Immediate Lymphatic Reconstruction with Vascularized Omentum Lymph Node Transplant: Reducing the Risk of Both Painful Contracture and Lymphedema.

Patients undergoing extensive lymph node dissection and radiation are at high risk for not only lymphedema but also painful contracture. In a standard lymphadenectomy, immediate lymphatic reconstruction using a lymphovenous bypass is effective in reconstructing the lymphatic defect. However, a more aggressive nodal clearance leaves the patient with a large cavity and skeletonized neurovascular structures, often resulting in severe contracture, pain, cosmetic deformity, and venous stricture. Adjuvant radiotherapy to the nodal bed can lead to severe and permanent disability despite physical therapy. Typically, these patients are referred to us after the fact, where surgery will rarely restore the patient to normal function. In an effort to avoid lymphedema and contracture, we have been reconstructing both the lymphatic and soft tissue defect during lymphadenectomy, using vascularized omentum lymphatic transplant (VOLT). A total of 13 patients underwent immediate reconstruction with VOLT at the time of axillary (n = 8; 61.5%) or groin (n = 5; 38.5%) dissection. No postoperative complications were observed. The mean follow-up time was 15.1 ±â€…12.5 months. Only one lower extremity patient developed mild lymphedema (11% volume differential), with excellent scores in validated patient-reported outcomes. All patients maintained full range of motion with no pain. None of the 13 patients required a compression garment. Immediate lymphatic reconstruction with VOLT is a promising procedure for minimizing the risk of lymphedema and contracture in the highest risk patients undergoing particularly extensive lymph node dissection and radiotherapy.

Patient metabolic profile defined by liver and muscle 18F-FDG PET avidity is independently associated with overall survival in gastric cancer.

BACKGROUND: PET-CT-based patient metabolic profiling is a novel concept to incorporate patient-specific metabolism into gastric cancer care. METHODS: Staging PET-CTs, demographics, and clinicopathologic variables of gastric cancer patients were obtained from a prospectively maintained institutional database. PET-CT avidity was measured in tumor, liver, spleen, four paired muscles, and two paired fat areas in each patient. The liver to rectus femoris (LRF) ratio was defined as the ratio of SUVmean of liver to the average SUVmean of the bilateral rectus femoris muscles. Kaplan-Meier and Cox-proportional hazards models were used to identify the impact of LRF ratio on OS. RESULTS: Two hundred and one patients with distal gastroesophageal (48%) or gastric (52%) adenocarcinoma were included. Median age was 65 years, and 146 (73%) were male. On univariate analysis, rectus femoris PET-CT avidity and LRF ratio were significantly associated with overall survival (p < 0.05). LRF ratio was significantly higher in males, early-stage cancer, patients with an ECOG 0 or 1 performance status, patients with albumin > 3.5 mg/dL, and those with moderately differentiated tumor histology. In multivariable regression, gastric cancer stage, albumin, and LRF ratio were significant independent predictors of overall survival (LRF ratio HR = 0.73 (0.56-0.96); p = 0.024). Survival curves showed that the prognostic impact of LRF was associated with metastatic gastric cancer (p = 0.009). CONCLUSIONS: Elevated LRF ratio, a patient-specific PET-CT-based metabolic parameter, was independently associated with an improvement in OS in patients with metastatic gastric cancer. With prospective validation, LRF ratio may be a useful, host-specific metabolic parameter for prognostication in gastric cancer.

Population-Based Validation of the MIA and MSKCC Tools for Predicting Sentinel Lymph Node Status.

Importance: Patients with melanoma are selected for sentinel lymph node biopsy (SLNB) based on their risk of a positive SLN. To improve selection, the Memorial Sloan Kettering Cancer Center (MSKCC) and Melanoma Institute Australia (MIA) developed predictive models, but the utility of these models remains to be tested. Objective: To determine the clinical utility of the MIA and MSKCC models. Design, Setting, and Participants: This was a population-based comparative effectiveness research study including 10 089 consecutive patients with cutaneous melanoma undergoing SLNB from the Swedish Melanoma Registry from January 2007 to December 2021. Data were analyzed from May to August 2023. Main Outcomes and Measures,: The predicted probability of SLN positivity was calculated using the MSKCC model and a limited MIA model (using mitotic rate as absent/present instead of count/mm2 and excluding the optional variable lymphovascular invasion) for each patient. The operating characteristics of the models were assessed and compared. The clinical utility of each model was assessed using decision curve analysis and compared with a strategy of performing SLNB on all patients. Results: Among 10 089 included patients, the median (IQR) age was 64.0 (52.0-73.0) years, and 5340 (52.9%) were male. The median Breslow thickness was 1.8 mm, and 1802 patients (17.9%) had a positive SLN. Both models were well calibrated across the full range of predicted probabilities and had similar external area under the receiver operating characteristic curves (AUC; MSKCC: 70.8%; 95% CI, 69.5-72.1 and limited MIA: 69.7%; 95% CI, 68.4-71.1). At a risk threshold of 5%, decision curve analysis indicated no added net benefit for either model compared to performing SLNB for all patients. At risk thresholds of 10% or higher, both models added net benefit compared to SLNB for all patients. The greatest benefit was observed in patients with T2 melanomas using a threshold of 10%; in that setting, the use of the nomograms led to a net reduction of 8 avoidable SLNBs per 100 patients for the MSKCC nomogram and 7 per 100 patients for the limited MIA nomogram compared to a strategy of SLNB for all. Conclusions and Relevance: This study confirmed the statistical performance of both the MSKCC and limited MIA models in a large, nationally representative data set. However, decision curve analysis demonstrated that using the models only improved selection for SLNB compared to biopsy in all patients when a risk threshold of at least 7% was used, with the greatest benefit seen for T2 melanomas at a threshold of 10%. Care should be taken when using these nomograms to guide selection for SLNB at the lowest thresholds.

Clinical and molecular characteristics of early-onset vs average-onset esophagogastric cancer.

BACKGROUND: The rate of esophagogastric cancer is rising among individuals under 50 years of age. It remains unknown whether early-onset esophagogastric cancer represents a unique entity. This study investigated the clinical and molecular characteristics of early-onset and average-onset esophagogastric cancer . METHODS: We reviewed the Memorial Sloan Kettering Cancer Center gastric, esophageal, and gastroesophageal junction cancer database. Associations between baseline characteristics and tumor and germline molecular alterations were compared between those with early-onset and average-onset esophagogastric cancer using Fisher exact tests and the Benjamini-Hochberg method for multiple-hypothesis correction. RESULTS: We included 1123 patients with early-onset esophagogastric cancer (n = 219; median age = 43 years [range = 18-49 years]) and average-onset esophagogastric cancer (n = 904; median age = 67 years [range = 50-94 years]) treated between 2005 and 2018. The early-onset group had more women (39% vs 28%, P = .002). Patients with early-onset esophagogastric cancer were more likely to have a gastric primary site (64% vs 44%, P < .0001). The signet ring cell and/or diffuse type was 3 times more common in the early-onset esophagogastric cancer group (31% vs 9%, P < .0001). Early-onsite tumors were more frequently genomically stable (31% vs 18%, P = .0002) and unlikely to be microsatellite instability high (2% vs 7%, P = .003). After restricting to adenocarcinoma and signet ring cell and/or diffuse type carcinomas, we observed no difference in stage (P = .40) or overall survival from stage IV diagnosis (median = 22.7 vs 22.1 months, P = .78). CONCLUSIONS: Our study supported a preponderance of gastric primary disease sites, signet ring histology, and genomically stable molecular subtypes in early-onset esophagogastric cancer. Our findings highlight the need for further research to define the underlying pathogenesis and strategies for early detection and prevention.

Clinical Utility of Melanoma Sentinel Lymph Node Biopsy Nomograms.

BACKGROUND: For patients with melanoma, the decision to perform sentinel lymph node biopsy (SLNB) is based on the estimated risk of lymph node metastasis. We assessed 3 melanoma SLNB risk-prediction models' statistical performance and their ability to improve clinical decision making (clinical utility) on a cohort of melanoma SLNB cases. STUDY DESIGN: Melanoma patients undergoing SLNB at a single center from 2003 to 2021 were identified. The predicted probabilities of sentinel lymph node positivity using the Melanoma Institute of Australia, Memorial Sloan Kettering Cancer Center (MSK), and Friedman nomograms were calculated. Receiver operating characteristic and calibration curves were generated. Clinical utility was assessed via decision curve analysis, calculating the net SLNBs that could have been avoided had a given model guided selection at different risk thresholds. RESULTS: Of 2,464 melanoma cases that underwent SLNB, 567 (23.0%) had a positive sentinel lymph node. The areas under the receiver operating characteristic curves for the Melanoma Institute of Australia, MSK, and Friedman models were 0.726 (95% CI, 0.702 to 0.750), 0.720 (95% CI, 0.697 to 0.744), and 0.721 (95% CI, 0.699 to 0.744), respectively. For all models, calibration was best at predicted positivity rates below 30%. The MSK model underpredicted risk. At a 10% risk threshold, only the Friedman model would correctly avoid a net of 6.2 SLNBs per 100 patients. The other models did not reduce net avoidable SLNBs at risk thresholds of ≤10%. CONCLUSIONS: The tested nomograms had comparable performance in our cohort. The only model that achieved clinical utility at risk thresholds of ≤10% was the Friedman model.

Perioperative versus total neoadjuvant chemotherapy in gastric cancer.

Background: Perioperative chemotherapy is standard of care management for locally advanced gastric cancer (GC), but a substantial proportion of patients do not complete adjuvant therapy due to postoperative complications and prolonged recovery. Administration of all chemotherapy prior to surgery in the form of total neoadjuvant therapy (TNT) may optimize complete delivery of systemic therapy. Methods: We performed a retrospective review of GC patients who had surgery at Memorial Sloan Kettering Cancer Center (MSKCC) from May 2014 to June 2020. Results: One hundred and forty-nine patients were identified; 121 patients received perioperative chemotherapy and 28 patients received TNT. TNT was chosen if patients had interim radiographic and/or clinical response to treatment. Baseline characteristics were well-balanced between the two group except for chemotherapy regimen; more TNT patients received FLOT compared to the perioperative group (79% vs. 31%). There was no difference in the proportion of patients who completed all planned cycles, but TNT patients received a higher proportion of cycles containing all chemotherapy drugs (93% vs. 74%, P<0.001). Twenty-nine patients (24%) in the perioperative group did not receive intended adjuvant therapy. There was no significant difference in hospital length of stay or surgical morbidity. The overall distribution of pathologic stage was similar between the two groups. Fourteen percent of TNT patients and 5.8% of perioperative patients achieved a pathologic complete response (P=0.6). There was no significant difference in recurrence free survival (RFS) or overall survival (OS) between the TNT and perioperative groups [24-month OS rate 77% vs. 85%, HR 1.69 (95% CI: 0.80-3.56)]. Conclusions: Our study was limited by a small TNT sample size and biases inherent to a retrospective analysis. TNT appears to be feasible in a select population, without any increase in surgical morbidity.

Are the MIA and MSKCC nomograms useful in selecting patients with melanoma for sentinel lymph node biopsy?

BACKGROUND AND METHODS: The Melanoma Institute of Australia (MIA) and Memorial Sloan Kettering Cancer Center (MSKCC) nomograms were developed to help guide sentinel lymph node biopsy (SLNB) decisions. Although statistically validated, whether these prediction models provide clinical benefit at National Comprehensive Cancer Network guideline-endorsed thresholds is unknown. We conducted a net benefit analysis to quantify the clinical utility of these nomograms at risk thresholds of 5%-10% compared to the alternative strategy of biopsying all patients. External validation data for MIA and MSKCC nomograms were extracted from respective published studies. RESULTS: The MIA nomogram provided added net benefit at a risk threshold of 9% but net harm at 5%-8% and 10%. The MSKCC nomogram provided added net benefit at risk thresholds of 5% and 9%-10% but net harm at 6%-8%. When present, the magnitude of net benefit was small (1-3 net avoidable biopsies per 100 patients). CONCLUSION: Neither model consistently provided added net benefit compared to performing SLNB for all patients. DISCUSSION: Based on published data, use of the MIA or MSKCC nomograms as decision-making tools for SLNB at risk thresholds of 5%-10% does not clearly provide clinical benefit to patients.

Risk prediction model of peritoneal seeding in advanced gastric cancer: A decision tool for diagnostic laparoscopy.

BACKGROUND: Selective diagnostic laparoscopy in gastric cancer patients at high risk of peritoneal metastasis is essential for optimal treatment planning. In this study available clinicopathologic factors predictive of peritoneal seeding in advanced gastric cancer (AGC) were identified, and this information was translated into a clinically useful tool. METHODS: Totally 2833 patients underwent surgery for AGC between 2003 and 2013. The study identified clinicopathologic factors associated with the risk of peritoneal seeding for constructing nomograms using a multivariate logistic regression model with backward elimination. A nomogram was constructed to generate a numerical value indicating risk. Accuracy was validated using bootstrapping and cross-validation. RESULTS: The proportion of seeding positive was 12.7% in females and 9.6% in males. Of 2833 patients who underwent surgery for AGC, 300 (10.6%) were intraoperatively identified with peritoneal seeding. Multivariate analysis revealed the following factors associated with peritoneal seeding: high American Society of Anesthesiologists score, fibrinogen, Borrmann type 3 or 4 tumors, the involvement of the middle, anterior, and greater curvature, cT3 or cT4cN1 or cN2 or cN3, cM1, and the presence of ascites or peritoneal thickening or plaque or a nodule on the peritoneal wall on computed tomography. The bootstrap analysis revealed a robust concordance between mean and final parameter estimates. The area under the ROC curve for the final model was 0.856 (95% CI, 0.835-0.877), which implies good performance. CONCLUSIONS: This nomogram provides effective risk estimates of peritoneal seeding from gastric cancer and can facilitate individualized decision-making regarding the selective use of diagnostic laparoscopy.

Survival of Locally Advanced MSI-high Gastric Cancer Patients Treated With Perioperative Chemotherapy: A Retrospective Cohort Study.

OBJECTIVE: To evaluate the efficacy of chemotherapy in patients with microsatellite instability (MSI)-high gastric cancer. BACKGROUND: Although MSI-high gastric cancer is associated with a superior prognosis, recent studies question the benefit of perioperative chemotherapy in this population. METHODS: Locally advanced gastric adenocarcinoma patients who either underwent surgery alone or also received neoadjuvant, perioperative, or adjuvant chemotherapy between 2000 and 2018 were eligible. MSI status, determined by next-generation sequencing or mismatch repair protein immunohistochemistry, was determined in 535 patients. Associations among MSI status, chemotherapy administration, overall survival (OS), disease-specific survival, and disease-free survival were assessed. RESULTS: In 535 patients, 82 (15.3%) had an MSI-high tumor and ∼20% better OS, disease-specific survival, and disease-free survival. Grade 1 (90%-100%) pathological response to neoadjuvant chemotherapy was found in 0 of 40 (0%) MSI-high tumors versus 43 of 274 (16%) MSS. In the MSI-high group, the 3-year OS rate was 79% with chemotherapy versus 88% with surgery alone ( P =0.48). In the MSS group, this was 61% versus 59%, respectively ( P =0.96). After multivariable interaction analyses, patients with MSI-high tumors had superior survival compared with patients with MSS tumors whether given chemotherapy (hazard ratio=0.53, 95% confidence interval: 0.28-0.99) or treated with surgery alone (hazard ratio=0.15, 95% confidence interval: 0.02-1.17). CONCLUSIONS: MSI-high locally advanced gastric cancer was associated with superior survival compared with MSS overall, despite worse pathological chemotherapy response. In patients with MSI-high gastric cancer who received chemotherapy, the survival rate was ∼9% worse compared with surgery alone, but chemotherapy was not significantly associated with survival.

Risk of Lymph Node Metastasis in T1b Gastric Cancer: An International Comprehensive Analysis from the Global Gastric Group (G3) Alliance.

OBJECTIVE: We sought to define criteria associated with low lymph node metastasis risk in patients with submucosal (pT1b) gastric cancer from 3 Western and 3 Eastern countries. SUMMARY BACKGROUND DATA: Accurate prediction of lymph node metastasis risk is essential when determining the need for gastrectomy with lymph node dissection following endoscopic resection. Under present guidelines, endoscopic resection is considered definitive treatment if submucosal invasion is only superficial, but this is not routinely assessed. METHODS: Lymph node metastasis rates were determined for patient groups defined according to tumor pathological characteristics. Clinicopathological predictors of lymph node metastasis were determined by multivariable logistic regression and used to develop a nomogram in a randomly selected subset that was validated in the remainder. Overall survival was compared between Eastern and Western countries. RESULTS: Lymph node metastasis was found in 701 of 3166 (22.1%) Eastern and 153 of 560 (27.3%) Western patients. Independent predictors of lymph node metastasis were female sex, tumor size, distal stomach location, lymphovascular invasion, and moderate or poor differentiation. Patients fulfilling the National Comprehensive Cancer Network guideline criteria, excluding the requirement that invasion not extend beyond the superficial submucosa, had a lymph node metastasis rate of 8.9% (53/594). Excluding moderately differentiated tumors lowered the rate to 3.4% (10/296). The nomogram's area under the curve was 0.690. Regardless of lymph node status, overall survival was better in Eastern patients. CONCLUSIONS: The lymph node metastasis rate was lowest in patients with well differentiated tumors that were ≤3 cm and lacked lymphovascular invasion. These criteria may be useful in decisions regarding endoscopic resection as definitive treatment for pT1b gastric cancer.

Distinct Differences in Gastroesophageal Junction and Gastric Adenocarcinoma in 2194 Patients: In Memory of Rebecca A. Carr, February 24, 1988-January 19, 2021.

OBJECTIVE: We sought to compare gastroesophageal junction (GEJ) cancer and gastric cancer (GC) and identify clinicopathological and oncological differences. SUMMARY BACKGROUND DATA: GEJ cancer and GC are frequently studied together. Although the treatment approach for each often differs, clinico-pathological and oncological differences between the 2 have not been fully evaluated. METHODS: We retrospectively identified patients with GEJ cancer or GC who underwent R0 resection at our center between January 2000 and December 2016. Clinicopathological characteristics, disease-specific survival (DSS), and site of first recurrence were compared. RESULTS: In total, 2194 patients were analyzed: 1060 (48.3%) with GEJ cancer and 1134 (51.7%) with GC. Patients with GEJ cancer were younger (64 vs 66 years; P < 0.001), more often received neoadjuvant treatment (70.9% vs 30.2%; P < 0.001), and had lower pathological T and N status. Five-year DSS was 62.2% in patients with GEJ cancer and 74.6% in patients with GC ( P < 0.001). After adjustment for clinicopathological factors, DSS remained worse in patients with GEJ cancer (hazard ratio, 1.78; 95% confidence interval, 1.40-2.26; P < 0.001). The cumulative incidence of recurrence was approximately 10% higher in patients with GEJ cancer ( P < 0.001). The site of first recurrence was more likely to be hematogenous in patients with GEJ cancer (60.1% vs 31.4%; P < 0.001) and peritoneal in patients with GC (52.9% vs 12.5%; P < 0.001). CONCLUSIONS: GEJ adenocarcinoma is more aggressive, with a higher incidence of recurrence and worse DSS, compared with gastric adenocarcinoma. Distinct differences between GEJ cancer and GC, especially in patterns of recurrence, may affect evaluation of optimal treatment strategies.

Fifty years of progress in surgical oncology: Melanoma.

This paper outlines the scientific and clinical advances in the treatment of melanoma over the past 50 years. Among the highlights of progress, the dominant themes include evidence-based reduction in the extent and morbidity of surgical procedures in patients with local or regional melanoma without compromising end results, and the introduction of effective systemic therapy, specifically targeted therapy matched to patients based on specific tumor mutations, and immune checkpoint blockade. Management of advanced disease has also changed dramatically, due to improved understanding of the genomic variability of the disease as well as continuing improvements in imaging.

Fifty years of progress in gastric cancer.

As with every human malignancy, the diagnosis, staging, and treatment of patients with gastric cancer have undergone enormous evidence-based change over the last 50 years, largely as a result of increasingly rapid developments in technology and science. Some of the changes in clinical practice have derived from prospective randomized controlled trials (RCTs), whereas others have come from study of meticulously maintained prospective databases, which define the disease's natural history over time, and occasionally from in-depth analysis of a single patient with an unexpectedly good or poor outcome. Herein we summarize the more important changes in gastric cancer management and the data supporting those changes.

Outcomes and Molecular Features of Brain Metastasis in Gastroesophageal Adenocarcinoma.

Importance: Brain metastasis (BrM) in gastroesophageal adenocarcinoma (GEA) is a rare and poorly understood phenomenon associated with poor prognosis. Objectives: To examine the clinical and genomic features of patients with BrM from GEA and evaluate factors associated with survival. Design, Setting, and Participants: In this single-institution retrospective cohort study, 68 patients with BrM from GEA diagnosed between January 1, 2008, and December 31, 2020, were identified via review of billing codes and imaging reports from the electronic medical record with follow-up through November 3, 2021. Genomic data were derived from the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets clinical sequencing platform. Exposures: Treatment with BrM resection and/or radiotherapy. Main Outcomes and Measures: Overall survival after BrM diagnosis. Results: Sixty-eight patients (median age at diagnosis, 57.4 years [IQR, 49.8-66.4 years]; 59 [86.8%] male; 55 [85.9%] White) participated in the study. A total of 57 (83.8%) had primary tumors in the distal esophagus or gastroesophageal junction. Median time from initial diagnosis to BrM diagnosis was 16.9 months (IQR, 8.5-27.7 months). Median survival from BrM diagnosis was 8.7 months (95% CI, 5.5-11.5 months). Overall survival was 35% (95% CI, 25%-48%) at 1 year and 24% (95% CI, 16%-37%) at 2 years. In a multivariable analysis, an Eastern Cooperative Oncology Group performance status of 2 or greater (hazard ratio [HR], 4.66; 95% CI, 1.47-14.70; P = .009) and lack of surgical or radiotherapeutic intervention (HR, 7.71; 95% CI, 2.01-29.60; P = .003) were associated with increased risk of all-cause mortality, whereas 3 or more extracranial sites of disease (HR, 1.85; 95% CI, 0.64-5.29; P = .25) and 4 or more BrMs (HR, 2.15; 95% CI, 0.93-4.98; P = .07) were not statistically significant. A total of 31 patients (45.6%) had ERBB2 (formerly HER2 or HER2/neu)-positive tumors, and alterations in ERBB2 were enriched in BrM relative to primary tumors (8 [47.1%] vs 7 [20.6%], P = .05), as were alterations in PTPRT (7 [41.2%] vs 4 [11.8%], P = .03). Conclusions and Relevance: This study suggests that that a notable proportion of patients with BrM from GEA achieve survival exceeding 1 and 2 years from BrM diagnosis, a more favorable prognosis than previously reported. Good performance status and treatment with combination surgery and radiotherapy were associated with the best outcomes. ERBB2 positivity and amplification as well as PTPRT alterations were enriched in BrM tissue compared with primary tumors; therefore, further study should be pursued to identify whether these variables represent genomic risk factors for BrM development.

A Novel Microbiome Signature in Gastric Cancer: A Two Independent Cohort Retrospective Analysis.

OBJECTIVE: The microbiome is hypothesized to have a significant impact on cancer development. In gastric cancer (GC), Helicobacter pylori is an established class I carcinogen. However, additional organisms in the intratumoral microbiome play an important role in GC pathogenesis and progression. In this study, we characterize the full spectrum of the microbes present within GC and identify distinctions among molecular subtypes. METHODS: A microbiome bioinformatics pipeline that is generalizable across multiple next-generation sequencing platforms was developed. Microbial profiles for alpha diversity and enrichment were generated for 2 large, demographically distinct cohorts: (1) internal Memorial Sloan Kettering Cancer Center (MSKCC) and (2) The Cancer Genome Atlas (TCGA) cohorts. A total of 520 GC samples were compared with select tumor-adjacent nonmalignant samples. Microbiome differences among the GC molecular subtypes were identified. RESULTS: Compared with nonmalignant samples, GC had significantly decreased microbial diversity in both MSKCC and TCGA cohorts ( P <0.05). Helicobacter , Lactobacillus , Streptococcus , Prevotella , and Bacteroides were significantly more enriched in GC samples when compared with nonmalignant tissue ( P <0.05). Microsatellite instability-high GC had distinct microbial enrichment compared with other GC molecular subtypes. CONCLUSION: Distinct patterns of microbial diversity and species enrichment were identified in patients with GC. Given the varied spectrum of disease progression and treatment response of GC, understanding unique microbial signatures will provide the landscape to explore key microbial targets for therapy.

Validation of the Memorial Sloan Kettering Gastric Cancer Post-Resection Survival Nomogram: Does It Stand the Test of Time?

BACKGROUND: The Memorial Sloan Kettering Cancer Center (MSK) nomogram combined both gastroesophageal junction (GEJ) and gastric cancer patients and was created in an era from patients who generally did not receive neoadjuvant chemotherapy. We sought to reevaluate the MSK nomogram in the era of multidisciplinary treatment for GEJ and gastric cancer. STUDY DESIGN: Using data on patients who underwent R0 resection for GEJ or gastric cancer between 2002 and 2016, the C-index of prediction for disease-specific survival (DSS) was compared between the MSK nomogram and the American Joint Committee on Cancer (AJCC) 8th edition staging system after segregating patients by tumor location (GEJ or gastric cancer) and neoadjuvant treatment. A new nomogram was created for the group for which both systems poorly predicted prognosis. RESULTS: During the study period, 886 patients (645 gastric and 241 GEJ cancer) underwent up-front surgery, and 999 patients (323 gastric and 676 GEJ) received neoadjuvant treatment. Compared with the AJCC staging system, the MSK nomogram demonstrated a comparable C-index in gastric cancer patients undergoing up-front surgery (0.786 vs 0.753) and a better C-index in gastric cancer patients receiving neoadjuvant treatment (0.796 vs 0.698). In GEJ cancer patients receiving neoadjuvant chemotherapy, neither the MSK nomogram nor the AJCC staging system performed well (C-indices 0.647 and 0.646). A new GEJ nomogram was created based on multivariable Cox regression analysis and was validated with a C-index of 0.718. CONCLUSIONS: The MSK gastric cancer nomogram's predictive accuracy remains high. We developed a new GEJ nomogram that can effectively predict DSS in patients receiving neoadjuvant treatment.

Phase II Trial Evaluating Esophageal Anastomotic Reinforcement with a Biologic, Degradable, Extracellular Matrix after Total Gastrectomy and Esophagectomy.

BACKGROUND: A biologic, degradable extracellular matrix (ECM) has been shown to support esophageal tissue remodeling, which could reduce the risk of anastomotic leak following total gastrectomy and esophagectomy. We evaluated the safety and efficacy of reinforcing the anastomosis with ECM in reducing anastomotic leak as compared to a matched cohort. STUDY DESIGN: In this single-center, nonrandomized phase II trial, gastric or esophageal adenocarcinoma patients undergoing total gastrectomy or esophagectomy were recruited from November 2013 through December 2018. ECM was surgically wrapped circumferentially around the anastomosis. Anastomotic leak was assessed clinically and by contrast study and defined as clinically significant if requiring invasive treatment (grade 3 or higher). Anastomotic stenosis, other adverse events, symptoms, and dysphagia score were collected by standardized forms at regular follow-up visits at approximately postoperative days (POD) 21 and 90. Patients receiving ECM were compared to a cohort matched for surgery type and age. RESULTS: ECM placement was not feasible in 9 of 75 patients (12%), resulting in 66 patients receiving ECM. Total gastrectomy was performed in 50 patients (76%) and esophagectomy in 16 (24%). Clinically significant anastomotic leak was diagnosed in 6 of 66 patients (9.1%) (3/50 [6.0%] after gastrectomy, 3/16 [18.8%] after esophagectomy); this rate did not differ from that in the matched cohort (p = 0.57). Stenosis requiring invasive treatment occurred in 8 patients (12.5%), and 10 patients (15.6%) reported not being able to eat a normal diet at POD 90. No adverse events related to ECM were reported. CONCLUSIONS: Esophageal anastomotic reinforcement after total gastrectomy or esophagectomy with a biologic, degradable ECM was mostly feasible and safe, but was not associated with a statistically significant decrease in anastomotic leak.

Defining and Targeting Esophagogastric Cancer Genomic Subsets With Patient-Derived Xenografts.

PURPOSE: Comprehensive genomic profiling has defined key oncogenic drivers and distinct molecular subtypes in esophagogastric cancer; however, the number of clinically actionable alterations remains limited. To establish preclinical models for testing genomically driven therapeutic strategies, we generated and characterized a large collection of esophagogastric cancer patient-derived xenografts (PDXs). MATERIALS AND METHODS: We established a biobank of 98 esophagogastric cancer PDX models derived from primary tumors and metastases. Clinicopathologic features of each PDX and the corresponding patient sample were annotated, including stage at diagnosis, treatment history, histology, and biomarker profile. To identify oncogenic DNA alterations, we analyzed and compared targeted sequencing performed on PDX and parent tumor pairs. We conducted xenotrials in genomically defined models with oncogenic drivers. RESULTS: From April 2010 to June 2019, we implanted 276 patient tumors, of which 98 successfully engrafted (35.5%). This collection is enriched for PDXs derived from patients with human epidermal growth factor receptor 2-positive esophagogastric adenocarcinoma (62 models, 63%), the majority of which were refractory to standard therapies including trastuzumab. Factors positively correlating with engraftment included advanced stage, metastatic origin, intestinal-type histology, and human epidermal growth factor receptor 2-positivity. Mutations in TP53 and alterations in receptor tyrosine kinases (ERBB2 and EGFR), RAS/PI3K pathway genes, cell-cycle mediators (CDKN2A and CCNE1), and CDH1 were the predominant oncogenic drivers, recapitulating clinical tumor sequencing. We observed antitumor activity with rational combination strategies in models established from treatment-refractory disease. CONCLUSION: The Memorial Sloan Kettering Cancer Center PDX collection recapitulates the heterogeneity of esophagogastric cancer and is a powerful resource to investigate mechanisms driving tumor progression, identify predictive biomarkers, and develop therapeutic strategies for molecularly defined subsets of esophagogastric cancer.

Prevalence of Germline Alterations on Targeted Tumor-Normal Sequencing of Esophagogastric Cancer.

Importance: Among patients with esophagogastric cancers, only individuals who present with known features of heritable cancer syndromes are referred for genetic testing. Broader testing might identify additional patients with germline alterations. Objectives: To examine the prevalence of likely pathogenic or pathogenic (LP/P) germline alterations among patients with esophagogastric cancer and to assess associations between germline variant prevalence and demographic and clinicopathologic features. Design, Setting, and Participants: This cross-sectional study was performed at a tertiary referral cancer center from January 1, 2014, to December 31, 2019, in 515 patients with esophagogastric cancer who consented to tumor and blood sequencing. Main Outcomes and Measures: Presence or absence of LP/P variants in up to 88 genes associated with cancer predisposition syndromes as identified by targeted sequencing (Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets). Results: Among 515 patients (median age, 59 years; range, 18-87 years; 368 [71.5%] male; 398 [77.3%] White), 243 (47.2%) had gastric cancer, 111 (21.6%) had gastroesophageal junction (GEJ) cancer, and 161 (31.3%) had esophageal cancer. A total of 48 patients with gastric cancer (19.8%), 16 (14.4%) with GEJ cancer, and 17 (10.6%) with esophageal cancer had LP/P germline variants. The number of LP/P variants in high- and moderate-penetrance genes was significantly higher in patients with gastric cancer (29 [11.9%]; 95% CI, 8.1%-16.7%) vs patients with esophageal cancer (8 [5.0%]; 95% CI, 2.2%-9.6%; P = .03), and the difference was greater for high-penetrance germline alterations in patients with gastric cancer (25 [10.3%]; 95% CI, 6.8%-14.8%) vs in patients with esophageal cancer (3 [1.9%]; 95% CI, 0.38%-5.3%; P = .001). The most frequent high- and moderate-penetrance LP/P alterations were in BRCA1/2 (14 [2.7%]), ATM (11 [2.1%]), CDH1 (6 [1.2%]), and MSH2 (4 [0.8%]). Those with early-onset disease (≤50 years of age at diagnosis) were more likely to harbor an LP/P germline variant (29 [21.0%]; 95% CI, 14.5%-28.8%) vs those with late-onset disease (patients >50 years of age at diagnosis) (52 [13.8%]; 95% CI, 10.5%-17.7%; P = .046). ATM LP/P variants occurred in 6 patients (4.3%; 95% CI, 1.6%-9.1%) with early-onset esophagogastric cancer vs 5 (1.3%; 95% CI, 0.4%-3.1%; P = .08) of those with late-onset esophagogastric cancer. Conclusions and Relevance: These results suggest that pathogenic germline variants are enriched in gastric and early-onset esophagogastric cancer and that germline testing should be considered in these populations. The role of ATM alterations in esophagogastric cancer risk warrants further investigation.