Comprehensive Analyses of Immune Subtypes of Stomach Adenocarcinoma for mRNA Vaccination.

Background: Although messenger RNA (mRNA) vaccines have unique advantages against multiple tumors, mRNA vaccine targets in stomach adenocarcinoma (STAD) remain unknown. The potential effectiveness of mRNA vaccines is closely associated with the tumor immune infiltration microenvironment. The present study aimed to identify tumor antigens of STAD as mRNA vaccine targets and systematically determine immune subtypes (ISs) of STAD that might be suitable for immunotherapy. Methods: Gene expression profiles and clinical data of patients with gastric cancer were downloaded from The Cancer Genome Atlas (TCGA; n = 409) and the Gene Expression Omnibus (GEO; n = 433), and genomic data were extracted from cBioPortal. Differential gene expression was analyzed using the limma package, genetic alterations were visualized using maftools, and prognosis was analyzed using ToPP. Correlations between gene expression and immune infiltration were calculated using TIMER software, and potential ISs were identified using ConsensusClusterPlus. Functional enrichment was analyzed in clusterProfiler, and r co-expression networks were analyzed using the weighted gene co-expression network analysis (WGCNA) package in R. Results: Overexpression of the prognostic and highly mutated antigens ADAMTS18, COL10A1, PPEF1, and STRA6 was associated with infiltration by antigen-presenting cells in STAD. Five ISs (IS1-IS5) in STAD with distinct prognoses were developed and validated in TCGA and GEO databases. The tumor mutational burden and molecular and clinical characteristics significantly differed among IS1-IS5. Both IS1 and IS2 were associated with a high mutational burden, massive infiltration by immune cells, especially antigen-presenting cells, and better survival compared with the other subtypes. Both IS4 and IS5 were associated with cold immune infiltration and correlated with advanced pathological stages. We analyzed the immune microenvironments of five subtypes of immune modulators and biomarkers to select suitable populations for mRNA vaccination and established four co-expressed key modules to validate the characteristics of the ISs. Finally, the correlation of these four mRNA vaccine targets with the transcription factors of DC cells, including BATF3, IRF4, IRF8, ZEB2, ID2, KLF4, E2-2, and IKZF1, were explored to reveal the underlying mechanisms. Conclusions: ADAMTS18, COL10A1, PPEF1, and STRA6 are potential mRNA vaccine candidates for STAD. Patients with IS1 and IS2 are suitable populations for mRNA vaccination immunotherapy.

Spatial Metabolomics Identifies Distinct Tumor-Specific Subtypes in Gastric Cancer Patients.

PURPOSE: Current systems of gastric cancer molecular classification include genomic, molecular, and morphological features. Gastric cancer classification based on tissue metabolomics remains lacking. This study aimed to define metabolically distinct gastric cancer subtypes and identify their clinicopathological and molecular characteristics. EXPERIMENTAL DESIGN: Spatial metabolomics by high mass resolution imaging mass spectrometry was performed in 362 patients with gastric cancer. K-means clustering was used to define tumor and stroma-related subtypes based on tissue metabolites. The identified subtypes were linked with clinicopathological characteristics, molecular features, and metabolic signatures. Responses to trastuzumab treatment were investigated across the subtypes by introducing an independent patient cohort with HER2-positive gastric cancer from a multicenter observational study. RESULTS: Three tumor- and three stroma-specific subtypes with distinct tissue metabolite patterns were identified. Tumor-specific subtype T1(HER2+MIB+CD3+) positively correlated with HER2, MIB1, DEFA-1, CD3, CD8, FOXP3, but negatively correlated with MMR. Tumor-specific subtype T2(HER2-MIB-CD3-) negatively correlated with HER2, MIB1, CD3, FOXP3, but positively correlated with MMR. Tumor-specific subtype T3(pEGFR+) positively correlated with pEGFR. Patients with tumor subtype T1(HER2+MIB+CD3+) had elevated nucleotide levels, enhanced DNA metabolism, and a better prognosis than T2(HER2-MIB-CD3-) and T3(pEGFR+). An independent validation cohort confirmed that the T1 subtype benefited from trastuzumab therapy. Stroma-specific subtypes had no association with clinicopathological characteristics, however, linked to distinct metabolic pathways and molecular features. CONCLUSIONS: Patient subtypes derived by tissue-based spatial metabolomics are a valuable addition to existing gastric cancer molecular classification systems. Metabolic differences between the subtypes and their associations with molecular features could provide a valuable tool to aid in selecting specific treatment approaches.

Fundic gland polyps related to diverse aetiologies show subtle morphological differences: a multicentre retrospective study.

AIMS: Fundic gland polyps (FGPs) comprise 66% of all gastric polyps. Although they are usually non-syndromic, they may be associated with various syndromes, including familial adenomatous polyposis (FAP) or gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS). We aimed to evaluate how histological features relate to distinct FGP subtypes. METHODS AND RESULTS: We performed a retrospective analysis of 118 FGPs from 109 patients for the architecture of fundic glands, microcyst lining, parietal cell hyperplasia and surface foveolar epithelial changes. Age, gender and history of FAP or GAPPS were collected. Based on combinations of histological features, three distinct patterns (A, B and C) of FGPs were delineated and correlated to the aetiologies. Non-syndromic FGPs were well-formed polyps composed of disordered fundic glands with intermediate-sized microcysts typically lined by a mixture of oxyntic and mucin-secreting cells (73%). Parietal cell hyperplasia (80%) and foveolar surface hyperplasia (78%) were common. FAP-associated cases demonstrated small microcysts that were predominantly lined by fundic epithelium (77%), with limited parietal cell hyperplasia (27%); foveolar hyperplasia was uncommon. GAPPS-related polyps were the largest, with prominent, mucin-secreting epithelium-lined microcysts (73%). Hyperproliferative aberrant pits were universally present, whereas parietal cell hyperplasia was uncommon. Pattern A was identified in most non-syndromic FGPs (74%) and in a minority of FAP-related FGPs (26%). The majority (82%) of FAP-related FGPs showed pattern B, but only 18% of non-syndromic FGPs did. Pattern C consisted exclusively of GAPPS-associated polyps. CONCLUSIONS: We conclude that, although FGPs share similar histomorphology, subtle differences exist between polyps of different aetiology. In the appropriate clinical setting, the recognition of these variations may help to consider syndromic aetiologies.

Immunoexpression of PTEN, HER2/neu, and Ki-67 in endoscopic gastric carcinoma biopsies; their correlation with histological subtypes and one-year survival.

BACKGROUND: Gastric carcinoma is a major cause of cancer-related morbidity and mortality worldwide. Gastric neoplasms arise from genetic and epigenetic changes in various genes. Present study evaluates the immunoexpression of PTEN, HER2/neu, and Ki-67 in endoscopic gastric carcinoma biopsies and correlates the expression of these proteins with clinicopathological features. MATERIAL AND METHODS: Adequate endoscopic biopsies of 27 cases of gastric carcinoma were evaluated for World Health Organization (WHO) and Lauren's classification subtypes along with HER2/neu, PTEN, and Ki-67 immunoexpression. HER2/neu immunostaining was scored as proposed in the Trastuzumab for gastric cancer (ToGA) trial while PTEN staining and downregulation were assessed using an immunoreactive score. The cut-off for Ki-67 expression was taken as 90th percentile of the values in adjacent non-neoplastic tissue. All statistical analysis was done at 5% level of significance with SPSS v22 statistical software. RESULTS: Tubular adenocarcinoma was the commonest WHO histological subtype and 56% of cases were of intestinal type as per Lauren's classification. 55.6% of cases showed a complete loss of PTEN expression in neoplastic tissue. 17 of the 19 cases with adjacent non-neoplastic tissue showed PTEN downregulation in neoplastic tissue. 81.5% of cases had a high Ki-67 index and HER2/neu overexpression was noted in 36% of cases. All the four cases who died had high Ki-67 proliferation indices; 3 patients had loss of PTEN expression and HER2/neu overexpression. CONCLUSION: We conclude that these immunomarkers can play important role in the behavior of gastric carcinomas and can be targeted for new therapies.

Expression of HER2/neu in gastric adenocarcinoma and its correlation with serum HER2/neu level and E-cadherin expression.

AIM: : To assess HER2/neu expressions and correlate with E-cadherin and Serum HER2 level in gastric carcinoma. METHOD: 31 gastric biopsies and 1 resected specimen were taken in the study with patient details and stained with H and E for histopathological details following Lauren's classification. Immunohistochemistry for HER2 and E-cadherin expression was conducted followed by serum HER2/neu ELISA. RESULT: Adenocarcinoma with 61% diffuse, 29% intestinal, and 10% other type were observed with predominant HER2 immunoexpression in intestinal-type than in diffuse-type adenocarcinoma. Other observations marked 44% as 3+/positive and 56% as 2+/equivocal in intestinal type while 26% cases as 3+/positive, 69% as 2+/equivocal, and 1% as 1+/negative were observed in diffuse type. The data presented 33% membranous positivity and 67% both membranous + cytoplasmic positivity in intestinal type while 2% showed membranous positivity, 47% both membranous + cytoplasmic, and 42% only cytoplasmic positivity in diffused type. On comparing the localization pattern of HER2 and E-cadherin, 25% of cases showed membranous staining while 50% of cases showed membranous with cytoplasmic staining for both. No cytoplasmic HER2 staining as well as no any staining for E-cadherin was shown by 6% cases. CONCLUSION: Thus, it can be concluded that cytoplasmic expression of HER2 in gastric adenocarcinoma (mainly diffuse type) may be due to shedding of its extracellular domain, leading to loss of membranous E-cadherin expression on immunohistochemistry. The loss of membranous expression of E-cadherin and increased serum HER2 ELISA were correlated well with these findings.

Risk factors for gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs): a three-centric case-control study.

PURPOSE: Risk factors for sporadic GEP-NENs are still not well defined. To identify the main clinical risk factors represents the aim of this study performed by three Italian referral centers for NENs. METHODS: We performed a retrospective case-control study including 148 consecutive sporadic GEP-NENs and 210 age- and sex-matched controls. We collected data on clinical features, cancer family history and other potential risk factors. RESULTS: Mean age was 58.3 ± 15.8 years; 50% males, primary site was pancreas (50.7%), followed by ileum (22.3%). The 62.8% and 29.1% of cases were G1 and G2, respectively; the 40% had locally advanced or metastatic disease at diagnosis. Independent risk factors for GEP-NENs were: family history of non-neuroendocrine GEP cancer (OR 2.16, 95% CI 1.31-3.55, p = 0.003), type 2 diabetes mellitus (T2DM) (OR 2.5, 95% CI 1.39-4.51, p = 0.002) and obesity (OR 1.88, 95% CI 1.18-2.99, p = 0.007). In the T2DM subjects, metformin use was a protective factor (OR 0.28, 95% CI 0.08-0.93, p = 0.049). T2DM was also associated with a more advanced (OR 2.39, 95% CI 1.05-5.46, p = 0.035) and progressive disease (OR 2.47, 95% CI 1.08-5.34, p = 0.03). Stratifying cases by primary site, independent risk factors for pancreatic NENs were T2DM (OR 2.57, 95% CI 1.28-5.15, p = 0.008) and obesity (OR 1.98, 95% CI 1.11-3.52, p = 0.020), while for intestinal NENs family history of non-neuroendocrine GEP cancer (OR 2.46, 95% CI 1.38-4.38, p = 0.003) and obesity (OR 1.90, 95% CI 1.08-3.33, p = 0.026). CONCLUSION: This study reinforces a role for family history of non-neuroendocrine GEP cancer, T2DM and obesity as independent risk factors for GEP-NENs and suggests a role of metformin as a protective factor in T2DM subjects. If confirmed, these findings could have a significant impact on prevention strategies for GEP-NENs.

Confusion and prospects for carcinogenesis of gastric adenoma and dysplasia: What is the correct answer currently?

There are differences in the diagnoses of superficial gastric lesions between Japan and other countries. In Japan, superficial gastric lesions are classified as adenoma or cancer. Conversely, outside Japan, the same lesion is classified as low-grade dysplasia (LGD), high-grade dysplasia, or invasive neoplasia. Gastric carcinogenesis occurs mostly de novo, and the adenoma-carcinoma sequence does not appear to be the main pathway of carcinogenesis. Superficial gastric tumors can be roughly divided into the APC mutation type and the TP53 mutation type, which are mutually exclusive. APC-type tumors have low malignancy and develop into LGD, whereas TP53-type tumors have high malignancy and are considered cancerous even if small. For lesions diagnosed as category 3 or 4 in the Vienna classification, it is desirable to perform complete en bloc resection by endoscopic submucosal dissection followed by staging. If there is lymphovascular or submucosal invasion after mucosal resection, additional surgical treatment of gastrectomy with lymph node dissection is required. In such cases, function-preserving curative gastrectomy guided by sentinel lymph node biopsy may be a good alternative.

Comprehensive Analysis of Alternative Splicing in Gastric Cancer Identifies Epithelial-Mesenchymal Transition Subtypes Associated with Survival.

Alternatively spliced RNA isoforms are a hallmark of tumors, but their nature, prevalence, and clinical implications in gastric cancer have not been comprehensively characterized. We systematically profiled the splicing landscape of 83 gastric tumors and matched normal mucosa, identifying and experimentally validating eight splicing events that can classify all gastric cancers into three subtypes: epithelial-splicing (EpiS), mesenchymal-splicing (MesS), and hybrid-splicing. These subtypes were associated with distinct molecular signatures and epithelial-mesenchymal transition markers. Subtype-specific splicing events were enriched in motifs for splicing factors RBM24 and ESRP1, which were upregulated in MesS and EpiS tumors, respectively. A simple classifier based only on RNA levels of RBM24 and ESRP1, which can be readily implemented in the clinic, was sufficient to distinguish gastric cancer subtypes and predict patient survival in multiple independent patient cohorts. Overall, this study provides insights into alternative splicing in gastric cancer and the potential clinical utility of splicing-based patient classification. SIGNIFICANCE: This study presents a comprehensive analysis of alternative splicing in the context of patient classification, molecular mechanisms, and prognosis in gastric cancer.

The potential diagnostic significance of crypt differentiation in gastric dysplasia.

AIMS: This study investigated the relationship between the differentiation of tumour cells into crypts, which is determined by cell differentiation into Paneth and neuroendocrine cells, and tumour infiltration in gastric dysplasia. METHODS AND RESULTS: The lesions were endoscopically biopsied low-grade dysplasia (LGD), endoscopically resected high-grade dysplasia (HGD) or cancer with submucosal invasion. LGD (n = 32) displayed crypt differentiation across the entire width of the tumour in all cases. Crypt differentiation was identified as a characteristic of tumours with low biological malignancy. HGD (n = 40) included tumours with a mixture of areas with and without crypt differentiation (n = 25) and tumours with crypt differentiation throughout the entire width (n = 15). Of the cancers with submucosal invasion (n = 30), the morphological progression of the HGD area with crypt differentiation, the HGD area without crypt differentiation and invasive cancer without crypt differentiation was confirmed for 23 samples. In two lesions, invasive cancer without crypt differentiation developed from HGD without crypt differentiation throughout the tumour width. In five samples, well-differentiated tubular adenocarcinoma with crypt differentiation developed from HGD with crypt differentiation and invaded with lamina propria-like stroma. CONCLUSIONS: Loss of crypt differentiation could be an objective indicator of infiltration in the progression of HGD to invasive cancer. The invasive potential of dysplasia depends upon the presence or absence of crypt differentiation.

A Proposed New Clinical Classification of Metastatic Gastric Cancer: Pyloric and Antral Gastric Cancer.

BACKGROUND: We aimed to classify metastatic pyloric/antral gastric cancer in terms of macroscopic morphology and metastatic form. METHODS: Thirty-eight patients with pyloric/antral gastric cancer were included in the study. Patients were classified according to a combination of Borrmann classification type and metastatic type, and the clinicopathological characteristics of each group were compared. RESULT: Of the 38 patients, 33 (type II: 9 and type III: 24) (87%) had ulcerative gastric cancer. Ulcerative gastric cancer was classified into four groups: lymphatic only group (L+H-P-), lymphatic + hematogenous group (L+H+P-), disseminated ± lymphatic group (L±H-P+), and lymphatic + hematogenous + disseminated group (L+H+P+). In the L+H-P- group, all patients had bulky lymph nodes and serum levels of both carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) were high; the condition of patients was good, and the therapeutic response was good. In the L+H+P- group, metastases other than liver metastases were rare, and serum CEA levels were high. In the L±H-P+ group, the predominant histological type was signet ring cell carcinoma; both serum CEA and CA19-9 levels were low. Patients in the L+H+P+ group had higher serum CA19-9 levels and were more prone to hematogenous metastasis to various organs; these patients had worse patient status and lower treatment response. Gastric cancer other than ulcerative type was only detected in five patients (type V: 3, type IV: 1, type I: 1). CONCLUSION: Classification by a combination of macroscopic and metastatic form in pyloric/antral metastatic gastric cancer might be useful for diagnosis and treatment.

Time to Classify Tumours of the Stomach and the Kidneys According to Cell of Origin.

Malignant tumours are traditionally classified according to their organ of origin and whether they are of epithelial (carcinomas) or mesenchymal (sarcomas) origin. By histological appearance the site of origin may often be confirmed. Using same treatment for tumours from the same organ is rational only when there is no principal heterogeneity between the tumours of that organ. Organ tumour heterogeneity is typical for the lungs with small cell and non-small cell tumours, for the kidneys where clear cell renal carcinoma (CCRCC) is the dominating type among other subgroups, and in the stomach with adenocarcinomas of intestinal and diffuse types. In addition, a separate type of neuroendocrine tumours (NETs) is found in most organs. Every cell type able to divide may develop into a tumour, and the different subtypes most often reflect different cell origin. In this article the focus is on the cells of origin in tumours arising in the stomach and kidneys and the close relationship between normal neuroendocrine cells and NETs. Furthermore, that the erythropoietin producing cell may be the cell of origin of CCRCC (a cancer with many similarities to NETs), and that gastric carcinomas of diffuse type may originate from the ECL cell, whereas the endodermal stem cell most probably gives rise to cancers of intestinal type.

Molecular characterization of metabolic subtypes of gastric cancer based on metabolism-related lncRNA.

Increasing evidence has demonstrated that lncRNAs are critical regulators in diverse biological processes, but the function of lncRNA in metabolic regulation remains largely unexplored. In this study, we evaluated the association between lncRNA and metabolic pathways and identified metabolism-related lncRNAs. Gastric cancer can be mainly subdivided into 2 clusters based on these metabolism-related lncRNA regulators. Comparative analysis shows that these subtypes are found to be highly consistent with previously identified subtypes based on other omics data. Functional enrichment analysis shows that they are enriched in distinct biological processes. Mutation analysis shows that ABCA13 is a protective factor in subtype C1 but a risk factor in C2. Analysis of chemotherapeutic and immunotherapeutic sensitivity shows that these subtypes tend to display distinct sensitivity to the same chemical drugs. In conclusion, these findings demonstrated the significance of lncRNA in metabolic regulation. These metabolism-related lncRNA regulators can improve our understanding of the underlying mechanism of lncRNAs and advance the research of immunotherapies in the clinical management of gastric cancer.

nPTD classification: an updated classification of gastric cancer location for function preserving gastrectomy based on physiological lymphatic flow.

BACKGROUND: The correlation between tumor location and lymphatic flow distribution in gastric cancer has been previously reported, and PTD (Proximal - Transitional - Distal) classification was proposed. Our group updated and developed the nPTD classification. METHOD: We retrospectively studied gastric cancer patients who underwent the dye method sentinel node biopsy from 1993 to 2020. The inclusion criteria were a single lesion type 0 cancer of ≤5 cm in the long axis, clinically node-negative, and invasion within the proper muscle layer pathologically. In this study, the distribution of dyed lymphatic flow was evaluated for each occupied area of the tumor. RESULTS: We included 416 patients in this study. The tumors located in the watershed of the right and left gastroepiploic arteries near greater curvature had extensive lymphatic flow; therefore, a newly circular region with a diameter of 5 cm is set on the watershed of the greater curvature between P and T zone as the 'n' zone. In addition, for cancers located in the lesser P curvature, lymphatic flow to the greater curvature was not observed. Therefore, the P zone was divided into two: the lesser curvature side (PL) and the greater curvature side (PG). CONCLUSIONS: The advantage of the nPTD classification is that it provides not only proper nodal dissection but also adequate function-preserving gastrectomy. If the tumor is localized within the PL, the proximal gastrectomy resection area can be further reduced. In contrast, for cancers located in the 'n' zone, near-total gastrectomy is required because of the extensive lymphatic flow.

A systematic review of primary gastric diffuse large B-cell lymphoma: Clinical diagnosis, staging, treatment and prognostic factors.

Primary gastric lymphoma (PGL) is a rare clinical entity accounting for the majority of extra-nodal non-Hodgkin lymphoma (EN-NHL). The most common histological subtype is the primary gastric diffuse large B-cell lymphoma (PG-DLBCL) with a media age of 50-60 years old, mostly in male. Pathogenesis is often related to some bacterial infection such as Helicobacter pylori (H. pylori) infection. However, due to various available staging system, there is still no consensus on the staging of PG-DLBCL. The international prognostic index (IPI) is the most valuable used for the stratification of almost all subtype of NHL and as well as for PG-DLBCL. As for treatment strategies, surgery, chemotherapy, radiation therapy and antibiotic therapy in various combinations have been applied in clinical treatment. There are a few well-known prognostic factors and some of them may constitute prognostic models. Due to the increasing incidence of this neoplasm, it is necessary for clinicians to make deep insight of the diagnosis, staging, treatment and prognostic factors of PG-DLBCL.

Comparison of the sixth, seventh, and eighth editions of the American Joint Committee on Cancer Tumor-Node-Metastasis staging system for gastric cancer: A single institution experience.

ABSTRACT: In 2018, the eighth edition of the American Joint Committee on Cancer Tumor-Node-Metastasis classification and staging system was implemented. Few reports were made comparing the performance of different editions of the American Joint Committee on Cancer (AJCC) system. Therefore, this study aimed to examine the prognostic predictability from the sixth to the eighth editions of the AJCC staging system for gastric cancer.A total of 414 patients with gastric cancer who underwent surgery at Changhua Christian Hospital from January 2007 to December 2017 were enrolled in the study. To identify the prognostic factors for gastric cancer death, univariate and multivariate analyses were performed. The homogeneity and discrimination abilities of the sixth to eighth editions of the staging system were compared using the likelihood ratio chi-square test, linear trend chi-square test, and Akaike information criterion.The sixth edition of the staging system had the lowest Akaike information criterion value, suggesting a better prognostic stratification than other editions. From the result of the likelihood ratio chi-square test, the T and N staging systems of the seventh and eighth editions had better homogeneity and discriminatory ability than the sixth edition. The eighth edition had better prognostic performance in patients at stage III compared with the seventh edition.The AJCC seventh and eighth editions had improved prognostic predictability of the T and N factors compared with the sixth edition. However, the overall staging performance of the eighth edition is not superior compared to the sixth edition. Further studies with larger sample size should be conducted to compare the performance of different editions of the AJCC staging system for different ethnic populations.

Gastric Cancer Risk of Intestinal Metaplasia Subtypes: A Systematic Review and Meta-Analysis of Cohort Studies.

INTRODUCTION: Intestinal metaplasia (IM) is an independent risk factor for gastric cancer (GC). However, the subtypes of IM as a risk factor for GC remain controversial. We performed a systematic review and meta-analysis to evaluate the relationship between IM subtypes and GC risk. METHODS: Systematic searches were conducted in PubMed, EMBASE, and the Cochrane Library for published cohort studies of patients with complete IM (type I) or incomplete IM (type II or type III) from inception to May 15, 2021. We extracted relevant data and calculated pooled risk ratios (RRs) and 95% confidence intervals (CIs) comparing the GC risk with IM subtypes. RESULTS: Twelve cohort studies comprising 6,498 individuals were included in the study. Compared with complete IM, the pooled relative risk of GC risk of patients with incomplete IM was 5.16 (95% CI, 3.28-8.12), and the GC risk of type III IM was the highest, with a pooled relative risk of 2.88 (95% CI, 1.37-6.04) compared with that of type II. Compared with complete IM, the pooled relative risk of dysplasia risk in patients with incomplete IM was 3.72 (95% CI, 1.42-9.72), and the dysplasia risk of type III IM was 11.73 (95% CI, 2.08-66.08) compared with that of type I. DISCUSSION: Patients with incomplete IM, especially type III, were at a higher risk of GC and dysplasia than those with complete IM. The current evidence indicates a potential correlation between IM subtypes and GC risk, which may support the use of IM subtypes in GC surveillance.

Assessment of Clinicopathological Characteristics and Development of an Individualized Prognostic Model for Patients With Hepatoid Adenocarcinoma of the Stomach.

Importance: Few studies have examined the clinicopathological characteristics and prognoses of patients with hepatoid adenocarcinoma of the stomach (HAS). Objective: To explore the clinicopathological characteristics and prognoses of patients with HAS and develop a nomogram to predict overall survival (OS). Design, Setting, and Participants: This prognostic study involved a retrospective analysis of data from 315 patients who received a diagnosis of primary HAS between April 1, 2004, and December 31, 2019, at 14 centers in China. Main Outcomes and Measures: OS and prognostic factors. Patients were randomly assigned to a derivation cohort (n = 220) and a validation cohort (n = 95). A nomogram was developed based on independent prognostic factors identified through a multivariable Cox mixed-effects model. Results: Among 315 patients with HAS (mean [SD] age, 61.9 [10.2] years; 240 men [76.2%]), 137 patients had simple HAS (defined as the presence of histologically contained hepatoid differentiation areas only), and 178 patients had mixed HAS (defined as the presence of hepatoid differentiation areas plus common adenocarcinoma areas). Patients with simple HAS had a higher median preoperative α-fetoprotein level than those with mixed HAS (195.9 ng/mL vs 48.9 ng/mL, respectively; P < .001) and a higher rate of preoperative liver metastasis (23 of 137 patients [16.8%] vs 11 of 178 patients [6.2%]; P = .003). The 3-year OS rates of patients with simple vs mixed HAS were comparable (56.0% vs 60.0%; log-rank P = .98). A multivariable Cox analysis of the derivation cohort found that the presence of perineural invasion (hazard ratio [HR], 2.13; 95% CI, 1.27-3.55; P = .009), preoperative carcinoembryonic antigen levels of 5 ng/mL or greater (HR, 1.72; 95% CI, 1.08-2.74; P = .03), and pathological node category 3b (HR, 3.72; 95% CI, 1.34-10.32; P = .01) were independent risk factors for worse OS. Based on these factors, a nomogram to predict postoperative OS was developed. The concordance indices of the nomogram (derivation cohort: 0.72 [95% CI, 0.66-0.78]; validation cohort: 0.72 [95% CI, 0.63-0.81]; whole cohort: 0.71 [95% CI, 0.66-0.76]) were higher than those derived using the American Joint Committee on Cancer's AJCC Cancer Staging Manual (8th edition) pathological tumor-node-metastasis (pTNM) staging system (derivation cohort: 0.63 [95% CI, 0.57-0.69]; validation cohort: 0.65 [95% CI, 0.56-0.75]; whole cohort: 0.64 [95% CI, 0.59-0.69]) and those derived using a clinical model that included pTNM stage and receipt of adjuvant chemotherapy (derivation cohort: 0.64 [95% CI, 0.58-0.69]; validation cohort: 0.65 [95% CI, 0.56-0.75]; whole cohort: 0.64 [95% CI, 0.59-0.69]). Based on the nomogram cutoff of 10 points, the whole cohort was divided into high-risk and low-risk groups. The 3-year OS rate of patients in the high-risk group was significantly lower than that of patients in the low-risk group (29.7% vs 75.9%, respectively; log-rank P < .001), and the 3-year prognosis of high-risk and low-risk groups could be further distinguished into pTNM stage I to II (33.3% vs 80.2%; exact log-rank P = .15), stage III (34.3% vs 71.3%; log-rank P < .001), and stage IV (15.5% vs 70.3%; log-rank P = .009). Conclusions and Relevance: This study found that perineural invasion, preoperative carcinoembryonic antigen levels of 5 ng/mL or greater, and pathological node category 3b were independent risk factors associated with worse OS. An individualized nomogram was developed to predict OS among patients with HAS. This nomogram had good prognostic value and may be useful as a supplement to the current American Joint Committee on Cancer TNM staging system.

A deep learning model for gastric diffuse-type adenocarcinoma classification in whole slide images.

Gastric diffuse-type adenocarcinoma represents a disproportionately high percentage of cases of gastric cancers occurring in the young, and its relative incidence seems to be on the rise. Usually it affects the body of the stomach, and it presents shorter duration and worse prognosis compared with the differentiated (intestinal) type adenocarcinoma. The main difficulty encountered in the differential diagnosis of gastric adenocarcinomas occurs with the diffuse-type. As the cancer cells of diffuse-type adenocarcinoma are often single and inconspicuous in a background desmoplaia and inflammation, it can often be mistaken for a wide variety of non-neoplastic lesions including gastritis or reactive endothelial cells seen in granulation tissue. In this study we trained deep learning models to classify gastric diffuse-type adenocarcinoma from WSIs. We evaluated the models on five test sets obtained from distinct sources, achieving receiver operator curve (ROC) area under the curves (AUCs) in the range of 0.95-0.99. The highly promising results demonstrate the potential of AI-based computational pathology for aiding pathologists in their diagnostic workflow system.

Molecular Landscapes of Gastric Pre-Neoplastic and Pre-Invasive Lesions.

Gastric carcinoma (GC) represents one of the most common and most lethal malignancies worldwide. The histopathological characterization of GC precursor lesions has provided great knowledge about gastric carcinogenesis, with the consequent introduction of effective strategies of primary and secondary prevention. In recent years, a large amount of data about the molecular events in GC development is emerging, flanking the histomorphological descriptions. In this review, we describe the landscape of molecular alterations in gastric pre-invasive lesions with a glance at their potential use in the diagnostic and therapeutic decision-making process.

Identification of four gastric cancer subtypes based on genetic analysis of cholesterogenic and glycolytic pathways.

Warburg phenomenon refers to the development of unique metabolic patterns during the growth of tumor cells. This study stratified gastric cancer into prognostic metabolic subgroups according to changes in gene expressions related to glycolysis and cholesterol synthesis. The RNA-seq expression data, single nucleotide variants (SNV), short insertions and deletions (InDel) mutation data, copy number variation (CNV) data and clinical follow-up information data of gastric cancer tissues were downloaded from The Cancer Genome Atlas (TCGA) database. ConsensusClusterPlus was used to stratify the metabolic subtypes of gastric cancer. Four metabolic subtypes (Cholesterogenic, Glycolytic, Mixed and Quiescent) of gastric cancer were identified, and patients with cholesterogenic tumors had the longest disease-specific survival (DSS). Genome-wide analysis showed that aberrant amplification of TP53 and MYC in gastric cancer was associated with abnormal cholesterol anabolic metabolism. The mRNA levels of mitochondrial pyruvate carriers 1 and 2 (MPC1/2) differed among the four subtypes. Tumors in the glycolytic group showed a higher PDCD1. A genomic signature based on tumor metabolism of different cancer types was established. This study showed that genes related to glucose and lipid metabolism play an important role in gastric cancer and facilitate a personalized treatment of gastric cancer.