A germline c.1546dupC MEN1 mutation in an MEN1 family: A case report.

RATIONALE: Multiple endocrine neoplasia type 1 (MEN1) is a rare tumor syndrome with an autosomal dominant inheritance, and genetic testing for MEN1 gene is important for both affected individuals and their relatives. We present a 2-person family affected by a germline c.1546dupC MEN1 mutation, and one of them had a full-spectrum of MEN-related endocrine tumors. PATIENT CONCERNS: A female patient aged 32 years presented with jejunal ulcer perforation due to gastrinoma. DIAGNOSES: We conducted genetic analysis and extensive biochemical/radiological evaluation for detecting other endocrine tumors. Multiple pancreatic neuroendocrine tumors (NETs), prolactinoma and primary hyperparathyroidism were diagnosed, and a frame-shift mutation, NM_130799.1:c.1546dupC (p.Arg516Profs∗15), was detected. One daughter of the proband, aged 12 years, had the same mutation for MEN1. INTERVENTION: She underwent pancreatic surgery for pancreatic NETs and total parathyroidectomy for primary hyperparathyroidism. OUTCOMES: After pancreatic surgery, long-term symptoms of epigastric soreness, acid belching, sweating, and palpitation in fasting were improved. Hypercalcemia was improved after parathyroidectomy and she was supplemented with oral calcium and vitamin D. Her daughter showed normal biochemical surveillance until 15 years of age. LESSONS: We report 2 people in a family affected by MEN1 with the heterozygous germline c.1546dupC mutation, a variant that should be surveilled for early development of full-blown MEN1-associated endocrine tumors.

Hyperthermic isolated liver perfusion with melphalan and bevacizumab.

Whereas surgical resection is the only curative treatment for liver tumors, effective treatment for isolated unresectable lesions when there is tumor progression in spite of several lines of chemotherapy remains to be found. We report herein two cases of patients treated by a 1-hour Hyperthermic Isolated Liver Perfusion (HILP) with a combination of melphalan and bevacizumab leading to complete response. The first patient had liver metastases secondary to previously resected malignant glucagonoma and the second, recurrent hepatocellular carcinoma. We used bevacizumab in association with melphalan for HILP because of the additional effect of an anti-VEGF antibody in these highly vascularized tumors and its locally restricted delivery to the isolated hepatic vascular compartment despite of its classic contraindication in association with surgery. The protocol was approved by the Ethics Committee. Enhanced CT scans during follow-up showed complete tumor necrosis as early as the second postoperative day. Patients had 27 and 7 months disease-free survival and 48 and 41 months overall survival after HILP, for neuroendocrine liver metastases and HILP plus liver transplantation for HCC respectively. Under very specific conditions, bevacizumab in HILP can provide excellent tumor response in hopeless clinical cases of liver tumors.

[Neuroendocrine tumors of the gastrointestinal tract]. / Neuroendokrine Tumoren des Gastrointestinaltraktes.

Neuroendocrine tumors (NET) of the gastrointestinal tract are rare and constitute 0.5-1% of all human malignancies. Based on their endocrine secretion, they are functional active or inactive. They are further classified into fore-, mid-, or hindgut tumors. The recently published WHO-classification grouped the tumors according to their tumor size, angioinvasion and Ki-67 index. NET are mainly diagnosed in an advanced tumor stadium because of the paucity of symptoms or when symptoms occur due to endocrine hypersecretion. NET are diagnosed serologically by their hormone secretion and by measuring Chromogranin A levels. They are further detected by CT, MRI or endoscopy including endoscopic ultrasound. Many NET have somatostatin receptors on their surface and can be diagnosed by somatostatin receptor scintigrafy with high sensitivity and specificity. Only by surgery NET can be cured. Because many tumors are diagnosed late, medical options are of utmost importance. Symptom control can be established by somatostatin analogues and interferon-ot. Diazoxid can further inhibit insulin secretion, proton pump inhibitors are the therapy of choice for acid hypersecretion in Zollinger-Ellison syndrome. Advanced neuroendocrine cancers can be treated with chemotherapy. Recently, radio receptor therapy with 90Y-DOTA Octreotid and 177Lu-DOTA Octreotate was established in advanced neuroendocrine cancers and is further evaluated in studies. Net of the gastrointestinal tract should be treated in a multidisciplinary approach with gastroenterologists, surgeons and experts in nuclear medicine. An overview about epidemiology, clinical features, diagnostic methods and therapy of NET of the gastrointestinal tract will is provided in this article.

Genetic regulation of mouse glycosylphosphatidylinositol-phospholipase D.

Glycosylphosphatidylinositol phospholipase D (GPI-PLD) has been proposed to be responsible for cleaving membrane-associated glycosylphosphatidyl inositol (GPI) molecules to generate inositol phosphoglycan (IPGs), which have growth factor-mimetic properties. We have cloned the mouse liver GPI-PLD cDNA, which has a sequence that differs from that previously isolated from a mouse glucagonoma cell library. Using a highly specific and very sensitive RNase protection assay, we found that the GPI-PLD expressed in adult/post-natal brain, antrum and insulin-producing cells is identical to that isolated from liver. The expression of mouse GPI-PLD in liver shows a complex genetic regulation with a mouse strain-specific variation. In addition, GPI-PLD mRNA levels were higher in 4-week old animals compared to older animals, and the GPI-PLD mRNA levels increased in mice that developed insulin dependent type 1 diabetes spontaneously. This suggests that the expression of liver GPI-PLD in mice is highly regulated.

Migratory necrolytic dermatitis presenting after cephalosporin administration in a patient with a pancreatic head mass.

Migratory necrotizing dermatitis is one of the most distressing presenting symptoms of glucagonomas. This rare functioning pancreatic endocrine tumor is third in incidence after insulinomas and gastrinomas and is often malignant at the time of diagnosis. Elevated serum glucagon levels cause decreased amino acid levels which is believed to be the principal cause of the dermatitis. Other symptoms include anemia, visual scotomata and mild diabetes mellitus. Medical treatment alone including octreotide and amino acid supplementation has been reported to eliminate the dermatitis. Nonetheless, surgical resection or debulking remains the definitive treatment when possible. Because of its rarity, diagnosis may be delayed by years accounting for the high rate of metastasis at presentation. Reported here is the case of a 77-year-old man who presented with a migratory necrotizing dermatitis after antibiotic treatment and whose diagnosis of a glucagonoma was then delayed for over 1 year.

Glucagonoma: evolución y tratamiento / Glucagonoma: evolution and treatment

Glucagonomas are alpha pancreatic islet cell tumors that, when they are active, produce a syndrome characterized by necrolytic migratory erythema, diabetes mellitus, weight loss, anemia, glossitis, thromboembolism, neuropsychiatric disturbances and hyperglucagonemia. We report a 43 years old male presenting with a five years history of dermatological lesions, associated with weight loss, glossitis and onicodystrophy. Serum glucagon was 2200 pg/ml and a CAT scan showed a tumor in the tail of the pancreas. The tumor was surgically excised but one year later, hepatic metastases were found. These were excised surgically, treated with long acting octeotride and finally treated with radiotherapy using Y-DOTATOC. In the last control in November, 2001, the patient is asymptomatic

Current imaging and possible therapeutic management of glucagonoma tumors: a case report.

Glucagonomas, like other neuroendocrine tumors, express somatostatin receptors in more than 80% of cases. Unfortunately, because of the rarity of these tumors, the sensitivity and specificity of somatostatin analog (octreotide) imaging have not been established. Nonetheless, there have been limited reports in the literature supporting the use of indium In-111 DTPA N-terminal D-phenylalanine (D-PHE1) octreotide for glucagonoma imaging and may be most beneficial as an adjuvant to conventional imaging for tumor staging and therapeutic decision making. Current therapeutic applications of octreotide focus on stabilization of disease in tumors expressing somatostatin receptors, and tumor destruction, using beta-emitting isotopes. In this report, imaging of a glucagonoma with In-111 DTPA-D-PHE1 octreotide scintigraphy is described in a 51-year-old woman examined for a large palpable abdominal mass.

The glucose sensor protein glucokinase is expressed in glucagon-producing alpha-cells.

Expression of glucokinase in hepatocytes and pancreatic 6-cells is of major physiologic importance to mammalian glucose homeostasis. Liver glucokinase catalyzes the first committed step in the disposal of glucose, and beta-cell glucokinase catalyzes a rate-limiting step required for glucose-regulated insulin release. The present study reports the expression of glucokinase in rat glucagon-producing alpha-cells, which are negatively regulated by glucose. Purified rat alpha-cells express glucokinase mRNA and protein with the same transcript length, nucleotide sequence, and immunoreactivity as the beta-cell isoform. Glucokinase activity accounts for more than 50% of glucose phosphorylation in extracts of alpha-cells and for more than 90% of glucose utilization in intact cells. The glucagon-producing tumor MSL-G-AN also contained glucokinase mRNA, protein, and enzymatic activity. These data indicate that glucokinase may serve as a metabolic glucose sensor in pancreatic alpha-cells and, hence, mediate a mechanism for direct regulation of glucagon release by extracellular glucose. Since these cells do not express Glut2, we suggest that glucose sensing does not necessarily require the coexpression of Glut2 and glucokinase.

A Case of Necrolytic Migratory erythema Induced by a Pancreatic Insufficiency / 대한피부과학회지

Necrolytic migratory erythema is a cutaneous reaction pattern with specific histopathologic features that is typically associated with a functioning pancreatic islet cell neoplasm such as a glucagonoma. However, cases without. glucagonoma have also been reported, such as, liver cirrhosis, chronic pancreatitis, celiac sprue etc. Other clinical features include anemia, glossitis and weight loss. We report a case of neccrolytic migratory erythema induced by a pancreatic insufficiency without glucagonoma. A 43-year-old male was seen at our department because of rnultiple erythematous, desquamative and erosive patches on the whole body for 1 month. He also had weight loss(25Kg) and stomatitis. Seven years previously he had a Whipple's procedure for a pancreatic head rupture. The laboratory data showed a low protein and zinc level, and high glucagon level. Histopathologic findings of the case showed epidermal edema and pallor, and superficial epiderrnal necrosis. The patient improved progressively after intravenous infusion of amino acids with a pancreatic enzyme supplementation.

[Necrolytic migrating erythema without glucagonoma]. / Erytheme necrolytique migrateur sans glucagonome.

INTRODUCTION: The glucagonoma syndrome is an uncommon but well-known entity associating erythema necroticans migrans (ENM) with glucagonoma. CASE REPORT: A 43-year-old man with a past history of alcoholic cirrhosis and ascitis was hospitalized for skin disorders which had developed over the past 4 months. Centrifugal erythematous skin lesions were observed, some with non-turgid bullae and marginal desquamation, others with an erosive center. Lesions first appeared on the hands then diffused widely without involving the periorifical areas, folds and lower limbs. Laboratory results revealed an anemia, hypovitaminosis K, cholestatic liver failure, a beta-gamma block and low zinc levels. Histology study of the skin biopsy demonstrated a << Neapolitan trench >> image suggestive of ENM. A paraneoplasic syndrome and pancreas tumor were not found. Despite supplementation with zinc, amino acids and vitamins, the patient died from his liver disease. DISCUSSION: There have been 4 cases of ENM reported in the literature, all in cirrhosis patients, two of which had low zinc levels. Our case is thus the third with cirrhosis and low zinc. Bazex's syndrome, acrodermatitis enteropathica, annular chronic lupus erythematosis and annular superficial pemphigus were eliminated as possible diagnoses. The failure of zinc and amino acid supplementation would favor the secondary nature of the zinc deficiency and the predominant role of cirrhosis in this skin disease. The possible role of essential fatty acids in ENM is raised.

[The glucagonoma syndrome--a not-so-well-known cutaneous paraneoplastic condition. Case report]. / Das Glukagonom-Syndrom--eine wenig bekannte kutane Paraneoplasie. Ein kasuistischer Bericht.

Report on a 50-year-old patient suffering from glucagonoma-syndrome caused by a metastatic pancreatic islet cell carcinoma which produced several peptide hormones. There was no chance of operative resection of the tumor because of liver metastases at the time of diagnosis. The patient was treated with DTIC, systemic corticosteroids and photochemotherapy. During this treatment the skin lesions disappeared completely.