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Gastroenterology Dec 2017The multiple endocrine neoplasia, type 1 (MEN1) locus encodes the nuclear protein and tumor suppressor menin. MEN1 mutations frequently cause neuroendocrine tumors such...
BACKGROUND & AIMS
The multiple endocrine neoplasia, type 1 (MEN1) locus encodes the nuclear protein and tumor suppressor menin. MEN1 mutations frequently cause neuroendocrine tumors such as gastrinomas, characterized by their predominant duodenal location and local metastasis at time of diagnosis. Diffuse gastrin cell hyperplasia precedes the appearance of MEN1 gastrinomas, which develop within submucosal Brunner's glands. We investigated how menin regulates expression of the gastrin gene and induces generation of submucosal gastrin-expressing cell hyperplasia.
METHODS
Primary enteric glial cultures were generated from the VillinCre:Men1:Sst mice or C57BL/6 mice (controls), with or without inhibition of gastric acid by omeprazole. Primary enteric glial cells from C57BL/6 mice were incubated with gastrin and separated into nuclear and cytoplasmic fractions. Cells were incubated with forskolin and H89 to activate or inhibit protein kinase A (a family of enzymes whose activity depends on cellular levels of cyclic AMP). Gastrin was measured in blood, tissue, and cell cultures using an ELISA. Immunoprecipitation with menin or ubiquitin was used to demonstrate post-translational modification of menin. Primary glial cells were incubated with leptomycin b and MG132 to block nuclear export and proteasome activity, respectively. We obtained human duodenal, lymph node, and pancreatic gastrinoma samples, collected from patients who underwent surgery from 1996 through 2007 in the United States or the United Kingdom.
RESULTS
Enteric glial cells that stained positive for glial fibrillary acidic protein (GFAP+) expressed gastrin de novo through a mechanism that required PKA. Gastrin-induced nuclear export of menin via cholecystokinin B receptor (CCKBR)-mediated activation of PKA. Once exported from the nucleus, menin was ubiquitinated and degraded by the proteasome. GFAP and other markers of enteric glial cells (eg, p75 and S100B), colocalized with gastrin in human duodenal gastrinomas.
CONCLUSIONS
MEN1-associated gastrinomas, which develop in the submucosa, might arise from enteric glial cells through hormone-dependent PKA signaling. This pathway disrupts nuclear menin function, leading to hypergastrinemia and associated sequelae.
Topics: Active Transport, Cell Nucleus; Animals; Cells, Cultured; Cyclic AMP-Dependent Protein Kinases; Duodenal Neoplasms; Duodenum; Gastrinoma; Gastrins; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Humans; Hyperplasia; Mice, Inbred C57BL; Mice, Knockout; Neuroglia; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Proteolysis; Proto-Oncogene Proteins; Proton Pump Inhibitors; Receptor, Cholecystokinin B; Receptors, Somatostatin; Time Factors; Ubiquitination
PubMed: 28859856
DOI: 10.1053/j.gastro.2017.08.038 -
Clinical and Translational... Nov 2021The genomic characterization of primary nonampullary duodenal adenocarcinoma indicates a genetic resemblance to gastric and colorectal cancers. However, a correlation...
INTRODUCTION
The genomic characterization of primary nonampullary duodenal adenocarcinoma indicates a genetic resemblance to gastric and colorectal cancers. However, a correlation between the clinical and molecular characteristics of these cancers has not been established. This study aimed to elucidate the clinicopathological features of sporadic nonampullary duodenal epithelial tumors, including their molecular characteristics and prognostic factors.
METHODS
One hundred forty-eight patients with sporadic nonampullary duodenal epithelial tumors were examined in this study. Patient sex, age, TNM stage, tumor location, treatment methods, histology, KRAS mutation, BRAF mutation, Fusobacterium nucleatum, mucin phenotype, and programmed death-ligand 1 (PD-L1) status were evaluated. KRAS and BRAF mutations, Fusobacterium nucleatum, mucin phenotype, and PD-L1 status were analyzed by direct sequencing, quantitative polymerase chain reaction, and immunochemical staining.
RESULTS
The median follow-up duration was 119.4 months. There were no deaths from duodenal adenoma (the primary disease). Kaplan-Meier analysis for duodenal adenocarcinoma showed a significant effect of TNM stage (P < 0.01). In univariate analysis of primary deaths from duodenal adenocarcinoma, TNM stage II or higher, undifferentiated, KRAS mutations, gastric phenotype, intestinal phenotype, and PD-L1 status were significant factors. In multivariate analysis, TNM stage II or higher (hazard ratio: 1.63 × 1010, 95% confidence interval: 18.66-6.69 × 1036) and KRAS mutation (hazard ratio: 3.49, confidence interval: 1.52-7.91) were significant factors.
DISCUSSION
Only KRAS mutation was a significant prognostic factor in primary sporadic nonampullary duodenal adenocarcinoma in cases in which TNM stage was considered.
Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; B7-H1 Antigen; Duodenal Neoplasms; Female; Fusobacterium nucleatum; Gastric Mucosa; Humans; Male; Middle Aged; Mutation; Neoplasm Staging; Phenotype; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras)
PubMed: 34797780
DOI: 10.14309/ctg.0000000000000424 -
The Turkish Journal of Gastroenterology... Oct 2023The aim of this study was to both classify data of familial adenomatous polyposis patients with and without duode- nal cancer and to identify important genes that may be...
BACKGROUND/AIMS
The aim of this study was to both classify data of familial adenomatous polyposis patients with and without duode- nal cancer and to identify important genes that may be related to duodenal cancer by XGboost model.
MATERIALS AND METHODS
The current study was performed using expression profile data from a series of duodenal samples from familial adenomatous polyposis patients to explore variations in the familial adenomatous polyposis duodenal adenoma-carcinoma sequence. The expression profiles obtained from cancerous, adenomatous, and normal tissues of 12 familial adenomatous polyposis patients with duodenal cancer and the tissues of 12 familial adenomatous polyposis patients without duodenal cancer were compared. The ElasticNet approach was utilized for the feature selection. Using 5-fold cross-validation, one of the machine learning approaches, XGboost, was utilized to classify duodenal cancer. Accuracy, balanced accuracy, sensitivity, specificity, positive predictive value, negative predictive value, and F1 score performance metrics were assessed for model performance.
RESULTS
According to the variable importance obtained from the modeling, ADH1C, DEFA5, CPS1, SPP1, DMBT1, VCAN-AS1, APOB genes (cancer vs. adenoma); LOC399753, APOA4, MIR548X, and ADH1C genes (adenoma vs. adenoma); SNORD123, CEACAM6, SNORD78, ANXA10, SPINK1, and CPS1 (normal vs. adenoma) genes can be used as predictive biomarkers.
CONCLUSIONS
The proposed model used in this study shows that the aforementioned genes can forecast the risk of duodenal cancer in patients with familial adenomatous polyposis. More comprehensive analyses should be performed in the future to assess the reliability of the genes determined.
Topics: Humans; Duodenal Neoplasms; Reproducibility of Results; Adenomatous Polyposis Coli; Adenoma; Duodenum; Calcium-Binding Proteins; DNA-Binding Proteins; Tumor Suppressor Proteins; Trypsin Inhibitor, Kazal Pancreatic
PubMed: 37565794
DOI: 10.5152/tjg.2023.22346 -
Revista Espanola de Enfermedades... May 2022An 83-year-old female with history of silicosis was referred for upper endoscopy due to duodenal wall thickness detected in thoracic computer tomography (CT). Upper...
An 83-year-old female with history of silicosis was referred for upper endoscopy due to duodenal wall thickness detected in thoracic computer tomography (CT). Upper endoscopy revealed multiple small (1 to 5 mm), whitish polypoid lesions, involving a discrete portion of the descending part of the duodenum with 3 cm extension.
Topics: Aged, 80 and over; Duodenal Neoplasms; Duodenum; Female; Humans; Lymphoma, Follicular
PubMed: 34470459
DOI: 10.17235/reed.2021.8233/2021 -
BMC Surgery Nov 2019Duodenal fibrolipoma and duodenum-jejunum intussusception are both rare occasions in clinical practice. The diagnosis of duodenal fibrolipoma mainly depends on endoscopy...
BACKGROUND
Duodenal fibrolipoma and duodenum-jejunum intussusception are both rare occasions in clinical practice. The diagnosis of duodenal fibrolipoma mainly depends on endoscopy examination, supplemented by CT and MRI. As the tumor grows, some severe symptoms need surgical intervention. As the development of endoscopic techniques, the operation plan should be made individually.
CASE PRESENTATION
A 47-year-old female with the complaint of upper abdominal pain and melena was reported. Abdominal examination revealed upper abdomen lightly tender and blood test showed severe anemia. Image and endoscopy examination exhibited "a giant mass" in the descending (D2) part of duodenum, dragged by the tumor into the distal intestinal canal and causing intussusception. Intermittent blood transfusion treatment, enteral and parenteral nutrition were adopted to adjust her general state. Two weeks later, the mass was resected together with the basement intestinal wall via the jejunum incision and then the intussuscepted D2 part was restored. The paraffin pathological diagnosis correlated with the preoperative judgment of fibrolipoma and the patient was discharged healthy on POD 14.
CONCLUSIONS
Duodenal fibrolipoma is a rare disease, infrequently causing intussusception and severe upper GIB. Duodenoscopy and endoscopic ultrasound contribute to making an appropriate diagnosis, and for patients with severe symptoms needed surgical intervention, operation plan should be individualized depending on the size and location of the lesion.
Topics: Duodenal Diseases; Duodenal Neoplasms; Duodenoscopy; Endosonography; Female; Gastrointestinal Hemorrhage; Humans; Intussusception; Jejunal Diseases; Laparoscopy; Lipoma; Middle Aged; Tomography, X-Ray Computed
PubMed: 31718616
DOI: 10.1186/s12893-019-0634-1 -
Revista Espanola de Enfermedades... May 2022Endoscopic treatment for duodenal neuroendocrine tumors (d-NET) is technically challenging due to the anatomical characteristics of the duodenum, and is associated with...
Endoscopic treatment for duodenal neuroendocrine tumors (d-NET) is technically challenging due to the anatomical characteristics of the duodenum, and is associated with a high risk of perforation and a positive vertical margin because of infiltration into the submucosa. We herein present a case of d-NET that was successfully removed by over-the-scope clip (OTSC)-assisted endoscopic resection. OTSC-assisted endoscopic resection is a safe and reliable treatment method that enables deep submucosal resection in a short time without the risk of perforation.
Topics: Duodenal Neoplasms; Endoscopy, Gastrointestinal; Female; Humans; Intestinal Neoplasms; Middle Aged; Neuroendocrine Tumors; Pancreatic Neoplasms; Stomach Neoplasms
PubMed: 34470453
DOI: 10.17235/reed.2021.8232/2021 -
World Journal of Gastroenterology Jun 2017To investigate the range of pathologies treated by pancreas preserving distal duodenectomy (PPDD) and present the outcome of follow-up.
AIM
To investigate the range of pathologies treated by pancreas preserving distal duodenectomy (PPDD) and present the outcome of follow-up.
METHODS
Neoplastic lesions of the duodenum are treated conventionally by pancreaticoduodenectomy. Lesions distal to the major papilla may be suitable for a pancreas-preserving distal duodenectomy, potentially reducing morbidity and mortality. We present our experience with this procedure. Selective intraoperative duodenoscopy assessed the relationship of the papilla to the lesion. After duodenal mobilisation and confirmation of the site of the lesion, the duodenum was transected distal to the papilla and beyond the duodenojejunal flexure and a side-to-side duodeno-jejunal anastomosis was formed. Patients were identified from a prospectively maintained database and outcomes determined from digital health records with a dataset including demographics, co-morbidities, mode of presentation, preoperative imaging and assessment, nutritional support needs, technical operative details, blood transfusion requirements, length of stay, pathology including lymph node yield and lymph node involvement, length of follow-up, complications and outcomes. Related published literature was also reviewed.
RESULTS
Twenty-four patients had surgery with the intent of performing PPDD from 2003 to 2016. Nineteen underwent PPDD successfully. Two patients planned for PPDD proceeded to formal pancreaticoduodenectomy (PD) while three had unresectable disease. Median post-operative follow-up was 32 mo. Pathologies resected included duodenal adenocarcinoma ( = 6), adenomas ( = 5), gastrointestinal stromal tumours ( = 4) and lipoma, bleeding duodenal diverticulum, locally advanced colonic adenocarcinoma and extrinsic compression ( = 1 each). Median postoperative length of stay (LOS) was 8 d and morbidity was low [pain and nausea/vomiting ( = 2), anastomotic stricture ( = 1), pneumonia ( = 1), and overwhelming post-splenectomy sepsis ( = 1, asplenic patient)]. PPDD was associated with a significantly shorter LOS than a contemporaneous PD series [PPDD 8 (6-14) d PD 11 (10-16) d, median (IQR), = 0.026]. The 30-d mortality was zero and 16 of 19 patients are alive to date. One patient died of recurrent duodenal adenocarcinoma 18 mo postoperatively and two died of unrelated disease (at 2 mo and at 8 years respectively).
CONCLUSION
PPDD is a versatile operation that can provide definitive treatment for a range of duodenal pathologies including adenocarcinoma.
Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Algorithms; Ampulla of Vater; Anastomosis, Surgical; Blood Transfusion; Case-Control Studies; Catheterization; Duodenal Neoplasms; Duodenoscopy; Duodenum; Female; Follow-Up Studies; Gastrointestinal Stromal Tumors; Humans; Lymph Nodes; Male; Middle Aged; Organ Sparing Treatments; Pancreas; Pancreaticoduodenectomy; Postoperative Period; Treatment Outcome
PubMed: 28694665
DOI: 10.3748/wjg.v23.i23.4252 -
BMC Cancer May 2018The relatively low incidence of duodenal gastrointestinal stromal tumors (GISTs) and the unique anatomy make the surgical management and outcomes of this kind of tumor... (Comparative Study)
Comparative Study
BACKGROUND
The relatively low incidence of duodenal gastrointestinal stromal tumors (GISTs) and the unique anatomy make the surgical management and outcomes of this kind of tumor still under debate. Thus, this study aimed to explore the optimal surgical strategy and prognosis of duodenal GISTs.
METHODS
A total of 300 cases of duodenal GISTs were obtained from our center (37 cases) and from case reports or series (263 cases) extracted from MEDLINE. Clinicopathological features, type of resections and survivals of duodenal GISTs were analyzed.
RESULTS
The most common location of duodenal GISTs was descending portion (137/266, 51.5%). The median tumor size was 4 cm (0.1-28). Most patients (66.3%) received limited resection (LR). Pancreaticoduodenectomy (PD) was mainly performed for GISTs with larger tumor size or arose from descending portion (both P < 0.05). For both the entire cohort and tumors located in the descending portion, PD was not an independent risk factor for disease-free survival (DFS) and disease-specific survival (DSS) (both P > 0.05). Duodenal GISTs were significantly different from gastric GISTs with respect to tumor size, mitotic index and NIH risk category (all P < 0.05). The DFS and DSS of duodenal GISTs was significantly worse than that of gastric GISTs (both P < 0.05).
CONCLUSIONS
LR was a more prevalent surgical procedure and PD was mainly performed for tumors with larger diameter or located in descending portion. Type of resection was not an independent risk factor for the prognosis of duodenal GISTs. Prognosis of duodenal GISTs was significantly worse than that of gastric GISTs.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Child; Disease-Free Survival; Duodenal Neoplasms; Duodenum; Female; Gastrointestinal Stromal Tumors; Humans; Male; Middle Aged; Pancreaticoduodenectomy; Prognosis; Retrospective Studies; Risk Factors; Stomach Neoplasms; Young Adult
PubMed: 29764388
DOI: 10.1186/s12885-018-4485-4 -
World Journal of Gastroenterology Oct 2022The frequency of primary small intestinal adenocarcinoma is increasing but is still low. Its frequency is approximately 3% of that of colorectal adenocarcinoma.... (Review)
Review
The frequency of primary small intestinal adenocarcinoma is increasing but is still low. Its frequency is approximately 3% of that of colorectal adenocarcinoma. Considering that the small intestine occupies 90% of the surface area of the gastrointestinal tract, small intestinal adenocarcinoma is very rare. The main site of small intestinal adenocarcinoma is the proximal small intestine. Based on this characteristic, dietary animal proteins/lipids and bile concentrations are implicated and reported to be involved in carcinogenesis. Since most nutrients are absorbed in the proximal small intestine, the effect of absorbable intestinal content is a suitable explanation for why small intestinal adenocarcinoma is more common in the proximal small intestine. The proportion of aerobic bacteria is high in the proximal small intestine, but the absolute number of bacteria is low. In addition, the length and density of villi are greater in the proximal small intestine. However, the involvement of villi is considered to be low because the number of small intestinal adenocarcinomas is much smaller than that of colorectal adenocarcinomas. On the other hand, the reason for the low incidence of small intestinal adenocarcinoma in the distal small intestine may be that immune organs reside there. Genetic and disease factors increase the likelihood of small intestinal adenocarcinoma. In carcinogenesis experiments in which the positions of the small and large intestines were exchanged, tumors still occurred in the large intestinal mucosa more often. In other words, the influence of the intestinal contents is small, and there is a large difference in epithelial properties between the small intestine and the large intestine. In conclusion, small intestinal adenocarcinoma is rare compared to large intestinal adenocarcinoma due to the nature of the epithelium. It is reasonable to assume that diet is a trigger for small intestinal adenocarcinoma.
Topics: Animals; Intestine, Small; Adenocarcinoma; Colorectal Neoplasms; Duodenal Neoplasms; Intestinal Mucosa; Risk Factors; Carcinogenesis
PubMed: 36338888
DOI: 10.3748/wjg.v28.i39.5658 -
Scientific Reports Jul 2019Non-ampullary duodenal adenocarcinoma (NADC) is extremely rare. Little is known about its clinicopathological and molecular features or its management. Herein we...
Non-ampullary duodenal adenocarcinoma (NADC) is extremely rare. Little is known about its clinicopathological and molecular features or its management. Herein we retrospectively analyzed the cases of 32 NADC patients, focusing on microsatellite instability (MSI), genetic mutations, CpG island methylator phenotype (CIMP), and immunostaining including mucin phenotype and PD-L1 expression. The incidence of MSI, KRAS/BRAF/GNAS mutations and CIMP was 51.6%, 34.4%/3.1%/6.5% and 28.1%, respectively. PD-L1 expression was seen in 34.4% of patients. No significant associations between clinicopathological features and KRAS/BRAF/GNAS genetic mutations or CIMP were found. Histologically non-well-differentiated-type NADCs and those in the 1st portion of the duodenum were significantly associated with later stages (stages III-IV) (P = 0.006 and P = 0.003, respectively). Gastric-phenotype NADCs were frequently observed in the 1st portion and in late-stage patients; their cancer cells more frequently expressed PD-L1. Histologically, the non-well-differentiated type was an independent predictor of PD-L1 expression in cancer cells (OR 25.05, P = 0.04) and immune cells (OR 44.14, P = 0.02). Only late-stage disease (HR 12.23, P = 0.01) was a prognostic factor for worse overall survival in a Cox proportional hazards regression model. Our observation of high proportions of MSI and PD-L1 expression may prompt the consideration of immune checkpoint inhibitors as a new treatment option for NADCs.
Topics: Adenocarcinoma; Aged; B7-H1 Antigen; Chromogranins; CpG Islands; DNA Methylation; DNA, Neoplasm; Duodenal Neoplasms; Female; GTP-Binding Protein alpha Subunits, Gs; Genes, Neoplasm; Genes, ras; Humans; Kaplan-Meier Estimate; Male; Microsatellite Instability; Middle Aged; Mutation; Neoplasm Proteins; Phenotype; Prognosis; Proportional Hazards Models; Proto-Oncogene Proteins B-raf; Retrospective Studies
PubMed: 31324814
DOI: 10.1038/s41598-019-46167-y