Search

von Hippel-Lindau (VHL) disease, caused by germline mutations in the VHL gene, is a hereditary autosomal-dominant disorder which predisposes the individual to various malignant and benign tumors. VHL acts as a tumor suppressor, mainly through the negative regulation of hypoxia-inducible factors. Molecular-targeted drugs against vascular endothelial growth factor-signaling pathways, a target of hypoxia-inducible factors, have recently been introduced into clinical practice for the treatment of patients with sporadic renal cell carcinoma and pancreatic neuroendocrine tumors. However, whether such treatments are effective in patients with VHL disease remains to be elucidated. We herein report a Japanese patient with VHL disease who was successfully treated with sunitinib for approximately 5 years.

Accumulating evidence suggests a role for angiotensin-converting enzymes involving the angiotensin II-receptor 1 (AT1-R) and the cyclooxygenase pathway in carcinogenesis. The effects of ASS and enalapril were assessed in vitro and in a transgenic mouse model of pancreatic neuroendocrine neoplasms (pNENs). The effects of enalapril and ASS on proliferation and expression of the AGTR1A and its target gene vascular endothelial growth factor (Vegfa) were assessed in the neuroendocrine cell line BON1. Rip1-Tag2 mice were treated daily with either 0.6 mg/kg bodyweight of enalapril i.p., 20 mg/kg bodyweight of ASS i.p., or a vehicle in a prevention (weeks 5-12) and a survival group (week 5 till death). Tumor surface, weight of pancreatic glands, immunostaining for AT1-R and nuclear factor kappa beta (NFKB), and mice survival were analyzed. In addition, sections from human specimens of 20 insulinomas, ten gastrinomas, and 12 non-functional pNENs were evaluated for AT1-R and NFKB (NFKB1) expression and grouped according to the current WHO classification. Proliferation was significantly inhibited by enalapril and ASS in BON1 cells, with the combination being the most effective. Treatment with enalapril and ASS led to significant downregulation of known target genes Vegf and Rela at RNA level. Tumor growth was significantly inhibited by enalapril and ASS in the prevention group displayed by a reduction of tumor size (84%/67%) and number (30%/45%). Furthermore, daily treatment with enalapril and ASS prolonged the overall median survival compared with vehicle-treated Rip1-Tag2 (107 days) mice by 9 and 17 days (P=0.016 and P=0.013). The AT1-R and the inflammatory transcription factor NFKB were abolished completely upon enalapril and ASS treatment. AT1-R and NFKB expressions were observed in 80% of human pNENs. Enalapril and ASS may provide an approach for chemoprevention and treatment of pNENs., (© 2014 Society for Endocrinology.)

Accurate visualization and quantification of β-cell mass is critical for the improved understanding, diagnosis, and treatment of both type 1 diabetes (T1D) and insulinoma. Here, we describe the synthesis of a bimodal imaging probe (PET/fluorescence) for imaging GLP-1R expression in the pancreas and in pancreatic islet cell tumors. The conjugation of a bimodal imaging tag containing a near-infrared fluorescent dye, and the copper chelator sarcophagine to the GLP-1R targeting peptide exendin-4 provided the basis for the bimodal imaging probe. Conjugation was performed via a novel sequential one-pot synthetic procedure including (64)Cu radiolabeling and copper-catalyzed click-conjugation. The bimodal imaging agent (64)Cu-E4-Fl was synthesized in good radiochemical yield and specific activity (RCY = 36%, specific activity: 141 μCi/μg, >98% radiochemical purity). The agent showed good performance in vivo and ex vivo, visualizing small xenografts (<2 mm) with PET and pancreatic β-cell mass by phosphor autoradiography. Using the fluorescent properties of the probe, we were able to detect individual pancreatic islets, confirming specific binding to GLP-1R and surpassing the sensitivity of the radioactive label. The use of bimodal PET/fluorescent imaging probes is promising for preoperative imaging and fluorescence-assisted analysis of patient tissues. We believe that our procedure could become relevant as a protocol for the development of bimodal imaging agents.

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., (Published by Elsevier B.V.)

Background: This study was designed to evaluate the role of the hedgehog pathway in tumor progression of murine islet cell tumors. Blockade of aberrant hedgehog activation has recently been proposed as a therapeutic target, but effects in models of islet cell tumors with a new orally bioavailable Smoothened (Smo) antagonist LDE225 have not been examined., Material and Methods: To assess in vivo effects, transgenic Rip1Tag2 mice, which develop islet cell neoplasms, were treated with vehicle or LDE225 (80 mg/kg/d) from week 5 until death. The resected pancreata were evaluated macroscopically and microscopically by iummohistochemsistry. Quantitative real-time polymerase chain reaction was performed for hedgehog target genes with RNA from islet, isolated from treated and untreated Rip1Tag2 mice., Results: LDE225 significantly reduced tumor volume by 95% compared with untreated control mice. Hedgehog inhibition with LDE225 significantly prolonged median survival in the used transgenic mouse model (105 vs 116 days; P = 0.02). Quantitative real-time polymerase chain reaction for downstream hedgehog target genes demonstrated significant downregulation in the islet cell tumors of Rip1Tag2 mice treated with LDE225, confirming the ability to achieve effective pharmacologic levels of LDE225 within the desired tissue site, in vivo., Conclusion: This is the first study to show that the orally bioavailable Smo antagonist LDE225 may provide a new option for therapy of islet cell neoplasms.

Angiogenesis inhibitors that block VEGF receptor (VEGFR) signaling slow the growth of many types of tumors, but eventually the disease progresses. Multiple strategies are being explored to improve efficacy by concurrent inhibition of other functionally relevant receptor tyrosine kinases (RTK). XL880 (foretinib, GSK1363089) and XL184 (cabozantinib) are small-molecule inhibitors that potently block multiple RTKs, including VEGFR and the receptor of hepatocyte growth factor c-Met, which can drive tumor invasion and metastasis. This study compared the cellular effects of XL880 and XL184 with those of an RTK inhibitor (XL999) that blocks VEGFR but not c-Met. Treatment of RIP-Tag2 mice with XL999 resulted in 43% reduction in vascularity of spontaneous pancreatic islet tumors over 7 days, but treatment with XL880 or XL184 eliminated approximately 80% of the tumor vasculature, reduced pericytes and empty basement membrane sleeves, caused widespread intratumoral hypoxia and tumor cell apoptosis, and slowed regrowth of the tumor vasculature after drug withdrawal. Importantly, XL880 and XL184 also decreased invasiveness of primary tumors and reduced metastasis. Overall, these findings indicate that inhibition of c-Met and functionally related kinases amplifies the effects of VEGFR blockade and leads to rapid, robust, and progressive regression of tumor vasculature, increased intratumoral hypoxia and apoptosis, and reduced tumor invasiveness and metastasis., (©2011 AACR.)

Cancer is a disease subject to both genetic and environmental influences. In this study, we used the RIP1-Tag2 (RT2) mouse model of islet cell carcinogenesis to identify a genetic locus that influences tumor progression to an invasive growth state. RT2 mice inbred into the C57BL/6 (B6) background develop both noninvasive pancreatic neuroendocrine tumors (PNET) and invasive carcinomas with varying degrees of aggressiveness. In contrast, RT2 mice inbred into the C3HeB/Fe (C3H) background are comparatively resistant to the development of invasive tumors, as are RT2 C3HB6(F1) hybrid mice. Using linkage analysis, we identified a 13-Mb locus on mouse chromosome 17 with significant linkage to the development of highly invasive PNETs. A gene residing in this locus, the anaplastic lymphoma kinase (Alk), was expressed at significantly lower levels in PNETs from invasion-resistant C3H mice compared with invasion-susceptible B6 mice, and pharmacological inhibition of Alk led to reduced tumor invasiveness in RT2 B6 mice. Collectively, our results demonstrate that tumor invasion is subject to polymorphic genetic control and identify Alk as a genetic modifier of invasive tumor growth.

Context: Insulinomas are rare tumors of the pancreatic islet cells that produce insulin. Approximately 5 to 10% of these tumors are cancerous, and control of insulin secretion and hypoglycemia may be difficult in these patients. Malignant insulinomas generally respond poorly to traditional chemotherapeutic agent regimens. At present, streptozotocin is the only approved drug for the treatment of pancreatic islet cell tumors. SETTING AND PATIENT: This report describes a case of an elderly gentleman with a metastatic pancreatic insulinoma and severe hypoglycemia. A continuous infusion of octreotide lowered the blood glucose levels further. He required diazoxide, a thiazide diuretic, phenytoin, and a constant infusion of glucose to control the hypoglycemia and elevated insulin levels., Intervention: Rapamycin was administered at an oral dose of 2 mg/d., Results: On the mTOR (mammalian target of rapamycin) agent rapamycin, he was weaned off all drugs except for the thiazide diuretic and maintained euglycemia with a reduction of circulating insulin levels. He remained euglycemic for the past year with no evidence of tumor progression based on Octreoscan. His quality of life is excellent, and he remains active having recently completed a triathlon., Conclusions: Rapamycin may provide a useful means of abrogating tumor growth and controlling hypoglycemia in malignant insulinomas by reducing the malignant beta-cell growth and proliferation as well as inhibiting insulin production.

Background: Hepatic metastases from neuroendocrine cancer dramatically reduce survival, introducing an important opportunity for intervention. Several treatment modalities have been examined, but an optimal treatment approach has been difficult to define. We evaluated a regimen combining hepatic artery chemoinfusion with chemoembolization., Methods: Patients with neuroendocrine cancer and diffuse hepatic metastases were treated with hepatic artery chemoinfusion and chemoembolization when they demonstrated disease progression despite octreotide therapy. Four monthly cycles of 5-fluorouracil were administered via hepatic artery infusion with chemoembolization after the final 2 cycles. Response was defined by radiologic response or symptomatic improvement., Results: Seventy-seven patients were treated; 18 received chemoinfusion only. The treatment-related mortality rate was 7%. The overall response rate was 80% for patients with carcinoid or islet cell neoplasms. Median progression-free survival was 19 months. Median disease-specific survival was 39 months from the first treatment; 1- and 5-year survival rates were 78% and 27%, respectively., Conclusion: Survival after initiating this regimen was over 3 years for the majority of patients exhibiting progression of extensive, unresectable hepatic disease despite octreotide therapy. The addition of hepatic artery chemoinfusion to chemoembolization offers a high probability of clinical benefit to patients who, otherwise, have severely limited therapeutic options and a dismal survival.

Purpose: Carcinoid and islet cell tumors are known to be highly vascular. There is no effective systemic therapy currently available for metastatic disease. We conducted a phase II trial to evaluate the efficacy of the anti-antiangiogenic agent thalidomide in metastatic neuroendocrine tumors., Patients and Methods: Eighteen patients with measurable, histologically proven metastatic carcinoid neuroendocrine carcinomas (well-differentiated, n = 13; moderately-differentiated, n = 5) were enrolled on this study. The majority of the patients had gastrointestinal primaries (small bowel, 8; pancreas, 5; colon, 1). All but one patient had hepatic metastases, and 12 patients (67%) had carcinoid syndrome. All patients had Eastern Cooperative Oncology Group performance status of zero or one. Eight patients (44%) had received previous hepatic artery chemoembolization and 11 (61%) had undergone surgical resection. Patients were started on oral thalidomide at a daily dose of 200 mg that was escalated to the target dose of 400 mg daily after 2 weeks. Tumor response was assessed at 12-week intervals using RECIST criteria. Planned treatment duration was 24 weeks unless unacceptable toxicity or disease progression was observed., Results: No patient achieved a partial remission or a complete remission. Best response was stable disease (SD) in 11 of 16 response-evaluable patients (69%). Serum pancreastatin results did not correlate with clinical response. Grade 3 toxicities included dizziness with orthostatic hypotension (n = 5), sensory neuropathy (n = 2), fatigue (n = 2), hemorrhagic cystitis (n = 1), and deep venous thrombosis (n = 1). Frequent Grade 1-2 toxicities were: fatigue (n = 13), constipation (n = 13), dry mouth (n = 12), somnolence (n = 12), dizziness/syncope (n = 10), weight gain (n = 5), and peripheral neuropathy (n = 5)., Conclusions: Thalidomide was fairly well tolerated in patients with metastatic carcinoid/islet cell tumors, but failed to reveal any objective responses. The single stage design of the trial makes it difficult to determine whether observed SD in a subset of patients was attributable to the indolent nature of these tumors, or to beneficial effect of thalidomide.

Background/aims: The use of chemoradiation in the management of locally advanced pancreatic endocrine tumors has not been reported in the medical literature. Patients with unresectable tumors are often included in trials of systemic chemotherapy, and use of external beam radiation has been only described in few case reports. Given the sensitivity of pancreatic endocrine tumors to cytotoxic agents including streptozocin, doxorubicin and 5-FU, we have hypothesized that the combination of concurrent and sequential chemotherapy and radiation will yield higher response rates than acheivable with chemotherapy alone., Methods: Six patients with locally advanced pancreatic endocrine tumors were treated with a protocol consisting of radiation concurrent with infusional 5-FU (or capecitabine) along with induction and consolidation chemotherapy (streptozocin and doxorubicin). We retrospectively determined the objective radiographic response rate., Results: The objective response rate was 80%. With a median follow-up of 29 months, all six patients in the study have had continued reduction in tumor size from the time of the first posttreatment scan to the most recent scan. None of the patients have experienced local or metastatic disease progression. Treatment was well tolerated with minimal toxicity., Conclusion: The combination of concurrent and sequential chemoradiotherapy appears to be a highly effective treatment for locally advanced pancreatic endocrine tumors., (Copyright 2007 S. Karger AG, Basel.)

Purpose: There are few treatment options for patients with metastasized or inoperable endocrine gastroenteropancreatic (GEP) tumors. Chemotherapy can be effective, but the response is usually less than 1 year. Here, we present the results of treatment with a radiolabeled somatostatin analog, [177Lu-DOTA0,Tyr3]octreotate (177Lu-octreotate)., Patients and Methods: One hundred thirty-one patients with somatostatin receptor-positive tumors were treated with up to a cumulative dose of 600 to 800 mCi (22.2 to 29.6 GBq) of 177Lu-octreotate., Results: One patient developed renal insufficiency, and another patient developed hepatorenal syndrome. Creatinine clearance did not change significantly in the other patients. WHO hematologic toxicity grade 3 or 4 occurred after less than 2% of the administrations. We observed complete remission in three patients (2%), partial remission in 32 patients (26%), minor response (tumor diameter decrease of 25% to 50%) in 24 patients (19%), stable disease (SD) in 44 patients (35%), and progressive disease (PD) in 22 patients (18%). Higher remission rates were positively correlated with high uptake on pretherapy somatostatin receptor imaging and a limited number of liver metastases, whereas PD was significantly more frequent in patients with a low performance score and extensive disease. Median time to progression in 103 patients who either had SD or tumor regression was more than 36 months., Conclusion: Treatment with 177Lu-octreotate results in tumor remission in a high percentage of patients with GEP tumors. Serious side effects are rare. The median time to progression compares favorably with chemotherapy. Results are better in patients with a limited tumor load. Therefore, early treatment, even in patients who have no PD, may be better.

Purpose: A transgenic mouse model has revealed parameters of the angiogenic switch during multistep tumorigenesis of pancreatic islets, and demonstrated efficacy of antiangiogenic therapies. Pericytes have been revealed as functionally important for tumor neovasculature, using kinase inhibitors targeting their platelet-derived growth factor receptors (PDGFRs). Additionally, vascular endothelial growth factor receptor (VEGFR) inhibitors and metronomic chemotherapy show modest benefit against early- but not late-stage disease., Materials and Methods: Seeking to improve efficacy against otherwise intractable end-stage pancreatic islet tumors, two receptor tyrosine kinase inhibitors, imatinib and SU11248, were used to disrupt PDGFR-mediated pericyte support of tumor endothelial cells in concert with maximum-tolerated dose (MTD) or metronomic chemotherapy and/or VEGFR inhibition., Results: Imatinib, despite equivocal efficacy as monotherapy, reduced pericyte coverage of tumor vessels and enhanced efficacy in combination with metronomic chemotherapy or VEGFR inhibition. A regimen involving all three was even better. MTD using cyclophosphamide caused transitory regression, but then rapid regrowth, in contrast to metronomic cyclophosphamide plus imatinib, which produced stable disease. The MTD regimen elicited apoptosis of tumor cells but not endothelial cells, whereas the other regimens increased endothelial cell apoptosis concordant with efficacy. A "chemo-switch" protocol, involving sequential MTD and then metronomic chemotherapy, overlaid with multitargeted inhibition of PDGFR and VEGFR, gave complete responses and unprecedented survival advantage in this model., Conclusion: This study demonstrates a potentially tractable clinical strategy in a stringent preclinical model, wherein standard-of-care chemotherapy is followed by a novel maintenance regimen: PDFGR is targeted to disrupt pericyte support, while metronomic chemotherapy and/or VEGFR inhibitors target consequently sensitized endothelial cells, collectively destabilizing pre-existing tumor vasculature and inhibiting ongoing angiogenesis.

A patient with a large prolactinoma developed a metastatic islet cell tumor secreting pancreatic polypeptide. Dopamine agonist drugs reduced the prolactin levels to normal, caused a 7-fold decrease in the pancreatic polypeptide levels, and inhibited the liver metastases. Elevated chromogranin A levels also normalized on the higher doses of bromocriptine. Dopamine receptors are found in many endocrine tissues, and the expression of dopamine-2 receptor on endocrine tumors establishes the potential for response to dopamine agonist treatment. The relatively benign risk profile of dopaminergic agents makes further testing of these drugs to treat neuroendocrine tumors a worthwhile endeavor.

Background: A phase II study of dacarbazine (DTIC), was conducted to determine the response rate, duration of response, toxicity and overall survival of patients with advanced pancreatic islet cell tumors., Patients and Methods: Fifty patients with advanced pancreatic islet cell tumors, having progressive symptoms or evidence of rapidly advancing disease were entered on this study. DTIC was given by IV infusion at a dose of 850 mg/m2, over 60-90 minutes, repeated every four weeks., Results: The response rate was 33% in 42 patients who had measurable tumor, and 34% in the 50 patients (90% confidence interval (90% CI): 23%-47%). The majority of the responses were seen in patients without prior chemotherapy. Median overall survival was 19.3 months. There were two lethal toxicities on the study, one septic shock and one myocardial infarction. Grade 4 toxicities were, hematological (5 patients), sepsis, neurological (depression and paranoid behavior) and bleeding (1 patient each). The most common toxicity was vomiting, grade 3 in 13% of patients., Conclusions: DTIC has activity in advanced previously untreated pancreatic islet cell tumors.

Islet cell tumors of the pancreas are rare, indolent, neuroendocrine tumors. Approximately 50% of the patients diagnosed with these tumors present with symptoms related to various biologically active hormones that are secreted by these neoplasms. Currently, the only curative treatment for islet cell tumors is complete surgical resection. Management of metastatic disease is conservative. Initial treatment of these tumors includes expectant observation and medical management of symptoms with clinical monitoring and serial CT scans to assess tumor growth. Patients with rapidly progressive disease, with local symptoms caused by tumor bulk, or with uncontrolled symptoms related to hormone secretion require more aggressive medical or surgical intervention. The somatostatin analogue octreotide may help control hormone secretion and stabilize tumor growth. Patients refractory to octreotide with tumor predominantly in the liver are potential candidates for mechanical ablative techniques, such as hepatic arterial embolization. Radiofrequency ablation and cryosurgical techniques may also be useful, although specific data are limited. Surgical resection of metastatic disease may offer palliative relief of symptoms related to hormone secretion in carefully selected patients. Chemotherapy may be used for palliation when ablative techniques have failed or when significant extrahepatic disease is present. Streptozicin-based combinations remain the first line standard, but major objective responses are less common than had been previously thought. Because of the overall modest success of current chemotherapeutic regimens, patients with advanced disease in need of treatment should be encouraged to enroll in clinical trials testing newer antineoplastic agents or newer treatment strategies.

Background: New agents with antitumor activity in patients with neuroendocrine tumors are sorely needed. A Phase II study of high-dose paclitaxel in patients with metastatic carcinoid and islet cell tumors was performed at the Mayo Clinic. Granulocyte-colony-stimulating factor (GCSF) also was administered to ameliorate neutropenia., Methods: Twenty-four patients (14 with carcinoid tumors, 9 with islet cell tumors, and 1 with an anaplastic tumor) were enrolled on this Phase II study of paclitaxel given as a 24-hour continuous infusion at a dose of 250 mg/m(2) every 3 weeks plus GCSF at a dose of 5 microg/kg/day subcutaneously, beginning 24 hours after the completion of the paclitaxel dose and continuing until the absolute neutrophil count was > 10,000/microL., Results: All 24 patients were evaluable for analysis. The overall response rate was 8% (95% confidence interval [95% CI], 0-0.11). At last follow-up all patients except 1 had developed disease progression, with an estimated median time to disease progression of 3.2 months (95% CI, 1.6-6.0 months). The estimated median survival was 1.5 years (95% CI, 1.0-1.8 years). Hematologic toxicity was significant with 12 of 24 patients developing Grade 4 (according to the National Cancer Institute Common Toxicity Criteria scale) neutropenia; however, there were no septic deaths reported. There were 17 episodes of Grade 4 neutropenia in these 12 patients and the duration of these events ranged from 2-5 days. More common nonhematologic toxicities included arthralgia (21 patients), anorexia (15 patients), nausea (15 patients), diarrhea (12 patients), and allergic reactions (2 patients)., Conclusions: Given the lack of antitumor activity of paclitaxel and the significant hematologic toxicity observed despite the use of GCSF support in the current study cohort of patients with neuroendocrine tumors, further studies of this combination in this particular patient population are not recommended., (Copyright 2001 American Cancer Society.)

Tumoral insulin-producing cells of the RINm5F line were cultured for 8-96 h in the absence or presence of 2-deoxy-D-glucose (0.15-0.80 mM) or its tetraacetate ester (0.08-0.80 mM). Despite the fact that over a short incubation of 120 min the utilization of D-[5-3H]glucose and oxidation of D-[U-14C]glucose were not more markedly decreased by 2-deoxy-D-glucose tetraacetate than by the unesterified glucose analogue, the growth of the tumoral cells, as assessed by either the generation of formazan from 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide or direct cell counting, was more severely affected by the ester than by 2-deoxy-D-glucose. At a high concentration (0.80 mM), the ester even decreased the cell number below its initial value. No restoration of cell growth was observed when the cells were exposed for only 8 h to 2-deoxy-D-glucose tetraacetate (0.80 mM) and then further cultured for 64 h in the absence of the ester. These findings indicate that such an ester acts as a powerful cytostatic and cytotoxic agent in this tumoral cell line.

Background: Octreotide, a long-acting somatostatin analogue, has demonstrated clinical utility in patients with carcinoid syndrome and malignant islet cell tumors of the pancreas. Prior studies have reported a greater than expected incidence of cholelithiasis in patients treated with octreotide for acromegaly. This study attempted to determine the incidence and morbidity of cholelithiasis in a group of patients with metastatic carcinoid or malignant pancreatic islet cell tumors who were receiving chronic therapy with octreotide., Methods: Forty-four of 55 patients on investigational protocols with octreotide were eligible for chart review; 10 patients were excluded due to prior cholecystectomy and 1 patient due to asymptomatic cholelithiasis at presentation. Patients fell into three treatment groups. The low dose (LD) group was comprised of 17 patients receiving 150 microg of subcutaneous octreotide 3 times a day. Twenty-one patients received high dose (HD) therapy comprised of 500 microg given 3 times a day. The low dose-high dose (LD-HD) group was comprised of 6 patients who had their dose escalated from 150 microg to 225-500 microg of octreotide 3 times a day., Results: The overall incidence of cholelithiasis and/or gallbladder sludge was found to be 52.3% in all 3 treatment groups. Three of the 44 patients (6.8%) had symptomatic disease requiring emergency cholecystectomy. Five other patients underwent elective or incidental gallbladder surgery. The incidence of cholelithiasis in the LD, LD-HD, and HD groups was 35.3%, 66.6%, and 61.9%, respectively. The incidence of acute cholecystitis in the three groups was 11.8%, 0%, and 4.8%, respectively., Conclusions: Although greater than 50% of patients receiving octreotide developed cholelithiasis, a much smaller percentage of patients had symptomatic gallbladder disease. Patients receiving chronic octreotide treatment require monitoring for the development of gallstones. However, prophylactic cholecystectomy is not indicated, unless it is performed in conjunction with bowel resection or cytoreductive hepatic surgery.

Angiogenesis is activated during multistage tumorigenesis prior to the emergence of solid tumors. Using a transgenic mouse model, we have tested the proposition that treatment with angiogenesis inhibitors can inhibit the progression of tumorigenesis after the switch to the angiogenic phenotype. In this model, islet cell carcinomas develop from multifocal, hyperproliferative nodules that show the histological hallmarks of human carcinoma in situ. Mice were treated with a combination of the angiogenesis inhibitor AGM-1470 (TNP-470), the antibiotic minocycline, and interferon alpha/beta. The treatment regimen markedly attenuated tumor growth but did not prevent tumor formation; tumor volume was reduced to 11% and capillary density to 40% of controls. The proliferation index of tumor cells in treated and control mice was similar, whereas the apoptotic index was doubled in treated tumors. This study shows that de novo tumor progression can be restricted solely by antiangiogenic therapy. The results suggest that angiogenesis inhibitors represent a valid component of anticancer strategies aimed at progression from discrete stages of tumorigenesis and demonstrate that transgenic mouse models can be used to evaluate efficacy of candidate antiangiogenic agents.

Antiproliferative treatment of patients with metastatic endocrine gastroenteropancreatic tumours (GEP) is based mainly on chemotherapeutic protocols whereby drug toxicity is a major handicap. Octreotide is the first choice in the control of hormone mediated symptoms. From retrospective and a few prospective studies it has been suggested that octreotide exhibits antiproliferative properties. The prospective German Sandostatin multicentre phase II trial investigated the effects of 200 micrograms octreotide thrice daily for one year on tumour growth and endocrine abnormalities in 103 patients. Octreotide treatment was continued in those patients responding to the drug until tumour progression occurred. In 28 of those with tumour progression during 200 micrograms thrice daily octreotide dose was increased to 500 micrograms thrice daily. The study sample consisted of 52 patients with computed tomography confirmed tumour progression and 13 patients with stable disease before octreotide treatment, whereas no preobservation period was available in 38 patients. Nineteen patients (36.5%) with computed tomography confirmed tumour progression experienced stabilisation of tumour growth lasting for at least three months. Median duration of stable disease was 18 months. At month 12, stable disease continued in 12 patients, declined after 24 months to nine patients, and after 36 months to five patients. Tumour regression has not been seen in this or other subgroups. In the subgroup with stable disease before octreotide, stable disease continued in 53.8% of patients over 12 months. Increase of octreotide dose to 500 micrograms thrice daily did not influence progression seen during the lower dose with the exception of one patient in whom tumour progression changed to stable disease. No association of tumour size response and patients' characteristics could be detected. The results suggest that octreotide inhibits tumour growth in patients with metastasised endocrine GEP tumours. The antiproliferative effect is, at least in some patients, longlasting. Currently, octreotide can only be recommended as an antiproliferative drug if patients with clearly progressive disease show stabilisation after treatment for three to six months.

Background: The unsatisfactory control of neuroendocrine tumor growth with chemotherapy and/or interferon (IFN-2a) stimulated us to investigate the role of the somatostatin analogue octreotide (SMS 201.995), which is reported to be highly effective in controlling carcinoid syndrome symptoms. Octreotide has been used in a wide range of doses, and it was postulated that higher doses might lead to an objective response., Methods: The aim of the present multicenter Phase II study was to determine the safety and efficacy of SMS 201.995 in controlling carcinoids and other neuroendocrine tumors. Fifty-eight patients were treated subcutaneously with 2 sequential doses of the drug (Sandostatina, Sandoz, Inc., S.b.A. Pharmaceuticals, Basel, Switzerland). The first 23 patients received 500 micrograms 3 times a day and the remaining 35 patients received 1000 micrograms 3 times a day. The treatment was continued until the tumor progressed., Results: All of the patients were adequately treated and evaluated. The predominant histotype was carcinoid, although there were instances of medullary thyroid carcinoma, pancreatic islet cell tumors, and Merkel cell carcinoma. Carcinoid syndrome was documented in 16 patients and abnormal urinary 5-hydroxyindoloacetic acid excretion in 15. The median treatment duration was 5 months (range, 2-31 months). The responses were evaluated in three categories: tumor regression for tumor growth control, symptom response, and biochemical response. There was an effect on tumor growth in two patients with carcinoids. Symptomatic control was achieved in 73% of patients and a biochemical response in 77% of patients. In twenty-seven patients, the disease stabilized for at least 6 months (range, 6-32+). The median survival time for all patients was 22 months (range, 1-32+)., Conclusions: In terms of tumor regression, octreotide is disappointing (partial response: 3%); symptomatic response and biochemical control are satisfactory. These data confirm that somatostatin analogues are comparable to interferons in the treatment of carcinoid syndrome, although other efforts are necessary to control tumor regression.

The adenosine analogue formycin A was recently introduced as a potent insulin secretagogue in normal pancreatic islet cells. In the present study, formycin A was found to inhibit insulin release and to exert a cytotoxic effect in tumor islet cells of the RINm5F line. The latter effect was concentration-related in the 10-100 microM range of formycin A concentrations, not rapidly reversed, and not reproduced by adenosine. This study thus reveals that formycin A may display cytotoxic potential in the same range of concentrations in which it causes a progressive increase of glucose-stimulated insulin secretion in normal pancreatic islets.

We performed a phase II study with mitoxantrone in patients with carcinoid tumours, islet cell tumours and medullary carcinomas of the thyroid. Thirty-five eligible patients received mitoxantrone 12 mg m-2 i.v. every 3 weeks. Among 18 previously untreated patients, three responded (17%, 95% CI = 4-41%); no responses were achieved in 17 previously treated patients. Of the 21 patients who had carcinoid tumours, 11 were previously untreated and two achieved a response (18%, 95% CI = 2-52%). Overall response rate was 9% (95% CI = 2-23%). At a median follow-up of 43 months, median overall survival was 16 months. The median survival of 21 patients with a normal alkaline phosphatase was 29 months and 9 months for 14 patients with elevated serum levels (P = 0.005). A similar observation was noticed for gamma-glutamyltransferase (P = 0.007). We concluded that mitoxantrone is not active in APUD tumours. Elevated alkaline phosphatase and gamma-glutamyltransferase are associated with a poor prognosis.

Background: Chemotherapy remains inadequate for patients with carcinoid tumors, islet cell tumors, and medullary carcinomas of the thyroid. Carboplatin has shown activity in oat cell carcinoma of the lung, another tumor of neuroectodermal origin., Methods: Forty-two patients with advanced APUD tumors (20 carcinoid tumors, 9 islet cell carcinomas, 5 medullary carcinomas of the thyroid, and 9 neuroendocrine tumors of unknown primary site) were treated with carboplatin in a Phase II study., Results: Carboplatin was inactive in carcinoid and islet cell tumors, with 0 of 20 and 0 of 9 patients responding, respectively. Of the 41 total patients evaluable for response, only 2 (5%) achieved a partial response. Both of these responding patients had neuroendocrine tumors of unknown primary site. No complete responses were seen. Toxicities were those previously noted with carboplatin, with myelosuppression, particularly thrombocytopenia, being dose limiting., Conclusions: Carboplatin is inactive in carcinoid tumors and did not show evidence of activity in islet cell tumors. Further investigations are needed to identify active agents in the treatment of neuroendocrine malignancies.

Gut tumor syndromes are rare, occurring in less than two cases per million population per year: Insulinomas are most common and gastrinomas are less common; all the others are extremely rare. Conventional treatment of the symptoms caused by these tumors has included surgery, hepatic arterial embolization, and chemotherapy; some patients with Zollinger-Ellison syndrome (ZES) have been treated with specific agents such as gastric antisecretory drugs. The development of octreotide, a synthetic, long-acting analogue of the natural peptide somatostatin, has offered an alternative to such therapies. Octreotide has a half life of > 100 minutes and inhibits both physiological- and tumor release of many peptides. It also has direct effects on the gut that modify secretion and motility. Octreotide has been shown to be particularly useful for the symptoms of tumors producing vasoactive intestinal peptide (VIP), and of the carcinoid syndrome. It is also useful in patients with glucagonomas, with growth hormone-releasing hormone producing tumors, and in some patients with Cushing's syndrome and unresectable insulinomas. Octreotide is effective in patients with ZES, but alternative therapies such as omeprazole are more effective, safer, and more convenient for those patients. Side effects of octreotide have not been troublesome in these patients, but the incidence of long term effects is still not entirely clear. Octreotide has proved to be a significant advance in the treatment of patients with islet cell tumors.

A prospective study was performed to determine the efficacy of octreotide (Sandostatin; SMS 201-995) 200 micrograms tid in controlling tumor growth. The study included 21 patients with metastasized endocrine GEP tumors: 6 gastrinomas, 8 carcinoid syndromes, 7 nonfunctioning tumors. Treatment was performed for 3 to 59 months (median 15 months). Evaluation of the response to octreotide was facilitated in 12 patients by a pretreatment observation period of 3 to 47 months (median 17 months) during which the natural growth behavior was determined. Based on the presence or absence of a control period prior to treatment, 5 patients were considered to be responders, 7 as questionable responders (no pretreatment phase available), and 9 as nonresponders. None of the 21 patients had documented shrinkage of the tumor mass. The most favorable response was tumor standstill. In all but one responder an escape to an initially favorable response occurred after 6 to 28 months (median 14 months). Proved inhibition of growth was paralleled by a reduction of serum and urine hormone parameters, whereas unaltered progression of tumor growth was observed also in the presence of hormone suppression. Tumor growth and hormone release was inhibited in the absence and presence of somatostatin receptors on the tumor. It is concluded that octreotide exerts a limited effect on metastatic GEP tumor growth. The evaluation of a response to octreotide is facilitated by an observation period prior to the drug that provides information on growth characteristics of the tumor. The presence of octreotide receptors does not predict the success of therapy.

Background: Although patients with neuroendocrine tumors typically exhibit an indolent clinical course, the pace of disease accelerates and the prognosis deteriorates once objective progression of disease begins. Thirty-four patients with advanced neuroendocrine tumors were treated with octreotide as antineoplastic therapy. This treatment was begun only after documentation of clear objective progression of disease., Methods: A Phase II trial was performed at a tertiary comprehensive cancer center., Results: The median survival for this patient population from the start of octreotide therapy has not been reached, with a median follow-up of 29 months (range, 1-47 months). No major objective tumor regressions were seen. Seventeen patients (50%) experienced a computed tomography-documented stabilization of disease that was maintainable for a minimum of 2 months (median, 5 months; range, 0-27 months). Of the 34 patients, 20 patients received octreotide as their first antineoplastic therapy. The median survival for these 20 patients has not been reached, with a median follow-up also of 29 months (range, 12-41 months)., Conclusions: Octreotide may influence the natural history of neuroendocrine tumors. The survival in patients treated with octreotide, as measured from the time of progression of disease, compares favorably with that of historical controls. Proof of a survival advantage for patients treated with octreotide would require a multicenter, randomized trial.

The use of inteferon (IFN) in neuroendocrine advanced tumors has achieved control of hormonal symptoms but low objective tumor response rate. In patients resistant to, or failing on, IFN a second line treatment may be required. Seventeen patients having received recombinant IFN alpha-2a as last treatment entered the study. There were 12 carcinoids, 3 medullary thyroid carcinomas, one Merkel cell carcinoma, and one neuroendocrine pancreatic tumor. Two different treatments were used: one radiometabolic therapy with metaiodobenzylguanidine (MIBG) in 3 patients with high MIGB uptake and one polychemotherapy regimen, including streptozotocin 500 mg/m2 intravenously days 1, 2, 3 and epirubicin 75 mg/m2 intravenously day 1, in the remaining 14 patients. Stable disease with relief of symptoms and tumor marker reduction was obtained in two patients receiving MIGB therapy, whereas the third patient had progressive disease. In the chemotherapy group only one partial response was obtained and neither tumor marker reduction nor subjective improvement were seen. Our second-line treatment was not especially effective but may be considered for rapidly progressive and/or symptomatic disease. The radiometabolic therapy appears promising in symptomatic patients with small tumor burden whereas our chemotherapy regimen appears ineffective.

In the present study, we have updated our results with chemotherapy, alpha-interferon, octreotide and combinations of treatment modalities in patients with malignant endocrine pancreatic tumor (EPT). In our patient material of 134 EPT, 92 subjects had malignant tumors as evidenced by the presence of metastases or growth into adjacent organs. Seventy-eight patients had liver metastases. Streptozotocin plus 5-fluorouracil produced objective responses in 17/31 (54%) patients with a median duration of response of 23 months. The use of 5-HT3-antagonists as antiemetics has dramatically improved the quality of life during treatment by reducing the frequency of nausea to only 12.5%. The objective response rate to alpha-interferon (alpha-IFN) treatment, given as first-line treatment in 29 patients and after chemotherapy in 28 patients, was 51% (29/57) with a median duration of response of 20 months. Octreotide, which is still used as third-line treatment in most patients, produced significant biochemical responses in 6/19 (31%) patients with a median duration of 16 months. Combinations of alpha-IFN plus chemotherapy and a alpha-IFN plus octreotide in a small number of patients might indicate additive or synergistic effects. The median survival from start of treatment in the 92 malignant cases was 56.5 months, and for those with liver metastases (n = 78) at start of treatment 50 months. In conclusion, there are at least three effective therapies for malignant EPT and by combining them simultaneously or consecutively, a median survival of more than four years can be obtained.

Purpose: A phase II trial that used fluorouracil (5-FU) and chlorozotocin (CTZ) was performed in patients with metastatic islet cell carcinoma to determine the response rate and toxicity., Patients and Methods: Patients received four cycles of induction chemotherapy. Good-risk patients received 5-FU 800 mg/m2/d days 1 to 4 as a continuous intravenous (IV) infusion (CIV) and CTZ 175 mg/m2 IV on day 1. Poor-risk patients (previous radiation to > or = 25% bone marrow-bearing areas; serum bilirubin > or = 5 mg/dL; creatinine > 1.0 mg/dL) received 5-FU 600 mg/m2/d and CTZ 75 mg/m2 in a similar manner. In responding or stable patients, reduced doses of 5-FU and CTZ were continued as maintenance therapy (maximum, 18 months)., Results: Forty-seven of 51 patients were eligible, and 44 received chemotherapy. Fourteen of 44 patients had partial responses, with 13 of 36 (36%; 95% confidence interval [CI], 21.0% to 54.0%) good-risk patients and one of eight (12%; 95% CI, 0.3 to 52.6%) poor-risk patients responding. Median survival of all patients was 25 months, and the median response duration was 11 months. Side effects were moderate to severe and included myelosuppression and gastrointestinal toxicity. Thirteen patients developed renal toxicity, which was severe or life-threatening in five. This seemed to be related to the administration of cumulative doses of CTZ > or = 1,500 mg., Conclusion: These results demonstrate that the combination of 5-FU and CTZ has activity in islet cell carcinoma, but the occurrence of renal toxicity secondary to CTZ may limit the use of this agent.

Background: The combination of streptozocin and fluorouracil has become the standard therapy for advanced islet-cell carcinoma. However, doxorubicin has also been shown to be active against this type of tumor, as has chlorozotocin, a drug that is structurally similar to streptozocin but less frequently causes vomiting., Methods: In this multicenter trial, we randomly assigned 105 patients with advanced islet-cell carcinoma to receive one of three treatment regimens: streptozocin plus fluorouracil, streptozocin plus doxorubicin, or chlorozotocin alone. The 31 patients in whom the disease did not respond to treatment were crossed over to chlorozotocin alone or to one of the combination regimens., Results: Streptozocin plus doxorubicin was superior to streptozocin plus fluorouracil in terms of the rate of tumor regression, measured objectively (69 percent vs. 45 percent, P = 0.05), and the length of time to tumor progression (median, 20 vs. 6.9 months; P = 0.001). Streptozocin plus doxorubicin also had a significant advantage in terms of survival (median, 2.2 vs. 1.4 years; P = 0.004) that was accentuated when we considered long-term survival (greater than 2 years). Chlorozotocin alone produced a 30 percent regression rate, with the length of time to tumor progression and the survival time equivalent to those observed with streptozocin plus fluorouracil. Crossover therapy after the failure of either chlorozotocin alone or one of the combination regimens produced an overall response rate of only 17 percent, and the responses were transient. Toxic reactions to all regimens included vomiting, which was least severe with chlorozotocin; hematologic depression; and, with long-term therapy, renal insufficiency., Conclusions: The combination of streptozocin and doxorubicin is superior to the current standard regimen of streptozocin plus fluorouracil in the treatment of advanced islet-cell carcinoma. Chlorozotocin alone is similar in efficacy to streptozocin plus fluorouracil, but it produces fewer gastrointestinal side effects than the regimens containing streptozocin. It therefore merits study as a constituent of combination drug regimens.

Thyrotropin-Releasing hormone (TRH)-degrading pyroglutamyl peptidase I (PGP I) and prolylendopeptidase (PE) activities have been demonstrated in rat insulinoma RINm 5F cell line. These two enzymes catalyze the conversion of TRH to Histydyl-Proline-Diketopiperazine and to acid TRH respectively. After cell fractionation, we found all the PGP I and PE activities in the cytosolic fraction. The membrane-bound PGP II activity is not detectable in the RINm 5F cells. Further investigations on these two cytosolic enzymes show that pyroglutamyl- and proline-containing peptides are inhibitors of each TRH-degrading enzyme. Gel filtration chromatography on Sephadex G100 shows that PGP I and PE activity have an apparent molecular mass of about 18 kDa and 57 kDa, respectively. Kinetic analysis with TRH as substrate, gives a Km of 44 microM and 235 microM, and a Vmax of 1.49 and 8.80 pmol/min/micrograms protein for PGP I and PE, respectively. Immunoreactive TRH, His-Pro-Diketopiperazine and acid TRH levels in the cell line extracts are 2.2 +/- 0.9, 22.5 +/- 11.1 and 28.7 +/- 14.6 pg/1O6 cells, respectively. When cells have been incubated for 2 to 72 hours with a P.E. inhibitor (Z-Gly-Pro-CHN2) at 5 x 10(-7) M, both cell PGP I and PE activities are inhibited. No change in the cellular content of immunoreactive TRH, His-Pro-Diketopiperazine and acid TRH have been observed in treated cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Forty-five patients with metastatic neuroendocrine tumors were treated with a regimen of etoposide 130 mg/m2/d for 3 days plus cisplatin 45 mg/m2/d on days 2 and 3. Both drugs were given by continuous intravenous infusion. Among 27 patients with well-differentiated carcinoid tumors or islet cell carcinomas, only two partial objective tumor regressions were observed (7%). Among 18 patients prospectively classified as having anaplastic neuroendocrine carcinomas, however, there were nine partial regressions and three complete regressions, an overall regression rate of 67%. For anaplastic disease, the median duration of regression was 8 months (range to 21 months). Tumor response was unrelated to primary site, endocrine hyperfunction, or prior therapy experience. The median survival of all patients with anaplastic tumors was 19 months; this seemed favorable when considering the small experiences with these rare tumors reported in the literature. Toxicity, which was severe for most patients, consisted primarily of vomiting, leukopenia, thrombocytopenia, anemia, alopecia, and neuropathy. The anaplastic neuroendocrine tumor is strongly responsive to therapy with combined etoposide and cisplatin. Patients with undifferentiated carcinomas, originating in typical neuroendocrine tumor sites (small and large bowel, pancreas, and stomach) or of unknown origin, who have consistent histologic findings by light microscopy should be evaluated for this possibility with appropriate immune staining or electron microscopy.

The SRIF analog octreotide (SMS 201-995) has been in clinical use for over 6 yr in the treatment of acromegaly and metastatic endocrine pancreatic and carcinoid tumors. The use of the analog in the treatment of acromegaly and TSH-secreting tumors is beyond the scope of this clinical review. Patient acceptance of the analog, given chronically by the sc route, has been excellent and side effects have been few with the exception of the development of gallstones. In endocrine pancreatic and carcinoid tumors the hypersecretion of hormones such as VIP, glucagon, and gastrin and the secretory products of carcinoid tumors (e.g. 5-hydroxytryptamine and tachykinins) and their clinical effects may be successfully blocked. This allows excellent palliation of such tumors and often enables the patients to return home and lead normal social lives. Initial hopes that long-term octreotide therapy would be an effective antitumor drug, reducing tumor growth, based on experimental animal models and human tumor cell lines, have not been born out in clinical practice. A reduction in gut tumor bulk due to octreotide, rarely or never occurs as a sustained phenomenon. Eventually a decrease in, and finally an absence of, clinical effectiveness occurs despite the reintroduction of other treatment modalities.

Hypercalcemia occurring in a patient with an islet cell carcinoma of the pancreas suggests the diagnosis of Multiple Endocrine Neoplasia Type I and associated hyperparathyroidism. We describe a patient with an islet cell carcinoma and hypercalcemia in whom low concentrations of PTH, the absence of skeletal metastases, hypophosphatemia, and elevated nephrogenous cAMP alternatively suggested the syndrome of humoral hypercalcemia of malignancy. The peptide PTHrP was measured in the patient's serum during the course of therapy by an immunoradiometric assay directed toward the midportion of the molecule. Hypercalcemia was treated with an investigational aminobisphosphonate. The concentration of PTHrP[56-86] increased over time and fell after the patient received chemotherapy directed toward the islet cell tumor.

A 45-yr-old man who presented with hypercalcemia was found to have an abdominal mass that was a pancreatic islet cell carcinoma. Although clinical features were suggestive of primary hyperparathyroidism, his parathyroid hormone level was not elevated. The patient underwent a radical resection of the pancreatic neoplasm which was situated in the tail of the gland. After surgery, the serum calcium fell within the normal range, suggesting that the tumor was responsible for production of a parathyroid hormone-like substance. Because of malignant histologic features of the lesion, a chemotherapeutic regimen including 5-fluorouracil and streptozotocin was indicated. Five years later, the tumor has remained in total remission.

Octreotide acetate is a somatostatin analogue that has been shown to ameliorate the side effects of excessive secretion of hormone from benign and malignant tumors. The ability of this drug to inhibit the growth of malignant cells and to control gastrointestinal hemorrhage will prompt additional clinical trials. Because some of these patients may have thrombocytopenia, platelet dysfunction, or a coagulopathy, we studied tests of platelet function and blood coagulation in 15 patients before and after 14 days of therapy with octreotide acetate at a dosage of 500 micrograms three times daily. We found no substantial change in the results of these tests, and no patient experienced bleeding or thrombosis. These results suggest that octreotide acetate does not adversely affect platelet function or the coagulation system in humans.

A phase II trial of chemotherapy in carcinoid and islet cell pancreatic tumours has been conducted with the FAP protocol: 5-fluorouracil 400 mg/m2 per day (5-FU) for 3 days, 50 mg/m2 doxorubicin on day 2, and 90 mg/m2 cisplatin on day 2, repeated every 4 weeks. 24 patients, 20 non-pretreated and 4 pretreated, were included. For non-pretreated patients we observed 1 complete response and 2 partial responses. The response rate was 15% (95% confidence interval 0-31%). No response was observed in the pretreated patients. The toxicity was mainly digestive and haematological with 7 patients experiencing vomiting grade 3 and 3 patients with leucopenia grade 3. We conclude that the FAP protocol is of poor efficiency in endocrine tumours.

Somatostatin (SS) receptor status was investigated in the tumor tissues from 62 patients with carcinoid tumors and 15 patients with islet cell carcinomas using receptor autoradiography techniques with two different iodinated somatostatin analogues as radioligands, a [Leu8, DTrp22, Tyr25]somatostatin-28 and a somatostatin octapeptide, Tyr3-octreotide. The carcinoid tumors were either primaries (n = 32) or metastases (n = 43), sampled as surgical specimens or as small needle liver biopsies. Fifty-four of 62 carcinoid patients had SS receptor-positive tumors (87%). All 15 islet cell carcinoma patients had positive tumors (4 primaries, 11 metastases), i.e., 3 vipomas, 3 insulinomas, 2 glucagonomas, 1 gastrinoma, 2 polyfunctional tumors, and 4 nonfunctioning tumors. Saturation and competition experiments on tissue sections revealed saturable, high affinity binding sites pharmacologically specific for bioactive SS analogues. In a majority of the tumors, the receptors were densely distributed and were always homogeneously found in the whole tumor. All except two tumors were labeled with both radioligands. Multiple liver metastases (n = 16) from three different patients were all shown to contain a comparable amount of receptors. SS receptors could be demonstrated even in very small tissue samples of liver metastases obtained by percutaneous liver biopsies (mean weight, 6.8 mg). The majority of the eight SS receptor-negative carcinoids were mainly bronchial carcinoids (n = 5), usually poorly differentiated. On the contrary, SS receptor-positive cases were never found to be anaplastic. All tumors except one from patients pretreated with octreotide (3 days to 3.8 years) were SS receptor positive. In the majority of carcinoids or islet cell carcinomas, the SS receptor status correlated with the in vivo biochemical response (hormone inhibition) to octreotide. These data demonstrate (a) the high prevalence of SS receptors in the primary tumors of both carcinoids and islet cell carcinomas, (b) their presence in metastases as well, (c) their continuous expression even during long term octreotide therapy, (d) the possibility of measuring SS receptors in percutaneous needle liver biopsies, and (e) the evidence of their functionality. This study therefore suggests that tumoral SS receptors may be the likely molecular basis for octreotide action and may be an important parameter for predicting the therapeutic efficacy of SS analogues in carcinoids and islet cell carcinomas.

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.