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.

Repeated endoscopic treatment of gastric antral vascular ectasia.

GAVE is a relatively rare acquired vascular disease. The most common treatment for GAVE is endoscopic therapy. Argon plasma coagulation（APC） is usually the first-line choice for endoscopic GAVE treatment, but its recurrence rate is high and often requires multiple repeated treatments. In this case, the GAVE patient recurred after two APC treatments. The results suggest that APC-treated patients with GAVE are prone to relapse. In conclusion, clinicians should regularly follow up patients who received APC treatment.

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 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.

Co-expression of receptor tyrosine kinases and CD8 T-lymphocyte genes is associated with distinct prognoses, immune cell infiltration patterns and immunogenicity in cancers.

Tumor angiogenesis and the immune microenvironment are 2 essential aspects of the tumor microenvironment (TME). The combination of receptor tyrosine kinase (RTK) inhibitor (TKI)-mediated antiangiogenic therapy and CD8 T-lymphocyte-mediated immunotherapy has become an important focus of cancer treatment, with good results for many tumor types. However, the complex regulatory interactions between these 2 treatment strategies have not been elucidated. Therefore, we systematically investigated the association between the RTKs and CD8 T-lymphocyte genes (CD8Ts) across cancers. We comprehensively evaluated alterations in RTK genes across cancers and examined the co-expression of RTKs and CD8Ts using a weighted gene co-expression network analysis. We found that RTKs exhibited extensive genetic alterations across cancers and were significantly related to the activity of cancer hallmark-related pathways. We identified co-expression between the RTKs and CD8Ts. The low co-expression score subtype was associated with significant better clinical benefits and was characterized by a hot immune microenvironment, including more infiltrating immune cells, higher chemokine expression, and stronger immunogenicity, such as the tumor mutation burden and neoantigens. Two immunotherapy cohorts confirmed that patients with low co-expression scores had an inflamed TME phenotype and significant therapeutic advantages. Then, 4 co-expression patterns were identified, with different patterns reflecting different prognoses and immune microenvironments. The RTKlowCD8Thigh group was associated with the best prognosis and immune-activated microenvironment. In summary, the present study indicates co-expression of RTKs and CD8Ts, which supports the potential application of the combination of inhibiting RTKs activity via TKI-targeted therapy and increasing CD8 T cell activity via immunotherapy in the treatment of cancer.

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.

A mutation-based gene set predicts survival benefit after immunotherapy across multiple cancers and reveals the immune response landscape.

BACKGROUND: Immune checkpoint inhibitor (ICI) therapy has revolutionized the treatment of many cancers. However, the limited population that benefits from ICI therapy makes it necessary to screen predictive biomarkers for stratifying patients. Currently, many biomarkers, such as tumor mutational burden (TMB), have been used in the clinic as indicative biomarkers. However, some high-TMB patients with mutations in genes that are closely related to immunotherapeutic resistance are not sensitive to ICI therapy. Thus, there is a need to move beyond TMB and identify specific genetic determinants of the response to ICI therapy. In this study, we established a comprehensive mutation-based gene set across different tumor types to predict the efficacy of ICI therapy. METHODS: We constructed and validated a mutational signature to predict the prognosis of patients treated with ICI therapy. Then, the underlying immune response landscapes of different subtypes were investigated with multidimensional data. RESULTS: This study included genomic and clinical data for 12,647 patients. An eleven-gene mutation-based gene set was generated to divide patients into a high-risk group and a low-risk group in a training cohort (1572 patients with 9 types of cancers who were treated with ICI therapy). Validation was performed in a validation cohort (932 patients with 5 types of cancers who were treated with ICI therapy). Mutations in these 11 genes were associated with a better response to ICI therapy. In addition, the mutation-based gene set was demonstrated to be an independent prognostic factor after ICI therapy. We further explored the role of the immune context in determining the benefits of immunotherapy in 10,143 patients with 33 types of cancers and found distinct immune landscapes for the high- and low-risk groups. CONCLUSIONS: The mutation-based gene set developed in this study can be used to reliably predict survival benefit across cancers in patients receiving ICI therapy. The close interplay between the extrinsic and intrinsic immune landscapes in the identified patient subgroups and the subgroups' differing responses to ICI therapy could guide immunotherapy treatment decisions for cancer patients.

Pan-cancer single-cell landscape of tumor-infiltrating T cells.

T cells play a central role in cancer immunotherapy, but we lack systematic comparison of the heterogeneity and dynamics of tumor-infiltrating T cells across cancer types. We built a single-cell RNA-sequencing pan-cancer atlas of T cells for 316 donors across 21 cancer types and revealed distinct T cell composition patterns. We found multiple state-transition paths in the exhaustion of CD8+ T cells and the preference of those paths among different tumor types. Certain T cell populations showed specific correlation with patient properties such as mutation burden, shedding light on the possible determinants of the tumor microenvironment. T cell compositions within tumors alone could classify cancer patients into groups with clinical trait specificity, providing new insights into T cell immunity and precision immunotherapy targeting T cells.

Genomic and transcriptomic profiling of hepatoid adenocarcinoma of the stomach.

Hepatoid adenocarcinoma of the stomach (HAS), a rare subtype of gastric cancer (GC), has a low incidence but a high mortality rate. Little is known about the molecular features of HAS. Here we applied whole-exome sequencing (WES) on 58 tumours and the matched normal controls from 54 HAS patients, transcriptome sequencing on 30 HAS tumours, and single-cell RNA sequencing (scRNA-seq) on one HAS tumour. Our results reveal that the adenocarcinomatous component and hepatocellular-like component of the same HAS tumour originate monoclonally, and HAS is likely to initiate from pluripotent precursor cells. HAS has high stemness and high methionine cycle activity compared to classical GC. Two genes in the methionine cycle, MAT2A, and AHCY are potential targets for HAS treatments. We provide the first integrative genomic profiles of HAS, which may facilitate its diagnosis, prognosis, and treatment.

Identification of NOTCH4 mutation as a response biomarker for immune checkpoint inhibitor therapy.

BACKGROUND: Immune checkpoint inhibitor (ICI) therapy elicits durable antitumor responses in patients with many types of cancer. Genomic mutations may be used to predict the clinical benefits of ICI therapy. NOTCH homolog-4 (NOTCH4) is frequently mutated in several cancer types, but its role in immunotherapy is still unclear. Our study is the first to study the association between NOTCH4 mutation and the response to ICI therapy. METHODS: We tested the predictive value of NOTCH4 mutation in the discovery cohort, which included non-small cell lung cancer, melanoma, head and neck squamous cell carcinoma, esophagogastric cancer, and bladder cancer patients, and validated it in the validation cohort, which included non-small cell lung cancer, melanoma, renal cell carcinoma, colorectal cancer, esophagogastric cancer, glioma, bladder cancer, head and neck cancer, cancer of unknown primary, and breast cancer patients. Then, the relationships between NOTCH4 mutation and intrinsic and extrinsic immune response mechanisms were studied with multiomics data. RESULTS: We collected an ICI-treated cohort (n = 662) and found that patients with NOTCH4 mutation had better clinical benefits in terms of objective response rate (ORR: 42.9% vs 25.9%, P = 0.007), durable clinical benefit (DCB: 54.0% vs 38.1%, P = 0.021), progression-free survival (PFS, hazard ratio [HR] = 0.558, P < 0.001), and overall survival (OS, HR = 0.568, P = 0.006). In addition, we validated the prognostic value of NOTCH4 mutation in an independent ICI-treated cohort (n = 1423). Based on multiomics data, we found that NOTCH4 mutation is significantly associated with enhanced immunogenicity, including a high tumor mutational burden, the expression of costimulatory molecules, and activation of the antigen-processing machinery, and NOTCH4 mutation positively correlates activated antitumor immunity, including infiltration of diverse immune cells and various immune marker sets. CONCLUSIONS: Our findings indicated that NOTCH4 mutation serves as a novel biomarker correlated with a better response to ICI therapy.

Construction and Validation of a Risk-Scoring Model that Preoperatively Predicts Lymph Node Metastasis in Early Gastric Cancer Patients.

OBJECTIVE: The aim of this study was to create a risk-scoring model to preoperatively predict the incidence of lymph node metastasis (LNM) in early gastric cancer (EGC) patients to guide treatment. METHODS: To construct the risk-scoring model, we retrospectively analyzed a primary cohort of 548 EGC patients. Univariate analysis and logistic regression were performed. A risk-scoring model for predicting LNM in EGC patients was developed based on preoperative factors, and another cohort of 73 patients was then analyzed to validate the model. RESULTS: In the primary cohort, LNM was pathologically confirmed in 72 (13.1%) patients. In the multivariate analysis, the presence of ulceration and tumor size on gastroscopy, undifferentiated histological type, and presence of enlarged lymph nodes on computed tomography or endoscopic ultrasonography were independent risk factors for LNM. A 17-point risk-scoring model was developed to predict LNM risk. The cut-off score of the model was 8, and the area under the receiver operating characteristic curve (AUC) of the model was 0.835 [95% confidence interval (CI) 0.784-0.886]. In the validation cohort, the AUC of the model was 0.829 (95% CI 0.699-0.959). CONCLUSIONS: We developed and validated an effective 17-point risk-scoring model that could preoperatively predict LNM for EGC patients.

Mutational spectrum and precision oncology for biliary tract carcinoma.

Background: The genomic spectrum of biliary tract carcinoma (BTC) has been characterized and is associated with distinct anatomic and etiologic subtypes, yet limited studies have linked genomic alterations with personalized therapies in BTC patients. Methods: This study analyzed 803 patients with BTC:164 with gallbladder cancer, 475 with intrahepatic cholangiocarcinoma (ICC) and 164 with extrahepatic cholangiocarcinoma. We determined genomic alterations, mutational signatures related to etiology and histopathology and prognostic biomarkers. Personalized targeted therapies for patients harboring potentially actionable targets (PATs) were investigated. Results: The median tumor mutation burden (TMB) was 1.23 Mut/Mb, with 4.1% of patients having hypermutated BTCs. Unlike the results obtained from the Western population, the most frequently altered cancer-related genes in our cohort included TP53 (53%), KRAS (26%), ARID1A (18%), LRP1B (14%) and CDKN2A (14%). Germline mutations occurred mostly in DNA damage repair genes. Notably, 35.8% of the ICCs harbored aristolochic acid related signatures and an elevated TMB. TP53 and KRAS mutations and amplified 7q31.2 were demonstrated to negatively affect patient prognosis. Moreover, 19 genes were proposed to be PATs in BTCs, with 25.4% of patients harboring these PATs. Forty-six patients received PAT-matched targeted therapies, achieving a 26.1% objective response rate; the median progression-free survival (PFS) was 5.0 months, with 56.8% of patients obtaining PFS benefits. Conclusions: Extensive genomic diversity and heterogeneity were observed among BTC patients, with contributions according to potential etiology exposures, anatomical subtypes and clinicopathological characteristics. We also demonstrated that patients with refractory BTCs who have PATs can derive considerable benefit from receiving a matched therapy, initiating further prospective clinical trials guided by molecular profiling among this aggressive cancer.

KK-LC-1 may be an effective prognostic biomarker for gastric cancer.

BACKGROUND: The objective of the study was to detect the expression of Kita-Kyushu lung cancer antigen-1 (KK-LC-1) in gastric cancer (GC) specimens and analyse the associations between KK-LC-1 expression and clinicopathological parameters and clinical prognosis. METHODS: All of the 94 patients in this study were GC patients who underwent surgical resection. KK-LC-1 protein expression in GC tissue was detected by immunohistochemistry. This report applies the histological score (H-score) to evaluate KK-LC-1 expression. To calculate this indicator, the number of positive cells in each section and their staining intensity were converted to corresponding values. The expression of KK-LC-1 in the cytoplasm of cancer and normal tissues was scored to obtain their respective H values. The chi-square test, Kaplan-Meier method and Cox regression were used to analyse the linear association between KK-LC-1 expression and clinicopathological data and prognosis. RESULTS: In the cytoplasm, KK-LC-1 expression in tumour tissues was significantly higher than that in normal tissues (P < 0.001). Using the median H-score as the cut-off value, we discovered that GC patients with high levels of KK-LC-1 expression in the cytoplasm had favourable overall survival (OS) (P = 0.016), and this result was statistically significant in the Cox regression analysis. Additionally, a negative correlation was found between KK-LC-1 protein expression and the pathological grade of the tumour (P = 0.036), with significantly more KK-LC-1 protein expression observed in the intestinal type of GC than in the diffuse type (P = 0.008). CONCLUSIONS: Our research data showed that KK-LC-1 expression was greater in GC tissues than in normal tissues, and higher KK-LC-1 expression was associated with longer OS of GC patients. KK-LC-1 can be used as a biomarker for a good prognosis in GC patients.