Deep Learning Histology for Prediction of Lymph Node Metastases and Tumor Regression after Neoadjuvant FLOT Therapy of Gastroesophageal Adenocarcinoma.

BACKGROUND: The aim of this study was to establish a deep learning prediction model for neoadjuvant FLOT chemotherapy response. The neural network utilized clinical data and visual information from whole-slide images (WSIs) of therapy-naïve gastroesophageal cancer biopsies. METHODS: This study included 78 patients from the University Hospital of Cologne and 59 patients from the University Hospital of Heidelberg used as external validation. RESULTS: After surgical resection, 33 patients from Cologne (42.3%) were ypN0 and 45 patients (57.7%) were ypN+, while 23 patients from Heidelberg (39.0%) were ypN0 and 36 patients (61.0%) were ypN+ (p = 0.695). The neural network had an accuracy of 92.1% to predict lymph node metastasis and the area under the curve (AUC) was 0.726. A total of 43 patients from Cologne (55.1%) had less than 50% residual vital tumor (RVT) compared to 34 patients from Heidelberg (57.6%, p = 0.955). The model was able to predict tumor regression with an error of ±14.1% and an AUC of 0.648. CONCLUSIONS: This study demonstrates that visual features extracted by deep learning from therapy-naïve biopsies of gastroesophageal adenocarcinomas correlate with positive lymph nodes and tumor regression. The results will be confirmed in prospective studies to achieve early allocation of patients to the most promising treatment.

Prognostic Relevance of the Proximal Resection Margin Distance in Distal Gastrectomy for Gastric Adenocarcinoma.

BACKGROUND: The risk for recurrence in patients with distal gastric cancer can be reduced by surgical radicality. However, dispute exists about the value of the proposed minimum proximal margin distance (PMD). Here, we assess the prognostic value of the safety distance between the proximal resection margin and the tumor. PATIENTS AND METHODS: This is a single-center cohort study of patients undergoing distal gastrectomy for gastric adenocarcinoma (2001-2021). Cohorts were defined by adequacy of the PMD according to the European Society for Medical Oncology (ESMO) guidelines (≥ 5 cm for intestinal and ≥ 8 cm for diffuse Laurén's subtypes). Overall survival (OS) and time to progression (TTP) were assessed by log-rank and multivariable Cox-regression analyses. RESULTS: Of 176 patients, 70 (39.8%) had a sufficient PMD. An adequate PMD was associated with cancer of the intestinal subtype (67% vs. 45%, p = 0.010). Estimated 5-year survival was 63% [95% confidence interval (CI) 51-78] and 62% (95% CI 53-73) for adequate and inadequate PMD, respectively. Overall, an adequate PMD was not prognostic for OS (HR 0.81, 95% CI 0.48-1.38) in the multivariable analysis. However, in patients with diffuse subtype, an adequate PMD was associated with improved oncological outcomes (median OS not reached versus 131 months, p = 0.038, median TTP not reached versus 88.0 months, p = 0.003). CONCLUSION: Patients with diffuse gastric cancer are at greater risk to undergo resection with an inadequate PMD, which in those patients is associated with worse oncological outcomes. For the intestinal subtype, there was no prognostic association with PMD, indicating that a distal gastrectomy with partial preservation of the gastric function may also be feasible in the setting where an extensive PMD is not achievable.

Isthmus progenitor cells contribute to homeostatic cellular turnover and support regeneration following intestinal injury.

The currently accepted intestinal epithelial cell organization model proposes that Lgr5+ crypt-base columnar (CBC) cells represent the sole intestinal stem cell (ISC) compartment. However, previous studies have indicated that Lgr5+ cells are dispensable for intestinal regeneration, leading to two major hypotheses: one favoring the presence of a quiescent reserve ISC and the other calling for differentiated cell plasticity. To investigate these possibilities, we studied crypt epithelial cells in an unbiased fashion via high-resolution single-cell profiling. These studies, combined with in vivo lineage tracing, show that Lgr5 is not a specific ISC marker and that stemness potential exists beyond the crypt base and resides in the isthmus region, where undifferentiated cells participate in intestinal homeostasis and regeneration following irradiation (IR) injury. Our results provide an alternative model of intestinal epithelial cell organization, suggesting that stemness potential is not restricted to CBC cells, and neither de-differentiation nor reserve ISC are drivers of intestinal regeneration.

Is neoadjuvant chemotherapy followed by surgery the appropriate treatment for esophagogastric signet ring cell carcinomas? A systematic review and meta-analysis.

Background: The impact of neoadjuvant chemotherapy (nCTX) on survival and tumor response in patients with esophagogastric signet ring cell carcinoma (SRCC) is still controversial. Methods: Two independent reviewers performed a systematic literature search in Medline, CENTRAL, and Web of Science including prospective and retrospective two-arm non-randomized and randomized controlled studies (RCTs). Data was extracted on overall survival (OS) and tumor regression in resected esophagogastric SRCC patients with or without nCTX. Survival data was analyzed using published hazard ratios (HR) if available or determined it from other survival data or survival curves. OS and histopathological response rates by type of tumor (SRCC vs. non-SRCC) were also investigated. Results: Out of 559 studies, ten (1 RCT, 9 non-RCTs) were included in this meta-analysis (PROSPERO CRD42022298743) investigating 3,653 patients in total. The four studies investigating survival in SRCC patients treated with nCTX + surgery vs. surgery alone showed no survival benefit for neither intervention, but heterogeneity was considerable (HR, 1.01; 95% CI, 0.61-1.67; p = 0.98; I2 = 89%). In patients treated by nCTX + surgery SRCC patients showed worse survival (HR, 1.45; 95% CI, 1.21-1.74; p < 0.01) and lower rate of major histopathological response than non-SRCC patients (OR, 2.47; 95% CI, 1.78-3.44; p < 0.01). Conclusion: The current meta-analysis could not demonstrate beneficial effects of nCTX for SRCC patients. Histopathological response to and survival benefits of non-taxane-based nCTX seem to be lower in comparison to non-SRC esophagogastric cancer. However, certainty of evidence is low due to the scarcity of high-quality trials. Further research is necessary to determine optimal treatment for SRCC patients. Systematic Review Registration: https://www.crd.york.ac.uk/, PROSPERO (CRD42022298743).

Inhibition of the Renin-Angiotensin System Improves Response to Neoadjuvant Therapy in Patients With Liver Metastasis of Colorectal Cancers.

INTRODUCTION: Renin-angiotensin-aldosterone system inhibitors (RAAS-I) have been shown to prolong overall survival in patients with liver metastasized colorectal cancer in combination with antiangiogenic treatment. The effects of RAAS-I combined with neoadjuvant chemotherapy on colorectal cancer liver metastasis remain unexplored. We aimed to study the response of patients undergoing liver resection to RAAS-I in combination with neoadjuvant therapy to elucidate their potential benefits. METHODS: Between February 2005 and May 2012, 62 patients fulfilled the inclusion criteria for distant metastasis (cM1) and comparable computed tomography or magnetic resonance tomography scans in the Picture Archiving Communication System of our center before and after neoadjuvant chemotherapy. Follow-up data and clinicopathological characteristics were collected from a prospective database and retrospectively investigated. The chemotherapeutic response to liver metastasis was evaluated according to the Response Evaluation Criteria in Solid Tumors criteria 1.1. RESULTS: Comparing the average reduction of measured lesions, a significant response to chemotherapy was detected in the patients receiving RAAS-I (n = 24) compared to those who did not (n = 38) (P = 0.031). Interestingly, the effect was more distinctive when the size reduction was compared between high responses with more than 50% size reduction of all measured lesions (P = 0.011). In the subgroup analysis of patients receiving bevacizumab treatment, high responses to chemotherapy were observed only in the RAAS-I cohort (28.6% versus 0%, P = 0.022). CONCLUSIONS: For neoadjuvantly treated patients, concomitant antihypertensive treatment with RAAS-I showed a higher total size reduction of liver metastasis as a sign of treatment response, especially in combination with antiangiogenic treatment with bevacizumab.

Targeting the receptor tyrosine kinase MerTK shows therapeutic value in gastric adenocarcinoma.

BACKGROUND: Despite multiple therapeutic modalities, the overall survival of patients with gastric adenocarcinoma remains poor, especially for advanced tumor stages. Although the tyrosine kinase MerTK has shown therapeutic relevance in several tumor entities, its potential effects in gastric adenocarcinoma have not yet been sufficiently characterized. METHODS: MerTK expression and its influence on patient survival were evaluated by immunohistochemistry in a cohort of 140 patients with gastric adenocarcinoma. CRISPR/Cas9 knockout and siRNA knockdown of MerTK in the gastric cancer cell lines SNU1, SNU5, and MKN45 was used to analyze protein expression, growth, migration, and invasion properties in vitro and in a murine xenograft model. MerTK was pharmacologically targeted with the small molecule inhibitor UNC2025 in vitro and in vivo. RESULTS: In patients, high MerTK expression was associated with decreased overall survival (OS) and lymph node metastasis especially in patients without neoadjuvant therapy (p < 0.05). Knockout and knockdown of MerTK reduced cell proliferation and migration both in vitro and in vivo. UNC2025, a small-molecule inhibitor of MerTK, exhibited a significant therapeutic response in vitro and in vivo. Additionally, MerTK expression attenuated the response to neoadjuvant treatment, and its inhibition sensitized tumor cells to 5-Fluorouracil (5-FU)-based chemotherapy in vitro. CONCLUSIONS: Our findings demonstrate the potential value of MerTK as a prognostic biomarker for gastric adenocarcinoma. Targeting MerTK may become a new treatment option, especially for patients with advanced tumors, and may overcome resistance to established chemotherapies.

[Evidence for Minimal Invasive Oesophageal Resection]. / Evidenz für die minimalinvasive Ösophagusresektion.

In the course of the last 20 years, minimally invasive therapy has become much more important in all areas. In particular, surgical procedures have been established in oncological surgery, even without generating the necessary evidence to assure that the quality is equal to that achieved with open procedures. For this purpose, it has only been in recent years that appropriate randomised controlled studies followed by meta-analyses have been carried out. In this article, we summarise the evidence for minimally invasive resection of the oesophagus and review current literature for each procedure.

Age-dependent benefit of neoadjuvant treatment in adenocarcinoma of the esophagus and gastroesophageal junction: a multicenter retrospective observational study of young versus old patients.

OBJECTIVES: The objective was to provide evidence for age-dependent use of neoadjuvant treatment by clinical comparisons of young (lower quartile, <56.6 years) versus old (upper quartile, >71.3 years) patients with esophageal and esophagogastric-junction adenocarcinoma. BACKGROUND: Neoadjuvant treatment is the standard of care for locally advanced and node-positive EAC. However, the effect of age on oncological outcomes is disputable as they are underrepresented in treatment defining randomized controlled trials. METHODS: Patients with EAC undergoing esophagectomy between 2001 and 2022 were retrospectively analyzed from three centers. Patients having distant metastases or clinical UICC-stage I were excluded. Cox proportional hazards regression was used to identify the variables associated with survival benefit. RESULTS: Neoadjuvant treatment was administered to 185/248 (74.2%) young and 151 out of 248 (60.9%) elderly patients ( P =0.001). Young age was associated with a significant overall survival (OS) benefit (median OS: 85.6 vs. 29.9 months, hazard ratio 0.62, 95% CI: 0.42-0.92) after neoadjuvant treatment versus surgery alone. In contrast, elderly patients did only experience a survival benefit equaling the length of neoadjuvant treatment itself (median OS: neoadjuvant 32.8 vs. surgery alone 29.3 months, hazard ratio 0.89, 95% CI: 0.63-1.27). Despite the clear difference in median OS benefit, histopathological regression was similar ((Mandard-TRG-1/2: young 30.7 vs. old 36.4%, P= 0.286). More elderly patients had a dose reduction or termination of neoadjuvant treatment (12.4 vs. 40.4%, P <0.001). CONCLUSION: Old patients benefit less from neoadjuvant treatment compared to younger patients in terms of gain in OS. Since they also experience more side effects requiring dose reduction, upfront surgery should be considered as the primary treatment option in elderly patients.

Pattern and time point of relapse in locally advanced esophagogastric adenocarcinoma after multimodal treatment: implications for a useful structured follow-up.

PURPOSE: Despite improvements in multimodal treatment of locally advanced esophagogastric adenocarcinoma, the majority of patients still relapses. The impact of structured follow-up for early detection of recurrence is unclear and controversially discussed. METHODS: Patients with locally advanced esophagogastric adenocarcinoma having received neoadjuvant/perioperative chemotherapy followed by tumor resection between 2009 and 2021, underwent a structured follow-up including three-monthly imaging during the first 2 years, followed by semiannual and annual examinations in year 3-4 and 5, respectively. Clinical outcome including pattern and time point of relapse was analyzed. RESULTS: Two hundred fifty-seven patients were included in this analysis. In 50.2% (n = 129) of patients, recurrent disease was diagnosed, with the majority (94.6%) relapsing within the first 2 years. The most common site of relapse were lymph node metastases followed by peritoneal carcinomatosis and hepatic and pulmonary metastases. 52.7% of patients presented with symptoms at the time of relapse. Cumulative risk and time point of relapse differed significantly between patient with a node-positive tumor (ypN+) after neoadjuvant treatment (high-risk group) and patients with node-negative primary tumor (ypN0) (low-risk group). High-risk patients had a significantly inferior disease-free survival (DFS) and overall survival (OS) with 11.1 and 29.0 months, respectively, whereas median DFS and OS were not reached for the low-risk group. CONCLUSIONS: The risk of relapse differs significantly between high- and low-risk patients. Only a part of relapses is associated with clinical symptoms. An individualized follow-up strategy is recommended for high- and low-risk patients considering the individual risk of relapse.

Impact of the Surgical Approach for Neoadjuvantly Treated Gastroesophageal Junction Type II Tumors: A Multinational, High-volume Center Retrospective Cohort Analysis.

OBJECTIVE: The aim of this study was to explore oncologic outcomes of transhiatal gastrectomy (THG) or transthoracic esophagectomy (TTE) for neoadjuvantly treated gastroesophageal junction (GEJ) Siewert type II adenocarcinomas, a multinational, high-volume center cohort analysis was undertaken. BACKGROUND: Neoadjuvant radiochemotherapy or perioperative chemotherapy (CTx) followed by surgery is the standard therapy for locally advanced GEJ. However, the optimal surgical approach for type II GEJ tumors remains unclear, as the decision is mainly based on individual experience and assessment of operative risk. METHODS: A retrospective analysis of 5 prospectively maintained databases was conducted. Between 2012 and 2021, 800 patients fulfilled inclusion criteria for type II GEJ tumors and neoadjuvant radiochemotherapy or CTx. The primary endpoint was median overall survival (mOS). Propensity score matching was performed to minimize selection bias. RESULTS: Patients undergoing THG (n=163, 20.4%) had higher American Society of Anesthesiologists (ASA) classification and cT stage ( P <0.001) than patients undergoing TTE (n=637, 79.6%). Neoadjuvant therapy was different as the THG group were mainly undergoing CTx (87.1%, P <0.001). The TTE group showed higher tumor regression ( P =0.009), lower ypT/ypM categories (both P <0.001), higher nodal yield ( P =0.009) and higher R0 resection rate ( P =0.001). The mOS after TTE was longer (78.0 vs 40.0 months, P =0.013). After propensity score matching a higher R0 resection rate ( P =0.004) and mOS benefit after TTE remained ( P =0.04). Subgroup analyses of patients without distant metastasis ( P =0.037) and patients only after neoadjuvant chemotherapy ( P =0.021) confirmed the survival benefit of TTE. TTE was an independent predictor of longer survival. CONCLUSION: Awaiting results of the randomized CARDIA trial, TTE should in high-volume centers be considered the preferred approach due to favorable oncologic outcomes.

Clinical Characteristics and Oncological Outcomes of Surgically Treated Early-Onset Gastric Adenocarcinoma - a Retrospective Cohort Study.

Introduction: The incidence of early-onset gastric adenocarcinoma (patients <50 years, EOGA) is rising. Tumors in younger patients are associated with prognostically unfavorable features. The impact of EOGA on patient survival, however, remains unclear. The aim of this study is to evaluate early-onset age as a prognostic factor compared to late-onset gastric adenocarcinoma (LOGA, >50years) in a surgical cohort and assess treatment options. Methods: We analyzed 738 patients (129 early-onset/609 late-onset) operated in curative intent from 2002 to 2021. Data was extracted from a prospectively managed database of an academic tertiary referral hospital. Differences in perioperative as well as oncological outcomes were calculated by chi-square test. Cox regression analysis was performed to assess disease-free survival (DFS) and overall survival (OS). Results: EOGA patients were more often treated with neoadjuvant therapy (62.8% vs. 43.7%, p<0.001) and extended surgical resections e.g. through additional resections (36.4% vs. 26.8%, p=0.027). EOGA was more often metastasized into regional lymph nodes (pN+ 67.4% vs. 55.3%, p=0.012) and to distant sites (pM+: 23.3% vs. 12.0%, p=0.001) and was more often poorly differentiated (G3/G4: 91.1% vs. 67.2%, p<0.001). There were no significant differences in overall complication rates (31.0% vs. 36.6%, p=0.227). Survival analysis showed shorter DFS (median DFS 25.6 months vs. not reached, p=0.006) but similar OS (median OS: 50.5 months vs. not reached, p=0.920) in EOGA compared to LOGA. Conclusions: This analysis confirmed that EOGA is associated with more aggressive tumor characteristics. Early-Onset was not a prognostic factor in the multivariate analysis. EOGA patients may be more capable to undergo intensive multimodal therapy including perioperative chemotherapy and extended surgery.

Dissecting the genetic heterogeneity of gastric cancer.

BACKGROUND: Gastric cancer (GC) is clinically heterogenous according to location (cardia/non-cardia) and histopathology (diffuse/intestinal). We aimed to characterize the genetic risk architecture of GC according to its subtypes. Another aim was to examine whether cardia GC and oesophageal adenocarcinoma (OAC) and its precursor lesion Barrett's oesophagus (BO), which are all located at the gastro-oesophageal junction (GOJ), share polygenic risk architecture. METHODS: We did a meta-analysis of ten European genome-wide association studies (GWAS) of GC and its subtypes. All patients had a histopathologically confirmed diagnosis of gastric adenocarcinoma. For the identification of risk genes among GWAS loci we did a transcriptome-wide association study (TWAS) and expression quantitative trait locus (eQTL) study from gastric corpus and antrum mucosa. To test whether cardia GC and OAC/BO share genetic aetiology we also used a European GWAS sample with OAC/BO. FINDINGS: Our GWAS consisting of 5816 patients and 10,999 controls highlights the genetic heterogeneity of GC according to its subtypes. We newly identified two and replicated five GC risk loci, all of them with subtype-specific association. The gastric transcriptome data consisting of 361 corpus and 342 antrum mucosa samples revealed that an upregulated expression of MUC1, ANKRD50, PTGER4, and PSCA are plausible GC-pathomechanisms at four GWAS loci. At another risk locus, we found that the blood-group 0 exerts protective effects for non-cardia and diffuse GC, while blood-group A increases risk for both GC subtypes. Furthermore, our GWAS on cardia GC and OAC/BO (10,279 patients, 16,527 controls) showed that both cancer entities share genetic aetiology at the polygenic level and identified two new risk loci on the single-marker level. INTERPRETATION: Our findings show that the pathophysiology of GC is genetically heterogenous according to location and histopathology. Moreover, our findings point to common molecular mechanisms underlying cardia GC and OAC/BO. FUNDING: German Research Foundation (DFG).

Outcome and prognostic factors in patients undergoing salvage therapy for recurrent esophagogastric cancer after multimodal treatment.

PURPOSE: Perioperative systemic treatment has significantly improved the outcome in locally advanced esophagogastric cancer. However, still the majority of patients relapse and die. Data on the optimal treatment after relapse are limited, and clinical and biological prognostic factors are lacking. METHODS: Patients with a relapse after neoadjuvant/perioperative treatment and surgery for esophagogastric cancer were analyzed using a prospective database. Applied treatment regimens, clinical prognostic factors and biomarkers were analyzed. RESULTS: Of 246 patients 119 relapsed. Among patients with a relapse event, those with an early relapse (< 6 months) had an inferior overall survival (OS 6.3 vs. 13.8 months, p < 0.001) after relapse than those with a late relapse (> 6 months). OS after relapse was longer in patients with a microsatellite-unstable (MSI) tumor. Systemic treatment was initiated in 87 patients (73% of relapsed pat.); among those OS from the start of first-line treatment was inferior in patients with an early relapse with 6.9 vs. 10.0 months (p = 0.037). In 27 patients (23% of relapsed pat.), local therapy (irradiation or surgical intervention) was performed due to oligometastatic relapse, resulting in a prolonged OS in comparison to patients without local therapy (median OS 35.2 months vs. 7.8 months, p < 0.0001). Multivariate analysis confirmed the prognostic benefit of the MSI status and a local intervention. CONCLUSION: Patients relapsing after multimodal treatment have a heterogeneous prognosis depending on the relapse-free interval (if systemic treatment applied), extent of metastatic disease as well as MSI status. The benefit of additional local intervention after relapse should be addressed in a randomized trial.

Machine learning for optimized individual survival prediction in resectable upper gastrointestinal cancer.

PURPOSE: Surgical oncologists are frequently confronted with the question of expected long-term prognosis. The aim of this study was to apply machine learning algorithms to optimize survival prediction after oncological resection of gastroesophageal cancers. METHODS: Eligible patients underwent oncological resection of gastric or distal esophageal cancer between 2001 and 2020 at Heidelberg University Hospital, Department of General Surgery. Machine learning methods such as multi-task logistic regression and survival forests were compared with usual algorithms to establish an individual estimation. RESULTS: The study included 117 variables with a total of 1360 patients. The overall missingness was 1.3%. Out of eight machine learning algorithms, the random survival forest (RSF) performed best with a concordance index of 0.736 and an integrated Brier score of 0.166. The RSF demonstrated a mean area under the curve (AUC) of 0.814 over a time period of 10 years after diagnosis. The most important long-term outcome predictor was lymph node ratio with a mean AUC of 0.730. A numeric risk score was calculated by the RSF for each patient and three risk groups were defined accordingly. Median survival time was 18.8 months in the high-risk group, 44.6 months in the medium-risk group and above 10 years in the low-risk group. CONCLUSION: The results of this study suggest that RSF is most appropriate to accurately answer the question of long-term prognosis. Furthermore, we could establish a compact risk score model with 20 input parameters and thus provide a clinical tool to improve prediction of oncological outcome after upper gastrointestinal surgery.

Minimally invasivE versus open total GAstrectomy (MEGA): study protocol for a multicentre randomised controlled trial (DRKS00025765).

INTRODUCTION: The only curative treatment for most gastric cancer is radical gastrectomy with D2 lymphadenectomy (LAD). Minimally invasive total gastrectomy (MIG) aims to reduce postoperative morbidity, but its use has not yet been widely established in Western countries. Minimally invasivE versus open total GAstrectomy is the first Western multicentre randomised controlled trial (RCT) to compare postoperative morbidity following MIG vs open total gastrectomy (OG). METHODS AND ANALYSIS: This superiority multicentre RCT compares MIG (intervention) to OG (control) for oncological total gastrectomy with D2 or D2+LAD. Recruitment is expected to last for 2 years. Inclusion criteria comprise age between 18 and 84 years and planned total gastrectomy after initial diagnosis of gastric carcinoma. Exclusion criteria include Eastern Co-operative Oncology Group (ECOG) performance status >2, tumours requiring extended gastrectomy or less than total gastrectomy, previous abdominal surgery or extensive adhesions seriously complicating MIG, other active oncological disease, advanced stages (T4 or M1), emergency setting and pregnancy.The sample size was calculated at 80 participants per group. The primary endpoint is 30-day postoperative morbidity as measured by the Comprehensive Complications Index. Secondary endpoints include postoperative morbidity and mortality, adherence to a fast-track protocol and patient-reported quality of life (QoL) scores (QoR-15, EUROQOL EuroQol-5 Dimensions-5 Levels (EQ-5D), EORTC QLQ-C30, EORTC QLQ-STO22, activities of daily living and Body Image Scale). Oncological endpoints include rate of R0 resection, lymph node yield, disease-free survival and overall survival at 60-month follow-up. ETHICS AND DISSEMINATION: Ethical approval has been received by the independent Ethics Committee of the Medical Faculty, University of Heidelberg (S-816/2021) and will be received from each responsible ethics committee for each individual participating centre prior to recruitment. Results will be published open access. TRIAL REGISTRATION NUMBER: DRKS00025765.