Mutation characteristics and molecular evolution of ovarian metastasis from gastric cancer and potential biomarkers for paclitaxel treatment.

Ovarian metastasis is one of the major causes of treatment failure in patients with gastric cancer (GC). However, the genomic characteristics of ovarian metastasis in GC remain poorly understood. In this study, we enroll 74 GC patients with ovarian metastasis, with 64 having matched primary and metastatic samples. Here, we show a characterization of the mutation landscape of this disease, alongside an investigation into the molecular heterogeneity and pathway mutation enrichments between synchronous and metachronous metastasis. We classify patients into distinct clonal evolution patterns based on the distribution of mutations in paired samples. Notably, the parallel evolution group exhibits the most favorable prognosis. Additionally, by analyzing the differential response to chemotherapy, we identify potential biomarkers, including SALL4, CCDC105, and CLDN18, for predicting the efficacy of paclitaxel treatment. Furthermore, we validate that CLDN18 fusion mutations improve tumor response to paclitaxel treatment in GC with ovarian metastasis in vitro and vivo.

Genomic and immune microenvironment features influencing chemoimmunotherapy response in gastric cancer with peritoneal metastasis: a retrospective cohort study.

BACKGROUND: Patients with peritoneal metastasis (PM) from gastric cancer (GC) exhibit poor prognosis. Chemoimmunotherapy offers promising clinical benefits; however, its efficacy and predictive biomarkers in a conversion therapy setting remain unclear. The authors aimed to retrospectively evaluate chemoimmunotherapy efficacy in a conversion therapy setting for GC patients with PM and establish a prediction model for assessing clinical benefits. MATERIALS AND METHODS: A retrospective evaluation of clinical outcomes encompassed 55 GC patients with PM who underwent chemoimmunotherapy in a conversion therapy setting. Baseline PM specimens were collected for genomic and transcriptomic profiling. Clinicopathological factors, gene signatures, and tumor immune microenvironment were evaluated to identify predictive markers and develop a prediction model. RESULTS: Chemoimmunotherapy achieved a 41.8% objective response rate and 72.4% R0 resection rate in GC patients with PM. Patients with conversion surgery showed better overall survival (OS) than those without the surgery (median OS: not reached vs 7.82 m, P<0.0001). Responders to chemoimmunotherapy showed higher ERBB2 and ERBB3 mutation frequencies, CTLA4 and HLA-DQB1 expression, and CD8+ T cell infiltration, but lower CDH1 mutation and naïve CD4+ T cell infiltration, compared to nonresponders. A prediction model was established integrating CDH1 and ERBB3 mutations, HLA-DQB1 expression, and naïve CD4+ T cell infiltration (AUC=0.918), which were further tested using an independent external cohort (AUC=0.785). CONCLUSION: This exploratory study comprehensively evaluated clinicopathological, genomic, and immune features and developed a novel prediction model, providing a rational basis for the selection of GC patients with PM for chemoimmunotherapy-involved conversion therapy.

Catheter-guided anvil insertion for circular stapler esophagojejunal anastomosis: a novel technique in laparoscopic total gastrectomy.

OBJECTIVE: This study evaluates feasibility, safety, and short-term outcomes of employing the catheter-guided stapler anvil insertion technique for esophagojejunal anastomosis using a circular stapler during laparoscopic total gastrectomy (LTG). MATERIALS AND METHODS: From September 2021 to April 2023, the catheter-guided stapler anvil insertion technique was employed in 80 patients undergoing laparoscopic total gastrectomy (LTG) for esophagojejunal anastomosis. A modified D2 dissection, according to the en bloc technique, was performed in the patients. Subsequently, a longitudinal incision, approximately 2 cm in length, was made on the anterior wall of the esophagus, about 2 cm above the tumor. The transection line was pre-marked with blue dye along the esophagus's minor axis, and the tail of the anvil was capped with a 10-cm length of catheter (F14 d4.7 mm). The surgeon secures the head of anvil and carefully inserts it into the esophagus, ensuring that only a 5-cm segment of the catheter remains outside the esophagus. A linear cutter was employed to transect and seal the lower end of the esophagus. Subsequently, esophagojejunostomy was performed under laparoscopic guidance using a circular stapler. RESULTS: Among patients undergoing esophagojejunal anastomosis with the new technique, postoperative complications included pneumonia or pleural effusion in 14 patients (17.5%), anastomotic stenosis in 3 patients (3.75%), abdominal infection in 2 patients (2.5%), and intestinal obstruction in 1 patient (1.25%). No instances of anastomotic leakage, anastomotic bleeding, or deaths were recorded. All patients experiencing complications improved with conservative treatment, without the need for secondary surgery. CONCLUSION: The catheter-guided stapler anvil insertion technique is demonstrated to be a safe and effective method for esophagojejunostomy, potentially reducing the occurrence of anastomotic leakage.

Prognostic significance of serum tumor markers in various pathologic subtypes of gastric cancer.

PURPOSE: This study aimed to assess the utility of 6 serum tumor markers in prognosis between gastric adenocarcinoma and gastric signet ring cell carcinoma (SRCC). METHODS: A cohort of 3131 cases of gastric adenocarcinoma and 275 cases of gastric SRCC was assembled. The serum levels of carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), carbohydrate antigen 125, alpha fetoprotein (AFP), carbohydrate antigen 242 (CA242), and carbohydrate antigen 724 (CA724) were measured in all cases. The study analyzed the association between the levels of these 6 tumor markers and the prognosis of gastric adenocarcinoma and SRCC. RESULTS: The study revealed that gastric SRCC exhibited lower concentrations of CEA (P < .001) and CA19-9 (P = .002), along with reduced positive rates of CEA (P = .041), CA19-9 (P = .003), AFP (P < .001), and CA242 (P = .006), while displaying higher positive rates of CA724 (P = .024) than gastric adenocarcinoma. Nevertheless, the receiver operating characteristic curve demonstrated that serum tumor markers did not hold clinical significance in differentiating between gastric adenocarcinoma and SRCC. Survival analysis substantiated that the combined criteria of serum tumor markers stood as an independent risk factor for both gastric adenocarcinoma and SRCC. Notably, the nomogram indicated that serum tumor markers exerted a more substantial influence on the prognosis of gastric adenocarcinoma than on gastric SRCC. CONCLUSION: The study concluded that the combined criteria of serum tumor markers emerge as independent risk factors for both subtypes of gastric cancer. Furthermore, this combined approach exhibited enhanced efficacy in prognosticating the outcome of gastric adenocarcinoma compared with gastric SRCC.

Comparison of Clinicopathological Features and Prognosis of Mucinous Gastric Carcinoma and other Gastric Cancers: A Retrospective Study of 4,417 Patients.

BACKGROUND: Mucinous gastric carcinoma (MGC) is a distinct histologic subtype of gastric cancer (GC) that is often diagnosed at an advanced stage. The clinicopathological characteristics and prognosis of MGC, when compared to adenocarcinoma and signet-ring cell carcinoma (SRCC), are currently subjects of debate and require further investigation. METHODS: In this study, we conducted an investigation on 4,417 patients who were hospitalized with GC at Zhejiang Cancer Hospital between April 2008 and December 2019. The objective was to compare the prognosis and clinicopathological characteristics of MGC with other types of GC. RESULTS: In comparison to adenocarcinoma, MGC patients exhibited more advanced tumor infiltration (p < 0.001), lower tumor differentiation (p < 0.001), and higher rates of preoperative tumor marker positivity (except for AFP and CA125) (all p < 0.05). However, after propensity score matching (PSM) to eliminate confounding factors, MGC patients surprisingly exhibited a better prognosis than adenocarcinoma patients (p = 0.008), and the results in multifactorial COX regression were similar (HR = 0.792, 95% CI 0.629-0.997, p = 0.047). Among patients with MGC, age, pN stage, as well as preoperative levels of CA125 and CA724 (all p < 0.05), emerged as independent prognostic markers. While overall survival did not significantly differ between MGC and SRCC (p = 0.196), significant survival disparities emerged in advanced-stage patients (p = 0.009), with MGC showing better survival rates. Furthermore, a nomogram was developed to predict 1-, 3-, and 5-year survival in gastric cancer patients based on various factors, achieving a C-index of 0.772 (95% CI: 0.745-0.799). CONCLUSIONS: While the poorer prognosis associated with MGC may be linked to its advanced stage and lower degree of differentiation, its biological behavior could contribute to improved survival.

The percentages of signet-ring cells (SRCs) affects the prognosis after radical gastrectomy for advanced gastric cancer.

PURPOSE: Only recently has the percentage of signet-ring cells (SRCs) been shown to affect the prognosis following gastric cancer surgery. It is uncertain whether the SRC percentage has a role in tumour biology or prognosis of gastric signet-ring cell carcinoma (GSRCC). For this research, we assessed the effect of the SRC percentage on the clinicopathological and prognostic characteristics of gastric cancer (GC) tumours and created and verified a prognostic nomogram to assess the overall survival (OS) of GSRCC patients. METHODS: In our study, 1100 GC patients with signet-ring cell carcinoma (SRCC) at Zhejiang Cancer Hospital from December 2013 to December 2018 who underwent curative gastric cancer resection were retrospectively analysed. The patients were separated into two groups: those with SRCC (SRC percentage >50%; n = 157) and those with partial signet-ring cell carcinoma (PSRCC) (SRC percentage ≤50%; n = 943). We compared the clinicopathological characteristics of both groups. To estimate OS and determine correlations with the SRC percentage, the Kaplan-Meier method and log-rank test were used. To develop the prognostic nomogram, independent prognostic indicators for OS were identified using Cox regression analyses. Predictions were assessed using the calibration curve and C-index. RESULTS: Our research showed that there was no discernible difference in OS between the two groups. The preoperative CA242 level, pT stage, pN stage, age, nerve invasion, neoadjuvant chemotherapy, postoperative chemotherapy, and maximum tumour diameter were independent prognostic risk factors for OS for GC (all p < 0.05). However, for advanced GC, the SRC percentage (HR = 1.571, 95% CI 1.072-2.302, p = 0.020) was an independent prognostic factor of OS. Other independent prognostic risk factors were age, pT stage, pN stage, nerve invasion, tumour location, neoadjuvant chemotherapy, postoperative chemotherapy, preoperative CA50 level, and preoperative CEA level (all p < 0.05). On these bases, nomograms were constructed for GC and advanced GC, with C-indexes of 0.806 (95%CI 0.782-0.830) and 0.728 (95%CI 0.697-0.759), respectively. CONCLUSIONS: In cases of advanced gastric cancer, the SRC percentage served as a standalone prognostic indicator for OS. An effective tool for assessing the prognosis of GSRCC was offered by the nomogram.

SOX combined with sintilimab versus SOX alone in the perioperative management of locally advanced gastric cancer: a propensity score-matched analysis.

OBJECTIVES: To evaluate the efficacy of SOX combined with a programmed cell death protein-1 (PD-1) inhibitor compared with SOX alone in the perioperative management of locally advanced gastric cancer and to explore biomarkers that may predict response to anti-PD-1 therapy. METHODS: Data of patients with clinical stage T3-4aN0-3M0 (IIb-III) gastric cancer were reviewed to create a primary database. Patients treated with perioperative SOX combined with sintilimab were included in Group A, while those treated with SOX alone were included in Group B. After one-to-one propensity score matching, pathological response and short-term survival outcomes were compared between the two groups. In addition, potential efficacy-related biomarkers were analyzed. RESULTS: Between January 2018 and December 2022, a total of 150 patients were included in the analysis, with 75 patients in each group. The rates of pathological complete response (21.3% vs. 4.0%; P = 0.001) and major pathological response (45.3% vs. 22.7%; P = 0.003) in Group A were statistically higher than those in Group B. There was no significant difference in 1-year overall survival (92.8% vs. 92.0%; P = 0.392) and disease-free survival (88.9% vs. 88.0%; P = 0.357) between the two groups. Subgroup analysis of Group A showed that the pathological complete response (40.6% vs. 8.6%; P = 0.002) and major pathological response (65.6% vs. 28.6%; P = 0.002) rates were significantly higher in programmed death ligand-1-positive patients with a combined positive score of ≥ 5. A pathological complete response was achieved in 42.9% patients (3/7) with mismatch repair deficiency. For the two patients confirmed as Epstein-Barr virus-positive, one patient achieved a pathological complete response and the other achieved a major pathological response. CONCLUSIONS: The adoption of SOX combined with a PD-1 inhibitor may improve the pathological response rate of patients with locally advanced gastric cancer, especially those with programmed death ligand-1 combined positive score ≥ 5, Epstein-Barr virus-positivity and mismatch repair deficiency. However, further prospective studies are still warranted to confirm the long-term survival benefit.

Hyperthermic intraperitoneal chemotherapy (HIPEC) plus systemic chemotherapy versus systemic chemotherapy alone in locally advanced gastric cancer after D2 radical resection: a randomized-controlled study.

BACKGROUND: Currently, there is a lack of an effective strategy for the prevention of peritoneal metastasis (PM) from locally advanced gastric cancer (AGC). This randomized-controlled study aimed to evaluate the outcome of D2 radical resection with hyperthermic intraperitoneal chemotherapy (HIPEC) plus systemic chemotherapy versus systemic chemotherapy alone in locally AGC patients. METHODS: All enrolled patients were randomly assigned to receive HIPEC plus systemic chemotherapy (HIPEC group) or systemic chemotherapy alone (non-HIPEC group) after radical gastrectomy. HIPEC was performed intraperitoneally with cisplatin (40 mg/m2) within 72 h after surgery, while systemic chemotherapy based on the SOX regimen (S-1 combined with oxaliplatin) was administered 4-6 weeks after radical surgery. Patterns of recurrence, adverse events, 3-year disease-free survival (DFS), and overall survival (OS) were analyzed. RESULTS: A total of 134 patients were enrolled in the present study. The 3-year DFS rate was 73.8% in the HIPEC group, which was significantly higher than that in the non-HIPEC group (61.2%, P = 0.031). The 3-year OS rate was 73.9% in the HIPEC group and 77.6% in the non-HIPEC group, with no significant difference (P = 0.737). PM was the most common distant metastasis in both groups. The occurrence rate of PM in the HIPEC group was statistically lower than that in the non-HIPEC group (20.9% vs. 40.3%, P = 0.015). Grade 3 or 4 adverse events occurred in 19 (14.2%) patients, and there was no significant difference between the two groups. CONCLUSION: Radical surgery followed by HIPEC combined with systemic chemotherapy is a safe and feasible strategy for locally AGC patients and could effectively improve DFS and reduce the occurrence of PM. However, more prospective randomized studies with a large sample size are warranted. TRIAL REGISTRATION: This study was registered with www.medresman.org.cn as ChiCTR2200055966 on 10/12/2016.

Efficacy of chemotherapy combined with surgical resection for gastric cancer with synchronous ovarian metastasis: A propensity score matching analysis.

BACKGROUND: Ovarian metastasis from gastric cancer (GC) is characterized by aggressive biological behavior and poor outcome. Currently, there is no standard treatment mode for such patients. Thus, we evaluated the efficacy of conversion therapy in patients with synchronous ovarian metastasis from GC in this study. METHODS: About 219 GC patients with ovarian metastasis in 2011-2020 were enrolled. Two groups were established based on the different treatment: the conversion therapy group (chemotherapy combined with surgical resection, CS group) and the non-conversion therapy group (NCS group). Propensity score matching (PSM) was used to analyze the efficacy of different treatment modes on the prognosis of these patients. RESULTS: Ninety-two patients were included according to PSM results, with 46 patients each in CS and NCS groups. The median overall survival (OS) in the CS group was notably better than that in the NCS group (p < 0.001). Twenty-six patients (56.52%) in the CS group achieved R0 resection, and they had a better prognosis (p = 0.003). Compared with patients who underwent simultaneous gastrectomy and ovarian metastasectomy (CSb group), those who underwent ovarian metastasectomy before systemic chemotherapy (CSa group) had a higher R0 resection rate (p = 0.016) and longer survival time (p = 0.002). A total of 38 patients (41.30%) across both groups received hyperthermic intraperitoneal chemotherapy (HIPEC), and these patients had a better survival (p = 0.043). CONCLUSION: The conversion therapy is safe and effective for patients with synchronous ovarian metastasis from GC and can improve their prognosis. However, our results need to be confirmed by more randomized controlled clinical studies.

Efficient plasma metabolic fingerprinting as a novel tool for diagnosis and prognosis of gastric cancer: a large-scale, multicentre study.

OBJECTIVE: Metabolic biomarkers are expected to decode the phenotype of gastric cancer (GC) and lead to high-performance blood tests towards GC diagnosis and prognosis. We attempted to develop diagnostic and prognostic models for GC based on plasma metabolic information. DESIGN: We conducted a large-scale, multicentre study comprising 1944 participants from 7 centres in retrospective cohort and 264 participants in prospective cohort. Discovery and verification phases of diagnostic and prognostic models were conducted in retrospective cohort through machine learning and Cox regression of plasma metabolic fingerprints (PMFs) obtained by nanoparticle-enhanced laser desorption/ionisation-mass spectrometry (NPELDI-MS). Furthermore, the developed diagnostic model was validated in prospective cohort by both NPELDI-MS and ultra-performance liquid chromatography-MS (UPLC-MS). RESULTS: We demonstrated the high throughput, desirable reproducibility and limited centre-specific effects of PMFs obtained through NPELDI-MS. In retrospective cohort, we achieved diagnostic performance with areas under curves (AUCs) of 0.862-0.988 in the discovery (n=1157 from 5 centres) and independent external verification dataset (n=787 from another 2 centres), through 5 different machine learning of PMFs, including neural network, ridge regression, lasso regression, support vector machine and random forest. Further, a metabolic panel consisting of 21 metabolites was constructed and identified for GC diagnosis with AUCs of 0.921-0.971 and 0.907-0.940 in the discovery and verification dataset, respectively. In the prospective study (n=264 from lead centre), both NPELDI-MS and UPLC-MS were applied to detect and validate the metabolic panel, and the diagnostic AUCs were 0.855-0.918 and 0.856-0.916, respectively. Moreover, we constructed a prognosis scoring system for GC in retrospective cohort, which can effectively predict the survival of GC patients. CONCLUSION: We developed and validated diagnostic and prognostic models for GC, which also contribute to advanced metabolic analysis towards diseases, including but not limited to GC.

Deep learning radio-clinical signatures for predicting neoadjuvant chemotherapy response and prognosis from pretreatment CT images of locally advanced gastric cancer patients.

BACKGROUND: Early noninvasive screening of patients who would benefit from neoadjuvant chemotherapy (NCT) is essential for personalized treatment of locally advanced gastric cancer (LAGC). The aim of this study was to identify radio-clinical signatures from pretreatment oversampled computed tomography (CT) images to predict the response to NCT and prognosis of LAGC patients. METHODS: LAGC patients were retrospectively recruited from six hospitals from January 2008 to December 2021. An SE-ResNet50-based chemotherapy response prediction system was developed from pretreatment CT images preprocessed with an imaging oversampling method (i.e. DeepSMOTE). Then, the deep learning (DL) signature and clinic-based features were fed into the deep learning radio-clinical signature (DLCS). The predictive performance of the model was evaluated based on discrimination, calibration, and clinical usefulness. An additional model was built to predict overall survival (OS) and explore the survival benefit of the proposed DL signature and clinicopathological characteristics. RESULTS: A total of 1060 LAGC patients were recruited from six hospitals; the training cohort (TC) and internal validation cohort (IVC) patients were randomly selected from center I. An external validation cohort (EVC) of 265 patients from five other centers was also included. The DLCS exhibited excellent performance in predicting the response to NCT in the IVC [area under the curve (AUC), 0.86] and EVC (AUC, 0.82), with good calibration in all cohorts ( P >0.05). Moreover, the DLCS model outperformed the clinical model ( P <0.05). Additionally, we found that the DL signature could serve as an independent factor for prognosis [hazard ratio (HR), 0.828, P =0.004]. The concordance index (C-index), integrated area under the time-dependent ROC curve (iAUC), and integrated Brier score (IBS) for the OS model were 0.64, 1.24, and 0.71 in the test set. CONCLUSION: The authors proposed a DLCS model that combined imaging features with clinical risk factors to accurately predict tumor response and identify the risk of OS in LAGC patients prior to NCT, which can then be used to guide personalized treatment plans with the help of computerized tumor-level characterization.

Does resection after neoadjuvant chemotherapy of docetaxel, oxaliplatin, and S-1 (DOS regimen) benefit for gastric cancer patients with single non-curable factor? a multicenter, prospective cohort study (Neo-REGATTA).

BACKGROUND: The Neo-REGATTA study evaluated the effectiveness and safety of Docetaxel, oxaliplatin, and S-1 (DOS regimen) followed by radical resection vs. chemotherapy in advanced gastric adenocarcinoma patients with single non-curable factor. METHODS: This cohort study prospectively enrolled advanced gastric adenocarcinoma patients with single non-curable factor between November 2017 and June 2021. Patients without progression after four cycles of DOS were divided into resection group and chemotherapy group. The outcomes included overall survival (OS), progression-free survival (PFS) and safety. Effectiveness analysis was also performed by propensity score matching (PSM). RESULTS: A total of 73 patients were enrolled and 13 patients were withdrawn due to disease progression after 4 cycles of DOS. Afterwards, 35 and 25 participants were in the resection and chemotherapy groups, respectively. After a median follow-up time of 30.0 months, the median PFS and OS were 9.0 months, and 18.0 months for the chemotherapy group, but not reached in the resection group. After PSM, 19 matched participants were in each group, and the median PFS and OS were longer in resection group than that in chemotherapy group. The most common grade 3 or 4 adverse events both in the resection group and chemotherapy groups were neutropenia (5.7%, 8.0%) and leukopenia (5.7%, 8.0%). CONCLUSIONS: Radical resection might provide survival benefit compared with continuous chemotherapy alone in advanced gastric adenocarcinoma patients who had a disease control after DOS, with a good safety profile. TRIAL REGISTRATION: The study protocol was registered on ClinicalTrial.gov (NCT03001726, 23/12/2016).

Integrative proteomic characterization of adenocarcinoma of esophagogastric junction.

The incidence of adenocarcinoma of the esophagogastric junction (AEG) has been rapidly increasing in recent decades, but its molecular alterations and subtypes are still obscure. Here, we conduct proteomics and phosphoproteomics profiling of 103 AEG tumors with paired normal adjacent tissues (NATs), whole exome sequencing of 94 tumor-NAT pairs, and RNA sequencing in 83 tumor-NAT pairs. Our analysis reveals an extensively altered proteome and 252 potential druggable proteins in AEG tumors. We identify three proteomic subtypes with significant clinical and molecular differences. The S-II subtype signature protein, FBXO44, is demonstrated to promote tumor progression and metastasis in vitro and in vivo. Our comparative analyses reveal distinct genomic features in AEG subtypes. We find a specific decrease of fibroblasts in the S-III subtype. Further phosphoproteomic comparisons reveal different kinase-phosphosubstrate regulatory networks among AEG subtypes. Our proteogenomics dataset provides valuable resources for understanding molecular mechanisms and developing precision treatment strategies of AEG.

A Novel Method for Dynamically Assessing the Prognosis of Patients with pT1 Gastric Cancer: A Large Population-Based Dynamic Prognostic Analysis.

Background: While early gastric cancer (EGC) patients are likely to experience relatively long postoperative survival, certain disease-related findings are associated with a poorer prognosis. This study sought to develop and validate a novel predictive model capable of estimating conditional disease-specific survival (CDSS) in EGC patients. Methods: A total of 3016 patients diagnosed with pT1NxM0 GC after gastrectomy between 1998 and 2016 were selected from the Surveillance, Epidemiology, and End Results (SEER) database and were separated into training and validation cohorts. Kaplan‒Meier curves and log-rank tests were employed to evaluate DSS, after which univariate and multivariate Cox regression analyses were used to construct a predictive nomogram and to estimate CDSS at 1, 2, and 3 years postoperatively in these patients. Results: In the training cohort, the 3-year CDSS rose from 89.1% to 94.6% from 0 to 5 years postoperatively, while the 5-year CDSS rose from 84.5% to 92.0%. Cox regression analyses led to the construction of a nomogram that was able to reliably predict 3- and 5-year CDSS at 1, 2, and 3 years postoperatively (all P < 0.05) based upon patient age, tumor size, pT stage, pN stage, and the number of retrieved lymph nodes. This model exhibited good discriminative power in the training and validation cohorts (concordance index: 0.791 and 0.813, respectively), and nomogram calibration curves confirmed that actual and predicted survival outcomes were close to one another. Conclusions: We herein developed a nomogram capable of accurately predicting the CDSS of EGC patients that had survived for multiple years after undergoing surgery.

Trastuzumab in combination with chemotherapy for HER2-positive metastatic gastric cancer patients underwent conversion therapy.

Background: Conversion surgery is a treatment that aims for R0 resection of primary advanced gastric cancers (GCs) that have responded well to systemic chemotherapy. We investigated the role of conversion therapy in initially unresectable metastatic cancer with positive HER2 status that responded to chemotherapy plus trastuzumab. Methods: A total of 32 metastatic GC patients who underwent systemic chemotherapy plus trastuzumab sequenced by conversion surgery at Zhejiang Cancer Hospital between 2015 and 2020 were retrospectively reviewed. Results: The observed overall survival (OS) and progression-free survival (PFS) for all the patients were 30.2 and 25.1 months, respectively. The 1-year survival rate was 81.25%, and the 1-year PFS rate was 78.13%. Univariate and multivariate analyses demonstrated that liver metastasis (P=0.021), peritoneal metastasis (P=0.047), para-aortic lymph node metastasis (16a1/b2) (P=0.048), macroscopic type 4 (P=0.027), number of noncurative factors (P=0.011), Yoshida et al. category (P=0.021), and inductive chemotherapy cycles (P=0.025) were independent prognostic factors for OS. Conclusions: HER2-positive patients with potentially resectable disease had a remarkably good prognosis after conversion gastrectomy following trastuzumab treatment. Adequate selection of metastatic GC patients for conversion surgery is recommended.

Efficacy analysis of Cheng's GIRAFFE reconstruction after proximal gastrectomy for adenocarcinoma of esophagogastric junction.

Objective: Reconstruction of the digestive tract for adenocarcinoma of esophagogastric junction (AEG) is in dispute. This study evaluated Cheng's gastric tube interposition esophagogastrostomy with reconstruction of His angle and fundus (Cheng's GIRAFFE anastomosis) in laparoscopic/open proximal gastrectomy for Siewert type II AEG, which was performed at Zhejiang Cancer Hospital and the First Affiliated Hospital of Zhejiang Chinese Medical University. Here, we discuss the preliminary results of gastric emptying and anti-reflux. Methods: From a retrospective database, 74 patients with advanced Siewert type II AEG underwent curative proximal gastrectomy with GIRAFFE anastomosis, and their gastric emptying and anti-reflux outcomes were evaluated by the Reflux Disease Questionnaire (RDQ) score, nuclide gastric emptying, 24-h impedance-pH monitoring and gastroscopy. Results: Seventy-four patients successfully completed proximal partial gastrectomy with Cheng's GIRAFFE esophagogastric anastomosis. RDQ score six months after the operation was 2.2±2.5. Results of nuclide gastric emptying examinations showed that the gastric half-emptying time was 67.0±21.5 min, the 1-h residual rate was (52.2±7.7)%, the 2-h residual rate was (36.4±5.1)%, and the 3-h residual rate was (28.8±3.6)%; 24-h impedance-pH monitoring revealed that the mean DeMeester score was 5.8±2.9. Reflux esophagitis was observed by gastroscopy in 7 patients six months after surgery. Conclusions: Cheng's GIRAFFE anastomosis is safe and feasible for Siewert type II AEG.

Associations of HER2 Mutation With Immune-Related Features and Immunotherapy Outcomes in Solid Tumors.

Background: HER2 is one of the most extensively studied oncogenes in solid tumors. However, the association between tumor microenvironment (TME) and HER2 mutation remains elusive, and there are no specific therapies for HER2-mutated tumors. Immune checkpoint inhibitors (ICIs) have been approved for some tumor subgroups that lack targeted therapies, while their effects are still unclear in HER2-mutated tumors. We examined whether HER2 mutation impacts treatment outcomes of ICIs in solid tumors via its association with anticancer immunity. Methods: Multi-omics data of solid tumors from The Cancer Genome Atlas (TCGA), the Asian Cancer Research Group and the Affiliated Hospital of Jiangsu University were used to analyze the association between HER2 mutations and tumor features. Data of patients with multiple microsatellite-stable solid tumors, who were treated by ICIs including antibodies against programmed cell death-1 (PD-1), programmed cell death ligand-1 (PD-L1), or cytotoxic T lymphocyte-associated protein 4 (CTLA-4) in eight studies, were collected to investigate the effects of HER2 mutations on immunotherapy outcomes. Results: The mutation rate of HER2 varied in solid tumors of TCGA, with an overall incidence of 3.13%, ranged from 0.39% to 12.2%. Concurrent HER2 mutations and amplifications were rare (0.26%). HER2 mutation was not associated with HER2 protein expression but was positively associated with microsatellite instability, tumor mutation and neoantigen burdens, infiltrating antitumor immune cells, and signal activities of antitumor immunity. Of 321 ICI-treated patients, 18 carried HER2 mutations (5.6%) and showed improved objective response rates compared with those with HER2 wild-type (44.4% vs. 25.7%, p=0.081), especially in the anti-PD-1/anti-PD-L1 subgroup (62.5% vs. 28.4%, p=0.04). Heterogeneity was observed among tumor types. Patients with HER2 mutations also had superior overall survival than those with HER2 wild-type (HR=0.47, 95%CI: 0.23-0.97, p=0.04), especially in the presence of co-mutations in ABCA1 (HR = 0.23, 95% CI: 0.07-0.73, p=0.013), CELSR1 (HR = 0.24, 95% CI: 0.08-0.77, p=0.016), LRP2 (HR = 0.24, 95% CI: 0.07-0.74, p=0.014), or PKHD1L1 (HR = 0.2, 95% CI: 0.05-0.8, p=0.023). Conclusions: HER2 mutations may improve the TME to favor immunotherapy. A prospective basket trial is needed to further investigate the impacts of HER2 mutations on immunotherapy outcomes in solid tumors.

Prediction of Peritoneal Cancer Index and Prognosis in Peritoneal Metastasis of Gastric Cancer Using NLR-PLR-DDI Score: A Retrospective Study.

OBJECTIVE: The peritoneal cancer index (PCI) is used to evaluate the peritoneal metastasis of gastric cancer. A higher value indicates more widespread and/or larger tumors in the peritoneal cavity. The neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) are representative blood markers of systemic inflammatory responses, and D-dimer (DDI) is the final stable product of fibrin. This study explores the association of NLR, PLR, and DDI with PCI and assesses the clinical utility of a new blood score combining the NLR, PLR, and DDI (NPD score) for PCI and the prognosis prediction of gastric cancer. METHODS: This was a single-center, nonrandomized, retrospective, cohort study. We evaluated the risk factors for high PCI (≥15) using univariate and multivariate analyses. According to the findings of the ROC analysis, we determined the cut-off values of NLR, PLR and DDI and created the NPD score. The patients were grouped into high-risk and low-risk groups based on their NPD score (<2 and ≥2, respectively). RESULTS: Univariate and multivariate analysis demonstrated that the NLR, PLR, and DDI were independent risk factors for high PCI (P < 0.05). The NPD score of the high-risk group was ≥2, and the NPD score of the low-risk group was <2. The median survival time was 14.2 in the high-risk group and 25.6 in the low-risk group. The NPD score was significantly higher in the high-PCI group than that in the low-PCI group. The survival of the high-risk group was significantly worse than that of the low-risk group (P = 0.003). NPD score decrease was an independent predictive factor for PCI decrease. CONCLUSION: NLR, PLR, and DDI are potential independent risk factors for high PCI in patients with peritoneal metastasis of gastric cancer. The NPD scoring system can help in predicting PCI and the prognosis of patients with peritoneal metastasis of gastric cancer.

Adjuvant SOX chemotherapy versus concurrent chemoradiotherapy after D2 radical resection of locally advanced esophagogastric junction (EGJ) adenocarcinoma: study protocol for a randomized phase III trial (ARTEG).

BACKGROUND: Survival benefit of adjuvant radiotherapy for locally advanced gastric cancer following gastrectomy plus D2 lymphadenectomy has always been controversial. Esophagogastric junction (EGJ) adenocarcinoma, which is usually classified as gastric cancer in East Asia, often has a higher locoregional recurrence rate after operation because of its special anatomical characteristics. The aim of this study is to determine whether adjuvant radiotherapy can improve survival of locally advanced EGJ adenocarcinoma after D2 radical resection. METHODS: In this phase III, randomized, open label, controlled trial, we plan to recruit 378 patients with Siewert type II and III adenocarcinoma of EGJ, who had undergone transabdominal radical surgery and D2 lymphadenectomy, and were divided into pathological stage IIB to IIIC. All patients will be randomized 1:1 to receive either adjuvant chemotherapy alone (control group) or adjuvant chemotherapy plus chemoradiotherapy (experimental group). Patients allocated to control group will receive eight cycles of S-1 plus oxaliplatin (SOX), while the experimental group will receive two cycles of SOX followed by 45-Gy RT combined with S-1 and four additional cycles of SOX. The primary endpoint is 3-year disease-free survival rate (DFS). The secondary endpoints are 3-year overall survival rate (OS), 3-year locoregional recurrence-free survival rate (LRFS), 3-year distant metastasis-free survival rate (DMFS), and quality of life (QoL). DISCUSSION: In the past, the adjuvant treatment of EGJ adenocarcinoma needs to draw on the experience of esophageal adenocarcinoma or gastric adenocarcinoma. In this study, EGJ adenocarcinoma is considered as an independent disease, and the conclusion will provide evidence for optimal adjuvant therapy of locally advanced EGJ adenocarcinoma after D2 radical resection. TRIAL REGISTRATION: ClinicalTrials.gov NCT03973008 . Registered on 1 June 2019 (retrospectively registered), URL: https://clinicaltrials.gov/ct2/show/NCT03973008?term=NCT03973008&draw=2&rank=1.

Perioperative or postoperative adjuvant oxaliplatin with S-1 versus adjuvant oxaliplatin with capecitabine in patients with locally advanced gastric or gastro-oesophageal junction adenocarcinoma undergoing D2 gastrectomy (RESOLVE): an open-label, superiority and non-inferiority, phase 3 randomised controlled trial.

BACKGROUND: The optimal perioperative chemotherapeutic regimen for locally advanced gastric cancer remains undefined. We evaluated the efficacy and safety of perioperative and postoperative S-1 and oxaliplatin (SOX) compared with postoperative capecitabine and oxaliplatin (CapOx) in patients with locally advanced gastric cancer undergoing D2 gastrectomy. METHODS: We did this open-label, phase 3, superiority and non-inferiority, randomised trial at 27 hospitals in China. We recruited antitumour treatment-naive patients aged 18 years or older with historically confirmed cT4a N+ M0 or cT4b Nany M0 gastric or gastro-oesophageal junction adenocarcinoma, with Karnofsky performance score of 70 or more. Patients undergoing D2 gastrectomy were randomly assigned (1:1:1) via an interactive web response system, stratified by participating centres and Lauren classification, to receive adjuvant CapOx (eight postoperative cycles of intravenous oxaliplatin 130 mg/m2 on day one of each 21 day cycle plus oral capecitabine 1000 mg/m2 twice a day), adjuvant SOX (eight postoperative cycles of intravenous oxaliplatin 130 mg/m2 on day one of each 21 day cycle plus oral S-1 40-60 mg twice a day), or perioperative SOX (intravenous oxaliplatin 130 mg/m2 on day one of each 21 day plus oral S-1 40-60 mg twice a day for three cycles preoperatively and five cycles postoperatively followed by three cycles of S-1 monotherapy). The primary endpoint, assessed in the modified intention-to-treat population, 3-year disease-free survival to assess the superiority of perioperative-SOX compared with adjuvant-SOX and the non-inferiority (hazard ratio non-inferiority margin of 1·33) of adjuvant-SOX compared with adjuvant-CapOx. Safety analysis were done in patients who received at least one dose of the assigned treatment. This study is registered with ClinicalTrials.gov, NCT01534546. FINDINGS: Between Aug 15, 2012, and Feb 28, 2017, 1094 patients were screened and 1022 (93%) were included in the modified intention-to-treat population, of whom 345 (34%) patients were assigned to the adjuvant-CapOx, 340 (33%) patients to the adjuvant-SOX group, and 337 (33%) patients to the perioperative-SOX group. 3-year disease-free survival was 51·1% (95% CI 45·5-56·3) in the adjuvant-CapOx group, 56·5% (51·0-61·7) in the adjuvant-SOX group, and 59·4% (53·8-64·6) in the perioperative-SOX group. The hazard ratio (HR) was 0·77 (95% CI 0·61-0·97; Wald p=0·028) for the perioperative-SOX group compared with the adjuvant-CapOx group and 0·86 (0·68-1·07; Wald p=0·17) for the adjuvant-SOX group compared with the adjuvant-CapOx group. The most common grade 3-4 adverse events was neutropenia (32 [12%] of 258 patients in the adjuvant-CapOx group, 21 [8%] of 249 patients in the adjuvant-SOX group, and 30 [10%] of 310 patients in the perioperative-SOX group). Serious adverse events were reported in seven (3%) of 258 patients in adjuvant-CapOx group, two of which were related to treatment; eight (3%) of 249 patients in adjuvant-SOX group, two of which were related to treatment; and seven (2%) of 310 patients in perioperative-SOX group, four of which were related to treatment. No treatment-related deaths were reported. INTERPRETATION: Perioperative-SOX showed a clinically meaningful improvement compared with adjuvant-CapOx in patients with locally advanced gastric cancer who had D2 gastrectomy; adjuvant-SOX was non-inferior to adjuvant-CapOx in these patients. Perioperative-SOX could be considered a new treatment option for patients with locally advanced gastric cancer. FUNDING: National Key Research and Development Program of China, Beijing Scholars Program 2018-2024, Peking University Clinical Scientist Program, Taiho, Sanofi-Aventis, and Hengrui Pharmaceutical. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.