Jesse Troy

BACKGROUND: Outcomes from Gram-negative bacteremia (GNB) in solid organ transplant (SOT) recipients are poorly understood. METHODS: This is a single center prospective cohort study comparing the clinical characteristics and outcomes of SOT recipients with GNB to immunocompetent non-SOT patients with GNB between 1/1/2002 through 12/31/2018. Outcomes of interest included incidence of septic shock, respiratory failure, and time to death. A multivariable logistic regression model was used to determine factors associated with incidence of septic shock and respiratory failure. Time to death was evaluated using Cox proportional hazard models. RESULTS: A total of 297 SOT and 1245 immunocompetent non-SOT patients were included. Incidence of septic shock did not significantly differ between the groups (SOT 25.3% vs. non-SOT 24.6%, p = .8225). Overall survival did not significantly differ by transplant status (30-day survival: SOT 76%, 95% confidence interval [CI] 70, 92, non-SOT 74%, 95% CI 71, 77: log rank: p = .76). SOT recipients taking three immunosuppressive medications had significantly lower odds of developing septic shock or respiratory failure requiring intubation and mechanical ventilation than those taking ≤1 agent (shock: adjusted odds ratio [aOR] 0.29, 95% CI 0.09, 0.90, p = .0316; respiratory failure: aOR 0.14, 95% CI: 0.04, 0.49, p = .0020). CONCLUSIONS: SOT recipients with GNB do not experience higher rates of septic shock, respiratory failure, or mortality than immnon-SOT recipients with GNB. Among SOT recipients, a greater number of immunosuppressive medications may be associated with improved outcomes during GNB. Future studies are needed to understand the potential relationship between levels of immunosuppression and clinical outcome in SOT recipients with GNB.

OBJECTIVES: There are limited real-world data about patient-reported outcomes with immunotherapies (IO) in metastatic non-small cell lung cancer (mNSCLC). We describe patient-reported distress and clinical outcomes with IO-based treatments or cytotoxic chemotherapies (Chemo). METHODS: We conducted a single-institution retrospective chart review of adults with mNSCLC treated at Duke from 03/2015 to 06/2020. At each visit, patients self-reported their distress level and sources of distress using the NCCN Distress Thermometer (DT) and its 39-item Problem List. We abstracted demographic, clinical, distress, and investigator assessed-clinical response data, then analyzed these using descriptive statistics and generalized estimating equations. RESULTS: Data from 152 patients were analyzed in four groups: Chemo alone, IO + Chemo, single agent IO, dual agent IO. Distress was worse before treatment start in all groups, and the odds of actionable distress (DT score > 4) decreased by 10 % per month. The most frequent sources of distress were physical symptoms (e.g., fatigue, pain), which remained high longitudinally. Patients receiving IO had higher clinical response rates and a lower rate of unplanned healthcare encounters compared to patients treated with Chemo alone. Only one-third of all patients were seen by palliative care. CONCLUSIONS: This single-center, real-world evidence study demonstrates that patients with mNSCLC experience significant distress prior to starting first-line treatment. IO treatment was associated with higher clinical benefit rates and lower healthcare utilization compared to chemotherapy. Symptom distress persists over time, highlighting potential unmet palliative and supportive care needs in mNSCLC care in the IO treatment era.

<jats:title>Abstract</jats:title> <jats:p>Four decades ago, Hal Broxmeyer demonstrated that umbilical cord blood (CB) contained hematopoietic stem cells (HSC) and hypothesized that CB could be used as a source of donor HSC for rescue of myeloablated bone marrow. In 1988, Gluckman et al reported the first successful cord blood transplant (CBT) of a child with Fanconi Anemia using matched sibling CB. This patient survives and 35 years later still has durable hematopoiesis from the CB donor graft. In 1991, Rubinstein et al established an unrelated donor (UD) CB bank and in 1993 the first UD CBT was using a unit from this bank. Since that time, &amp;gt;40,000 CBTs have been performed worldwide. We hypothesized that changes in cord blood banking (increased size, diversity, and quality of banked units enabling selection of units with higher cell doses and closer HLA matching) and in transplantation (less use of steroids, availability of newer therapies for prophylaxis and treatment of graft versus host disease [GVHD], improved antifungal and antiviral detection and therapeutics) have improved outcomes of CBT today.</jats:p> <jats:p>To address this hypothesis, we performed a retrospective study combining data from Eurocord and Duke University in a large cohort of children transplanted with a single UD CB unit (CBU) from 1993-2019. Standard transplant outcomes (overall survival [OS], disease free survival [DFS], acute and chronic GVHD, treatment related mortality [TRM], and relapse) and changes in outcomes over 3 time periods (1:&amp;lt;2005, n=1297; 2:2005-2010, n=1735; and 3:&amp;gt;2010, n=1802) were studied. Relative contributions of cell dose and HLA matching to transplant outcomes over time were assessed.</jats:p> <jats:p>A total of 4834 patients (4015 from Eurocord and 819 from Duke) were analyzed. The majority of patients, (59%, n=2839) had malignant diagnoses including 1422 with ALL, 887 with AML and 167 with MDS. Of the 1995 with non-malignant diagnoses, 761 had inborn errors of metabolism, 644 had primary immunodeficiency, 325 had a bone marrow failure syndrome and 206 had a histiocytic disorder. Half of the patients had positive serologies for CMV prior to transplant. The median age of the cohort fell from 5.2 to 3.25 years over time. In patients with malignancies, use of total body irradiation decreased over time. The median total nucleated cell (TNC) and CD34+ cell doses administered were 8.07x10e7 and 6.17x10e5 cells/kg and increased over time. HLA matching and transplantation of patients in earlier disease states also increased over time, p&amp;lt;0.001 for both. The probability of 5-year OS in the entire cohort was 53.48% and improved over time: 42%; 57.4%; and 60.4%, in periods 1,2,3 respectively (p&amp;lt;0.0001). OS improved with closer HLA matching, higher cell dose, myeloablative conditioning, and negative pre-transplant CMV serologies. For patients with malignancies, DFS increased and TRM and acute GVHD decreased over time. In contrast, leukemic relapse did not change throughout the years. OS was higher in patients with inborn errors of metabolism and also improved over time with 57.8% surviving before 2005, 69.4% from 2005-2010, and 71% after 2010 (p=0.0141). Similar results were seen in the cohort with immune deficiencies. In the entire cohort, the median time to neutrophil engraftment decreased from 25 days (period 1) to 19 days (period 3). In multivariate analysis for engraftment, a higher TNC dose (p=0.001) up to but not beyond the median cell dose (8.07x10e7 cells/kg), total body irradiation, and the use of ATG improved engraftment. Acute GVHD decreased from 35% before 2005 to 27.1% after 2010 (p=0.0556) while the incidence of chronic GvHD was stable. The use of ATG reduced the risk of acute GVHD and closer HLA matching reduced the risk of both acute and chronic GVHD. In this population of patients receiving high cell doses, outcomes were predominantly influenced by HLA matching and increasing cell dose did not abrogate HLA mismatching.</jats:p> <jats:p>In conclusion, we analyzed the largest cohort of pediatric patients undergoing CBT over the past 3 decades. OS, DFS and engraftment have improved over time accompanied by decreases in TRM and acute GVHD. Relapse and chronic GVHD were stable and remain low. These improvements are explained by the increased availability of high quality banked CBUs enabling selection of closer HLA matching and units with higher cell doses. The numbers of CBTs have decreased in the past decade, but these results support the ongoing use of CBT in children lacking matched related or unrelated donors.</jats:p> <jats:p>Figure 1 Figure 1.</jats:p> <jats:p /> <jats:sec> <jats:title>Disclosures</jats:title> <jats:p>Kurtzberg: Neurogene: Consultancy; CryoCell: Patents &amp; Royalties: Duke licensed IP, and data and regulatory packages for manufacturing and use of cord blood and cord tissue MSCs in the treatment of patients with hypoxic ischemic encephalopathy, cerebral palsy, autism, acute ischemic stroke, COVID-ARDS, and COVID-MIS-C. ; Sinocell: Patents &amp; Royalties: Duke licensed IP, data, and regulatory packages for use of autologous and sibling cord blood to treat children with cerebral palsy.; Celularity: Current holder of stock options in a privately-held company. Troy: SinoCell: Patents &amp; Royalties; CryoCell: Patents &amp; Royalties; Bristol Myers Squibb: Research Funding; Synthetic Biologics: Honoraria; Gamida Cell: Consultancy; The EMMES Corporation: Consultancy; The Community Data Roundtable: Consultancy; AegisCN: Consultancy.</jats:p> </jats:sec>

<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Introduction</jats:title> <jats:p>SARS-CoV-2 infection results in the COVID-19 disease that caused a global pandemic. In severe cases, COVID-19 leads to acute respiratory distress syndrome (ARDS), due to direct lung injury and hyperinflammatory response. COVID-related ARDS treatment now includes remdesivir, dexamethasone, and anti-inflammatory monoclonal antibodies, which have decreased the mortality rate, yet patients continue to die from sepsis or multiorgan failure and new treatments are needed. The use of mesenchymal stromal cells (MSC) offers a unique therapeutic option that may shorten time to lung injury resolution through anti-inflammatory, immune-modulatory, and regenerative mechanisms.</jats:p> </jats:sec> <jats:sec> <jats:title>Objective</jats:title> <jats:p>The aim of this study was to test the safety of human cord tissue-derived MSCs (hCT-MSC) in patients with COVID-related ARDS. This study was funded by The Marcus Foundation.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>In this phase I multisite study, 10 adults with COVID- related ARDS were treated with 3 daily intravenous infusions of hCT-MSCs (1 million cells/kg/dose, maximum dose 100 million cells with a post thaw viability ≥70%). Patients were excluded if they had evidence of multiorgan failure, immunodeficiency, or were receiving extracorporeal membrane oxygenation or not expected to survive more than 24 hours. The primary endpoint was short-term safety of hCT-MSC infusions. The secondary endpoints included 28-day survival and changes in the Murray Lung Injury Score.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>From August to November 2020, 10 patients (7 females, 3 males; 2 Black, 6 White, 2 other; 3 Hispanic or Latino), with a median age of 61.5 years (range 39-97), were enrolled at 2 sites. There were no infusion-related or study-related adverse events. The average cell dose administered was 0.94 ± 0.29 cells/kg, and average cell viability was 85% ± 11%; 5 of 30 (17%) doses were less than the study dose, and 29 of 30 (97%) met the ≥70% viability criteria. There were 28 non-serious adverse events in 3 unique patients and 2 serious adverse events in 2 unique patients, which were expected and deemed unrelated to the study product. Five patients died: 3 by day 28 and 2 by day 90. All deaths were determined to be unrelated to the hCT-MSCs. The Murray Lung Injury Score did not appear to change over the 28-day study period.</jats:p> </jats:sec> <jats:sec> <jats:title>Discussion</jats:title> <jats:p>hCT-MSCs infusions are safe in patients with COVID-related ARDS. Future studies determining their efficacy are warranted.</jats:p> </jats:sec>