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Purpose: Zollinger Ellison syndrome (ZES) is a rare syndrome caused by gastrin hypersecretion from a gastrinoma. Gastrinoma treatment has two goals: the control of acid hypersecretion and the control of tumor growth. While therapy for the syndrome is univocally based on proton pump inhibitors, the one for disease control is still debated. We here aimed at evaluating the role of somatostatin analogs (SSAs) in the control of tumor progression in a series of ZES patients., Methods: A retrospective analysis of a prospectively collected database of ZES patients, followed and managed from 1990 to 2019, was performed. The patients' clinical, pathological, treatment, and follow-up data were analyzed. Data regarding SSAs therapy start, dosage, duration, and side effects were collected., Results: 33 patients with ZES were diagnosed. Fourteen patients (42%) had a grade 1 (G1) neuroendocrine neoplasm (NEN), five had G2 (15%), none had G3. Fifteen patients (45%) had metastatic disease. Overall, 12 (36%) underwent SSAs therapy. The median treatment duration was 36 months. Eight patients (67%) had a sustained response to SSAs, four (33%) showed an early progression, with a significant difference in terms of PFS between the patients with early and late progression (84 vs 2 months, p = 0.004). No differences in terms of OS and PFS were observed between the treated and non-treated patients, despite the proportion of metastatic patients was greater in the SSAs-treated group (75% vs 29% in the non-treated group, p = 0.01)., Conclusion: Present data support the use of SSAs in ZES, considering that gastrinoma is mainly a well-differentiated low-grade tumor (G1 or G2), with a high expression of somatostatin receptors., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

This article reviews the role of surgical and medical management in patients with Zollinger-Ellison syndrome (ZES) due to a gastrin-secreting neuroendocrine tumor (gastrinoma). It concentrates on the status at present but also briefly reviews the changes over time in treatment approaches. Generally, surgical and medical therapy are complementary today; however, in some cases, such as patients with ZES and multiple endocrine neoplasia type 1, the treatment approach remains controversial., (Published by Elsevier Inc.)

Introduction: Ectopic Cushing's syndrome (ECS) is a rare condition caused by ACTH secretion by extrapituitary tumors. Its low frequency makes it difficult to acquire experience in its management. The aim of this study was to describe patients with ECS seen at the endocrinology department of a tertiary hospital over 15 years., Methods: This was a retrospective study of the clinical, biochemical and radiographic data, treatment, and course of patients with ECS seen from 2000 to 2015., Results: Nine patients (6 of them female) with a mean age of 47 years were included in the study. The clinical syndrome developed in less than 3 months in all cases but one, and most patients also had edema, hyperpigmentation and/or hypokalemia. Mean urinary free cortisol and ACTH levels were 2,840μg/24h and 204pg/mL respectively. The ectopic origin was confirmed by a combination of dynamic non-invasive tests and radiographic studies in most cases. The tumor responsible could be identified in 8 cases, and 7 patients had metastatic dissemination. Primary treatment was surgery in one patient, surgery combined with systemic therapy in 3, and chemotherapy in the other 3 patients. Bilateral adrenalectomy was required in 4 patients to control hypercortisolism. After a mean follow-up of 40 months, 3 patients died, 5 were still alive, and one had been lost to follow-up., Conclusions: Our study confirms that ECS covers a wide spectrum of tumors of different aggressiveness and nature. The ectopic origin of Cushing's syndrome can usually, be suspected and confirmed in most cases without the need for invasive tests. Control of both hypercortisolism and the tumor requires multiple treatment modalities, and multidisciplinary management is recommended., (Copyright © 2018 SEEN y SED. Publicado por Elsevier España, S.L.U. All rights reserved.)

Purpose: Analyze the role of somatostatin analogues (SSAs) in the treatment of sporadic and MEN1-related gastrinomas, trying to define whether recent trials have changed the landscape of gastrinoma therapy., Methods: We evaluate the rationale of SSA use in the treatment of gastrinomas, summarize the current literature concerning the effect of SSAs on the control of Zollinger-Ellison syndrome (ZES) and gastrinomas tumor progression and discuss their role in the most recent guidelines., Results: The medical treatment of gastrinoma and related ZES is aimed at controlling acid hypersecretion and tumor progression, in inoperable patients. The use of proton pump inhibitors (PPIs) to control the syndrome is a cornerstone in the ZES therapy. SSAs are not usually indicated for antisecretory purpose, because PPIs are considered the treatment of choice, due to their long lasting high efficacy and oral availability. The antiproliferative effect of SSAs has been established by two placebo-controlled trials that have clearly demonstrated a significant increase in progression free survival in patients affected by non-functioning well-differentiated advanced neuroendocrine tumors (NETs). The recent ENETS guidelines recommend the use of SSAs in advanced well differentiated NETs as antiproliferative agents., Conclusions: The high sstr-expression in gastrinomas make them highly responsive to SSAs and support the use of such drugs to counteract the tumour growth in patients not amenable to surgical cure. Unfortunately, limited data, mainly case reports or small series, support the use of SSAs in advanced gastrinomas, therefore, it is difficult to quantify their ability to control tumour growth and disease progression.

A 40-year-old man admitted to our hospital with diarrhea underwent abdominal computed tomography (CT) which showed multiple masses in the liver and pancreatic tail. Although there were no abnormal accumulations with fluorodeoxyglucose ((18)F) positron emission tomography (FDG-PET), (68)Ga-DOTATOC-PET/CT detected obvious abnormal accumulations for the both lobes of liver and pancreatic tail tumors. The serum gastrin was markedly high, and liver tumor biopsy demonstrated the presence of malignant cells with round nuclei that were positive for gastrin and somatostatin receptor. The patient was diagnosed with pancreatic tail gastrinoma with multiple liver metastases and treated with octreotide, everolimus, and a proton pump inhibitor which functionally controlled tumor growth. This case demonstrates (68)Ga-DOTATOC-PET/CT as a useful modality for the localization, qualitative diagnosis, and treatment of gastrinoma.

Introduction: The role of pharmacotherapy in the management of patients with Zollinger-Ellison syndrome (ZES) is often equated with the medical management of acid hypersecretion. However, pharmacotherapy is also increasingly involved in the other management areas of these patients., Areas Covered: This paper reviews the role of pharmacotherapy in all aspects of the management of patients with ZES. Newer aspects are emphasized. This includes the difficulty of diagnosing ZES in patients taking proton pump inhibitors. Also covered is the role of pharmacotherapy in controlling acid hypersecretion and other hormonal hypersecretory states these patients may develop, including hyperparathyroidism in patients with multiple endocrine neoplasia type 1 and ZES; tumor localization; and the treatment of advanced metastatic disease. The last includes chemotherapy, liver-directed therapies, biotherapy (somatostatin/interferon), peptide radio-receptor therapy and molecular-targeted therapies including the use of mTor inhibitors (everolimus) and tyrosine kinase inhibitors (sunitinib)., Expert Opinion: Pharmacotherapy is now involved in all aspects of the management of patients with ZES, with the result that ZES has progressed from being considered an entirely surgical disease initially to the present where medical treatment plays a major role in almost all aspects of the management of these patients.

The rare hereditary syndrome, multiple endocrine neoplasia type1 (MEN-1), is known to predispose affected individuals to endocrine neoplasms in a variety of tissues such as the parathyroid glands, the pituitary gland and the gastrointestinal tract. We describe the case of a man with traditionally-described manifestations (hyperparathyroidism and gastrinoma) and with other tumoral lesions arising from endocrine cells (insulinoma, gastric carcinoid, adrenal adenoma and pancreatic non-functioning neuroendocrine tumors) and non-endocrine cells (lipoma and collagenoma). Frequent recurrences in susceptible tissues that are not totally removed (as occurs in hyperparathyroidism and duodenal gastrinoma) and their unknown clinical significance have aroused current controversies in the therapeutic management of these entities, which is briefly reviewed., (Copyright © 2010 SEEN. Published by Elsevier Espana. All rights reserved.)

A 30-year-old woman had a history of prolactinoma and primary hyperparathyroidism. She was diagnosed as having multiple endocrine neoplasia type 1 with gastrinoma and liver metastases. Octreotide therapy was started and the serum gastrin level decreased immediately. Octreotide continued to suppress gastrin secretion over the next 7 years. The Ki67/MIB1 proliferation index of this tumor was only 0.5 % and somatostatin receptor (SSTR) 2 expression was very strong in both 2002 and 2009. This case suggests the importance of investigating the Ki67/MIB1 index and SSTR expression in patients with metastatic gastrinoma.

Neuroendocrine tumors of the pancreas comprise a class of rare tumors that can be associated with symptoms of hormone overproduction. Five distinct clinical endocrinopathies are associated with neuroendocrine tumors; however, most of these tumors remain asymptomatic and follow an indolent course. Complete surgical resection offers the only hope for cure, but understanding the basic biology of the tumors has advanced the medical management in metastatic disease. Surgical resection of hepatic metastases offers survival advantage and should be performed when feasible. Although hepatic artery embolization is currently the preferred mode of nonsurgical palliation for pain and hormonal symptoms, other modalities may play a role in metastatic disease.

Gastrinomas may occur in the pancreas, duodenum or peripancreatic lymph nodes. The gastrin overproduction leads to the Zollinger-Ellison syndrome with multiple gastric and duodenal ulcers and diarrhea. About two thirds of gastrinomas are malignant. Diagnosis is made by clinical history, gastroscopy, and measurement of serum gastrin, gastric juice pH, CT scan, endoscopic ultrasonography and somatostatin receptor scintigraphy. Surgery should always be considered if the liver is not involved. Proton pump inhibitors offer symptomatic relief. Medical therapy for tumor control includes biotherapy with alpha-interferon and somatostatin analogs yielding a response rate of about 10-15%, chemotherapy or targeted radiotherapy. We describe a patient with almost complete response on treatment with Sandostatin LAR, a long-acting somatostatin analog. In patients with metastatic gastrinomas not suitable for chemotherapy, interferon or targeted radiotherapy, single therapy with somatostatin analogs may be an alternative., (Copyright 2008 S. Karger AG, Basel.)

Background: Zollinger Ellison syndrome (ZES), an ulcerative disease of the upper gastrointestinal tract that involves the production of high levels of gastrin and gastric acid, is a rare, symptomatic, endocrine neoplastic disease., Case: We report a rare case of gastrinoma that was first diagnosed during pregnancy in which the primary tumor was located in the liver. The ZES was well controlled with Zoton (Lansoprazole) following surgery. The patient had an uneventful pregnancy and delivery without significant complications., Conclusions: The present case suggests that treatment with Zoton for ZES during pregnancy is safe and effective.

Previous experiments reported desensitization to SS action in rat anterior pituitary cells and cell lines. The aim of the study was to verify whether the lack of desensitization to SS analogs (SSa) observed in acromegalic patients was also present in subjects with normal hypothalamic-pituitary function. The effect of chronic treatment with octreotide long-acting release (o-LAR, 10-30 mg/28 days) on IGF-I levels was then evaluated in 23 patients with gastroenteropancreatic (GEP) endocrine tumors (8 gastrinomas, 6 carcinoids, and 9 functioning pancreatic tumors). Serum IGF-I, clinical symptoms, plasma chromogranin-A (CgA) and markers of hepatic synthesis were evaluated before and after a short-term period in all the patients (median 4.5 months), after a medium-term period in 12 (median 18 months) and after a long-term follow-up period in 9 of them (median 48 months). Mean IGF-I levels decreased from 17.3+/-7.0 to 12.8+/-6.2 nmol/l in the short-term (p<0.005) being reduced from baseline concentrations in 87% and under the normal range for age in 35% of patients. Afterwards, they always remained stable both in the medium- and long-term periods, still being low in 3/12 and 2/9 patients, respectively. No alterations in biochemical markers of liver function were found either before or during therapy. No correlation between IGF-I levels, CgA concentrations and/or clinical definitive outcome was observed. In conclusion, the study demonstrated that: a) similarly to that observed in acromegalic patients, chronic o-LAR treatment did not induce desensitization of pituitary SS receptors (SSR) in humans with intact hypothalamic-pituitary axis, and b) in patients with GEP endocrine tumors, GH/IGF-I inhibition did not contribute to SSa efficacy.

The Zollinger-Ellison syndrome is characterized pathophysiologically by a significant hypergastrinemia derived from a gastrin-secreting neuroendocrine tumor with a primary location in the pancreas or duodenum. Chronic hypergastrinemia in turn triggers gastric acid hypersecretion yielding in chronic or recurrent or refractory peptic ulcer disease and/or chronic diarrhea. One half of patients with ZES will have distant metastases in the liver by the time the diagnosis is established and one half of all patients with ZES will experience chronic diarrhea as chief complaint rather than peptic ulcer-related symptoms and signs. Gastrinomas have been reported to either manifest sporadically or to occur in conjunction with the genetic background of the MEN-I syndrome. Diagnosis is based on the patients history which is typically characterized by recurrent episodes of peptic ulcer disease or by severe reflux esophagitis and/or diarrhea or by acid-related symptoms which fail to respond to standard treatment regimens. Upper gastrointestinal tract endoscopy will provide evidence for peptic ulcer disease in anatomical regions located aborally the duodenal bulb within the descending part of the duodenum or even farther distally within the jejunum. Peptic ulcers frequently occur in groups indicating some substantial acid hypersecretion. A gastric pH > 2 is mutually exclusive for ZES. Increased serum gastrin levels confirm the diagnosis biochemically. Gastrin secretion can be determined in the basal state or following stimulation with secretin or calcium. High sensitivity and specificity for the diagnosis of ZES is provided by determining the ratio of basal versus pentagastrin-stimulated gastric acid secretion: The ratio of BAO / MAO > 0.6 is highly specific for gastrinoma. To localize the gastrin-secreting tumor computer-assisted tomography, endoscopic ultrasound, and somatostatin receptor scintigraphy provide useful help but most recently, endoscopic ultrasound with high resolution transducers appear to improve preoperative site localization. If modern imaging techniques fail to elucidate the site of the tumor, intraoperative diaphany may help to detect gastrinomas within the duodenal wall. Definitive treatment will only be achieved by total surgical resection of the gastrin-producing tumor in the pancreas or duodenum including dissection of the regional lymph nodes. Control of symptoms will have to be achieved by administration of highly potent proton pump inhibitors in up to 2-3-fold increased standard doses to inhibit gastric acid hypersecretion. Elevation of gastric pH > 4 will be the therapeutic target to protect the mucosa of the upper gastrointestinal tract. Basal acid output should be reduced to less than 10 mEq H(+) per hour which requires administration of highly potent proton pump inhibitors with a recommended starting dose of 60 mg omeprazole equivalents per day.

Gastrinomas are functional neuroendocrine tumors of the gastroenteropancreatic system. Surgery is first line treatment in gastrinomas, however often fails to be curative. This manuscript reviews current strategies of medical treatment of surgically non-curable gastrinoma. Symptomatic treatment with H(+)-K(+)-ATPase proton-pump inhibitors suppresses hypersecretion of gastric acid and substantially improves quality of life in patients with Zollinger-Ellison syndrome. Further medical therapy is only recommended in cases of progressive metastatic gastrinoma. In well differentiated neuroendocrine carcinoma (G1 and G2) a so-called biotherapy with somatostatin analogues exists as first-line and chemotherapy with streptocotozin plus doxorubicine/5-FU as second-line medical treatment option. In poorly differentiated neuroendocrine carcinoma (G3) chemotherapy with etoposide plus cisplatin is possible. Prospective future therapeutic strategies may include treatment with novel somatostatin analogues as well as angiogenesis inhibitors and kinase inhibitors targeting tumor-specific signaling cascades.

Ectopic Cushing's syndrome due to various malignancies is not uncommon. However, a few cases of ectopic Cushing's syndrome caused by corticotropin-releasing hormone (CRH), or CRH with adrenocorticotropic hormone (ACTH) have been reported. A 28-year-old woman presented with acute upper gastrointestinal bleeding caused by an active ulcer, located atypically in the 2nd portion of duodenum. Further work-up revealed high gastrin levels and abdominal computed tomography (CT) scans showed a large pancreatic head mass with multiple liver metastases. The serum cortisol and ACTH levels were checked due to hypokalemia with metabolic alkalosis and recent amenorrhea. Cortisol and ACTH were both highly elevated with pituitary hyperplasia and elevated CRH. The existence of ectopic ACTH and CRH in the liver biopsy was also demonstrated immunohistochemically. Since an operation was not feasible, chemotherapy was conducted using paclitaxel and etoposide. These two drugs were chosen according to the IN VITRO chemotherapy response assay to maximize the treatment. This report demonstrates concurrent ACTH- and CRH-related ectopic Cushing's syndrome caused by malignant gastrinoma with multiple liver metastases that was treated with marginal success using a multidisciplinary medical approach.

Case History: A 6.2 kg, 8-year-old, spayed female Australian Terrier was presented with weight loss, inappetence, lethargy and a 2-day history of intermittent vomiting., Clinical Findings: The dog had cranial abdominal pain and there was melaena present on digital rectal examination. Haematology revealed a marked, acute leucogram., Diagnosis and Treatment: Fasting serum gastrin levels were markedly elevated and gastrinoma was suspected. Treatment was initiated with omeprazole, ranitidine and sucralfate. The dog remained clinically normal for 26 months, at which time exploratory surgery was undertaken and the dog subsequently euthanised due to extensive metastases. Histopathology and immunocytochemistry confirmed the diagnosis of metastatic gastrinoma., Clinical Relevance: This is a rare condition infrequently reported. Although the number of cases treated with omeprazole are too few to draw firm conclusions, it would appear that proton pump inhibitors are useful and should be considered for cases of gastrinoma managed medically. Long-term prognosis is poor, and survival times range from 1 to 147 weeks. Many treatment options are discussed in the medical literature though not all are feasible in veterinary patients.

Background: A 64-year-old woman presented to the emergency room with a 3-month history of intermittent abdominal cramps, accompanied by nausea, vomiting, anorexia, and decreased bowel movements consistent with a partial intestinal obstruction. She had a 12-year history of peptic ulcers, which had been treated with histamine-2 blockers., Investigations: Physical examination, abdominal X-ray, abdominal CT scan, colonoscopy and assessment of gastrin levels., Diagnosis: Duodenal neuroendocrine neoplasm showing gastrin expression and stage III (T3N2M0), poorly differentiated adenocarcinoma of the cecum arising from hyperplastic polyposis., Management: Right-sided hemicolectomy with ileocolonic anastomosis, duodenal resection, leucovorin and 5-fluorouracil chemotherapy, annual colonoscopic surveillance, and polypectomy.

Background: Patients with a gastrinoma are treated with proton pump inhibitors (PPI) and histamine type-2 receptor antagonists (H2). In order to diagnose a gastrinoma these drugs must be discontinued, but this increases the risk of gastrointestinal perforation. We aimed to determine if a gastrinoma could be diagnosed without cessation of PPI/H2 therapy., Methods: In all, 90 patients (controls and patients diagnosed with a gastrinoma both on and off PPI/H2 therapy) were recruited, and plasma gastrin measured., Results: Patients with a gastrinoma on PPI/H2 medication had a significantly higher fasting plasma gastrin concentration than control patients on PPI/H2 medication (298+/-33 versus 204+/-30 pmol/L, P = 0.01). However, there was substantial overlap between gastrin levels in these two groups., Conclusion: This study confirms that a gastrinoma cannot be diagnosed on the basis of a fasting plasma gastrin assay while patients remain on PPI/H2 therapy.

Proton pump inhibitors are being increasingly used and for longer periods of time, especially in patients with gastroesophageal reflux disease. Each of these trends has led to numerous studies and reviews of the potential risk-benefit ratio of the long-term use of proton pump inhibitors. Both long-term effects of hypergastrinaemia due to the profound acid suppression caused by proton pump inhibitors as well as the effects of hypo-/achlorhydria per se have been raised and studied. Potential areas of concern that have been raised in the long-term use of proton pump inhibitors, which could alter this risk-benefit ratio include: gastric carcinoid formation; the development of rebound acid hypersecretion when proton pump inhibitor treatment is stopped; the development of tolerance; increased oxyntic gastritis in H. pylori patients and the possibility of increasing the risk of gastric cancer; the possible stimulation of growth of non-gastric tumours due to hypergastrinaemia; and the possible effect of the hypo/achlorhydria on nutrient absorption, particularly iron and vitamin B12. Because few patients with idiopathic gastro-oesophageal reflux disease/peptic ulcer disease have been treated long-term (i.e., >10 years), there is little known to address the above areas of potential concern. Most patients with gastrinomas with Zollinger-Ellison syndrome have life-long hypergastrinaemia, require continuous proton pump inhibitors treatment and a number of studies report results of >5-10 years of tratment and follow-up. Therefore, an analysis of Zollinger-Ellison syndrome patients can provide important insights into some of the safety concerns raised above. In this paper, results from studies of Zollinger-Ellison syndrome patients and other recent studies dealing with the safety concerns above, are briefly reviewed.

Endocrine pancreatic tumours (EPTs) are uncommon tumours occurring in approximately 1 in 100,000 of the population, representing 1-2% of all pancreatic neoplasms. Some of the tumours may be part of multiple endocrine neoplasia type one (MEN-1) syndrome or von Hippel-Lindau (vHL) disease. EPTs are classified as functioning or non-functioning tumours on the basis of their clinical manifestation. The biochemical diagnosis of EPT is based on hormones and amines released. Besides specific markers such as insulin, there are also general tumour markers such as chromogranin A, which is the most valuable marker and has been reported to be increased in plasma in 50-80% of patients with EPTs and correlates with tumour burden. The location of endocrine tumours of the pancreas includes different techniques, from endoscopic investigations to scintigraphy (e.g. somatostatin receptor scintigraphy) and positron emission tomography. The medical treatment of endocrine pancreatic tumours consists of chemotherapy, somatostatin analogues and alpha-interferon. None of these can cure a patient with malignant disease. In future, therapy will be custom-made and based on current knowledge of tumour biology and molecular genetics.

Preoperative localization is important for the successful treatment of gastrinomas. The aim of this study was to investigate whether selective intra-arterial calcium injection and hepatic venous sampling was able to localize gastrinomas in four patients who remained on proton pump inhibitor or H2 antagonist therapy. Calcium gluconate was injected directly into the arteries supplying the pancreas and liver after standard selective angiography. Gastrin levels were then measured in samples taken from the right hepatic vein. Calcium gluconate produced a diagnostic rise (at least 2-fold) in serum gastrin and unequivocally localized the tumour to a specific vascular territory in each case. One patient did not undergo surgery. In the remaining three patients, surgery confirmed the position and histology of the tumour. This study shows that in four patients with a confirmed gastrinoma we were able to localize the gastrinoma by selective intra-arterial calcium injection and hepatic venous sampling, whilst the patients remained on proton pump inhibitor or H2 antagonist therapy, thereby reducing their risk of gastrointestinal perforation.

Purpose of Review: A comprehensive literature review of more than 200 original manuscripts published in the last 18 months was conducted to summarize landmark studies performed on the molecular biology, diagnosis, imaging, and treatment of endocrine tumors of the pancreas., Recent Findings: Recent achievements occurred on many fronts. Identification of a novel insulin splice variant with increased translation efficiency moved forward the understanding of the molecular biology of insulinomas. Results of a 29-year prospective study from the National Institutes of Health clarified the epidemiology of multiple endocrine neoplasia-1 syndrome. Chromogranin A was identified as a promising marker for pancreatic endocrine tumors. New imaging, including F-dopa positron emission tomography and laparoscopic ultrasound, and the effective combination of existing modalities localized and staged tumors with greater accuracy. Nonoperative treatment strategies show promise; discovery of the antiangiogenic properties of octreotide and the overexpression of tyrosine kinase receptors such as c-kit, epidermal growth factor receptor, and platelet-derived growth factor receptor on malignant endocrine pancreatic tumors may lead to promising pharmacologic treatment., Summary: There have been exciting recent advancements in research surrounding endocrine pancreas that hopefully will pave the way for potential improvement in clinical outcomes for patients with these tumors.

Gastrinomas of the stomach are extremely rare endocrine tumors producing Zollinger-Ellison syndrome. We report here the case of a patient with gastrinoma of the stomach who presented regional and hepatic metastases at the time of diagnosis. The endocrine tumor was discovered incidentally 8 yr after the onset of symptoms related to peptic ulcer, which responded to medical treatment with a proton pump inhibitor. Surgery did not cure the patient, as demonstrated by provocative tests showing serum gastrin responses indicative of residual disease. A long-term treatment with the somatostatin analog lanreotide induced a biochemical response and was associated with a substantially stable disease.

The gastroenteropancreatic endocrine tumor is relatively rare tumor that originate from pancreas, duodenum, and a variety of neuroendocrine cells. The differential diagnosis and preoperative localization of the tumor are important, because surgical resection of the tumor is the first choice of treatment. Of these tumors, insulinomas and gastrinomas are usually small in size (less than 2.0 cm), and methods of preoperative localization such as ultrasonography, computed tomography or magnetic resonance imaging often fail to identify them. These tumors often malignant, and tumors as small as 1 to 2 mm might develop lymph node metastases especially in gastrinomas. Recent studies have shown that selective arterial calcium stimulation test and hepatic venous sampling using intraarterial calcium injection as the insulin secretagogue are useful for detection of small insulinomas, and the selective intraarterial injection of secretin test combined with venous sampling (Imamura technique), for detection of small gastrinomas. In addition, somatostatin-receptor scintigraphy is widely used in Western countries. Moreover, detection of the tumor during operation using ultrasonography delivered much better results than preoperative diagnoses. These tumors may be associated with multiple endocrine neoplasia type 1, and MEN1 gene mutation analysis is necessary in those patients.

The somatostatin analogue octreotide was effective in controlling systemic effects related to multiple liver metastases from a gastrinoma. A 61-year-old man underwent distal gastrectomy for gastrinoma in the duodenum, because a curative resection was not feasible due to metastases found in paraaortic lymph nodes during operation. Multiple liver metastases, associated with an increase in serum gastrin concentration, were found by magnetic resonance imaging 16 months after the operation. Although chemotherapy with dimethyltrizenoimidazole carboxamide was not effective, subcutaneous administration of octreotide was effective in controlling the growth of the liver metastases and in stabilizing serum gastrin. The patient now receives subcutaneous injections of octreotide, at 200 microg a day, twice a week, as an outpatient.

Therapeutic strategy of neuroendocrine tumours is complex, due to their heterogeneity and to the fact that although generally slow growing, a significant proportion demonstrates aggressive tumour growth. Symptomatic carcinoid syndrome and various pancreatic endocrine tumours with symptomatic syndromes are well controlled with somatostatin analogues. Surgery remains the mainstay of treatment if the tumour can be resected. Metastatic pancreatic neuroendocrine tumour are treated when resection is not feasible with combination chemotherapy using adriamycin and streptozotocin, which remains a standard of care. In well differentiated tumour of the gut or the lung there is no clear standard of chemotherapy and treatment vary according to the tumour course. In indolent cases, somatostatin analogues are the best treatment, in case of aggressive tumours chemoembolisation should be preferred when the disease is located or predominant in the liver. Poorly differentiated tumours are treated by combination chemotherapy with etoposide and cisplatin, and surgery has no indication. Gastrinoma and other pancreatic tumours arising in the context of multiple endocrine neoplasia type I disease need a specific therapeutic strategy.

Background: Malignant pancreatic endocrine tumors (PETs) have a poor prognosis and existing antitumor treatments are unsatisfactory. Recent studies have shown somatostatin analogues to have antitumor growth effects in patients with malignant PETs; however, to the authors' knowledge, little information exists regarding their efficacy or effect on survival in patients with progressive malignant gastrinoma, the most common symptomatic malignant PET. The purpose of the current study was to study prospectively the efficacy, safety, and effect on survival of long-term treatment with octreotide in consecutive patients with progressive malignant gastrinoma., Methods: Fifteen consecutive patients with malignant gastrinoma with progressive hepatic metastases were studied. All patients underwent conventional imaging studies (computed tomography scan, magnetic resonance imaging, ultrasound, and, if needed, selective angiography) and somatostatin receptor scintigraphy prior to treatment and at 3-6-month intervals while receiving treatment. The patients all were treated initially with octreotide, 200 microg every 12 hours, and at last follow-up were being maintained on long-acting release octreotide, 20-30 mg every month. Tumor size and/or number were used to classify patient responses as either no tumor response or tumor response (stabilization or decrease in size). Treatment response was correlated with tumor and clinical characteristics., Results: Tumors in 8 of the 15 patients studied (53%) responded at 3 months, with 47% (7 of 15 patients) demonstrating tumor stabilization and 6% (1 of 15 patients) demonstrating a decrease in tumor size. The mean duration of response was 25.0+/-6.1 months (range, 5.5-54.1 months). Six of the eight responders were continuing to respond at the time of last follow-up. Tumor response did not correlate with any clinical parameter (e.g., tumor extent, fasting gastrin, or acid secretory rates). However, slow-growing tumors were more likely to respond prior to treatment (86% vs. 0%) (P < 0.0014). During follow-up (range, 4-8 years), 25% of the responders died compared with 71% of the nonresponders, a difference that approached statistical significance (P = 0.10). Two patients (13%) developed serious side effects that required the withdrawal of octreotide., Conclusions: Octreotide is an effective antitumor treatment in patients with progressive malignant gastrinoma. In approximately 50% of these patients octreotide has an antigrowth effect; treatment is associated with a low incidence of serious side effects compared with other antitumor treatments commonly used and, in contrast to many studies, the growth response is long-lasting. The results of the current study suggest that octreotide treatment should replace chemotherapy as the standard treatment for these patients, especially those patients with slow-growing tumors. Additional studies involving larger numbers of patients will be needed to determine a convincing effect on survival.

Somatostatin analogs and alpha-interferon induce good responses as single drugs in the treatment of endocrine pancreatic tumors. We examined the efficacy and tolerability of the combination of alpha-interferon and somatostatin analogs in 16 patients with metastatic endocrine pancreatic tumors. All patients except one had received prior treatment and were in a progressive state. Doses of alpha-interferon and somatostatin analogs were individually titrated. The alpha-interferon doses varied between 9 and 25 million units per week and were combined with 100-1500 microg of octreotide or 6000 microg of lanreotide daily. Radiological response was seen in 3 of 16 (19%) patients (median duration 23 mo). Biochemical response was seen in 10 of 16 (62.5%) patients (median duration 22 mo). All three patients previously progressing on both alpha-interferon and somatostatin analog as single drugs achieved a stabilization of the disease when treated with the combination (median duration 10 mo). Seven of eight (88%) patients previously progressing on alpha-interferon treatment benefited from the combination with biochemical partial response or stabilization. All six patients previously progressing during somatostatin analog treatment achieved biochemical partial response or stabilization. More than 80% of patients who progressed during previous treatment with either drug benefited from the combined treatment, which also was well tolerated. Thus, a combination of alpha-interferon and somatostatin analogs may be considered for patients previously progressing on treatment with alpha-interferon or somatostatin analogs. However, in this study, the value of sequential treatment has not been evaluated.

Long-acting depot forms of somatostatin analogs administered by intramuscular injections are now available for the treatment of neuroendocrine tumors (NETs). In the present study, we investigated the efficacy and tolerability of a slow-release form of lanreotide in patients with advanced NETs. From July 1996 to January 1999, 25 patients with advanced NETs (12 carcinoids, 13 endocrine pancreatic tumors) were enrolled in the study. Thirteen patients were pretreated with subcutaneous octreotide, chemotherapy, or hepatic metastasis alcoholization. All the patients had measurable disease. Seventeen patients were symptomatic and 20 patients had elevated serum and/or urine markers. Octreotide scintigraphy was positive in 23 of 25 patients. Lanreotide was administered as intramuscular injections at the dose of 30 mg every 2 weeks until there was objective, biochemical, or symptomatic tumor progression. Objective partial responses (PRs) were documented in 2 patients (8%), whereas 10 patients (40%) had tumor stabilization. The PRs were observed in patients with midgut carcinoids, of whom one was pretreated with subcutaneous octreotide. The response duration was 21+ and 24+ months in responding patients; the median duration of disease stabilization was 8.5 months (range, 4-21+). The overall biochemical response rate was 42%, including 2 complete responses (CRs) (10.5%) and 6 PRs (31.5%); all biochemical responses were observed mostly in patients with carcinoid tumors; the duration of response was 18+ and 30+ months for CRs; the median duration of biochemical response was 7 months (range, 4-18+) for PRs. The overall symptomatic response rate was 70% with a median duration of 7.5, 18, and 18+ months for diarrhea, abdominal pain, and flushing, respectively. Median duration of lanreotide treatment was 10 months (range, 2-30+). No significant side effects were reported. Depot lanreotide 30 mg shows significant efficacy in terms of objective response rate and in biochemical and symptomatic control, in pretreated patients as well as nonpretreated patients with advanced NETs. Tolerability is good, with good patient compliance.

Background: The thyroid gland and the adrenal glands are the most common sites of endocrine carcinomas (see Part I of this review, Med Klin 2000;95: 20-5, Nr. 1). Less frequent are endocrine malignancies of the gastrointestinal tract (gastrinomas, insulinomas, glucagonomas, carcinoids and others)., Treatment: Because of the rarity and missing prospective studies as well as radiotherapy and chemotherapy resistance of these tumors, generally accepted conventional therapy guidelines for these endocrine carcinomas do not exist. Surgery and radionucleotide treatment should be considered as first line therapy. Somatostatin analogs (octreotide) are frequently used as well. Chemotherapy is usually not effective. Common substances are streptozotocin, 5-fluorouracil, doxorubicin, dacarbazine and cyclophosphamide.

Neuroendocrine tumours are rare and often include insulinoma, gastrinoma and other low frequency tumours that secrete gastrointestinal hormones. Their preoperative localization, despite continuous medical advances, is extremely difficult but helpful in guiding the surgeon towards a proper form of treatment. After presenting their cases, the authors conclude that the treatment of choice for these tumours is surgery due to their anatomopathological features (benign, scarcely malign or invasive, slow growth). On the other hand, medical therapy plays an important role in either preparing the surgical intervention or alleviating symptoms when the patient is inoperable.

Medical treatment is the elective therapy for patients with gastrinoma when the tumor is not found at surgery or is unresectable or when there is a metastatic disease. H2-blockers and omeprazol are able to control gastric acid secretion and, in addition, somatostatin analogues decrease gastrin levels. A new long-acting and slow release formulation of a somatostatin analogue (lanreotide, SR-L) has been developed. We treated two patients suffering from gastrinoma, total gastrectomy and hepatic metastases with 30 mg intramuscular injections of SR-L every 15 and 10 days, respectively, for a seven-month period. After the treatment, gastrin levels decreased from 35,494 and 15,086 ng/l to 3,211 and 167 ng/l (92 and 98% below pre-treatment levels) in case 1 and 2 respectively, with a relief of symptoms and no side effects.

Background and Aim: Somatostatin analogues are able to control symptoms and to detect tumour localisation in gastro-entero-pancreatic endocrine tumour patients. Few studies have evaluated the efficacy of somatostatin analogues in controlling tumoural growth during long-term treatment and, generally, a low efficacy has been reported in studies using multiple daily octreotide dosages. In the present study a single daily dose of octreotide (500 micrograms) for 1 year was used in the treatment of 10 patients with progressive gastro-entero-pancreatic metastatic tumour., Patients: Ten consecutive patients (3 females, 7 males age range 40-62 years) were studied of whom 4 had Zollinger-Ellison syndrome (2 with MEN-1), 3 had a carcinoid syndrome, and 3 had a non-functional neuro-endocrine tumour. All patients, 6-12 months before octreotide treatment, showed tumour progression. In all patients, somatostatin receptor status was assessed by Somatostatin Receptor Scintigraphy and tumoural lesions by Magnetic Resonance Imaging. Appropriate tumoural markers were also evaluated., Results: At the three-month control, two patients (non-functional) showed an aggressive progression of tumoural growth despite treatment and were excluded from the study. One patient was lost during follow-up. Of the 7 remaining patients, imaging evaluation studies revealed, after 1 year of treatment, stable disease in 6 patients, whereas a partial tumoural response was observed in one patient (gastrinoma). Biochemical tumoural markers decreased with respect to basal values of 53-78% in these seven patients at the end of therapy., Conclusions: These results suggest that one year of octreotide in a single daily dose (500 micrograms) is effective in the long-term stabilization of tumoural progression in metastatic gastro-entero-pancreatic tumour patients.

Objectives: Lanreotide is a somatostatin analogue whose activity persists for 10-14 days. In this study, we treated a group of patients with gastrointestinal endocrine tumors with lanreotide to assess its therapeutic efficacy and tolerability., Methods: Eighteen patients, 12 male and six female, mean age 58 yr (range, 25-80 yr) were studied. Ten had carcinoid tumors, five had nonfunctioning endocrine tumors, two had glucagonomas, and the remaining one had a gastrinoma. All patients had somatostatin receptors, demonstrated by octreoscan scintigraphy. Lanreotide was administered intramuscularly at a dose of 30 mg every 10 days, for a mean of 12 months (range, 5-18 months). Fifteen of the 18 patients had been previously treated with octreotide., Results: In patients with carcinoid tumors, lanreotide markedly reduced daily bowel movements and flushing episodes. A reduction was also observed in urinary serotonin and urinary 5-hydroxyindoleacetic acid, although it was not statistically significant. A marked reduction in symptoms, and in plasma glucagon and serum gastrin levels, was also observed in patients with glucagonoma and gastrinoma. In the five patients with nonfunctioning endocrine tumors, as in all the other 13 patients, no significant effects were noted in the size of the tumor. The administration of lanreotide did not cause side effects, apart from transient abdominal pain and pain at the injection site in two patients. Only in the patient with gastrinoma was lanreotide suspended, because of the appearance of attacks of marked hypoglycemia. In the 15 patients previously treated with octreotide, no differences in the effects were noted with lanreotide., Conclusions: Lanreotide has a satisfactory therapeutic efficacy and tolerability in the treatment of gastrointestinal endocrine tumors; its effects are similar to those of octreotide. However, unlike octreotide, it can be administered once every 10-14 days, instead of 2 or 3 times daily and for this reason, it is preferable in clinical practice.

Gastrinoma when associated with liver metastasis results in markedly reduced survival. However, a standard chemotherapeutic protocol for patients with unresectable tumors has not been established. We treated two patients with gastrinoma with multiple liver metastases with intravenous administration of 5-dimethyltriazenoimidazole-4-carboxamide (DTIC; dacarbazine) at a dose of 200 mg/body for 5 consecutive days. The first patient showed a marked decrease in serum gastrin levels, from 338 000 pg/ml to 22 900 pg/ml (normal range, >220pg/ml), as well as a decrease in the size and number of peripancreatic and liver tumors, after four courses of DTIC. An additional nine courses of the treatment were given, and the peripancreatic tumor was resected. The patient has been in good overall condition for more than 3(1/2) years. The second patient was treated with a total of ten courses of DTIC. Serum gastrin levels did not increase and the hepatic tumor did not change in size for more than 4 years. DTIC was effective in controlling the clinical and biochemical manifestations of gastrinoma associated with liver metastasis without serious side effects. As the toxity of DTIC is minimal, (e.g., nausea and vomiting) DTIC therapy should be considered useful for islet cell carcinomas with multiple metastases.

A 9-year-old male German Shepherd Dog was presented with the primary complaints of vomiting, profuse watery diarrhea, anorexia, and severe weight loss. The dog developed hematemesis and melena, which were unresponsive to treatment with an H2-receptor antagonist and a gastrointestinal protectant. A marked neutrophilia, panhypoproteinemia, hypokalemia, and mildly increased activities of alkaline phosphatase and alanine aminotransferase were the only relevant abnormalities found on a CBC, serum biochemical profile, and urinalysis. An exploratory laparotomy revealed several small nonresectable masses at the root of the mesentery, which were identified histologically as a neuroendocrine neoplasm. Immunohistochemical staining of the neoplasm was positive for gastrin and negative for insulin, glucagon, pancreatic polypeptide, and vasoactive intestinal polypeptide. Fasting serum gastrin concentrations were high. Zollinger-Ellison syndrome was diagnosed, and the dog was treated with omeprazole, an H+,K(+)-ATPase inhibitor. All clinical signs resolved, and the dog remains asymptomatic 2 years later. Omeprazole may be the gastric acid antisecretory drug of choice for dogs with gastrinoma.

Gastrinomas in dogs are difficult to diagnose, localise and treat. In humans, somatostatin analogues have improved localisation and treatment of gastrinomas. The somatostatin analogues pentetreotide and octreotide were evaluated for the detection and treatment of gastrinoma in a dog. 111indium-pentetreotide scintigraphy revealed multiple areas of activity in the patient's mid-ventral abdomen which were consistent with masses in the pancreas and liver at laparotomy. Immunohistochemistry, electron microscopy and binding of 125I-[Tyr3]-octreotide in vitro confirmed the lesion as a gastrinoma which expressed somatostatin receptors. Octreotide at doses of 2, 4 and 8 micrograms/kg caused transient decreases in circulating gastrin. Plasma somatostatin peaked at one hour after octreotide and was still detectable at four and six hours after administration of octreotide. Combination therapy with famotidine, omeprazole, sucralfate and increasing doses of octreotide allowed patient survival for 14 months.

Multiple Endocrine Neoplasia type 1 (MEN 1) syndrome comprises tumors or hyperplasia of different glands, including parathyroid, pituitary, adrenal cortex and the gastroenteropancreatic system. The vast majority of MEN 1 are found in familial clusters, although a few cases are sporadic. Hypercalcemia and/or nephrocalcinosis are the first and most common clinical manifestation in familial MEN 1 syndrome, followed by islet cell tumors (especially those secreting gastrin or insulin) and pituitary dysfunction due to either functioning or non-functioning microadenomas. Genetic studies indicate that familial MEN 1 syndrome is inherited through a dominant gene with incomplete penetrance and variable expression. The diagnosis of MEN 1 syndrome is mainly based on the careful assessment of the clinical history, symptoms physical evaluation along with the assay of serum electrolytes (i.e., calcium, phosphorus, etc.) and hormonal substances (i.e., gastrin, insulin, pancreatic polypeptide, prolactin, adrenocorticotropic hormone, etc.). In addition, several provocative tests have been used to identify endocrine tumors (particularly those of the gastroenteropancreatic system) and imaging techniques play a crucial role for the diagnostic approach in MEN 1 syndrome. Even though in the long term, the prognosis of MEN 1 syndrome is unfavourable. Recently, however, many therapeutic strategies, including both surgical and pharmacological options, have been developed to reduce the size of the neoplasm and control symptoms associated with hormone oversecretion.

Proton pump inhibitors (PPIs) have been established as the new "gold standard" for traditional acid-inhibitory treatment of the so called "peptic" diseases. Due to the high antisecretory and ulcer-healing potency of omeprazole, no major improvements of the efficacy in ulcer healing and pain relief can be expected. Pantoprazole, as a further development in PPIs, is characterized by improved pharmacokinetic behavior as well as by higher tissue selectivity and binding specificity and by a very low potential to interact with the cytochrome P450 enzyme system. These characteristics may provide the basis for a low potential for side effects and for a more favorable interaction profile, although the clinical relevance of these potential advantages remains to be proven. Reflux esophagitis will also remain a domain for the traditional use of PPIs in the future. However, in the treatment of gastroduodenal ulcers, the acid inhibitory potential of PPIs will be used mainly to facilitate the eradication of H. pylori.

Long-acting somatostatin analogs, such as octreotide, comprise the therapeutic modality of choice for the symptomatic relief of flush and diarrhea in patients with carcinoid syndrome. The sequelae of gastric acid hypersecretion in patients with gastrin-producing duodenal carcinoids (gastrinoma) are perfectly controlled by proton pump inhibitors. Antiproliferative medical strategies to control the growth of metastatic carcinoid tumors include long-acting somatostatin analogs, interferon alpha, and the combination of the two. However, the success rate is less than 50%, and it is questionable whether true tumor regression can be expected. Controlled prospective studies are mandatory to address the question whether interferon or somatostatin analogs or the combination of the two should be used as first-line medical strategies and if hepatic artery embolization in patients with liver metastases should be performed before beginning medical therapy. Chemotherapy, including etoposide and cisplatin, has been shown to be effective only for purely differentiated neuroendocrine carcinomas and not for slowly growing carcinoids.

In an open phase III study, octastatin was given as a continuous subcutaneous (s.c.) infusion to 35 patients (mean age 62 years) with malignant neuroendocrine gastro-intestinal tumours and the carcinoid syndrome. The wash-out was often incomplete because of the advanced stage of disease. The starting dose of 1.5 mg/24 h was increased up to 3.0 mg/24 h at 3 months in some patients. The carcinoid syndrome disappeared in 20% of patients at 3 months and in 23% at 6 months, with 43 and 45% of patients, respectively, experiencing an improvement. The mean Karnovsky index increased by > 10% in 40% of patients at 3 and 6 months. Urinary 5-hydroxyindoleacetic acid (U-5-HIAA) levels at 3 months normalised in 1 patient, fell in 20% (by > 50%; p = 0.0021) and stabilised in 66%. The respective values at 6 months were 1, 17% (p = 0.023) and 60%. There was also a significant decrease in plasma chromogranin levels at 3 months (p = 0.042), which did not persist at 6 months. Tumour size fell (by > 50%) in 1 patient by 6 months but this patient had undergone chemoembolisation one month prior to the start of the study. Most patients had tumour size stabilisation (76 and 68%) or progression (20 and 24%) at 3 and 6 months, respectively. Dose escalation from 1.5 to 3.0 mg did not significantly improve clinical, biochemical or tumour responses. The treatment was well tolerated with minor adverse events. In an open pilot phase II study of 19 patients (mean age 58 years), patients were given high dose somatuline with a maintenance dose of 12,000 mg/day in 4 divided s.c. injections. U-5-HIAA, which was elevated in 13 patients with a mean of 444 mumol/day before the start, was reduced to 58% of baseline at 3 months, 68% at 6 months (p = 0.04), 66% at 9 months and 75% at 12 months (p = 0.14). P-chromogranin was elevated in 18 patients, with a mean of 5,300 micrograms/l before the start, and was reduced to 52, 55, 63 and 64% of the baseline at 3, 6 (p = 0.039), 9 and 12 (p = 0.013) months, respectively. In the responding patients, apoptosis was induced.

Methods: We used PET to characterize the uptake and decarboxylation of 11C-L-DOPA in vivo in two patients with endocrine pancreatic tumors: one glucagonoma and one gastrinoma., Results: With L-DOPA labeled with 11C in the beta position, in which the radioactive label follows the molecule through decarboxylation to dopamine, significant uptake was observed in the tumors. With L-DOPA labeled in the carboxyl group, in which the label is rapidly eliminated from the tissue as 11CO2 if decarboxylation takes place, an almost complete lack of uptake is noted., Conclusion: This study shows that, using selective position labeling, an in vivo action of enzymatic activity can be observed with PET and that significant decarboxylation occurs in the tested endocrine pancreatic tumors. Also, marked retention of radioactivity occurs after treatment with somatostatin analogs. It is hypothesized that this is a reflection of a reduction of exocytosis which is induced by this treatment.

A midaged lady suffering from ulcer disease for about seven years had undergone several surgical and drug therapies without any satisfying success. Then the diagnosis of a gastrinoma was made. By this time there were already multiple liver metastases. First the large supposed primary tumor of the pancreas was resected and within six months later the resection of the progressing liver metastases became necessary because of local tumor complications. The additional drug therapy with octreotide (Sandostatin) given three times daily subcutaneously prevented further tumor progress. Until now this combination of surgical and medical treatment has proved to be a successful palliative method of treating the malignant gastrinoma for 2.5 years.

To determine the value of somatostatin-receptor scintigraphy in the localization of various endocrine gastrointestinal tumors, we compared the results obtained with this new technique with the results obtained with computed tomography and sonography. We could not find an overall advantage of somatostatin-receptor scintigraphy as compared to computed tomography or sonography in the localization of intestinal carcinoids (n = 13), gastrinomas (n = 12), functionally non-active endocrine pancreatic tumors (n = 8) and various other endocrine pancreatic tumors (n = 4). In 2 patients with endocrine pancreatic tumors however, the tumors were localized preoperatively only by somatostatin-receptor scintigraphy. Somatostatin-receptor scintigraphy may occasionally be helpful in the localization of gastrointestinal endocrine tumors if these tumors are not localized by conventional imaging studies. Somatostatin-receptor scintigraphy does not solve the problem to localize small endocrine tumors.