Combined surgical and medical management of a cat with gastrinoma.

Gastrinomas are gastrin-secreting pancreatic tumours rarely diagnosed in cats. A 12-year-old female spayed cat was presented for vomiting, anorexia and weight loss. Physical exam revealed lethargy, dehydration and thin body condition. Pertinent laboratory abnormalities included a mild mature neutrophilia and borderline hypoalbuminaemia. Imaging of the abdomen revealed a mass-like change to the proximal duodenum. Exploratory laparotomy was performed, and the duodenal mass along with a 3-mm pancreatic nodule was removed. Immunohistochemical staining of the pancreatic nodule confirmed a gastrinoma. Following surgery, treatment was initiated with omeprazole and toceranib. Toceranib was discontinued after 8 weeks due to hyporexia. The patient was continued on omeprazole long term and has survived more than 35 months since diagnosis. Little information regarding treatment and prognosis for feline gastrinomas is available. In this case report, long-term survival was achieved with a combined surgical and medical approach using omeprazole and toceranib.

Somatostatin analogs in patients with Zollinger Ellison syndrome (ZES): an observational study.

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.

Gastrinomas: Medical or Surgical Treatment.

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.

Ectopic Cushing syndrome: Report of 9 cases. / Síndrome de Cushing ectópico: descripción de 9 casos.

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.

The Zollinger-Ellison syndrome: is there a role for somatostatin analogues in the treatment of the gastrinoma?

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.

(68)Ga-DOTATOC-PET/CT for effective diagnosis and treatment of pancreatic tail gastrinoma with multiple liver metastases: a case report.

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.

Pharmacotherapy of Zollinger-Ellison syndrome.

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.

[About a case of multiple endocrine neoplasia type 1. Review of some clinical manifestations and treatment controversies]. / A propósito de un caso de neoplasia endocrina múltiple tipo 1. Revisión de algunas manifestaciones clínicas y controversias en el tratamiento.

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.

A propósito de un caso de neoplasia endocrina múltiple tipo 1. Revisión de algunas manifestaciones clínicas y controversias en el tratamiento / About a case of multiple endocrine neoplasia type1. Review of some clinical manifestations and treatment controversies

La neoplasia endocrina múltiple de tipo 1 (MEN1) es un síndrome hereditario raro conocido por la predisposición a la aparición de neoplasias endocrinas en distintos tejidos como paratiroides, hipófisis y tracto gastrointestinal. Se presenta el caso de un varón en el que además de manifestaciones tradicionalmente descritas (hipeparatiroidismo y gastrinoma) se objetivan otras lesiones tumorales procedentes de células de estirpe endocrinológica (insulinoma, carcinoide gástrico, adenoma suprarrenal, tumores neuroendocrino no funcionantes del páncreas) y no endocrinológica (lipoma y colagenoma). La frecuente recurrencia de las lesiones sobre los tejidos susceptibles no resecados en su totalidad (como en el caso del hiperparatiroidismo y del gastrinoma duodenal) y las dudas sobre su significado clínico en el MEN1 suscitan cierta controversia en la actualidad sobre las recomendaciones en el manejo terapéutico de dichas lesiones que se revisa brevemente (AU)

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-endocrinecells (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 (AU)

Long-term suppressive effect of octreotide on progression of metastatic gastrinoma with multiple endocrine neoplasia type 1: seven-year follow up.

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.

The surgical and systemic management of neuroendocrine tumors of the pancreas.

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.

Regression of a large malignant gastrinoma on treatment with Sandostatin LAR: a case report.

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.

Diagnosis and treatment of gastrinoma in the era of proton pump inhibitors.

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.

Medical treatment of gastrinomas.

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.

Evaluation of IGF-I levels during long-term somatostatin analogs treatment in patients with gastroenteropancreatic endocrine tumors.

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.

Ectopic Cushing's syndrome due to concurrent corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) secreted by malignant gastrinoma.

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.

Zollinger Ellison syndrome, treated with lansoprazole, during pregnancy.

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.