apoptosis. Because malignant cells have higher protein synthesis rates than normal cells, they may be more prone to protein aggregation and proteotoxicity and possess increased sensitivity to bortezomib-induced apoptosis. Taken together, the results show that bortezomib induces a unique type of ER stress compared with other ER stress agents characterized by an absence of eif2alpha phosphorylation, ubiquitylated protein accumulation, and proteotoxicity.

Authors

Nawrocki, ST; Carew, JS; Dunner, K; Boise, LH; Chiao, PJ; Huang, P; Abbruzzese, JL; McConkey, DJ

MLA Citation

Nawrocki, ST, Carew, JS, Dunner, K, Boise, LH, Chiao, PJ, Huang, P, Abbruzzese, JL, and McConkey, DJ. "Bortezomib inhibits PKR-like endoplasmic reticulum (ER) kinase and induces apoptosis via ER stress in human pancreatic cancer cells." Cancer Research 65.24 (December 2005): 11510-11519.

PMID

16357160

Source

epmc

Published In

Cancer Research

Volume

65

Issue

24

Publish Date

2005

Start Page

11510

End Page

11519

DOI

10.1158/0008-5472.can-05-2394

Bortezomib (PS-341, Velcade) is a potent and selective inhibitor of the proteasome that is currently under investigation for the treatment of solid malignancies. We have shown previously that bortezomib has activity in pancreatic cancer models and that the drug induces endoplasmic reticulum (ER) stress but also suppresses the unfolded protein response (UPR). Because the UPR is an important cytoprotective mechanism, we hypothesized that bortezomib would sensitize pancreatic cancer cells to ER stress-mediated apoptosis. Here, we show that bortezomib promotes apoptosis triggered by classic ER stress inducers (tunicamycin and thapsigargin) via a c-Jun NH(2)-terminal kinase (JNK)-dependent mechanism. We also show that cisplatin stimulates ER stress and interacts with bortezomib to increase ER dilation, intracellular Ca(2+) levels, and cell death. Importantly, combined therapy with bortezomib plus cisplatin induced JNK activation and apoptosis in orthotopic pancreatic tumors resulting in a reduction in tumor burden. Taken together, our data establish that bortezomib sensitizes pancreatic cancer cells to ER stress-induced apoptosis and show that bortezomib strongly enhances the anticancer activity of cisplatin.

Authors

Nawrocki, ST; Carew, JS; Pino, MS; Highshaw, RA; Dunner, K; Huang, P; Abbruzzese, JL; McConkey, DJ

MLA Citation

Nawrocki, ST, Carew, JS, Pino, MS, Highshaw, RA, Dunner, K, Huang, P, Abbruzzese, JL, and McConkey, DJ. "Bortezomib sensitizes pancreatic cancer cells to endoplasmic reticulum stress-mediated apoptosis." Cancer Research 65.24 (December 2005): 11658-11666.

PMID

16357177

Source

epmc

Published In

Cancer Research

Volume

65

Issue

24

Publish Date

2005

Start Page

11658

End Page

11666

DOI

10.1158/0008-5472.can-05-2370

Hepatocellular cancer (HCC) is the fifth most common solid tumor worldwide, accounting for 500,000 new cases annually. Although less common in the United States, HCC is expected to increase in incidence over the next two decades largely because of the prevalence of hepatitis C virus infection. A majority of patients present with advanced disease and are not candidates for liver transplantation, surgical resection, or regional therapy. In 60% to 80% of patients with HCC, treatment is complicated by underlying liver cirrhosis and hepatic dysfunction. Systemic treatments are minimally effective, can have significant toxicity, and have not been shown to improve patient survival. New approaches targeting molecular abnormalities specific to HCC are needed to improve patient outcome. This review summarizes the state of knowledge of those key aspects of the molecular pathogenesis of HCC that may represent rational therapeutic targets in this disease. Relevant preclinical and clinical information on novel compounds directed toward abnormalities in HCC is reviewed.

Authors

Thomas, MB; Abbruzzese, JL

MLA Citation

Thomas, MB, and Abbruzzese, JL. "Opportunities for targeted therapies in hepatocellular carcinoma." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 23.31 (November 2005): 8093-8108. (Review)

PMID

16258107

Source

epmc

Published In

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology

Volume

23

Issue

31

Publish Date

2005

Start Page

8093

End Page

8108

DOI

10.1200/jco.2004.00.1537

We screened an orthotopic nude mouse model of human pancreatic cancer for candidate serum biomarkers and examined their presence in the plasma of pancreatic cancer patients. Nude mice were injected in the pancreas with L3.9pl human pancreatic cancer cells. One week later, the mice were randomized into 4 treatment groups: i) control, saline; ii) oral STI 571; iii) intraperitoneal gemcitabine; and iv) STI 571 and gemcitabine. After 1, 2, and 3 weeks of treatment, sera and tumors were collected from mice in each group as well as uninjected mice. All sera were analyzed by surface enhanced laser desorption ionization mass spectrometry using ProteinChip technology. Protein profiles were analyzed with the Biomarker Wizard software package. The concentration of candidate proteins was evaluated in mouse sera and plasma from 135 pancreatic cancer patients, 7 pancreatitis patients, and 113 healthy volunteers. The combination therapy inhibited tumor growth. A 11.7-kDa protein peak correlating with tumor weight was purified by gel filtration, separated by SDS-PAGE, and identified as mouse serum amyloid A (SAA) by amino acid sequencing and public database searches. The expression of SAA in mouse sera was confirmed by Western blotting and correlated with tumor weight. The level of SAA in plasma of pancreatic cancer patients correlated with clinical stage and was significantly higher than in normal volunteers (mean value: 180.1 microg/ml vs 27.9 microg/ml: P<0.01) or pancreatitis patients. For SAA used as a single tumor marker with a cut-off of 75 microg/ml, the sensitivity for pancreatic cancer was 96.5% and specificity was 31.9%. Our search for specific marker proteins to identify pancreatic cancer was unsuccessful. Although SAA is not specific for pancreatic cancer and not sensitive enough to detect stage I patients, it may be a candidate biomarker for detecting and monitoring the progressive growth of pancreatic cancer.

Authors

Yokoi, K; Shih, L-CN; Kobayashi, R; Koomen, J; Hawke, D; Li, D; Hamilton, SR; Abbruzzese, JL; Coombes, KR; Fidler, IJ

MLA Citation

Yokoi, K, Shih, L-CN, Kobayashi, R, Koomen, J, Hawke, D, Li, D, Hamilton, SR, Abbruzzese, JL, Coombes, KR, and Fidler, IJ. "Serum amyloid A as a tumor marker in sera of nude mice with orthotopic human pancreatic cancer and in plasma of patients with pancreatic cancer." International journal of oncology 27.5 (November 2005): 1361-1369.

PMID

16211233

Source

epmc

Published In

International Journal of Oncology

Volume

27

Issue

5

Publish Date

2005

Start Page

1361

End Page

1369

Although gemcitabine has been approved as the first-line chemotherapeutic reagent for pancreatic cancer, its response rate is low and average survival duration is still only marginal. Because epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR), and platelet-derived growth factor receptor (PDGFR) modulate tumor progression, we hypothesized that inhibition of phosphorylation of all three on tumor cells, tumor-associated endothelial cells, and stroma cells would improve the treatment efficacy of gemcitabine in an orthotopic pancreatic tumor model in nude mice and prolong survival. We implanted L3.6pl, a human pancreatic cancer cell, in the pancreas of nude mice. We found that tumor-associated endothelial cells in this model highly expressed phosphorylated EGFR, VEGFR, and PDGFR. Oral administration of AEE788, a dual tyrosine kinase inhibitor against EGFR and VEGFR, decreased phosphorylation of EGFR and VEGFR. PDGFR phosphorylation was inhibited by STI571. Although i.p. injection of gemcitabine did not inhibit tumor growth, its combination with AEE788 and STI571 produced >80% inhibition of tumor growth and prolonged survival in parallel with increases in number of tumor cells and tumor-associated endothelial cell apoptosis, decreased microvascular density, decreased proliferation rate, and prolonged survival. STI571 treatment also decreased pericyte coverage on tumor-associated endothelial cells. Thus, inhibiting phosphorylation of EGFR, VEGFR, and PDGFR in combination with gemcitabine enhanced the efficacy of gemcitabine, resulting in inhibition of experimental human pancreatic cancer growth and significant prolongation of survival.

Authors

Yokoi, K; Sasaki, T; Bucana, CD; Fan, D; Baker, CH; Kitadai, Y; Kuwai, T; Abbruzzese, JL; Fidler, IJ

MLA Citation

Yokoi, K, Sasaki, T, Bucana, CD, Fan, D, Baker, CH, Kitadai, Y, Kuwai, T, Abbruzzese, JL, and Fidler, IJ. "Simultaneous inhibition of EGFR, VEGFR, and platelet-derived growth factor receptor signaling combined with gemcitabine produces therapy of human pancreatic carcinoma and prolongs survival in an orthotopic nude mouse model." Cancer Research 65.22 (November 2005): 10371-10380.

PMID

16288027

Source

epmc

Published In

Cancer Research

Volume

65

Issue

22

Publish Date

2005

Start Page

10371

End Page

10380

DOI

10.1158/0008-5472.CAN-05-1698

Syntaxin 17 (STX17) is a divergent member of the syntaxin family of proteins first discovered by Scheller and colleagues in a yeast two-hybrid screen designed to identify novel mammalian SNAREs (soluble N-ethylmaleimide-sensitive factor-attachment protein receptors). We recently independently identified STX17 as a novel Ras-interacting protein, but immunohistochemical studies suggested that STX17 is localized to the nucleus in normal pancreatic ductal epithelial, acinar, and islet cells in contrast to previous reports of cytoplasmic localization, albeit in other cell types. Therefore, we have conducted a more thorough survey of various human and mouse tissues to better establish the expression pattern of STX17 in different tissues and cell types. Although RT-PCR experiments demonstrate ubiquitous expression of STX17, closer examination by immunohistochemistry reveal that STX17 expression is limited to certain cell types. Furthermore, in contrast to the cytoplasmic localization previously reported in a limited number of cell types, we find that in many other cell types, syntaxin 17 can be found in the nucleus. Finally, we demonstrate that in human hepatocellular carcinoma cell lines, STX17 localization is altered relative to normal hepatocytes, although the localization of STX17 differs even between these established human cancer cell lines and fresh human hepatocellular carcinoma cells, emphasizing the caution that must be exercised in drawing conclusions from data gathered in cell lines. The sequence divergence of STX17, the unexpected nuclear localization of STX17 in many cell types, and the altered localization of STX17 in malignant cells argue for a novel function of syntaxin 17 distinct from its hypothesized role in mediating membrane fusion events.

Authors

Zhang, Q; Li, J; Deavers, M; Abbruzzese, JL; Ho, L

MLA Citation

Zhang, Q, Li, J, Deavers, M, Abbruzzese, JL, and Ho, L. "The subcellular localization of syntaxin 17 varies among different cell types and is altered in some malignant cells." The Journal of Histochemistry and Cytochemistry : Official Journal of the Histochemistry Society 53.11 (November 2005): 1371-1382.

PMID

15956034

Source

epmc

Published In

The Journal of Histochemistry and Cytochemistry : Official Journal of the Histochemistry Society

Volume

53

Issue

11

Publish Date

2005

Start Page

1371

End Page

1382

DOI

10.1369/jhc.4a6508.2005

Phosphoinositide 3-kinase (PI3K) is activated in pancreatic cancer cells and plays a central role in their proliferation, survival, and drug resistance. Although the mechanism is unclear, PI3K activation in these cells could be due to physical interaction between its regulatory subunit (p85) and specific tyrosine kinases or their mediators. Consistent with this possibility, PI3K was precipitated with anti-phosphotyrosine antibodies and Akt phosphorylation was blocked by the tyrosine kinase inhibitors SU6656 and PD158780 in quiescent pancreatic cancer cells. Pull-down assays with a fusion protein (GST-p85NC-SH2), and coimmunoprecipitation studies, indicated that the insulin receptor substrate (IRS), and not the epidermal growth factor and insulin-like growth factor receptors or the Src tyrosine kinase, was physically associated with PI3K in these cells. Our data also indicated that SU6656 and PD158780 inhibited Akt activation in pancreatic cancer cells by interfering with the ability of IRS-1 to recruit PI3K. Furthermore, IRS-1 was phosphorylated on a p85-binding site (Y(612)), and IRS-specific small interfering RNA potently inhibited activation of PI3K and Akt in transfected cells. Taken together, these observations indicate that IRS is a mediator of PI3K activation in quiescent pancreatic cancer cells.

Authors

Asano, T; Yao, Y; Shin, S; McCubrey, J; Abbruzzese, JL; Reddy, SAG

MLA Citation

Asano, T, Yao, Y, Shin, S, McCubrey, J, Abbruzzese, JL, and Reddy, SAG. "Insulin receptor substrate is a mediator of phosphoinositide 3-kinase activation in quiescent pancreatic cancer cells." Cancer research 65.20 (October 2005): 9164-9168.

PMID

16230374

Source

epmc

Published In

Cancer Research

Volume

65

Issue

20

Publish Date

2005

Start Page

9164

End Page

9168

DOI

10.1158/0008-5472.can-05-0779

Ninety per cent of pancreatic adenocarcinomas (PC) contain mutations of the K-Ras proto-oncogene resulting in constitutively activated Ras protein. A critical step in Ras activation is farnesylation of Ras protein. Farnesyl transferase inhibitors are compounds that inhibit farnesylation. We report the results of a phase II trial of R115777, an oral farnesyl transferase inhibitor, in patients with surgically incurable locally advanced or metastatic PC. Between 6/1/2000 and 11/20/2001, 58 cases were accrued, 53 of whom were eligible and analyzable. Patients were required to have a performance status (PS) 0 to 1, be able to take oral medications, and to have adequate renal, hepatic, and hematologic functions. Fifty-five percent were male. Median age was 64.7 years (38.9 to 80.6), and patients had no previous systemic therapy for advanced PC. Treatment consisted of R115777 300 mg po bid given for 3 out of every 4 weeks. Toxicities were as follows: Grade 3 in 19/53 (36%), grade 4 in 53 (173%), and grade 5 in 53 (8%). Most frequent toxicities were: anemia 35/53 (66%), fatigue and malaise 33/53 (62%), nausea 31/53 (58%). Grade 5 toxicities included: thromboembolism 1, infection 2, other 1. Median survival was 2.6 months (mo) (95% CI 2.1-3.6), 6-mo survival is 19% (95% CI, 8-29%), median time to treatment failure was 1.4 mo (95% GI 1.1-1.6). R115777 is ineffective as monotherapy in advanced pancreatic cancer.

Authors

Macdonald, JS; McCoy, S; Whitehead, RP; Iqbal, S; Wade, JL; Giguere, JK; Abbruzzese, JL

MLA Citation

Macdonald, JS, McCoy, S, Whitehead, RP, Iqbal, S, Wade, JL, Giguere, JK, and Abbruzzese, JL. "A phase II study of farnesyl transferase inhibitor R115777 in pancreatic cancer: a Southwest oncology group (SWOG 9924) study." Investigational New Drugs 23.5 (October 2005): 485-487.

PMID

16133800

Source

epmc

Published In

Investigational New Drugs

Volume

23

Issue

5

Publish Date

2005

Start Page

485

End Page

487

DOI

10.1007/s10637-005-2908-y

Soy isoflavone genistein exhibits growth inhibitory activity against human pancreatic cancer cell lines. We previously reported the potential of genistein to augment chemotherapeutic response of pancreatic cancer cells in vitro. In the present study, we investigated whether genistein pretreatment could be used as a novel strategy for gemcitabine-induced killing in vitro and enhanced antitumor activity in vivo using an orthotopic tumor model. We conducted our studies using paired isogenic human pancreatic cancer cell line with differences in metastatic behavior (COLO 357 and L3.6pl). In vitro studies were done to measure growth inhibition and degree of apoptotic cell death induced by either genistein alone, gemcitabine alone, or genistein followed by gemcitabine. Our results show that pretreatment of cells with genistein for 24 hours followed by gemcitabine resulted in 60% to 80% growth inhibition compared with 25% to 30% when gemcitabine was used alone. The overall growth inhibition was directly correlated with apoptotic cell death irrespective of the metastatic potential of cells. Several genes that are known to inhibit apoptosis and contribute to chemoresistance such as nuclear factor-kappaB (NF-kappaB) and Akt were assessed to investigate the basis for the observed chemosensitizing effects of genistein. Genistein potentiated the gemcitabine-induced killing by down-regulation of NF-kappaB and Akt. In contrast, Akt and NF-kappaB were found to be up-regulated when pancreatic cancer cells were exposed to gemcitabine alone, suggesting the potential mechanism of acquired chemoresistance. In addition to in vitro results, we show here for the first time, that genistein in combination with gemcitabine is much more effective as an antitumor agent compared with either agent alone in our orthotopic tumor model. But most importantly, our data also showed that a specific target, such as NF-kappaB, was inactivated in genistein-treated animal tumors and that gemcitabine-induced activation of NF-kappaB was completely inhibited in animal tumors treated with genistein and gemcitabine. These results provide strong molecular in vivo evidence in support of our hypothesis that inactivation of NF-kappaB signaling pathway by genistein could also abrogate gemcitabine-induced activation of NF-kappaB resulting in the chemosensitization of pancreatic tumors to gemcitabine, which is likely to be an important and novel strategy for the treatment of pancreatic cancer.

Authors

Banerjee, S; Zhang, Y; Ali, S; Bhuiyan, M; Wang, Z; Chiao, PJ; Philip, PA; Abbruzzese, J; Sarkar, FH

MLA Citation

Banerjee, S, Zhang, Y, Ali, S, Bhuiyan, M, Wang, Z, Chiao, PJ, Philip, PA, Abbruzzese, J, and Sarkar, FH. "Molecular evidence for increased antitumor activity of gemcitabine by genistein in vitro and in vivo using an orthotopic model of pancreatic cancer." Cancer Research 65.19 (October 2005): 9064-9072.

PMID

16204081

Source

epmc

Published In

Cancer Research

Volume

65

Issue

19

Publish Date

2005

Start Page

9064

End Page

9072

DOI

10.1158/0008-5472.can-05-1330

BACKGROUND: Pancreaticobiliary malignancies respond poorly to conventional chemotherapy, and novel agents are needed. Dolatstatin-10 is a potent antimitotic pentapeptide isolated from the marine mollusk Dolabella auricularia that inhibits microtubule assembly. We conducted 2 parallel phase II trials of dolastatin-10 in patients with advanced hepatobiliary cancers and pancreatic adenocarcinoma. PATIENTS AND METHODS: Eligible patients had histologically-confirmed metastatic pancreatic adenocarcinoma or metastatic, locally advanced or recurrent cancer of the liver, bile duct or gallbladder, and had received no prior chemotherapy for advanced disease. Dolastatin-10 400 microg/m(2) was administered intravenously by bolus every 21 days. Restaging CT scans were obtained every 2 cycles. RESULTS: Twenty-eight patients (16 hepatobiliary, including 7 hepatomas, 6 cholangiocarcinomas, 2 gallbladder carcinomas, and 12 pancreatic carcinomas) enrolled; 27 were evaluable for response. There were no objective responses. Grade 3/4 neutropenia occurred in 59% of patients and neutropenic fever in 18%. Median and 1-year survival were 5.0 months and 17% for the pancreatic cancer patients, and 3.0 months and 29% for the hepatobiliary patients. Median time to progression was 1.3 months for the pancreatic cancer patients and 1.6 months for the hepatobiliary patients. CONCLUSIONS: Dolastatin-10 is inactive against hepatobiliary and pancreatic carcinomas.

Authors

Kindler, HL; Tothy, PK; Wolff, R; McCormack, RA; Abbruzzese, JL; Mani, S; Wade-Oliver, KT; Vokes, EE

MLA Citation

Kindler, HL, Tothy, PK, Wolff, R, McCormack, RA, Abbruzzese, JL, Mani, S, Wade-Oliver, KT, and Vokes, EE. "Phase II trials of dolastatin-10 in advanced pancreaticobiliary cancers." Investigational new drugs 23.5 (October 2005): 489-493.

PMID

16133801

Source

epmc

Published In

Investigational New Drugs

Volume

23

Issue

5

Publish Date

2005

Start Page

489

End Page

493

DOI

10.1007/s10637-005-2909-x

Prostate growth and differentiation are under androgenic control, and prior studies suggested that tumors that develop in hypogonadal men are more aggressive. We examined whether prostate weight was associated with tumor grade, advanced disease, or risk of biochemical progression after radical prostatectomy (RP).We evaluated the association of prostate weight with pathologic tumor grade, positive surgical margins, extracapsular disease, and seminal vesicle invasion using logistic regression and with biochemical progression using Cox proportional hazards regression among 1,602 men treated with RP between 1988 and 2003 at five equal-access medical centers, which composed the Shared Equal Access Regional Cancer Hospital (SEARCH) Database.In outcome prediction models including multiple predictor variables, it was found that the predictor variable of prostate weight was significantly inversely associated with the outcomes of high-grade disease, positive surgical margins, extracapsular extension (all P < or = .004), and biochemical progression (comparing prostate weight < 20 v > or = 100 g: relative risk = 8.43; 95% CI, 2.9 to 24.0; P < .001). Similar associations were seen between preoperative transrectal ultrasound-measured prostate volume and high-grade disease, positive surgical margins, extracapsular extension (all P < or = .005), seminal vesicle invasion (P = .07), and biochemical progression (P = .06).Men with smaller prostates had more high-grade cancers and more advanced disease and were at greater risk of progression after RP. These results suggest that prostate size may be an important prognostic variable that should be evaluated for use pre- and postoperatively to predict biochemical progression.

Authors

Freedland, SJ; Isaacs, WB; Platz, EA; Terris, MK; Aronson, WJ; Amling, CL; Presti, JC; Kane, CJ

MLA Citation

Freedland, SJ, Isaacs, WB, Platz, EA, Terris, MK, Aronson, WJ, Amling, CL, Presti, JC, and Kane, CJ. "Prostate size and risk of high-grade, advanced prostate cancer and biochemical progression after radical prostatectomy: a search database study." Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology 23.30 (October 2005): 7546-7554.

PMID

16234520

Source

epmc

Published In

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology

Volume

23

Issue

30

Publish Date

2005

Start Page

7546

End Page

7554

DOI

10.1200/jco.2005.05.525

Although gemcitabine has been accepted as the first-line chemotherapeutic reagent for advanced pancreatic cancer, improvement of response rate and survival is not sufficient and patients often develop resistance. We hypothesized that the inhibition of phosphorylation of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) on tumor cells and tumor-associated endothelial cells, combined with gemcitabine, would overcome the resistance to gemcitabine in orthotopic pancreatic tumor animal model. L3.6pl, human pancreatic cancer cells growing in the pancreas, and tumor-associated endothelial cells in microorgan environment highly expressed phosphorylated EGFR, VEGFR, and Akt, which regulates antiapoptotic mechanism. Oral administration of AEE788 (dual tyrosine kinase inhibitor against EGFR and VEGFR) inhibited the phosphorylation of EGFR, VEGFR, and Akt on tumor-associated endothelial cells as well as tumor cells. Although intraperitoneal (i.p.) injection of gemcitabine showed limited inhibitory effect on tumor growth, combination with AEE788 and gemcitabine produced nearly 95% inhibition of tumor growth in parallel with a high level of apoptosis on tumor cells and tumor-associated endothelial cells, and decreased microvascular density and proliferation rate. Collectively, these data indicate that dual inhibition of phosphorylation of EGFR and VEGFR, in combination with gemcitabine, produces apoptosis of tumor-associated endothelial cells and significantly suppresses human pancreatic cancer in nude mice.

Authors

Yokoi, K; Kim, S-J; Thaker, P; Yazici, S; Nam, D-H; He, J; Sasaki, T; Chiao, PJ; Sclabas, GM; Abbruzzese, JL; Hamilton, SR; Fidler, IJ

MLA Citation

Yokoi, K, Kim, S-J, Thaker, P, Yazici, S, Nam, D-H, He, J, Sasaki, T, Chiao, PJ, Sclabas, GM, Abbruzzese, JL, Hamilton, SR, and Fidler, IJ. "Induction of apoptosis in tumor-associated endothelial cells and therapy of orthotopic human pancreatic carcinoma in nude mice." Neoplasia (New York, N.Y.) 7.7 (July 2005): 696-704.

PMID

16026649

Source

epmc

Published In

Neoplasia (New York, N.Y.)

Volume

7

Issue

7

Publish Date

2005

Start Page

696

End Page

704

DOI

10.1593/neo.05193

The use of serial serum measurements of the carbohydrate antigen 19-9 (CA19-9) to guide treatment decisions and serve as a surrogate end point in clinical trial design requires further validation. We investigated whether CA19-9 decline represents an accurate surrogate for survival and time to treatment failure (TTF) in a cohort of 76 patients with advanced pancreatic cancer receiving fixed-dose rate gemcitabine in three separate studies. Statistically significant correlations between percentage CA19-9 decline and both overall survival and TTF were found, with median survival ranging from 12.0 months for patients with the greatest degree of biomarker decline (> 75%) compared with 4.3 months in those whose CA19-9 did not decline during therapy (P < 0.001). Using specific thresholds, patients with > or = 25% decline in CA19-9 during treatment had significantly better outcomes than those who did not (median survival and TTF of 9.6 and 4.6 months vs 4.4 and 1.5 months; P < 0.001). Similar results were seen using both 50 and 75% as cutoff points. We conclude that serial CA19-9 measurements correlate well with clinical outcomes in this patient population, and that decline in this biomarker should be entertained for possible use as a surrogate end point in clinical trials for the selection of new treatments in this disease.

Authors

Ko, AH; Hwang, J; Venook, AP; Abbruzzese, JL; Bergsland, EK; Tempero, MA

MLA Citation

Ko, AH, Hwang, J, Venook, AP, Abbruzzese, JL, Bergsland, EK, and Tempero, MA. "Serum CA19-9 response as a surrogate for clinical outcome in patients receiving fixed-dose rate gemcitabine for advanced pancreatic cancer." British journal of cancer 93.2 (July 2005): 195-199.

PMID

15999098

Source

epmc

Published In

British Journal of Cancer

Volume

93

Issue

2

Publish Date

2005

Start Page

195

End Page

199

DOI

10.1038/sj.bjc.6602687

Authors

Asano, T; Yao, Y; Zhu, J; Li, D; Abbruzzese, JL; Reddy, SAG

MLA Citation

Asano, T, Yao, Y, Zhu, J, Li, D, Abbruzzese, JL, and Reddy, SAG. "Erratum: The PI 3-kinase/Akt signaling pathway is activated due to aberrant Pten expression and targets transcription factors NF-κB and c-Myc in pancreatic cancer cells (Oncogene (2004) 23 (8571-8580) DOI: 10.1038/sj.onc.1207902)." Oncogene 24.26 (June 16, 2005): 4320-null.

Source

scopus

Published In

Oncogene

Volume

24

Issue

26

Publish Date

2005

Start Page

4320

DOI

10.1038/sj.onc.1208766

PURPOSE: To evaluate whether celecoxib alters the conversion of gemcitabine into its active metabolite, difluorodeoxycytidine triphosphate (dFdCTP), in peripheral blood mononuclear cells (PBMCs). METHODS: Patients with advanced pancreatic cancer who had not received chemotherapy and had acceptable organ function were eligible for the study. The initial dose of gemcitabine was 750 mg/m(2) administered intravenously at a rate of 10 mg/m(2)/min on days 1, 8, and 15 every 4 weeks. Celecoxib was administered orally at 400 mg twice a day starting 2 days after the first dose of gemcitabine. Serial blood samples were taken during the first and second gemcitabine infusions and the cellular dFdCTP levels from PBMCs were analyzed. RESULTS: Five patients received gemcitabine at 750 mg/m(2) and six patients received it at 650 mg/m(2). Severe adverse events included neutropenia, thrombocytopenia, enteritis, and gastric perforation. Two patient died early during treatment. Cellular pharmacology studies showed that the conversion of gemcitabine into dFdCTP was not affected by celecoxib. CONCLUSION: Despite the increased clinical toxicities encountered with the combination, celecoxib did not alter the conversion of gemcitabine into its active metabolites in PBMCs. Gemcitabine 650 mg/m(2) infusion over 65 min on days 1, 8, and 15 every 4 weeks in combination with celecoxib at 400 mg twice a day was the dose recommended for further study.

Authors

Xiong, HQ; Plunkett, W; Wolff, R; Du, M; Lenzi, R; Abbruzzese, JL

MLA Citation

Xiong, HQ, Plunkett, W, Wolff, R, Du, M, Lenzi, R, and Abbruzzese, JL. "A pharmacological study of celecoxib and gemcitabine in patients with advanced pancreatic cancer." Cancer chemotherapy and pharmacology 55.6 (June 2005): 559-564.

PMID

15726370

Source

epmc

Published In

Cancer Chemotherapy and Pharmacology

Volume

55

Issue

6

Publish Date

2005

Start Page

559

End Page

564

DOI

10.1007/s00280-004-0916-9