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Background: This study reports the 2-year outcomes and biomarker analysis results of patients with locally advanced gastric and gastroesophageal junction (G/GEJ) adenocarcinoma who received neoadjuvant chemotherapy and immunotherapy in a phase II WuhanUHGI001 trial., Methods: Eligible patients with cT3/4aN+M0 locally advanced G/GEJ adenocarcinoma were screened, enrolled, and treated with 3 cycles of neoadjuvant tislelizumab and SOX followed by D2 gastrectomy and another 5 cycles of postoperative adjuvant SOX. The primary endpoint was major pathological response., Results: Of the 49 included patients, 24 (49.0%) achieved major pathological response and 13 (26.5%) achieved pathological complete response. During a median follow-up of 26.8 months, the 2-year progression-free survival (PFS) and overall survival (OS) rates were 69.4% and 81.2%, respectively. Grade 3-4 adverse events occurred in six patients (12.2%) during the neoadjuvant period, eight patients (17.0%) during the postoperative period, and seven patients (15.2%) during the adjuvant period. Biomarker analysis revealed that the pathological complete response showed no association with 2-year PFS and OS. Major pathological response showed a potentially strong association with improved 2-year PFS and OS rates. In addition, preoperative circulating tumor cells combined with pathological responses are helpful in prognosis assessment. In addition, our results showed that T downstaging, lymphocyte-to-monocyte ratio, and CD3+ T cells were independent factors that affect PFS. The signet ring cell component (SRCC), T downstaging, and neutrophil-to-lymphocyte ratio were independent factors affecting OS. Prognostic nomograms of PFS and OS constructed based on the multivariate Cox regression results demonstrated suitable calibration and discrimination ability., Conclusions: Neoadjuvant tislelizumab plus SOX exhibits promising efficacy and acceptable toxicity in patients with locally advanced G/GEJ adenocarcinoma. In addition, our study established a prognostic risk signature and nomograms based on clinicopathological characteristics, which can accurately predict patient outcomes and aid in personalized treatment planning., (© 2024. Society of Surgical Oncology.)

Background: Although multiple treatment options exist for gastroesophageal junction (GEJ) cancer, surgery remains the mainstay for potential cure. Extended nodal dissection with a D2 lymphadenectomy (LAD) remains controversial for Siewert II GEJ cancer. Although D2 LAD may lead to a greater lymph node harvest, its effect on survival remains elusive. The authors hypothesized that additional D2 dissection in Siewert II GEJ cancer does not lead to increased survival., Methods: This study reviewed Siewert II patients who received a D1 or D2 LAD in addition to minimally invasive esophagectomy (MIE) after receiving neoadjuvant chemoradiation or perioperative chemotherapy (2012-2022). The patients were followed for up to 5 years. The outcomes measured were survival, number of nodes sampled, and operative time. The association between D1 or D2 LAD and overall survival was analyzed with Kaplan-Meier methods and a multivariable Cox regression model., Results: Among 155 patients, 74 % underwent D1 and 26 % underwent D2 LAD. The patients with D2 had more than 15 lymph nodes harvested more frequently than those who had D1 (83 % vs 48 %; p < 0.001), with no difference in positive nodes (2.8 ± 5.2 vs 2.1 ± 4.2; p = 0.4). The patients with D2 LAD had a longer median operative time than those who with D1 LAD (362 vs 244 min; p < 0.001). In Kaplan-Meier and multivariable Cox regression models, overall survival did not differ significantly between the patients undergoing D2 and those who had D1 (adjusted hazard ratio [aHR], 0.52; 95 % confidence interval [CI], 0.25-1.00; p = 0.067)., Conclusions: Little consensus exists regarding the optimal lymph node harvest for GEJ cancers. In Siewert II cancer, D2 LAD may not be mandatory and may lead to increased operative morbidity with no significant difference in survival., (© 2024. The Author(s).)

Background: Nivolumab + chemotherapy is now a standard of care for HER2-negative, previously untreated, unresectable or recurrent gastric/gastroesophageal junction cancer (advanced gastric cancer), but long-term follow-up data of clinical trials are limited., Methods: ATTRACTON-4 was a phase 3, double-blind, placebo-controlled trial in Japan, South Korea, and Taiwan. Patients were randomized to either nivolumab or placebo, both combined with the physician's choice of SOX (oral S-1 [tegafur-gimeracil-oteracil potassium] + oxaliplatin) or CAPOX (capecitabine + oxaliplatin). We report the primary endpoints-centrally assessed progression-free survival (PFS) and overall survival (OS)-and landmark analyses of OS among patients alive using 3-year follow-up data., Results: At the cutoff date (May 10, 2021), 17/359 patients in the nivolumab + chemotherapy group and 6/358 in the placebo + chemotherapy group were continuing study treatment. PFS (centrally assessed) was longer in the nivolumab + chemotherapy group (median 10.94 vs. 8.48 months; hazard ratio [HR] 0.67, 95% confidence interval [CI] 0.55-0.82). Although OS did not differ between the two groups (median 17.45 vs. 17.15 months; HR 0.89, 95% CI 0.75-1.05), the landmark analysis of OS, calculating HRs at each landmark time point (every month), was getting numerically better in the nivolumab + chemotherapy group over time. Approximately 80% of patients who achieved complete response in the nivolumab + chemotherapy group were alive at 3 years. No new safety signals or major late-onset select treatment-related adverse events were observed for nivolumab + chemotherapy., Conclusion: This 3-year follow-up of ATTRACTION-4 confirmed the long-term clinical benefit and manageable safety of nivolumab + chemotherapy in patients with previously untreated advanced gastric cancer., Trial Registration: NCT02746796., (© 2024. The Author(s).)

Purpose: Based on the comparison of ramucirumab monoclonal antibody with control treatments in randomized controlled trials, this study aims to elucidate the role of ramucirumab monoclonal antibody in cancer therapy and its potential side effects, providing scientific evidence for clinical treatment., Methods: PubMed, Embase, Cochrane, and Web of Science were searched systematically to obtain the trials on ramucirumab in the treatment of gastric or gastroesophageal junction (GEJ) adenocarcinoma up to April 13, 2023. We included randomized controlled trials (RCTs) evaluating the efficacy and safety of ramucirumab as monotherapy and in combination with other chemotherapy agents as interventions for treating gastric or gastroesophageal junction (GEJ) adenocarcinoma., Results: After screening 2200 studies, we finally included 8 eligible studies (involving a total of 3,283 participants). Meta-analysis results showed that compared to the control group, ramucirumab monotherapy significantly improved overall survival (OS) (hazard ratio [HR] = 0.77, 95% confidence interval [CI] [0.67, 0.89]) and progression-free survival (PFS) (HR = 0.48, 95% CI [0.40, 0.58]). Similar results were obtained for ramucirumab combined with paclitaxel. In the treatment combining ramucirumab with paclitaxel, compared to monotherapy, three severe adverse reactions (grade ≥ 3) were observed with significantly increased risks (OR > 2). These include proteinuria (OR = 5.37, 95% CI [1.22, 23.54]), hypertension (OR = 4.02, 95% CI [2.63, 6.14]), and gastrointestinal perforation (OR = 4.64, 95% CI [1.00, 21.60]). Subgroup analysis further indicated that ramucirumab is effective in both non-East Asian and East Asian populations, with East Asian patients more prone to developing proteinuria, while having a lower incidence of hypertension. Additionally, ramucirumab demonstrated comparable efficacy between first-line and second-line treatments, with a higher incidence of proteinuria observed in second-line therapy., Conclusion: Ramucirumab significantly improves the prognosis of patients with gastric or gastroesophageal junction adenocarcinoma. When used in combination with paclitaxel, close monitoring of adverse reactions such as proteinuria (especially in East Asian populations), hypertension (especially in non-East Asian populations), and gastrointestinal perforation is essential., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: There is no optimal reconstruction technique after proximal gastrectomy. The esophagogastrostomy (EG) is a rather simple procedure technically, but the incidences of reflux esophagitis and anastomotic stricture are higher. While the double-tract reconstruction (DTR) can lessen postoperative reflux esophagitis, it is technically complex with a long operation time. The purpose of this study was to evaluate the quality of life (QoL) and short-term outcomes of the two reconstruction techniques., Methods: We retrospectively collected consecutive patients with upper-third gastric adenocarcinoma and adenocarcinoma of the esophagogastric junction (AEG) at our center between 2019 June and 2023 May. Patients who underwent laparoscopic proximal gastrectomy (LPG) with EG or DTR were included in this study. A comparison was made between the clinical and pathological characteristics of patients and their surgical parameters, postoperative complications, and its 1-year QoL in two groups. The QoL of the two groups was assessed by Visick grading, the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and EORTC QLQ-STO22 scales at 1 year after operation. The nutritional status of the two groups was evaluated by BMI, hemoglobin and serum albumin., Results: AII the qualified patients were divided EG group (n = 63) and DTR group (n = 93). Compared to the DTR group, the blood loss volume of EG group was more (p = 0.001). There were no significant differences in operation duration, number of lymph nodes dissected, and postoperative length of stay between the two groups(p > 0.05). No statistical differences were observed in terms of the incidence of early complications and Clavien-Dindo classification as well(p > 0.05). After one year, the Visick grade of the DTR group was better than EG group (p = 0.040). The multivariable logistic regression analysis showed the only independent risk factor for reflux esophagitis was the reconstruction method. According to the EORTC QLQ-C30 questionnaire, patients in the DTR group had a better global health status(p = 0.001) and complained less about nausea and vomiting(p = 0.033), and appetite loss (p = 0.022). Patients in the DTR group complained less about reflux (p = 0.030) based on the EORTC QLQ-STO22 questionnaire. The multiple linear regression analysis revealed that the reconstruction method, reflux esophagitis and age had a linear relationship with the global health status score. Regarding nutritional status, BMI of the two groups both decreased 1 year after operation, and BMI decline value of the DTR group was lower than EG group (p = 0.001). There is no statistically significant difference between the two groups as for postoperative change in hemoglobin and serum albumin., Conclusion: Our findings suggest that it is possible for skilled surgeons to achieve minimal blood loss volume without significantly increasing operation duration when performing DRT, which does not raise risk. In terms of anti-reflux, postoperative QoL and BMI maintenance, 1-year postoperative follow-up outcomes reveal the DTR is superior to EG, which deserve further research and promotion., (© 2024. The Author(s).)

Purpose: With relatively few direct comparisons among treatment options for previously treated advanced gastric cancer or gastroesophageal junction (GEJ) cancer, network meta-analysis (NMA) may inform evidence-based decision-making. Ramucirumab plus paclitaxel (RAM + PTX) is a preferred regimen in guideline recommendations. NMA of key outcomes may further characterize the relative clinical value of RAM + PTX., Methods: A systematic literature review of randomized controlled trials of adult patients with previously treated advanced gastric/GEJ cancer informed a NMA which compared overall survival, progression-free survival, and discontinuations due to adverse events. Comparisons were reported relative to placebo/best supportive care (BSC) when possible, otherwise relative to RAM + PTX., Results: The base-case NMA focused on second-line treatment only, from 19 of 28 studies identified. For overall survival, seven of 16 regimens were favorable relative to placebo/BSC, with RAM + PTX as the most favorable. For progression-free survival, five of 14 regimens were unfavorable relative to RAM + PTX. For discontinuations due to adverse events, two of 13 regimens were similar to placebo/BSC: ramucirumab monotherapy and fluorouracil; relative to RAM-PTX, all regimens were similar except ramucirumab monotherapy which was favorable and irinotecan + cisplatin which was unfavorable., Conclusion: This NMA of trials of previously treated gastric/GEJ cancer suggests that RAM + PTX has one of the more favorable clinical profiles., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Serum fibrinogen and albumin play important roles in systemic inflammation and are implicated in tumor progression. The fibrinogen-to-albumin ratio (FAR) has shown a prognostic impact in several malignancies. This study aims to assess the prognostic value of the pretherapeutic FAR in patients with adenocarcinoma of the gastroesophageal junction (AEG) who underwent upfront resection., Methods: Consecutive patients who underwent surgical resection at the Department of Surgery at the Medical University of Vienna between 1992 and 2014 were included into this study. Optimal cut-off values were determined with the receiver-operating characteristic (ROC) curve, uni- and multivariate analyzes were calculated by the Cox proportional hazard regression model for overall survival (OS)., Results: Among 135 included patients, the majority were male (79.26%), with a mean age of 66.53 years. Elevated FAR correlated significantly (p = 0.002) with shorter OS in univariate analysis, also confirmed as independent prognostic factor (p = 0.005) in multivariable analysis. The ROC curve of FAR (AUC = 0.744) outperformed fibrinogen (AUC = 0.738) and albumin (AUC = 0.378) in predicting OS for AEG patients., Conclusion: The FAR serves as an independent prognostic factor for OS in patients undergoing primarily resection for AEG. Given its routine availability and ease of calculation, FAR could help in diagnosis and treatment selection for AEG patients. Further validation studies are warranted to confirm these findings conclusively., (© 2024. The Author(s).)

Competing Interests: Competing interests: None declared.

Background: Adenocarcinoma of the esophagogastric junction (AEGJ) is most common in men and the elderly, but the disease is becoming more common in female and young adult persons. We have investigated the clinicoepidemiological characteristics of female and young adult patients with AEGJ and the 12-year trends in the Kurashiki area for young adult patients with AEGJ., Methods: Patients diagnosed with AEGJ in 12 hospitals between January 2008 and December 2019 were included in this study. Patients were divided into three groups by age (young adult [≤50 years], middle-aged [51 to 70 years], and elderly [>70 years]). Factors associated with AEGJ such as obesity, smoking, hiatal hernia and male, which were reported in our previous study, were identified., Results: One hundred and eighty-eight AEGJ patients, including 36 females and 20 young adults, were characterized. There was no significant change in the annual incidence of AEGJ among female (p=0.078) and young adult patients (p=0.89). Female patients without any associated factors, accounting for 53% (19/36) of the female patients and young adult patients, had significantly more histologically undifferentiated cancers than patients with at least one associated factor (58% [11/19] vs. 30% [50/169], p=0.025) and middle-aged and elderly patients (60% [12/20] vs. 30% [25/83] vs. 28% [24/85], p =0.026). Smoking was significantly less common in women than in men (8% [3/36] vs. 57% [87/152], p < 0.01). There were no significant differences between ages in the proportions of these associated factors., Conclusions: Histologically undifferentiated AEGJ cancers were more frequent in female patients without any associated factors and in young adult patients. Factors associated with AEGJ may differ between women and men, but they are similar in young adults and older adults. No increase in young adult patients with AEGJ was observed in the 12-year study., (© 2024. The Author(s).)

Background: This study compares first-line pembrolizumab plus chemotherapy with chemotherapy alone for patients with HER2-negative advanced gastric cancer (GC) and gastroesophageal junction cancer (GEJC) in China., Methods: A Markov state-transition model was developed based on the phase 3 randomized KEYNOTE-859 clinical trial data. The health state utility values and direct medical costs were derived from the KEYNOTE-859 clinical trial, the relevant literature, and local charges. The measured outcomes included quality-adjusted life-years (QALYs) and the incremental cost-effectiveness ratio (ICER). Probabilistic and one-way sensitivity analyses (OWSA) were performed to assess the uncertainty of the model., Results: In the base analysis, the incremental effectiveness and cost of pembrolizumab plus chemotherapy versus chemotherapy alone were 0.22 QALYs and $16,627.31, respectively, resulting in an ICER of $76,936.60/QALY, which is higher than the willingness-to-pay threshold in China ($35,864.61/QALY). Subgroup analyses revealed that the ICERs of pembrolizumab plus chemotherapy versus chemotherapy alone were $72,762.68 and $34,813.70 in the populations with PD-L1 CPS of 1 or higher (CPS ≥ 1) and PD-L1 CPS ≥ 10 (CPS ≥ 10), respectively., Conclusions: As first-line therapy for patients with locally advanced or metastatic HER2-negative GC/GEJC in China, pembrolizumab plus chemotherapy is less cost-effective than chemotherapy alone, however, in the CPS ≥ 10 subgroup is more.

Background: Immunotherapy in combination with chemotherapy has been approved as an initial treatment strategy for unresectable advanced gastric cancer (GC). However, the efficacy of adding immunotherapy to perioperative chemotherapy in locally advanced resectable gastric or gastroesophageal junction adenocarcinoma (GC/GEJC) remains uncertain. Therefore, a meta-analysis of randomized controlled trials (RCTs) was performed to compare the effectiveness of perioperative immune checkpoint inhibitors (ICIs) plus chemotherapy versus chemotherapy alone in patients with locally advanced resectable GC/GEJC., Methods: A comprehensive search of online databases was conducted to identify RCTs published until November 30, 2023. Odds ratios (ORs) with 95% confidence interval (CI) were calculated for primary outcomes, including R0 resection rate, D2 lymphadenectomy, pathologic complete response (pCR), and treatment-related adverse events (TRAEs)., Results: A total of 2718 patients from five RCTs (six reports) were included in the analysis. The pooled ORs of R0 resection rate and D2 lymphadenectomy demonstrated that combination therapy with ICIs showed no significant difference compared to chemotherapy alone. However, the addition of ICIs significantly improved pCR rates (OR = 3.43, 95 % CI 2.61-4.50, p < 0.0001). There were no significant differences observed in the incidence of any grade TRAEs and grade 3-4 TRAEs. However, ICIs combination therapy was associated with significantly higher incidences of any grade irAEs (OR = 4.03, 95 % CI: 2.70-6.00, p < 0.0001), as well as grade 3-4 irAEs (OR = 4.51, 95 % CI: 2.27-8.97, p < 0.0001)., Conclusions: This study represents the first meta-analysis to demonstrate that perioperative combination therapy with ICIs yields superior pCR rates for patients with locally advanced GC/GEJC compared to chemotherapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Sitravatinib is a spectrum-selective tyrosine kinase inhibitor targeting TAM (TYRO3, AXL, MER), VEGFR-2, KIT, and MET. SAFFRON-104 (NCT03941873) was a multicohort phase Ib/II study investigating sitravatinib with/without tislelizumab, an anti-programmed cell death protein 1 (PD-1) antibody, in patients with advanced hepatocellular carcinoma (HCC) or gastric cancer/gastroesophageal junction cancer (GC/GEJC)., Methods: Eligible patients had histologically/cytologically confirmed advanced HCC or GC/GEJC. Phase I determined the recommended phase II dose (RP2D) of sitravatinib with/without tislelizumab. Phase II evaluated sitravatinib monotherapy in patients with pretreated HCC, and sitravatinib plus tislelizumab in anti-PD-(L)1-naïve or -treated HCC and anti-PD-(L)1-naïve GC/GEJC. Primary endpoints were safety/tolerability (phase I) and objective response rate (ORR) (phase II)., Results: At data cutoff (March 31, 2023), 111 patients were enrolled; 102 were efficacy-evaluable (median study follow-up 9.1 months [range: 0.7-36.9]). The RP2D of sitravatinib was determined as 120 mg orally once daily. In patients receiving sitravatinib monotherapy and sitravatinib in combination with tislelizumab, grade ≥ 3 treatment-related adverse events occurred in 14 (51.9%) and 42 (50.0%) patients, respectively. The ORR was 25% (95% confidence interval [CI]: 8.7-49.1) in patients with pretreated HCC receiving sitravatinib monotherapy. In patients receiving sitravatinib with tislelizumab, the ORR was 11.5% (95% CI 2.4-30.2) with anti-PD-(L)1-naïve HCC, 9.5% (95% CI 1.2-30.4) with anti-PD-(L)1-treated HCC, and 16.1% (95% CI 5.5-33.7) in patients with anti-PD-(L)1-naïve GC/GEJC., Conclusions: Sitravatinib with/without tislelizumab was generally well tolerated and showed preliminary antitumor activity in patients with advanced HCC and GC/GEJC., (© 2024. The Author(s).)

Background: Fusobacterium nucleatum inhabits the oral cavity and affects the progression of gastrointestinal cancer. Our prior findings link F. nucleatum to poor prognosis in oesophageal squamous cell carcinoma via NF-κB pathway. However, its role in oesophagogastric junction and gastric adenocarcinoma remains unexplored. We investigated whether F. nucleatum influences these cancers, highlighting its potential impact., Methods: Two cohorts of EGJ and gastric adenocarcinoma patients (438 from Japan, 380 from the USA) were studied. F. nucleatum presence was confirmed by qPCR, FISH, and staining. Patient overall survival (OS) was assessed based on F. nucleatum positivity. EGJ and gastric adenocarcinoma cell lines were exposed to F. nucleatum to study molecular and phenotypic effects, validated in xenograft mouse model., Results: In both cohorts, F. nucleatum-positive EGJ or gastric adenocarcinoma patients had notably shorter OS. F. nucleatum positivity decreased in more acidic tumour environments. Cancer cell lines with F. nucleatum showed enhanced proliferation and NF-κB activation. The xenograft model indicated increased tumour growth and NF-κB activation in F. nucleatum-treated cells. Interestingly, co-occurrence of F. nucleatum and Helicobacter pylori, a known risk factor, was rare., Conclusions: F. nucleatum can induce the NF-κB pathway in EGJ and gastric adenocarcinomas, leading to tumour progression and poor prognosis., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Molecularly targeted therapy for receptor tyrosine kinases (RTKs) has faced limitations in gastric and gastroesophageal junction (G/GEJ) cancer except for HER2-targeted agents, possibly due to inappropriate assay selection that has hindered identification of sensitive patients, in addition to coexisting genetic abnormalities as well as intratumoral heterogeneity. Immunohistochemistry of RTKs has, thus, proved largely unsuccessful for patient selection, and detection of RTK gene amplification as a true oncogenic driver is problematic given the small numbers of affected individuals. FGFR2 amplification is associated with poor prognosis in G/GEJ cancer, and immunohistochemistry of the FGFR2b protein isoform has proved effective for the detection of such FGFR2-dependent tumors. Phase III and Ib/III trials of the FGFR2-targeted antibody bemarituzumab for G/GEJ cancer overexpressing FGFR2b are ongoing based on the promising result in a phase II trial, especially in cases with an FGFR2b positivity of ≥ 10%. Challenges to EGFR- and MET-targeted therapies are being tackled with antibody-drug conjugates (ADCs) and bispecific antibodies. CLDN18.2 is expressed in some G/GEJ tumors but lacks oncogenic driver potential, and the CLDN18.2-targeted antibody zolbetuximab prolonged the survival of CLDN18.2-positive G/GEJ cancer patients in phase III trials. Antibody-drug conjugates and ADCs that target CLDN18.2 are also being pursued for treatment of such patients. Similarly, targeting of nondriver molecules such as DKK1, TROP2, and CEACAM5 is under investigation in early-stage clinical trials. This shift in focus from target molecules with driver potential to markers for precise drug delivery should increase the number of possible targets in G/GEJ cancer., (© 2024. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Recently, the presence of "Stroma AReactive Invasion Front Areas" (SARIFA) has been described as a promising adverse prognostic factor in gastric cancer. However, the validity of this approach still needs to be tested. The aim of this study was to independently assess the utility of the proposed method in a well-characterised cohort of primary resected adenocarcinomas of stomach and gastrooesophageal junction (n = 392). SARIFA status was analysed on routine slides of resection specimens. Cases were divided into SARIFA-positive and negative groups and analysed in relation to clinicopathological and survival data. SARIFA positivity was found in 15.1% (n = 59) cases and was significantly associated with Lauren phenotype (p < 0.001), pT (p = 0.001), pN (p = 0.018), UICC stage (p = 0.031), tumour budding (p = 0.002), overall survival (p < 0.001) and cancer-specific survival (p < 0.001). SARIFA-positive tumours had a worse prognosis in the multivariate setting (HR = 1.847, 95% CI: 1.300-2.624, p = 0.001). SARIFA status is an independent prognostic factor in gastric cancer, in particular in locally advanced tumours., (© 2024. The Author(s).)

Background: A minority of patients with MSS tumors present a high tumor mutation burden (TMB) without underlying MMR defects., Methods: Publicly available genomic series were assessed for identification of patients with MSS gastric gastroesophageal junction, and esophageal adenocarcinomas and a high TMB, defined as more than 10 mutations per Mb. These were compared with MSS cancers and a low TMB for genetic alterations and for survival outcomes., Results: Patients with MSS cancers with high TMB in the MSK series were older but did not differ in other clinicopathologic parameters compared with MSS patients with low TMB. Mutations in tumor suppressors TP53 and APC and oncogenes KRAS and ERBB4 as well as amplifications of ERBB2 were more prevalent in the high TMB group of MSS cancers. Mutations in DDR associated genes, in epigenetic modifiers and in genes associated with immune response were more prevalent in the hIgh TMB group patients. However, high TMB was not associated with an improved survival in MSS gastric/gastroesophageal junction/esophageal adenocarcinomas (Log Rank p  = 0.5)., Conclusion: MSS Gastric/gastroesophageal junction/esophageal adenocarcinomas with TMB above 10 mutations per Mb possess a genomic landscape with increased alteration frequencies in common gastroesophageal cancer genes and pathways.

Background: Limited data exist for global prevalence of claudin 18 isoform 2 (CLDN18.2) positivity and association of CLDN18.2 status with clinical and tumor characteristics in patients with locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma. We report prevalence of CLDN18.2 positivity (phase 3; SPOTLIGHT, NCT03504397; GLOW, NCT03653507) and concordance of CLDN18.2 status between a subset of pair-matched tumor samples (phase 2, ILUSTRO, NCT03505320; phase 1, NCT03528629) from clinical studies of zolbetuximab., Methods: Tumor samples from patients with LA unresectable or mG/GEJ adenocarcinoma were tested for CLDN18.2 status by immunohistochemistry. Human epidermal growth factor receptor 2 (HER2) expression was tested per central or local assessment., Results: Across SPOTLIGHT and GLOW, the prevalence of CLDN18.2 positivity (≥ 75% of tumor cells demonstrating moderate-to-strong membranous CLDN18 staining) was 38.4%. Prevalence was similar in gastric versus GEJ adenocarcinoma samples and regardless of collection method (biopsy versus resection) or collection site (primary versus metastatic). CLDN18.2 positivity was most prevalent in patients with diffuse-type tumors. In ILUSTRO and the phase 1 study, concordance of CLDN18.2 positivity was 61.1% between archival (i.e., any time before treatment) and baseline (i.e., ≤ 3 months before first treatment) samples, and concordance of any CLDN18 staining (≥ 1% of tumor cells demonstrating moderate-to-strong membranous CLDN18 staining) was 88.9%., Conclusions: CLDN18.2 was a highly prevalent biomarker in patients with HER2-negative, LA unresectable or mG/GEJ adenocarcinoma. CLDN18.2 positivity remained relatively stable over time in many patients. Biomarker testing for CLDN18.2 should be considered in standard clinical practice in these patients., (© 2024. The Author(s).)

Background: In the FIGHT study (NCT03694522) bemarituzumab, a humanized monoclonal antibody selective for fibroblast growth factor receptor 2b (FGFR2b), plus mFOLFOX6 showed clinically meaningful efficacy in patients with FGFR2b-positive (2+/3+ membranous staining by immunohistochemistry) locally advanced unresectable/metastatic gastric/gastroesophageal cancer (G/GEJC). A meaningful proportion of patients in FIGHT were enrolled in East Asia, reflecting global epidemiology of G/GEJC., Methods: This subgroup analysis of the global, phase 2, double-blind FIGHT study included all patients enrolled in East Asian sites. Patients were randomized 1:1 to bemarituzumab-mFOLFOX6 (15 mg/kg and one 7.5 mg/kg dose on cycle 1, day 8) or matching placebo-mFOLFOX6. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate, and safety. Efficacy was evaluated after a minimum follow-up of 24 months., Results: The East Asian subgroup comprised 89 patients (57% of overall study population); 45 were randomized to bemarituzumab-mFOLFOX6 and 44 to placebo-mFOLFOX6. Median PFS (95% confidence interval [CI]) was 12.9 months (8.8-17.9) with bemarituzumab-mFOLFOX6 and 8.2 months (5.6-10.3) with placebo-mFOLFOX6 (HR 0.50, 95% CI 0.29-0.87); median OS (95% CI) was 24.7 months (13.8-33.1) vs 12.9 months (9.3-21.4), respectively (HR 0.56, 95% CI 0.32-0.96). Treatment benefit was more pronounced in patients with FGFR2b-positive G/GEJC in ≥ 10% of tumor cells. No new safety signals were reported., Conclusion: In East Asian patients with FGFR2b-positive advanced/metastatic G/GEJC enrolled in the global FIGHT study, bemarituzumab-mFOLFOX6 showed clinically meaningful outcomes over placebo-mFOLFOX6., (© 2024. The Author(s).)

Objective: To investigate the significance of endoscopic grading (Hill's classification) of gastroesophageal flap valve (GEFV) in the examination of patients with gastroesophageal reflux disease (GERD)., Methods: One hundred and sixty-two patients undergoing gastroscopy in the Department of Gastroenterology, Xingyi People's Hospital between Apr. 2022 and Sept. 2022 were selected by convenient sampling, and data such as GEFV grade, and findings of esophageal high-resolution manometry (HRM) and esophageal 24-h pH/impedance reflux monitoring, and Los Angeles (LA) classification of reflux esophagitis (RE) were collected and compared., Results: Statistically significant differences in age (F = 9.711, P < 0.001) and hiatal hernia (χ = 35.729, P < 0.001) were observed in patients with different GEFV grades. The resting LES pressures were 12.12 ± 2.79, 10.73 ± 2.68, 9.70 ± 2.29, and 8.20 ± 2.77 mmHg (F = 4.571, P < 0.001) and LES lengths were 3.30 ± 0.70, 3.16 ± 0.68, 2.35 ± 0.83, and 2.45 ± 0.62 (F = 3.789, P = 0.011), respectively, in patients with GEFV grades I-IV. DeMeester score (Z = 5.452, P < 0.001), AET4 (Z = 5.614, P < 0.001), acid reflux score (upright) (Z = 7.452, P < 0.001), weak acid reflux score (upright) (Z = 3.121, P = 0.038), liquid reflux score (upright) (Z = 3.321, P = 0.031), acid reflux score (supine) (Z = 6.462, P < 0.001), mixed reflux score (supine) (Z = 3.324, P = 0.031), gas reflux score (supine) (Z = 3.521, P = 0.024) were different in patients with different GEFV grades, with statistically significant differences. Pearson correlation analysis revealed a positive correlation between RE grade and LA classification of GERD (r = 0.662, P < 0.001), and the severity of RE increased gradually with the increase of the Hill grades of GEFV., Conclusion: The Hill grade of GEFV is related to age, hiatal hernia, LES pressure, and the consequent development and severity of acid reflux and RE. Evaluation of esophageal motility and reflux based on the Hill grade of GEFV is of significance for the diagnosis and treatment of GERD., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Human epidermal growth factor receptor-2 (HER2), programmed death-ligand 1 (PD-L1), and microsatellite (MS) status are well-established biomarkers in gastroesophageal adenocarcinomas (GEAs). However, it is unclear how the combination of these biomarkers is associated with clinicopathological factors and prognosis. This retrospective study included baseline metastatic GEA patients who were tested for all three biomarkers (HER2, PD-L1, and MS status) at the MD Anderson Cancer Center between 2012 and 2022. Stratification was performed according to the combination of biomarker profiles: triple negative (TN), single positive (SP), and multiple positive (MP). Comparative analyses of clinicopathological factors and survival using combinations of biomarkers were performed. Among the 698 GEA patients analyzed, 251 (36.0%) were classified as TN, 334 (47.9%) as SP, and 113 (16.1%) as MP. The MP group showed a significant association with tumors located in the esophagus (p < .001), well to moderate differentiation (p < .001), and the absence of signet ring cells (p < .001). In the survival analysis, MP group had a significantly longer overall survival (OS) compared to the other groups (MP vs. TN, p < .001 and MP vs. SP, p < .001). Multivariate Cox regression analysis revealed that MP serves as an independent positive prognostic indicator for OS (hazard ratio = 0.63, p < .01). Our findings indicate that MP biomarkers are associated with a favorable prognosis in metastatic GEA. These results are reflective of clinical practice and offer valuable insights into how therapeutics and future biomarkers could influence therapy/prognosis., (© 2024 UICC.)

No study has unequivocally proven that chemotherapy prolongs overall survival (OS) in advanced esophageal cancer. We conducted a Phase III randomized study in first-line advanced unresectable/metastatic esophageal/GEJ cancer. Patients aged 18-70 years, with performance status 0-2, were randomized to best supportive care (BSC) alone, or BSC with weekly paclitaxel 80 mg/m 2 . BSC comprised, as indicated, education, counselling, radiation, stenting, feeding tube placement, nutritional supplementation, medications like analgesics, and referral to a support group and palliative care. The primary endpoint was OS; secondary endpoints included progression free survival (PFS), response, toxicity, and QoL. Between May 2016-December 2020, we recruited 281 patients: 143 to chemotherapy and 138 to BSC. Histopathology was squamous in 269 (95.7%) patients. Median number of paclitaxel doses was 12 (IQR, 7-23). Median OS was 4.2 months (95% CI, 3.42-5.32) in BSC, and 9.2 months (95% CI, 8.02-10.48) in chemotherapy; HR, 0.49 (95% CI, 0.39-0.64); p < .001. As compared to BSC, chemotherapy increased response (2.9% to 39%), median PFS (2.1 to 4.2 months), 1-year OS (11% to 32%), 2-year OS (0 to 9%), median dysphagia-free survival (2.9 to 14.8 months), and global and esophagus-specific QoL, without significantly increasing all-grade or grade ≥3 toxicities. Using ESMO clinical benefit scale and ASCO Value Framework, palliative chemotherapy scored as having "substantial value." Our study provides the first level 1 evidence that chemotherapy prolongs survival in advanced esophageal/GEJ carcinoma. BSC alone is no longer appropriate. Weekly paclitaxel is an attractive option, especially in LMICs with limited access to immunotherapy., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Competing Interests: The authors declare that they have no conflict of interest.

Standardized assessment of the gastroesophageal valve during endoscopy, attainable via the Hill classification, is important for clinical assessment and therapeutic decision making. The Hill classification is associated with the presence of hiatal hernia (HH), a common endoscopic finding connected to gastro-esophageal reflux disease. A novel efficient medical artificial intelligence (AI) training pipeline using active learning (AL) is designed. We identified 21,970 gastroscopic images as training data and used our AL to train a model for predicting the Hill classification and detecting HH. Performance of the AL and traditionally trained models were evaluated on an external expert-annotated image collection. The AL model achieved accuracy of 76%. A traditionally trained model with 125% more training data achieved 77% accuracy. Furthermore, the AL model achieved higher precision than the traditional one for rare classes, with 0.54 versus 0.39 (p < 0.05) for grade 3 and 0.72 versus 0.61 (p < 0.05) for grade 4. In detecting HH, the AL model achieved 94% accuracy, 0.72 precision and 0.74 recall. Our AL pipeline is more efficient than traditional methods in training AI for endoscopy., (© 2024. The Author(s).)

Preclinical studies suggest that simultaneous HER2/VEGF blockade may have cooperative effects in gastroesophageal adenocarcinomas. In a single-arm investigator initiated clinical trial for patients with untreated advanced HER2+ gastroesophageal adenocarcinoma, bevacizumab was added to standard of care capecitabine, oxaliplatin, and trastuzumab in 36 patients (NCT01191697). Primary endpoint was objective response rate and secondary endpoints included safety, duration of response, progression free survival, and overall survival. The study met its primary endpoint with an objective response rate of 81% (95% CI 65-92%). Median progression free and overall survival were 14.0 (95% CI, 11.3-36.4) and 23.2 months (95% CI, 16.6-36.4), respectively. The median duration of response was 14.9 months. The regimen was well tolerated without unexpected or severe toxicities. In post-hoc ctDNA analysis, baseline ctDNA features were prognostic: Higher tumor fraction and alternative MAPK drivers portended worse outcomes. ctDNA at resistance identified oncogenic mutations and these were detectable 2-8 cycles prior to radiographic progression. Capecitabine, oxaliplatin, trastuzumab and bevacizumab shows robust clinical activity in HER2+ gastroesophageal adenocarcinoma. Combination of VEGF inhibitors with chemoimmunotherapy and anti-PD1 regimens is warranted., (© 2024. The Author(s).)

N 6-Methyladenosine (m 6 A) modification and its regulators play critical roles in human cancers, but their functions and regulatory mechanisms in adenocarcinoma of the esophagogastric junction (AEG) remain unclear. Here, we identified that IGF2BP3 is the most significantly up-regulated m 6 A regulator in AEG tumors versus paired normal adjacent tissues from the expression profile of m 6 A regulators in a large cohort of AEG patients. Silencing IGF2BP3 inhibits AEG progression in vitro and in vivo . By profiling transcriptome-wide targets of IGF2BP3 and the m 6 A methylome in AEG, we found that IGF2BP3-mediated stabilization and enhanced expression of m 6 A-modified targets, including targets of the cell cycle pathway, such as CDC25A , CDK4 , and E2F1 , are critical for AEG progression. Mechanistically, the increased m 6 A modification of CDC25A accelerates the G1-S transition. Clinically, up-regulated IGF2BP3, METTL3, and CDC25A show a strong positive correlation in TCGA pan-cancer, including AEG. In conclusion, our study highlights the role of post-transcriptional regulation in modulating AEG tumor progression and elucidates the functional importance of the m 6 A/IGF2BP3/CDC25A axis in AEG cells., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Most patients with metastatic gastroesophageal adenocarcinoma (mGEA) progress on immune checkpoint inhibitors (ICIs). Novel approaches to overcome resistance to ICI in mGEA are needed. Cabozantinib is a multi-tyrosine kinase inhibitor thought to enhance the immunomodulatory effects of ICI. This study evaluated the combination of cabozantinib and pembrolizumab in ICI refractory or resistant mGEA., Methods: Investigator-initiated, single-arm, single institution, and phase II study in patients with mGEA. Patients had progressed on ICI and/or had PD-L1 CPS score ≤10%. Cabozantinib dose was 40 mg p.o. daily on days 1-21 of a 21-day cycle, with pembrolizumab 200 mg i.v. on day 1. The primary endpoint was progression-free survival at 6 months (PFS-6)., Results: Twenty-seven patients were enrolled. Median age 58 years (24-87), female (n = 14), ECOG 0/1 = 13/14, GC/GEJ = 16/11, and non-Hispanic White/Hispanic/Asian = 12/8/7. The primary endpoint was met. After a median follow-up of 31.4 months (range 3.3-42.5), PFS-6 was 22.2% (95% CI 9.0-39.0). The median PFS and OS are 2.3 months (95% CI 1.7-4.1) and 5.5 months (3.1-14.0), respectively. The most common mutations were TP53 (78.3%) and CDH1/PIK3CA/CTNNB1 (17.4% each). The most common grade (G) treatment-related adverse events (TRAE) were diarrhea (25.9%), fatigue (18.5%), hypertension, and muscle cramps (14.8% each). G3-4 TRAE were seen in n = 3 patients (hypertension, thromboembolic event, esophageal perforation; each n = 1). No G5 was observed., Conclusions: The addition of cabozantinib to pembrolizumab shows clinical benefit in ICI-resistant or refractory mGEA with a tolerable safety profile. (ClinicalTrials.gov Identifier: NCT04164979. IRB Approved: UCI 18-124, University of California Irvine IRB#20195426.)., (© The Author(s) 2024. Published by Oxford University Press.)

Letter to the Editor Regarding 'Impact of the number of therapy lines on survival in advanced gastric and esophagogastric adenocarcinoma - a real-world retrospective analysis from Croatia', published in Neoplasma 2024; 71: 201-208. https://doi.org/10.4149/neo&#95;2024&#95;231209N633.

Background: First-line zolbetuximab plus chemotherapy (SPOTLIGHT, mFOLFOX6; GLOW, CAPOX) significantly improved progression-free survival (PFS) and overall survival (OS) versus placebo plus chemotherapy in patients with human epidermal growth factor receptor 2-negative, locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma whose tumors were claudin 18 isoform 2-positive in the phase III SPOTLIGHT (NCT03504397) and GLOW (NCT03653507) studies. We present patient-reported outcomes (PROs) from these studies., Materials and Methods: Health-related quality of life (HRQoL) was measured in the full analysis sets using the European Organisation for Research and Treatment of Cancer Quality of Life of Cancer Patients Core Questionnaire (QLQ-C30) and Oesophago-Gastric Module (QLQ-OG25), Global Pain, and 5-level EQ-5D (EQ-5D-5L) questionnaires. Analyses focused on key PRO domains: global health status (GHS)/QoL, physical functioning, abdominal pain and discomfort, and nausea/vomiting. Least squares mean (LSM) changes from baseline and time to first definitive deterioration (TTDD) were evaluated combined across SPOTLIGHT and GLOW and for individual studies. Time to confirmed deterioration (TTCD) was evaluated independently for SPOTLIGHT and GLOW., Results: The combined analysis set included 1072 patients (zolbetuximab plus chemotherapy, 537; placebo plus chemotherapy, 535). Compliance rates were similar between treatment arms. Similar trends were observed in the zolbetuximab versus placebo arms for LSM changes from baseline in key PRO domains, with no clinically meaningful deterioration. Nausea/vomiting worsened during the first few zolbetuximab cycles but later returned to baseline levels. Overall TTCD and TTDD results were similar between arms in both studies., Conclusions: Patients in SPOTLIGHT and GLOW maintained measured HRQoL relative to baseline when treated with first-line zolbetuximab added to chemotherapy. Zolbetuximab plus chemotherapy improved PFS and OS without negatively affecting HRQoL in key PRO domains compared with placebo plus chemotherapy., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The development of programmed cell death receptor-1 and its ligand (PD-L1) have offered new treatment options for several cancers, but the clinical benefit of tislelizumab in the gastroesophageal junction (GEJ) adenocarcinoma is still murky. Thus, we aim to investigate the efficacy and safety of tislelizumab combined with chemotherapy in patients with GEJ cancer. In this study, 90 GEJ patients were retrospectively enrolled including 45 patients who received chemotherapy plus tislelizumab while 45 underwent chemotherapy only. Overall response rate (ORR), overall survival (OS), and progression-free survival (PFS) were estimated and safety was assessed by treatment-related adverse events between two arms. The ORR was significantly higher in the tislelizumab group than in patients with chemotherapy alone (71.1 vs. 44.4%). The PFS [54.7% (47.2-62.2) vs. 33.3% (26.3-40.3), P  = 0.047] and OS [62.1% (54.5-69.7) vs. 40.0% (32.5-47.5), P  = 0.031] were also significantly improved in patients with concomitant use of tislelizumab. When stratified by PD-L1 combined positive score (CPS), patients with PD-L1 CPS ≥ 1 also with significantly higher PFS and OS when taking tislelizumab ( P  = 0.015 and P  = 0.038). The incidence of hematologic toxicity was similar in the combination arm compared to the chemotherapy alone arm and the number of adverse events was not significantly increased by adding tislelizumab (all P  > 0.05). Concomitant use of tislelizumab and chemotherapy in GEJ patients may be with optimal therapeutic effect and similar incidence of adverse events than chemotherapy alone. Further studies with larger number of patients are warranted to confirm it., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The z-line refers to the squamocolumnar junction which marks the transition between the normal stratified squamous epithelium of the distal esophagus and the columnar epithelium of the gastric cardia. An "irregular" z-line refers to an irregular appearing squamocolumnar junction characterized by the presence of columnar mucosa less than 1 cm in length that extends above the gastroesophageal junction. In contrast, Barrett's esophagus is diagnosed when columnar mucosa of at least 1 cm is seen in the distal esophagus extending above the gastroesophageal junction with biopsies demonstrating specialized intestinal metaplasia. Current guidelines recommend against taking routine biopsies from a normal or irregular z-line in the absence of visible abnormalities and advise against endoscopic surveillance in this patient population, in large part due to multiple studies demonstrating lack of progression to advanced neoplasia such as high-grade dysplasia or esophageal adenocarcinoma in patients with an irregular z-line. Despite these recommendations, a sizable number of patients without Barrett's esophagus undergo biopsies from the z-line and are subsequently recommended to have surveillance endoscopies. Furthermore, patients with an irregular z-line are often mislabelled as Barrett's esophagus resulting in significant downstream consequences including higher healthcare costs and reduced health-related quality of life. In this review, we highlight the importance of landmark identification of the distal esophagus and gastroesophageal junction at the time of endoscopy, share recommendations from current guidelines related to the z-line, examine rates of neoplastic progression in those with an irregular z-line, discuss consequences of routinely biopsying an irregular z-line, and highlight strategies on how to approach an irregular z-line if seen on endoscopy. A careful, high-quality endoscopic examination can help to identify visible abnormalities at the z-line, which, if present, should be targeted for biopsies to rule out dysplasia and neoplasia., (© 2024. The Author(s).)

Purpose: To describe the global landscape of clinical research into interventions for gastroesophageal cancers (GECs), with examination of trial characteristics, geographic distribution of trial sites, and factors associated with trial termination., Methods: We queried ClinicalTrials.gov to identify all completed or terminated phase III interventional studies investigating GECs (esophageal squamous cell carcinoma [ESCC], esophageal adenocarcinoma [EAC], gastroesophageal junctional [GEJ], and gastric adenocarcinoma). Data on all reported trial characteristics were extracted. Pearson's chi-square and Fisher's exact tests were used to compare differences in completed and terminated trials. Multivariate logistic regression evaluated predictors of termination., Results: A total of 179 trials were identified; of these, 90% were therapeutic. Most included sites in Asia (61%) and Europe (32%); few included sites in Africa (4%). Thirty percent included sites in low- and middle-income countries (LMICs). Most (70%) focused on gastric or GEJ adenocarcinoma, 13% on EAC and ESCC, and 9% on ESCC alone. Sixteen percent (n = 29) of trials terminated prematurely. In multivariate analysis, study site number, location of recruitment sites, and patient population emerged as predictors of termination. Trials recruiting from US-based sites were more likely to terminate (odds ratio [OR], 7.22 [95% CI, 1.59 to 32.69]). Trials conducted exclusively in LMICs were less likely to terminate (OR, 0.04 [95% CI, 0.01 to 0.59] v conducted in high-income countries [HICs] alone). Studies on ESCC were more likely to terminate (OR, 17.74 [95% CI, 1.49 to 210.69])., Conclusion: Although 80% of GECs occur in LMICs, trial activity disproportionately occurs in HICs. Few trials focus on EAC/ESCC despite being highly fatal, highlighting an unmet need. Overall, this study highlights (1) a missed opportunity to recruit patients from high-incidence regions globally; and (2) a pressing need for increasing funding, infrastructure, and support for GEC trials in LMICs.

Background: Neoadjuvant therapy regimens have significantly improved the prognosis of GEJ (gastroesophageal junction) cancer; however, there are a significant percentage of patients who benefit from earlier resection or adapted therapy regimens, and the true response rate can only be determined histopathologically. Methods that allow preoperative assessment of response are lacking., Purpose: The purpose of this retrospective study is to assess the potential of pretherapeutic and posttherapeutic spectral CT iodine density (IoD) in predicting histopathological response to neoadjuvant chemotherapy in patients diagnosed with adenocarcinoma of the GEJ., Methods: In this retrospective cohort study, a total of 62 patients with GEJ carcinoma were studied. Patients received a multiphasic CT scan at diagnosis and preoperatively. Iodine-density maps were generated based on spectral CT data. All tumors were histopathologically analyzed, and the tumor regression grade (TRG) according to Becker et al ( Cancer . 2003;98:1521-1530) was determined. Two experienced radiologists blindly placed 5 defined ROIs in the tumor region of highest density, and the maximum value was used for further analysis. Iodine density was normalized to the aortic iodine uptake. In addition, tumor response was assessed according to standard RECIST measurement. After assessing interrater reliability, the correlation of IoD values with treatment response and with histopathologic TRG was evaluated., Results: The normalized ΔIoD (IoD at diagnosis - IoD after neoadjuvant treatment) and the normalized IoD after neoadjuvant treatment correlated significantly with the TRG. For the detection of responders and nonresponders, the receiver operating characteristic (ROC) curve for normalized ΔIoD yielded the highest area under the curve of 0.95 and achieved a sensitivity and specificity of 92.3% and 92.1%, respectively. Iodine density after neoadjuvant treatment achieved an area under the curve of 0.88 and a sensitivity and specificity of 86.8% and 84.6%, respectively (cutoff, 0.266). Iodine density at diagnosis and RECIST did not provide information to distinguish responders from nonresponders. Using the cutoff value for IoD after neoadjuvant treatment, a reliable classification of responders and nonresponders was achieved for both readers in a test set of 11 patients. Intraclass correlation coefficient revealed excellent interrater reliability (intraclass correlation coefficient, >0.9). Lastly, using the cutoff value for normalized ΔIoD as a definition for treatment response, a significantly longer survival of responders was shown., Conclusions: Changes in IoD after neoadjuvant treatment of GEJ cancer may be a potential surrogate for therapy response., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Zolbetuximab (VYLOY™), a recombinant, chimeric, anti-claudin 18.2 (CLDN18.2) monoclonal antibody (mAb), is being developed by Astellas Pharma Inc. for the treatment of patients with HER2-negative (HER2 - ), CLDN18.2-positive (CLDN18.2 + ) advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma and CLDN18.2 + advanced pancreatic adenocarcinoma. In March 2024, zolbetuximab was approved in Japan for the treatment of patients with HER2 - , CLDN18.2 + unresectable, advanced/recurrent gastric cancer (the gastric cancer indication includes GEJ cancer). Zolbetuximab is also undergoing regulatory review for HER2 - , CLDN18.2 + advanced gastric or GEJ adenocarcinoma in the USA, the EU, China, Australia and several other countries. This article summarizes the milestones in the development of zolbetuximab leading to this first approval for the treatment of patients with CLDN18.2 + gastrointestinal malignancies., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: There is a consensus that identifying the distal end of the palisade vessels (DEPV) is important for diagnosing gastroesophageal junction (GEJ). However, optimum observation methods have not been established. This study investigated the use of effective image-enhanced endoscopy (IEE) for DEPV detection., Methods: One hundred endoscopic images in 20 cases of columnar metaplastic mucosa of the GEJ recorded with white-light imaging (Olympus-WLI and Fujifilm-WLI) and IEEs (narrow-band imaging; RDI1/2/3, red dichromatic imaging; texture and color enhancement imaging 1/2; blue-laser imaging; and LCI, linked color imaging) from two manufacturers were extracted and evaluated by 10 evaluators. Up to 24 radial straight lines from the center of the lumen were placed on the image, and the evaluators placed markings according to confidence level (high, low, and not detectable) at the DEPV locations. The detectability and reproducibility at the rate of the confidence level and coefficient of variance of markings among the evaluator were analyzed., Results: In total, 15,180 markings were obtained. In terms of detectability, RDI1 (49.4%), RDI2 (53.0%), RDI3 (54.1%), TXI2 (49.7%), and LCI (34.6%) had a significantly higher rate of high confidence among the IEEs in each manufacturer. By contrast, Olympus-WLI (40.6%), Fujifilm-WLI (17.6%), narrow-band imaging (15.9%), and blue laser imaging (9.8%) presented with a significantly lower rates of high confidence. Regarding reproducibility, RDI3 and LCI had the lowest coefficient of variance for each manufacturer., Conclusions: RDI and LCI could be reliable modalities for detecting DEPVs in the columnar metaplastic mucosa of the GEJ zone., (© 2024. Japanese Society of Gastroenterology.)

Background: In Asia, adjuvant chemotherapy after gastrectomy with D2 or more extensive lymph-node dissection is standard treatment for people with pathological stage III gastric or gastro-oesophageal junction (GEJ) cancer. We aimed to assess the efficacy and safety of adjuvant nivolumab plus chemotherapy versus placebo plus chemotherapy administered in this setting., Methods: ATTRACTION-5 was a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial conducted at 96 hospitals in Japan, South Korea, Taiwan, and China. Eligible patients were aged between 20 years and 80 years with histologically confirmed pathological stage IIIA-C gastric or GEJ adenocarcinoma after gastrectomy with D2 or more extensive lymph-node dissection, with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 and available tumour tissue for PD-L1 expression analysis. Patients were randomly assigned (1:1) to receive either nivolumab plus chemotherapy or placebo plus chemotherapy via an interactive web-response system with block sizes of four. Investigational treatment, either nivolumab 360 mg or placebo, was administered intravenously for 30 min once every 3 weeks. Adjuvant chemotherapy was administered as either tegafur-gimeracil-oteracil (S-1) at an initial dose of 40 mg/m 2 per dose orally twice per day for 28 consecutive days, followed by 14 days off per cycle, or capecitabine plus oxaliplatin consisting of an initial dose of intravenous oxaliplatin 130 mg/m 2 for 2 h every 21 days and capecitabine 1000 mg/m 2 per dose orally twice per day for 14 consecutive days, followed by 7 days off treatment. The primary endpoint was relapse-free survival by central assessment. The intention-to-treat population, consisting of all randomly assigned patients, was used for analysis of efficacy endpoints. The safety population, defined as patients who received at least one dose of trial drug, was used for analysis of safety endpoints. This trial is registered with ClinicalTrials.gov (NCT03006705) and is closed., Findings: Between Feb 1, 2017, and Aug 15, 2019, 755 patients were randomly assigned to receive either adjuvant nivolumab plus chemotherapy (n=377) or adjuvant placebo plus chemotherapy (n=378). 267 (71%) of 377 patients in the nivolumab group and 263 (70%) of 378 patients in the placebo group were male; 110 (29%) of 377 patients in the nivolumab group and 115 (31%) of 378 patients in the placebo group were female. 745 patients received assigned treatment (371 in the nivolumab plus chemotherapy group; 374 in the placebo plus chemotherapy group), which was the safety population. Median time from first dose to data cutoff was 49·1 months (IQR 43·1-56·7). 3-year relapse-free survival was 68·4% (95% CI 63·0-73·2) in the nivolumab plus chemotherapy group and 65·3% (59·9-70·2) in the placebo plus chemotherapy group; the hazard ratio for relapse-free survival was 0·90 (95·72% CI 0·69-1·18; p=0·44). Treatment-related adverse events occurred in 366 (99%) of 371 patients in the nivolumab plus chemotherapy group and 364 (98%) of 374 patients in the placebo plus chemotherapy group. Discontinuation due to adverse events was more frequent in the nivolumab plus chemotherapy group (34 [9%] of 371 patients) than the placebo plus chemotherapy group (13 [4%] of 374 patients). The most common treatment-related adverse events were decreased appetite, nausea, diarrhoea, neutrophil count decreased, and peripheral sensory neuropathy., Interpretation: The results of this trial do not support the addition of nivolumab to postoperative adjuvant therapy for patients with untreated, locally advanced, resectable gastric or GEJ cancer., Funding: Ono Pharmaceutical and Bristol Myers Squibb., Competing Interests: Declaration of interests Y-KK is a consultant for ALX Oncology, Amgen, Blueprint Medicines, Bristol Myers Squibb, DAE HWA Pharmaceutical, Macrogenics, Novartis, Surface Oncology, and Zymeworks. MT receives honoraria from Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Intuitive Surgical, Johnson & Johnson, Eli Lilly, Medtronic, Olympus, Ono Pharmaceutical, Pfizer, Taiho Pharmaceutical, Takeda Pharmaceuticals, and Yakult Honsha and receives institutional research funding from Ono Pharmaceutical. NB receives honoraria from Bristol Myers Squibb Japan, Daiichi Sankyo, Ono Pharmaceutical, and Taiho Pharmaceutical and receives institutional research funding from Ono Pharmaceutical and Takeda Pharmaceuticals. HCC is an employee of MDBiolab; is a consultant for Amgen, BeiGene, Bristol Myers Squibb, Celltrion, Gloria Biosciences, Eli Lilly, Merck Serono Pharmaceutical, MSD, Quintiles, Taiho Pharmaceutical, and Zymeworks; receives speakers fees from Foundation Medicine, Eli Lilly, and Merck Serono; and receives institutional research funding from Amgen, BeiGene, Bristol Myers Squibb, GlaxoSmithKline, Incyte, Eli Lilly, Merck Serono, MSD, Taiho Pharmaceutical, and Zymeworks. J-SC receives research funding from Amgen, Astellas Pharma, AstraZeneca, Janssen, Merck, MSD Oncology, Ono Pharmaceutical, Roche, Senhwa Biosciences, and TTY Biopharm. L-TC is independent director of ScinoPharm; receives honoraria from ACT Genomics, AstraZeneca, Bristol Myers Squibb, Eli Lilly, MSD, Novartis, Ono Pharmaceutical, PharmaEngine, SynCoreBio, and TTY Biopharm; is a consultant for AstraZeneca, Bristol Myers Squibb, CStone Pharmaceuticals, Ipsen Pharma, Eli Lilly, MSD, Ono Pharmaceutical, Onward Therapeutics, Taivex Therapeutics, and TTY Biopharm; receives institutional research funding from ACT Genomics, Celgene, Novartis, OBI Pharma, Pfizer, Polaris Pharmaceuticals, SynCoreBio, and TTY Biopharm; and holds patents, royalties, and other intellectual property related to anti-α-enolase monoclonal antibody from HuniLife Biotechnology. M-HR receives honoraria from AstraZeneca, Bristol Myers Squibb, DAE HWA Pharmaceutical, Daiichi Sankyo, Eli Lilly, MSD, Novartis, Ono Pharmaceutical, and Taiho Pharmaceutical; is a consultant for AstraZeneca, Bristol Myers Squibb, DAE HWA Pharmaceutical, Daiichi Sankyo, Eli Lilly, MSD, Novartis, Ono Pharmaceutical, and Taiho Pharmaceutical. TO receives honoraria and institutional research funding from Daiichi Sankyo. SYR is a consultant for Amgen, Astellas Pharma, AstraZeneca, Daiichi Sankyo, Eisai, Eutilex, Indivumed, LG Chem, MSD Oncology, and Ono Pharmaceutical; receives speakers fees from Amgen, AstraZeneca, Bristol Myers Squibb, Ono Pharmaceutical, Daiichi Sankyo, Union Chimique Belge Japan, Eisai, Eli Lilly, and MSD Oncology; and receives research funding from Amgen (paid to their institution), ASLAN Pharmaceuticals, Astellas Pharma, AstraZeneca, Bayer, BeiGene, Bristol Myers Squibb, Daichii Sankyo, Eisai, Indivumed, Eli Lilly, MSD Oncology, Roche–Genentech, Sillajen, and Zymeworks. TY receives honoraria from Bristol Myers Squibb, Johnson & Johnson, Janssen, Ono Pharmaceutical, and Taiho Pharmaceutical. MS receives honoraria from Chugai Pharmaceutical, Daiichi Sankyo, Ono Pharmaceutical, and Taiho Pharmaceutical. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Trifluridine/tipiracil (FTD/TPI) is approved in third-line treatment of patients with advanced/metastatic gastric and gastroesophageal junction adenocarcinomas (aGA/GEJA). The association of oxaliplatin with FTD/TPI is promising and the combination of FTD/TPI + oxaliplatin + nivolumab has shown a predictable and manageable safety profile., Aims: The aim is to evaluate the efficacy and safety of FTD/TPI plus oxaliplatin with or without nivolumab in patients, with HER2 negative aGA/GEJA, unfit for triplet chemotherapy (TFOX/mFLOT regimen), in the first-line metastatic setting in comparison with the standard of care FOLFOX with or without nivolumab., Methods: This study is a prospective randomised, open label, comparative, multicentre, phase II trial designed to include 118 patients. The primary objective is to evaluate the superiority of FTD/TPI plus oxaliplatin with or without nivolumab over FOLFOX regimen with or without nivolumab in terms of PFS in a population of patients non candidate for triplet chemotherapy. Nivolumab will be used for patients whose tumour express PD-L1 with a CPS score ≥5., Discussion: PRODIGE73-UCGI40-LOGICAN study will provide efficacy and safety data on the association of FTD/TPI plus oxaliplatin with or without nivolumab versus FOLFOX regimen with or without nivolumab in first-line palliative setting, in patients with aGA/GEJA (NCT05476796)., Competing Interests: Conflict of interest D.B. reports personal fees as a speaker and/or in an advisory role from Accord Healthcare, Amgen, Sanofi, Servier, and Pierre Fabre, outside the submitted work. O.B. reports personal fees as a speaker and/or in an advisory role from Merck, Bayer, Apmonia Therapeutics, Deciphera, Takeda, MSD, Amgen, Servier, and Pierre Fabre, outside the submitted work. C.C. reports personal fees as speaker and/or in an advisory role from Amgen, Astra-Zeneca, Pierre Fabre, Daiichy Sankyo, BMS, MSD, Merck Serono, Servier, outside the submitted work. O.D. reports personal fees as speaker and/or in an advisory role from Astra-Zeneca, BMS, MSD, Merck Serono, Sanofi, Servier outside the submitted work. DT: Honoraria: Amgen, Roche, Sanofi, Bristol Myers Squibb, Merck Serono, MSD, Bristol Myers Squibb, Servier, Ipsen, Pierre Fabre, AstraZeneca, Takeda, BeiGene, Astra Zeneca. Consulting or Advisory Role: Sanofi, MSD, Pierre Fabre, AstraZeneca, Novartis, Takeda. Research Funding: AstraZeneca (Inst), Servier (Inst), Roche (Inst), MSD (Inst), BTG (Inst). Travel, Accommodations, Expenses: Roche, Amgen, Bristol Myers Squibb, MSD, Pierre Fabre. CDLF: Honoraria: Amgen, AstraZeneca,Bayer, BeiGene, Bristol Myers Squibb, Ipsen, Merck, MSD, Pierre Fabre, Servier, Roche, Sanofi, Takeda. Consulting or Advisory Role: MSD, Pierre Fabre, AstraZeneca, Takeda. Research Funding: Servier (Inst), Roche (Inst), MSD (Inst). Travel, Accommodations, Expenses: Roche, Amgen, MSD, Pierre Fabre, Servier., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Importance: The prognosis of patients with adenocarcinoma of the esophagus and esophagogastric junction (AEG) is poor. From current evidence, it remains unclear to what extent preoperative chemoradiotherapy (CRT) or preoperative and/or perioperative chemotherapy achieve better outcomes than surgery alone., Objective: To assess the association of preoperative CRT and preoperative and/or perioperative chemotherapy in patients with AEG with overall survival and other outcomes., Data Sources: Literature search in PubMed, Cochrane Library, Cumulative Index to Nursing and Allied Health Literature, ClinicalTrials.gov, and International Clinical Trials Registry Platform was performed from inception to April 21, 2023., Study Selection: Two blinded reviewers screened for randomized clinical trials comparing preoperative CRT plus surgery with preoperative and/or perioperative chemotherapy plus surgery, 1 intervention with surgery alone, or all 3 treatments. Only data from participants with AEG were included from trials that encompassed mixed histology or gastric cancer. Among 2768 initially identified studies, 17 (0.6%) met the selection criteria., Data Extraction and Synthesis: The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines were followed for extracting data and assessing data quality by 2 independent extractors. A bayesian network meta-analysis was conducted using the 2-stage approach., Main Outcomes and Measures: Overall and disease-free survival, postoperative morbidity, and mortality., Results: The analyses included 2549 patients (2206 [86.5%] male; mean [SD] age, 61.0 [9.4] years) from 17 trials (conducted from 1989-2016). Both preoperative CRT plus surgery (hazard ratio [HR], 0.75 [95% credible interval (CrI), 0.62-0.90]; 3-year difference, 105 deaths per 1000 patients) and preoperative and/or perioperative chemotherapy plus surgery (HR, 0.78 [95% CrI, 0.64-0.91]; 3-year difference, 90 deaths per 1000 patients) showed longer overall survival than surgery alone. Comparing the 2 modalities yielded similar overall survival (HR, 1.04 [95% CrI], 0.83-1.28]; 3-year difference, 15 deaths per 1000 patients fewer for CRT). Similarly, disease-free survival was longer for both modalities compared with surgery alone. Postoperative morbidity was more frequent after CRT plus surgery (odds ratio [OR], 2.94 [95% CrI, 1.01-8.59]) than surgery alone. Postoperative mortality was not significantly more frequent after CRT plus surgery than surgery alone (OR, 2.50 [95% CrI, 0.66-10.56]) or after chemotherapy plus surgery than CRT plus surgery (OR, 0.44 [95% CrI, 0.08-2.00])., Conclusions and Relevance: In this meta-analysis of patients with AEG, both preoperative CRT and preoperative and/or perioperative chemotherapy were associated with longer survival without relevant differences between the 2 modalities. Thus, either of the 2 treatments may be recommended to patients.

Background: Few studies have focused on palliative surgery in patients with advanced gastroesophageal junction (GEJ) or gastric cancer. We sought to evaluate clinical observational outcomes following palliative surgery in this population., Patients and Methods: Patients with GEJ or gastric cancer who underwent palliative surgery (1/2010-11/2022) were identified. The primary outcomes were symptom improvement, ability to tolerate an oral diet, discharge to home, 30 "good days" without hospitalization, and receipt of systemic treatment. Postoperative outcomes and survival were secondarily evaluated., Results: Among 93 patients, the median age was 59 (IQR 47-68) years, and the median Eastern Cooperative Oncology Group Performance Status (ECOG-PS) was 1 (range 0-3). The most frequent indication for palliative surgery was primary tumor obstruction [75 (81%) patients]. The most common procedures were feeding tube placement in 60 (65%) and intestinal bypass in 15 (16%) patients. A total of 75 (81%) patients experienced symptom improvement. Of these, 19 (25%) developed recurrent and 49 (65%) developed new symptoms. ECOG-PS was significantly associated with symptom-free time. Among those who underwent a bypass, resection, or ostomy creation for malignant obstruction, 16 (80%) tolerated an oral diet. Postoperatively, 87 (94%) were discharged home, 72 (77%) had 30 good days, and 64 (69%) received systemic treatment. Postoperative complications occurred in 35 (38%) patients, and 7 (8%) died within 30 days. The median survival time was 7.7 (95% CI 6.4-10.40) months., Conclusions: Patients with incurable GEJ or gastric cancer can benefit from palliative surgery. Prognosis and performance status should inform goals-of-care discussions and patient selection for surgical palliation., (© 2024. Society of Surgical Oncology.)

The vascular endothelial growth factor pathway plays a key role in the pathogenesis of gastric cancer. In the multicenter, double-blind phase 3 FRUTIGA trial, 703 patients with advanced gastric or gastroesophageal junction adenocarcinoma who progressed on fluorouracil- and platinum-containing chemotherapy were randomized (1:1) to receive fruquintinib (an inhibitor of vascular endothelial growth factor receptor-1/2/3; 4 mg orally, once daily) or placebo for 3 weeks, followed by 1 week off, plus paclitaxel (80 mg/m 2 intravenously on days 1/8/15 per cycle). The study results were positive as one of the dual primary endpoints, progression-free survival (PFS), was met (median PFS, 5.6 months in the fruquintinib arm versus 2.7 months in the placebo arm; hazard ratio 0.57; 95% confidence interval 0.48-0.68; P < 0.0001). The other dual primary endpoint, overall survival (OS), was not met (median OS, 9.6 months versus 8.4 months; hazard ratio 0.96, 95% confidence interval 0.81-1.13; P = 0.6064). The most common grade ≥3 adverse events were neutropenia, leukopenia and anemia. Fruquintinib plus paclitaxel as a second-line treatment significantly improved PFS, but not OS, in Chinese patients with advanced gastric or gastroesophageal junction adenocarcinoma and could potentially be another treatment option for these patients. ClinicalTrials.gov registration: NCT03223376 ., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

To investigate the short-term clinical efficacy of laparoscopic proximal gastrectomy with modified Kamikawa anastomosis and laparoscopic total gastrectomy with Roux-en-Y anastomosis. Retrospective cohort study was conducted. The clinicopathological data of 268 patients who underwent laparoscopic proximal gastrectomy for adenocarcinoma of esophagogastric junction and upper gastric adenocarcinoma from January 2016 to October 2022 were collected. Among 268 patients, 26 underwent laparoscopic proximal gastrectomy with modified Kamikawa anastomosis were assigned to Kamikawa group and 242 underwent laparoscopic total gastrectomy with Roux-en-Y anastomosis were assigned to Roux-en-Y group. The sex, age, BMI, preoperative albumin, maximum tumor diameter, histological grade, and pathological stage of patients in the Kamikawa group and the Roux-en-Y group were subjected to 1:1 propensity score matching. After matching, 16 patients in Kamikawa group and Roux-en-Y group were respectively included in this study. Outcome measures: (1) Intraoperative condition. (2) Postoperative recovery. (3) Follow-up information. The patients' nutritional status, reflux esophagitis and anastomotic stoma were investigated by outpatient and telephone follow-up. Nutritional status assessment comprising body mass index and Nutritional Risk Screening 2002 score. (1) Intraoperative condition. All patients successfully underwent laparoscopic proximal gastrectomy and total gastrectomy. Compared with Roux-en-Y group, the digestive tract reconstruction time in Kamikawa group was longer 93.0(74.0-111.0)min vs. 39.7(35.1-46.2)min, t = -2.001, P = 0.055., and the difference was statistically significant (P < 0.05). There was no statistically significant difference in total operation time and intraoperative blood loss (P > 0.05). (2) Postoperative recovery. There was no statistically significant difference between Kamikawa group and Roux-en-Y group in first anal exhaust time, first postoperative liquid intake time, postoperative hospitalization time, and postoperative complications (P > 0.05). (3) Follow-up information. All patients were followed up. BMI and NRS 2002 scores in Kamikawa group were better than those in Roux-en-Y group at 6 and 12 months after surgery 22.9 ± 3.0 kg/m2 vs. 20.8 ± 2.2 kg/m2, t = 2.165, P = 0.038; 23.1 ± 3.0 kg/m2 vs. 20.3 ± 2.2 kg/m2, t = 3.022, P = 0.005 and 2 (1-2) vs. 2 (1-3), Z = -2.585, P = 0.010; 2 (1-2) vs. 2 (1-3), Z = -2.273, P = 0.023., the difference was statistically significant (P < 0.05). There was no significant difference in GERD scale score and occurrence of ≥ Grade B reflux esophagitis at 6 and 12 months after surgery between Kamikawa group and Roux-en-Y group (P > 0.05). Anastomotic stenosis was not found in all patients by postoperative upper gastrointestinal angiography. Laparoscopic proximal gastrectomy with modified Kamikawa anastomosis is safe and feasible for the treatment of esophagogastric junction and upper gastric adenocarcinoma, and can achieve good anti-reflux effect. Besides, compared with traditional laparoscopic total gastrectomy, its postoperative nutritional status is better., (© 2024. The Author(s).)

Background: Esophagogastric junction cancer (EJC) refers to malignant tumors that develop at the junction between the stomach and the esophagus. TUSC1 is a recently identified tumor suppressor gene known for its involvement in various types of cancer. The objective of this investigation was to elucidate the regulatory influence of DNA methylation on TUSC1 expression and its role in the progression of EJC., Methods: Bioinformatics software was utilized to analyze the expression of TUSC1, enriched pathways, and highly methylated sites in the promoter region. TUSC1 expression in EJC was assessed using quantitative reverse transcription polymerase chain reaction (qRT-PCR), western blot (WB), and immunohistochemistry. Methylation-specific PCR was employed to detect the methylation level of TUSC1. To analyze the effects of TUSC1 and 5-AZA-2 on tumor cell proliferation, migration, invasion, cell cycle, and apoptosis, several assays including CCK-8, colony formation, transwell, and flow cytometry were conducted. The expression of MDM2 was assessed using qRT-PCR and WB. WB detected the expression of p53, and p-p53, markers for EJC cell proliferation, epithelial-mesenchymal transition, and apoptosis. The role of TUSC1 in tumor occurrence in vivo was examined using a xenograft mouse model., Results: TUSC1 expression was significantly downregulated in EJC. Overexpression of TUSC1 and treatment with 5-AZA-2 inhibited the malignant progression of EJC cells. In EJC, low methylation levels promoted the expression of TUSC1. Upregulation of TUSC1 suppressed the expression of MDM2 and activated the p53 signaling pathway. Inactivation of this pathway attenuated the inhibitory effect of TUSC1 overexpression on EJC cell proliferation, migration, invasion, and other behaviors. Animal experiments demonstrated that TUSC1 overexpression inhibited EJC tumor growth and metastasis in vivo., Conclusion: TUSC1 was commonly downregulated in EJC and regulated by methylation. It repressed the malignant progression of EJC tumors by mediating the p53 pathway, suggesting its potential as a diagnostic and therapeutic target for EJC., (© 2024. The Author(s).)

Background: Analyze the pattern of lymph node metastasis in Siewert II adenocarcinoma of the esophagogastric junction (AEG) and provide a basis for the principles of surgical access., Methods: The clinical data of 112 Siewert type II AEG patients admitted to the Fifth Department of Thoracic Surgery, the Fourth Hospital of Hebei Medical University from 2020 to 2022 were retrospectively collected. The probability of lymph node metastasis in each site and the clearance rate of lymph nodes in each site by different surgical approaches were analyzed., Results: The lymph node metastasis rates in the middle and upper mediastinum group, the lower mediastinum group, the upper perigastric + supra pancreatic group, and the lower perigastric + hepatoduodenal group were 0.0%, 5.4%, 61.6%, and 17.1%, (P < 0.001). The number of lymph nodes cleared in the middle and upper mediastinum group was 0.00, 0.00, 4.00 in the transabdominal approach (TA), left thoracic approach (LT), and Ivor-Lewis (IL) group, (P < 0.001); The number of lymph nodes cleared in the lower mediastinal group was 0.00, 2.00, 2.00, (P < 0.001); The number of lymph node dissection in the perigastric + hepatoduodenal group was 3.00, 0.00, and 8.00, (P < 0.001). The overall complication rates were 25.7%, 12.5%, and 36.4%, (P = 0.058)., Conclusion: Siewert II AEG has the highest rate of lymph node metastasis in the upper perigastric + supra-pancreatic region, followed by the lower perigastric + hepatoduodenal, lower mediastinal, middle, and upper mediastinal regions. Ivor-Lewis can be used for both thoracic and abdominal lymph node dissection and does not increase the incidence of postoperative complications., (© 2024. The Author(s).)