Invasive Gastric Adenocarcinoma Research Articles

Abstract 4407: Simultaneous spatial epigenomic and transcriptomic analysis of gastric adenocarcinoma reveals regulatory patterns governing tumor and microenvironment architecture at the cellular level

Abstract Recent advances in spatial transcriptomics and spatial proteomics have enabled increasingly complex questions on the nature of gene regulation and expression in cellular subtypes in tumor tissue and the tumor microenvironment. However, most spatial omics techniques do not profile the epigenomic landscape responsible for downstream gene expression. Furthermore, current spatial technologies have yet to profile the epigenome and transcriptome simultaneously, and thus it remains a challenge to correlate multi-omics data across sections of extremely heterogenous tumor tissue. Recently, co-profiling of spatial epigenomics and transcriptomics using principles of Deterministic Barcoding in Tissue for spatial omics sequencing (DBiT-seq) has been demonstrated on normal brain tissue. Joint spatial profiling of chromatin states and whole transcriptome in tissue allows for parallel characterization of gene regulation programs across all cell types, while preserving the tissue architecture for greater understanding of the cellular environment. Here we present the first application of spatial ATAC-seq and spatial transcriptomics on the same tissue section to characterize the tumor microenvironment of an invasive gastric adenocarcinoma (GAC) and adjacent normal tissue. GAC is the fifth most common cancer and commonly exhibits mutations in epigenetic modifiers, including ARID1A and MLL1-4. Distinct spatial clusters representing different cell subtypes were identified via both spatial chromatin accessibility and spatial transcriptomics. Spatial ATAC-seq profiling of accessible regulatory elements correlated well with RNA expression of target genes. Spatial patterns of transcription factor motif accessibility also correlated well with the observed transcriptional program of tumor tissue. When compared to adjacent normal tissue, spatial co-profiling of chromatin accessibility and the transcriptome revealed that the epigenetic landscape is significantly altered in tumorigenesis of GAC. Future work will focus on development of co-profiling of histone modifications and the transcriptome to enable the study of another layer of the epigenomic landscape, especially as targeting epigenetic modifiers such as EZH2 has been identified as a potential therapeutic strategy in GACs. Overall, we present a solution to profile multiple layers of gene regulation and expression with spatial context, which can be applied to most tumor types for better understanding of tumorigenesis and the consequences of new targeted therapies. Citation Format: Katelyn J. Noronha, Jennifer M. Garbarino, Daniel Massucci, Abigail R. Tyree, Colin Ng. Simultaneous spatial epigenomic and transcriptomic analysis of gastric adenocarcinoma reveals regulatory patterns governing tumor and microenvironment architecture at the cellular level [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4407.

Tumor regression grade after neoadjuvant chemotherapy in patients with locally advanced gastric cancer treated with modern chemotherapy (FLOT): Experience in patients in Guatemala.

287 Background: Perioperative chemotherapy is the standard of care for locally advanced gastric cancers in Western populations. At this moment perioperative chemotherapy with FLOT (Fluorouracil, leucovorin, oxaliplatin and docetaxel) regimen is recommended in patients who are medically fit with benefit in progression-free survival (PFS) and overall survival (OS). However, the impact of response to this treatment is not well established. The objective of this study is to find the pathological response to FLOT chemotherapy measured by the degree of tumor regression (TRG), the benefit on disease-free survival (DFS) and OS, in patients with gastric cancer locally advanced treated with FLOT chemotherapy. Methods: Patients from the Instituto Guatemalteco de Seguridad Social (IGSS) from Guatemala City, who underwent radical gastrectomy for non-metastatic invasive gastric adenocarcinoma after perioperative chemotherapy (T1-4/N0/N+cM0) from 2019 to 2023 were included. Demographic data, clinical staging, histologic phenotype, surgical factors, tumor regression grade after gastrectomy and survival outcomes were included. The association between ORR and OS were evaluated. OS and DFS were estimated using the Kaplan Meier method with adjustment for covariates using Cox regression. Results: Thirty-eight patients with locally advanced cancer gastric were identified. The median age was 58 years (29-79), most of the patients were men (23, 61%), 35 (92%) patients have primary gastric tumor, 26 (68%) has cT3/T4 tumors and 22 (58%) has intestinal gastric cancer, all patients underwent to surgery. Two patients (6%) had TRG of 1 (complete and almost complete), 8 patients (21%) had an TGR of 2, and 28 patients (74%) had an TGR of 3; 13 patients (38%) developed recurrence, median DFS was 5.2 months (95% CI: 1.0–28). The median OS was 15.3 months (95% CI: 3.0-45). Lack of tumor regression (TRG 3) was significantly associated with lower survival HR 1.42 (1.05-2.24) p= 0.008. Clinical T4 tumors and diffuse histology were associated with poor prognostic (cT4 HR 3.04, p = 0.038, diffuse histology HR 2.08 (p = 0.001) (Table). Conclusions: Since cT4 tumors are an independent risk factor associated with poor prognostic HR 3.04, p = 0.038, it is important to make an adequate clinical staging before deciding to use three-drug treatment regimens of chemotherapy. Other factors in addition to clinical ones should be investigated, such as molecular factors that may be related to this poor response and survival in patients with cT4. This study of molecular factors is currently underway at our institution. [Table: see text]

S4117 Beyond the "Pale": Invasive Gastric Adenocarcinoma Hiding in Plain Sight

S4117 Beyond the "Pale": Invasive Gastric Adenocarcinoma Hiding in Plain Sight

METTL3-mediated downregulation of splicing factor SRSF11 is associated with carcinogenesis and poor survival of cancer patients.

N6-methyladenosine (m6A) is one of the most abundant post-transcriptional modifications in eukaryotic RNA. As m6A modifications play an important role in RNA processing, abnormal m6A regulation caused by aberrant expression of m6A regulators is closely related to carcinogenesis. In this study, we aimed to determine the role of METTL3 expression in carcinogenesis, regulation of splicing factor expression by METTL3, and their effects in survival period and cancer-related metabolisms. We investigated the correlation between each splicing factor and METTL3 in breast invasive ductal carcinoma (BRCA), colon adenocarcinoma (COAD), lung adenocarcinoma (LUAD) and gastric adenocarcinoma (STAD). Survival analysis was performed based on the expression of each splicing factor. To determine the molecular mechanism of SRSF11 in carcinogenesis, gene set enrichment analysis using RNA sequencing data was performed according to SRSF11 expression. Among the 64 splicing factors used for correlation analysis, 13 splicing factors showed a positive correlation with METTL3 in all four cancer types. We found that when METTL3 expression was decreased, the expression of SRSF11 was also decreased in all four types of cancer tissue when compared to that in normal tissue. Decreased SRSF11 expression was associated with poor survival in patients with BRCA, COAD, LUAD, and STAD. Gene set enrichment analysis according to SRSF11 expression showed that the p53/apoptosis, inflammation/immune response, and ultraviolet/reactive oxygen species stimulus-response pathways were enriched in cancers with decreased SRSF11 expression. These results suggest that METTL3 regulates SRSF11 expression, which could influence mRNA splicing in m6A modified cancer cells. METTL3-mediated downregulation of SRSF11 expression in cancer patients correlates with poor prognosis.

Two Cases of Duodenal Neuroendocrine (Carcinoid) Tumor Concurrent with Invasive Gastric Adenocarcinoma and Pancreatic Intraductal Papillary Mucinous Neoplasm

Abstract Introduction/Objective Neuroendocrine (carcinoid) tumors of the duodenum are extremely rare and account for only 2-4% of gastrointestinal tract neuroendocrine tumors. We report two cases of incidentally discovered duodenal neuroendocrine tumor which respectively occurred in a patient with invasive gastric adenocarcinoma and in a patient with pancreatic intraductal papillary mucinous neoplasm (IPMN). Methods/Case Report The first case involved a 60-year old male who presented with melena and symptomatic anemia and was found on EGD to have a large circumferential mass at the gastric antrum/pylorus, which was revealed to be an invasive gastric adenocarcinoma on biopsy. At the time of distal gastrectomy for this malignancy, a concurrent, 0.6 cm-sized, low grade neuroendocrine tumor was incidentally discovered at the duodenal margin. The duodenal tumor consisted of nests and trabeculae of monotonous cells with ovoid/round nuclei, finely speckled “salt and pepper” chromatin, and low mitotic rate (< 2 mitoses/2 mm2), and invaded only into submucosa. The tumor cells were strongly and diffusely positive for neuroendocrine markers chromogranin, synaptophysin, and CD56, positive for CK7 and CDX2, negative for CK20, and with low Ki67 proliferation index (< 3%). The second case involved a 69-year old female who presented with epigastric pain and was found on abdominal CT to have a 4 cm-sized cystic mass in the pancreatic head. While biopsy of the pancreatic mass revealed an IPMN, a separate biopsy of an incidentally discovered, 1 cm-deep ulcer in the duodenum bulb revealed a low-grade neuroendocrine tumor with similar morphologic features, mitotic rate, and immunohistochemical staining pattern as the prior case while also negative for IMP3 stain. The patient had normal serum gastrin and urine HIAA levels, but elevated serum chromogranin-A levels. Results (if a Case Study enter NA) NA. Conclusion Duodenal carcinoids are rare (1-3% of primary duodenal tumors) and are mostly non-functional and unifocal. The duodenum is also the least common site (2-4%) for GI tract neuroendocrine tumors. The pathophysiology of these tumors is still poorly understood, with the majority occurring sporadically and a minority in the setting of hereditary cancer syndromes. This report documents two very rare instances of duodenal neuroendocrine tumor incidentally discovered with invasive gastric adenocarcinoma and pancreatic IPMN.

An Umbilical Mass in a Young Female

Question: A 38-year-old woman with a past medical history of invasive signet ring cell gastric adenocarcinoma, status post total gastrectomy, presented with a newly swollen and painful umbilical mass. She completed 6 cycles of adjuvant chemotherapy (FOLFOX) followed by radiotherapy, that has been stable on imaging for two years. On physical examination, it is an erythematous, firm, and tender umbilical mass that is not reducible on examination (Figure A).

Tumor regression grade and overall survival following gastrectomy with neoadjuvant therapy for gastric cancer.

355 Background: Perioperative chemotherapy is the standard of care for locoregional gastric cancers in western populations. However, the impact of response to therapy as a biomarker of cancer survival has not been fully defined. This study focuses on the pathological response to neoadjuvant chemotherapy, as measured by tumor regression grade (TRG), for gastric cancer and its impact on patient outcomes, primarily overall survival. Methods: Patients undergoing gastrectomy for nonmetastatic invasive gastric adenocarcinoma following perioperative chemotherapy (clinical T2+/N+cM0) were identified from an institutional database (2000-2021). Demographics, clinical staging including histologic grade, surgical factors and survival outcomes were included. The association between TRG and overall survival from time of surgery was assessed. OS was estimated using the Kaplan Meier method with adjustment for covariates using Cox regression. Results: One hundred seventeen patients were identified. Median age was 65 years (IQR 57–73). The majority of the patients were male (n = 64, 55%). Seventy-six patients underwent total gastrectomy, 22 subtotal gastrectomy, and 19 distal gastrectomy. Six patients (5.1%) had a TRG of 0, 18 patients (15.4%) had a TRG of 1, 25 patients (21.4%) had a TRG of 2, and 68 patients (58.1%) had a TRG of 3. Median survival overall was 40.9 months (95% CI 28.7–66.4). TRG status was not significantly different between chemotherapy regimens (doublet vs triplet, p = 0.96). Median survival was longest in the TRG 0 group (86.9 months), followed sequentially by TRG 1 (74.5 months), TRG 2 (51.5 months), and lastly, TRG 3 group with 27.0 months. Increased tumor regression (lower TRG) was significantly associated with prolonged survival (p < 0.01 by log-rank for trend). After adjustment for clinical patient factors and tumor factors, TRG remained significantly associated with overall survival (Table; TRG hazard ratio 1.62, p = 0.007). In addition to TRG status, clinical T4 tumors and diffuse histology were associated with poor survival (cT4 hazard ratio 2.09, p = 0.039, diffuse histology hazard ratio 1.82 (p = 0.071). Conclusions: In patients receiving perioperative chemotherapy for treatment of gastric cancer, response to therapy as defined by TRG is independently prognostic of survival.[Table: see text]

364 IMPACT ON SURGICAL AND ONCOLOGIC OUTCOMES OF NEOADJUVANT CHEMOTHERAPY VERSUS SURGERY ALONE IN ELDERLY PATIENTS WITH LOCALLY INVASIVE GASTROESOPHAGEAL CANCER

Abstract Neoadjuvant chemotherapy (nCT) has an increasingly important role in the treatment of locally invasive gastric and esophageal adenocarcinoma. However, its outcomes have not been examined in cohorts of exclusively elderly patients who may not experience the same benefits as younger patients and are more vulnerable to adverse events from the treatment. The purpose of this study is to determine the impact of nCT on outcomes among elderly patients with gastric and gastroesophageal adenocarcinoma. Methods All patients who underwent curative-intent surgery for gastric and gastroesophageal adenocarcinoma between 2010 and 2018 at a high-volume multidisciplinary referral center were identified from a prospectively collected database. Early stage tumours at diagnosis (T1N0 or T2N0) and emergency resections were excluded. Patient characteristics, surgical outcomes and oncologic outcomes were verified by chart review and death dates verified using provincial registry data. Comparison was made for all variables between patients who were treated with nCT and those who were treated with surgery alone (SA). Subgroup analysis among patients aged 70+ was conducted to determine differences in outcomes among elderly patients. Results Of 766 cases in the database, 354 met inclusion criteria (SA: 99 vs nCT: 255). Of those who received nCT, 77 (30.3%) were ≥ 70 years of age. When compared to younger patients, this cohort experienced significantly more high-grade toxicity from chemotherapy (<70: 32 (18.1%); 70+: 25 (32.5%); p = 0.017), but completion rates and timely progression to surgery were similar between groups (Table 1). Multivariate analysis among elderly patients showed that patients who had nCT had similar overall survival (HR 1.04, 95% CI 0.35-1.19) and disease-free survival (HR 1.04, 95% CI 0.41-1.36) to those who were treated with SA. Conclusion Neoadjuvant chemotherapy administered to elderly patients with locally advanced gastroesophaeal adenocarcinoma results in higher rates of high-grade toxicity with no difference in long term oncologic outcomes when compared to surgery alone. Consideration should be given to upfront surgery for elderly patients with resectable gastric and gastroesophageal tumours at presentation.

Insufficient lymph node assessment in gastric adenocarcinoma

BackgroundThis study aimed to investigate the sufficient (≥ 16) lymph node assessment in 449 patients with gastric adenocarcinoma and literature review.MethodsFour hundred and forty-nine patients with pathologically confirmed locoregional invasive gastric adenocarcinoma from 2004 to 2013 were included. A standard surgical resection was performed for all the patients with (n = 16) or without (n = 433) neoadjuvant treatment.ResultsIn this study, 301 men and 148 women with a median age of 58 (range 21–88) years were included. The median total numbers of examined lymph nodes were 9 (range 0–55). Ninety-five patients (21.2%) had adequate (≥ 16) lymph node examination, and 70 patients (15.6%) had no examined lymph nodes. In univariate analysis, total or near total gastrectomy (P < 0.001), advanced node stage (P < 0.001), primary tumor size > 6 cm (P < 0.001), and the presence of perineural invasion (P = 0.039) were associated with more average number of examined lymph nodes. On multivariate analysis, node stage (P < 0.001) and type of surgery (P = 0.008) were independent predictive factors.ConclusionIn this study, approximately one in five patients with gastric adenocarcinoma had sufficient lymph node assessment. More studies are suggested for identifying a true inadequate lymph node dissection from insufficient lymph node assessment.

2679 An Unusual Presentation of Invasive Gastric Adenocarcinoma

INTRODUCTION: Gastric cancer rarely occurs before the age of 40, but it’s incidence rises thereafter and peaks in the seventh decade of life. Most patients with gastric cancer in the United States are symptomatic and already have advanced disease at the time of presentation. We present a case where neither the patient history nor physical exam provided any early indication to the diagnosis of gastric adenocarcinoma. CASE DESCRIPTION/METHODS: A 32-year old Jamaican female was admitted for right lower quadrant abdominal pain since five days. Pain was constant, sharp, radiating from the pelvis to lower back. Review of systems was positive for dyspnea on exertion and 35-pound weight loss over past 3 months. She denied any past medical or surgical history, alcohol and tobacco use. Family history was significant for breast cancer in an aunt. On physical exam patient was afebrile, blood pressure and pulse were 120/76 mmhg and 86/min respectively. She had right lower quadrant tenderness on deep palpation but rest of the physical exam was unremarkable. CT thorax, abdomen and pelvis was negative for PE but demonstrated mediastinal, hilar, retroperitoneal and mesenteric lymphadenopathy. Infectious and autoimmune workup were unremarkable. Endoscopic intervention revealed a 7 cm ulcerated friable gastric mass near the pylorus and internal hemorrhoids on colonoscopy. Biopsy of the mass revealed poorly differentiated gastric adenocarcinoma. Hospital course was complicated with pericardial tamponade. Pericardial biopsy revealed metastatic poorly differentiated carcinoma. Patient was not a candidate for chemotherapy as she was spiking fevers on antibiotics. After over a month long hospital course, patient succumbed to multi-organ dysfunction related to her malignancy. DISCUSSION: Greater than 50% of patients present with unresectable locally advanced or metastatic gastric adenocarcinoma. The American Society for Gastrointestinal Endoscopy recommends endoscopic surveillance for high-risk individuals. Mass endoscopic/radiologic screening is not recommended in United states. Patients with advanced stage IV disease as in our patient, are usually referred for palliative therapy depending on their functional status. Our case illustrates an unusual presentation of a primary gastric mass, however with careful history, physical examination and timely endoscopic intervention, we can possibly prevent the significant delay in diagnosis and allow for timely management of gastric adenocarcinoma.

Gastric adenocarcinoma and proximal polyposis of the stomach: diagnosis and clinical perspectives.

Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) is a recently described, rare gastric polyposis syndrome. It is characterized by extensive involvement of the fundus and body of the stomach with fundic gland polyps sparing the antrum and lesser curvature, an autosomal dominant inheritance pattern with incomplete penetrance, and a significant predisposition for the development of gastric adenocarcinoma. Due to the recent discovery of APC promotor IB mutations (c.-191T>C, c.-192A>G, and c.-195A>C), which reduce binding of the transcription factor Yin Yang 1 (YY1) and transcriptional activity of the promotor, as its underlying genetic perturbation, GAPPS has been added to the growing molecular class of APC-associated disorders. Recent reports on family members afflicted by gastric polyposis due to GAPPS have described the development of metastatic cancer or the presence of invasive gastric adenocarcinoma in total gastrectomy specimens after variable periods of endoscopic surveillance emphasizing the need for an improved understanding of the to-date poorly characterized natural history of the syndrome. There are, however, currently no guidelines on screening, timing of prophylactic gastrectomy, or endoscopic surveillance for GAPPS available. In this review, we summarize the clinical, pathological, and genetic aspects of GAPPS as well as management approaches to this rare cancer predisposition syndrome, highlighting the need for early recognition, a multidisciplinary approach, and the creation of prospective family registries and consensus guidelines in the near future.

Clinicopathologic score predicting lymph node metastasis in T1 gastric cancer

BackgroundAlthough gastrectomy with adequate regional nodal examination is considered the standard of care for invasive gastric adenocarcinoma, endoscopic resection has been adopted increasingly in select patients with T1 gastric cancer. The objective of this study was to identify preoperative predictors of lymph node metastasis in patients in the United States with T1 gastric cancer. MethodsPatients who underwent operative resection for T1 gastric cancer between 2000 and 2012 were identified from a multi-institutional database. Clinicopathologic predictors of lymph node metastasis were determined using univariate and multivariate logistic regression. A preoperative score was created, assigning points based on each variable's regression coefficient. ResultsAmong 835 patients with gastric cancer undergoing curative-intent surgical resection, 176 patients (20.5%) had T1 disease confirmed on final pathology. Of those, 38 patients (22%) had lymph node metastasis. Independent predictors of lymph node involvement on multivariate analysis were poor differentiation, T1b stage, lymphovascular invasion, and tumor size >2 cm. A clinicopathologic risk score composed of these 4 variables was created. Receiver operating curve analysis showed excellent discrimination (area under the curve = 0.79) and 100% sensitivity in detecting lymph node metastasis when only one of the aforementioned factors was present. ConclusionsIn this cohort of U.S. patients with T1 gastric adenocarcinoma, the lack of lymph node involvement could be predicted by the absence of several unfavorable factors, including T stage, poor differentiation, lymphovascular invasion, and size >2 cm.

A case of small invasive gastric cancer arising from Helicobacter pylori-negative gastric mucosa: Fundic gland-type adenocarcinoma.

This study showed that we need to bear in mind the possibility of gastric adenocarcinoma of the fundic gland type upon encounter with such elevated lesions originating from Helicobacter pylori (H. pylori)-negative gastric mucosa. We believe that our study makes a significant contribution to the literature because small invasive gastric adenocarcinoma of the fundic gland type is a rare disease entity, which exhibits a submucosal tumor-like or superficial flat-type elevated lesion on H. pylori-negative gastric mucosa in the endoscopic examinations.

Comparative immunohistochemical characteristic of expression levels of Ki-67, p53, caspase 3 in non-invasive and invasive intestinal-type gastric adenocarcinoma

Aim. Comparison analysis of expression levels of Ki-67, p53, and caspase 3 was performed between the tumor cells and the stromal cells of non-invasive intestinal-type gastric adenocarcinoma on the one hand and the tumor cells and the stromal cells of invasive intestinal-type gastric adenocarcinoma on the other hand.Materials and methods. For this purpose, pathohistological and immunohistochemical studies were used. The surgical material of 10 patients with non-invasive (pTis, pT1) intestinal-type gastric adenocarcinoma and 10 patients with invasive (pT2, pT3, pT4) intestinal-type gastric adenocarcinoma were analyzed.Results. It was established that intestinal-type gastric adenocarcinoma is characterized by the medium Ki-67 labeling index, the low expression level of p53, the low expression level of caspase 3 in the tumor cells, and also the low Ki-67 labeling index and the extremely low expression level of caspase 3 in the stromal cells. The tumor cells of invasive intestinal-type gastric adenocarcinoma are characterized by the 2 times higher expression level of p53, than the tumor cells of non-invasive intestinal-type gastric adenocarcinoma. Moreover, direct correlation between the medium Ki-67 labeling index of the tumor cells and the low Ki-67 labeling index of the stromal cells, and also direct correlation between the medium Ki-67 labeling index in the tumor cells of intestinal-type gastric adenocarcinoma and the low expression level of p53 in these cells were identified.Conclusions. These data demonstrate a significantly more activity of proliferation and apoptosis in the tumor cells of intestinal-type gastric adenocarcinoma, in comparison with the stromal cells of this tumor. Invasive intestinal-type gastric adenocarcinoma differs by the 2 times higher expression level of p53, in comparison with the same index for non-invasive carcinoma. Furthermore, a tight association between proliferative processes in the tumor cells and in the stromal cells of intestinal-type gastric adenocarcinoma, and also an association between proliferative processes and accumulation of mutant protein p53 in the tumor cells of intestinal-type gastric adenocarcinoma were identified.

Dysphagia and Food Impaction: An Unexpected Etiology

Malignant pseudoachalasia is a rare disease that presents with similar radiographic and manometric features as primary achalasia; however their clinical presentation may vary. Pseudoachalasia usually occurs in advanced age individuals with an acute onset and significant weight loss. This is the case of an 83-year-old man with a medical history of atrial fibrillation on chronic anticoagulation with warfarin, chronic kidney disease stage three and ischemic cerebrovascular accident, who was evaluated due to progressive dysphagia to solid food of four months in evolution. Three days prior to evaluation, the patient had an episode of food impaction after a solid meal in which he wasn't able to tolerate neither water nor his own pills. Symptomatology progressed developing nausea and vomiting of undigested food contents as well as a ten pound weight loss. Initial laboratories revealed normochromic, normocytic anemia and pre-renal azotemia. Chest computed tomography (CT) revealed dilation of esophagus with retained debris consistent with food impaction. Esophagogastroduodenoscopy revealed evidence of food impaction at mid esophagus, removed with overtube assistance for airway protection using a basket and Roth net. Upon stomach inspection, a mass like ulceration was observed at the distal body of the stomach, multiple biopsies were obtained, which latter confirmed moderately differentiated invasive gastric adenocarcinoma. Endoscopic ultrasound showed a hypoechoic lesion with infiltration of submucosa and muscularis propria layer of the gastric wall. without lymphadenopathies, for a tumor staging of T2N0M0. PET/CT showed no metastasis. Barium swallow revealed a proximal dilation with distal narrowing consistent with achalasia. Manometry was remarkable for aperistalsis and increased lower esophageal sphincter resting pressure. Anti-neuronal nuclear antibodies, Anti-Hu and Anti-Ach were normal. Final diagnosis of pseudoachalasia secondarily to infiltrative gastric adenocarcinoma causing myenteric plexus dysfunction at muscularis propria on distal body was made. Rare etiology since most common cause of pseudoachalasia is compression of the esophagus by an extraluminal mass at fundus or cardia. Due to poor functional status patient wasn't a surgical candidate and was started on chemotherapy with 5FU and cisplatin.

The changing trends in epidemiological characteristics of gastric adenocarcinoma: a Tunisian center experience

Background: Gastric adenocarcinoma is a frequent disease characterized by recent changing trends in epidemiological features, mainly in developed countries. The aim of our study is to describe any changing trends, mainly, in distal and proximal gastric adenocarcinomas rates and signet ring cells adenocarcinomas rate. Methods: This is a retrospective monocentric study of 169 consecutive cases of primary invasive gastric adenocarcinoma, covering a period of 20 years. We have divided these cases into 2 equal-period groups. The rates of proximal cancers (cardia cancers), distal cancers (non-cardia cancers) and signet ring cells adenocarcinomas had been compared. Other parameters have been studied and compared such as gender, age and surgery types. Results: There is a statistically significant difference between the 2 groups regarding the rates of signet ring cells adenocarcinoma. The cardia cancer rates and non-cardia cancer rates are not statistically different between the 2 groups (p=0.074). However, there is an increasing trend in cardia cancers rate (7.6% to 16.7%) and a decreasing in non-cardia cancers rate (92.4% to 83.3%). There is no difference in regards to age, sex and type of surgery. Conclusions: The database of our retrospective study regarding age & sex incidence, clinicopathological features and therapeutic outcome was comparable to other studies in various literatures.

Trefoil factor 1 expression suppresses Helicobacter pylori-induced inflammation in gastric carcinogenesis.

Infection with Helicobacter pylori, a high-risk factor for gastric cancer, is frequently associated with chronic inflammation through activation of nuclear factor κB (NF-κB). Trefoil factor 1 (TFF1) is a constitutively expressed protein in the stomach that has tumor-suppressor functions and plays a critical role in maintaining mucosal integrity. This study investigated the role of TFF1 in regulating the proinflammatory response to H. pylori infections. For in vitro studies, immunofluorescence, luciferase reporter assays, Western blots, and quantitative real-time polymerase chain reaction were performed to investigate the activation of NF-κB and its target genes in response to infections with H. pylori strains J166 and 7.13. In addition, Tff1-knockout (KO) and Tff1-wild-type mice were used for infections with the H. pylori strain called premouse Sydney strain 1. The reconstitution of TFF1 expression in gastric cancer cells significantly suppressed H. pylori-mediated increases in NF-κB-p65 nuclear staining, transcriptional activity, and expression of proinflammatory cytokine genes (tumor necrosis factor α, interleukin 1β, chemokine [C-X-C motif] ligand 5, and interleukin 4 receptor) that were associated with reductions in the expression and phosphorylation of NF-κB-p65 and IκB kinase α/β proteins. The in vivo studies using the Tff1-KO mouse model of gastric neoplasia confirmed the in vitro findings. Furthermore, they demonstrated increases in chronic inflammation scores and in the frequency of invasive gastric adenocarcinoma in the Tff1-KO mice infected with H. pylori versus the uninfected Tff1-KO mice. These findings underscore an important protective role of TFF1 in abrogating H. pylori-mediated inflammation, a crucial hallmark of gastric tumorigenesis. Therefore, loss of TFF1 expression could be an important step in H. pylori-mediated gastric carcinogenesis.

Pathologic diagnostics of HER2 positivity in gastroesophageal adenocarcinoma.

The human epidermal growth factor receptor 2 (HER2) oncogene shows overexpression in 15% to 30% of gastroesophageal adenocarcinomas. Targeted anti-HER2 therapy with trastuzumab has been recently validated in advanced gastric and gastroesophageal junction cancer treatment. A standardized modified scoring system was recently introduced for gastroesophageal HER2 scoring. We aimed to validate this scoring system, including an analysis of interobserver variability of immunohistochemistry (IHC) scoring. In total, 323 patients with histologically confirmed invasive gastric or esophageal adenocarcinoma were examined for HER2 by IHC and chromogenic in situ hybridization (CISH). IHC 3 + or IHC 2 +/CISH positive tumors were considered HER2 positive. Interobserver variability on IHC scoring using the currently standard modified HER2 scoring system was determined among three clinical pathologists. Clinicopathologic characteristics were retrospectively retrieved from the patient records. HER2 positivity was found in 50 (15.5%) of 323 patients. Interobserver agreement on IHC scoring was high (κ = 0.78). Most disagreement was found in diffuse or mixed tumor types and in weak to moderate stained samples (IHC 2 +). The HER2 IHC scoring system is sensitive in differentiating HER2 status before ISH. The currently used standardized HER2 scoring system is an excellent, clinically applicable method to establish HER2 status in appropriately educated and trained pathologists.

Epstein-Barr Virus-associated Gastric Lymphoepithelioma Like Carcinoma

Case Presentation: A 69-year-old female presented with a six-month history of intermittent epigastric pain associated with 15-pound weight loss. She denied any past medical or surgical history. Physical exam was benign but her lab results were significant for microcytic anemia. Computed tomography (CT) of the abdomen with oral contrast demonstrated thickening of the anterior and posterior walls of the body and antrum of the stomach. Upper endoscopy revealed a large, friable, ulcerated, malignant-appearing mass in the antrum. Biopsy indicated invasive gastric adenocarcinoma, poorly differentiated with ulceration. The patient underwent a subtotal distal gastrectomy with gastrojejunostomy, followed by radiation therapy. Pathologic findings of the resected stomach showed a well demarcated tumor with raised border and central shallow ulcer in the antrum extending to and involving the lesser curvature, partially involving but not obstructing the pylorus. Microscopically, an undifferentiated carcinoma with intense lymphoid infiltration, invading through muscularis propria and subserosal connective tissue was detected. The tumor cells were polygonal with pale eosinophilic cytoplasm. Carcinoma cells stained strongly positive for both EBV and cytokeratin. CD3 was positive, evenly distributed throughout the tumor with intimate contact with individual carcinoma cells. CD20 was positive, sparsely scattered within the tumor. Three out of 15 lymph nodes along the lesser curvature were positive for metastatic carcinoma with lymphovascular invasion. The case was diagnosed as a gastric lymphoepithelioma-like carcinoma and the pathologic staging was T3N2M0 or UICC/AJCC Stage IIIb. Surveillance endoscopy performed two months post gastrectomy revealed chronic gastritis; however, no tumor was detected. No positron emission tomography evidence of metastatic spread of tumor was observed. Discussion: Lymphoepithelioma-like carcinoma (LELC) is a descriptive term for poorly differentiated carcinoma accompanied by prominent infiltration of lymphocytes; notably seen in nasopharyngeal and gastric carcinomas. Lymphoepithelioma-like gastric carcinoma is a rare neoplasm of the stomach most often seen in males, with a better prognosis than conventional adenocarcinoma. More than 80% of gastric LELC have been found to be related to EBV infection. EBV associated LELC is associated with 4-16% of gastric adenomas, with variations across populations. Even rarer is EBV associated LELC with lymph node metastasis. Fortunately for our patient, surveillance endoscopy has been negative for malignancy, to date.

Infiltrating gastric adenocarcinoma with disseminated osteoblastic metastases

We report the case of a man with a diagnosis of invasive gastric adenocarcinoma associated with scattered osteoblastic metastases. This 65-year-old patient was admitted with nausea, vomiting and abdominal pain, in addition to loss of weight (13 Kg in 3 months). Upper digestive endoscopy revealed extensive infiltrating changes in the body of the stomach, and histopathologic data confirmed the diagnosis of a Borrmann IV gastric adenocarcinoma. Complementary exams were indicative of a gastric cancer with bone metastases, characterized by disseminated osteoblastic images of the scintigraphy of the skeleton. Palliative chemotherapy was the treatment of first choice. High serum levels of CA 19-9, CEA and alkaline phosphatase can constitute useful indicative tools of this challenging condition. Images from a scintigraphy study of the skeleton can characterize the type and extension of bone metastases. The aim of this case study is to report a case of a very uncommon condition, considering that disseminated osteoblastic metastases rarely develop in this kind of tumor.