Cadonilimab with chemotherapy in HER2-negative gastric or gastroesophageal junction adenocarcinoma: the phase 1b/2 COMPASSION-04 trial.

Treatment with anti-programmed cell death protein 1 (PD-1) therapy and chemotherapy prolongs the survival of patients with unresectable advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma. The benefit from anti-PD-1 therapy is enriched in patients with programmed cell death 1 ligand 1 (PD-L1) combined positive score (CPS)-positive or CPS-high tumors compared with patients with PD-L1 CPS-negative or CPS-low tumors. In this phase 1b/2 study, we evaluated the efficacy and safety of cadonilimab, a bispecific antibody targeting PD-1 and cytotoxic T-lymphocyte antigen-4, plus chemotherapy as first-line treatment in patients with human epidermal growth factor receptor 2-negative unresectable advanced or metastatic gastric or GEJ adenocarcinoma. The primary endpoint was the recommended phase 2 dose (RP2D) for phase 1b and the objective response rate for phase 2. Secondary endpoints included disease control rate, duration of response, time to response, progression-free survival, overall survival (OS) and safety. The primary endpoint was met. No dose-limiting toxicities were observed during dose escalation in phase 1b; the recommended phase 2 dose was determined as 6 mg kg-1 every 2 weeks. The objective response rate was 52.1% (95% confidence interval (CI) = 41.6-62.5), consisting of complete and partial responses in 4.3% and 47.9% of patients, respectively. The median duration of response, progression-free survival and OS were 13.73 months (95% CI = 7.79-19.12), 8.18 months (95% CI = 6.67-10.48) and 17.48 months (95% CI = 12.35-26.55), respectively. The median OS in patients with a PD-L1 CPS ≥ 5 was 20.32 months (95% CI = 4.67-not estimable); in patients with a PD-L1 CPS < 1, the median OS reached 17.64 months (95% CI = 11.63-31.70). The most common treatment-related grade 3 or higher adverse events were decreased neutrophil count (19.1%), decreased platelet count (16.0%), anemia (12.8%) and decreased leukocyte count (8.5%). No new safety signal was identified. The current regimen showed promising clinical activity and manageable safety in patients with gastric or GEJ adenocarcinoma regardless of PD-L1 expression. Chinadrugtrials.org.cn registration: CTR20182027.

Safety and short-term outcomes of a modified valvuloplastic esophagogastrostomy versus gastric tube anastomosis after laparoscopy-assisted proximal gastrectomy: a retrospective cohort study.

BACKGROUND: There is no optimal reconstruction method after proximal gastrectomy. The valvuloplastic esophagogastrostomy can reduce postoperative reflux esophagitis, but it is technically complex with a long operation time. The gastric tube anastomosis is technically simple, but the incidences of reflux esophagitis and anastomotic stricture are higher. METHODS: We have devised a modified valvuloplastic esophagogastrostomy after laparoscopy-assisted proximal gastrectomy (LAPG), the arch-bridge anastomosis. After reviewing our prospectively maintained gastric cancer database, 43 patients who underwent LAPG from November 2021 to April 2023 were included in this cohort study, with 25 patients received the arch-bridge anastomosis and 18 patients received gastric tube anastomosis. The short-term outcomes were compared between the two groups to evaluate the efficacy of the arch-bridge anastomosis. Reporting was consistent with the STROCSS 2021 guideline. RESULTS: The median operation time was 180 min in the arch-bridge group, significantly shorter than the gastric tube group (p = 0.003). In the arch-bridge group, none of the 25 patients experienced anastomotic leakage, while one patient (4%) experienced anastomotic stricture requiring endoscopic balloon dilation. The postoperative length of stay was shorter in the arch-bridge group (9 vs. 11, p = 0.034). None of the patients in the arch-bridge group experienced gastroesophageal reflux and used proton pump inhibitor (PPI), while four (22.2%) patients in the gastric tube group used PPI (p = 0.025). The incidence of reflux esophagitis (Los Angeles grade B or more severe) by endoscopy was lower in the arch-bridge group (0% vs. 25.0%). CONCLUSION: The arch-bridge anastomosis is a safe, time-saving, and feasible reconstruction method. It can reduce postoperative reflux and anastomotic stricture incidences in a selected cohort of patients undergoing laparoscopy-assisted proximal gastrectomy.

Pre- and Post-treatment Double-Sequential-Point Dynamic Radiomic Model in the Response Prediction of Gastric Cancer to Neoadjuvant Chemotherapy: 3-Year Survival Analysis.

BACKGROUND: Prognosis prediction of patients with gastric cancer after neoadjuvant chemotherapy is suboptimal. This study aims to develop and validate a dynamic radiomic model for prognosis prediction of patients with gastric cancer on the basis of baseline and posttreatment features. PATIENTS AND METHODS: This single-center cohort study included patients with gastric adenocarcinoma treated with neoadjuvant chemotherapy from June 2009 to July 2015 in the Gastrointestinal Cancer Center of Peking University Cancer Hospital. Their clinicopathological data, pre-treatment and post-treatment computed tomography (CT) images, and pathological reports were retrieved and analyzed. Four prediction models were developed and validated using tenfold cross-validation, with death within 3 years as the outcome. Model discrimination was compared by the area under the curve (AUC). The final radiomic model was evaluated for calibration and clinical utility using Hosmer-Lemeshow tests and decision curve analysis. RESULTS: The study included 205 patients with gastric adenocarcinoma [166 (81%) male; mean age 59.9 (SD 10.3) years], with 71 (34.6%) deaths occurring within 3 years. The radiomic model alone demonstrated better discrimination than the pathological T stage (ypT) stage model alone (cross-validated AUC 0.598 versus 0.516, P = 0.009). The final radiomic model, which incorporated both radiomic and clinicopathological characteristics, had a significantly higher cross-validated AUC (0.769) than the ypT stage model (0.516), the radiomics alone model (0.598), and the ypT plus other clinicopathological characteristics model (0.738; all P < 0.05). Decision curve analysis confirmed the clinical utility of the final radiomic model. CONCLUSIONS: The developed radiomic model had good accuracy and could be used as a decision aid tool in clinical practice to differentiate prognosis of patients with gastric cancer.

Efficacy of chemotherapy versus surgery as initial treatment for gastric cancer with positive peritoneal cytology.

BACKGROUND: The prognosis of gastric cancer (GC) patients with positive peritoneal cytology (CY1) without other distant metastasis is poor, and there are no standard treatment strategies. Our study aimed to compare the survival outcomes of CY1 GC patients receiving chemotherapy or surgery as initial treatment. METHODS: From February 2017 to January 2020, clinical and pathological data of patients diagnosed with CY1 GC without other distant metastasis in the Peking University Cancer Hospital was reviewed. Patients were divided into two groups: chemotherapy-initial group and surgery-initial group. In chemotherapy-initial group, patients received preoperative chemotherapy initially. According to the treatment response, the patients were divided into three subgroups: conversion gastrectomy group, palliative gastrectomy group, and further systematic chemotherapy group. In surgery-initial group, patients underwent gastrectomy followed by postoperative chemotherapy. RESULTS: A total of 96 CY1 GC patients were included with 48 patients in each group. In chemotherapy-initial group, preoperative chemotherapy yielded an objective response rate of 20.8% and disease control rate of 87.5%. Conversion to CY0 after preoperative chemotherapy was obtained in 24 (50%) patients. The median overall survival was 36.1 months in chemotherapy-initial group and 29.7 months in surgery-initial group (p = 0.367). The median progression-free survival was 18.1 months in chemotherapy-initial group and 16.1 months in surgery-initial group (p = 0.861). The 3-year overall survival rates were 50.0% and 47.9%, respectively. In chemotherapy-initial group, twenty-four patients who converted to CY0 by preoperative chemotherapy and received surgery obtained a significantly better prognosis. The median overall survival was still not reached in these patients. CONCLUSION: There was no significant difference in survival outcomes between chemotherapy-initial group and surgery-initial group. CY1 GC patients who converted to CY0 by preoperative chemotherapy and received radical surgery could obtain a favorable long-term prognosis. Further investigation should focus on preoperative chemotherapy to eliminate peritoneal cancer cell. TRIAL REGISTRATION: This study is retrospectively registered.

Efficacy and safety of preoperative immunotherapy alone followed by surgery in the treatment of advanced gastric cancer with MSI-H/dMMR or EBV-positive.

BACKGROUND: At present, there is no consensus on whether preoperative immunotherapy (PIT) without chemotherapy followed by surgery could benefit patients with advanced gastric cancer (AGC). Here, we report a six-case series study to describe the safety and efficacy of PIT plus gastrectomy in patients with AGC. METHODS: This study involved six patients with AGC who received PIT and surgery at our center between January 2019 and July 2021. Demographic characteristics, preoperative gastroscope biopsy pathology, surgical tissue pathology, radicalness of tumor resection, surgical safety, and recovery parameters were reported. RESULTS: Six patients, including four patients with Epstein-Barr virus (EBV)-positive gastric cancer (GC) and two patients with microsatellite instability-high (MSI-H)/expression deficiency of mismatch repair (dMMR) protein GC, were enrolled in this study. Four patients experienced immunotherapy-related adverse events (irAEs), without severe adverse events (SAEs). Five patients underwent R0 resection, and one patient underwent palliative gastrectomy due to liver and hilar lymph node metastasis. Pathologic responses from the surgical tissue were observed in all patients, including two pathological complete response (pCR). No operative complications or postoperative deaths occurred. Three patients (50%) experienced mild or moderate postoperative complications without severe postoperative complications. All six patients eventually recovered and were discharged. CONCLUSION: This study indicated that PIT was effective and tolerant in some patients with MSI-H/dMMR and/or EBV-positive AGC. PIT followed by gastrectomy might be an alternative treatment option for these selected patients.

Exploration and optimization of surgical techniques for laparoscopic transhiatal lower mediastinal lymph node dissection for adenocarcinoma of esophagogastric junction: A prospective IDEAL 2a study with qualitative design.

Objective: To explore the change and feasibility of surgical techniques of laparoscopic transhiatal (TH)-lower mediastinal lymph node dissection (LMLND) for adenocarcinoma of the esophagogastric junction (AEG) according to Idea, Development, Exploration, Assessment, and Long-term follow-up (IDEAL) 2a standards. Methods: Patients diagnosed with AEG who underwent laparoscopic TH-LMLND were prospectively included from April 14, 2020, to March 26, 2021. Clinical and pathological information as well as surgical outcomes were quantitatively analyzed. Semistructured interviews with the surgeon after each operation were qualitatively analyzed. Results: Thirty-five patients were included. There were no cases of transition to open surgery, but three cases involved combination with transthoracic surgery. In qualitative analysis, 108 items under three main themes were detected: explosion, dissection, and reconstruction. Revised instruction was subsequently designed according to the change in surgical technique and the cognitive process behind it. Three patients had anastomotic leaks postoperatively, with one classified as Clavien-Dindo IIIa. Conclusions: The surgical technique of laparoscopic TH-LMLND is stable and feasible; further IDEAL 2b research is warranted.

ALCAM, Activated Leukocyte Cell Adhesion Molecule, in Clinical Gastric Cancer and Patient's Response to Chemotherapies.

BACKGROUND/AIM: Activated leukocyte cell adhesion molecule (ALCAM/CD166), a member of the immunoglobulin superfamily, has been shown to regulate cell adhesion through both homotypic and heterotypic interactions. In cancer, it might be involved in disease progression and chemotherapy drug resistance. The present study explored the clinical and prognostic significance of ALCAM in gastric cancer and its impact on patient's responses to neoadjuvant chemotherapies and cancer cells' response to chemodrugs in vitro. MATERIALS AND METHODS: Two independent cohorts were included to evaluate the link between ALCAM and the clinical outcomes and pathological factors of the patients. The gastric cancer cell lines HGC27 and AGS were used to generate ALCAM knockdown cell models. The cytotoxicity of chemotherapy drugs was examined using ALCAM knockdown cell models. RESULTS: Patients with gastric cancer who had high levels of ALCAM transcripts showed a significantly shorter overall survival in both cohorts (p=0.043 and 0.006, respectively). Patients who resisted to neoadjuvant chemotherapy had marginally higher levels of ALCAM than those responded (p=0.056). Patients with low levels of ALCAM expression and resisted to neoadjuvant chemotherapy had the worst clinical outcome with a significantly shorter overall survival (p=0.004) and disease-free survival (p=0.006), whereas such results did not appear in high ALCAM expression patients. ALCAM knockdown cells were more sensitive to Cisplatin, Oxaliplatin and 5-Fluorouracil compared with their respective control cells. CONCLUSION: ALCAM acts as a negative prognostic indicator in patients with gastric cancer and high levels of ALCAM expression result in increased chemotherapy drug resistance.

Safety and short-term outcomes of gastrectomy after preoperative chemotherapy plus immunotherapy versus preoperative chemotherapy: a retrospective cohort study.

BACKGROUND: The safety and short-term outcomes of gastrectomy after preoperative chemotherapy plus immunotherapy (PCIT) versus preoperative chemotherapy (PCT) in patients with advanced gastric cancer (AGC) remain unclear. This study was conducted to compare the safety and short-term efficacy of PCIT with those of PCT in patients with AGC. METHODS: We retrospectively reviewed the data of patients with AGC who received PCIT or PCT at Peking University Cancer Hospital and Institute Gastrointestinal Cancer Center I between January 2019 and June 2021. The clinical characteristics were recorded, and short-term oncological outcomes were compared. Independent t tests, Mann‒Whitney U tests, chi-square tests, and Fisher's exact tests were used to calculate differences. The correlation analyses were performed using Pearson correlation. All p values were two-sided, and a p value < 0.05 was considered statistically significant. All the above statistical analyses were conducted by the SPSS version 24.0 software package (IBM Corp., Armonk, NY, USA). RESULTS: A total of 162 AGC patients were included in this study, including 25 patients who received PCIT and 137 patients who received PCT. There were no significant differences in preoperative treatment-related adverse events (TRAEs) between the PCIT group and the PCT group (p = 0.088). Compared with the PCT group, the PCIT group had comparable postoperative functional recovery, with no significant differences in terms of time to first aerofluxus (p = 0.349), time to first defecation (p = 0.800), time to liquid diet (p = 0.233), or length of stay (p = 0.278). No significant differences were observed in terms of postoperative complications (p = 0.952), postoperative pain intensity at 24, 48, or 72 h (p = 0.375, p = 0.601, and p = 0.821, respectively), or postoperative supplementary analgesic use between the two groups (p = 0.881). In addition, the postoperative complication rate was 33.3% following laparoscopic approaches and 31.2% following open approaches in the PCIT group, with no significant difference (p = 1.000). CONCLUSION: In patients with AGC, gastrectomy with D2 or D2 + lymphadenectomy after PCIT had comparable short-term oncological outcomes to PCT.

Short-and long-term outcomes of laparoscopic versus open gastrectomy in patients with gastric cancer: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Laparoscopic gastrectomy (LG) for gastric cancer has rapidly developed and become more popular in recent decades. Additional high-quality randomized controlled trial (RCT) studies comparing LG versus open gastrectomy (OG) for gastric cancer (GC) have been published in recent years. An updated systematic review is warranted. The aim of our meta-analysis was to comprehensively evaluate the short- and long-term outcomes of LG versus OG for GC. MATERIALS AND METHODS: The PubMed, Embase, Web of Science, and Cochrane Center Register of Controlled Trials databases were comprehensively searched to identify RCTs comparing LG versus OG for GC published between January 1994 and December 7, 2021. This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Cochrane Collaboration and the Quality of Reporting of Meta-analyses (QUORUM) guidelines. All RCTs comparing the short- and long-term outcomes of LG with those of OG were included. A random effects model was adopted with significant heterogeneity (I2 > 50%), while a fixed effects model was employed in all other cases (I2 ≤ 50%). RESULTS: A total of 26 RCTs with 8301 patients were included in this meta-analysis. The results indicated that the intraoperative complication rate was comparable between the LG group and the OG group (OR=1.14, 95% CI [0.76, 1.70], I2=0%, p=0.53). The LG group had fewer postoperative complications than the OG group (OR=0.65, 95% CI [0.57, 0.74], I2=26%, p<0.00001). However, the severe postoperative complication rate and perioperative mortality were comparable between the two groups (OR=0.83, 95% CI [0.67, 1.04], I2=10%, p=0.10; OR=1.11, 95% CI [0.59, 2.09], I2=0%, p=0.74, respectively). The number of lymph nodes retrieved by the LG group was less than that of the OG group (MD=-1.51, 95% CI [-2.29, -0.74], I2=0%, p<0.0001). The proximal resection margin distance in the LG group was shorter than that in the OG group (MD=-0.34, 95% CI [-0.57, -0.12], I2=23%, p=0.003), but the distal resection margin distance in the two groups was comparable (MD=-0.21, 95% CI [-0.47, 0.04], I2=0%, p=0.10). The time to first ambulation was shorter in the LG group than in the OG group (MD=-0.14, 95% CI [-.26, -0.01], I2=40%, p=0.03). The time to first flatus was also shorter in the LG group than in the OG group (MD=-0.15, 95% CI [-0.23, -0.07], I2=4%, p=0.0001). However, the first time on a liquid diet was comparable between the two groups (MD=-0.30, 95% CI [-0.64, 0.04], I2=88%, p=0.09). Furthermore, the postoperative length of stay was shorter in the LG group than in the OG group (MD=-1.26, 95% CI [-1.99, -0.53], I2=90%, p=0.0007). The 5-year overall survival (OS) was comparable between the two groups (HR=0.97, 95% CI [0.80, 1.17], I2=0%, p=0.73), and the 5-year disease-free survival (DFS) was also similar between the LG group and OG group (HR=1.08, 95% CI [0.77, 1.52], I2=0%, p=0.64). CONCLUSION: LG is a technically safe and feasible alternative to OG with the advantages of a fewer postoperative complication rate, faster recovery of gastrointestinal function, and greater cosmetic benefit for patients with GC. Meanwhile, LG has comparable long-term outcomes to OG for GC.

Laparoscopic vs. open lower mediastinal lymphadenectomy for Siewert type II/III adenocarcinoma of esophagogastric junction: An exploratory, observational, prospective, IDEAL stage 2b cohort study (CLASS-10 study).

Objective: This study aims to verify the feasibility and efficacy of laparoscopic lower mediastinal lymphadenectomy for Siewert type II/III adenocarcinoma of esophagogastric junction (AEG). Setting: An exploratory, observational, prospective, cohort study will be carried out under the Idea, Development, Exploration, Assessment and Long-term Follow-up (IDEAL) framework (stage 2b). Participants: The study will recruit 1,036 patients with cases of locally advanced AEG (Siewert type II/III, clinical stage cT2-4aN0-3M0), and 518 will be assigned to either the laparoscopy group or the open group. Interventions: Patients will receive lower mediastinal lymphadenectomy along with either total or proximal gastrectomy. Primary and secondary outcome measures: The primary endpoint is the number of lower mediastinal lymph nodes retrieved, and the secondary endpoints are the surgical safety and prognosis, including intraoperative and postoperative lower-mediastinal-lymphadenectomy-related morbidity and mortality, rate of rehospitalization, R0 resection rate, 3-year local recurrence rate, and 3-year overall survival. Conclusions: The study will provide data for the guidance and development of surgical treatment strategies for AEG. Trial registration number: The study has been registered in ClinicalTrials.gov (No. NCT04443478).

Genomic landscape of microsatellite instability in Chinese tumors: A comparison of Chinese and TCGA cohorts.

Microsatellite instability (MSI) is an important biomarker for predicting the response to immunotherapy and prognosis that mainly results from a defective DNA mismatch repair (MMR) system and strongly correlates with high tumor mutation burden (TMB). Herein, we developed a novel method that integrates MSI score, MMR mutation status and TMB level to identify MSI status from next-generation sequencing (NGS) data. The novel method displays a sensitivity of 96.80%, a specificity of 99.96% and an overall accuracy of 99.89%, compared to current standards. Using our novel method, we analyzed 11 395 Chinese patients across 30 cancer types. High microsatellite instability (MSI-H) was detected in 210 (1.84%) samples in 18 of 30 cancer types assessed. Mutations in ACVR2A (73%), KMT2D (68%), KMT2B (66%) and MMR-related genes (MLH1, MSH2, MSH6 and PMS2) were enriched in MSI-H samples. Furthermore, MSI-H samples were more likely to have high TMB (P < .01), high PD-L1 expression (P < .05) and more tumor-infiltrating immune cells than microsatellite-stable (MSS) samples. Compared to the TCGA patients, the prevalence of MSI-H in the Chinese cohort was significantly lower in colorectal, gastric and pancreatic cancer, while significantly higher in urinary and prostate cancer. Mutations in ACVR2A (73% vs 28%, P < .01) and MMR-related genes (51.4% vs 21.3%, P < .01) were significantly higher in the Chinese population. Thus, our study suggests the fraction of MSI-H attributable to MMR inactivation mutations were lower in European than in Chinese patients, while the proportion of MSI-H due to other events may be higher.

Effect of neoadjuvant chemotherapy on the immune microenvironment in gastric cancer as determined by multiplex immunofluorescence and T cell receptor repertoire analysis.

BACKGROUND: The combination of immune checkpoint blockade and chemotherapy has revolutionized the treatment of advanced gastric cancer (GC). It is crucial to unravel chemotherapy-induced tumor microenvironment (TME) modulation and identify which immunotherapy would improve antitumor effect. METHODS: In this study, tumor-associated immune cells (TAICs) infiltration in residual tumor after neoadjuvant chemotherapy (NAC) together with 1075 cases of treatment-naïve GC patients was analyzed first. Then we performed multiplex fluorescence staining of a panel of immune markers (CD3, CD4, CD8, FOXP3 and PDL1) and T cell receptor ß-chain sequencing to phenotype and enumerate T cell subpopulations and clonal expansion in paired GC samples (prechemotherapy and postchemotherapy) from another cohort of 30 cases of stage II/III GC patients. RESULTS: Infiltration of CD68+ macrophages in residual tumors after NAC was significantly decreased compared with treatment-naïve GC patients, while no significant difference observed with respect to other immune markers. In residual tumors, post-NAC CD8 +T cells and CD68+ macrophages levels were significantly associated with chemotherapy response. Post-NAC CD8+ T cell levels remained as an independent predictor for favorable prognosis. Furthermore, when comparing the paired samples before and after NAC from 30 cases of stage II/III GC patients, we found FOXP3+ regulatory T cells proportion significantly decreased after chemotherapy. Pre-NAC FOXP3+ T reg cells level was much richer in the response group and decreased more significantly in the stromal compartment. CD8+ cytotoxic T lymphocytes levels were elevated after chemotherapy, which was more significant in the group treated with XELOX regimen and in patients with better response, consistent with the TCR diversity elevation. CONCLUSIONS: These findings have deepened our understanding of the immune modulating effect of chemotherapy and suggest that the immune profile of specimens after standard chemotherapy should be considered for the personalized immunotherapy to ultimately improve clinical outcome in patients with GC.

The significance of time interval between perioperative SOX/XELOX chemotherapy and clinical decision model in gastric cancer.

Introduction: To investigate the influences of time interval between multimodality therapies on survival for locally advanced gastric cancer (LAGC) patients, 627 patients were included in a retrospective study, and 350 who received neoadjuvant chemotherapy (NACT) based on SOX (S-1 plus Oxaliplatin)/XELOX (Capecitabine plus Oxaliplatin) treatment, radical surgery, and adjuvant chemotherapy (AC) from 2005.01 to 2018.06 were eligible for analyses. Methods: Three factors were used to assess influences, including time interval from NACT accomplishment to AC initiation (PECTI), time to surgery after NACT accomplishment (TTS), and time to adjuvant chemotherapy after surgery (TAC). Results: Concerning PECTIs, 99 (28.29%) experienced it within 9 weeks, 188 (53.71%) within 9-13 weeks, 63 (18.00%) over 13 weeks. Patients' 5-year overall survival (OS) significantly decreased as trichotomous PECTI increased (78.6% vs 66.7% vs 55.7%, P = .02). Analogously, there was a significant decrease for dichotomous TTS (within vs over 5 weeks) in OS (P = .03) and progression free survival (PFS) (P = .01) but not for dichotomous TAC (within vs over 6 weeks) in OS and PFS (P = .40). Through multivariate Cox analyses, patients with PECTI over 13 weeks had significantly worse OS (P = .03) and PFS (P = .02). Furthermore, extended TTS had significantly worse OS and PFS but insignificantly worse OS and PFS than extended TAC. Therefore, gastric patients receiving perioperative SOX/XELOX chemotherapy and surgery with extended PECTI over 9 weeks or TTS over 5 weeks would have a negative correlation with PFS and OS, and worse when PECTI over 13 weeks. Nomograms (including PECTI, ypT, ypN, Area Under Curve (AUC) = 0.81) could predict patient survival probability and guide intervention with net benefit. Discussion: In control of PECTI, TTS could be extended appropriately, and shortened TAC might make a remedy, and delayed TAC might be allowed when TTS was shortened.

Duration of Perioperative Chemotherapy in Locally Advanced Gastric Cancer: A "Less Is More" Question When ypN0 Is Achieved.

BACKGROUNDS: Perioperative chemotherapy (PEC) and neoadjuvant chemotherapy (NAC) have become a vital part of locally advanced gastric cancer (LAGC) treatment, but the optimal duration of PEC has not been studied. The aim of this study was to demonstrate the possibility of duration reduction in PEC in the adjuvant chemotherapy (AC) phase for ypN0 patients. METHODS: We included LAGC patients who achieved ypN0 after NAC in our institution from 2005 to 2018. The risk/benefit of AC and other covariates were majorly measured by overall survival (OS) and progression-free survival (PFS). We developed a survival-tree-based model to determine the optimal PEC duration for ypN0 patients in different classes. RESULTS: A total of 267 R0 resection patients were included. There were 55 patients who did not receive AC. The 5-year OS was 74.34% in the non-AC group and 83.64% in the AC group with a significant difference (p = 0.012). Multivariate Cox regression revealed that both AC (AC vs. non-AC: HR, 0.49; 95%CI, 0.27-0.88; p = 0.018) and ypT stages (ypT3-4 vs. ypT0-2: HR, 2.00; 95%CI, 1.11-3.59; p = 0.021) were significant protective/risk factors on patients OS and PFS. A decision tree model for OS indicated an optimal four to six cycles of PEC, which was recommended for ypT0-2N0 patients, while a minimum of five PEC cycles was recommended for ypT3-4N0 patients. CONCLUSION: AC treatment is still necessary for ypN0. The duration reduction could be applied for the ypT0-2N0 stage patients but may not be suitable for higher ypT stages and beyond. A multicenter-based study is required.

Prognostic and predictive value of mismatch repair deficiency in gastric and gastroesophageal junction adenocarcinoma patients receiving neoadjuvant or adjuvant chemotherapy.

BACKGROUND AND OBJECTIVES: Evidence is inconclusive regarding the prognostic significance of deficient DNA mismatch repair (dMMR) in gastric and gastroesophageal junction (GEJ) adenocarcinoma patients receiving chemotherapy. We aim to explore such associations with a large cohort. METHODS: We retrospectively identified a consecutive cohort of patients who had histology proven gastric or GEJ adenocarcinoma and received neoadjuvant chemotherapy plus surgery or upfront surgery plus adjuvant chemotherapy. MMR status was assessed by immunohistochemistry staining on surgical specimen. The association of MMR status with tumor regression grade (TRG), overall survival (OS), and disease-free survival (DFS) were analyzed. RESULTS: In total, 1568 patients received neoadjuvant or adjuvant chemotherapy, of which 128 (8.2%) had dMMR tumors. No significant difference was found in the frequencies of TRG categories between proficient MMR (pMMR) and dMMR tumors (p = .62). Among patients receiving neoadjuvant chemotherapy, dMMR status was associated with better OS (log-rank p = .044) and DFS (log-rank p = .022) in the univariate analysis; this association became nonsignificant after adjusting for pathologic stages and other prognostic factors. Similar results were found for patients receiving adjuvant chemotherapy. CONCLUSIONS: dMMR status was not significantly associated with OS and DFS among gastric and GEJ adenocarcinoma patients with neoadjuvant and adjuvant platinum and fluorouracil-based chemotherapy.

Tumor mutation burden is correlated with response and prognosis in microsatellite-stable (MSS) gastric cancer patients undergoing neoadjuvant chemotherapy.

BACKGROUND: Neoadjuvant chemotherapy (NACT) before radical gastrectomy is preferred for locally advanced gastric cancer (GC). However, clinical practices demonstrate that a considerable proportion of GC patients do not benefit from NACT, largely due to the lack of biomarkers for patient selection and prognosis prediction. A recent study revealed that patients with microsatellite instability-high (MSI-H) may be resistant to NACT, however, most tumors in Chinese GC patients (~ 95%) are characterized by microsatellite stability (MSS). Here, we aimed to discover new molecular biomarkers for this larger population. METHODS: We performed whole-exome sequencing on 46 clinical samples (pre- and post-treatment) from 30 stage II/III MSS GC patients whose response to NACT was rigorously defined. Serum tumor markers (TMs), including AFP, CEA, CA199, CA724 and CA242 were measured during the course. RESULTS: High tumor mutation burden (TMB-H) and 19q12 amplification (19q12 +) were positively associated with the NACT response. When TMB and 19q12 amplification were jointly analyzed, those with TMB-H or 19q12 + showed favorable response to NACT (p = 0.035). Further, TMB-H was negatively correlated with ypN stage, lymph node metastasis, and macrophage infiltration. Patients with TMB-H showed better disease-free survival (DFS) than those with TMB-L (P = 0.025, HR = 0.1331), and this was further validated using two larger GC datasets: TCGA-STAD (p = 0.004) and ICGC-CN (p = 0.045). CONCLUSION: The combination of TMB-H and 19q12 + can serve as an early indicator of response to NACT. Superior to traditional clinical indicators, TMB-H is a robust and easily accessible candidate biomarker associated with better DFS, and can be evaluated at the time of diagnosis.

Short-term outcomes after totally laparoscopic total gastrectomy with esophagojejunostomy constructed by π-shaped method versus overlap method.

BACKGROUND: Regarding the overlap anastomosis and recently introduced π-shaped anastomosis, there is no consensus on which intracorporeal esophagojejunostomy (EJS) methods are preferred using linear stapler in totally laparoscopic total gastrectomy (TLTG). This study aims to evaluate the short-term outcomes using two methods. METHODS: Patients with upper gastric cancer underwent TLTG with either π-shaped (n = 48) or the modified overlap method using knotless barbed sutures (MOBS) (n = 37) were included in our study. Intraoperative and perioperative outcomes were compared. RESULTS: All patients achieved R0 resection margin. The overall esophagojejunal (E-J)-related complications rate was 7.06%. There was no significant difference between the two groups in terms of postoperative complications, margin distance, numbers of lymph nodes (LNs), length of stay. In the π-shaped group, anastomosis time (19.61 ± 7.17 min vs. 27.09 ± 3.59 min, p < 0.001) was significantly lower. The consumable costs for surgery were similar (44 507.74¥ [42 933.03-46 937.29] vs. 43 718.36¥ [42 743.25-47 256.06], p = 0.825). The first defection time was significantly longer in π-shaped group (131.00 h [93.75-171.25] vs. 100.00 h [85.00-120.00], p = 0.026), whereas the other postoperative recovery parameters were similar. No mortality was observed. CONCLUSIONS: Both methods showed similar short-term postoperative outcomes. The π-shaped technique was faster than the MOBS method without significantly increasing the supplies costs. Large prospective studies are warranted.

Combination of tumor markers predicts progression and pathological response in patients with locally advanced gastric cancer after neoadjuvant chemotherapy treatment.

BACKGROUND: The prognostic values of preoperative tumor markers (TMs) remain elusive in patients with locally advanced gastric cancer (LAGC) after neoadjuvant chemotherapy treatment (NACT). This study aimed to assess and establish a novel scoring system incorporating carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), carbohydrate antigen 72-4 (CA72-4) to enhance prognostic accuracy for progression-free survival (PFS) and pathological response (pCR). METHODS: Patients' data were retrospectively analyzed from December 2006 to December 2017 in our center. The cutoff value of TMs was determined using the time-dependent receiver operating test characteristics method. These three TMs were allocated 1 point each for the post neoadjuvant chemotherapy combination of tumor markers (post-NACT CTM) scores. The training group comprised 533 patients, responsible for full analysis, and the validation group comprised 137 patients based on the selection protocol. RESULTS: Of 533 enrolled patients, 138, 233, 117, and 45 patients scored 0, 1, 2, 3 respectively. The 3-year PFS rate Multivariate analysis revealed that post-NACT CTM score was an independent predictor of PFS (0 vs. 1, HR: 1.34, 95% CI: 0.92-1.96, P = 0.128; 0 vs. 2, HR: 2.03, 95% CI: 1.35-3.05, P = 0.001; 0 vs. 3, HR: 2.98, 95% CI: 1.83-4.86, P < 0.001). The time-dependent area under curve (AUC) revealed a consistent highest level for post-NACT CTM than other three single TMs. Lower post-NACT CTM score significantly correlated with higher pCR rate based on multivariate logistic regression (2/3 vs. 1, OR: 2.77, 95% CI: 0.90-8.53, P = 0.077; 2/3 vs. 0, OR: 4.33, 95% CI: 1.38-13.61, P = 0.012). A nomogram was formed with both internal and external validation. CONCLUSIONS: The post-NACT CTM score system served as a strong independent predictor for PFS and pCR in LAGC patients who received NACT. Further population-based studies are required to confirm our results.

Treatment Switch in Poor Responders with Locally Advanced Gastric Cancer After Neoadjuvant Chemotherapy.

BACKGROUND: Among locally advanced gastric cancer (LAGC) patients, poor response to initial neoadjuvant chemotherapy (NAC) is associated with unfavorable outcomes; however, changing the postoperative therapy regimen in this group of patients is unclear. We compared the poor responders who continued the original protocols with that of patients who switched treatment after NAC plus D2 gastrectomy. METHODS: Our study included LAGC patients who achieved tumor regression grade 3 according to the American Joint Committee on Cancer/College of American Pathologists system, after NAC, between December 2006 and December 2017 at our institution. Outcomes were overall survival (OS), progression-free survival (PFS), and adverse events during postoperative treatment. The propensity score matching method was used to match patients. RESULTS: Overall, 160 patients were enrolled in the final analysis set, including 21 switched cases and 139 non-switched cases. A 1:2 matched cohort (21 switching vs. 42 non-switching) was generated to eliminate all confounding factors. No statistical differences were observed in OS and PFS, either in the whole patients (OS: log-rank p = 0.804; PFS: log-rank p = 0.943) or in the matched cohort (OS: log-rank p = 0.907; PFS: log-rank p = 0.670) between the two groups. Patients with changed regimens had a significantly higher rate of peripheral neurotoxicity (p = 0.045). Contrarily, a lower rate of overall adverse events was observed in the non-switching group with marginal significance (p = 0.069). CONCLUSION: Adjusting to a non-cross-resistant regimen only by post-NAC pathological evaluation may not be sufficient for designing an effective treatment route for LAGC poor responders. Treatment change required a more scrutinized clinical track, which involved a multifaceted assessment.

EPLIN Expression in Gastric Cancer and Impact on Prognosis and Chemoresistance.

Epithelial protein lost in neoplasm (EPLIN) has been implicated as a suppressor of cancer progression. The current study explored EPLIN expression in clinical gastric cancer and its association with chemotherapy resistance. EPLIN transcript expression, in conjunction with patient clinicopathological information and responsiveness to neoadjuvant chemotherapy (NAC), was explored in two gastric cancer cohorts collected from the Beijing Cancer Hospital. Kaplan-Meier survival analysis was undertaken to explore EPLIN association with patient survival. Reduced EPLIN expression was associated with significant or near significant reductions of overall, disease-free, first progression or post-progression survival in the larger host cohort and Kaplan Meier plotter datasets. In the larger cohort EPLIN expression was significantly higher in the combined T1 + T2 gastric cancer group compared to the T3 + T4 group and identified to be an independent prognostic factor of disease-free survival and overall survival by multivariate analysis. In the smaller, NAC cohort, EPLIN expression was found to be significantly lower in tumour tissues than in paratumour tissues. EPLIN expression was significantly associated with responsiveness to chemotherapy which contributes to overall survival. Together, EPLIN appears to be a prognostic factor and may be associated with patient sensitivity to NAC.