Surgical and Perioperative Treatments for Esophagogastric Junction Cancer.

Esophagogastric junction cancer (EGJC) is a rare malignant disease that occurs in the gastroesophageal transition zone. In recent years, its incidence has been rapidly increasing not only in Western countries but also in East Asia, and it has been attracting the attention of both clinicians and researchers. EGJC has a worse prognosis than gastric cancer (GC) and is characterized by complex lymphatic drainage pathways in the mediastinal and abdominal regions. EGJC was previously treated in the same way as GC or esophageal cancer, but, in recent years, it has been treated as an independent malignant disease, and treatment focusing only on EGJC has been developed. A recent multicenter prospective study revealed the frequency of lymph node metastasis by station and established the optimal extent of lymph node dissection. In perioperative treatment, the combination of multi-drug chemotherapy, radiation therapy, molecular targeted therapy, and immunotherapy is expected to improve the prognosis. In this review, we summarize previous clinical trials and their important evidence on surgical and perioperative treatments for EGJC.

Open left diaphragm method enables safe surgery with a good visual field in a laparoscopic transhiatal approach for esophagogastric junction adenocarcinoma laparoscopic transhiatal reconstruction via an open left diaphragm method.

BACKGROUND: Despite being oncologically acceptable for esophagogastric junction adenocarcinoma with an esophageal invasion length of 3-4 cm, the transhiatal approach has not yet become a standard method given the difficulty of reconstruction in a narrow space and the risk of severe anastomotic leakage. This study aimed to clarify the safety and feasibility of the open left diaphragm method during the transhiatal approach for esophagogastric junction adenocarcinoma. METHODS: This retrospective study compared the clinical outcomes of patients who underwent proximal or total gastrectomy with lower esophagectomy for Siewert type II/III adenocarcinomas with esophageal invasion via the laparoscopic transhiatal approach with or without the open left diaphragm method from April 2013 to December 2021. RESULTS: Overall, 42 and 13 patients did and did not undergo surgery with the open left diaphragm method, respectively. The median operative time was only slightly shorter in the open left diaphragm group than in the non-open left diaphragm group (369 vs. 482 min; P = 0.07). Grade ≥ II postoperative respiratory complications were significantly less common in the open left diaphragm group than in the non-open left diaphragm group (17% vs. 46%, P = 0.03). Neither group had grade ≥ IV anastomotic leakage, and two cases of anastomotic leakage requiring reoperation were drained using the left diaphragmatic release technique. CONCLUSIONS: Transhiatal lower esophagectomy with gastrectomy using the open left diaphragm method is safe, highlighting its advantages for Siewert type II/III esophagogastric junction adenocarcinoma with an esophageal invasion length of ≤ 4 cm.

Interpretable machine learning for predicting the response duration to Sintilimab plus chemotherapy in patients with advanced gastric or gastroesophageal junction cancer.

Background: Sintilimab plus chemotherapy has proven effective as a combination immunotherapy for patients with advanced gastric and gastroesophageal junction adenocarcinoma (GC/GEJC). A multi-center study conducted in China revealed a median progression-free survival (PFS) of 7.1 months. However, the prediction of response duration to this immunotherapy has not been thoroughly investigated. Additionally, the potential of baseline laboratory features in predicting PFS remains largely unexplored. Therefore, we developed an interpretable machine learning (ML) framework, iPFS-SC, aimed at predicting PFS using baseline (pre-treatment) laboratory features and providing interpretations of the predictions. Materials and methods: A cohort of 146 patients with advanced GC/GEJC, along with their baseline laboratory features, was included in the iPFS-SC framework. Through a forward feature selection process, predictive baseline features were identified, and four ML algorithms were developed to categorize PFS duration based on a threshold of 7.1 months. Furthermore, we employed explainable artificial intelligence (XAI) methodologies to elucidate the relationship between features and model predictions. Results: The findings demonstrated that LightGBM achieved an accuracy of 0.70 in predicting PFS for advanced GC/GEJC patients. Furthermore, an F1-score of 0.77 was attained for identifying patients with PFS durations shorter than 7.1 months. Through the feature selection process, we identified 11 predictive features. Additionally, our framework facilitated the discovery of relationships between laboratory features and PFS. Conclusion: A ML-based framework was developed to predict Sintilimab plus chemotherapy response duration with high accuracy. The suggested predictive features are easily accessible through routine laboratory tests. Furthermore, XAI techniques offer comprehensive explanations, both at the global and individual level, regarding PFS predictions. This framework enables patients to better understand their treatment plans, while clinicians can customize therapeutic approaches based on the explanations provided by the model.

Clinical outcomes and biomarker exploration of first-line PD-1 inhibitors plus chemotherapy in patients with low PD-L1-expressing of gastric or gastroesophageal junction adenocarcinoma.

BACKGROUND: The beneficial effects of first-line programmed death-1 (PD-1) inhibitors plus chemotherapy in patients with low programmed death-ligand 1 (PD-L1)-expressing advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma are controversial. METHODS: We conducted a retrospective analysis of patients with G/GEJ adenocarcinoma who had undergone first-line treatment with PD-1 inhibitors plus chemotherapy between October 2017 and May 2022. The primary outcomes were objective response rate (ORR) and progression-free survival (PFS). SPSS software V27.0 was used for data analysis. RESULTS: Of 345 enrolled patients, 290 had measurable lesions. The overall ORR was 59.3%. PD-L1 status was available in 171 patients, and 67.8% of them were considered as low PD-L1 expression level (combined positive score (CPS) < 5). Patients with PD-L1 CPS < 5 showed a lower response rate (51.1% vs 70.8%, P = 0.024) and a worse PFS (P = 0.009) compared to those with PD-L1 CPS ≥ 5. In the PD-L1 low-expression cohort, patients with non-diffuse type, GEJ cancer, synchronous metastasis, distant lymph node metastasis, liver metastasis, non-peritoneal metastasis, and HER2 positive were significantly associated with higher response rates to PD-1 inhibitors plus chemotherapy (P < 0.05). The presence of peritoneal metastasis (P = 0.028) and diffuse type (P = 0.046) were identified as independent predictors of poor PFS in multivariate analysis of the PD-L1 CPS < 5 subgroup. When evaluated for correlation with overall survival (OS) in the PD-L1 low-expression subgroup, peritoneal metastasis was found to be the only independent prognostic factor of an increased risk of death (hazard ratio: 2.31, 95% CI 1.09-4.90; P = 0.029). CONCLUSIONS: PD-L1 CPS ≥ 5 is significantly associated with improved response and extended PFS in G/GEJ cancer patients treated with a combination of PD-1 inhibitors and chemotherapy. Specific subgroups within the low PD-L1-expressing population, such as those with non-diffuse-type tumors and without peritoneal metastases, may also benefit from immunotherapy combined with chemotherapy.

Efficacy and safety of surufatinib plus toripalimab, a chemotherapy-free regimen, in patients with advanced gastric/gastroesophageal junction adenocarcinoma, esophageal squamous cell carcinoma, or biliary tract cancer.

BACKGROUND: The programmed death 1 inhibitor toripalimab plus the angio-immuno kinase inhibitor surufatinib showed a tolerable safety profile and preliminary efficacy in patients with advanced solid tumors in a phase I study. METHODS: This open-label, multi-cohort study in China enrolled patients with advanced solid tumors who had failed or were intolerable to standard treatment into tumor-specific cohorts. Patients received surufatinib (250 mg orally, once daily) plus toripalimab (240 mg intravenously, once every three weeks). Results for three cohorts (gastric/gastroesophageal junction [GC/GEJ] adenocarcinoma, esophageal squamous cell carcinoma [ESCC], and biliary tract carcinoma [BTC]) are reported here. The primary endpoint was investigator-assessed objective response rate (ORR) per Response Evaluation criteria in Solid Tumors version 1.1. RESULTS: Between December 17, 2019, and January 29, 2021, 60 patients were enrolled (GC/GEJ, n = 20; ESCC, n = 20; BTC, n = 20). At data cutoff (February 28, 2023), ORRs were 31.6%, 30.0%, and 11.1%, respectively. Median progression-free survival was 4.1, 2.7, and 2.9 months, respectively. Median overall survival was 13.7, 10.4, and 7.0 months, respectively. Overall, grade ≥ 3 treatment-related adverse events occurred in 28 (46.7%) patients. CONCLUSIONS: Surufatinib plus toripalimab showed promising antitumor activity and a tolerable safety profile in immunotherapy-naïve patients with GC/GEJ adenocarcinoma, ESCC, or BTC. These findings warrant further study in larger randomized trials comparing surufatinib plus toripalimab with standard therapies in these tumors. CLINICALTRIALS: gov NCT04169672.

Contemporary outcomes for resected type 1-3 gastroesophageal junction adenocarcinoma: a single-center experience.

BACKGROUND: Surgical resection remains the mainstay of treatment for tumors of the gastroesophageal junction (GEJ). However, contemporary analyses of the Western experience for GEJ adenocarcinoma are sparsely reported. METHODS: Patients with GEJ adenocarcinoma undergoing resection between 2012 and 2022 at a single institution were grouped based on Siewert subtype and analyzed. Pathologic and treatment related variables were assessed with relation to outcomes. RESULTS: A total of 302 patients underwent resection: 161 (53.3%) with type I, 116 (38.4%) with type II, and 25 (8.3%) with type III tumors. Most patients received neoadjuvant therapy (86.4%); 86% of cases were performed in a minimally invasive fashion. Anastomotic leak occurred in 6.0% and 30-day mortality in only 0.7%. The rate of grade 3+ morbidity was lower for the last 5 years of the study than for the first 5 years (27.5% vs 49.3%, P < .001), as was median length of stay (7 vs 8 days, P < .001). There was a significantly greater number of signet ring type tumors among type III tumors (44.0%) than type I/II tumors (11.2/12.9%, P < .001). Otherwise, there was no difference in the distribution of pathologic features among Siewert subtypes. Notably, there was a significant difference in 3-year overall survival based on Siewert classification: type I 60.0%, type II 77.2%, and type III 86.3% (P = .011). Siewert type I remained independently associated with worse survival on multivariable analysis (hazard ratio, 4.5; P = .023). CONCLUSIONS: In this large, single-institutional series, operative outcomes for patients with resected GEJ adenocarcinoma improved over time. On multivariable analysis, type I tumors were an independent predictor of poor survival.

Implementation of perioperative FLOT compared to ECX/EOX chemotherapy regimens in resectable esophagogastric adenocarcinomas: an analysis of real-world data.

BACKGROUND AND PURPOSE: Perioperative 5-FU, leucovorin, oxaliplatin, and docetaxel (FLOT) is recommended in resectable esophagogastric adenocarcinoma based on randomised trials. However, the effectiveness of FLOT in routine clinical practice remains unknown as randomised trials are subject to selection bias limiting their generalisability. The aim of this study was to evaluate the implementation of FLOT in real-world patients. METHODS: Retrospectively collected data were analysed in consecutive patients treated before or after the implementation of FLOT. The primary endpoint was complete pathological response (pCR) and secondary endpoints were margin-free resection (R0), overall survival (OS), relapse-free survival (RFS) tolerability of chemotherapy and surgical complications. RESULTS: Mean follow-up time for patients treated with FLOT (n = 205) was 37.7 versus 47.0 months for epirubicin, cis- or oxaliplatin, and capecitabine (ECX/EOX, n = 186). Surgical resection was performed in 88.0% versus 92.0%; pCR were observed in 3.8% versus 2.4%; and R0 resections were achieved in 78.0% versus 86.0% (p = 0.03) in the ECX/EOX and FLOT cohorts, respectively. Survival analysis indicated no significant difference in RFS (p = 0.17) or OS (p = 0.37) between the cohorts with a trend towards increased OS in performance status 0 (hazard ratio [HR] = 0.73, 95% confidence interval [CI]: 0.50-1.04). More patients treated with ECX/EOX completed chemotherapy (39% vs. 28%, p = 0.02). Febrile neutropenia was more common in the FLOT cohort (3.8% vs. 11%, p = 0.0086). 90-days mortality (1.2% vs. 0%) and frequency of anastomotic leakage (8% vs. 6%) were equal and low. INTERPRETATION: Patients receiving FLOT did not demonstrate improved pCR, RFS or OS. However, R0 rate was improved and patients in good PS trended towards improved OS.

Impact of the number of therapy lines on survival in advanced gastric and esophagogastric adenocarcinoma - a real-world retrospective analysis from Croatia.

The aim of the study was to conduct a retrospective database analysis to understand the current treatment patterns and outcomes to plan potential improvements in therapy delivery and patient selection. The electronic patient medical records of 225 patients with advanced gastric and esophagogastric adenocarcinoma treated at two Croatian high-volume tertiary centers from January 2018 to December 2021 were analyzed. Patients ineligible for chemotherapy (66 of 291, 22.7%) due to poor general condition or co-morbidities were not included in the study. The median overall survival (OS) for the whole cohort was 11.0 months (95% confidence interval (CI) 9.7-12.0). Of the 225 patients who received first-line therapy, 47.6%, 16.9%, and 3.1% received second-, third-, and fourth-line therapy, respectively. Survival correlated significantly with the number of treatment lines received (p<0.001), with a median OS from diagnosis of 7.8 (95% CI 6.6-9.4), 12.0 (95% CI 10.0-14.0), and 20.0 months (95% CI 18.0-23.0) for patients receiving 1, 2, and ≥3 lines of treatment, respectively. This study confirmed the positive impact of the number of chemotherapy lines on OS. This highlights the importance of the ratio of patients receiving multiple lines of therapy as well as the availability of new and effective drugs in real-life clinical practice. The selection of optimal therapy for each patient in the first-line therapy is important because a significant number of patients do not receive second-line therapy.

Bibliometric and visual analysis of esophagogastric junction cancer research from 2002 to 2021.

Numerous studies related to esophagogastric junction cancer (EGC) have been published, and bibliometric analysis of these publications may be able to identify research hotspots and frontiers of EGC. Studies published on EGC between 2002 and 2021 were retrieved from the Web of Science Core Collection. The collaboration network of countries/regions, institutions, authors, co-citation network of journals, co-occurrence network, and overlay visualization of keywords were analyzed using the VOSviewer software. Cluster and timeline analyses of references were performed using the CiteSpace software. A total of 5109 English articles were published across 691 journals by authors affiliated with 4727 institutions from 81 countries/regions. The annual number of publications related to EGC research has exhibited an increasing trend. The United States, China, and Japan emerged as the top 3 prolific countries/regions. Institutions in the United States, Japan, and South Korea exhibited significant collaboration with one another. Diseases of the Esophagus was the most prolific journal, and Annals of Surgical Oncology, World Journal of Gastroenterology, and Gastric Cancer had also published more than 100 studies. Jaffer A Ajani was the most productive author while David Cunningham ranked the first in terms of total citations and average citations per article. Barrett's esophagus, gastroesophageal reflux disease, Helicobacter pylori, and obesity were common topics in earlier research, and recent years had seen a shift towards the topics of immunotherapy, targeted therapy, and neoadjuvant chemotherapy. In conclusion, growing attention is paid to EGC research, especially in terms of immunotherapy, targeted therapy, and neoadjuvant chemotherapy.

[Chinese expert consensus on surgical continuous quality improvement goals in esophageal cancer and esophagogastric junction cancer (2024 edition)].

Improving the quality and efficiency of surgical diagnosis and treatment guarantees the outcome for most patients with esophageal cancer and esophagogastric junction cancer, and the continuous quality improvement mechanism oriented to the "textbook outcome" is the best choice. To ensure the successful implementation of the "Quality Control Indicators for Standardized Diagnosis and Treatment of Esophageal Cancer in China (2022 Version)" aligning with it more effectively is crucial. The Expert Committee on Quality Control of Esophageal Cancer at the National Cancer Center leads work teams comprised of multidisciplinary experts, particularly those in thoracic surgery, to establish a consensus. The current consensus comprises eight "textbook outcomes" to standardize, promote, and consolidate surgical quality management and continuously improve the surgical quality of esophageal cancer and esophagogastric junction cancer.

Best Practices for Managing Patients with Unresectable Metastatic Gastric and Gastroesophageal Junction Cancer in Canada.

Gastric cancer (GC) is one of the most common types of cancer and is associated with relatively low survival rates. Despite its considerable burden, there is limited guidance for Canadian clinicians on the management of unresectable metastatic GC and gastroesophageal junction cancer (GEJC). Therefore, we aimed to discuss best practices and provide expert recommendations for patient management within the current Canadian unresectable GC and GEJC landscape. A multidisciplinary group of Canadian healthcare practitioners was assembled to develop expert recommendations via a working group. The often-rapid progression of unresectable GC and GEJC and the associated malnutrition have a significant impact on the patient's quality of life and ability to tolerate treatment. Hence, recommendations include early diagnosis, identification of relevant biomarkers to improve personalized treatment, and relevant support to manage comorbidities. A multidisciplinary approach including early access to registered dietitians, personal support networks, and palliative care services, is needed to optimize possible outcomes for patients. Where possible, patients with unresectable GC and GEJC would benefit from access to clinical trials and innovative treatments.

Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first line treatment for advanced gastric or gastro-oesophageal junction adenocarcinoma: RATIONALE-305 randomised, double blind, phase 3 trial.

OBJECTIVE: To evaluate the efficacy and safety of tislelizumab added to chemotherapy as first line (primary) treatment for advanced gastric or gastro-oesophageal junction adenocarcinoma compared with placebo plus chemotherapy. DESIGN: Randomised, double blind, placebo controlled, phase 3 study. SETTING: 146 medical centres across Asia, Europe, and North America, between 13 December 2018 and 28 February 2023. PARTICIPANTS: 1657 patients aged ≥18 years with human epidermal growth factor receptor 2 negative locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma, regardless of programmed death-ligand 1 (PD-L1) expression status, who had not received systemic anticancer therapy for advanced disease. INTERVENTIONS: Patients were randomly (1:1) assigned to receive either tislelizumab 200 mg or placebo intravenously every three weeks in combination with chemotherapy (investigator's choice of oxaliplatin and capecitabine, or cisplatin and 5-fluorouracil) and stratified by region, PD-L1 expression, presence or absence of peritoneal metastases, and investigator's choice of chemotherapy. Treatment continued until disease progression or unacceptable toxicity. MAIN OUTCOME MEASURES: The primary endpoint was overall survival, both in patients with a PD-L1 tumour area positivity (TAP) score of ≥5% and in all randomised patients. Safety was assessed in all those who received at least one dose of study treatment. RESULTS: Of 1657 patients screened between 13 December 2018 and 9 February 2021, 660 were ineligible due to not meeting the eligibility criteria, withdrawal of consent, adverse events, or other reasons. Overall, 997 were randomly assigned to receive tislelizumab plus chemotherapy (n=501) or placebo plus chemotherapy (n=496). Tislelizumab plus chemotherapy showed statistically significant improvements in overall survival versus placebo plus chemotherapy in patients with a PD-L1 TAP score of ≥5% (median 17.2 months v 12.6 months; hazard ratio 0.74 (95% confidence interval 0.59 to 0.94); P=0.006 (interim analysis)) and in all randomised patients (median 15.0 months v 12.9 months; hazard ratio 0.80 (0.70 to 0.92); P=0.001 (final analysis)). Grade 3 or worse treatment related adverse events were observed in 54% (268/498) of patients in the tislelizumab plus chemotherapy arm versus 50% (246/494) in the placebo plus chemotherapy arm. CONCLUSIONS: Tislelizumab added to chemotherapy as primary treatment for advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma provided superior overall survival with a manageable safety profile versus placebo plus chemotherapy in patients with a PD-L1 TAP score of ≥5%, and in all randomised patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT03777657.

Retrospective Study of Claudin 18 Isoform 2 Prevalence and Prognostic Association in Gastric and Gastroesophageal Junction Adenocarcinoma.

PURPOSE: Claudin 18 isoform 2 (CLDN18.2) is an emerging biomarker and therapeutic target in gastric and gastroesophageal junction (G/GEJ) adenocarcinoma. This study aimed to obtain deeper understanding of CLDN18.2 positivity patterns, prognostic implications, and associations with various demographic, clinical, and molecular characteristics in G/GEJ adenocarcinoma. METHODS: Archived tumor tissue samples from 304 patients with G/GEJ adenocarcinoma in the United States were assessed for CLDN18.2 positivity by immunohistochemistry. CLDN18.2 positivity was defined as ≥50% or ≥75% of tumor cells with CLDN18 staining intensity ≥2+. CLDN18.2 positivity patterns were analyzed for association with prognosis and clinicopathologic/demographic characteristics. Where possible, CLDN18.2 positivity was analyzed for matched tissue samples to assess concordance between primary and metastatic tumors and concordance before and after chemotherapy. RESULTS: The overall prevalence of CLDN18.2-positive tumors (with ≥75% cutoff) was 44.4% (n = 135 of 304). CLDN18.2-positive tumors had a prevalence of 51.4% (n = 91 of 177) in gastric and 34.6% (n = 44 of 127) in GEJ adenocarcinoma. With a ≥50% cutoff, the prevalence of CLDN18.2-positive tumors was 64.4% (n = 114 of 177) in gastric adenocarcinoma and 44.9% (n = 57 of 127) in GEJ adenocarcinoma. There was no association between overall survival and CLDN18.2 positivity using either threshold. Statistically significant associations were noted between CLDN18.2 positivity and sex, histologic type of G/GEJ adenocarcinoma, and adenocarcinoma subtype (≥75% cutoff), and metastasis site and tumor grade (≥50% cutoff). The overall concordance of CLDN18.2 positivity (≥75% cutoff) was 73% (27 of 37) for matched primary versus metastatic tumor samples and 74% (29 of 39) for matched samples before and after chemotherapy. CONCLUSION: This study demonstrated that CLDN18.2 positivity did not correlate with survival in G/GEJ adenocarcinoma, consistent with published data. On the basis of matched sample analysis, CLDN18.2 appears to demonstrate >70% concordance as a biomarker. Observed correlations with certain patient/tumor characteristics warrant further study.

Technical variety of anastomotic techniques used in proximal gastrectomy with double-tract-reconstruction - a narrative review.

In the past 40 years, the incidence of esophagogastric junction cancer has been gradually increasing worldwide. Currently, surgical resection remains the main radical treatment for early gastric cancer. Due to the rise of functional preservation surgery, proximal gastrectomy has become an alternative to total gastrectomy for surgeons in Japan and South Korea. However, the methods of digestive tract reconstruction after proximal gastrectomy have not been fully unified. At present, the principal methods include esophagogastrostomy, double flap technique, jejunal interposition, and double tract reconstruction. Related studies have shown that double tract reconstruction has a good anti-reflux effect and improves postoperative nutritional prognosis, and it is expected to become a standard digestive tract reconstruction method after proximal gastrectomy. However, the optimal anastomoses mode in current double tract reconstruction is still controversial. This article aims to review the current status of double tract reconstruction and address the aforementioned issues.

Novel reconstruction using pedicled ileocolic interposition with intrathoracic esophago-ileal anastomosis after distal esophagectomy for esophagogastric junction cancer: A report of two cases.

There is no optimal reconstruction after radical distal esophagectomy for cancers of the esophagogastric junction. We designed a novel reconstruction technique using pedicled ileocolic interposition with intrathoracic anastomosis between the esophagus and the elevated ileum. Two patients underwent the surgery. Case 1 was a 70-year-old man with esophagogastric junction adenocarcinoma with 3 cm of esophageal invasion. Case 2 was a 70-year-old man with squamous cell carcinoma of the esophagogastric junction; the epicenter of which was located just at the junction. These two patients underwent radical distal esophagectomy and pedicled ileocolic interposition with intrathoracic anastomosis. They were discharged on postoperative days 17 and 14, respectively, with no major complication. Pedicled ileocolic interposition is characterized by sufficient elevation and perfusion of the ileum, which is fed by the ileocolic artery and vein. As a result, we can generally adapt this reconstruction method to most curable esophagogastric junction cancers.

Neoadjuvant immunotherapy improves outcomes for resectable gastroesophageal junction cancer: A systematic review and meta-analysis.

BACKGROUND: In recent years, neoadjuvant immunotherapy (NAIT) has developed rapidly in patients with gastroesophageal junction cancer (GEJC). The suggested neoadjuvant treatment regimens for patients with GEJC may vary in light of the efficacy and safety results. METHODS: A search of the Cochrane Library, PubMed, Embase, and Web of Science was completed to locate studies examining the safety and effectiveness of NAIT for resectable GEJC. We analyzed the effect sizes (ES) and 95% confidence intervals (CI) in addition to subgroups and heterogeneity. Meta-analyses were performed using Stata BE17 software. RESULTS: For these meta-analyses, 753 patients were chosen from 21 studies. The effectiveness of NAIT was assessed using the pathological complete response (pCR), major pathological response (MPR), and nodal downstage to ypN0 rate. The MPR, pCR, and nodal downstage to ypN0 rate values in NAIT were noticeably higher (MPR: ES = 0.45; 95% CI: 0.36-0.54; pCR: ES = 0.26; 95% CI: 0.21-0.32; nodal downstage to ypN0 rate: ES = 0.60; 95% CI: 0.48-0.72) than those of neoadjuvant chemotherapy (nCT) or neoadjuvant chemoradiotherapy (nCRT) (MPR < 30%; pCR: ES = 3%-17%; nodal downstage to ypN0 rate: ES = 21%-29%). Safety was assessed using the treatment-related adverse events (trAEs) incidence rate, surgical delay rate, surgical complications incidence rate, and surgical resection rate. In conclusion, the incidence of trAEs, incidence of surgical complications, and surgical delay rate had ES values of 0.66, 0.48, and 0.09, respectively. These rates were comparable to those from nCT or nCRT (95% CI: 0.60-0.70; 0.15-0.51; and 0, respectively). The reported resection rates of 85%-95% with nCT or nCRT were comparable to the mean surgical resection rate of 90%. CONCLUSION: NAIT is an effective treatment for resectable GEJC; additionally, the level of NAIT toxicity is acceptable. The long-term effects of NAIT require further study.

Molecular Landscape and Clinical Implication of CCNE1-amplified Esophagogastric Cancer.

Cyclin E overexpression as a result of CCNE1 amplification is a critical driver of genomic instability in gastric cancer, but its clinical implication is largely unknown. Thus, we integrated genomic, transcriptomic, and immune profiling analysis of 7,083 esophagogastric tumors and investigated the impact of CCNE1 amplification on molecular features and treatment outcomes. We identified CCNE1 amplification in 6.2% of esophageal adenocarcinoma samples, 7.0% of esophagogastric junction carcinoma, 4.2% of gastric adenocarcinoma samples, and 0.8% of esophageal squamous cell carcinoma. Metastatic sites such as lymph node and liver showed an increased frequency of CCNE1 amplification relative to primary tumors. Consistent with a chromosomal instability phenotype, CCNE1 amplification was associated with decreased CDH1 mutation and increased TP53 mutation and ERBB2 amplification. We observed no differences in immune biomarkers such as PD-L1 expression and tumor mutational burden comparing CCNE1-amplified and nonamplified tumors, although CCNE1 amplification was associated with changes in immune populations such as decreased B cells and increased M1 macrophages from transcriptional analysis. Real-world survival analysis demonstrated that patients with CCNE1-amplified gastric cancer had worse survival after trastuzumab for HER2-positive tumors, but better survival after immunotherapy. These data suggest that CCNE1-amplified gastric cancer has a distinct molecular and immune profile with important therapeutic implications, and therefore further investigation of CCNE1 amplification as a predictive biomarker is warranted. SIGNIFICANCE: Advanced gastric cancer has a relatively dismal outcome with a 5-year overall survival of less than 10%. Furthermore, while comprehensive molecular analyses have established molecular subtypes within gastric cancers, biomarkers of clinical relevance in this cancer type are lacking. Overall, this study demonstrates that CCNE1 amplification is associated with a distinct molecular profile in gastric cancer and may impact response to therapy, including targeted therapy and/or immunotherapy.

First-Line Nivolumab and Relatlimab Plus Chemotherapy for Gastric or Gastroesophageal Junction Adenocarcinoma: The Phase II RELATIVITY-060 Study.

PURPOSE: Open-label phase II study (RELATIVITY-060) to investigate the efficacy and safety of first-line nivolumab, a PD-1-blocking antibody, plus relatlimab, a lymphocyte-activation gene 3 (LAG-3)-blocking antibody, plus chemotherapy in patients with previously untreated advanced gastric cancer (GC) or gastroesophageal junction cancer (GEJC). METHODS: Patients with unresectable, locally advanced or metastatic GC/GEJC were randomly assigned 1:1 to nivolumab + relatlimab (fixed-dose combination) + chemotherapy or nivolumab + chemotherapy. The primary end point was objective response rate (ORR; per RECIST v1.1 by blinded independent central review [BICR]) in patients whose tumors had LAG-3 expression ≥1%. RESULTS: Of 274 patients, 138 were randomly assigned to nivolumab + relatlimab + chemotherapy and 136 to nivolumab + chemotherapy. Median follow-up was 11.9 months. In patients with LAG-3 expression ≥1%, BICR-assessed ORR (95% CI) was 48% (38 to 59) in the nivolumab + relatlimab + chemotherapy arm and 61% (51 to 71) in the nivolumab + chemotherapy arm; median progression-free survival (95% CI) by BICR was 7.0 months (5.8 to 8.4) versus 8.3 months (6.9 to 12.1; hazard ratio [HR], 1.41 [95% CI, 0.97 to 2.05]), and median overall survival (95% CI) was 13.5 months (11.9 to 19.1) versus 16.0 months (10.9 to not estimable; HR, 1.04 [95% CI, 0.70 to 1.54]), respectively. Grade 3 or 4 treatment-related adverse events (TRAEs) occurred in 69% and 61% of all treated patients, and 42% and 36% of patients discontinued because of any-grade TRAEs in the nivolumab + relatlimab + chemotherapy and nivolumab + chemotherapy arms, respectively. CONCLUSION: RELATIVITY-060 did not meet its primary end point of improved ORR in patients with LAG-3 expression ≥1% when relatlimab was added to nivolumab + chemotherapy compared with nivolumab + chemotherapy. Further studies are needed to address whether adding anti-LAG-3 to anti-PD-1 plus chemotherapy can benefit specific GC/GEJC patient subgroups.

Immunotherapy combined with apatinib in the treatment of advanced or metastatic gastric/gastroesophageal tumors: a systematic review and meta-analysis.

BACKGROUND: Immunotherapy or apatinib alone has been used as third-line adjuvant therapy for advanced or metastatic gastric/gastroesophageal junction (G/GEJ) tumors, but the efficacy of combining them with each other for the treatment of patients with advanced or metastatic G/GEJ is unknown; therefore, we further evaluated the efficacy and safety of immunotherapy combined with apatinib in patients with advanced or metastatic G/GEJ. METHODS: The main search was conducted on published databases: Embase, Cochrane library, PubMed.The search was conducted from the establishment of the database to December 2023.Clinical trials with patients with advanced or metastatic G/GEJ and immunotherapy combined with apatinib as the study variable were collected. Review Manager 5.4 software as well as stata 15.0 software were used for meta-analysis. RESULTS: A total of 651 patients from 19 articles were included in this meta-analysis. In the included studies, immunotherapy combined with apatinib had a complete response (CR) of 0.03 (95% CI: 0.00 -0.06), partial response (PR) of 0.34 (95% CI: 0.19-0.49), stable disease (SD) of 0.43 (95% CI: 0.32-0.55), objective response rate (ORR) was 0.36 (95% CI: 0.23-0.48), disease control rate (DCR) was 0.80 (95% CI: 0.74-0.86), and median progression-free survival (PFS) was 4.29 (95% CI: 4.05-4.52), median Overall survival (OS) was 8.79 (95% CI: 7.92-9.66), and the incidence of grade ≥ 3 TRAEs was 0.34 (95% CI: 0:19-0.49). PR, ORR, DCR, median PFS and median OS were significantly higher in the immunotherapy and apatinib combination chemotherapy group (IAC) than in the immunotherapy combination apatinib group (IA). And the difference was not significant in the incidence of SD and grade ≥ 3 TRAEs. CONCLUSION: This meta-analysis shows that immunotherapy combined with apatinib is safe and effective in the treatment of advanced or metastatic G/GEJ, where IAC can be a recommended adjuvant treatment option for patients with advanced or metastatic G/GEJ. However, more large multicenter randomized studies are urgently needed to reveal the long-term outcomes of immunotherapy combined with apatinib treatment.