Zollinger-Ellison Syndrome Publications (3511)


Zollinger-Ellison Syndrome Publications

Am. J. Med.
Am J Med 2016 Dec 20. Epub 2016 Dec 20.
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Mayo Clinic, Rochester MN. Electronic address:

Zollinger-Ellison syndrome is a rare cause of tumoral hypergastrinemia; one out of 5 patients with this syndrome also has multiple endocrine neoplasia type 1. The diagnosis of this disease is complicated by the widespread use of proton pump inhibitors that can elevate serum gastrin levels, the cornerstone for biochemical diagnosis. Abrupt discontinuation of proton pump inhibitors could lead to adverse outcomes. Read More

Clinician awareness regarding the relationship of Zollinger Ellison syndrome and multiple endocrine neoplasia type 1, could lead to a safer diagnostic pathway.
Retrospective review of a cohort of patients with multiple endocrine neoplasia type 1.
287 patients with multiple endocrine neoplasia type 1 (73 with gastrinoma) were evaluated between 1997-2014. Two patients experienced adverse events after proton pump inhibitor therapy was discontinued to re-measure serum gastrin level during the evaluation of severe peptic ulcer disease. In both cases, the diagnosis of multiple endocrine neoplasia type 1 was made after proton pump therapy was discontinued.
Abrupt discontinuation of proton pump therapy can lead to adverse outcome in patients with Zollinger-Ellison syndrome. Clinical assessment for features of multiple endocrine neoplasia type 1 (eg, serum calcium levels, personal and family history of hypercalcemia, pituitary or pancreatic tumors), could identify patients with higher risk for a tumoral source of hypergastrinemia where imaging studies can help support the diagnosis without the potential side effects of abrupt discontinuation of proton pump therapy.

Zhonghua Wei Chang Wai Ke Za Zhi
Zhonghua Wei Chang Wai Ke Za Zhi 2016 Nov;19(11):1241-1246
Department of Integrative Oncology, China-Japan Friendship Hospital, Beijing 100029, China.

To study subtype classification of gastric neuroendocrine neoplasm (NEN) and their clinicopathological characteristics in order to provide reference for clinical practice.
Clinicopathological data of 241 gastric NEN patients (174 cases from China-Japan Friendship Hospital and 67 cases from The First Affiliated Hospital of Sun Yat-Sen University) between January 2011 and June 2016 were retrospectively summarized. According to serum gastrin, 24-hour intragastric pH monitoring and pathological grade, patients with gastric NEN were divided into 4 types: type I( (hypergastrinemia and achlorhydria, related to autoimmune chronic atrophic gastritis), type II( [hypergastrinemia and Zollinger-Ellison syndrome, related to gastrinoma or multiple endocrine neoplasia type I( (MEN-I()], type III( (sporadic disease with normal serum gastrin level), and type IIII( [poorly differentiated gastric neuroendocrine carcinoma (NEC) and mixed adenoneuroendocrine carcinoma (MANEC)]. Read More

Clinicopathological features, treatment and prognosis of 4 types were analyzed.
Of 241 gastric NEN cases, there were 86 cases (35.7%) in type I(, 7 cases (2.9%) in type II(, 61 cases (25.3%) in type III( and 87 cases(36.1%) in type IIII(. Among 86 cases of type I( gastric NEN, 73 cases (84.9%) were multiple lesions,tumor size of 66 cases (76.7%) was less than 1 cm, all the 86 cases were polypoid or granular lesions. 2 cases(2.3%)presented distant metastasis, 69 cases (80.2%) had pathological grading as NET G1; most of them received endoscopic surgery treatment and follow-up; somatostatin analogs(SSA) was used in patients with multiple lesions and repeated recurrence after endoscopic treatment. Among 7 cases of type II(, 4 cases were gastrinoma, 3 cases MEN-I(; 5 cases presented distant metastasis; treatment included surgery, SSA and proton pump inhibitor (PPI) therapy. Among 61 cases of type III( gastric NEN, 49 cases(80.3%) were single lesion,tumor size of 25 cases(41.0%) was more than 2 cm, 29 cases(47.5%) had lymph node metastasis or distant metastasis; treatment included endoscopic resection, surgery or SSA therapy according to the tumor staging. Among 87 patients of type IIII( gastric NEN, 74 cases(85.0%) had single lesion,tumor size of 51 cases (58.6%) was more than 2 cm; lesions were found in gastric cardia in 35 cases (40.2%); 65 cases (74.7%) had lymph node metastasis or distant metastasis; treatment included chemotherapy, or surgery plus chemotherapy. At the end of follow-up(June 30, 2016), 58 patients were dead, including 1 case of type I(, 12 cases of type III( and 45 cases of type IIII(. The overall survival rate of all the patients was 74.2%, and was 98.8%, 100%, 79.3%, 39.2% of types I(, II(, III(, IIII( respectively. The overall survival rate between type III( and type IIII( gastric NEN was significantly different(P = 0.000).
Subtype classification of gastric NEN is very significant for making therapeutic decisions and prognostic evaluation. Patients of type I( or type II( gastric NEN have good prognosis,while those of type III( and type IIII( have poor prognosis, and those of type IIII( have the worst prognosis.

Zhonghua Wei Chang Wai Ke Za Zhi
Zhonghua Wei Chang Wai Ke Za Zhi 2016 Nov;19(11):1217-1221
Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China.

Gastrointestinal neuroendocrine tumors are a group of highly heterogeneous tumors. Their incidences have increased in the Western countries as well as in Asia for years. In recent years, predominant progression has been made in the basic and translational studies on gastrointestinal neuroendocrine tumors. Read More

Gastric neuroendocrine neoplasmas are classified as four types: type I( occurs on the basis of autoimmune atrophic gastritis, type II( clinically manifests as multiple endocrine tumor type I( and Zollinger-Ellison syndrome, type III( is sporadic neuroendocrine neoplasmas, and type IIII( is neuroendocrine carcinoma. According to the location of primary tumor, intestinal neuroendocrine neoplasmas are classified as small intestine neuroendocrine neoplasmas and colorectal neuroendocrine neoplasmas. The latest finding shows that familial type I( gastric neuroendocrine neoplasmas exists homozygous missense mutation (c.2107C>T) of ATP4A gene. A number of researches focus on small intestine neuroendocrine neoplasmas recently. The chromosome instability, whole genome low methylation and abnormal expression of microRNA can be found in small intestine neuroendocrine neoplasmas. Part of them presents heterozygous mutations and loss of heterozygosity of CDKN1B gene. A recent study showed the heterozygous mutations of IPMK gene (c.990-993del) in familial small intestinal neuroendocrine neoplasmas. PROX1 and Annexin A1 may be involved in the malignant progression of rectal neuroendocrine neoplasmas via the Wnt pathway. The molecular mechanism of gastrointestinal neuroendocrine carcinoma is significantly different from gastrointestinal neuroendocrine tumors. The expression of mTOR, thymidylate synthase and PD-L1 protein, and gene mutation of BRAF V600E and KRAS have been exclusively found in gastrointestinal neuroendocrine carcinoma. The expression of thymidylate synthase, p27, p16, Gα15, PROX1 and Annexin A1 in gastrointestinal neuroendocrine neoplasmas is associated with the prognosis of these patients. Neurokinin A is a specific peripheral blood tumor biomarker for the prognosis and response to the treatment of patients with small intestinal neuroendocrine neoplasmas. INSL5 can be used as a unique biomarker for rectal neuroendocrine neoplasmas.

Surgery 2016 Nov 15. Epub 2016 Nov 15.
Department of Surgery and Translational Medicine, University of Florence, Florence, Italy.

Distal pancreatectomy is the most frequent operation for insulinomas complicating multiple endocrine neoplasia type 1 insulinoma, although there are conditions for which a different operative approach might be preferable. In this article, we report the operative experience of a referral center for multiple endocrine neoplasia type 1 insulinoma.
Twelve patients underwent operations between 1992 and 2015: 8 underwent a distal pancreatic resection, and 4 underwent a pancreatoduodenectomy. Read More

Enucleation of other macroadenomas present in the remnant pancreas was performed in 9 out of these 12 patients.
Operative complications (2 pancreatic fistulas and 2 cases of pancreatitis) occurred in 4 of the 8 distal pancreatic resections. In 1 patient, reoperation was required to resolve the complications of the first operation. At pathologic analysis, multiple insulinomas were found in 5 patients, lymph-nodal metastasis positive for insulin in 2 patients, multiple nonfunctioning pancreatic tumors in all patients, glucagonoma in 4 patients, and gastrinoma in the duodenum or lymph nodes in 4 patients. All the patients were treated successfully for the hypoglycemic/hyperinsulinemic syndrome with no clinical recurrence at a mean follow-up of 85 months (range 4-242 months). Recurrent nonfunctioning pancreatic tumor macroadenomas in the remnant pancreas occurred in only 1 of the 12 patients, and no progression of the gastrinomas was observed. None of the patients developed diabetes mellitus.
Resection of the most severely affected part of the pancreas, whether left or right, associated with enucleation of concomitant macroadenomas in the preserved pancreas is recommended for the treatment of hypoglycemic/hyperinsulinemic syndrome and to prevent malignant progression of nonfunctioning pancreatic tumors in patients with multiple endocrine neoplasia type 1. If the head of the pancreas is the most affected site and the Zollinger-Ellison syndrome is concomitant, then pancreatoduodenectomy should be preferred over distal pancreatectomy.

BMC Med 2016 Nov 9;14(1):172. Epub 2016 Nov 9.
Centre for Evidence-Based Medicine, Nuffield Department of Primary Care Health Sciences, University of Oxford, Radcliffe Observatory Quarter, Oxford, OX2 6GG, UK.

Inhibition of the H(+)/K(+)-adenosine triphosphatase (the proton pump) is the final common mechanistic pathway in reducing gastric acid secretion pharmacologically. Proton pump inhibitors are widely used in upper gastrointestinal diseases, including gastric and duodenal ulcers, eradication of Helicobacter pylori in combination with antibiotics, gastroesophageal reflux disease, Zollinger-Ellison syndrome, eosinophilic esophagitis, and prevention of non-steroidal anti-inflammatory drug-induced peptic ulceration. Reviewing their benefits and harms in BMC Medicine, Scarpignato et al. Read More

report effectiveness in these conditions, and harms that are generally mild and uncommon (1-3 %). Serious adverse reactions, such as tubulointerstitial nephritis, are rare. However, the risks of gastric and pancreatic cancer are unclear. Drug-drug interactions can occur through effects on P glycoprotein and cytochrome P450 (CYP) isoenzymes. Several questions remain. Do all proton pump inhibitors carry the same risks of serious adverse reactions? Which individuals are most susceptible? What are the time courses of individual reactions? What monitoring strategies are best? New drugs for the same indications continue to emerge, including potassium-competitive acid blockers, inhibitors of transient lower esophageal sphincter relaxation, serotonergic agents/prokinetics, mucosal protectants, histamine H3 receptor agonists, anti-gastrin agents, and esophageal pain modulators. Their benefit to harm balance remains to be discovered.Please see related article: https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-016-0718-z.

BMC Med 2016 Nov 9;14(1):179. Epub 2016 Nov 9.
Division of Pharmacology, Department of Clinical & Experimental Medicine, University of Pisa, Pisa, Italy.

The introduction of proton pump inhibitors (PPIs) into clinical practice has revolutionized the management of acid-related diseases. Studies in primary care and emergency settings suggest that PPIs are frequently prescribed for inappropriate indications or for indications where their use offers little benefit. Inappropriate PPI use is a matter of great concern, especially in the elderly, who are often affected by multiple comorbidities and are taking multiple medications, and are thus at an increased risk of long-term PPI-related adverse outcomes as well as drug-to-drug interactions. Read More

Herein, we aim to review the current literature on PPI use and develop a position paper addressing the benefits and potential harms of acid suppression with the purpose of providing evidence-based guidelines on the appropriate use of these medications.
The topics, identified by a Scientific Committee, were assigned to experts selected by three Italian Scientific Societies, who independently performed a systematic search of the relevant literature using Medline/PubMed, Embase, and the Cochrane databases. Search outputs were distilled, paying more attention to systematic reviews and meta-analyses (where available) representing the best evidence. The draft prepared on each topic was circulated amongst all the members of the Scientific Committee. Each expert then provided her/his input to the writing, suggesting changes and the inclusion of new material and/or additional relevant references. The global recommendations were then thoroughly discussed in a specific meeting, refined with regard to both content and wording, and approved to obtain a summary of current evidence.
Twenty-five years after their introduction into clinical practice, PPIs remain the mainstay of the treatment of acid-related diseases, where their use in gastroesophageal reflux disease, eosinophilic esophagitis, Helicobacter pylori infection, peptic ulcer disease and bleeding as well as, and Zollinger-Ellison syndrome is appropriate. Prevention of gastroduodenal mucosal lesions (and symptoms) in patients taking non-steroidal anti-inflammatory drugs (NSAIDs) or antiplatelet therapies and carrying gastrointestinal risk factors also represents an appropriate indication. On the contrary, steroid use does not need any gastroprotection, unless combined with NSAID therapy. In dyspeptic patients with persisting symptoms, despite successful H. pylori eradication, short-term PPI treatment could be attempted. Finally, addition of PPIs to pancreatic enzyme replacement therapy in patients with refractory steatorrhea may be worthwhile.
Overall, PPIs are irreplaceable drugs in the management of acid-related diseases. However, PPI treatment, as any kind of drug therapy, is not without risk of adverse effects. The overall benefits of therapy and improvement in quality of life significantly outweigh potential harms in most patients, but those without clear clinical indication are only exposed to the risks of PPI prescription. Adhering with evidence-based guidelines represents the only rational approach to effective and safe PPI therapy. Please see related Commentary: doi: 10.1186/s12916-016-0724-1 .

Expert Opin Pharmacother
Expert Opin Pharmacother 2016 Nov 23;17(16):2191-2205. Epub 2016 Sep 23.
b Digestive Diseases Branch , NIDDK, NIH , Bethesda , MD , USA.

Neuroendocrine tumors(NETs), once thought rare, are increasing in frequency in most countries and receiving increasing-attention. NETs present two-treatment problems. A proportion is aggressive and a proportion has a functional, hormone-excess-state(F-NET), each of which must be treated. Read More

Recently, there have been many advances, well-covered in reviews/consensus papers on imaging-NETs; new, novel anti-tumor treatments and understanding their pathogenesis. However, little attention has been paid to advances in the treatment of the hormone-excess-state. These advances are usually reported in case-series, and case-reports with few large studies. In this paper these advances are reviewed. Areas covered: Advances in the last 5-years are concentrated on, but a review of literature from the last 10-years was performed. PubMed and other databases (Cochrane, etc.) were searched for F-NET-syndromes including carcinoid-syndrome, as well as meeting-abstracts on NETs. All advances that controlled hormone-excess-states or facilitated-control were covered. These include new medical-therapies [serotonin-synthesis inhibitors(telotristat), Pasireotide, new agents for treating ACTHomas], increased dosing with conventional therapies (octreotide-LAR, Lanreotide-Autogel), mTor inhibitors(everolimus), Tyrosine-kinase inhibitors(sunitinib),cytoreductive surgery, liver-directed therapies (embolization, chemoembolization, radioembolization, RFA), peptide radio-receptor-therapy(PRRT) and (131)I-MIBG, ablation of primary F-NETs. Expert opinion: Although many of the newer therapies controlling the hormone-excess-states in F-NETs are reported in relatively few patients, all the approaches show promise. Their description also generates some controversies/unresolved areas,such as the order of these new treatments, their longterm-efficacy, and effectiveness of combinations which may require large,controlled studies.

World J. Gastroenterol.
World J Gastroenterol 2016 Aug;22(30):6817-28
Yuichi Sato, Satoru Hashimoto, Ken-ichi Mizuno, Manabu Takeuchi, Shuji Terai, Department of Gastroenterology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8121, Japan.

Gastrointestinal neuroendocrine tumors (GI-NETs) are rare neoplasms, like all NETs. However, the incidence of GI-NETS has been increasing in recent years. Gastric NETs (G-NETs) and duodenal NETs (D-NETs) are the common types of upper GI-NETs based on tumor location. Read More

G-NETs are classified into three distinct subgroups: type I, II, and III. Type I G-NETs, which are the most common subtype (70%-80% of all G-NETs), are associated with chronic atrophic gastritis, including autoimmune gastritis and Helicobacter pylori associated atrophic gastritis. Type II G-NETs (5%-6%) are associated with multiple endocrine neoplasia type 1 and Zollinger-Ellison syndrome (MEN1-ZES). Both type I and II G-NETs are related to hypergastrinemia, are small in size, occur in multiple numbers, and are generally benign. In contrast, type III G-NETs (10%-15%) are not associated with hypergastrinemia, are large-sized single tumors, and are usually malignant. Therefore, surgical resection and chemotherapy are generally necessary for type III G-NETs, while endoscopic resection and follow-up, which are acceptable for the treatment of most type I and II G-NETs, are only acceptable for small and well differentiated type III G-NETs. D-NETs include gastrinomas (50%-60%), somatostatin-producing tumors (15%), nonfunctional serotonin-containing tumors (20%), poorly differentiated neuroendocrine carcinomas (< 3%), and gangliocytic paragangliomas (< 2%). Most D-NETs are located in the first or second part of the duodenum, with 20% occurring in the periampullary region. Therapy for D-NETs is based on tumor size, location, histological grade, stage, and tumor type. While endoscopic resection may be considered for small nonfunctional D-NETs (G1) located in the higher papilla region, surgical resection is necessary for most other D-NETs. However, there is no consensus regarding the ideal treatment of D-NETs.