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.

Asymptomatic somatostatinoma of the pancreatic head: Report of a case.

A 44-year-old man was attending routine follow-up 5 years after colon cancer resection, when ultrasonography detected a pancreatic tumor with a low echoic area. He had no symptoms. Computed tomography (CT) showed a protruding-type tumor, 4 cm in diameter, in the pancreatic head with central necrosis. Angiography revealed that the tumor was hypervascular. The serum somatostatin level was elevated, at 27 pg/ml (normal range, 1.0-12 pg/ml). As somatostatinoma of the pancreas was suspected, we performed pylorus-preserving pancreaticoduodenectomy. Histological and immunohistochemical staining confirmed somatostatinoma of the pancreas without nodal metastasis. Thus, if an endocrine tumor of the pancreas is suspected in a patient with a hypervascular tumor, the possibility of somatostatinoma should be included in the differential diagnosis.

Pancreatic somatostatinoma manifested as severe hypoglycemia.

Somatostatinoma is a rare somatostatin-producing endocrine tumor, probably malignant. Due to its nonspecific symptoms such as vague abdominal pain, weight loss, or occult clinical features, misdiagnosis occurs. We report a case of pancreatic somatostatinoma with severe hypoglycemia. The patient had experienced severe hypoglycemic attacks for 11 months periodically. Contrast computed tomography scan revealed an isodensity mass about 2 cm in the head of the pancreas. Ultimately, a local excision was carried out as the tumor was located exactly on the surface of the pancreas. Somatostatinoma was established after immunohistochemical technique. The patient led a normal life without any complaint at 1 year follow-up.

7B2, a possible marker for nonfunctioning pancreatic islet cell tumor.

Plasma 7B2 was measured in 13 patients with pancreatic islet cell tumors, 11 with pancreatic adenocarcinoma and 31 normal subjects as a control. The mean (+/- SD) concentrations of plasma 7B2 in the normal subjects and the patients with pancreatic islet cell tumors were 67 +/- 10 and 1041 +/- 1786 pmol/l, respectively, and the value in the patients with pancreatic islet cell tumors was significantly higher than that in the normal subjects (p less than 0.01). Elevation of plasma 7B2 over the normal range, defined as less than the mean + 3SD value of those in the normal subjects, was found in 10 of 13 patients with pancreatic islet cell tumors including 4 with nonfunctioning tumor. Plasma 7B2 dropped into the normal range postoperatively in 3 patients with nonfunctioning tumor. Plasma 7B2 concentrations in the patients with pancreatic adenocarcinoma remained in the normal range. These results raise a possibility that 7B2 is a useful marker for pancreatic islet cell tumors, in particular nonfunctioning tumor.

Natural killer cell activity in patients with neuroendocrine tumours of the gastrointestinal tract; relation with circulating gastrointestinal hormones.

We have evaluated the peripheral blood natural killer (NK) cell activity and the in vitro effect of recombinant gamma-interferon (r gamma-IFN) on NK cell activity in 23 patients with a neuroendocrine tumour of the pancreas, small intestine or liver, and 23 healthy controls. Patients with a gastrinoma showed a NK cell activity which was not different from that of the control group, whereas patients with another type of neuroendocrine tumour had a decreased NK cell activity compared to the controls (p less than 0.05) and the gastrinoma patients (p less than 0.02). The impaired NK cell activity in these patients was as such not related to the presence of liver metastasis or performance status of the patients. r gamma-IFN significantly stimulated the NK cell activity in patients and controls. However, the cytotoxic response of the patients with a hormone production other than gastrin remained lower than in the two other groups. Follow-up studies in 8 patients showed NK cell activities not to vary with stable disease, to decrease with progressive disease, and to increase with regression of disease. In conclusion, NK cell activity is suppressed in patients with neuroendocrine tumours that produce hormones other than gastrin. This impairment is not related to the presence of metastasis but seems to be related to the course of the disease.

The effects of sodium valproate on plasma somatostatin and insulin in humans.

To determine the role of gamma-aminobutyric acid (GABA) in islet tissue, sodium valproate (1600 mg/day) was administered for 6 days to 10 normal subjects and 1 patient with a somatostatinoma. Plasma valproate concentrations reached a steady state by the third day accompanied by elevation of plasma GABA concentrations. Sodium valproate administration resulted in a 40% decrease in plasma somatostatin concentrations in the normal subjects and a 63% decrease in the somatostatinoma patient, respectively, compared to the response to placebo. Plasma C-peptide concentrations did not change in any subject. Fasting blood glucose levels decreased in the somatostatinoma patient during sodium valproate administration. These results suggest that endogenous GABA may play some role in the release of somatostatin, but not in the release of insulin.

Somatostatin-secreting islet cell tumor (somatostatinoma): suppression of growth hormone (GH) release induced by GH-releasing hormone.

A patient with a somatostatin (SRIH)-secreting islet cell tumor, whose only symptoms were dyspepsia and anemia, is described. The diagnosis of somatostatinoma was based on high plasma SRIH concentrations and immunocytochemical findings. The pancreatic exocrine response to secretin was decreased, whereas the insulin and/or glucagon responses to glucose and arginine were normal. Although the basal plasma GH concentration was normal, the plasma GH response to GHRH was subnormal. Gel permeation chromatography studies indicated that SRIH-14 was the predominant form of SRIH in plasma as well as in tumor tissue.

Pancreatic somatostatinoma: presentation with recurrent episodes of severe hyperglycaemia and ketoacidosis.

A 47-year-old woman was admitted on four occasions over a four-year period with severe hyperglycaemia associated with marked ketoacidosis. She had weight loss with hepatomegaly and ultrasonography indicated a pancreatic tumour which was shown to be a somatostatinoma. Resection resulted in prolonged survival. The biochemical and morphological features of this rare tumour are presented, and an explanation for the unusual presentation of a somatostatinoma with episodes of ketoacidosis is given.

Five cases of somatostatinoma: clinical heterogeneity and diagnostic usefulness of basal and tolbutamide-induced hypersomatostatinemia.

Five cases of somatostatinoma are reported, four being primarily located in the pancreas and one in the duodenum. The diagnosis was based upon the histological and immunochemical characteristics of tumoral and metastatic tissue. A marked clinical heterogeneity was noted: one patient presented with gallstones, steatorrhea, and diabetes, two patients suffered from severe hypoglycemic attacks, and two cases were admitted for obstructive jaundice. This varying symptomatology was related to differences in the circulating levels of biologically active somatostatin and to a variable cellular composition of the tumor. In all cases, a basal and/or tolbutamide-induced hypersomatostatinemia was measured. It is concluded that the clinical and hormonal features of the earlier defined somatostatinoma syndrome are no requisite for the diagnosis of somatostatinoma; the analysis of plasma somatostatin immunoreactivity might lead to a higher detection rate of this endocrine tumor.