The search for the primary tumor in metastasized gastroenteropancreatic neuroendocrine neoplasm.

Gastroenteropancreatic neuroendocrine tumors (NETs) often present as liver metastasis from a carcinoma of unknown primary. We recently showed that primary NETs from the pancreas, small intestine and stomach as well as their respective liver metastases differ from each other by the expression profile of the three genes CD302, PPWD1 and ABHB14B. The gene and protein expression of CD302, PPWD1, and ABHB14B was studied in abdominal NET metastases to identify the site of the respective primary tumors. Cryopreserved tissue from NET metastases collected in different institutions (group A: 29, group B: 50, group C: 132 specimens) were examined by comparative genomic hybridization (Agilent 105 K), gene expression analysis (Agilent 44 K) (groups A and B) and immunohistochemistry (group C). The data were blindly evaluated, i.e. without knowing the site of the primary. Gene expression analysis correctly revealed the primary in the ileum in 94 % of the cases of group A and in 58 % of group B. A pancreatic primary was predicted in 83 % (group A) and 20 % (group B), respectively. The combined sensitivity of group A and B was 75 % for ileal NETs and 38 % for pancreatic NETs. Immunohistochemical analysis of group C revealed an overall sensitivity of 80 %. Gene and protein expression analysis of CD302 and PPWD1 in NET metastases correctly identifies the primary in the pancreas or the ileum in 80 % of the cases, provided that the tissue is well preserved. Immunohistochemical profiling revealed CD302 as the best marker for ileal and PPWD1 for pancreatic detection.

[The relevance of PET/CT for the surgical management of neuroendocrine neoplasms]. / Bedeutung der PET/CT für die Chirurgie neuroendokriner Neoplasien.

Neuroendocrine neoplasms (NEN) are rare malignancies with a wide spectrum of metastatic potential which originate from the endocrine cells of the body and express somatostatin receptors. The (68)gallium somatostatin receptor positron emission tomography-computed tomography (PET/CT) technique is the most sensitive method of assessment of well-differentiated NENs and for the detection of cancer of unknown primary (CUP syndrome) NENs. Imaging with 18F-fluorodeoxyglucose (18F-FDG PET/CT) is indicated in poorly differentiated neuroendocrine carcinomas. The receptor-dependent imaging of NENs has a decisive impact on further management.

[Hereditary syndromes of neuroendocrine tumours]. / Hereditäre Syndrome neuroendokriner Tumore.

Diffuse localised neuroendocrinal cells represent the largest population of endocrinally active cells and can degenerate to malignant neuroendocrine tumours (NET). In this review the most important hereditary syndromes that predispose for endocrine and neuroendocrine tumours are presented and discussed. NET occur mainly as sporadic tumours. Current investigations on the pathogenesis of sporadic neuroendocrine tumours have revealed a close relationship between hereditary and sporadic neuroendocrine tumours. In the course of hereditary syndromes, such as multiple endocrine neoplasia, endocrine and neuroendocrine tumours as well as non-endocrine neoplasias can occur. In order to recognise these syndromes in good time a knowledge of the predisposing syndromes and their cardinal symptoms is essential. In this way not only individualised diagnosis and therapy can be planned but also an appropriate early management of first degree relatives can be initiated.

Pancreatic neuroendocrine neoplasms.

Pancreatic neuroendocrine tumors originate from the diffuse neuroendocrine system in the pancreatic region. These tumors exhibit a rising incidence despite their rareness and due to their benign behavior a considerable prevalence. Pathogenesis of pancreatic neuroendocrine tumors is characterized by common pathways of hereditary and sporadic tumors. Pancreatic neuroendocrine tumors may secrete peptide hormones or biogenic amines in an autonomous fashion as functional active tumors. Pathological grading and staging by TNM systems has been established in recent years classifying well and moderately differentiated pancreatice neuroendocrine tumors and poorly differentiated neuroendocrine carcinomas. Chromogranin A and less so pancreatic polypeptide are suitable tumor markers for pancreatic neuroendocrine tumors. Expression of receptors for somatostatin is the basis of treatment of pancreatic neuroendocrine tumors with somatostatin analogues as antisecretive and antiproliferative agents. In addition, somatostatin scintigraphy or PET/CT allows comprehensive diagnosis of pancreatic neuroendocrine tumors, which should be supported by (endoscopic and contrast enhanced) ultrasound, CT and MRI. Therapy of pancreatic neuroendocrine tumors consists of somatostatin analogues, chemotherapy, targeted therapy and peptide receptor radionuclide therapy. Two molecular substances hav been registered for pancreatic neuroendocrine tumors recently, sunitinib (Sutent®) and everolimus (Afinitor®). Predominant tumor load in the liver may be treated by local ablative therapy or liver transplantation. These treatment options have been included in guidelines of several professional societies and weighted for sequential therapy of patients with pancreatic neuroendocrine tumors according to effects and side effects.

Monthly ibandronate for the prevention of bone loss in patients after liver transplantation.

BACKGROUND: Osteopenia and osteoporosis are diseases frequently occurring after liver transplantation (OLT). PURPOSE: In a prospective study, we have investigated the effect of ibandronate, vitamin D(3), and calcium on the prevention and treatment of posttransplant osteopenia and osteoporosis. METHODS: The bone mineral density (BMD) of the lumbar spine (LS) and of the femoral neck (FN) were measured in 74 patients prospectively pre- and post-OLT. RESULTS: Postoperatively the study group showed a consistent percentage increase in BMD (g/cm(2)) and a significantly increased BMD after 12 and 24 months in the LS (12 months: 1.05 ± 0.21 g/cm(2); P < .001 24 months: 1.11 ± 0.19 g/cm(2); P < .001) and the FN (12 months: 0.88 ± 0.16 g/cm(2); P < .002 24 months: 0.90 ± 0.15 g/cm(2); P < .001) in comparison with baseline pre-OLT (LS pre-OLT 0.98 ± 0.19 g/cm(2), FN 0.86 ± 0.14 g/cm(2)). The overall bone fracture rate was 5.4% up to 24 months. CONCLUSION: Ibandronate once monthly per os significantly increased the BMD in the LS and FN after OLT at 12 and 24 months. The increased BMD limits the risk of fracture.

[Expert dialogue: neuroendocrine tumours of the lungs and gastroenteropancreatic system]. / Expertendialog: Neuroendokrine Tumore der Lunge und des gastroenteropankreatischen Systems.

BACKGROUND: Neuroendocrine tumours of the lung exhibit an increasing incidence and prevalence. However, data on the diagnosis of and therapy for these tumours are sparse compared to neuroendocrine tumours of the gastroenteropancreatic system. METHODS: The present article reflects a dialogue between experts on neuroendocrine tumors of the lung and the gastroenteropancreatic system held on February 25th and 26th in Weimar, Germany. RESULTS: Many similarities exist between neuroendocrine tumours of the lung and the gastroenteropancreatic system but there are also significant differences. Similarities exist mainly concerning pathology, diagnosis and therapy. Differences exist regarding the systemic therapy and the significantly lower incidence of paraneoplastic syndromes. Somatostatin receptor PET/CT with gallium-68 labelled somatostatin analogues and peptide receptor radiotherapy are innovative methods for the diagnosis of and therapy for neuroendocrine tumours of the lung. The first treatment option remains complete resection of the tumour. Small molecules like everolimus (Afinitor®) have been tested in clinical trials and have been shown to prolong progression-free survival. CONCLUSIONS: Additional studies are necessary and efforts should be undertaken to establish a registry to increase data on methods suitable for he diagnosis of and therapy for neuroendocrine tumours of the lung.

Current treatment options for neuroendocrine tumors.

Neuroendocrine tumors are heterogeneous in their clinical behavior and require therapies specially tailored according to staging and grading, origin and expression of peptide receptors. Somatostatin analogues act as antisecretory and antiproliferative agents. Chemotherapy is mandatory for poorly differentiated neuroendocrine carcinomas and is also effective in neuroendocrine tumors of the pancreas and of the bronchial system. For localized neuroendocrine tumors, surgery should be performed with curative intent and is also an option in advanced or metastasized neuroendocrine tumors with the goal to debulk tumor masses. Local ablative therapies may be applied to decrease tumor load in the liver; however, results are often of short duration. Peptide receptor radiotherapy is a new treatment method applying radionuclide-targeted somatostatin receptor agonists for internal cytotoxic radiotherapy in somatostatin receptor-expressing neuroendocrine tumors. Retrospective and prospective clinical studies indicate prolonged progression-free survival and overall survival of patients responding by stable disease or any kind of remission with this innovative treatment, which is, however, available only in a few specialized centers. Finally, small-molecule inhibitors of vascular endothelial growth factor and serine/threonine-protein kinase mTOR pathways have been shown to delay progression in patients with neuroendocrine tumors. In summary, treatment options for neuroendocrine tumors have expanded considerably in the last years leading to prolonged overall survival.

Bone histomorphometry and biochemical markers of bone turnover in patients with chronic kidney disease Stages 3 - 5.

AIMS: Precise identification of renal osteodystrophy requires bone histomorphometry. Several markers of bone turnover may be useful to predict classification and severity of renal osteodystrophy, but there are only limited data whether these markers correlate with bone histomorphometry. METHODS: In 36 patients with chronic kidney disease (CKD) Stage 3/4 and in 96 patients with CKD Stage 5 bone histomorphometry was performed and renal osteodystrophy was classified according to the standardized international nomenclature. Blood samples were taken at the time of bone biopsy, stored and analyzed at the end of the study. RESULTS: Osteitis fibrosa (OF) was the most frequent histomorphometric form, occurred in 47.2% in CKD Stages 3 - 4 and in 61.4% in CKD Stage 5. There was no difference in the frequency of adynamic renal bone disease (ARBD). The correlation coefficients between bone turnover markers and histomorphometric parameters were higher in CKD 5 patients with high bone turnover lesions. The predictive value for high versus low/normal bone turnover status was comparable for alkaline phosphatase (APH), bone alkaline phosphatase (BAP), pyridinoline (Pyd), desoxypyridinoline (Dpyd), tartrat-resistent acid phosphatase (TRAP Vb) and parathyroid hormone (PTH) in CKD Stage 5 patients, but was insufficient for APH and TRAP Vb in CKD Stage 3 - 4 patients. CONCLUSIONS: Besides parathyroid hormone, biochemical parameters of bone turnover provide a moderate discrimination and prediction of bone turnover status only in patients with CKD Stage 5. Due to a large variability, they are of limited use in predicting the histomorphometric type of renal osteodystrophy. Bone histology remains necessary for an exact classification of underlying pathology.