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Nature Communications Feb 2021Genetic factors are recognized to contribute to peptic ulcer disease (PUD) and other gastrointestinal diseases, such as gastro-oesophageal reflux disease (GORD),...
Genetic factors are recognized to contribute to peptic ulcer disease (PUD) and other gastrointestinal diseases, such as gastro-oesophageal reflux disease (GORD), irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). Here, genome-wide association study (GWAS) analyses based on 456,327 UK Biobank (UKB) individuals identify 8 independent and significant loci for PUD at, or near, genes MUC1, MUC6, FUT2, PSCA, ABO, CDX2, GAST and CCKBR. There are previously established roles in susceptibility to Helicobacter pylori infection, response to counteract infection-related damage, gastric acid secretion or gastrointestinal motility for these genes. Only two associations have been previously reported for duodenal ulcer, here replicated trans-ancestrally. The results highlight the role of host genetic susceptibility to infection. Post-GWAS analyses for PUD, GORD, IBS and IBD add insights into relationships between these gastrointestinal diseases and their relationships with depression, a commonly comorbid disorder.
Topics: ABO Blood-Group System; Antigens, Neoplasm; CDX2 Transcription Factor; Depression; Duodenal Ulcer; Female; Fucosyltransferases; GPI-Linked Proteins; Galactosyltransferases; Gastroesophageal Reflux; Gastrointestinal Diseases; Genetic Predisposition to Disease; Genome-Wide Association Study; Helicobacter Infections; Helicobacter pylori; Humans; Inflammatory Bowel Diseases; Male; Mucin-1; Mucin-6; Neoplasm Proteins; Peptic Ulcer; Galactoside 2-alpha-L-fucosyltransferase
PubMed: 33608531
DOI: 10.1038/s41467-021-21280-7 -
Journal of Gastroenterology Dec 2022Duodenal cancer is considered to be a small intestinal carcinoma in terms of clinicopathology. In Japan, there are no established treatment guidelines based on...
Duodenal cancer is considered to be a small intestinal carcinoma in terms of clinicopathology. In Japan, there are no established treatment guidelines based on sufficient scientific evidence; therefore, in daily clinical practice, treatment is based on the experience of individual physicians. However, with advances in diagnostic modalities, it is anticipated that opportunities for its detection will increase in future. We developed guidelines for duodenal cancer because this disease is considered to have a high medical need from both healthcare providers and patients for appropriate management. These guidelines were developed for use in actual clinical practice for patients suspected of having non-ampullary duodenal epithelial malignancy and for patients diagnosed with non-ampullary duodenal epithelial malignancy. In this study, a practice algorithm was developed in accordance with the Minds Practice Guideline Development Manual 2017, and Clinical Questions were set for each area of epidemiology and diagnosis, endoscopic treatment, surgical treatment, and chemotherapy. A draft recommendation was developed through a literature search and systematic review, followed by a vote on the recommendations. We made decisions based on actual clinical practice such that the level of evidence would not be the sole determinant of the recommendation. This guideline is the most standard guideline as of the time of preparation. It is important to decide how to handle each case in consultation with patients and their family, the treating physician, and other medical personnel, considering the actual situation at the facility (and the characteristics of the patient).
Topics: Humans; Duodenal Neoplasms; Endoscopy; Japan; Neoplasms, Glandular and Epithelial
PubMed: 36260172
DOI: 10.1007/s00535-022-01919-y -
Endoscopy Apr 20211: ESGE recommends against diagnostic/therapeutic papillectomy when adenoma is not proven.Strong recommendation, low quality evidence. 2: ESGE recommends endoscopic...
1: ESGE recommends against diagnostic/therapeutic papillectomy when adenoma is not proven.Strong recommendation, low quality evidence. 2: ESGE recommends endoscopic ultrasound and abdominal magnetic resonance cholangiopancreatography (MRCP) for staging of ampullary tumors.Strong recommendation, low quality evidence. 3: ESGE recommends endoscopic papillectomy in patients with ampullary adenoma without intraductal extension, because of good results regarding outcome (technical and clinical success, morbidity, and recurrence).Strong recommendation, moderate quality evidence. 4: ESGE recommends en bloc resection of ampullary adenomas up to 20-30 mm in diameter to achieve R0 resection, for optimizing the complete resection rate, providing optimal histopathology, and reduction of the recurrence rate after endoscopic papillectomy.Strong recommendation, low quality evidence. 5: ESGE suggests considering surgical treatment of ampullary adenomas when endoscopic resection is not feasible for technical reasons (e. g. diverticulum, size > 4 cm), and in the case of intraductal involvement (of > 20 mm). Surveillance thereafter is still mandatory.Weak recommendation, low quality evidence. 6: ESGE recommends direct snare resection without submucosal injection for endoscopic papillectomy.Strong recommendation, moderate quality evidence. 7: ESGE recommends prophylactic pancreatic duct stenting to reduce the risk of pancreatitis after endoscopic papillectomy.Strong recommendation, moderate quality evidence. 8: ESGE recommends long-term monitoring of patients after endoscopic papillectomy or surgical ampullectomy, based on duodenoscopy with biopsies of the scar and of any abnormal area, within the first 3 months, at 6 and 12 months, and thereafter yearly for at least 5 years.Strong recommendation, low quality evidence.
Topics: Ampulla of Vater; Common Bile Duct Neoplasms; Duodenal Neoplasms; Endoscopy, Gastrointestinal; Humans; Neoplasm Recurrence, Local; Pancreatic Ducts
PubMed: 33728632
DOI: 10.1055/a-1397-3198 -
World Journal of Gastroenterology Sep 2021Zollinger-Ellison syndrome (ZES) associated with pancreatic or duodenal gastrinoma is characterized by gastric acid hypersecretion, which typically leads to... (Review)
Review
Zollinger-Ellison syndrome (ZES) associated with pancreatic or duodenal gastrinoma is characterized by gastric acid hypersecretion, which typically leads to gastroesophageal reflux disease, recurrent peptic ulcers, and chronic diarrhea. As symptoms of ZES are nonspecific and overlap with other gastrointestinal disorders, the diagnosis is often delayed with an average time between the onset of symptoms and final diagnosis longer than 5 years. The critical step for the diagnosis of ZES is represented by the initial clinical suspicion. Hypergastrinemia is the hallmark of ZES; however, hypergastrinemia might recognize several causes, which should be ruled out in order to make a final diagnosis. Gastrin levels > 1000 pg/mL and a gastric pH below 2 are considered to be diagnostic for gastrinoma; some specific tests, including esophageal pH-recording and secretin test, might be useful in selected cases, although they are not widely available. Endoscopic ultrasound is very useful for the diagnosis and the local staging of the primary tumor in patients with ZES, particularly in the setting of multiple endocrine neoplasia type 1. Some controversies about the management of these tumors also exist. For the localized stage, the combination of proton pump inhibitory therapy, which usually resolves symptoms, and surgery, whenever feasible, with curative intent represents the hallmark of gastrinoma treatment. The high expression of somatostatin receptors in gastrinomas makes them highly responsive to somatostatin analogs, supporting their use as anti-proliferative agents in patients not amenable to surgical cure. Other medical options for advanced disease are super-imposable to other neuroendocrine neoplasms, and studies specifically focused on gastrinomas only are scant and often limited to case reports or small retrospective series. The multidisciplinary approach remains the cornerstone for the proper management of this composite disease. Herein, we reviewed available literature about gastrinoma-associated ZES with a specific focus on differential diagnosis, providing potential diagnostic and therapeutic algorithms.
Topics: Gastrinoma; Humans; Multiple Endocrine Neoplasia Type 1; Pancreatic Neoplasms; Retrospective Studies; Zollinger-Ellison Syndrome
PubMed: 34629807
DOI: 10.3748/wjg.v27.i35.5890 -
Neuroendocrinology 2021The better understanding of the biological behavior of multiple endocrine neoplasia type 1 (MEN1) organ manifestations and the increase in clinical experience warrant a... (Review)
Review
Multiple Endocrine Neoplasia Type 1 and the Pancreas: Diagnosis and Treatment of Functioning and Non-Functioning Pancreatic and Duodenal Neuroendocrine Neoplasia within the MEN1 Syndrome - An International Consensus Statement.
The better understanding of the biological behavior of multiple endocrine neoplasia type 1 (MEN1) organ manifestations and the increase in clinical experience warrant a revision of previously published guidelines. Duodenopancreatic neuroendocrine neoplasias (DP-NENs) are still the second most common manifestation in MEN1 and, besides NENs of the thymus, remain a leading cause of death. DP-NENs are thus of main interest in the effort to reevaluate recommendations for their diagnosis and treatment. Especially over the last 2 years, more clinical experience has documented the follow-up of treated and untreated (natural-course) DP-NENs. It was the aim of the international consortium of experts in endocrinology, genetics, radiology, surgery, gastroenterology, and oncology to systematically review the literature and to present a consensus statement based on the highest levels of evidence. Reviewing the literature published over the past decade, the focus was on the diagnosis of F- and NF-DP-NENs within the MEN1 syndrome in an effort to further standardize and improve treatment and follow-up, as well as to establish a "logbook" for the diagnosis and treatment of DP-NENs. This shall help further reduce complications and improve long-term treatment results in these rare tumors. The following international consensus statement builds upon the previously published guidelines of 2001 and 2012 and attempts to supplement the recommendations issued by various national and international societies.
Topics: Consensus; Duodenal Neoplasms; Humans; Multiple Endocrine Neoplasia Type 1; Pancreatic Neoplasms
PubMed: 32971521
DOI: 10.1159/000511791 -
Gastroenterology Nov 2020Pancreatic ductal adenocarcinomas (PDACs) are hypovascular, resulting in the up-regulation of hypoxia inducible factor 1 alpha (HIF1A), which promotes the survival of...
BACKGROUND & AIMS
Pancreatic ductal adenocarcinomas (PDACs) are hypovascular, resulting in the up-regulation of hypoxia inducible factor 1 alpha (HIF1A), which promotes the survival of cells under low-oxygen conditions. We studied the roles of HIF1A in the development of pancreatic tumors in mice.
METHODS
We performed studies with Kras;Trp53;Pdx1-Cre (KPC) mice, KPC mice with labeled pancreatic epithelial cells (EKPC), and EKPC mice with pancreas-specific depletion of HIF1A. Pancreatic and other tissues were collected and analyzed by histology and immunohistochemistry. Cancer cells were cultured from PDACs from mice and analyzed in cell migration and invasion assays and by immunoblots, real-time polymerase chain reaction, and liquid chromatography-mass spectrometry. We performed studies with the human pancreatic cancer cell lines PATU-8988T, BxPC-3, PANC-1, and MiaPACA-2, which have no or low metastatic activity, and PATU-8988S, AsPC-1, SUIT-2 and Capan-1, which have high metastatic activity. Expression of genes was knocked down in primary cancer cells and pancreatic cancer cell lines by using small hairpin RNAs; cells were injected intravenously into immune-competent and NOD/SCID mice, and lung metastases were quantified. We compared levels of messenger RNAs in pancreatic tumors and normal pancreas in The Cancer Genome Atlas.
RESULTS
EKPC mice with pancreas-specific deletion of HIF1A developed more advanced pancreatic neoplasias and PDACs with more invasion and metastasis, and had significantly shorter survival times, than EKPC mice. Pancreatic cancer cells from these tumors had higher invasive and metastatic activity in culture than cells from tumors of EKPC mice. HIF1A-knockout pancreatic cancer cells had increased expression of protein phosphatase 1 regulatory inhibitor subunit 1B (PPP1R1B). There was an inverse correlation between levels of HIF1A and PPP1R1B in human PDAC tumors; higher expression of PPP1R1B correlated with shorter survival times of patients. Metastatic human pancreatic cancer cell lines had increased levels of PPP1R1B and lower levels of HIF1A compared with nonmetastatic cancer cell lines; knockdown of PPP1R1B significantly reduced the ability of pancreatic cancer cells to form lung metastases in mice. PPP1R1B promoted degradation of p53 by stabilizing phosphorylation of MDM2 at Ser166.
CONCLUSIONS
HIF1A can act a tumor suppressor by preventing the expression of PPP1R1B and subsequent degradation of the p53 protein in pancreatic cancer cells. Loss of HIF1A from pancreatic cancer cells increases their invasive and metastatic activity.
Topics: Animals; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Cell Movement; Disease Models, Animal; Dopamine and cAMP-Regulated Phosphoprotein 32; Epithelial-Mesenchymal Transition; Female; Gene Expression Regulation, Neoplastic; Homeodomain Proteins; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Lung Neoplasms; Male; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Neoplasm Invasiveness; Pancreatic Neoplasms; Proteolysis; Proto-Oncogene Proteins p21(ras); Signal Transduction; Trans-Activators; Tumor Hypoxia; Tumor Microenvironment; Tumor Suppressor Protein p53; Up-Regulation
PubMed: 32768595
DOI: 10.1053/j.gastro.2020.07.046 -
Gastroenterology Sep 2019Little is known about mechanisms of perineural invasion (PNI) by pancreatic ductal adenocarcinomas (PDAs) or other tumors. Annexin A2 (ANXA2) regulates secretion of...
BACKGROUND & AIMS
Little is known about mechanisms of perineural invasion (PNI) by pancreatic ductal adenocarcinomas (PDAs) or other tumors. Annexin A2 (ANXA2) regulates secretion of SEMA3D, an axon guidance molecule, which binds and activates the receptor PLXND1 to promote PDA invasion and metastasis. We investigated whether axon guidance molecules promote PNI and metastasis by PDA cells in mice.
METHODS
We performed studies in a dorsal root ganglion (DRG) invasion system, wild-type C57BL/6 mice (controls), mice with peripheral sensory neuron-specific disruption of PlxnD1 (PLAC mice), LSL-KRAS;LSL-TP53;PDX-1-CRE (KPC) mice, and KPC mice crossed with ANXA2-knockout mice (KPCA mice). PDA cells were isolated from KPC mice and DRG cells were isolated from control mice. Levels of SEMA3D or ANXA2 were knocked down in PDA cells with small hairpin and interfering RNAs and cells were analyzed by immunoblots in migration assays, with DRGs and with or without antibodies against PLXND1. PDA cells were injected into the pancreas of control and PLAC mice, growth of tumors was assessed, and tumor samples were analyzed by histology. DRG cells were incubated with SEMA3D and analyzed by live imaging. We measured levels of SEMA3D and PLXND1 in PDA specimens from patients with PNI and calculated distances between tumor cells and nerves.
RESULTS
DRG cells increase the migration of PDC cells in invasion assays; knockdown of SEMA3D in PDA cells or antibody blockade of PLXND1 on DRG cells reduced this invasive activity. In mice, orthotopic tumors grown from PDA cells with knockdown of SEMA3D, and in PLAC mice, orthotopic tumors grown from PDA cells, had reduced innervation and formed fewer metastases than orthotopic tumors grown from PDA cells in control mice. Increased levels of SEMA3D and PLXND1 in human PDA specimens associated with PNI.
CONCLUSIONS
DRG cells increase the migratory and invasive activities of pancreatic cancer cells, via secretion of SEMA3D by pancreatic cells and activation of PLXND1 on DRGs. Knockdown of SEMA3D and loss of neural PLXND1 reduces innervation of orthotopic PDAs and metastasis in mice. Increased levels of SEMA3D and PLXND1 in human PDA specimens associated with PNI. Strategies to disrupt the axon guidance pathway mediated by SEMA3D and PLXND1 might be developed to slow progression of PDA.
Topics: Animals; Annexin A2; Axon Guidance; Carcinoma, Pancreatic Ductal; Cell Communication; Cell Movement; Ganglia, Spinal; Gene Expression Regulation, Neoplastic; Genes, p53; Genes, ras; Genetic Predisposition to Disease; Homeodomain Proteins; Humans; Intracellular Signaling Peptides and Proteins; Membrane Glycoproteins; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Neoplasm Invasiveness; Nerve Tissue Proteins; Neuronal Outgrowth; Pancreatic Neoplasms; Phenotype; Semaphorins; Signal Transduction; Trans-Activators; Tumor Cells, Cultured
PubMed: 31163177
DOI: 10.1053/j.gastro.2019.05.065 -
Cancers Jan 2023The conceptual description of Follicular lymphoma (FL) in the 5th edition of the World Health Organization (WHO) classification of haematolymphoid tumors (WHO-HAEM5) has... (Review)
Review
The conceptual description of Follicular lymphoma (FL) in the 5th edition of the World Health Organization (WHO) classification of haematolymphoid tumors (WHO-HAEM5) has undergone significant revision. The vast majority of FL (85%) with a follicular growth pattern are composed of centrocytes and centroblasts, harbor the t(14;18)(q32;q21) translocation and are now termed classic FL (cFL). They are set apart from three related subtypes, FL with predominantly follicular growth pattern, FL with unusual cytological features (uFL) and follicular large B-cell lymphoma (FLBCL). In contrast to the revised 4th edition of the WHO classification of haematolymphoid tumors (WHO-HAEM4R), grading of cFL is no longer mandatory. FL with a predominantly diffuse growth pattern had been previously recognized in WHO-HAEM4R. It frequently occurs as a large tumor in the inguinal region and is associated with CD23 expression. An absence of the fusion and frequent mutations along with 1p36 deletion or mutation is typical. The newly introduced subtype of uFL includes two subsets that significantly diverge from cFL: one with "blastoid" and one with "large centrocyte" variant cytological features. uFL more frequently displays variant immunophenotypic and genotypic features. FLBCL is largely identical to WHO-HAEM4R FL grade 3B and renaming was done for reasons of consistency throughout the classification. In-situ follicular B-cell neoplasm, pediatric-type FL, duodenal-type FL and primary cutaneous follicle center lymphoma are categorized as discrete entities. In addition, novel findings concerning underlying biological mechanisms in the pathogenesis of early and systemic follicular lymphoma will be presented.
PubMed: 36765742
DOI: 10.3390/cancers15030785 -
Gland Surgery Sep 2019Groove pancreatitis (GP) is an uncommon form of chronic pancreatitis (CP) involving the space between duodenum, pancreatic head and common bile duct (CBD) known as... (Review)
Review
Groove pancreatitis (GP) is an uncommon form of chronic pancreatitis (CP) involving the space between duodenum, pancreatic head and common bile duct (CBD) known as pancreatic-duodenal groove. Although an association with long-standing ethanol assumption is reported a definite etiology of GP is unknown. Since thickening of the duodenal wall, pancreatic head enlargement, CBD stricture and dilatation of pancreatic duct system are common findings the differential diagnosis with pancreatic head neoplasm by means of imaging can be challenging. However, some imaging findings such as fibrotic changes of the pancreatic groove and presence of duodenal wall cysts may suggest the correct diagnosis. In this paper we review clinical and imaging features of GP with emphasis on computed tomography (CT) and magnetic resonance imaging (MRI) findings.
PubMed: 31559185
DOI: 10.21037/gs.2019.04.06 -
Chirurgia (Bucharest, Romania : 1990) 2020Post-gastrectomy complications have been the associated sequelae after curative gastrectomy for long time. They include a conundrum of symptoms ranging from serious... (Review)
Review
Post-gastrectomy complications have been the associated sequelae after curative gastrectomy for long time. They include a conundrum of symptoms ranging from serious metabolic alterations to disorders attributed to mechanical and neural factors after reconstruction of the digestive continuity. Though, with the advancement in the surgical expertise and techniques and shift towards medical and endoscopic management for benign gastro-duodenal ulcer disease, there has been a decline in the incidence of these complications; they continue to raise "red flags" after major oncologic gastric resections. Identification of these symptoms and protocol based management of the same is of utmost importance in the surgical armamentarium of trainees and practicing physicians and surgeons.
Topics: Gastrectomy; Humans; Postgastrectomy Syndromes; Stomach Diseases; Stomach Neoplasms; Treatment Outcome
PubMed: 32876015
DOI: 10.21614/chirurgia.115.4.423