Efficacy of T cell assays for the diagnosis of primary defects in cytotoxic lymphocyte exocytosis.

Primary hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder associated with autosomal recessive variants in genes required for perforin-mediated lymphocyte cytotoxicity. A rapid diagnosis is crucial for successful treatment. Although defective cytotoxic T lymphocyte (CTL) function causes pathogenesis, quantification of natural killer (NK) cell exocytosis triggered by K562 target cells currently represents a standard diagnostic procedure for primary HLH. We have prospectively evaluated different lymphocyte exocytosis assays in 213 patients referred for evaluation for suspected HLH and related hyperinflammatory syndromes. A total of 138 patients received a molecular diagnosis consistent with primary HLH. Compared to routine K562 cell-based assays, assessment of Fc receptor-triggered NK-cell and T cell receptor-triggered CTL exocytosis displayed higher sensitivity and improved specificity for the diagnosis of primary HLH, with these assays combined providing a sensitivity of 100% and specificity of 98.3%. By comparison, NK-cell exocytosis following K562 target cell stimulation displayed a higher inter-individual variability, in part explained by differences in NK-cell differentiation or large functional reductions following shipment. We thus recommend combined analysis of T cell receptor-triggered CTL and Fc receptor-triggered NK-cell exocytosis for the diagnosis of patients with suspected familial HLH or atypical manifestations of congenital defects in lymphocyte exocytosis.

A Comprehensive Approach to Addressing the Burnout Crisis Among US Health Care Workers: The Houston Methodist Experience.

Health care workers experience high rates of burnout and psychiatric distress. A large health care system in the southwest United States developed a comprehensive mental health service model for employees. Services offered range from traditional benefits (eg, Employee Assistance Program), resiliency and well-being initiatives, and innovative technology solutions, to access to peer support services for professional practice issues. The latest innovation in services is a free, self-insured outpatient mental health clinic designed exclusively for health care workers and their dependents. In this article, the authors describe the development of expanded mental health programming for health care workers and discuss how this unique service model proactively reduces common barriers to the receipt of high-quality care. This approach to caring for the workforce may serve as a model for other health care organizations across the United States. By providing mental health support to employees, health care organizations are mitigating the risk of burnout and related consequences to the system.

Occurrence of recreational water quality monitoring general fecal indicator bacteria and fecal source identification genetic markers in gray seal scat.

The number of gray seals (Halichoerus grypus) observed along the United States Northwest Atlantic region has been increasing for decades. These colonial animals often haul-out on beaches seasonally in numbers ranging from a few individuals to several thousands. While these larger aggregations are an important part of gray seal behavior, there is public concern that haul-outs could lead to large amounts of fecal waste in recreational areas, potentially resulting in beach closures. Yet, data to confirm whether these animals contribute to beach closures is lacking and minimal information is available on the occurrence of key water quality monitoring genetic markers in gray seal scat. This study evaluates the concentration of E. coli (EC23S857), enterococci (Entero1a), and fecal Bacteroidetes (GenBac3) as well as six fecal source identification genetic markers (HF183/BacR287, HumM2, CPQ_056, Rum2Bac, DG3, and GFD) measured by qPCR in 48 wild gray seal scat samples collected from two haul-out areas in Cape Cod (Massachusetts, U.S.A.). Findings indicate that FIB genetic markers are shed in gray seal scat at significantly different concentrations with the Entero1a genetic marker exhibiting the lowest average concentration (-0.73 log10 estimated mean copies per nanogram of DNA). In addition, systematic testing of scat samples demonstrated that qPCR assays targeting host-associated genetic markers indicative of human, ruminant, and canine fecal pollution sources remain highly specific in waters frequented by gray seals (>97 % specificity).

Th17/1 and ex-Th17 cells are detected in patients with polyarticular juvenile arthritis and increase following treatment.

BACKGROUND: A better understanding of the pathogenesis of polyarticular juvenile idiopathic arthritis (polyJIA) is needed to aide in the development of data-driven approaches to guide selection between therapeutic options. One inflammatory pathway of interest is JAK-STAT signaling. STAT3 is a transcription factor critical to the differentiation of inflammatory T helper 17 cells (Th17s). Previous studies have demonstrated increased STAT3 activation in adult patients with rheumatoid arthritis, but less is known about STAT3 activation in polyJIA. We hypothesized that Th17 cells and STAT3 activation would be increased in treatment-naïve polyJIA patients compared to pediatric controls. METHODS: Blood from 17 patients with polyJIA was collected at initial diagnosis and again if remission was achieved (post-treatment). Pediatric healthy controls were also collected. Peripheral blood mononuclear cells were isolated and CD4 + T cell subsets and STAT activation (phosphorylation) were evaluated using flow cytometry. Data were analyzed using Mann-Whitney U and Wilcoxon matched-pairs signed rank tests. RESULTS: Treatment-naïve polyJIA patients had increased Th17 cells (CD3 + CD4 + interleukin(IL)-17 +) compared to controls (0.15% v 0.44%, p < 0.05), but Tregs (CD3 + CD4 + CD25 + FOXP3 +) from patients did not differ from controls. Changes in STAT3 phosphorylation in CD4 + T cells following ex vivo stimulation were not significantly different in patients compared to controls. We identified dual IL-17 + and interferon (IFN)γ + expressing CD4 + T cells in patients, but not controls. Further, both Th17/1 s (CCR6 + CD161 + IFNγ + IL-17 +) and ex-Th17s (CCR6 + CD161 + IFNγ + IL-17neg) were increased in patients' post-treatment (Th17/1: 0.3% v 0.07%, p < 0.05 and ex-Th17s: 2.3% v 1.4%, p < 0.05). The patients with the highest IL-17 expressing cells post-treatment remained therapy-bound. CONCLUSIONS: Patients with polyJIA have increased baseline Th17 cells, potentially reflecting higher tonic STAT3 activation in vivo. These quantifiable immune markers may identify patients that would benefit upfront from pathway-focused biologic therapies. Our data also suggest that inflammatory CD4 + T cell subsets not detected in controls but increased in post-treatment samples should be further evaluated as a tool to stratify patients in remission on medication. Future work will explore these proposed diagnostic and prognostic biomarkers.

Understanding Post-Esophagectomy Complications and Their Management: The Early Complications.

Esophagectomy is a technically complex operation performed for both benign and malignant esophageal disease. Medical and surgical advancements have led to improved outcomes in esophagectomy patients over the past several decades; however, surgeons must remain vigilant as complications happen often and can be severe. Post-esophagectomy complications can be grouped into early and late categories. The aim of this review is to discuss the early complications of esophagectomy along with their risk factors, work-up, and management strategies with special attention given to anastomotic leaks.

Characterization of an Mtbp Hypomorphic Allele in a Diethylnitrosamine-Induced Liver Carcinogenesis Model.

MTBP is implicated in cell cycle progression, DNA replication, and cancer metastasis. However, the function of MTBP remains enigmatic and is dependent on cellular contexts and its cellular localization. To understand the in vivo physiological role of MTBP, it is important to generate Mtbp knockout mice. However, complete deletion of the Mtbp gene in mice results in early embryonic lethality, while its heterozygous deletion shows modest biological phenotypes, including enhanced cancer metastasis. To overcome this and better characterize the in vivo physiological function of MTBP, we, for the first time, generated mice that carry an Mtbp hypomorphic allele (MtbpH) in which Mtbp protein is expressed at approximately 30% of that in the wild-type allele. We treated wild-type, Mtbp+/-, and MtbpH/- mice with a liver carcinogen, diethylnitrosamine (DEN), and found that the MtbpH/- mice showed worse overall survival when compared to the wild-type mice. Consistent with previous reports using human liver cancer cells, mouse embryonic fibroblasts (MEFs) from the MtbpH/- mice showed an increase in the nuclear localization of p-Erk1/2 and migratory potential. Thus, MtbpH/- mice and cells from MtbpH/- mice are valuable to understand the in vivo physiological role of Mtbp and validate the diverse functions of MTBP that have been observed in human cells.

Characterization of Schistosome Sox Genes and Identification of a Flatworm Class of Sox Regulators.

Schistosome helminths infect over 200 million people across 78 countries and are responsible for nearly 300,000 deaths annually. However, our understanding of basic genetic pathways crucial for schistosome development is limited. The sex determining region Y-box 2 (Sox2) protein is a Sox B type transcriptional activator that is expressed prior to blastulation in mammals and is necessary for embryogenesis. Sox expression is associated with pluripotency and stem cells, neuronal differentiation, gut development, and cancer. Schistosomes express a Sox-like gene expressed in the schistosomula after infecting a mammalian host when schistosomes have about 900 cells. Here, we characterized and named this Sox-like gene SmSOXS1. SmSoxS1 protein is a developmentally regulated activator that localizes to the anterior and posterior ends of the schistosomula and binds to Sox-specific DNA elements. In addition to SmSoxS1, we have also identified an additional six Sox genes in schistosomes, two Sox B, one SoxC, and three Sox genes that may establish a flatworm-specific class of Sox genes with planarians. These data identify novel Sox genes in schistosomes to expand the potential functional roles for Sox2 and may provide interesting insights into early multicellular development of flatworms.

Impact of Morbid Obesity on Post-esophagectomy Leak Rate: a NSQIP Analysis.

BACKGROUND: Morbid obesity is becoming more prevalent and is a known risk factor for esophageal cancer. Esophagectomy in this population is technically more challenging than the non-obese, thus increasing the risks of surgery. This study hypothesizes that higher body mass index (BMI) is associated with higher anastomotic leak rates after esophagectomy. METHODS: This study is a retrospective review of patients undergoing esophagectomy in the National Surgical Quality Improvement Program (NSQIP) Targeted Esophagectomy database from 2016 to 2019. Patients were stratified by BMI < 35 versus BMI > 35, with the primary outcome being leak post-esophagectomy. Univariate analyses were performed for demographics and post-operative outcomes, and multivariate analyses were performed specifically for the primary outcome of anastomotic leak (all diagnoses and malignancy/dysplasia subgroup). This study was approved by the Institutional Review Board. RESULTS: Of 4165 patients, 439 (10.5%) had a BMI > 35. Patients with BMI > 35 were often younger (mean age 60 vs 64 years, p < 0.001), White (p < 0.001), female (p < 0.001), non-smoker (p < 0.001), diabetic (p < 0.001), with hypertension (p < 0.001), and ASA ≥ 3 (p < 0.001). There were no differences between BMI groups with regard to indication for esophagectomy (malignancy/dysphasia vs other), conversion to open, mortality, or length of stay. The BMI > 35 cohort reported higher operative times (p < 0.001), open operative approach (p = 0.04), superficial surgical site infection (p < 0.001), return to operating room (p = 0.01), and leak (13.5% vs 10.1%, p = 0.01). BMI > 35 was not an independent predictor of leak for all diagnoses; however, the subgroup analysis of esophagectomy for malignancy/dysplasia demonstrated that BMI > 35 was predictive of leak (OR 1.42, 95% CI 1.05-1.91), as well as operative time and hypertension. CONCLUSION: Patients with a BMI > 35 and who undergo esophagectomy have a higher rate of anastomotic leak. BMI > 35 was also an independent predictor of leak when esophagectomy was performed for malignancy/dysplasia, but not for all diagnoses. The risk of anastomotic leak should be considered in morbidly obese patients undergoing esophagectomy, particularly for malignancy.

Relationship between pathogenic microorganisms and the occurrence of esophageal carcinoma based on pathological type: a narrative review.

INTRODUCTION: Esophageal cancer (EC) is one of the most common malignant tumors of the upper gastrointestinal tract. The etiology of EC is complicated and increasing evidence has shown that microbial infection is closely related to the occurrence of various malignant tumors. Though many studies have been focused on this subject in recent years, the exact relationship between microbial infection and the occurrence of EC remains unclear. AREAS COVERED: In this review, we searched all eligible literature reports, summarized the most recent studies in this research field, and analyzed the pathogenic microorganisms associated with EC, providing the latest evidence and references for the prevention of pathogenic microorganism-related EC. EXPERT OPINION: In recent years, increasing evidence has shown that pathogenic microbial infections are closely associated with the development of EC. Therefore, it is necessary to describe in detail the relationship between microbial infection and EC and clarify its possible pathogenic mechanism, which will shed a light on clinical prevention and treatment of cancer caused by pathogenic microbial infection.

The Right to Protest During a Pandemic: Using Public Health Ethics to Bridge the Divide Between Public Health Goals and Human Rights.

Public protest continued to represent a prominent form of social activism in democratic societies during the COVID-19 pandemic. In Australia, a lack of specific legislation articulating protest rights has meant that, in the context of pandemic restrictions, such events have been treated as illegal mass gatherings. Numerous large protests in major cities have, indeed, stirred significant public debate regarding rights of assembly during COVID-19 outbreaks. The ethics of infringing on protest rights continues to be controversial, with opinion divided as to whether public health goals or human rights should take precedence. This paper applies public health ethical theory to an in-depth analysis of arguments on both sides of the debate. Using the Nuffield Council on Bioethics framework as a backdrop, proportionality and necessity of restrictions are understood as key concepts that are common to both public health and human rights perspectives. The analysis presented here finds a middle-ground between the prevailing arguments on opposing sides and is further able to rationalize the use of protest itself as an important element of a mature public health ethics response to restrictive policy. Thus, this paper aims to influence public health policy and legislation regarding protest rights during public health emergencies.

Deploying Digital Health Technologies for Remote Physical Activity Monitoring of Rural Populations With Chronic Neurologic Disease.

Objective: The objective of this pilot study was to examine the feasibility of a remote physical activity monitoring program, quantify baseline activity levels, and examine predictors of activity among rurally residing adults with Parkinson disease (PD) or stroke. Design: Thirty-day observational study. Participants completed standardized assessments, connected a wearable device, and synced daily step counts via a remote monitoring platform. Setting: Community-based remote monitoring. Participants: Rurally residing adults with PD or stroke enrolled in the Veterans Health Administration. Intervention: N/A. Main Outcome Measures: Feasibility was evaluated using recruitment data (response rates), study completion (completed assessments and connected the wearable device), and device adherence (days recording ≥100 steps). Daily step counts were examined descriptively. Predictors of daily steps were explored across the full sample, then by diagnosis, using linear mixed-effects regression analyses. Results: Forty participants (n=20 PD; n=20 stroke) were included in the analysis with a mean (SD) age of 72.9 (7.6) years. Participants resided 252.6 (105.6) miles from the coordinating site. Recruitment response rates were 11% (PD) and 6% (stroke). Study completion rates were 71% (PD) and 80% (stroke). Device adherence rates were 97.0% (PD) and 95.2% (stroke). Participants with PD achieved a median [interquartile range] of 2618 [3896] steps per day and participants with stroke achieved 4832 [7383] steps. Age was the only significant predictor of daily steps for the full sample (-265 steps, 95% confidence interval [-407, -123]) and by diagnosis (PD, -175 steps, [-335, -15]; stroke, -357 steps [-603, -112]). Conclusions: A remote physical activity monitoring program for rurally residing individuals with PD or stroke was feasible. This study establishes a model for a scalable physical activity program for rural, older populations with neurologic conditions from a central coordinating site.

Prognostic Implications of Skin Invasion in Locally Advanced Oral Cavity Squamous Cell Carcinoma.

OBJECTIVE: To evaluate the effect of histopathologic skin invasion on 2- and 5-year disease-free survival (DFS) and overall survival (OS) in patients treated with primary surgery for locally advanced oral cavity squamous cell carcinoma (OCSCC). STUDY DESIGN: A retrospective case-control study was performed comparing previously untreated patients with pT4a OCSCC with and without skin invasion. SETTING: Academic medical center. METHODS: Propensity score-matched cohorts were derived by age, sex, surgical margins, pathologic N classification, adjuvant treatment, and primary tumor site. The Kaplan-Meier method was used to evaluate 2- and 5-year OS and DFS, which were compared between cohorts via the log rank (Mantel-Cox) test statistic. RESULTS: Overall 25 patients were identified to have pathologic skin invasion, and 50 were selected for the matched control group. OS was significantly lower for patients with skin invasion as compared with controls at 2 years (30.8% vs 53.3%, P = .018) and 5 years (16.6% vs 42.2%, P = .01). DFS was significantly lower for patients with skin invasion vs controls at 2 years (23.7% vs 47.7, P = .037) and 5 years (15.8% vs 41.4%, P = .024). CONCLUSION: Histopathologic skin invasion in OCSCC is associated with dismal prognosis in patients who underwent primary surgical treatment. OS outcomes for patients with skin invasion are comparable to survival of patients with recurrent/metastatic disease and T4N2 disease.

Comparison of neoadjuvant regimens for resectable gastroesophageal junction cancer: a systematic review of randomized clinical trials across three decades.

Background: The optimal perioperative treatment for adenocarcinoma of gastroesophageal junction (GEJ) tumor remains uncertain. The systematic review aims to assess the best neoadjuvant modality, namely chemotherapy (CT) versus chemoradiotherapy (CRT) based on randomized controlled trials (RCTs) for resectable gastric, esophageal and GEJ tumors. Methods: We performed a comprehensive PubMed database and Cochrane Library search to identify relevant RCTs related to neoadjuvant treatment for resectable GEJ adenocarcinoma. We included all published RCTs (phase 2 or 3) that tested specific neoadjuvant therapies (CT or CRT) if the patient population included GEJ tumors. We applied the Version 2 Cochrane risk-of-bias tool (RoB 2) to all the eligible studies. Outcomes examined included R0 resection and pathological response based on intention-to-treat (ITT) analysis, surgical outcomes, notable adverse events, and overall survival (OS). Each randomized group of every study was noted to be neoadjuvant CRT, CT, or surgery alone in order to compare the outcomes among these treatment approaches. Results: We identified 25 RCTs with 7,855 patients published from 1996 to 2019. Seven studies tested preoperative CT versus surgery alone, 7 tested preoperative radiotherapy (RT) or CRT versus surgery alone, 4 tested preoperative RT or CRT versus preoperative CT, and 7 tested other combinations. The R0 resection ranged 47-100% and the 3-year OS ranged 6-66.1% in all the study arms. In an exploratory analysis, CRT strategies showed a superior R0 resection rate [80.2%; 95% confidence interval (CI): 79.8-80.6%] to surgery alone (60.9%; 95% CI: 60.4-61.3%; P<0.01) and to preoperative CT (63.9%; 95% CI: 63.6-64.2%; P<0.01). When comparing 3- and 5-year OS, improvement was noted when comparing CRT to surgery alone (P<0.01), and perioperative CT to surgery alone (P<0.01), but no definite difference was noted between CRT versus CT. Discussion: Preoperative CRT showed improvement in R0 resection rate to surgery alone and preoperative CT. However, there is no significant difference in OS between CRT and CT. Both neoadjuvant strategies remain clinically meaningful options for patients with resectable GEJ tumors. Lack of patient-level data and inconsistent reporting of key outcomes across studies were the main limitations of our study.

Gait abnormalities and non-motor symptoms predict abnormal dopaminergic imaging in presumed drug-induced Parkinsonism.

Drug-induced parkinsonism (DIP) can be clinically indistinguishable from degenerative parkinsonism, and bedside assessments are needed to differentiate between these conditions. We examined 34 U.S. Veterans with DIP using 123I-FP-CIT (DAT-SPECT) to identify underlying nigrostriatal degeneration. Participants were 94% male with mean age of 64.5 ± 7.1 years. DAT-SPECT was abnormal in 12/34 (35%). Comparing normal and abnormal imaging groups, there were no differences in age, sex, race/ethnicity, psychiatric diagnosis, motor severity, or RBD Screening Questionnaire scores. Those with underlying neurodegeneration reported significantly more non-motor symptoms (NMS), worse olfactory function on the University of Pennsylvania Smell Identification Test, and greater turning duration/steps on the instrumented Timed Up and Go. Area under the curve (AUC) combining poor olfaction and total NMS burden was 0.84 (CI 0.71-0.97), while AUC for turn steps was 0.91 (CI 0.81-1.00). Gait impairment, hyposmia, and NMS may be useful alone and in combination to identify DIP patients with underlying dopaminergic degeneration.

Single-cell analysis of human glioma and immune cells identifies S100A4 as an immunotherapy target.

A major rate-limiting step in developing more effective immunotherapies for GBM is our inadequate understanding of the cellular complexity and the molecular heterogeneity of immune infiltrates in gliomas. Here, we report an integrated analysis of 201,986 human glioma, immune, and other stromal cells at the single cell level. In doing so, we discover extensive spatial and molecular heterogeneity in immune infiltrates. We identify molecular signatures for nine distinct myeloid cell subtypes, of which five are independent prognostic indicators of glioma patient survival. Furthermore, we identify S100A4 as a regulator of immune suppressive T and myeloid cells in GBM and demonstrate that deleting S100a4 in non-cancer cells is sufficient to reprogram the immune landscape and significantly improve survival. This study provides insights into spatial, molecular, and functional heterogeneity of glioma and glioma-associated immune cells and demonstrates the utility of this dataset for discovering therapeutic targets for this poorly immunogenic cancer.

Reoperations after sleeve gastrectomy: a dual academic institutional experience.

BACKGROUND: Although laparoscopic sleeve gastrectomy (LSG) is the most common bariatric operation performed worldwide, patients can experience complications and poor outcomes that warrant reoperations. The incidence, indications, and outcomes of reoperations are not well understood. OBJECTIVE: To describe indications and outcomes for reoperations after LSG. SETTING: Two academic, tertiary care hospitals. METHODS: We performed a retrospective observational cohort review of institutional Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program data from 2014-2018 and reviewed charts of all reoperations after LSG. We analyzed demographics, preoperative symptoms and work-up, and postoperative outcomes. RESULTS: Fifty-seven reoperations after LSG represented 3.0% of 1965 bariatric cases performed. Most LSGs (56.1%) were performed outside our academic centers. Median time to reoperation and follow-up were 2.63 and 1.2 years, respectively. Conversion to gastric bypass was the most common reoperation (77.2%). More than half of the patients (52.6%) had multiple indications for reoperation. Reflux was the most common primary indication for reoperation (47.3%), followed by incisural strictures (20.1%), inadequate weight loss (17.5%), and leak/fistulae (12.2%). Reoperations were most successful when performed for reflux (92.5%) and oral intolerance from strictures (92%), whereas only 71.4% of leak/fistulas resolved. Surgery for inadequate weight loss resulted in total weight loss of 24.7 ± 10.1%. Complications occurred in 36.2% of cases but varied by indication. CONCLUSION: Symptoms and complications after LSG can persist, and patients may require reoperation. Reoperations can successfully treat the primary indications for reoperation and should be offered, but they have higher complication rates than initial operations.

Circulating Hybrid Cells: A Novel Liquid Biomarker of Treatment Response in Gastrointestinal Cancers.

BACKGROUND: Real-time monitoring of treatment response with a liquid biomarker has potential to inform treatment decisions for patients with rectal adenocarcinoma (RAC), esophageal adenocarcinoma (EAC), and colorectal liver metastasis (CRLM). Circulating hybrid cells (CHCs), which have both immune and tumor cell phenotypes, are detectable in the peripheral blood of patients with gastrointestinal cancers, but their potential as an indicator of treatment response is unexplored. METHODS: Peripheral blood specimens were collected from RAC and EAC patients after neoadjuvant therapy (NAT) or longitudinally during therapy and evaluated for CHC levels by immunostaining. Receiver operating characteristics (ROCs) and the Kaplan-Meier method were used to analyze the CHC level as a predictor of pathologic response to NAT and disease-specific survival (DSS), respectively. RESULTS: Patients with RAC (n = 23) and EAC (n = 34) were sampled on the day of resection, and 11 patients (32%) demonstrated a pathologic complete response (pCR) to NAT. On ROC analysis, CHC levels successfully discriminated pCR from non-pCR with an area under the curve of 0.82 (95% confidence interval [CI], 0.71-0.92; P < 0.001). Additionally, CHC levels in the EAC patients correlated with residual nodal involvement (P = 0.026) and 1-year DSS (P = 0.029). The patients with RAC who were followed longitudinally during NAT (n = 2) and hepatic arterial infusion therapy for CRLM (n = 2) had CHC levels that decreased with therapy response and increased before clinical evidence of disease progression. CONCLUSION: Circulating hybrid cells are a novel blood-based biomarker with potential for monitoring treatment response and disease progression to help guide decisions for further systemic therapy, definitive resection, and post-therapy surveillance. Additional validation studies of CHCs are warranted.

Risk Prediction Model of 90-Day Mortality After Esophagectomy for Cancer.

Importance: Ninety-day mortality rates after esophagectomy are an indicator of the quality of surgical oncologic management. Accurate risk prediction based on large data sets may aid patients and surgeons in making informed decisions. Objective: To develop and validate a risk prediction model of death within 90 days after esophagectomy for cancer using the International Esodata Study Group (IESG) database, the largest existing prospective, multicenter cohort reporting standardized postoperative outcomes. Design, Setting, and Participants: In this diagnostic/prognostic study, we performed a retrospective analysis of patients from 39 institutions in 19 countries between January 1, 2015, and December 31, 2019. Patients with esophageal cancer were randomly assigned to development and validation cohorts. A scoring system that predicted death within 90 days based on logistic regression ß coefficients was conducted. A final prognostic score was determined and categorized into homogeneous risk groups that predicted death within 90 days. Calibration and discrimination tests were assessed between cohorts. Exposures: Esophageal resection for cancer of the esophagus and gastroesophageal junction. Main Outcomes and Measures: All-cause postoperative 90-day mortality. Results: A total of 8403 patients (mean [SD] age, 63.6 [9.0] years; 6641 [79.0%] male) were included. The 30-day mortality rate was 2.0% (n = 164), and the 90-day mortality rate was 4.2% (n = 353). Development (n = 4172) and validation (n = 4231) cohorts were randomly assigned. The multiple logistic regression model identified 10 weighted point variables factored into the prognostic score: age, sex, body mass index, performance status, myocardial infarction, connective tissue disease, peripheral vascular disease, liver disease, neoadjuvant treatment, and hospital volume. The prognostic scores were categorized into 5 risk groups: very low risk (score, ≥1; 90-day mortality, 1.8%), low risk (score, 0; 90-day mortality, 3.0%), medium risk (score, -1 to -2; 90-day mortality, 5.8%), high risk (score, -3 to -4: 90-day mortality, 8.9%), and very high risk (score, ≤-5; 90-day mortality, 18.2%). The model was supported by nonsignificance in the Hosmer-Lemeshow test. The discrimination (area under the receiver operating characteristic curve) was 0.68 (95% CI, 0.64-0.72) in the development cohort and 0.64 (95% CI, 0.60-0.69) in the validation cohort. Conclusions and Relevance: In this study, on the basis of preoperative variables, the IESG risk prediction model allowed stratification of an individual patient's risk of death within 90 days after esophagectomy. These data suggest that this model can help in the decision-making process when esophageal cancer surgery is being considered and in informed consent.