[A Case of Primary Somatostatin-Producing Tumor of the Duodenum with Liver Metastases with Long-Term Survival of More than 20 Years].

A 52-year-old woman underwent esophagogastroduodenoscopy after an abnormal medical examination, which revealed a mass lesion over half the circumference of the superior duodenal angulus. Immunostaining was diffusely positive for somatostatin, synaptophysin, and chromogranin A. A 3 cm-sized mass in the pancreaticoduodenal region and multiple nodular lesions of a few mm in both lobes of the liver were revealed by CT. The diagnosis is primary somatostatin-producing tumor of the duodenum with multiple liver metastases. She underwent gastric jejunal bypass for impaired transit. Afterwards hepatic infusion and systemic chemotherapy were continued, and 5 years passed without progression. When she stopped chemotherapy for 6 months, she started somatostatin analogue therapy because of the increase of the tumors. The tumors did not increase, and 20 years have passed since the start of treatment. We report a case of primary somatostatin-producing tumor of the duodenum with liver metastases that is still alive for a long period of time, with a review of the literature.

Influence of pretreatment with everolimus or sunitinib on the subacute hematotoxicity of 177Lu-DOTATATE PRRT.

Background: Peptide receptor radionuclide therapy (PRRT) is a validated treatment for somatostatin receptor overexpressing neuroendocrine tumors (NETs). The NETTER-1 trial demonstrated a pronounced positive effect on progression-free-survival compared to high dose somatostatin analogs (SSAs), with a strong tendency toward overall survival benefit. Our aim was to investigate the influence of pretreatment with everolimus and/or sunitinib on subacute hematotoxicity of PRRT. To assess the influence of prior treatment with everolimus/sunitinib might be of clinical relevance due to the link between short-term hematotoxicity and increased incidence of late hematotoxicity.Material and methods: Our single-center retrospective study enrolled all patients treated with 177Lu-DOTATATE PRRT (1-4 cycles of 7.4 GBq), between November 2013 and July 2018. Patients were assigned to two groups according to their pretreatment: no targeted agents (N = 41), or targeted agents (everolimus, sunitinib or both; N = 41). The end point was subacute hematotoxicity, defined as the nadir value between the first administration until 3 months after the last administration, using the CTCAE 4.03 classification. The impact of splenectomy was also explored.Results: Eighty percent of patients had a primary gastroenteropancreatic NET. No statistically significant differences in severe subacute hematotoxicity were seen in the pretreated group vs. the naive group for hemoglobin (grade 3/4: 12% vs. 22%), neither for leucocytes (grade 3/4: 10% vs. 7%), neutrophils (grade 3/4: 5% vs. 7%), lymphocytes (grade 3/4: 49% vs. 37%) and platelets (grade 3/4: 15% vs. 15%). Furthermore, we observed significantly lower toxicity for total white blood cells, lymphocytes and platelets in the subgroup that had splenectomy (N = 12). Limitations of this study include the potential bias in lack of use of targeted agents in patients more susceptible to toxicity, and the limited number of patients and events.Conclusions: In a patient cohort with NET pretreated with everolimus and/or sunitinib, we could not demonstrate a significant effect of prior/pretreatment with everolimus and/or sunitinib on the subacute hematotoxicity of 177Lu-DOTATATE PRRT.

A new twist in neuroendocrine tumor research: Pacak-Zhuang syndrome, HIF-2α as the major player in its pathogenesis and future therapeutic options.

UNLABELLED: Backround. There is increasing evidence of the role of hypoxia or pseudohypoxia in tumorigenesis, including pheochromocytoma (PHEO) and paraganglioma (PGL). (Pseudo)hypoxia leads to activation of hypoxia-inducible transcription factors (HIFs) and thus, promotes the transcription of hypoxia-responsive genes which are involved in tumorigenesis. Recently identified is a new syndrome consisting of multiple and recurrent PGLs or PHEOs, somatostatinoma, and congenital polycythemia, due to somatic hypoxia-inducible factor 2α gene (HIF2A) mutations. METHODS AND RESULTS: PubMed and Web of Science online databases were used to search reviews and original articles on the HIF, PHEO/PGL, and Pacak-Zhuang syndrome. CONCLUSIONS: The novel somatic and germline gain-of-function HIF2A mutations described latterly emphasize the role of the HIF-2α in the PHEO/PGL development and these findings designate HIF, especially HIF-2α, as a promising treatment target.

Gastrointestinal hormones stimulate growth of Foregut Neuroendocrine Tumors by transactivating the EGF receptor.

Foregut neuroendocrine tumors [NETs] usually pursuit a benign course, but some show aggressive behavior. The treatment of patients with advanced NETs is marginally effective and new approaches are needed. In other tumors, transactivation of the EGF receptor (EGFR) by growth factors, gastrointestinal (GI) hormones and lipids can stimulate growth, which has led to new treatments. Recent studies show a direct correlation between NET malignancy and EGFR expression, EGFR inhibition decreases basal NET growth and an autocrine growth effect exerted by GI hormones, for some NETs. To determine if GI hormones can stimulate NET growth by inducing transactivation of EGFR, we examined the ability of EGF, TGFα and various GI hormones to stimulate growth of the human foregut carcinoid,BON, the somatostatinoma QGP-1 and the rat islet tumor,Rin-14B-cell lines. The EGFR tyrosine-kinase inhibitor, AG1478 strongly inhibited EGF and the GI hormones stimulated cell growth, both in BON and QGP-1 cells. In all the three neuroendocrine cell lines studied, we found EGF, TGFα and the other growth-stimulating GI hormones increased Tyr(1068) EGFR phosphorylation. In BON cells, both the GI hormones neurotensin and a bombesin analogue caused a time- and dose-dependent increase in EGFR phosphorylation, which was strongly inhibited by AG1478. Moreover, we found this stimulated phosphorylation was dependent on Src kinases, PKCs, matrix metalloproteinase activation and the generation of reactive oxygen species. These results raise the possibility that disruption of this signaling cascade by either EGFR inhibition alone or combined with receptor antagonists may be a novel therapeutic approach for treatment of foregut NETs/PETs.

Endocrine tumours of the pancreas.

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.

Use of the somatostatin analogue octreotide to localise and manage somatostatin-producing tumours.

BACKGROUND: Somatostatin receptor scintigraphy (SRS) and octreotide therapy have both changed the management of gastroenteropancreatic endocrine tumours, but very few data are available on the use of SRS and octreotide to visualise and treat somatostatinomas. METHOD: The results of SRS and octreotide treatment in three somatostatinoma patients were examined. RESULTS: SRS was able to detect extensive hepatic involvement in patient 1, one hepatic and one pancreatic lesion in patient 2, and one hepatic lesion in patient 3. Octreotide therapy (0.5 mg/day subcutaneously) was effective in decreasing plasma levels of somatostatin in all three patients. Symptoms (diabetes and diarrhoea) were greatly improved in the two patients with "somatostatinoma syndrome". CONCLUSION: The study shows that somatostatinoma, like most other gastroenteropancreatic endocrine tumours, possesses functioning somatostatin receptors.

Somatostatinoma of the pancreas with hypercalcaemia. A case report.

A unique case of somatostatinoma of the pancreas complicated by severe hypercalcaemia is described. Surgical resection was not possible owing to tumour extent. A dramatic and prolonged clinical and biochemical response was achieved with streptozotocin.

A case of somatostatinoma: responses to food and SMS 201-995 administration.

Plasma somatostatin response to food and the administration of the long-acting somatostatin analogue SMS 201-995, as well as pituitary responses to insulin-induced hypoglycemia, growth hormone-releasing hormone (GHRH) and thyrotropin-releasing hormone (TRH), were assessed in a 60-year-old woman with biopsy-proven metastatic somatostatinoma. SMS 201-995 alone did not change plasma somatostatin-like immunoreactivity (SRIF), but levels of low-molecular-weight forms (SRIF-14 and SRIF-28) more than doubled in response to a standard meal. This postprandial response was not affected by pretreatment with SMS 201-995. Although a growth hormone response to insulin-induced hypoglycemia and supramaximal GHRH was absent, the patient's thyroid-stimulating hormone response to TRH was normal. These results suggest that somatostatin analogues may not influence tumor autonomy and that a SRIF response to food may contribute to early satiety in patients with somatostatinoma. In addition, the long-term use of somatostatin analogues to suppress hormone production by other peptide-secreting tumors may not have predictable results.

Somatostatinoma do pâncreas / Pancreatic somatostatinoma

Os autores descrevem um caso de somatostatinoma pancreático diagnosticado no pós-operatório através de imunohistiquímica. Paciente de sexo feminino, 48 anos, apresentava dor, massa abdominal e emagrecimento, sem diabete ou litíase vesicular. Näo foi possível o estudo de níveis séricos de somatostatinoma. A tomografia computadorizada revelou massa sólida no corpo e cauda de pâncreas, englobando o baço. A arteriografia seletiva do tronco celíaco revelou tumoraçäo hipervascularizada do corpo e causa de páncreas. foi efetuada esplenopancreatectomia distal. Um nódulo metastático no fígado foi também ressecado. A imunohistoquímica, a presença de enolase neuro-especifica (NSE) definiu neoplasia neuroendócrina e a detecçäo de grande quantidade de somatostatinoma no citoplasma de células tumorais fez o diagnóstico de somtostatinoma. No pós-operatório foi efetuada quimioterapia com estreptozotocina e 5-fluoracil

Treatment of malignant endocrine pancreatic tumours with human leucocyte interferon.

22 patients with advanced malignant endocrine pancreatic tumours were treated with human leucocyte interferon 3-6 X 10(6) IU per day. Objective responses (more than 50% reduction in tumour markers or tumour size) were seen in 7/7 with watery diarrhoea/hypokalaemia/achlorhydria syndrome, 3/4 with the Zollinger-Ellison syndrome, 6/9 with "non-functioning" tumours, and 1 with a mixed tumour mainly producing somatostatin. The median duration of response was 8.5 months, and all responders improved clinically. Adverse effects seemed more tolerable than those of cytotoxic treatment.

Somatostatinoma syndrome. Clinical, morphological and metabolic features and therapeutic aspects.

A case of somatostatinoma syndrome in a 30-year-old woman is presented. Basal levels of growth hormone and of pancreatic and gastric hormones were reduced and the response of growth hormone, insulin and C-peptide to stimuli such as arginine, glucose, glibenclamide and calcium was virtually abolished. Similarly, gastric acid secretion, pancreatic exocrine function and intestinal absorption were significantly reduced. On the other hand, basal and stimulated levels of adrenocorticotropic hormone (ACTH), luteinizing hormone (LH), follicle-stimulating hormone (FSH) and thyroid-stimulating hormone (TSH) were within the normal range. Plasma somatostatin-like immunoreactivity was increased to 600-2,000 pg/ml (normal: 88-140 pg/ml). Immunocytochemical studies demonstrated the presence of somatostatin immunoreactive material in the primary tumour in the head of the pancreas and in the liver metastases. In spite of two courses of chemotherapy with streptozotocin and 5-fluorouracil the patient died due to liver failure 5 months after the first admission to hospital.