HER2 in gastric adenocarcinoma: where do we stand today?

Aim: HER2 is a proto-oncogene expressed in 10–30% of gastric adenocarcinomas and is an ideal target for inhibition in malignancy with high recurrence and dismal survival rates. Materials & methods: A systematic search was conducted via PubMed, Google Scholar and the clinicaltrials.gov database to report the results of ongoing and past studies investigating HER2- inhibitors in gastric cancer. Results: Twenty-five studies were included; ToGA trial is the pivotal trial approving the use of trastuzumab in metastatic gastric cancer, followed by more studies investigating other HER2- inhibitors in this setting, as well as in local and locoregional malignancy. Conclusion: Anti-HER2 molecules are proving efficacy and safety in gastric cancer; the evidence is growing and association with other cancer agents is under investigation.

NF-Y subunits overexpression in gastric adenocarcinomas (STAD)

NF-Y is a pioneer transcription factor—TF—formed by the Histone-like NF-YB/NF-YC subunits and the regulatory NF-YA. It binds to the CCAAT box, an element enriched in promoters of genes overexpressed in many types of cancer. NF-YA is present in two major isoforms—NF-YAs and NF-YAl—due to alternative splicing, overexpressed in epithelial tumors. Here we analyzed NF-Y expression in stomach adenocarcinomas (STAD). We completed the partitioning of all TCGA tumor samples (450) according to molecular subtypes proposed by TCGA and ACRG, using the deep learning tool DeepCC. We analyzed differentially expressed genes—DEG—for enriched pathways and TFs binding sites in promoters. CCAAT is the predominant element only in the core group of genes upregulated in all subtypes, with cell-cycle gene signatures. NF-Y subunits are overexpressed, particularly NF-YA. NF-YAs is predominant in CIN, MSI and EBV TCGA subtypes, NF-YAl is higher in GS and in the ACRG EMT subtypes. Moreover, NF-YAlhigh tumors correlate with a discrete Claudinlow cohort. Elevated NF-YB levels are protective in MSS;TP53+ patients, whereas high NF-YAl/NF-YAs ratios correlate with worse prognosis. We conclude that NF-Y isoforms are associated to clinically relevant features of gastric cancer.

Gastric Cancers Missed at Upper Endoscopy in Central Norway 2007 to 2016—A Population-Based Study

Background: The rates of missed gastric cancers (MGC) at upper endoscopy (UE) has been reported at 5–10% in Western countries. We aimed to calculate the rate of MGC and identify factors associated with MGC. Methods: Retrospective population-based cohort study including 730 patients diagnosed with gastric adenocarcinoma in Central Norway 2007–2016. MGCs were incident gastric adenocarcinomas diagnosed 6–36 months after a previous UE. Factors associated with MGC were examined. Definitely missed (UE 6–12 months prior) and potentially missed (UE 12–36 months prior) MGCs were compared. Results: Sixty-seven (9.2%) of 730 gastric cancers were MGC. MGC were associated with localization (p = 0.009) and more frequent in the corpus, Lauren’s histological type (p = 0.028) and diffuse type more prevalent, and previous Billroth 2-operation (14.9% vs. 4.7%, p = 0.001). MGCs were diagnosed at earlier stages (p = 0.037). An ulceration was more common in patients with definitely missed than potentially MGC (40.9% vs. 17.8%, p = 0.041). Conclusions: MGC accounted for 9.2% of gastric cancers in Central Norway. MGC were associated with localization in the corpus, Lauren´s diffuse type and previous Billroth-2-operation. Intensified follow-up and adequate biopsy sampling of patients with gastric ulcerations could reduce the rate of missed gastric cancers.

M1 Polarized Tumor-Associated Macrophages (TAMs) as Promising Prognostic Signature in Stage I–II Gastric Adenocarcinomas

Tumor-associated macrophages (TAMs) may be noticed in gastric carcinomas (GC), but their clinicopathological significance has not been yet explored. From a histological review of 400 cases of tubular/papillary adenocarcinomas, 24 cases of stage I–II gastric adenocarcinomas with intraglandular and stromal TAMs were identified. Their clinicopathological features were compared with 72 pT-matched as well as stage-matched control cases of adenocarcinomas without TAMs. TAMs present in GC cases were present either in glands or in neoplastic stroma, showing an immunoreactivity for CD68 and CD80; sometimes, they were organized in mature granulomas with occasional giant cells. Therefore, the stained TAMs were reminiscent of a specific polarized macrophage M1 phenotype; however, in any case of our cohort, no M2 phenotype macrophages were documented by CD 163 and CD 204 immunostainings. Statistically, no significant differences in age, gender, tumor location, size, and lymphovascular and perineural invasion between the case group with TAMs and pT- as well as stage-matched controls were reported; furthermore, the case group showed lower frequency of lymph node metastasis (p = 0.02). In addition, a significantly different clinical course and overall survival rate were also observed in gastric adenocarcinomas with M1 TAMs (p = 0.02) in comparison to controls. These results suggest that tumor-associated M1 macrophages are related to a quite indolent growth and a better prognosis of patients with this peculiar variant of gastric adenocarcinomas.

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.

Hyperprogressive Disease After Combined Anti-PD-L1 and Anti-CTLA-4 Immunotherapy for MSI-H/dMMR Gastric Cancer: A Case Report

Immune checkpoint inhibitors (ICI) have been developed in gastric adenocarcinomas and approved in first-line metastatic setting (in combination with chemotherapy) as well as in pretreated patients. Microsatellite instability-high (MSI-H) tumors are predicted to derive high benefit from ICI but data in gastric locations are limited. Here, we describe the case of a 68-year old patient with stage IV MSI-H gastric adenocarcinoma, referred to our center to receive immunotherapy after failure of standard of care (surgery with perioperative platin-based chemotherapy and paclitaxel plus ramucirumab at disease progression). The patient received one injection of durvalumab and tremelimumab and was hospitalized eighteen days after because of occlusive syndrome. The CT scan showed hyperprogression of the lymph nodes and hepatic lesions, compressing the gastric stump. He died few days later. Molecular analyses did not explain this outcome. To our knowledge, this is one of the first reported cases of hyperprogressive disease after combined ICI for a patient with MSI-H tumor. We review the potential causes and discuss the emerging literature regarding predictive factors of hyperprogression in the particular subset of MSI-H patients. If some data were available in retrospective studies, validation of strong predictive factors is needed to avoid such dramatic evolutions.

Epidemiological and Histopathological Profile of Gastric Adenocarcinoma at Brazzaville University Hospital

Introduction: Gastric adenocarcinoma is the most common gastric malignancy (over 90% of gastric cancers) and remains a global public health problem. The aim of the study was to determine the epidemiological and histopathological aspects of gastric adenocarcinoma in Brazzaville. Material and Methods: The epidemiological and histopathological profile is determined through a descriptive study, collecting retrospective data spread over a period of 11 years (January 2008- December 2018), based on consultation of the departmental histology registers. pathological anatomy and cytology. For each case, age, sex, location, pTNM stage, location and histological type were collected. Results: 93 histologically confirmed gastric adenocarcinomas were collected during the 11-year period. The mean age of the patients was 54.5 years. The sex ratio was 2 in favor of men. The antral and fundal localization were more frequent (74.2% and 20.4% respectively). Of the 2 operative parts collected, one was T2N1 and the other T1N0. Tubular adenocarcinoma was the most common histologic type (51.6%), followed by independent cell adenocarcinoma (34.4%), papillary adenocarcinoma (11.8%), and mucinous adenocarcinoma (2, 2%). Conclusion: gastric tubular adenocarcinoma was the most common histological type in Brazzaville. Key words: epidemiology, gastric adenocarcinoma, histological type.