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Genomic profiling can provide prognostic and predictive information to guide clinical care. Biomarkers that reliably predict patient response to chemotherapy and immune checkpoint inhibition in gastric cancer are lacking. In this retrospective analysis, we use our machine learning algorithm NTriPath to identify a gastric-cancer specific 32-gene signature. Using unsupervised clustering on expression levels of these 32 genes in tumors from 567 patients, we identify four molecular subtypes that are prognostic for survival. We then built a support vector machine with linear kernel to generate a risk score that is prognostic for five-year overall survival and validate the risk score using three independent datasets. We also find that the molecular subtypes predict response to adjuvant 5-fluorouracil and platinum therapy after gastrectomy and to immune checkpoint inhibitors in patients with metastatic or recurrent disease. In sum, we show that the 32-gene signature is a promising prognostic and predictive biomarker to guide the clinical care of gastric cancer patients and should be validated using large patient cohorts in a prospective manner. The ability to predict the survival and response to treatment of cancer patients may improve patient care. Here, the authors generate a 32 gene signature that can predict the survival and response to treatment in gastric cancer patients.

BackgroundMinimally invasive pancreaticoduodenectomy (MIPD) is being performed with increasing frequency for pancreatic cancer, but the most oncologically efficacious surgical platform, whether robotic or laparoscopic, is yet to be determined. Currently, there are no national studies comparing the oncological outcomes between robotic (RPD) and laparoscopic (LPD) pancreaticoduodenectomy.MethodsThis was a retrospective study using the National Cancer Database between 2010 and 2013. We compared the perioperative, pathological, and mid-term oncological outcomes between RPD and LPD.ResultsThere were 1623 MIPD cases, of which 90% were LPD and 10% were RPD. Most LPD (63%) and RPD (51%) cases were performed at institutions with a volume of ≤ 5 MIPDs per year. There were no differences in patient- and tumor-related factors between the groups. The majority of treated tumors were adenocarcinoma (90.1% for RPD and 89.1% for LPD). RPDs were more likely to be performed at academic centers (89.1%) compared to LPDs (68.1%, P < 0.001) and at higher-volume centers (median MIPD/year of 4.7 for RPD vs 3.6 for LPD, P < 0.001). There was no difference in the median number of examined lymph nodes, margin status, median length of stay, 90-day mortality, or 30-day readmission between groups. There was no difference in median overall survival for pancreatic adenocarcinoma between LPD (20.7 months) and RPD (22.7 months; log-rank P = 0.445). The 1- and 3-year overall survival rates were 74 and 31% for LPD and 71 and 33% for RPD.ConclusionIn this national cohort of patients, LPD and RPD were associated with equivalent perioperative, pathological, and mid-term oncological outcomes.

BackgroundPerformance of technically complex surgery at high-volume (HV) centers is associated with improved outcomes.ObjectiveThe aim of this study was to assess whether hospital gastrectomy volume is associated with surgical outcomes, and what threshold of case volume meaningfully impacts surgical outcomes.MethodsWe conducted a retrospective review of adult NCDB patients with gastric adenocarcinoma undergoing gastrectomy between 2004 and 2015. A multivariable Cox proportional hazards model with restricted cubic splines was used to examine the association of annual hospital gastrectomy volume and overall survival. Bootstrap simulation was used to estimate the cut-point corresponding to maximum change in log hazard ratio. Hospitals were divided into HV (≥ 17 cases/year) and low-volume (LV; < 17 cases/year) groups. We examined the relationship between volume groups and adequate nodal examination, R0 resection, unplanned readmission, and 30- and 90-day mortality.ResultsOur cohort consisted of 29,559 patients (7.8% treated at an HV center). Treatment at an HV center was associated with an increased likelihood of adequate nodal examination [odds ratio (OR) 2.12, 95% confidence interval (CI) 1.94–2.32] and R0 resection among patients with cardia tumors (OR 1.42, 95% CI 1.07–1.88). Patients treated at HV centers had decreased 30- and 90-day postoperative mortality, which was more pronounced in those undergoing total gastrectomy.ConclusionsTreatment at an HV gastrectomy center is associated with improved surgical outcomes. Our study identified 17 cases/year as a clinically meaningful distinction between HV and LV centers. This definition of an HV center should be considered when evaluating regionalization of gastric cancer care to improve patient outcomes.

Background An increasing body of literature is supporting the safety of minimally invasive pancreaticoduodenectomy compared to open pancreaticoduodenectomy, but there are limited comparative studies between laparoscopic and robotic pancreaticoduodenectomy. The aim of this study was to compare the rate of postoperative 30-day overall complications between laparoscopic and robotic pancreaticoduodenectomy. Methods Patients who underwent laparoscopic and robotic pancreaticoduodenectomy were abstracted from the 2014–2015 pancreas-targeted American College of Surgeons National Surgical Quality Improvement Program. A multivariable logistic regression model was developed to determine if the type of minimally invasive approach was associated with 30-day overall complications. Results We identified 428 minimally invasive pancreaticoduodenectomy cases, of which 235 (55%) were performed laparoscopically and 193 (45%) robotically. Patients who underwent the robotic approach were more likely to be white compared to those who underwent the laparoscopic approach and were less likely to have pulmonary disease, undergo preoperative radiotherapy, and have vascular and multivisceral resection. On multivariable analysis, we found that the type of minimally invasive approach, whether laparoscopic or robotic, was not associated with overall complications. The predictors of 30-day overall complications were higher body mass index (odds ratio [OR], 1.05; 95% confidence interval [CI], 1.02–1.09), vascular resection (OR, 2.10; 95% CI, 1.23–3.58), and longer operative time (OR, 1.002; 95% CI, 1.001–1.004). Conclusions Robotic pancreaticoduodenectomy was associated with a similar 30-day overall complication rate to laparoscopic pancreaticoduodenectomy. Further studies are needed to corroborate these findings and to establish the best approach to perform this complex operation.

Background Data on the risk factors for conversion during minimally invasive distal pancreatectomy (MIDP) and its effect on postoperative outcomes are limited. Methods This retrospective study used the pancreas-targeted American College of Surgeons National Surgical Quality Improvement Program database to compare MIDP requiring unplanned conversion with completed MIDP and open distal pancreatectomy (ODP). Results Of the 2926 cases identified in this study, 48.8% had ODP, 42.8% had MIDP, and 7.9% had conversion to MIDP. The conversion rate was 15.3% overall, 17.3% for laparoscopic surgery, and 8.5% for robotic surgery ( p  < 0.001). The risk factors associated with conversion were higher body mass index (BMI), low preoperative albumin level, a current smoking habit, and malignant T3/T4 disease or chronic pancreatitis compared with benign tumor smaller than 5 cm. A robotic approach was associated with a lower adjusted conversion rate than laparoscopy (odds ratio [OR] 0.32; 95% confidence interval [CI] 0.19–0.52). After adjustment, conversion was associated with a higher overall complication rate than MIDP (OR 1.89; 95% CI 1.35–2.66) or ODP (OR 1.41; 95% CI 1.00–1.98). Conclusions Chronic pancreatitis, large malignant tumors, higher BMI, lower serum albumin, and a current smoking habit were shown to be independent risk factors for conversion during MIDP. A robotic approach was associated with a lower conversion rate than laparoscopic MIDP. Conversion of MIDP was associated with a higher overall complication rate than completed MIDP or ODP. Adequate patient selection for MIDP may prevent conversion and associated increased morbidity.

Background Lenvatinib is a multitargeted tyrosine kinase inhibitor that is being tested in combination with immune checkpoint inhibitors to treat advanced gastric cancer; however, little data exists regarding the efficacy of lenvatinib monotherapy. Patient-derived xenografts (PDX) are established by engrafting human tumors into immunodeficient mice. The generation of PDXs may be hampered by growth of lymphomas. In this study, we compared the use of mice with different degrees of immunodeficiency to establish PDXs from a diverse cohort of Western gastric cancer patients. We then tested the efficacy of lenvatinib in this system. Methods PDXs were established by implanting gastric cancer tissue into NOD.Cg- Prkdc scid Il2rg tm1Wjl /SzJ (NSG) or Foxn1 nu (nude) mice. Tumors from multiple passages from each PDX line were compared histologically and transcriptomically. PDX-bearing mice were randomized to receive the drug delivery vehicle or lenvatinib. After 21 days, the percent tumor volume change (%Δv tumor ) was calculated. Results 23 PDX models were established from Black, non-Hispanic White, Hispanic, and Asian gastric cancer patients. The engraftment rate was 17% (23/139). Tumors implanted into NSG (16%; 18/115) and nude (21%; 5/24) mice had a similar engraftment rate. The rate of lymphoma formation in nude mice (0%; 0/24) was lower than in NSG mice (20%; 23/115; p  < 0.05). PDXs derived using both strains maintained histologic and gene expression profiles across passages. Lenvatinib treatment (mean %Δv tumor : -33%) significantly reduced tumor growth as compared to vehicle treatment (mean %Δv tumor : 190%; p  < 0.0001). Conclusions Nude mice are a superior platform than NSG mice for generating PDXs from gastric cancer patients. Lenvatinib showed promising antitumor activity in PDXs established from a diverse Western patient population and warrants further investigation in gastric cancer.

Determining tumor microsatellite status has significant clinical value because tumors that are microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) respond well to immune checkpoint inhibitors (ICIs) and oftentimes not to chemotherapeutics. We propose MSI-SEER, a deep Gaussian process-based Bayesian model that analyzes H&E whole-slide images in weakly-supervised-learning to predict microsatellite status in gastric and colorectal cancers. We performed extensive validation using multiple large datasets comprised of patients from diverse racial backgrounds. MSI-SEER achieved state-of-the-art performance with MSI prediction by integrating uncertainty prediction. We achieved high accuracy for predicting ICI responsiveness by combining tumor MSI status with stroma-to-tumor ratio. Finally, MSI-SEER’s tile-level predictions revealed novel insights into the role of spatial distribution of MSI-H regions in the tumor microenvironment and ICI response.

Background Current preoperative risk stratification modalities for pancreatic ductal adenocarcinoma (PDA) patients are inadequate. Elevated serum matrix metalloproteinase 7 (MMP7) is associated with metastatic PDA. We evaluated preoperative MMP7 level as a prognostic marker in patients with resectable PDA. Methods From a prospectively maintained database, we identified PDA patients who underwent operation with curative intent from 2004 to 2008 and had serum collected preoperatively. MMP7 was measured by enzyme-linked immunosorbent assay. Patients were defined as having advanced disease if they were found to be unresectable at the time of operation or had nodal involvement on final pathology. Results Preoperative serum samples were available for 134 patients. Using a cutoff of 13.5 ng/mL, MMP7 was highly predictive for advanced disease. For patients who underwent R0 resection, MMP7 > 13.5 ng/mL was strongly associated with N1 status, T3/T4 stage, moderate/poor differentiation, and perineural invasion. The median recurrence-free survival was 5.0 months in patients with MMP7 > 13.5 ng/mL versus 9.9 months for patients with lower values ( P  = 0.004). Conclusions Very elevated serum MMP7 was highly predictive of unresectable disease and nodal involvement despite favorable preoperative cross-sectional imaging. MMP7 should be further evaluated as a biomarker to risk-stratify PDA patients prior to operation.