Emerging therapies for advanced insulinomas and glucagonomas.

Pancreatic neuroendocrine neoplasms (panNENs) are rare relatively malignancies that, despite their frequently slow-growing pattern, have the ability to metastasize. Metastatic and/or advanced insulinomas and glucagonomas are functioning panNENs emerging from the pancreas displaying unique peculiarities, depending on their hormonal syndromes and increased malignant potential. Advanced insulinomas management follows usually the panNENs therapeutic algorithm, but some distinctions are well advised together with aiming to control hypoglycemias that occasionally can be severe and refractory to treatment. When first-generation somatostatin analogues (SSAs) fail to control hypoglycemia syndrome, second-generation SSAs and everolimus have to be considered for exploiting their hyperglycemic effect. There is evidence that everolimus is still effective after rechallenge retaining its hypoglycemic effect independently of its antitumor effect that seems to be mediated by different molecular pathways. Peptide receptor radionuclide therapy (PRRT) constitutes a promising therapeutic option for both its antisecretory and antitumoral action. Similarly, advanced and/or metastatic glucagonomas management also follows the panNENs therapeutic algorithm, but the clinical syndrome has to be addressed by aminoacid infusion and by first-generation SSAs to improve the patient performance status. PRRT seems to be an effective treatment when surgery and SSAs fail. The application of these therapeutic modalities has been shown to be efficacious in controlling the manifestations of the secretory syndrome and prolonging the overall survival of patients suffering from these malignancies.

Hypercalcemia appeared in a patient with glucagonoma treated with octreotide acetate long-acting release.

PABCREATIC neuroendocrine tumours are uncommon neoplasms of the pancreas. They may cause a clinical syndrome due to hormone overproduction. Glucagonoma is a rare kind of pancreatic tumors. Here we report a case of glucagonoma. Hypercalcemia occurred when the patient underwent octreotide acetate long-acting release.

Glucagonoma and the glucagonoma syndrome - cumulative experience with an elusive endocrine tumour.

OBJECTIVE: Glucagonoma is a pancreatic neuroendocrine tumour that arises from alpha cells in the pancreas and is often accompanied by a characteristic clinical syndrome. DESIGN: In this report, we present the cumulative experience and clinical characteristics of six patients diagnosed with glucagonoma and the glucagonoma syndrome and treated at our centre during the past 25 years. RESULTS: Although the course of the disease was variable, some features were similar. The median age at diagnosis was 53·5 years; the median time from onset of symptoms to diagnosis was 39 months. Presenting symptoms were as follows: weight loss 5/6 (83%), necrotizing migratory erythema (NME) 5/6 (83%), diabetes mellitus 4/6 (66%) and diarrhoea, weakness and thrombosis 2/6 (33%). Plasma glucagon was elevated in all patients upon diagnosis (range 200-10,000 pm; N < 50). Skin biopsy was diagnostic only in 1/6 specimens obtained, even after revision. Metastatic disease developed in all patients; 4/6 initially presented with hepatic metastasis. All patient symptoms responded to somatostatin analogue therapy. In 4/6, the NME responded to amino acid solutions. Other modes of therapy were as follows: surgery in 3/6 patients, peptide receptor radioligand therapy with (90) Y-DOTATOC (PRRT) in 3/6 patients (two responses) and chemotherapy in three patients (two responded). Four out of six patients died of the disease, and median survival time was 6·25 years (range 2-11) from diagnosis and 8 years (range 8-16) from initial symptoms. Five-year survival was 66%. CONCLUSION: Our data indicate that somatostatin analogues and an aggressive surgical approach offer symptom relief and tumour control. Among other available treatment modalities, PRRT seems to hold the most promise.

[Dramatic efficacy of chemotherapy with 5-fluorouracil and dacarbazine in a patient with metastatic glucagonoma and cardiac insufficiency]. / Efficacité spectaculaire d'une chimiothérapie par 5-fluoro-uracile et dacarbazine chez un malade atteint de glucagonome métastatique avec insuffisance cardiaque.

Malignant glucagonoma is an exceptional pancreatic endocrine tumour, with frequent dermatologic symptoms, diabetes and degradation of the general health status. Prognosis is unfavourable when liver metastases are present due to the usual inefficiency of chemotherapy. We report here an observation of a patient who was treated for a glucagonoma with multiple liver metastases, migratory necrolytic erythema, dilated cardiomypathy and diabetes that dramatically improved after a dacarbazin-based chemotherapy, allowing subsequent surgical resection of the primary. The patient was still alive and asymptomatic without progressive disease nearly two years after surgery.

[Necrolytic migratory erythema in glucagonoma syndrome]. / Erythema necroticans migrans bei Glucagonomsyndrom.

The glucagonoma syndrome is a rare disease in which a typical skin lesion, necrolytic migratory erythema, is often one of the presenting symptoms. A 68-year-old woman developed erythematous polycyclic migratory lesions with advancing scaling borders and crusts over several years. Skin biopsies, laboratory studies and imaging confirmed the diagnosis of necrolytic migratory erythema as part of a glucagonoma syndrome.

Identification of somatostatin receptor subtypes and an implication for the efficacy of somatostatin analogue SMS 201-995 in treatment of human endocrine tumors.

The presence of somatostatin receptors has been demonstrated in various endocrine tumors as well as in normal tissues. We recently have cloned five human somatostatin receptor subtypes (SSTR1-SSTR5). These mRNAs are expressed in a tissue-specific manner. In this study, we have determined the somatostatin receptor subtypes expressed in various endocrine tumors using a reverse transcriptase polymerase chain reaction method. In two cases of glucagonoma and its metastatic lymph nodes in one case, all the SSTR subtype mRNAs except SSTR5 mRNA were expressed. In four cases of insulinoma, SSTR1 and SSTR4 mRNAs were detected, but SSTR2 mRNA was not detected in one case and SSTR3 mRNA was not detected in two cases, indicating a heterogeneous expression of SSTR subtypes in insulinomas. Interestingly, SSTR3 mRNA, which is highly expressed in rat pancreatic islets, is not expressed in normal human pancreatic islets, while SSTR1, SSTR2, and SSTR4 mRNAs are expressed. In three cases of pheochromocytoma, SSTR1 and SSTR2 mRNAs were detected, showing an expression pattern identical to that of normal adrenal gland. In a carcinoid, SSTR1 and SSTR4 mRNAs were detected. We have also found that human SSTR2 shows a high affinity for SMS 201-995, which has been used clinically for the treatment of endocrine tumors. Since SMS 201-995 was effective in the treatment of a patient with glucagonoma in which SSTR2 mRNA was present, but had no effect in a patient with carcinoid in which SSTR2 mRNA was not detected, this study suggests that the efficacy of SMS 201-995 may depend, at least in part, on the expression of SSTR2 in tumors.

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.

Effects of sandostatin on plasma chromogranin-A levels in neuroendocrine tumors.

We have determined the effects of Sandostatin (SMS 201-995, Sandoz) on chromogranin-A (CgA) in the blood of 14 patients with neuroendocrine tumors of the gastroenteropancreatic axis, 7 with carcinoid tumors, 5 with gastrinomas, and 1 each with a glucagonoma and tumor-secreting vasoactive intestinal peptide. Two thirds of the patients had elevated plasma CgA. Sandostatin administration suppressed CgA in 12 of the 14 patients. In 8 of 10, the clinical response to Sandostatin paralleled the reduction in CgA levels. There was a strong correlation between the change in CgA levels and the respective blood concentration of the hormone produced by the tumor. Serial measurement of CgA may provide an additional means of monitoring these tumors and their secretory activity where other measures are not available.

Reversal of a neurologic paraneoplastic syndrome with octreotide (Sandostatin) in a patient with glucagonoma.

A 69-year-old woman with classic glucagonoma syndrome had associated progressive neurologic disease manifest as dementia, ataxia, optic atrophy, and lower limb weakness. Visual evoked responses (VERs) were absent bilaterally. After an attempt at resection was unsuccessful, therapy was started with somatostatin analogue (Sandostatin, SMS 201-995). Over the ensuing 3 months, there was a decrease in the plasma glucagon level, resolution of the rash, weight gain, reversal of the dementia, and an improvement in coordination and limb weakness. Subsequent VERs revealed bilateral delayed responses.

Iodine-123-Tyr-3-octreotide uptake in pancreatic endocrine tumors and in carcinoids in relation to hormonal inhibition by octreotide.

UNLABELLED: Uptake of 123I-Tyr-3-octreotide (TOCT) by hormone-secreting abdominal tumors was studied to compare scintigraphic observations with the reduction in hormone levels brought about by a brief therapeutic test. METHODS: A prospective study was conducted on 17 patients, totalizing 46 proven lesions, with endocrine tumors of the pancreas (10 patients, 20 lesions) and/or carcinoid metastases (8 patients, 26 lesions). Tumor hormonal hypersecretion was inhibited by octreotide. RESULTS: There was good agreement between the results of these examinations. CONCLUSIONS: The detection of abdominal tumors using this radiotracer is strongly related to its functional characteristics. Variations in the scintigraphic and test results according to different tumor types were in agreement with published data on the density of somatostatin receptors measured by in vitro studies or scintigraphy and by the therapeutic effects of octreotide.

In vivo demonstration of enzyme activity in endocrine pancreatic tumors: decarboxylation of carbon-11-DOPA to carbon-11-dopamine.

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.

An uncommon tumor in a renal graft recipient: a diagnostic and therapeutic challenge.

The development of malignancies after solid organ transplantation represents an increasing clinical problem complicating the long-term follow-up of transplant recipients. In this case report the authors describe the rare triple combination of a simultaneous hepatocellular carcinoma with a glucagonoma and a splenic hamartoma in a renal allograft recipient. It is not only the first published report of a glucagonoma occurring after renal transplantation but serves also as an illustration of the therapeutic decision making in the setting of the immune-compromised host. This case report also illustrates the different imaging modalities that can be used for the diagnosis of neuroendocrine tumors.

DTIC therapy in patients with malignant intra-abdominal neuroendocrine tumors.

Malignant intra-abdominal neuroendocrine tumors are rare; consequently, a standard chemotherapeutic protocol for patients with unresectable disease has not been established. This prompted a review of our experience with dimethyltriazeno imidazole carboxamide (dacarbazine) (DTIC) treatment for these tumors. From 1976 to 1986, 14 patients were treated with DTIC for metastatic neuroendocrine tumors. There were seven men and seven women whose ages ranged from 19 to 76 years. Diagnoses included eight nonfunctioning islet-cell carcinomas, three retroperitoneal neuroendocrine tumors, two glucagonomas, and one ileal carcinoid. Before DTIC chemotherapy, four patients were treated with streptozotocin and 5-FU, and one was treated with cytoxan and methotrexate without response. Two patients who were initially treated with DTIC with no response were subsequently treated with streptozotocin and 5-FU without benefit. Standard treatment with DTIC consisted of monthly cycles of 250 mg/m2/day administered intravenously for 5 days. Seven patients had an objective response to DTIC with both improvement in quality of life and a decrease of more than 50% in tumor size on computerized tomography (CT) or liver scanning. Response duration ranged from 1 to 10 years. One patient with a glucagonoma was treated for two years and had no evidence of disease at laparotomy 7 years later. Four patients with nonfunctioning islet cell carcinoma had a positive response to DTIC, but three of these patients had tumor recurrence 3 to 6 years after treatment. Two patients with retroperitoneal neuroendocrine tumors had a positive response to DTIC treatment. One patient with a glucagonoma and one with a nonfunctioning islet-cell tumor had equivocal responses with transient clinical improvement but no objective changes in tumor size. Five patients did not respond; two were given DTIC therapy as a last resort and died 1 and 12 days later. Of the other three patients, two died 6 months and one 2 years after treatment. DTIC chemotherapy was effective in 50% of patients with intra-abdominal neuroendocrine tumors. Although DTIC therapy was associated with nausea, no major gastrointestinal, hematologic, or renal complications were noted. This favorable experience with DTIC chemotherapy for nonresectable intra-abdominal neuroendocrine tumors indicates that further clinical evaluation and use are warranted.

Somatostatin analogue in treatment of coexisting glucagonoma and pancreatic pseudocyst: dissociation of responses.

After an acute episode of pancreatitis, a 63-year-old man was found to have a pancreatic glucagonoma. The tumor was resected without evidence of metastases. Three years later he had symptoms of uncontrolled diabetes, no skin lesions, and diarrhea and was found to have a pancreatic pseudocyst and multiple hepatic metastases. Glucagon concentrations were raised but were suppressible by glucose and somatostatin and responded to arginine stimulation. He was treated for 6 months with octreotide (Sandostatin), which reduced his symptoms; the pseudocyst resolved, but liver metastases continued to grow. Although spontaneous resolution of the pseudocyst is possible, this case appears to illustrate differences in sensitivity of endocrine and exocrine tissues to suppression by Sandostatin.

Use of a somatostatin analog (SMS 201-995) in the glucagonoma syndrome.

A long-acting somatostatin analog, SMS 201-995, is now available to treat the hormonal manifestations of islet cell tumors. We report its use in a patient with a metastatic glucagonoma refractory to conventional therapy. This patient, who was severely disabled by the rash of necrolytic migratory erythema and brittle diabetes mellitus, allowed us to evaluate the therapeutic efficacy of SMS 201-995 and to gain insight into the origin of the rash. SMS 201-995 was administered subcutaneously (.05 mg twice a day). The rash improved markedly within 48 hours and was completely resolved within 1 week of treatment. Insulin requirements decreased from 90 U/day to zero during the first week of treatment. Corresponding to improvement in clinical symptoms circulating glucagon levels showed a marked decrease. There was no substantial change in plasma or urinary levels of zinc or in plasma amino acid levels. When SMS 201-995 was stopped, the rash recurred within 36 hours and it improved within 48 hours of readministration. The rash and diabetes have remained well controlled during 8 months of therapy but no change in tumor size has been seen on CT scan. The rapid changes in the rash related to the administration of SMS 201-995 indicate that the pathogenesis of necrolytic migratory erythema is probably due to circulating hyperglucagonemia or some other hormonal substance produced by the tumor.

Immunologic characterization of plasma glucagon components in a patient with malignant glucagonoma.

Plasma immunoreactive glucagon (IRG) components were analyzed by gel filtration on either a Bio-Gel P-30 or a Sephadex G-150 column (1.0 X 68 cm) in a 47-year-old male with biopsy-proven malignant glucagonoma. Plasma samples were obtained before and after 20 courses of streptozotocin treatment as well as after administration of a somatostatin-derivative (SRIF-D, 0.38 mg, subcutaneous), regular insulin (0.2 U/kg, intravenous), and secretin (2 U/kg, intravenous). The fractions from the columns were assayed for IRG by simultaneous radioimmunoassay with C-terminal (Unger 30 K) and N-terminal (OAL 196) antibodies to glucagon. Four IRG components were observed. The largest had a molecular weight of approximately 150,000 daltons and cross-reacted much more strongly with the N-terminal antibody than with the C-terminal. The second IRG component appeared to be about 9000 daltons and cross-reacted more strongly with the N-terminal antibody. The third and major IRG component comprised 51.8% to 88.1% of the total IRG as measured with C-terminal antibody, corresponded in molecular weight to synthetic 3500 dalton glucagon, and reacted roughly equally with each of the two antibodies. The fourth IRG component cross-reacted only with N-terminal antibody and appeared to be smaller than 3500 daltons. The plasma IRG level decreased from 8829 pg/mL to 1421 pg/mL (averages of five consecutive determinations) after 20 courses of treatment with streptozotocin with significant clinical improvement. A marked (74%) but transient decrease in plasma IRG was observed after the SRIF-D injection, whereas secretion and insulin caused increases in plasma IRG level of 53% and 22%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Somatostatin analog-induced remission of necrolytic migratory erythema without changes in plasma glucagon concentration.

A 41-year-old woman with metastatic glucagonoma and the characteristic disabling rash, necrolytic migratory erythema, was treated with a synthetic somatostatin analog while waiting to undergo curative surgical resection. Plasma glucagon concentration (1,500-3,300 pg/ml, normal less than 200) remained elevated during analog therapy as the rash cleared. Only with surgical resection (partial pancreatectomy and partial hepatectomy) did glucagon levels return to normal. The therapeutic benefit caused by the analog in this syndrome differs from that in other endocrine tumor syndromes such as pancreatic cholera, carcinoid, or gastrinoma where circulating levels of tumor-produced agents are suppressed in conjunction with control of symptoms.