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Background In participants with concomitant chronic coronary disease and advanced chronic kidney disease (CKD), the effect of treatment strategies on the timing of dialysis initiation is not well characterized. Methods and Results In ISCHEMIA‐CKD (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches–Chronic Kidney Disease), 777 participants with advanced CKD and moderate or severe ischemia were randomized to either an initial invasive or conservative management strategy. Herein, we compare the proportion of randomized participants with non–dialysis‐requiring CKD at baseline (n=362) who initiated dialysis and compare the time to dialysis initiation between invasive versus conservative management arms. Using multivariable Cox regression analysis, we also sought to identify the effect of invasive versus conservative chronic coronary disease management strategies on dialysis initiation. At a median follow‐up of 23 months (25th–75th interquartile range, 14–32 months), dialysis was initiated in 18.9% of participants (36/190) in the invasive strategy and 16.9% of participants (29/172) in the conservative strategy (P= 0.22). The median time to dialysis initiation was 6.0 months (interquartile range, 3.0–16.0 months) in the invasive group and 18.2 months (interquartile range, 12.2–25.0 months) in the conservative group (P= 0.004), with no difference in procedural acute kidney injury rates between the groups (7.8% versus 5.4%; P =0.26). Baseline clinical factors associated with earlier dialysis initiation were lower baseline estimated glomerular filtration rate (hazard ratio [HR] associated with 5‐unit decrease, 2.08 [95% CI, 1.72–2.56]; P <0.001), diabetes (HR, 2.30 [95% CI, 1.28–4.13]; P =0.005), hypertension (HR, 7.97 [95% CI, 1.09–58.21]; P =0.041), and Hispanic ethnicity (HR, 2.34 [95% CI, 1.22–4.47]; P =0.010). Conclusions In participants with non–dialysis‐requiring CKD in ISCHEMIA‐CKD, randomization to an invasive chronic coronary disease management strategy (relative to a conservative chronic coronary disease management strategy) is associated with an accelerated time to initiation of maintenance dialysis for kidney failure. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01985360.

Polygenic diseases, which are genetic disorders caused by the combined action of multiple genes, pose unique and significant challenges for the diagnosis and management of affected patients. A major goal of cardiovascular medicine has been to understand how genetic variation leads to the clinical heterogeneity seen in polygenic cardiovascular diseases (CVDs). Recent advances and emerging technologies in artificial intelligence (AI), coupled with the ever-increasing availability of next generation sequencing (NGS) technologies, now provide researchers with unprecedented possibilities for dynamic and complex biological genomic analyses. Combining these technologies may lead to a deeper understanding of heterogeneous polygenic CVDs, better prognostic guidance, and, ultimately, greater personalized medicine. Advances will likely be achieved through increasingly frequent and robust genomic characterization of patients, as well the integration of genomic data with other clinical data, such as cardiac imaging, coronary angiography, and clinical biomarkers. This review discusses the current opportunities and limitations of genomics; provides a brief overview of AI; and identifies the current applications, limitations, and future directions of AI in genomics.

TPS376 Background: Human epidermal growth factor receptor 2 ( HER2) gene amplification or protein overexpression (HER2+) occurs in many gastrointestinal (GI) cancers; thus, there is interest in evaluating HER2-targeted therapies in these tumor types. Tucatinib (TUC) is a highly selective HER2-directed tyrosine kinase inhibitor with minimal EGFR inhibition, approved in multiple regions for HER2+ metastatic breast cancer. In patient-derived xenograft models of HER2+ tumors (including esophageal, gastric, and colorectal cancers), TUC + trastuzumab showed superior anti-tumor activity compared with either agent alone (Kulukian 2020). In the MOUNTAINEER study, TUC + trastuzumab in HER2+ metastatic colorectal cancer (CRC) resulted in an objective response rate of 52% and a median duration of response of 10.4 months (interim results, Strickler 2019). The SGNTUC-024 study (NCT04430738) will evaluate TUC + trastuzumab with and without oxaliplatin-based chemotherapy or pembrolizumab in patients with unresectable or metastatic GI cancers. Methods: SGNTUC-024 is an open-label, dose escalation and expansion phase 1b/2 trial. Phase 1b assesses the safety and tolerability of TUC + trastuzumab + either FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine and oxaliplatin) with or without pembrolizumab. One chemotherapy-free cohort is planned (TUC + trastuzumab + pembrolizumab). The initial phase 1b cohort enrolled patients with gastric, esophageal, and gastroesophageal junction (GEJ) adenocarcinomas; cholangiocarcinoma; gallbladder carcinoma; and CRC to receive TUC (150 mg oral [PO] twice daily [BID]) + trastuzumab + FOLFOX. Subsequent phase 1b cohorts will receive TUC (300 mg PO BID) + trastuzumab + either FOLFOX or CAPOX. Once the recommended dose for use with oxaliplatin is identified, cohorts enrolling patients with gastric, esophageal, and GEJ adenocarcinomas will open with patients receiving TUC (300 mg PO BID) + trastuzumab + pembrolizumab with or without either FOLFOX or CAPOX. Phase 2 will expand the assessment of safety and efficacy and enroll 2 cohorts: patients with gastric, esophageal, and GEJ adenocarcinomas (to receive TUC + trastuzumab + pembrolizumab + either FOLFOX or CAPOX, Cohort A) and patients with CRC (to receive TUC + trastuzumab + FOLFOX, Cohort B). Safety and efficacy will be summarized with descriptive statistics. Patients that receive chemotherapy must be eligible for an oxaliplatin-based regimen as standard of care. Patients with irradiated or resected central nervous system (CNS) lesions may enroll, and patients with known active CNS lesions may be eligible for phase 2. The phase 1b portion of the trial is currently enrolling. Clinical trial information: NCT04430738.

Abstract Background and Rationale: Axi-cel is a standard-of-care treatment for relapsed or refractory LBCL after 2 or more lines of systemic therapy. Some patients who would have been ineligible for ZUMA-1 criteria due to comorbidities have been treated with axi-cel in the real-world setting. We interrogated a large registry of patients treated with standard-of-care axi-cel for a definitive report on the impact of age or certain comorbidities on safety and efficacy outcomes after axi-cel infusion. Methods: From October 2017 to August 2020, 1500 patients were enrolled in the postapproval safety observational study of axi-cel treated at 79 centers. Patients eligible for the protocol and followed up for at least 6 months with complete data entry by the time of analyses were included. One patient rescinded consent and 1 was deemed ineligible. Patients previously treated with immune effector cell therapy (n=31), with incomplete follow-up reporting (n=92), or alive but last contacted &lt;180 days postinfusion (n=32) were excluded from analysis. Main efficacy outcomes included complete and objective response rates (CR and ORR), duration of response (DOR), progression-free and overall survival (PFS and OS). Safety endpoints of interest included cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Outcomes were assessed and compared by age and preselected coexisting disease or organ impairment within 3 months prior to the infusion included in the hematopoietic cell transplantation comorbidity index. Multivariate logistic and Cox regression models were used to assess the impact of age or coexistent organ dysfunction on outcomes via odds ratio (OR) or hazard ratio (HR) and their 95% CIs. Results A total of 1343 patients were included in the analysis with a median 25.1 months (range, 10.3-42.7 months) for potential follow-up, defined from infusion to data cutoff date, and a median 11.8 months (range, 0.1-38.8 months) for actual follow-up time, defined from infusion to date of death or last contact. Of these, 38% were 65 years or older (median 62 years), 4% had a performance score ≥2, 13% had cardiac comorbidities, 16% had a prior cancer, 9% were obese, 2% had moderate to severe hepatic comorbidities, and 2% had renal comorbidities. Transformed lymphoma, double or triple-hit by fluorescence in situ hybridization, prior autologous transplant and refractory disease were present in 28%, 15%, 27% and 66%, respectively. Bridging therapy was administered in 21% of patients. Overall, ORR was 74%, (CR 56%), and probabilities of DOR, PFS, and OS at 18 months were 61% (95% CI, 57-65%), 42% (95% CI, 39-45%) and 52% (95% CI, 49-55%), respectively. Overall rates of CRS and ICANS were 83% and 55%, respectively. ORR was 78% (CR 62%, median OS 17.5 [95% CI, 16.0-not evaluated (NE)] months) for patients ≥65 years, ORR 57% (CR 29%; median OS 4.3 [95% CI, 2.5-8.3] months) for patients with hepatic dysfunction, ORR 70% (CR 43%; median OS 8.9 [95% CI, 3.8-NE] months) for patients with renal dysfunction; and ORR 47% (CR 20%, median OS 4 [95% CI, 2.6-6.9] months) for patients with Eastern Cooperative Oncology Group (ECOG) 2 or 3. Multivariate analyses indicated that advanced age (≥65 years vs &lt;65 years; OR 1.38; 95% CI, 1.05-1.83), moderate to severe pulmonary disease (yes vs no; OR 0.74; 95% CI, 0.55-0.98), and ECOG (2-3 vs 0-1; OR 0.31, 95% CI, 0.18-0.53) impacted ORR (Table). Age ≥65 years did not have an impact on survival (HR 1.05, 95% CI, 0.88-1.26), although it was associated with CRS (OR 1.42, 95% CI, 1.03-1.96) and ICANS (OR 1.78, 95% CI, 1.39-2.28). Coexistent cardiac disease (HR 1.44, 95% CI, 1.12-1.83), renal disease (HR 2.13, 95% CI, 1.32-3.46) and hepatic dysfunction (HR 2.65, 95% CI, 1.69-4.14) had an impact on OS, but not on response, CRS, and ICANS. ECOG significantly impacted all efficacy outcomes. None of the other comorbidities tested significantly impacted outcomes. Conclusion: Advanced age (≥65 years) was not associated with worse efficacy outcomes after axi-cel, despite higher rates of CRS and ICANS, which require closer monitoring. Performance status rather than age should be accounted for in patient selection and treatment decisions with axi-cel. Most coexistent organ dysfunctions have no clinically significant impact on axi-cel objective response and safety outcomes. Figure 1 Figure 1. Disclosures Locke: Moffitt Cancer Center: Patents & Royalties: field of cellular immunotherapy; Allogene Therapeutics: Consultancy, Other: Scientific Advisory Role, Research Funding; Amgen: Consultancy, Other: Scientific Advisory Role; Bluebird Bio: Consultancy, Other: Scientific Advisory Role; EcoR1: Consultancy; Emerging Therapy Solutions: Consultancy; Gerson Lehrman Group: Consultancy; Iovance Biotherapeutics: Consultancy, Other: Scientific Advisory Role; Takeda: Consultancy, Other; Novartis: Consultancy, Other, Research Funding; Wugen: Consultancy, Other; GammaDelta Therapeutics: Consultancy, Other: Scientific Advisory Role; Umoja: Consultancy, Other; Cellular Biomedicine Group: Consultancy, Other: Scientific Advisory Role; Calibr: Consultancy, Other: Scientific Advisory Role; Cowen: Consultancy; BMS/Celgene: Consultancy, Other: Scientific Advisory Role; Legend Biotech: Consultancy, Other; Kite, a Gilead Company: Consultancy, Other: Scientific Advisory Role, Research Funding; Janssen: Consultancy, Other: Scientific Advisory Role. Jacobson: Axis: Speakers Bureau; Nkarta: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Other: Travel support, Research Funding; AbbVie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel support; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Other: Travel support; Precision Biosciences: Consultancy, Honoraria, Other: Travel support; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support; Lonza: Consultancy, Honoraria, Other: Travel support; Humanigen: Consultancy, Honoraria, Other: Travel support; Clinical Care Options: Speakers Bureau. Ma: Kite, a Gilead Company: Current Employment. Dong: Kite, a Gilead Company: Current Employment. Hu: Kite, a Gilead Company: Research Funding; Novartis: Research Funding; Celgene: Research Funding. Siddiqi: BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Oncternal: Research Funding; Janssen: Speakers Bureau; Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; TG Therapeutics: Research Funding. Ahmed: Seagen: Research Funding; Tessa Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Xencor: Research Funding. Ghobadi: Atara: Consultancy; Wugen: Consultancy; Amgen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Celgene: Consultancy. Miklos: Pharmacyclics: Patents & Royalties; Kite, a Gilead Company, Amgen, Atara, Wugen, Celgene, Novartis, Juno-Celgene-Bristol Myers Squibb, Allogene, Precision Bioscience, Adicet, Pharmacyclics, Janssen, Takeda, Adaptive Biotechnologies and Miltenyi Biotechnologies: Consultancy; Pharmacyclics, Amgen, Kite, a Gilead Company, Novartis, Roche, Genentech, Becton Dickinson, Isoplexis, Miltenyi, Juno-Celgene-Bristol Myers Squibb, Allogene, Precision Biosciences, Adicet, Adaptive Biotechnologies: Research Funding; Adaptive Biotechnologies, Novartis, Juno/Celgene-BMS, Kite, a Gilead Company, Pharmacyclics-AbbVie, Janssen, Pharmacyclics, AlloGene, Precision Bioscience, Miltenyi Biotech, Adicet, Takeda: Membership on an entity's Board of Directors or advisory committees. Lin: Kite, a Gilead Company: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Legend: Consultancy; Vineti: Consultancy; Sorrento: Consultancy; Gamida Cell: Consultancy; Janssen: Consultancy, Research Funding; Juno: Consultancy; Bluebird Bio: Consultancy, Research Funding; Novartis: Consultancy; Merck: Research Funding; Takeda: Research Funding. Perales: Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Nektar Therapeutics: Honoraria, Other; Miltenyi Biotec: Honoraria, Other; MorphoSys: Honoraria; NexImmune: Honoraria; Sellas Life Sciences: Honoraria; Cidara: Honoraria; Merck: Honoraria; Omeros: Honoraria; Servier: Honoraria; Celgene: Honoraria; Novartis: Honoraria, Other; Kite/Gilead: Honoraria, Other; Incyte: Honoraria, Other; Medigene: Honoraria; Karyopharm: Honoraria; Equilium: Honoraria. Lunning: Daiichi-Sankyo: Consultancy; TG Therapeutics: Consultancy; Kite, a Gilead Company: Consultancy; ADC Therapeutics: Consultancy; Spectrum: Consultancy; Beigene: Consultancy; Celgene, a Bristol Myers Squibb Co.: Consultancy; Legend: Consultancy; AbbVie: Consultancy; AstraZeneca: Consultancy; Morphosys: Consultancy; Verastem: Consultancy; Novartis: Consultancy; Myeloid Therapeutics: Consultancy; Janssen: Consultancy; Acrotech: Consultancy; Kyowa Kirin: Consultancy; Karyopharm: Consultancy. Hill: Gentenech: Consultancy, Honoraria, Research Funding; Incyte/Morphysis: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy, Honoraria; Celgene (BMS): Consultancy, Honoraria, Research Funding. Nikiforow: Kite/Gilead: Other: ad HOC Advisory Boards; Novartis: Other: ad Hoc Advisory Boards; Iovance: Other: ad Hoc Advisory Boards; Glaxo Smith Kline (GSK): Other: ad Hoc Advisory Boards. Xu: Gilead Sciences: Other: stock or other ownership ; Kite, A Gilead Company: Current Employment. Pasquini: Bristol Myers Squibb: Consultancy, Research Funding; Novartis: Research Funding; Kite Pharma: Research Funding; GlaxoSmithKline: Research Funding.

Abstract Background: CD19 CAR T cell therapies have demonstrated high initial complete remission (CR) rates of 70-80% in relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) with durable remissions observed in a subset of patients. Despite the remarkable initial CR rate, relapses occur in 20-45% of patients and with increasing use of CD19 CAR T cell therapies in ALL, a key remaining clinical question is the role of post-CAR HCT. Methods: Patients up to 26 years treated with the commercial (i.e., tisagenlecleucel) or investigational CD19 CAR T cell products from 2014 to 2019 in the United States were included. The objectives were to examine the impact of post-CAR HCT on mortality, disease-free survival (DFS), leukemia relapse, GVHD and transplant related mortality among HCT recipients. The intent of HCT was analyzed as consolidation when there was no evidence of post-CAR T cell relapse prior to HCT. Cox regression multivariable analysis used HCT as time-dependent variable along with age, performance status and time from diagnosis to CAR-T cell infusion to evaluate its impact on outcomes. Results: We identified 347 patients who received CD19 CAR T cells from 86 centers. Median age was 13 (range, 0.4-26 years) with 39% of patients from Hispanic or Latino ethnic origin. Patients were high risk and heavily pretreated; 56% had poor cytogenetics, 51% had ≥3 line of prior therapies and 34% had prior HCT. Most of the patients (74%) received tisagenlecleucel. Disease burden at the time of CAR T cell infusion included morphologic disease (≥5% bone marrow blasts) (65%), measurable residual disease (MRD) positive (16%) and negative CR (18%). CRS of all grades was observed in 57.6% and grade 3-4 CRS in 13%; neurotoxicity of all grades was observed in 25% and grade 3-4 in 8%. With a median follow-up of 12.7 months (range, 2.2-60.3), DFS at 3, 6 and 12 months following CAR T cell infusion was 80.9% % (95% CI: 76.6%-84.9%), 71.2% (95% CI: 66.1%-76.0%) and 57.6% (95% CI: 51.8%-63.3%), respectively. OS at 3, 6 and 12 months was 93.6% (95% CI: 90.8%-96.0%), 89.8% (95% CI: 86.4%-92.8%) and 79.4% (95% CI: 74.7%-83.6%), respectively. Incidences of relapse without censoring at subsequent HCT at month 3, 6 and 12 were 18.5% (95% CI: 14.5%-22.8%), 28.2% (95% CI: 23.5%-33.3%), and 40.6% (95% CI: 35.0%-46.3%), respectively. Of the 347 patients who received CD19 CAR therapy, 62 patients (18%) had subsequent HCT in CR as a consolidation post-CAR with a median time from CAR T to HCT of 4.7 months (range, 1.1-18.6). 36% had a prior HCT (i.e., pre-CAR), 87% received myeloablative regimen and among the 57 patients with MRD evaluation 56 were negative (98%). Frequencies of post-CAR HCT did not change during the 5-year study period. Overall, transplant related mortality (TRM) at month 6 was 8.9% (95% CI: 3.6-16.1), and grade 2-4 acute GvHD was observed in 38.0% (95% CI: 28.4-48.2) of patients at month 6. Post-CAR HCT used as a consolidation was associated with lower relapse (hazard ratio (HR) 0.37; p=0.037) but no significant impact on mortality (HR 0.75, p=0.51) or DFS (HR=0.46, p=0.057). When accounting for any HCT performed after CAR T cell, HCT was associated with higher mortality (Figure). Conclusions: This is the largest clinical series to date examining the impact of post-CAR HCT on clinical outcome of R/R B-ALL patients. We found that 18% of the patients had post-CAR HCT as a consolidation therapy with a favorable safety profile of 8.9% TRM rate despite a prior transplant rate of 36%. Consolidation HCT after CAR T cell resulted in significant reduction in leukemia relapse with a trend towards better DFS. Consolidation HCT seem safe and incurred a benefit by reducing disease relapse. Further studies in understanding the role of consolidation HCT as planned, or post-CAR T cell response-based strategy or treatment for early B-cell recovery are needed to further define the best candidates for HCT after tisagenlecleucel . Figure 1 Figure 1. Disclosures Park: BMS: Consultancy; Affyimmune: Consultancy; Kite Pharma: Consultancy; Curocel: Consultancy; Novartis: Consultancy; Minerva: Consultancy; Innate Pharma: Consultancy; PrecisionBio: Consultancy; Intellia: Consultancy; Amgen: Consultancy; Autolus: Consultancy; Servier: Consultancy; Artiva: Consultancy; Kura Oncology: Consultancy. Nikiforow: Kite/Gilead: Other: ad HOC Advisory Boards; Novartis: Other: ad Hoc Advisory Boards; Iovance: Other: ad Hoc Advisory Boards; Glaxo Smith Kline (GSK): Other: ad Hoc Advisory Boards. Hu: Kite/Gilead: Research Funding; Novartis: Research Funding; Celgene: Research Funding. Ahmed: Merck: Research Funding; Tessa Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seagen: Research Funding; Xencor: Research Funding. Badar: Pfizer Hematology-Oncology: Membership on an entity's Board of Directors or advisory committees. Cairo: Servier: Speakers Bureau; Sanofi: Speakers Bureau; Amgen: Speakers Bureau; Jazz Pharmaceutical: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sobi: Speakers Bureau; Omeros: Membership on an entity's Board of Directors or advisory committees; Nektar: Membership on an entity's Board of Directors or advisory committees. Dholaria: Janssen: Research Funding; Takeda: Research Funding; Jazz: Speakers Bureau; MEI: Research Funding; Pfizer: Research Funding; Angiocrine: Research Funding; Poseida: Research Funding; Celgene: Speakers Bureau. Grover: Kite: Other: Advisory Board; Genentech: Research Funding; ADC: Other: Advisory Board; Tessa: Consultancy; Novartis: Consultancy. Locke: Gerson Lehrman Group: Consultancy; Emerging Therapy Solutions: Consultancy; Moffitt Cancer Center: Patents & Royalties: field of cellular immunotherapy; Calibr: Consultancy, Other: Scientific Advisory Role; BMS/Celgene: Consultancy, Other: Scientific Advisory Role; Wugen: Consultancy, Other; Legend Biotech: Consultancy, Other; Janssen: Consultancy, Other: Scientific Advisory Role; Iovance Biotherapeutics: Consultancy, Other: Scientific Advisory Role; Novartis: Consultancy, Other, Research Funding; GammaDelta Therapeutics: Consultancy, Other: Scientific Advisory Role; Takeda: Consultancy, Other; EcoR1: Consultancy; Cowen: Consultancy; Umoja: Consultancy, Other; Kite, a Gilead Company: Consultancy, Other: Scientific Advisory Role, Research Funding; Cellular Biomedicine Group: Consultancy, Other: Scientific Advisory Role; Bluebird Bio: Consultancy, Other: Scientific Advisory Role; Amgen: Consultancy, Other: Scientific Advisory Role; Allogene Therapeutics: Consultancy, Other: Scientific Advisory Role, Research Funding. Murthy: CRISPR Therapeutics: Research Funding. Mussetti: GILEAD: Other: Clinical trials participation, Research Funding; TAKEDA: Honoraria; NOVARTIS: Honoraria, Other: Clinical trials participation. Pulsipher: Jasper Therapeutics: Honoraria; Adaptive: Research Funding; Equillium: Membership on an entity's Board of Directors or advisory committees. Qayed: Novartis: Membership on an entity's Board of Directors or advisory committees; Medexus: Membership on an entity's Board of Directors or advisory committees; Mesoblast: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; BMS: Other. Reshef: Gilead, BMS, Precision, Immatics, Atara, Takeda, Shire, Pharmacyclics, Incyte: Research Funding; Gilead and Novartis: Honoraria; Bayer, BMS, Regeneron, TScan, Synthekine, Atara, Jasper: Consultancy. Rizzieri: Kite: Honoraria, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Stemline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Acrotech: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Celltrion: Membership on an entity's Board of Directors or advisory committees; Mustang: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria; Pharmacyclics: Honoraria. Sharma: Vertex Pharmaceuticals/CRISPR Therapeutics: Other: Salary support paid to institution; Medexus Inc: Consultancy; CRISPR Therapeutics: Other, Research Funding; Vindico Medical Education: Honoraria; Spotlight Therapeutics: Consultancy; Novartis: Other: Salary support paid to institution. Schultz: BMS DSMB: Other: payment; Sobi: Membership on an entity's Board of Directors or advisory committees. Turtle: Century Therapeutics Ad hoc advisory boards (last 12 months): Nektar Therapeutics, Allogene, PACT Pharma, Astra Zeneca, Amgen: Membership on an entity's Board of Directors or advisory committees; Precision Biosciences: Membership on an entity's Board of Directors or advisory committees; Eureka Therapeutics: Membership on an entity's Board of Directors or advisory committees; Caribou Biosciences: Membership on an entity's Board of Directors or advisory committees; T-CURX: Membership on an entity's Board of Directors or advisory committees; Myeloid Therapeutics: Membership on an entity's Board of Directors or advisory committees; ArsenalBio: Membership on an entity's Board of Directors or advisory committees; Minerva: Other; Nektar Therapeutics: Other; Juno Therapeutics/BMS: Other: Payments, Patents & Royalties: Patent licensed to Juno Therapeutics.; Precision Biosciences, Eureka Therapeutics, Caribou Biosciences, Myeloid Therapeutics, ArsenalBio: Current holder of stock options in a privately-held company. Pasquini: Kite Pharma: Research Funding; Novartis: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; GlaxoSmithKline: Research Funding. Perales: MorphoSys: Honoraria; Cidara: Honoraria; Bristol-Myers Squibb: Honoraria; Miltenyi Biotec: Honoraria, Other; Sellas Life Sciences: Honoraria; Takeda: Honoraria; Karyopharm: Honoraria; Celgene: Honoraria; Omeros: Honoraria; Nektar Therapeutics: Honoraria, Other; Equilium: Honoraria; Novartis: Honoraria, Other; NexImmune: Honoraria; Incyte: Honoraria, Other; Kite/Gilead: Honoraria, Other; Merck: Honoraria; Servier: Honoraria; Medigene: Honoraria.

AbstractObjectivesStudies on the association between metformin use and the risk of oesophageal cancer (OC) have generated controversial findings. This updated meta-analysis was conducted to reassess the effects of metformin on OC.MethodsA comprehensive search strategy was conducted to select relevant studies from origination to February 2021. Heterogeneity was evaluated through the Q test and I2 statistics. HRs and 95% CIs were pooled through either random-effect or fixed-effect models. Meta-regression, subgroup analyses, sensitivity analysis and publication bias diagnosis were also performed.ResultsSeven studies with 5 426 343 subjects were included. Metformin use was associated with reduced risk of OC (HR=0.69, 95% CI 0.54 to 0.87, p&lt;0.001). Sensitivity analysis suggested that the results were relatively stable.ConclusionMetformin is associated with a reduced risk of OC. More well-designed studies are still needed to further elaborate on these associations.PROSPERO registration numberCRD42021237127.

AbstractCorticosteroid dosing in the range of 0.5–2 mg/kg/day of methylprednisolone equivalents has become a standard part of the management of intensive care unit (ICU) patients with COVID‐19 pneumonia based on positive results of randomized trials and a meta‐analysis. Alongside such conventional dosing, administration of 1 gm of methylprednisolone daily (pulse dosing) has also been reported in the literature with claims of favorable outcomes. Comparisons between such disparate approaches to corticosteroids for Coronavirus disease 2019 (COVID‐19) pneumonia are lacking. In this retrospective study of patients admitted to the ICU with COVID‐19 pneumonia, we compared patients treated with 0.5–2 mg/kg/day in methylprednisolone equivalents (high‐dose corticosteroids) and patients treated with 1 gm of methylprednisolone (pulse‐dose corticosteroids) to those who did not receive any corticosteroids. The endpoints of interest were hospital mortality, ICU‐free days at Day 28, and complications potentially attributable to corticosteroids. Pulse‐dose corticosteroid therapy was associated with a significant increase in ICU‐free days at Day 28 compared to no receipt: adjusted relative risk (aRR): 1.45 (95% confidence interval [CI]: 1.05–2.02; p = 0.03) and compared with high‐dose corticosteroid administration (p = 0.003). Nonetheless, receipt of high‐dose corticosteroids—but not of pulse‐dose corticosteroids—significantly reduced the odds of hospital mortality compared to no receipt: adjusted Odds ratio (aOR) 0.31 (95% CI: 0.12–0.77; p = 0.01). High‐dose corticosteroids reduced mortality compared to pulse‐dose corticosteroids (p = 0.04). Pulse‐dose corticosteroids—but not high‐dose corticosteroids—significantly increased the odds of acute kidney injury requiring renal replacement therapy compared to no receipt: aOR 3.53 (95% CI: 1.27–9.82; p = 0.02). The odds of this complication were also significantly higher in the pulse‐dose group when compared to the high‐dose group (p = 0.05 for the comparison). In this single‐center study, pulse‐dose corticosteroid therapy for COVID‐19 pneumonia in the ICU was associated with an increase in ICU‐free days but failed to impact hospital mortality, perhaps because of its association with development of severe renal failure. In line with existing trial data, the effect of high‐dose corticosteroids on mortality was favorable.

Significance The sorting nexin proteins are critical for endosomal trafficking and signaling. SNX17 and SNX27 are two SNX proteins displaying high similarity in domain structure, including a common FERM domain; however, they mediate distinct endocytic recycling pathways. We now solve this mystery by demonstrating that the FERM domains of SNX17 and SNX27 have different functions. Whereas the FERM domain of SNX17 recognizes the NPxY/NxxY motif, the same domain in SNX27 binds to a novel “DLF” motif within the N termini of SNX1/2. The interaction between SNX27 and SNX1/2 not only helps efficient retrieval of multiple cargoes but also promotes endosomal recruitment of SNX27. We further demonstrate that the SNX27–SNX1/2 interaction is crucial to neuronal growth and brain development in zebrafish.