Immunohistochemical characteristics and potential therapeutic regimens of hepatoid adenocarcinoma of the stomach: a study of 139 cases.

Hepatoid adenocarcinoma of stomach (HAS) is a special subtype of gastric cancer with poor prognosis. Immunohistochemical analysis could provide important clues for the treatment of HAS. A total of 159 patients were diagnosed as HAS and 139 were enrolled in this study. Statistical differences were determined using relative test methods and survival analyses were performed by the Kaplan-Meier method to find survival differences. All tumors in this study were negative for Epstein-Barr virus-encoded small RNAs (EBERs) and almost all showed no loss of mismatch repair (MMR) proteins and were positive for alpha fetoprotein (AFP or spalt like transcription factor 4 (SALL4). About half of the tumors had a positive programmed death-ligand 1 combined positive score (CPS) and 17.3% were positive for human epidermal growth factor receptor 2 (HER2). In addition, there was a relatively high proportion of cmet expression. We also found that HAS patients with recurrent disease treated by emerging therapy had a better survival than those treated with traditional chemotherapy (p = 0.002, median recurrence-to-death survival: 23 months versus 6 months); HAS patients who received anti-HER2 therapy or harbored MMR deficiency had favorable prognosis. Overall, high proportions of MMR protein proficiency, positivity for AFP or SALL4, overexpression of HER2, CPS and cmet, as well as negative EBER findings, are distinctive characteristics of HAS patients. While negative EBER and MMR proficiency indicate molecular features of HAS, positivity for AFP or SALL4 could aid in the diagnosis of HAS. In addition, HAS patients could benefit from anti-HER2 therapy, immunotherapy, and anti-angiogenesis therapy.

Exploration of molecular markers related to chemotherapy efficacy of hepatoid adenocarcinoma of the stomach.

PURPOSE: Preoperative neoadjuvant chemotherapy may not improve the prognosis of patients with hepatoid adenocarcinoma of the stomach (HAS), a rare pathological type of gastric cancer. Thus, the study aimed at the genomic and transcriptomic impacts of preoperative chemotherapy on HAS. METHODS: Patients with HAS who underwent surgical resection at Peking University Cancer Hospital were retrospectively included in this study. Whole exome sequencing and transcriptome sequencing were performed on pre-chemotherapy, non-chemotherapy and post-chemotherapy samples. We then compared the alterations in molecular markers between the post-chemotherapy and non-chemotherapy groups, and between the chemotherapy-effective and chemotherapy-ineffective groups, respectively. RESULTS: A total of 79 tumor samples from 72 patients were collected. Compared to the non-chemotherapy group, the mutation frequencies of several genes were changed after chemotherapy, including TP53. In addition, there was a significant increase in the frequency of frameshift mutations and cytosine transversion to adenine (C > A), appearance of COSMIC signature 6 and 14, and a reduced gene copy number amplification. Interestingly, the same phenomenon was observed in chemotherapy-ineffective patients. In addition, many HAS patients had ERBB2, FGFR2, MET and HGF gene amplification. Moreover, the expression of immune-related genes, especially those related to lymphocyte activation, was down-regulated after chemotherapy. CONCLUSION: Chemotherapy is closely associated with changes in the molecular characteristics of HAS. After chemotherapy, at genomic and transcriptome level, many features were altered. These changes may be molecular markers of poor chemotherapeutic efficacy and play an important role in chemoresistance in HAS. In addition, ERBB2, FGFR2, MET and HGF gene amplification may be potential therapeutic targets for HAS.

Research progress of minimally invasive surgery for gastric cancer.

Since the first laparoscopic radical surgery for early gastric cancer 30 years ago, there has been a gradual shift from "open" to "minimally invasive" surgery for gastric cancer. This transition is due to advancements in refined anatomy, enlarged field of view, faster recovery, and comparable oncological outcomes. Several high-quality clinical studies have demonstrated the safety and effectiveness of laparoscopy in the treatment of both early and locally advanced gastric cancer. The role of perioperative chemotherapy in managing locally advanced gastric cancer has been widely recognized, and there have been continuous breakthroughs in the exploration of targeted therapy and immunotherapy for perioperative treatment. Additionally, the application of indocyanine green near-infrared imaging technology, 3D laparoscopic technology, and robotic surgery systems has further improved the accuracy and minimally invasive nature of gastric cancer surgeries. Looking ahead, the field of minimally invasive surgery for gastric cancer is expected to become more standardized, resulting in a significant enhancement in the quality of life for gastric cancer patients.

Liquid biopsy: circulating tumor DNA monitors neoadjuvant chemotherapy response and prognosis in stage II/III gastric cancer.

A good response to neoadjuvant chemotherapy (NACT) is strongly associated with a higher curative resection rate and favorable outcomes for patients with gastric cancer (GC). We examined the utility of serial circulating tumor DNA (ctDNA) testing for monitoring NACT response and prognosis in stage II-III GC. Seventy-nine patients were enrolled to receive two cycles of NACT following gastrectomy with D2-lymphadenectomy. Plasma at baseline, post-NACT, and after surgery, and tissue at pretreatment and surgery were collected. We used a 425-gene panel to detect genomic alterations (GAs). Results show that the mean cell-free DNA concentration of patients with clinical stage III was significantly higher than patients with stage II (15.43 ng·mL-1 vs 14.40 ng·mL-1 ). After receiving NACT and surgery, the overall detection rate of ctDNA gradually reduced (59.5%, 50.8%, and 47.4% for baseline, post-NACT, and postsurgery). The maximum variant allele frequency (max-VAF) and the number of GAs decreased from 0.50% to 0.08% and from 2.9 to 1.7 after NACT. For patients with a partial response after NACT, the max-VAF and the number of GAs declined significantly, but they increased for patients with progressive disease. Patients with detectable ctDNA at baseline, after NACT, or after surgery have a worse overall survival (OS) than patients with undetectable ctDNA. The estimated 3-year OS was 73% for the post-NACT ctDNA-negative patients and 34% for ctDNA-positive. Patients with perpetual negative ctDNA before and after NACT have the best prognosis. In conclusion, ctDNA was proposed as a potential biomarker to predict prognosis and monitor the NACT response for stage II-III GC patients.

Spatially resolved multi-omics highlights cell-specific metabolic remodeling and interactions in gastric cancer.

Mapping tumor metabolic remodeling and their spatial crosstalk with surrounding non-tumor cells can fundamentally improve our understanding of tumor biology, facilitates the designing of advanced therapeutic strategies. Here, we present an integration of mass spectrometry imaging-based spatial metabolomics and lipidomics with microarray-based spatial transcriptomics to hierarchically visualize the intratumor metabolic heterogeneity and cell metabolic interactions in same gastric cancer sample. Tumor-associated metabolic reprogramming is imaged at metabolic-transcriptional levels, and maker metabolites, lipids, genes are connected in metabolic pathways and colocalized in the heterogeneous cancer tissues. Integrated data from spatial multi-omics approaches coherently identify cell types and distributions within the complex tumor microenvironment, and an immune cell-dominated "tumor-normal interface" region where tumor cells contact adjacent tissues are characterized with distinct transcriptional signatures and significant immunometabolic alterations. Our approach for mapping tissue molecular architecture provides highly integrated picture of intratumor heterogeneity, and transform the understanding of cancer metabolism at systemic level.

Prognostic impact of sarcopenia in patients with locally advanced adenocarcinoma of the esophagogastric junction treated with neoadjuvant chemoradiotherapy.

Background: Few studies have evaluated the significance of sarcopenia in predicting the outcomes of patients with adenocarcinoma of the esophagogastric junction (AEG), especially those who received neoadjuvant chemoradiotherapy (NCRT). We aimed to identify the sarcopenic status and its impact on the outcomes of patients with locally advanced AEG who received NCRT followed by radical surgery or systemic therapy. Materials and methods: Patients with T3-4N+M0 AEG with accessible abdominal computed tomography (CT) before and after NCRT were retrospectively analyzed. Body composition parameters, particularly the skeletal muscle index (SMI), were assessed using a CT-based method, and sarcopenia was defined using a predetermined SMI cutoff value. Survival analysis was conducted using the Kaplan-Meier method. A Cox proportional hazards regression model was used to identify independent prognostic factors. Receiver operating characteristic curve analysis was carried out, and the area under the curve (AUC) was calculated to test the prognostic accuracy of different factors. Results: A total of 63 patients were enrolled, 65.1 and 79.4% of whom developed pre- and post-NCRT sarcopenia, respectively. Patients with pre-NCRT sarcopenia had lower radical surgery rates (70.7 vs. 95.5%, p = 0.047) than those without sarcopenia; however, sarcopenic status did not affect other short-term outcomes, including treatment-related toxicity and efficacy. Pre-NCRT sarcopenia was identified as an independent predictive factor for poor overall survival (OS) [adjusted hazard ratio (HR), 6.053; p = 0.002] and progression-free survival (PFS) (adjusted HR, 2.873; p = 0.031). Compared with nutritional indices such as the Nutritional Risk Screening 2002, weight loss during NCRT, and post-NCRT sarcopenia, pre-NCRT sarcopenia was regarded as the best predictive index for the 5-year OS (AUC = 0.735) and PFS rates (AUC = 0.770). Conclusion: Pre-NCRT sarcopenia may be an independent predictive factor for OS and PFS rates in patients with locally advanced AEG receiving multimodal treatment.

Prognostic significance of preoperative serum tumor markers in hepatoid adenocarcinoma of stomach (HAS).

BACKGROUND: The role of preoperative serum tumor markers in HAS patients was vague, we designed the study to explore the effect of preoperative serum tumor markers on predicting the prognosis of HAS patients. METHODS: A total of 139 patients were included according to the different tumor makers. X-tile tool was employed to identify the optimal cut-off values of respective tumor makers. Multivariate analyses were conducted to determine independent risk factors. RESULTS: The optimal cut-off value of alpha-fetoprotein (AFP) for 3-years overall survival (OS) and recurrence-free survival (RFS) was 516 ng/mL. Patients with high-level AFP values assumed significantly worse OS and RFS than those with low-level AFP values (P = 0.028 and P = 0.011, respectively). The optimal cut-off value of Carbohydrate antigen (CA)19-9 for OS and RFS was 51.3 U/mL. And the survival results were similar with AFP in the aspects of OS and RFS (P = 0.009 and P < 0.001, respectively). Multivariate analyses showed that high serum AFP was an independent risk factor for OS and RFS of HAS patients (HR7.264; 95% CI 1.328-39.738; P = 0.022 and HR 2.688; 95% CI 0.922-7.836; P = 0.070, respectively). CA19-9 could perform as a fair substitute to predict the HAS patients' OS and RFS when the preoperative serum AFP was unavailable (HR 7.816; 95% CI 2.084-29.308; P = 0.002 and HR 4.386; 95% CI 1.824-10.547; P = 0.001, respectively). Other tumor markers didn't present significant influences. CONCLUSIONS: Applying preoperative serum AFP level to predict the HAS patients' prognosis is feasible and preoperative serum high-AFP is an independent risk factor for OS and RFS of HAS patients. Preoperative serum CA19-9 could be an alternative choice when AFP was absent.

Double-tract reconstruction is superior to esophagogastrostomy in controlling reflux esophagitis and enhancing quality of life after proximal gastrectomy: Results from a prospective randomized controlled clinical trial in China.

Objective: The aim of this study was to prospectively compare double-tract reconstruction (DTR) and esophagogastrostomy (EG) after proximal gastrectomy (PG) regarding the incidence of reflux esophagitis, quality of life (QOL), nutritional status and surgical safety. Methods: This study was a randomized controlled trial. Patients eligible for PG were enrolled and randomly assigned to the EG group and DTR group. The characteristics of patients, parameters for surgical safety, incidence of reflux esophagitis, nutrition status and QOL were collected and compared between the two groups. Univariate analysis and multivariate analysis were performed to determine the significant factors affecting the incidence of reflux esophagitis after PG. Results: Thirty-seven patients of the EG group and 36 patients of the DTR group were enrolled. The incidence of reflux esophagitis was significantly lower in the DTR group than in the EG group (8.3% vs. 32.4%, P=0.019). The DTR group demonstrated a more favorable QOL than the EG group after PG. The nutritional status was balanced within the EG group and the DTR group. The operation time was longer in the DTR group than in the EG group (191 min vs. 221 min, P=0.001), while surgical safety was similar in the two groups. Conclusions: Our research demonstrated that DTR is superior to EG after PG in terms of the incidence of reflux esophagitis and provides a more satisfactory QOL without increasing surgical complications or sacrificing nutritional status.

Parallel single-cell and bulk transcriptome analyses reveal key features of the gastric tumor microenvironment.

BACKGROUND: The tumor microenvironment (TME) has been shown to strongly influence treatment outcome for cancer patients in various indications and to influence the overall survival. However, the cells forming the TME in gastric cancer have not been extensively characterized. RESULTS: We combine bulk and single-cell RNA sequencing from tumors and matched normal tissue of 24 treatment-naïve GC patients to better understand which cell types and transcriptional programs are associated with malignant transformation of the stomach. Clustering 96,623 cells of non-epithelial origin reveals 81 well-defined TME cell types. We find that activated fibroblasts and endothelial cells are most prominently overrepresented in tumors. Intercellular network reconstruction and survival analysis of an independent cohort imply the importance of these cell types together with immunosuppressive myeloid cell subsets and regulatory T cells in establishing an immunosuppressive microenvironment that correlates with worsened prognosis and lack of response in anti-PD1-treated patients. In contrast, we find a subset of IFNγ activated T cells and HLA-II expressing macrophages that are linked to treatment response and increased overall survival. CONCLUSIONS: Our gastric cancer single-cell TME compendium together with the matched bulk transcriptome data provides a unique resource for the identification of new potential biomarkers for patient stratification. This study helps further to elucidate the mechanism of gastric cancer and provides insights for therapy.

Characteristics of lymph node stations/basins metastasis and construction and validation of a preoperative combination prediction model that accurately excludes lymph node metastasis in early gastric cancer.

Objective: To explore the candidate indications for function-preserving curative gastrectomy and sentinel lymph node navigation surgery in early gastric cancer (EGC). Methods: The clinicopathological data of 561 patients with EGC who underwent radical gastrectomy for gastric cancer at Peking University Cancer Hospital from November 2010 to November 2020 with postoperative pathological stage pT1 and complete examination data, were collected. Pearson's Chi-square test was used and binary logistic regression was employed for univariate and multivariate analyses. Combined analysis of multiple risk and protective factors for lymph node metastasis (LNM) of EGC was performed. A negative predictive value (NPV) combination model was built and validated. Results: LNM occurred in 85 of 561 patients with EGC, and the LNM rate was 15.15%. NPV for LNM reached 100% based on three characteristics, including ulcer-free, moderately well differentiation and patient <65 years old or tumor located at the proximal 1/3 of the stomach. Regarding lymphatic basin metastasis, multivariate analysis showed that the metastatic proportion of the left gastric artery lymphatic basin was significantly higher in male patients compared with female patients (65.96% vs. 38.89%, P<0.05). The proportion of right gastroepiploic artery lymphatic basin metastasis in patients with a maximum tumor diameter >2 cm was significantly greater than that noted in patients with a maximum tumor diameter ≤2 cm (60.78% vs. 28.13%, P<0.05). Conclusions: Characteristics of lymph node stations/basins metastasis will facilitate precise lymph node resection. The NPV for LNM reaches 100% based on the following two conditions: young and middle-aged EGC patients, well-differentiated tumors, and without ulcers; or well-differentiated tumors, without ulcers, and tumors located in the proximal stomach. These findings can be used as the recommended indications for function-preserving curative gastrectomy and sentinel lymph node navigation surgery.

Correlation between imaging features on computed tomography and combined positive score of PD-L1 expression in patients with gastric cancer.

Objective: To explore the correlation between computed tomography (CT) features and combined positive score (CPS) of programmed cell death ligand 1 (PD-L1) expression in patients with gastric cancer (GC). Methods: This study reviewed an institutional database of patients who underwent GC operation without neoadjuvant chemotherapy between December 2019 and September 2020. The CPS results of PD-L1 expression of postoperative histological examination were recorded by pathology. Baseline CT features were measured, and their correlation with CPS 5 or 10 score groups of PD-L1 expression was analyzed. Results: Data for 153 patients with GC were collected. Among them, 124 were advanced GC patients, and 29 were early GC patients. None of the CT features significantly differed between CPS groups with a cutoff score of 5 and a score of 10 in patients with early GC. In advanced GC, the presence of lymph nodes with short diameters >10 mm was significantly different (P=0.024) between the CPS<5 and CPS≥5 groups. CT features such as tumor attenuation in the arterial phase, long and short diameter of the largest lymph node, the sum of long diameter of the two largest lymph nodes, the sum of short diameter of the two largest lymph nodes, and the presence of lymph nodes with short diameters >10 mm significantly differed between the CPS<10 and CPS≥10 groups in advanced GC. The sensitivity, specificity and area under receiver operating characteristic (ROC) curve of logistic regression model for predicting CPS≥10 was 71.7%, 50.0% and 0.671, respectively. Microsatellite instability (MSI) status was significantly different in CPS groups with cutoff score of 5 and 10 in advanced GC patients. Conclusions: CT findings of advanced GC patients with CPS≥10 showed greater arterial phase enhancement and larger lymph nodes. CT has the potential to help screen patients suitable for immunotherapy.

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).

Establishment of prognostic models for adenocarcinoma of oesophagogastric junction patients with neoadjuvant chemoradiotherapy: a real-world study.

BACKGROUND: Multimodal therapies based on surgical resection have been recommended for the treatment of adenocarcinoma of the oesophagogastric junction (AEG). We aimed to evaluate prognostic factors in AEG patients receiving neoadjuvant chemoradiotherapy and to build predictive models. METHODS: T3 - T4N + M0 AEG patients with resectable Siewert type II/III tumours were enrolled in this study. All patients underwent neoadjuvant chemoradiation, followed by radical surgery or systemic therapy according to clinical response. Survival analysis was performed using the Kaplan-Meier method; multivariate analysis using the Cox proportional hazards method was also conducted. The Harrell concordance index (C-index) was used to test the prognostic value of models involving prognostic factors, and consistency between actual and predicted survival rates was evaluated by calibration curves. RESULTS: From February 2009 to February 2018, 79 patients were treated with neoadjuvant chemoradiotherapy; 60 patients of them underwent radical surgery. The R0 resection rate was 98.3%, and 46.7% of patients achieved a major pathologic response (MPR), namely, a residual tumour issue less than 10%. The 5-year overall survival (OS) rate was 63%, and the 5-year progression-free survival (PFS) rate was 48%. The incidence of grade 3 complications was 21.5%, and no grade 4 complications were reported. According to the results of univariate and multivariate analyses, we included the neutrophil-lymphocyte ratio (NLR), prognostic nutrition index (PNI), eosinophilic granulocyte (EOS) and postoperative pathologic stage in nomogram analysis to establish prediction models for OS and PFS; the C-index of each model was 0.814 and 0.722, respectively. Both the C-index and calibration curves generated to validate consistency between the actual and predicted survival indicated that the models were well calibrated and of good predictive value. CONCLUSIONS: AEG patients achieved favourable downstaging and pathologic response after neoadjuvant chemoradiation, with acceptable adverse effects. Inflammation-based and nutrition-related factors and postoperative pathologic stage had a significant influence on OS and PFS, and the predictive value was verified through prognostic models.

Immune phenotypic linkage between colorectal cancer and liver metastasis.

The tumor microenvironment (TME) is connected to immunotherapy responses, but it remains unclear how cancer cells and host tissues differentially influence the immune composition within TME. Here, we performed single-cell analyses for autologous samples from liver metastasized colorectal cancer to disentangle factors shaping TME. By aligning CD45+ cells across different tissues, we classified exhausted CD8+ T cells (Texs) and activated regulatory T cells as M-type, whose phenotypes were associated with the malignancy, while natural killer and mucosal-associated invariant T cells were defined as N-type, whose phenotypes were associated with the niche. T cell receptor sharing between Texs in primary and metastatic tumors implicated the presence of common peripheral non-exhausted precursors. For myeloid cells, a subset of dendritic cells (DC3s) and SPP1+ macrophages were M-type, and the latter were predominant in liver metastasis, indicating its pro-metastasis role. Our analyses bridge immune phenotypes of primary and metastatic tumors, thereby helping to understand the tumor-specific contexture and identify the pro-metastasis components.

A Practical Nomogram for Predicting the Prognosis of Elderly Patients with Gastric Adenocarcinoma After Gastrectomy.

PURPOSE: To establish a pragmatic prognostic nomogram for predicting the survival of elderly patients undergoing gastrectomy for gastric adenocarcinoma. PATIENTS AND METHODS: Data of elderly patients undergoing gastrectomy for gastric adenocarcinoma between 2004 and 2015 were obtained from the Surveillance, Epidemiology, and End Results database. Prognostic factors were identified by the Kaplan-Meier method and the Cox proportional hazards model. Based on these factors, we developed a nomogram to predict the overall survival (OS) and gastric cancer-specific survival (GCSS). Concordance index (C-index) and calibration curve are employed to assess the predictive accuracy of the model. Decision curve analysis (DCA) and receiver operating characteristic curve (ROC) analysis are applied to further appraise the clinical utility of the model. RESULTS: A total of 8401 cases were incorporated into this research. After univariate and multivariate analyses, nine prognostic factors of OS were identified, including age (P < 0.001), race (P < 0.001), marital status (P < 0.001), tumor site (P < 0.001), tumor size (P = 0.024), differentiation (P < 0.001), T stage (P < 0.001), N stage (P < 0.001), and M stage (P < 0.001); ten prognostic factors of GCSS were identified, including age (P < 0.001), race (P < 0.001), tumor site (P < 0.001), tumor size (P = 0.002), differentiation (P < 0.001), T stage (P < 0.001), N stage (P < 0.001), M stage (P < 0.001), radiotherapy (P < 0.001) and chemotherapy (P < 0.001). The C-index of the constructed nomogram for OS was 0.708 (95% CI: 0.701-0.715) while for GCSS was 0.745 (95% CI: 0.737-0.753). The calibration curves of the nomogram predictions and actual observations displayed good agreement for the 3- and 5-year OS and GCSS probabilities. The results of DCA and the area under the curve calculated by ROC analysis showed that the developed model was superior than TNM stage. CONCLUSION: The nomogram we established could accurately predict the prognosis of individual elderly patients who underwent gastrectomy for gastric adenocarcinoma.