David J. Gross

Germline mutations in the Von Hippel-Lindau disease (VHL) gene in families from North America, Europe, and Japan

Germline mutation analysis was performed in 469 VHL families from North America, Europe, and Japan. Germline mutations were identified in 300/469 (63%) of the families tested; 137 distinct intragenic germline mutations were detected. Most of the germline VHL mutations (124/137) occurred in 1–2 families; a few occured in four or more families. The common germline VHL mutations were: delPhe76, Asn78Ser, Arg161Stop, Arg167Gln, Arg167Trp, and Leu178Pro. In this large series, it was possible to compare the effects of identical germline mutations in different populations. Germline VHL mutations produced similar cancer phenotypes in Caucasian and Japanese VHL families. Germline VHL mutations were identified that produced three distinct cancer phenotypes: (1) renal carcinoma without pheochromocytoma, (2) renal carcinoma with pheochromocytoma, and (3) pheochromocytoma alone. The catalog of VHL germline mutations with phenotype information should be useful for diagnostic and prognostic studies of VHL and for studies of genotype‐phenotype correlations in VHL.

Pre‐clinical Cushing's syndrome: an unexpected frequent cause of poor glycaemic control in obese diabetic patients

OBJECTIVEu2002Autonomous cortisol secretion without clinical stigmata of Cushings syndrome (CS) has been recently recognized and termed pre‐clinical or sub‐clinical CS. The common assumption is that CS is an extremely rare cause of uncontrolled diabetes; however, the prevalence of this entity has not been studied. We assessed the prevalence of pre‐clinical CS among obese patients with uncontrolled diabetes.

LONG ACTING SOMATOSTATIN ANALOGUES ARE AN EFFECTIVE TREATMENT FOR TYPE 1 GASTRIC CARCINOID TUMOURS

BACKGROUNDnGastric carcinoid tumours type 1 (GCA1) originate from hyperplastic enterochromaffin-like (ECL) cells secondary to hypergastrinaemia. Treatment with somatostatin analogues (SSA) might impede ECL-cell hyperplasia by suppressing gastrin secretion and/or by a direct anti-proliferative effect on ECL cells. We conducted a multicentre prospective study to assess the effects of long-acting SSA on hypergastrinaemia and ECL-cell proliferation in patients with GCA1.nnnMETHODSnWe studied 15 patients with GCA1 treated with monthly long-acting release octreotide (LAR) (20-30 mg; n=14) or Lanreotide 90 mg (n=1) for at least 6 months. Patients had serum gastrin and chromogranin A measurements performed and biopsies taken from both tumours and surrounding mucosa before, and every 6-12 months following treatment. Sections were immunostained for neuroendocrine markers. The cell proliferation index Ki-67, intensity of staining before and after treatment and the degree of gastric wall invasion were also assessed.nnnRESULTSnAll patients tolerated treatment well (mean follow-up of 18 months). In 11 patients (73%), a complete disappearance of the tumours at 1 year of treatment was observed on endoscopy, while in three patients (20%), the tumours decreased significantly in number and size. Gastrin levels normalized in 25% of patients, and were reduced by more than 80% in the remaining 75%.nnnCONCLUSIONSnTreatment with SSAs in GCA1 leads to a substantial tumour load reduction, with a concomitant decrease of serum gastrin levels. Our data indicate an important anti-proliferative effect of SSA on ECL cells, providing clinical benefit and obviating, at least temporarily, the need for invasive therapies for GCA1.

Sporadic phaeochromocytomas are rarely associated with germline mutations in the von Hippel-Lindau and RET genes.

von Hippel‐Lindau (VHL) disease and multiple endocrine neoplasia type 2 (MEN2) are autosomal dominant cancer syndromes. In both conditions, phaeochromocytoma is a prominent feature. It has recently been suggested that phaeochromocytoma can be the presenting and sole clinical manifestation of these multi–organ syndromes. The aim of this study was to ascertain the incidence of VHL and MEN2 among patients with sporadic phaeochromocytoma by mutational analysis.

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

Objectiveu2002 Glucagonoma is a pancreatic neuroendocrine tumour that arises from alpha cells in the pancreas and is often accompanied by a characteristic clinical syndrome.

High-resolution ultrasonography: highly sensitive, specific technique for preoperative localization of parathyroid adenoma in the absence of multinodular thyroid disease.

Abstract. The objective of this prospective study was to evaluate the role of preoperative ultrasonography (US) for parathyroid lesion localization in patients with primary hyperparathyroidism (PHPT) prior to initial surgery. Fifty-two consecutive patients with PHPT, diagnosed in our institution within a period of 2 years, were referred for preoperative US and subsequently for bilateral surgical neck exploration. The combination of a confirmatory pathologic report and normalization of blood calcium concentration for a period of at least 3 months was considered an operative success. In 50 patients (96.2%) a single parathyroid adenoma was excised, and in one patient (1.9%) hyperplasia of three glands was found at surgery. In the one surgical failure, no parathyroid pathology was identified in the neck; therefore the operative success in this series was 98%. The sensitivity of preoperative US was 83% with a specificity of 100%. In the absence of thyroid multinodular disease (MND), the sensitivity of preoperative US increased to 90%, whereas in patients with MND the sensitivity was only 64%. Our findings support the notion that patients with PHPT should be investigated with US before initial surgery. Bilateral surgical exploration is warranted in patients with MND. In the absence of such thyroid pathology, an US finding positive for adenoma should allow the surgeon to perform unilateral neck exploration only, with consequent reduction of operation time and postoperative complications.

Metastatic type 1 gastric carcinoid: a real threat or just a myth?

AIMnTo describe disease characteristics and treatment modalities in a group of rare patients with metastatic gastric carcinoid type 1 (GCA1).nnnMETHODSnInformation on clinical, biochemical, radiological, histopathological findings, the extent of the disease, as well as the use of different therapeutic modalities and the long-term outcome were recorded. Patients data were assessed at presentation, and thereafter at 6 to 12 monthly intervals both clinically and biochemically, but also endoscopically and histopathologically. Patients were evaluated for the presence of specific symptoms; the presence of autoimmune disorders and the presence of other gastrointestinal malignancies in other family members were also recorded. The evaluation of response to treatment was defined using established WHO criteria.nnnRESULTSnWe studied twenty consecutive patients with a mean age of 55.1 years. The mean follow-up period was 83 mo. Twelve patients had regional lymph node metastases and 8 patients had liver metastases. The primary tumor mean diameter was 20.13 ± 10.83 mm (mean ± SD). The mean Ki-67 index was 6.8% ± 11.2%. All but one patient underwent endoscopic or surgical excision of the tumor. The disease was stable in all but 3 patients who had progressive liver disease. All patients remained alive during the follow-up period.nnnCONCLUSIONnMetastatic GCA1 carries a good overall prognosis, being related to a tumor size of ≥ 1 cm, an elevated Ki-67 index and high serum gastrin levels.

Carcinoid Heart Disease: From Pathophysiology to Treatment--'Something in the Way It Moves'.

Carcinoid heart disease (CHD) is a rare cardiac manifestation occurring in patients with advanced neuroendocrine tumours and the carcinoid syndrome, usually involving the right-sided heart valves and eventually leading to right heart failure. The pathophysiology of CHD is still obscure and believed to be multifactorial, as a variety of vasoactive substances secreted by the tumour appear to be involved. The management of patients with CHD is complex, as both the systemic malignant disease and the heart involvement have to be addressed. Timely diagnosis and early surgical treatment in appropriately selected patients are of outmost importance, as CHD is associated with increased morbidity and mortality. Valve replacement surgery alleviates right heart failure and may also contribute to improved survival. In the present study we have comprehensively reviewed the existing literature to date, mainly focusing on the pathophysiology of CHD. Other aspects of CHD (such as the clinical presentation, diagnostic tools and therapeutic approach) are addressed in brief.

Ga-68 DOTA-NOC uptake in the pancreas: pathological and physiological patterns.

Objective: Gallium-68 (Ga-68) DOTA-1-NaI3-octreotide (DOTA-NOC) positron emission tomography (PET)/computed tomography (CT) is increasingly used for neuroendocrine tumors (NETs), often found primarily in the pancreas. However, physiologic uptake of DOTA-NOC has been described in the uncinate process of the pancreas. We studied DOTA-NOC uptake in this organ. Materials and Methods: Ninety-six patients underwent 103 DOTA-NOC scans, with pathology-proven pancreatic NET (n = 40) and nonpancreatic NET or biochemical suspicion of NET (n = 63). Results: DOTA-NOC uptake was detected in 35 documented pancreatic tumor sites (SUV: 5.5–165; mean: 25.7 ± 28.8; median: 17.8). Among 63 cases without previous known pathology, uptake was suspicious for tumor in 24 sites (SUV: 4.7–35; mean 16.3 ± 8.0; median: 14.1), and in 38 sites, it was judged as physiological, generally lower relative to adjacent structures (SUV: 2.2–12.6; mean: 6.6 ± 2.2; median: 6.2). In 24 scans with suspected tumor and in 37 of 38 scans with physiological uptake, diagnostic computed tomography or magnetic resonance imaging or endoscopic ultrasonography failed to detect tumor. Conclusions: Pancreatic DOTA-NOC uptake must be interpreted with caution, and further studies are required.

The immunomodulator Linomide: role in treatment and prevention of autoimmune diabetes mellitus.

Insulin-dependent diabetes mellitus (IDDM) is considered to be an autoimmune disorder characterized by destruction of the pancreatic beta-cells by auto-reacting lymphocytes. An attractive therapeutic approach to this disease would be to abrogate the autoimmune process at an early stage, thus preserving a critical mass of pancreatic beta-cells necessary for maintenance of normal glucose tolerance. Linomide (quinoline-3-carboxamide, Roquinimex, LS 2616), is a novel, orally absorbed, immunomodulatory drug that has been shown to be effective in various models of autoimmunity without causing non-specific immunosuppression. In this review, we describe the efficacy of Linomide for ameliorating the autoimmune process and diabetes in the non-obese diabetic (NOD) model of IDDM when administered at early stages of the disease. We also show that advanced disease in the NOD mouse can be treated effectively by combining Linomide with therapeutic modalities designed to increase pancreatic beta-cell mass. Subsequent clinical studies have shown that Linomide preserves beta-cell function in individuals with new-onset IDDM. Based on these data, Linomide or derivatives thereof might be useful for treatment of human IDDM.