Intestinal-type Gastric Adenocarcinoma Research Articles

OLGA- and OLGIM-Based Staging in the Patients with Gastritis and Endoscopy Indications.

Gastric cancer is one of the most common cancers with high mortality. In Iran, the high-risk regions include Northern and Northwestern parts. The aim of this study was to assess the operative link on gastritis assessment- and operative link on gastric intestinal metaplasia-based staging in patients with upper gastrointestinal symptoms. Totally, 345 patients underwent upper gastrointestinal endoscopy. Also, the status of Helicobacter pylori infection was evaluated using rapid urease test and histological method. Moreover, histological changes were assessed using the Update Sydney System. The operative link on gastritis assessment- and operative link on gastric intestinal metaplasia-based stages of 0-II were considered as low-risk stages and stages III and IV were considered as high-risk stages. Most of the patients were lower than 60 years (245 patients, 71%), and 71.9% of our patients had H. pylori infection. The frequency of atrophic gastritis and intestinal metaplasia was 44.9% and 25.2%, respectively (P < .001). Eleven patients (73.7%) with gastric adenocarcinoma had a low risk and 2 patients with low-grade dysplasia had a high risk of operative link on gastritis assessment and operative link on gastric intestinal metaplasia. Almost, 62.5% of gastric cancer patients with an intestinal type of gastric adenocarcinoma were at low-risk stages. Although high stages of operative link on gastritis assessment and operative link on gastric intestinal metaplasia need further follow-up, lower stages of atrophy or intestinal metaplasia also require follow-up. Furthermore, operative link on gastritis assessment method in detecting a greater number of patients who need follow-up is more successful and profitable.

Resection of Gastric Cancer Liver Metastases: Literature Review and Case Report

Introduction: The treatment of gastric cancer has undergone changes in recent years, significantly impacting the morbidity and mortality caused by the disease. However, the treatment of metastatic disease remains a challenge. Whether in the intestinal or Lauren's diffuse tumor, the presence of liver metastases in gastric cancer is considered to be an unfavorable prognosis, given the possibility of the existence of other occult metastases at the time of this diagnosis. Given the changes in the panorama of this disease, it is necessary to review the proposed treatment, considering the possibility of oncological benefit from liver metastasectomy and which patients would benefit from this therapy. Clinical case: FAM, female, 65 years old, diagnosed with Lauren's intestinal-type gastric adenocarcinoma submitted to subtotal gastrectomy with D2 lymphadenectomy. Clinical staging IIIB (T4N2M0), referred for adjuvant chemotherapy protocol. At the time no synchronous distant metastases was identified. One year later PET-CT showed a liver nodule at the right lobe and peri-portal nodule. Submitted to right hepatectomy + peri-portal lymphadenectomy. Anatomopathological exame confirmed gastric adenocarcinoma. Conclusion: Review of published studies in the literature showed that patients who would benefit from this therapy would be those with 1-3 metastatic liver lesions, up to 5 cm in length in the largest one, without serosa invasion in the primary lesion and whose lymph node involvement was ≤ N1 . Overall patient survival was increased from 9.5-14.1 months to 31.1-40.8 months in these groups. We therefore conclude that there is benefit in resection of liver metastases in selected cases of gastric cancer.

Grading of tumor budding in intestinal-type early gastric adenocarcinoma and its role in assessing the risk of lymph node metastasis

Objective: To investigate the role of tumor budding (TB) in predicting lymph node metastasis of intestinal-type early gastric adenocarcinoma, and to determine the optimal cutoff value of TB number. Methods: A total of 202 patients with intestinal-type early gastric adenocarcinoma, who underwent surgical operation at the Affiliated Wuxi People's Hospital of Nanjing Medical University, Jiangsu, China from 2008 to 2018 were included. According to the International Tumor Budding Consensus Conference (ITBCC) criteria, the number of TB for each case was assessed. The receiver operating characteristic (ROC) curve was employed to determine the optimal cutoff value of TB number for predicting lymph node metastasis, and multivariate logistic regression was used to analyze whether a high TB number was an independent risk factor for lymph node metastasis. In addition, in the patients, who met the indications for endoscopic resection and developed lymph node metastasis, the association of a high number of TB with lymph node metastasis was examined. Results: TBs were observed in 63.4% (128/202) of intestinal-type early gastric adenocarcinomas. Using ROC curve, 4 TBs was found as the optimal cutoff value to predict lymph node metastasis (area under the curve 0.767; sensitivity 0.657; specificity 0.780). Therefore, the 202 cases were divided into two groups: the high-budding (≥4 TBs) group (n=60) and the low-budding (<4 TBs) group (n=142). The high-budding group exhibited a higher rate of lymph node metastasis than that of the low-budding group (41.7% vs 9.1%, P<0.01), and ≥4 TBs was associated with deeper invasion and lymph vessel invasion (P<0.01). The multivariate regression model showed that ≥4 TBs was an independent risk factor for lymph node metastasis (Hazard ratio=8.760, 95%CI 2.648-28.987; P<0.01). Meanwhile, 4 TBs as the cutoff value could better predict lymph node metastasis than the cutoff value advised by the ITBCC. In addition, 3 cases were found to have developed lymph node metastasis even that they met the expanded indications for endoscopic resection, and 2 of these 3 cases exhibited a higher TB number (≥4 TBs). Conclusions: More than 4 TBs are a useful indicator for predicting lymph node metastasis in intestinal-type early gastric adenocarcinoma. It may be used to as an endoscopic resection criterion for patients with a high risk of lymph node metastasis.

Diagnostic and therapeutic potencies of miR-18a-5p in mixed-type gastric adenocarcinoma.

Mixed‐type gastric adenocarcinoma (by Lauren Classification) has poor clinical outcomes with few targeted treatment options. The primary objective of this study was to find the prognostic factors, accurate treatment approaches, and effective postoperative adjuvant therapy strategies for patients with mixed‐type gastric adenocarcinoma (GA). A microRNA sequencing data set and the corresponding clinical parameters of patients with gastric cancer were obtained from The Cancer Genome Atlas. Differentially expressed microRNAs (DEMs) of diffuse‐ and intestinal‐type GA were, respectively, determined. Kaplan–Meier and log‐rank tests were subsequently carried out to evaluate the prognostic relevance of each DEM. To study the common factors between diffuse‐ and intestinal‐type GA, a pathway enrichment analysis was performed on the target genes of identified DEMs using the PANTHER database. After data preprocessing, we analyzed a total of 230 samples from 210 patients with GA. Eighty‐six DEMs in diffuse‐type GA samples and 59 DEMs in intestinal‐type GA samples were, respectively, identified (p 2.0). The Kaplan–Meier survival method further screened out six prognosis‐related DEMs for diffuse‐type GA and seven prognosis‐related DEMs for intestinal‐type GA (p < 0.05). MiR‐18a‐5p was found to be the only common prognosis‐related DEM between diffuse‐ and intestinal‐type GA. The common signaling pathways further revealed that target genes of miR‐18a‐5p are involved in mixed‐type GA progression. This study suggests that miR‐18a‐5p acts as a potential target for treatment, and common signal pathways provide a rich basis to seek reliable and effective molecular targets for the diagnosis, clinical treatment, and postoperative adjuvant therapy strategy of mixed‐type GA.

The Prognostic Significance of c-Met and p53 Immunohistochemical Expression in Gastric and Colorectal Carcinomas

BACKGROUND: Colorectal and gastric carcinomas are the most common and deadly gastrointestinal (GIT) malignancies. AIM: This study aimed to evaluate the expression of c-Met and p53 in gastric and colorectal carcinomas (CRCs) as well as colorectal adenomas using immunohistochemistry. MATERIALS AND METHODS: c-Met and p53 immunohistochemical expression was conducted on 66 cases of gastric adenocarcinomas and total of 60 colonic cases (36 CRCs and 24 colorectal adenomas). RESULTS: In this study, c-Met was positively expressed in 54.5% of gastric carcinomas and 50% of CRCs. In addition, p53 was positively expressed in 56.1% of gastric carcinomas and 72.2% of CRCs. Moreover, higher expression of both c-Met (p = 0.001) and p53 expression (p &lt; 0.001) was reported in CRCs compared to colorectal adenomas. In the same context, c-Met and p53 expressions were positively correlated with intestinal type gastric adenocarcinoma (p &lt; 0.001 and p = 0.03, respectively). Moreover, c-Met was correlated with non-mucinous adenocarcinomas (p = 0.008) and lower grades (p &lt; 0.001) of gastric carcinomas. As regard survival analysis in gastric carcinomas, median overall survival (OS) was better in p53 positive patients (p = 0.05), patients with negative lymph node metastasis (p = 0.03), and patients with better response to neoadjuvant chemotherapy (p = 0.04). In contrast, c-Met did not exhibit significant correlation with OS (p &gt; 0.05). Both c-Met and p53 did not reveal significant correlation with tumor stage and site in both CRCs and gastric carcinomas (p &gt; 0.05). CONCLUSION: We concluded that c-Met and p53 are expressed in the most common GIT malignancies addressing them as potential biomarkers. In addition, c- Met and p53 may have a potential role in colorectal cancer development as they showed higher positivity in CRCs compared to adenomas.

In vivo assessment of Lauren classification for gastric adenocarcinoma using diffusion MRI with a fractional order calculus model.

To evaluate the performance of a fractional order calculus (FROC) diffusion model for imaging-based assessment of Lauren classification in gastric adenocarcinoma. In this study, 43 patients (15 females, 28 males) with gastric adenocarcinoma underwent MRI at 1.5 T. According to pathology-based Lauren classification, 10 patients had diffuse-type, 20 had intestinal-type, and 13 had mixed-type lesions. The diffuse and mixed types were combined as diffuse-and-mixed type to be differentiated from the intestinal type using diffusion MRI. Diffusion-weighted images were acquired by using eleven b-values (0-2000 s/mm2). Three FROC model parameters comprising diffusion coefficient D, intravoxel diffusion heterogeneity β, and a microstructural quantity μ, together with a conventional apparent diffusion coefficient (ADC), were estimated. The mean parameter values in the tumour were computed by using a percentile histogram analysis. Individual or linear combinations of the mean parameters in the tumour were used to differentiate the diffuse-and-mixed type from the intestinal type using descriptive statistics and receiver operating characteristic (ROC) analyses. Significant differences were observed between diffuse-and-mixed-type and intestinal-type lesions in D (0.99 ± 0.20 μm2/ms vs. 1.11 ± 0.23 μm2/ms; p = 0.036), β (0.37 ± 0.08 vs. 0.43 ± 0.11; p = 0.043), μ (7.92 ± 2.79 μm vs. 9.87 ± 1.52 μm; p = 0.038), and ADC (0.81 ± 0.34 μm2/ms vs. 0.96 ± 0.19 μm2/ms; p = 0.033). Among the individual parameters, μ produced the largest area under the ROC curve (0.739). The combinations of (D, β, μ) and (β and μ) produced the best overall performance with a sensitivity of 0.739, specificity of 0.750, accuracy of 0.744, and area under the curve of 0.793 (95% confidence interval: 0.657-0.929). Diffusion MRI with the FROC model holds promise for non-invasive assessment of Lauren classification for gastric adenocarcinoma. • High b-value diffusion MRI with a FROC model that is sensitive to tissue microstructures can differentiate the diffuse-and-mixed type from intestinal type of gastric adenocarcinoma. • The combination of FROC parameters produced the best result for distinguishing the diffuse-and-mixed type from the intestinal type with an area under the receiver operating characteristic curve of 0.793. • The FROC model parameters, individually or conjointly, hold promise for repeated, non-invasive evaluations of gastric adenocarcinoma at various time points throughout disease progression or regression to complement conventional Lauren classification.

Prevalence of Helicobacter pylori infection and the incidence of the associated malignant and peptic ulcer disease (PUD) at Nelson Mandela Academic Hospital: a retrospective analysis

Background H. pylori infection is associated with both benign and malignant gastrointestinal diseases. However, no studies have been conducted locally describing the prevalence of H. pylori and its associated GIT diseases. The objectives of this study are to determine the prevalence of H. pylori, and the incidence of PUD and gastric malignancies among patients who are infected with H. pylori or who have the stigmata of previous exposure to H. pylori. Material and methods Data was collected retrospectively from files of adult patients with upper gastro-intestinal symptoms from January to December, 2012. The gastric mucosal biopsy specimens were analyzed for the presence of H. pylori, chronic gastritis, PUD, and gastric malignancies. Results Of 156 records there were 70 (45%) males and 86 (55%) females, with a median age of 56.5. The prevalence of H. pylori was 54.5%; 95% of 156 had chronic gastritis (CG). Ninety-sever percent of the 85 H. pylori positive and 93% of the 71 H. pylori negative patients had CG. However, the difference was not statistically significant (97% vs 93%, p = 0.322). The incidence of PUD was 16% and 10 (6.4%) had gastric malignancies, of which four (2.7%) and three (2%) were antral intestinal-type and proximal diffuse types, respectively. Three (2%) had gastric MALT lymphoma. The risk of both gastric malignancies and PUD was demonstrated to increase with advancing age. Discussion and conclusion The prevalence of H. pylori was equivalent to the global prevalence; however, high prevalence of CG may be indicative of high local infection rate. The incidence of H. pylori and/or chronic gastritis-associated intestinal-type gastric adenocarcinoma, MALT lymphoma, and PUD is equivalent to that reported globally. Advancing age and active H. pylori infection or stigmata of past exposure thereto are associated with increased risk of peptic ulcers and malignant gastric diseases.

Морфологическая характеристика диспластических процессов в слизистой оболочке, прилежащей к опухоли, при раке желудка кишечного типа

Introduction. Despite a significant number of publications and a concept known as Correa’s cascade, dysplas-tic processes and the mechanisms of gastric carcinogenesis, are still far from being completely understood. Dysplasia and the processes in the mucous membrane adjacent to the tumor node, their significance, and their role in the field cancerization have also been studied insufficiently. The aim of this work was to analyze the frequency of occurrence and some characteristics of high- and low-grade dysplasia in the gastric mucosa at variable distances from the tumor node. Materials and methods. We carried out a prospective histological study of surgical specimens from 49 patients with intestinal type gastric adenocarcinoma. We studied tissues from the tumor node and adjacent gastric mucosa at various distances from the tumor and assessed the frequency of occurrence and some characteristics of low- and high-grade dysplasia. Results. In the mucous membrane adjacent to the intestinal type adenocarcinoma, 73.5% of cases demon-strated low- and high-grade dysplasia. In all cases, background and precancerous processes were found in areas adjacent to the tumor node with low- and high-grade dysplasia. Conclusion. The incidence of low- and high-grade dysplasia detected in the mucous membrane adjacent to intestinal type gastric adenocarcinoma significantly decreases as the distance from the tumor node in-creases. Dysplastic changes are associated with epithelial hyperplasia, intestinal metaplasia, and inflamma-tory and atrophic changes. The results obtained support field cancerization and highlight the need to study morphological, molecular, and genetic alterations in the gastric mucosa adjacent to the tumor more deeply. The dysplastic changes present at the resection line area indicate that this fact must be considered when determining the resection line. Keywords: gastric cancer, low-grade dysplasia, high-grade dysplasia, epithelial dysplasia, intestinal meta-plasia, inflammatory infiltration, atrophy

Massively parallel sequencing analysis of 68 gastric-type cervical adenocarcinomas reveals mutations in cell cycle-related genes and potentially targetable mutations.

Gastric-type cervical adenocarcinoma (GCA) is an aggressive type of endocervical adenocarcinoma characterized by mucinous morphology, gastric-type mucin, lack of association with human papillomavirus (HPV) and resistance to chemo/radiotherapy. We characterized the landscape of genetic alterations in a large cohort of GCAs, and compared it with that of usual-type HPV-associated endocervical adenocarcinomas (UEAs), pancreatic adenocarcinomas (PAs) and intestinal-type gastric adenocarcinomas (IGAs).GCAs (n=68) were subjected to massively parallel sequencing targeting 410–468 cancer-related genes. Somatic mutations and copy number alterations (CNAs) were determined using validated bioinformatics methods. Mutational data for UEAs (n=21), PAs (n=178) and IGAs (n=148) from The Cancer Genome Atlas (TCGA) were obtained from cBioPortal.GCAs most frequently harbored somatic mutations in TP53 (41%), CDKN2A (18%), KRAS (18%) and STK11 (10%). Potentially targetable mutations were identified in ERBB3 (10%), ERBB2 (8%) and BRAF (4%). GCAs displayed low levels of CNAs with no recurrent amplifications or homozygous deletions. In contrast to UEAs, GCAs harbored more frequent mutations affecting cell cycle related genes including TP53 (41% vs 5%, p<0.01) and CDKN2A (18% vs 0%, p=0.01), and fewer PIK3CA mutations (7% vs 33%, p=0.01). TP53 mutations were less prevalent in GCAs compared to PAs (41% vs 56%, p<0.05) and IGAs (41% vs 57%, p<0.05). GCAs showed a higher frequency of STK11 mutations than PAs (10% vs 2%, p<0.05) and IGAs (10% vs 1%, p<0.05). GCAs harbored more frequent mutations in ERBB2 and ERBB3 (9% vs 1%, and 10% vs 0.5%, both p<0.01) compared to PAs, and in CDKN2A (18% vs 1%, p<0.05) and KRAS (18% vs 6%, p<0.05) compared to IGAs.GCAs harbor recurrent somatic mutations in cell cycle-related genes and in potentially targetable genes, including ERBB2/3. Mutations in genes such as STK11 may be used as supportive evidence to help distinguish GCAs from other adenocarcinomas with similar morphology in metastatic sites.

Hypergastrinemia is associated with an increased risk of gastric adenocarcinoma with proximal location: A prospective population-based nested case-control study.

The incidence of proximal gastric adenocarcinoma is increasing among younger adults. Rodent models have shown that hypergastrinemia causes carcinogenesis in the proximal stomach. The aim of our study was therefore to assess if hypergastrinemia was associated with an increased risk of developing gastric adenocarcinoma also in humans. A prospective population‐based nested case‐control study within the Nord‐Trøndelag Health Study (HUNT) cohort, Norway, was used to assess this association. Serum was collected from 78 962 participants in 1995 to 1997 and 2006 to 2008. In the cohort, 181 incident gastric adenocarcinoma cases were identified from the Norwegian Cancer and Patient Registries through 2015 and matched with 359 controls. The risk of gastric adenocarcinoma was compared between participants with prediagnostic hypergastrinemia (>60 pmol/L) and normal serum gastrin (≤60 pmol/L). Logistic regression provided odds ratios (ORs) with 95% confidence intervals (CIs), adjusted for body mass index, tobacco smoking and comorbidity. Hypergastrinemia was associated with increased risk of gastric adenocarcinoma overall (OR 2.2, 95% CI 1.4‐3.4) and in particular for gastric adenocarcinoma with proximal location (OR 6.1, 95% CI 2.7‐13.8), but not with gastric adenocarcinoma with distal location (OR 1.7, 95% CI 0.9‐3.4). Moreover, hypergastrinemia was associated with an increased risk of gastric adenocarcinoma of intestinal histological type (OR 3.8, 95% CI 1.8‐7.9), but not for diffuse histological type (OR 1.6, 95% CI 0.7‐3.7). In conclusion, hypergastrinemia was associated with an increased risk of proximal and intestinal type gastric adenocarcinoma.

Lauren Classification Is A Predictor For Pathological Response Of Preoperative Chemoradiotherapy Compared With Preoperative Chemotherapy In Patients With Locally Advanced Gastric Cancer

To investigate the predictive value of Lauren classification to tumor pathological response after preoperative chemoradiotherapy (CRT) vs. preoperative chemotherapy (ChT) in locally advanced gastric adenocarcinoma (LAGC). From June 2013 to Dec, 2019, 182 patients in our hospital were enrolled into an ongoing multicentric phase III clinical trial comparing preoperative CRT (induction XELOX × 1 + 45Gy/25f with concurrent dose-reduced XELOX × 2) with preoperative ChT (XELOX × 3) in LAGC (NCT01815853). The clinical stage should be cT3N2-3M0, cT4aN+M0, or cT4bNanyM0. There were 124 males and 58 females, median age was 60 yrs (range 26-75 yrs). The interval between end of RT and surgery was 6-8 weeks. 65 out of 91 patients in the ChT group and 61 out of 91 patients in the CRT group had completed the preoperative treatments and the following radical D2 gastrectomy. Pathological response of primary tumor was categorized with NCCN tumor regression grade (TRG). Favorable pathological response (FPR) was defined as TRG0-1 with ypN0. At enrollment, patients’ baseline and tumor characteristics were well-balanced between the two groups. Proximal GC was in 58.2% (53/91) and 50.5(46/91) of the CRT and ChT group, respectively. Intestinal type (IT) GC was identified in 33(36.3%) patients of the ChT group, and in 36(39.6%) patients of the CRT group (X2 = 0.51, p = 0.916). After D2 gastrectomy, proportions of IT were 32.3% (21/65 pts) in the ChT group, and 50.8% (31/61 pts) in the CRT group, showing obvious shift towards resectability favoring IT vs. non-intestinal (n-IT, diffused plus mixed) type (X2 = 8.61, P = 0.035) after CRT. CRT group achieved higher rate of pCR (21.3% vs 3.1%, P = 0.002). There were 30, 37, and 22 patients obtained TRG0-1, ypN0, and FPR, respectively in the CRT group, while only 10, 14, and 5 patients did in the ChT group (P<0.001 for all). In the CRT group, ypN0 and FPR were observed in 80.6% and 45.2% of patients with IT tumor, but only in 35.7% and 21.4% with n-IT tumors (ypN0:P<0.001; FPR: P = 0.054), respectively. Logistic regression revealed IT tumor with higher probability of achieving ypN0 (OR = 7.500, 95%CI: 1.838-30.730; P = 0.005) than n-IT tumors. In contrast, no such differences were observed in the ChT group. Primary tumor locations were not predictive for ypN0 or TRG. In all patients with IT tumors, CRT was associated with higher rates of TRG0-1 (51.6% vs. 14.3%, P = 0.006), ypN0 (80.6% vs. 19.0%, P<0.001), FPR (45.2% vs. 0%, P<0.001) , pCR (22.6% vs. 0%, P = 0.033), and upstage 0-II (93.5% vs. 50.0%, P = 0.001) than ChT, while in patients with n-IT GC, only TRG showed significant improvement favoring CRT than ChT(TRG0-1: 42.9% vs. 15.9%, P = 0.011). Intestinal type gastric adenocarcinomas showed better responses to preoperative CRT vs. preoperative ChT than diffuse or mixed type GC did. This is the first set of data to date suggesting the predictive value of Lauren classification to tumor response after preoperative treatment in gastric cancer.

Intestinal-type gastric adenocarcinoma in a patient with ataxia-telangiectasia syndrome.

We introduce a 20-year-old patient, with prior diagnosis of ataxia-telangiectasia syndrome, urgently assesed because of an upper gastrointestinal bleeding, identifying in the urgent endoscopy an intestinal-type gastric adenocarcinoma as its origin.

Limb-bud and heart as a novel biomarker for gastric intestinal type adenocarcinoma.

The present study compared the expression levels of limb-bud and heart (LBH) between gastric intestinal-type adenocarcinoma (GITA) and healthy gastric tissues; with the aim of investigating the possible effect of LBH on the prognosis of patients with GITA and to analyze the associated signaling pathways in GITA. Three Oncomine gastric datasets were utilized for the preliminary prediction of the expression levels of LBH mRNA in GITA and healthy gastric tissues. Gene expression and corresponding clinical data of 163 patients with GITA were downloaded from The Cancer Genome Atlas. Wilcoxon signed rank-sum test was used to distinguish the clinical value of LBH expression in the various clinicopathological features. Subsequently, Kaplan-Meier univariate and Cox multivariate survival analyses were performed to determine the prognostic significance of LBH expression in patients with GITA. Function enrichment analysis was conducted for the co-expression gene of LBH, defined as correlation coefficient r>0.06 and P<0.05 using Pearson's χ2 test. Bioinformatics data demonstrated that compared with that in the normal gastric mucosa, LBH mRNA expression was dramatically higher in GITA tissues (P<0.05). There were significant relationships between the differential expression levels of LBH and clinicopathological parameters in GITA patients (all p<0.05), including pathological stage T (T3-4 vs. T1-2), lymph node metastasis (no vs. yes), distant metastasis (no vs. yes), histological grade (grade 3 vs. grades 1–2) and tumor stage (stages 3–4 vs. stages 1–2). Additionally, the overall survival and disease-free survival (DFS) of patients in the high expression group were poorer compared with those in the low expression group (P<0.05). Cox multivariate survival analysis indicated that increased LBH expression was an independent predictor of poor DFS prognosis in patients with GITA (P=0.045). In summary, LBH is highly expressed in GITA, which can be used as an independent predictor of poor prognosis in patients with GITA. LBH co-expressed genes are closely associated with GITA tumor migration and metastasis.

Trop2 is upregulated in the transition to dysplasia in the metaplastic gastric mucosa.

Intestinal-type gastric adenocarcinoma arises in a field of pre-existing metaplasia. While biomarkers of cancer and metaplasia have been identified, the definition of dysplastic transition as a critical point in the evolution of cancer has remained obscure. We have evaluated Trop2 as a putative marker of the transition from metaplasia to dysplasia in the stomach in multiple mouse models of metaplasia induction and progression. In addition, TROP2 expression was evaluated in human samples by immunostaining tissue microarrays for metaplasia, dysplasia, and gastric cancer. Dysplastic mouse organoids were evaluated in vitro following shRNA knockdown of Trop2 expression. In mouse models, no Trop2 was observed in the normal corpus and Trop2 was not induced in acute models of metaplasia induction with either L635 or DMP-777. In Mist1-Kras mice, Trop2 expression was not observed in metaplasia at 1 month after Kras induction, but was observed in dysplastic glands at 3-4 months after Kras induction. In human tissues, no Trop2 was observed in normal corpus mucosa or SPEM, but Trop2 expression was observed in incomplete intestinal metaplasia, with significantly less expression in complete intestinal metaplasia. Trop2 expression was observed in all dysplastic and 84% of gastric cancer lesions, although expression levels were variable. Dysplastic mouse organoids from Mist1-Kras mice expressed Trop2 strongly. Knockdown of Trop2 with shRNA markedly reduced organoid growth and budding behavior, and induced the upregulation of apical villin expression. We conclude that Trop2 is upregulated in the transition to dysplasia in the stomach and promotes dysplastic cell behaviors. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Mining topoisomerase isoforms in gastric cancer.

DNA topoisomerases essentially remove topological strains generated during DNA replication, transcription, DNA repair, and other cytogenetic processes. However, distinct expression level and prognostic significance of individual topoisomerase isoforms in gastric cancer (GC) remain largely unexplored. In this study, we utilized Oncomine and Kaplan-Meier plotter database to detect the mRNA expression level of individual topoisomerase isoforms as well as assess their prognostic significance in GC patients. With the exception of TOP3B and TOP2B, levels of all topoisomerase isoforms were found to be elevated in GC patients when compared to the normal tissues. Elevated expression of TOP1 and TOP1MT was relevant to longer overall survival (OS) in GC and gastric intestinal type adenocarcinoma (GITA) patients, but not in diffuse gastric adenocarcinoma (DFA) patients. Increased expression of TOP2A and TOP2B was related to better OS in GC, as well as in GITA and DFA patients. In contrast, increased expression TOP3A and TOP3B was associated with shorter OS in GC, as well as in GITA and DFA patients. We also applied the Tumor IMmune Estimation Resource (TIMER) tool to assess the correlations between distinct topoisomerase isoforms and the infiltrating immune cell landscape. Furthermore, we found that down-regulating the expression of TOP3A by shRNA significantly inhibited the proliferation and colony formation in GC cells compared to control shRNA treated cells. Thus our study lays the framework for utilizing topoisomerases in better understanding the complexity and heterogeneity of GC and for developing strategies for novel customized therapy in GC patients.

Natural Course of Atrophic Gastritis and Intestinal Metaplasia

Atrophic gastritis (AG) and intestinal metaplasia (IM) are considered the main precursor lesions of gastric cancer, and the risk of gastric cancer in the gastric mucosa increases in the presence of AG and IM. The development of intestinal-type gastric adenocarcinoma represents the last step of an inflammation-metaplasia-dysplasia-carcinoma sequence, called the Correa cascade of multistep gastric carcinogenesis. The incidences of both AG and IM tend to increase with age. &lt;i&gt;Helicobacter pylori&lt;/i&gt; is regarded the most important factor in the development of IM; the progression of AG to IM is also affected by numerous environmental factors and individual genetic factors. Therefore, understanding the natural course of AG and IM is very important, especially in areas with a high prevalence of gastric cancer such as Korea.

Radiotherapy benefited the survival of patients with intestinal-type gastric adenocarcinoma: a SEER population-based study.

Currently, the role of adjuvant radiotherapy (RT) in the treatment of patients with intestinal-type gastric adenocarcinoma (IGA) has not been well established. This study aimed to elucidate the survival impact of RT on such patients. The Surveillance, Epidemiology, and End Results (SEER) database was utilized to select eligible patients. The recruited patients were dichotomized into those not received RT versus those received RT. The 1:1 propensity score matching (PSM) analysis was conducted to balance the confounding factors between the two comparison groups. The categorical variables were assessed by Chi-square test. Cancer-specific survival (CSS) and overall survival (OS) of the patients were compared by Kaplan-Meier (KM) methods. Cox proportional hazard models were used to identify prognostic factors associated with CSS. A total of 3572 eligible patients were enrolled for our analysis, of which, 2896(81.1%) patients did not receive RT and 676(18.9%) patients received RT. Before PSM, except race and tumor size, significant differences in patients' baseline characteristics were observed in no RT versus RT group. The KM plots before PSM indicated that RT exerted significant survival benefits for the recruited patients (p < 0.001). After PSM, most confounders were well balanced between the two comparison groups. The KM plots showed significantly superior CSS and OS in the RT group (p < 0.05). Grade IV, stage II-IV, and N3 were identified as independent risk factors, while LN examined > 15 and RT were independent protective factors for favorable prognosis. Subgroup survival analysis revealed that RT brought a significant CSS advantage for the stage IV patients. Based on PSM analysis of the cohort from SEER database, RT showed significant survival benefits for patients with IGA. Our study supports adjuvant RT for this specific cohort.

Prognostic significance of peritumoural and intratumoural budding in intestinal-type gastric adenocarcinoma

Background and study aimsTumour budding (TB) at the invasive front, termed peritumoural budding (PTB), is an established prognostic factor for many solid tumours. However, intratumoural budding (ITB) in gastric adenocarcinoma (GAC), which is frequently observed at the tumour centre, particularly in tumour biopsy tissues, remains poorly understood. Hence, we aimed to determine the correlation of ITB with PTB and their connection with clinicopathological characteristics as well as their prognostic value in GAC. Patients and methodsWe investigated a total of 153 cases of GAC wherein tissues were primarily resected and their related clinicopathological data. A continuous series of paraffin-embedded tissues was stained by haematoxylin–eosin staining, and budding cells were identified by immunohistochemical staining. PTB and ITB were counted in five fields with the highest density of tumour buds. The selected area was examined under 40 high-power field. Cases were divided into low-grade TB and high-grade TB groups according to the median bud count. ResultsAmong the 153 patients with GAC, 51 underwent simultaneous observation of ITB and PTB, which were found to have a significant positive correlation. A higher grade of ITB in tumours was associated with positive lymph node metastasis and could predict a worse prognosis. Additionally, patients with simultaneous PTB and ITB had a shorter overall survival than those with PTB alone, suggesting a worse prognosis. ConclusionPTB and ITB were found to be adverse prognostic factors and high-risk indicators of intestinal-type GAC, and ITB plays an important role in evaluating GAC prognosis in gastroscopic biopsy tissues. Additionally, TB might become a useful index for predicting GAC prognosis in the future.

TP53 mutation analysis in gastric cancer and clinical outcomes of patients with metastatic disease treated with anti-angiogenic or standard chemotherapy regimens.

e16571 Background: Current data support the angiogenic potential of cancer cells with mutant p53 and VEGF-A up-regulation in solid tumors. These findings have renewed interest in the p53 role as a predictive/prognostic factor in cancer therapy. We investigated TP53 mutations in gastric adenocarcinoma (GA) samples of metastatic patients (pts) who underwent anti-angiogenic Paclitaxel-Ramucirumab (PR) therapy. The analysis was also performed in a control group of pts who received first-line chemotherapy (CT) with platinum derivates and fluoropyrimidines. Methods: TP53 mutations were identified by next-generation sequencing in 110 GA primary tumors of two retrospective metastatic series including 48 pts who were treated with second-line PR and 62 pts who received first-line CT with Cisplatin or Oxaliplatin plus 5-Fluorouracil or Capecitabine. Detected TP53 mutations were classified for TP53 mutant-specific residual transcriptional activity scores ( TP53 RTAS) (Fischer NW et al JCI Insight 2018). TP53 RTAS results were used for stratifying pts in survival analyses. Primary end-point was overall survival (OS). Results: In the PR group, TP53 mutations were detected in 29 out of 48 tumor samples (60.4%) with 10 having TP53 RTAS 0%-to-&lt;1%. In the CT group, TP53 mutations were found in 40 out of 62 tumor samples (64.5%) with 11 having TP53 RTAS 0%-to-&lt;1%. In the PR group, the 10 cases with a TP53 mutation causing no residual or minimal activity ( TP53 RTAS 0%-to-&lt;1%) showed better OS in comparison with pts in the remaining groups (wild-type and TP53 RTAS &gt; 1%). This effect was retained in the multivariate model analysis (Hazard Ratio = 0.29, 95% confidence interval 0.17-0.85, p = 0.02). An opposite effect was seen in the CT group with the worst OS in carriers of TP53 RTAS 0%-to-&lt;1% mutations (Hazard Ratio = 2.64, 95% confidence interval 1.17-5.95, p = 0.02). Notably, in the whole group of 110 pts, TP53 mutations (any type) occurred more frequently in the intestinal-type GA group (p = 0.02). Conclusions: Additional studies are warranted to explore the favorable role of TP53 mutations in cancer pts undergoing anti-angiogenic therapies. TP53 mutations frequently occur in GA and these findings would lead to novel tailored therapy strategies in this lethal disease.

Potential value of CT radiomics in the distinction of intestinal-type gastric adenocarcinomas.

The purpose of the study was to investigate the role of CT radiomics for the preoperative distinction of intestinal-type gastric adenocarcinomas. A total of 187 consecutive patients with preoperative contrast CT examination and pathologically proven gastric adenocarcinoma were retrospectively collected. Patients were divided into a training set (n = 150) and a test set (n = 37). Arterial phase (AP), portal phase (PP), and delay phase (DP) images were retrieved for analysis. A dedicated postprocessing software was used to segment the lesions and extract radiomics features. Random forest (RF) algorithm was applied to construct the classifier models. A nomogram was developed by incorporating multiphase radiomics scores. Receiver operating characteristic (ROC) curves were used to evaluate the performance of the radiomics model and nomogram in both sets. The radiomics model showed a favorable capability in the distinction of intestinal-type gastric adenocarcinomas. The areas under curves (AUCs) of the AP, PP, and DP radiomics models were 0.754 (95% CI: 0.676, 0.820), 0.815 (95% CI: 0.744, 0.874), and 0.764 (95% CI: 0.688, 0.829) in the training set, respectively, which were confirmed in the test set with AUCs of 0.742 (95% CI: 0.572, 0.872), 0.775 (95% CI: 0.608, 0.895), and 0.857 (95% CI: 0.703, 0.950), respectively. The nomogram yielded excellent performance for distinguishing intestinal-type adenocarcinomas in both sets, with AUCs of 0.928 (95%: 0.875, 0.964) and 0.904 (95% CI: 0.761, 0.976). The multiphase CT radiomics nomogram holds promise for the individual preoperative discrimination of intestinal-type gastric adenocarcinoma. • CT radiomics has a potential role in the distinction of intestinal-type gastric adenocarcinomas. • Single-phase enhanced CT-based radiomics showed favorable capability in distinguishing intestinal-type tumors. • The nomogram which incorporates the multiphase radiomics scores could facilitate the individual prediction of intestinal-type lesions.