Diffuse-type Gastric Adenocarcinoma Research Articles

Association of E-Cadherin Expression with Histological Type and Grade of Gastric Adenocarcinoma

Objectives: To determine the immune expression of E-Cadherin in gastric adenocarcinomas and its association with tumor histological type and grade to evaluate its prognostic significance. Methodology: This descriptive cross-sectional study was conducted at the Pakistan Institute of Medical Sciences Islamabad, from December 2017 to January 2021. Eighty-one patients from both genders, aged 21 to 83 years, undergoing gastric biopsies and Gastrectomy specimens to diagnose gastric adenocarcinoma were included in our study. Immunohistochemical processing was performed and the results were interpreted by the consultant pathologist for the expression of E-cadherin on gastric adenocarcinoma. The data were analyzed with SPSS version 17. Results: There was a significant statistical association between loss of E-Cadherin with histological type of adenocarcinoma (p = 0.000). In total 81 cases, there were 53 (65%) cases of intestinal type adenocarcinoma and 28 (35%) cases of diffuse type adenocarcinoma. Of the 28 cases with diffuse type gastric Adenocarcinoma, 10 cases showed complete loss of E-Cadherin. This complete loss of Cadherin was also seen in four out of 53 cases of intestinal adenocarcinoma, all of which were poorly differentiated intestinal type of adenocarcinomas. Total cases of well differentiated type of adenocarcinoma were nine; all of these showed high expression of E-Cadherin. Conclusion: There is a strong association of E-Cadherin expression with the histological type and grade of gastric adenocarcinoma according to Lauren’s classification. As the grade of the adenocarcinoma gets higher there is more loss of E-Cadherin expression which proves its prognostic significance. It was also established that gastric adenocarcinoma is a disease of elderly with male predominance.

E-cadherin loss drives diffuse-type gastric tumorigenesis via EZH2-mediated reprogramming.

Diffuse-type gastric adenocarcinoma (DGAC) is a deadly cancer often diagnosed late and resistant to treatment. While hereditary DGAC is linked to CDH1 mutations, the role of CDH1/E-cadherin inactivation in sporadic DGAC tumorigenesis remains elusive. We discovered CDH1 inactivation in a subset of DGAC patient tumors. Analyzing single-cell transcriptomes in malignant ascites, we identified two DGAC subtypes: DGAC1 (CDH1 loss) and DGAC2 (lacking immune response). DGAC1 displayed distinct molecular signatures, activated DGAC-related pathways, and an abundance of exhausted T cells in ascites. Genetically engineered murine gastric organoids showed that Cdh1 knock-out (KO), KrasG12D, Trp53 KO (EKP) accelerates tumorigenesis with immune evasion compared with KrasG12D, Trp53 KO (KP). We also identified EZH2 as a key mediator promoting CDH1 loss-associated DGAC tumorigenesis. These findings highlight DGAC's molecular diversity and potential for personalized treatment in CDH1-inactivated patients.

ASSOCIATION OF HER2/NEU EXPRESSION WITH PATIENT PROGNOSIS IN PRIMARY GASTRIC ADENOCARCINOMA

Introduction: Gastric carcinoma is the second leading cause of cancer related deaths in the world. Aim of the present study was to determine the association of HER2 overexpression with prognostic factors in gastric adenocarcinoma affected Pakistani patients.
 Methods: For this purpose, immunohistochemical staining of gastric cancer patients (n=200) was performed. HER2 was found to be overexpressed in 70% of cases included in the study. Association of HER2 expression with age greater than 40 years at the time of diagnosis, histological types and moderately differentiated grades of primary gastric adenocarcinoma was observed.
 Results: HER2 was found to be overexpressed in 20% of cases. No association of HER2 was identified with the gender of the patients. Interestingly, HER2, overexpression was present in 75% of intestinal and 37% of diffuse type gastric adenocarcinoma. Based on tumor differentiation, well-differentiated (grade I) and moderately differentiated type (grade II) adenocarcinoma showed overexpression of HER2 in 90 and 80% patients respectively. Moreover, 60% patients having poorly differentiated adenocarcinoma (grade III) also exhibited HER2 overexpression.
 Conclusion: Due to presence of HER2 overexpression in diffuse type gastric carcinoma as well, it is suggested that every case of gastric adenocarcinoma should be tested for HER2 overexpression so that they can be offered targeted molecular therapy for better survival.

Bacterial Involvement in Progression and Metastasis of Adenocarcinoma of the Stomach.

Simple SummaryInfectious bacteria influence primary gastric carcinogenesis, organotropism, and metastatic progression by altering the microenvironment at the primary and secondary tumors. Key species include Helicobacter pylori (H. pylori) and Mycoplasma hyorhinis (M. hyorhinis). Inflammation caused by H. pylori virulence factors, such as CagA, VacA, and oipA, disrupt epithelial integrity, which allows the primary tumor to progress through the metastatic process. Evidence supports the activation of aquaporin-5 by CagA-positive H. pylori infection, promoting epithelial–mesenchymal transition via the extracellular signal-regulated kinase/mitogen-activated protein kinase (MEK/ERK) pathway, thus laying the foundation for metastatic disease. M. hyorhinis has also been implicated in gastric neoplasia via β-catenin stabilization and subsequent activation of the WNT-signaling pathway, promoting gastric cancer cell motility and inciting cancer progression.Gastric cancer metastasis is a process in which the tumor microenvironment may carry significant influence. Helicobacter pylori (H. pylori) infection is well-established as a contributor to gastric carcinoma. However, the role that these bacteria and others may play in gastric carcinoma metastasis is a current focus of study. A review of the literature was conducted to elucidate the process by which gastric adenocarcinoma metastasizes, including its ability to utilize both the lymphatic system and the venous system to disseminate. Studies that investigate the tumor microenvironment at both the primary and secondary sites were assessed in detail. H. pylori and Mycoplasma hyorhinis (M. hyorhinis) were found to be important drivers of the pathogenesis of gastric adenocarcinoma by modifying various steps in cell metastasis, including epithelial–mesenchymal transition, cell migration, and cell invasion. H. pylori is also a known driver of MALT lymphoma, which is often reversible simply with the eradication of infection. M. hyorhinis has been implicated in gastric neoplasia via β-catenin stabilization and subsequent activation of the WNT-signaling pathway, promoting gastric cancer cell motility and inciting cancer progression. Fusobacterium nucleatum (F. nucleatum) and its association with worse prognosis in diffuse-type gastric adenocarcinoma are also reviewed. Recognition of the roles that bacteria play within the metastatic cascade is vital in gastrointestinal adenocarcinoma treatment and potential reoccurrence. Further investigation is needed to establish potential treatment for metastatic gastric carcinoma by targeting the tumor microenvironment.

S3614 Gastric Linitis Plastica - An Easily Missed Diagnosis

Introduction: Gastric cancer remains one of the most common malignancies worldwide, with large variations based on genetic, ethnic, geographic, and socioeconomic factors. Patients can present with nonspecific abdominal pain, weight loss, early satiety, or anemia from occult gastrointestinal bleeding. Gastric linitis plastica, a diffuse type of gastric adenocarcinoma, results in proliferation of fibrous tissue in the submucosa and muscle layers of the stomach wall. Biopsy will show classic signet ring cells or poorly differentiated tumor cells. Case Description/Methods: A 54-year-old Caucasian male with a past medical history of end stage renal disease, hypertension, type II diabetes mellitus presented to the hospital for fatigue and melena. His hemoglobin was 7.3 g/dL, which was approximately 3g lower than his most recent hospitalization two weeks prior. He underwent upper endoscopy, which revealed a well-demarcated region of severely congested, erythematous, and friable mucosa with a reticular appearance localized to the gastric cardia, fundus, and body (Figure A and B). Histopathology revealed intramucosal adenocarcinoma with high-grade signet ring features (Figure C), consistent with gastric linitis plastica. Staining for Helicobacter pylori was negative. He was treated with acid suppression. The patient had a prolonged hospital course complicated by hypoxic respiratory failure and eventual cardiac arrest resulting in his death. Discussion: We present here a case of gastric linitis plastica. This is a diffuse type of gastric adenocarcinoma that involves the deeper layers of the stomach wall, making the stomach firm and non-distensible. It is not associated with Helicobacter pylori infection. Diagnostic upper endoscopy remains the gold standard for evaluation, however such malignancies that spare the mucosa can be easily missed on endoscopy or histopathology. The lack of mucosal involvement decreases the yield of endoscopy and biopsy, and findings on computed tomography imaging of the abdomen lack specificity. Early diagnosis remains challenging, as endoscopic findings are less sensitive. Clinicians should maintain a high index of suspicion for this condition with findings of localized congested-appearing gastric mucosa, especially with distinct demarcation and regional non-distensibility of the gastric lumen. Deeper biopsies using “bite-on-bite” technique or endoscopic ultrasound guided fine needle biopsy should be considered.Figure 1.: A and B. Reticular appearance of gastric mucosa in linitis plastica. Figure C. Pathology of gastric biopsy demonstrating the classic appearance of signet ring cells in linitis plastica.

Somatic Mutational Landscape in Mexican Patients: CDH1 Mutations and chr20q13.33 Amplifications Are Associated with Diffuse-Type Gastric Adenocarcinoma.

The Hispanic population, compared with other ethnic groups, presents a more aggressive gastric cancer phenotype with higher frequency of diffuse-type gastric adenocarcinoma (GA); this could be related to the mutational landscape of GA in these patients. Using whole-exome sequencing, we sought to present the mutational landscape of GA from 50 Mexican patients who were treated at The Instituto Nacional de Cancerología from 2019 to 2020. We performed a comprehensive statistical analysis to explore the relationship of the genomic variants and clinical data such as tumor histology and presence of signet-ring cell, H. pylori, and EBV. We describe a potentially different mutational landscape between diffuse and intestinal GA in Mexican patients. Patients with intestinal-type GA tended to present a higher frequency of NOTCH1 mutations, copy number gains in cytobands 13.14, 10q23.33, and 12q25.1, and copy number losses in cytobands 7p12, 14q24.2, and 11q13.1; whereas patients with diffuse-type GA tended to present a high frequency of CDH1 mutations and CNV gains in cytobands 20q13.33 and 22q11.21. This is the first description of a mutational landscape of GA in Mexican patients to better understand tumorigenesis in Hispanic patients and lay the groundwork for discovering potential biomarkers and therapeutic targets.

Metastatic gastric adenocarcinoma to the uterine cervix—a case report and review of the literature

BackgroundPoorly differentiated diffuse-type gastric adenocarcinoma often presents at an advanced stage. While gastric cancer typically metastasizes to the liver, lung and bone, metastasis to the uterine cervix is extremely rare. To our knowledge, less than forty cases have been described in the medical literature.Case presentationWe report a case of a 47-year-old woman who presented to us with symptomatic uterine leiomyomas and subsequently underwent a successful total laparoscopic hysterectomy and bilateral salpingo-oophorectomy. The diagnosis of metastatic cancer involving the cervix was established incidentally on histopathology, which demonstrated atypical signet ring cells in the lymphovascular spaces of the cervix. Further investigations for a primary malignancy revealed a poorly differentiated diffuse-type gastric adenocarcinoma.ConclusionGastric cancer involving the uterine cervix is rare and associated with a poor prognosis. When presented with isolated cervical metastases, the gastrointestinal tract should be considered as a possible primary source. Due to the limited publications on this clinical entity, we expect to raise awareness and study this unique manifestation of gastric cancer by presenting our case.

Tumorigenic mechanisms of estrogen and Helicobacter pylori cytotoxin-associated gene A in estrogen receptor α-positive diffuse-type gastric adenocarcinoma.

Diffuse-type gastric cancer (DGC), for which Helicobacter pylori infection is a causal factor, is associated with poor prognosis among young women, possibly due to female hormones such as estrogen. We aimed to identify the carcinogenesis induced by estrogen and H. pylori in DGC. We screened and selected estrogen receptor alpha (ERα)-positive (MKN45) and ERα-negative (SNU5) DGC cell lines. H. pylori strain 60190 and its isogenic mutant strain lacking cytotoxin-associated gene A (60190ΔCagA) were used to infect MKN45 cells. And the cytotoxin-related gene A (CagA) cDNA which was cloned into pSP65-SR-HA (cagA-pSP65SRa) vector was used to transfect MKN45 cells. Tumor samples were used for DGC organoid culture. In MKN45 cells, we found that estradiol promotes epithelial-mesenchymal transition (EMT) and stemness phenotypes via HOTAIR expression. These effects were further enhanced by the addition of CagA secreted by H. pylori but were reversed by co-treatment with fulvestrant (ICI 182,780), a selective ER degrader. We also validated the effect of estrogen on DGC organoids. ERα expression was associated with tumor invasion and HOTAIR expression in DGC patients with overt H. pylori infection. These findings may explain the rapid DGC progression in young women with physiologically high levels of estrogen and suggest that fulvestrant with ovarian function suppression could serve as a tumor-suppressive agent in premenopausal patients with DGC.

Genomic landscape of a mouse model of diffuse-type gastric adenocarcinoma

BackgroundThere is a need for a model of diffuse-type gastric cancer that captures the features of the disease, facilitates the study of its mechanisms, and aids the development of potential therapies. One such model may be Cdh1 and Trp53 double conditional knockout (DCKO) mice, which have histopathological features similar to those of human diffuse-type gastric cancer. However, a genomic profile of this mouse model has yet to be completed.MethodsWhole-genome sequences of tumors from eight DCKO mice were analyzed and their molecular features were compared with those of human gastric adenocarcinoma.ResultsDCKO mice gastric cancers harbored single nucleotide variations and indel patterns comparable to those of human genomically stable gastric cancers, whereas their copy number variation fraction and ploidy were more similar to human chromosomal instability gastric cancers (perhaps due to Trp53 knockout). Copy number variations dominated changes in cancer-related genes in DCKO mice, with typical high-level amplifications observed for oncogenic drivers, e.g., Myc, Ccnd1, and Cdks, as well as gastrointestinal transcription factors, e.g., Gata4, Foxa1, and Sox9. Interestingly, frequent alterations in gastrointestinal transcription factors in DCKO mice indicated their potential role in tumorigenesis. Furthermore, mouse gastric cancer had a reproducible but smaller number of mutational signatures than human gastric cancer, including the potentially acid-related signature 17, indicating shared tumorigenic etiologies in humans and mice.ConclusionsCdh1/Trp53 DCKO mice have similar genomic features to those found in human gastric cancer; hence, this is a suitable model for further studies of diffuse-type gastric cancer mechanisms and therapies.

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.

Differential prognostic implications of gastric adenocarcinoma based on Lauren's classification: a Surveillance, Epidemiology, and End Results (SEER)-based cohort study.

BackgroundOur study aims to analyze the association between Lauren’s classification and gastric adenocarcinoma prognosis using comprehensive statistical analyses.MethodsAccording to the selection criteria, patients were included from the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate Cox regression, propensity score matching, and a multivariate competing risk model were used to investigate the association between Lauren’s classification and prognosis. Subgroup analysis was used to investigate the role of confounding factors on the association between Lauren types and prognosis.ResultsAfter exclusion, a total of 20,218 patients from the SEER database were included, with 14,374 intestinal types and 5,844 diffuse types. The univariate Cox regression analysis revealed that the diffuse type had a poorer cancer-specific survival (CSS) rate [hazard ratio (HR), 1.44; 95% confidence interval (CI), 1.38–1.50]. After adjusting for confounding variables, the diffuse type also showed a higher risk of cancer-specific death (HR, 1.20; 95% CI, 1.15–1.20). Sensitivity analysis showed that after propensity score matching, the diffuse type had a poorer CSS rate (HR, 1.23; 95% CI, 1.10–1.36), and the competing risk model further validated these results [subdistribution HR (SHR), 1.32; 95% CI, 1.23–1.41]. Moreover, subgroup analysis demonstrated stable results in the subgroups, except for patients with T1 stage (HR, 1.06; 95% CI, 0.87–1.28) and a tumor size <2 cm (HR, 1.00; 95% CI, 0.83–1.21).ConclusionsDiffuse-type gastric adenocarcinoma had an overall poorer prognosis compared to the intestinal type. However, in patients with T1 stage and tumor size <2 cm, the diffuse type had a comparable survival rate with the intestinal type.

Preoperatively Treated Diffuse-Type Gastric Adenocarcinoma: Glucose vs. Other Energy Sources Substantially Influence Prognosis and Therapy Response.

Simple SummaryThe diffuse type of gastric adenocarcinoma (dGAC) generally confers a poor prognosis compared to intestinal type. Some dGACs are not avid on fluorine-18 fluoro-2-deoxy-D-glucose PET (FDG-PET) while others seem to consume glucose avidly. We analyzed the outcomes based on the avidity of the primary on baseline FDG-PET. Our data suggest that if dGACs used glucose as an energy source then the prognosis was very poor while non-glucose sources improved prognosis. Multi-platform (including metabolomics) profiling of dGACs would yield useful biologic understanding.Diffuse type of gastric adenocarcinoma (dGAC) generally confers a poor prognosis compared to intestinal type. Some dGACs are not avid on fluorine-18 fluoro-2-deoxy-D-glucose PET (FDG-PET) while others seem to consume glucose avidly. We analyzed the outcomes based on the avidity (high with standardized uptake value (SUV) > 3.5 or low with SUV ≤ 3.5) of the primary on baseline FDG-PET. We retrospectively selected 111 localized dGAC patients who had baseline FDG-PET (all were treated with preoperative chemotherapy and chemoradiation). FDG-PET avidity was compared with overall survival (OS) and response to therapy. The mean age was 59.4 years and with many females (47.7%). The high-SUV group (58 (52.3%) patients) and the low-SUV group (53 (47.7%) patients) were equally divided. While the median OS for all patients was 49.5 months (95% CI: 38.5–98.8 months), it was 98.0 months (95% CI: 49.5–NE months) for the low-SUV group and 36.0 months for the high-SUV (p = 0.003). While the median DFS for all patients was 38.2 months (95% CI: 27.7–97.6 months), it was 98.0 (95% CI: 36.9–NE months) months for the low-SUV group was and only 27.0 months (95% CI: 15.2–63.2 months) for the high-SUV group (p = 0.005). Clinical responses before surgery were more common in the low-SUV group but overall we observed only 4 pathologic complete responses in 111 patients. Our unique data suggest that if dGACs used glucose as an energy source then the prognosis was very poor while non-glucose sources improved prognosis. Multi-platform (including metabolomics) profiling of dGACs would yield useful biologic understanding.

Localized diffuse-type gastric adenocarcinoma: Influence of baseline positron emission tomography on survival and therapy response.

176 Background: Diffuse type of gastric adenocarcinoma (dGAC) confers a poor but variable prognosis compared to intestinal type of GAC. The value of baseline uptake of FDG-PET in localized dGAC is unclear and ~40% are not FDG-PET avid. We analyzed outcomes based on the avidity (high with SUV &gt; 3.5 or low with SUV ≤3.5) of the primary on baseline FDG-PET. Methods: We retrospectively selected 111 localized dGAC cases who had baseline FDG-PET for staging. We compared the FDG-PET avidity with overall survival (OS) and response to preoperative therapy. Standard statistical methods were utilized. Results: The mean age was 59.4 years and with many female patients (47.7%). All patients had dGAC. The high-SUV group (58 [52.3%] patients) and the low-SUV group (53 [47.7%] patients) were equally divided. While the median OS for all patients was 49.5 months (95% CI: 38.5 – 98.8 months), it was 98.0 months for the low-SUV group and 36.0 months for the high-SUV ( p value = 0.003). While the median PFS for all patients was 38.2 months (95%CI: 27.7 – 97.6 months), it was 98.0 months for the low-SUV group was and 27.0 months for the high-SUV group ( p value = 0.005). Clinical responses before surgery were more common in the low-SUV group but there were only 4 patients with pathologic complete response in the entire cohort. Conclusions: Our unique data suggest that localized dGAC patients with low SUV fare better than those with high SUV meaning highly metabolic GACs consuming glucose confer poor prognosis and overall all dGACs seem resistant to therapy.

Anti-fibrotic properties of an adiponectin paralog protein, C1q/TNF-related protein 6 (CTRP6), in diffuse gastric adenocarcinoma.

Patients with advanced gastric cancer, especially diffuse-type gastric cancer, which is often accompanied by stromal fibrosis, commonly exhibit a poor prognosis. This study was designed to unravel the potential roles of C1q/TNF-related protein 6 (CTRP6) in the fibrotic cancer microenvironment of diffuse-type gastric adenocarcinoma. A total of 49 diffuse-type gastric cancer samples were evaluated in this study, and 23 of these samples exhibited focal CTRP6 immunoreactivity. CTRP6 immunoreactivity was found to be correlated with favorable survival outcomes, in terms of both overall and relapse-free survival rates, but this trend did not reach significance (P = 0.15). By contrast, CTRP6 immunoreactivity was significantly correlated with relapse-free survival rates in patients with diffuse-type gastric cancer at a distal site (P = 0.028). Notably, most gastric cancer cells at the cancer invasive front were CTRP6 negative, especially in areas of robust fibrosis. Double immunohistochemical staining demonstrated an inverse expression profile for CTRP6 and the activated fibroblast marker alpha smooth muscle actin (α-sma) in stromal and gastric cancer cells at the cancer invasion front. The addition of recombinant CTRP6 protein attenuated the TGF-β-induced α-sma expression in cultured human fibroblasts but did not alter the proliferation rate or Matrigel-invasion activity of the cultured gastric cancer cells. In addition, CTRP6 did not affect the viability of normal human gastric epithelial cells. This study suggests that CTRP6 may have potential application in combating stromal fibrosis in diffuse-type gastric cancers.

Metastatic pattern in esophageal and gastric cancer: Influenced by site and histology.

BACKGROUNDDetailed information on metastatic patterns in of patients with esophageal and gastric cancer is limited. Early recognition of metastases is important to avoid futile locoregional treatments. Furthermore, knowledge on metastatic patterns is necessary for further development of personalized treatment modalities.AIMTo gain insight into the metastatic pattern of gastroesophageal cancer. METHODSA nationwide retrospective autopsy study of 3876 patients with adenocarcinoma (AC) or squamous cell carcinoma (SCC) of the esophagus or stomach between 1990 and 2017 was performed. Only patient with metastases were included for analysis. The metastatic pattern was analyzed according to the primary tumor location and histological subtype. RESULTSMetastatic disease was found in 268 esophageal and 331 gastric cancer patients. In esophageal cancer, the most common metastatic locations were liver (56%), distant lymph nodes (53%) and lung (50%). Esophageal AC showed more frequently metastases to the peritoneum and bone compared with esophageal SCC. In gastric cancer, the most common metastatic locations were distant lymph nodes (56%), liver (53%) and peritoneum (51%). Intestinal-type AC of the stomach showed metastases to the liver more frequently, whereas metastases to the bone, female reproductive organs and colorectum were observed more frequently in diffuse-type gastric AC.CONCLUSIONThis study showed differences in metastatic patterns of patients with esophageal and gastric cancer according to the primary tumor location and histological subtype.

Unusual Skin Metastasis from Gastric Cancer: A Case Report

Background: Skin metastasis from gastric cancer are relatively rare, but they have important clinical significance because they usually indicate a worse prognosis. Skin metastasis from gastric cancer may spread through lymphatic ducts, blood vessels in the ligamentum teres, contiguous extension, or embryologic remnants of the umbilicus. Purpose: To report an unusual skin metastasis from gastric cancer that clinically resembles as a benign lesion of skin papules. Case: A rare metastasis from gastric cancer origin in a 61-year-old male in the abdominal skin. Gastric cancer metastasis in an unusual site such as the abdominal skin often resembles as dermatitis, especially in the early course of metastatic spreading, which looked like common papules on the skin. Discussion: In the beginning, the skin papules were not suspected to be a metastatic process because there was no palpable or no tenderness in the subcutan or fascia underneath. The appearance resembled common dermatitis. However, as papules rapidly spread to the surrounding skin, the malignancy was then suspected. The incisional biopsy from the papules was performed and showed that it was metastatic diffuse-type gastric adenocarcinoma. Conclusion: The skin metastasis was different from general nodules, but rather as skin papules of general dermatitis in initial appearance. The surgeon and dermatologist should be alert if they find any benign appearance of a skin lesion on the abdominal wall in a patient with a history of gastric cancer surgery.

The Metastatic Pattern of Intestinal and Diffuse Type Gastric Adenocarcinoma – A Dutch National Cohort Study.

Background: The Laurén classification of gastric adenocarcinoma was introduced in 1965 and is still widely used in clinical care. The classification involves three histological subtypes, the intestinal type, the diffuse type and a combination of the two, the mixed type. The subtypes differ in epidemiology, tumour biology and patients’ survival. Studies on the metastatic pattern of gastric adenocarcinoma by histological subtype according to Laurén are missing.

Inverse association of Helicobacter pylori cagPAI genotypes with risk of cardia and non-cardia gastric adenocarcinoma.

Iran is a high‐risk country for cardia gastric adenocarcinoma (CGA) in Central Asia, with an incidence rate five times the average global rate, and shows a high infection rate for Helicobacter pylori (69%). The aim was to examine the associations of multiple H. pylori cagPAI genotypes (ie cagH, cagL, cagG, and orf17) with the risk of CGA, non‐CGA, and different histological types of GA in Iran. A large number of H. pylori strains (N = 336) were successfully cultured and genotyped. Histopathological evaluations were performed. The analysis showed an inverse association between the cagH+ genotype and the risk of CGA and intestinal‐type gastric adenocarcinoma (IGA) (adjusted ORs; 0.312 and 0.283, respectively), where the controls were nontumors. The orf17 + genotype decreased the risk of non‐CGA and diffuse‐type gastric adenocarcinoma (DGA)(adjusted ORs; 0.310 and 0.356, respectively). When the controls were those with nonatrophic gastritis, the cagG + genotype was negatively associated with the risk of CGA, non‐CGA, IGA, and DGA (adjusted ORs; 0.324, 0.366, 0.306, and 0.303, respectively). We did not find such a significant association for the cagL+ genotype in multiple logistic regression analysis. Combination of the vacA c2 and cagPAI genotypes further decreased the risk estimates for GAs. This study showed the reverse association of H. pylori cagPAI genotypes—cagH + and cagG +—with the risk of CGA in male patients aged ≥ 55 in Iran. Presence of the vacA c2 genotype in combination with cagPAI genotypes showed strong inverse associations with the risk of CGA and non‐CGA. These findings may reveal a coordinated relationship between the vacA c2 and cagPAI genotypes.

Differential gene expression in growth factors, epithelial mesenchymal transition and chemotaxis in the diffuse type compared with the intestinal type of gastric cancer.

Gastric cancer (GC) is a highly heterogeneous disease and one of the major causes of cancer-related mortality worldwide. Diffuse-type gastric adenocarcinoma (or poorly cohesive- with independent cells) is characterized by aggressive behavior (rapid invasion, chemoresistance and peritoneal metastasis), as compared with intestinal-subtype adenocarcinoma. Diffuse subtype GC additionally has a substantially increasing incidence rate in Europe and the USA, and was often associated with younger age. Our objective was to analyze the expression and clinical significance of genes involved in several signaling pathways in diffuse-type GC. Tumors samples and non-malignant gastric tissues were obtained from patients with GC (diffuse-type and intestinal-subtype adenocarcinoma). The expression of 33 genes coding for proteins involved in four categories, growth factors and receptors, epithelial-mesenchymal transition, cell proliferation and migration, and angiogenesis was determined by reverse transcription-quantitative polymerase chain reaction. The expression of 22 genes was significantly upregulated in diffuse-type GC and two were downregulated (including CDH1) compared with normal tissues. Among these genes, acompared with intestinal-subtype adenocarcinoma, diffuse-type GC revealed elevated levels of IGF1 and IGF1R, FGF7 and FGFR1, ZEB2, CXCR4, CXCL12 and RHOA, and decreased levels of CDH1, MMP9 and MKI67. The expression of selected genes was compared with other genes and according to clinical parameters. Furthermore, TGF-β expression was significantly increased in linitis, a sub-population of diffusely infiltrating type associated with extensive fibrosis and tumor invasion. Our study identified new target genes (IGF1, FGF7, CXCR4, TG-β and ZEB2) whose expression is associated with aggressive phenotype of diffuse-type GC.

S-1 plus oxaliplatin versus S-1 plus cisplatin as first-line treatment for advanced diffuse-type or mixed-type gastric/gastroesophageal junction adenocarcinoma: A randomized, phase 3 trial.

4017 Background: Diffuse-type or mixed-type gastric adenocarcinoma is associated with poor prognosis, and more effective treatment is needed. In Asia, S-1 plus cisplatin (SP) is the standard first-line chemotherapy regimen for advanced gastric cancer. Nevertheless, some clinical data suggested that oxaliplatin-based chemotherapy might be more efficacious and more tolerant than cisplatin-based chemotherapy. Methods: This trial is a multicenter, randomized, parallel-group, open-label, phase 3 trial in China. Patients aged 18-75 years, with PS 0-2, adequate organ function, histology confirmed, unresectable, advanced diffuse-type or mixed-type gastric adenocarcinoma/GEJA were randomized 1:1 to S-1 plus oxaliplatin group (SOX) (S-1: 40-60mg bid on d1-14, q3w; oxaliplatin: 130 mg/m2 on d1, q3w) or SP group (S-1: 40-60mg bid on d1-14, q3w; cisplatin: 60 mg/m2 d1, q3w). The primary endpoint was overall survival (OS) in the full analysis set (FAS). The secondary endpoints were progression-free survival (PFS), time to treatment failure (TTF) and safety. Results: Between Jul 2013 and Jul 2018, 576 patients were randomized and 558 initiated treatment (279 patients/group). The median number of chemotherapy cycles was four in each group. In the FAS, the SOX group showed improved OS (13.0 vs. 11.8 months, HR = 0.764, 95% CI: 0.636-0.918), PFS (5.7 vs. 4.9 months, HR = 0.752, 95%CI: 0.632-0.895), and TTF (5.2 vs. 4.7 months, HR = 0.763, 95%CI: 0.641-0.909) compared with the SP group. In terms of grade≥3 adverse events, SOX showed lower occurrences of neutropenia (10.0% vs. 22.9%), leukopenia (9.7% vs. 21.9%), anemia (4.3% vs. 14.3%),vomiting (3.9% vs. 10.4%), nausea (2.2% vs. 10.4%), anorexia (2.2% vs. 6.8%), and febrile neutropenia (2.5% vs. 6.8%) than SP (all P &lt; 0.05). The occurrence of grade≤2 sensory neuropathy(41.6% vs. 12.2%, P &lt; 0.001)was higher with SOX than with SP. Conclusion: Compared with SP, SOX was more effective and less toxic (except neurosensory toxicity ) in patients with previously untreated advanced diffuse-type or mixed-type gastric adenocarcinoma/GEJA. Clinical trial information: NCT01824459.