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.

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.

Induction of benign symmetric lipomatosis (Launois-Bensaude syndrome) in a female patient after liver transplantation.

Benign symmetric lipomatosis, also known as Madelung's disease or Launois-Bensaude syndrome, is a rare disease, the etiology of which is still unknown. The presence of multiple, symmetric, nonencapsulated lipomatous masses in the face, neck, upper arms and upper trunk is typical. Until now many causes have been discussed among which liver dysfunctions are described frequently. In up to 90% of patients, alcoholism is observed. In our case the Launois-Bensaude syndrome developed after liver transplantation in a 49-year-old female patient suffering from decompensated cirrhosis (Child-Pugh C score: 12 points). Shortly after the transplantation a slow progress in tissue-building appeared on both upper arms, cervical areas as well as in the face. During postsurgical prednisolone therapy, a massive increase in fluid in the tissue developed, which led to a discontinuation of this therapy regimen. In the further course there was an increase in weight of 20 kg. As far as we know, this case is the first description of the induction of a Launois-Bensaude syndrome following liver transplantation.

[Primary liposarcoma of the liver--a rare mesenchymal tumor]. / Primäres Liposarkom der Leber--ein seltener mesenchymaler Tumor.

Primary sarcoms of the liver are rare. Most often angiosarcomas have been reported. Primary liposarcoma of the liver is extremely rare. We report a case of primary liposarcoma of the liver in a 48-year-old woman and compare it with the 13 cases found in the literature. Histologic analysis showed a well differentiated liposarcoma. The treatment of choice is wide local tumor resection.

Conversion to mycophenolate mofetil for modulating recurrent hepatitis C in liver transplant recipients.

BACKGROUND: The aim of this study was to analyze the influence of cyclosporine A (CsA) taper in conjunction with mycophenolate mofetil (MMF) therapy on recurrent hepatitis C virus (HCV) in liver transplant patients. PATIENTS AND METHODS: Nineteen liver recipients with serologically and morphologically confirmed recurrent HCV were included in this study. After MMF introduction up to a maximum dose of 2000 mg/day, CsA dose was significantly tapered. In the control group immunosuppression remained unchanged. Allograft function and morphology, viral loads, and renal function were analyzed continuously. RESULTS: MMF treatment was well tolerated without risk of rejection. Allograft fibrosis progressed in 6 patients of the MMF group (66.6%) and none (0%) of the controls at 12-month biopsy (P=0.005). Moreover, aminotransferases and viral loads increased slightly in the MMF-treated patients. Renal function improved significantly (serum creatinine: 239.3+/-90.2 micromol/L vs. 175.8+/-46.0 micromol/L; P=0.008) in the treatment group, while deteriorating (serum creatinine: 156.8+/-44.6 micromol/L vs. 214.8+/-120.1 micromol/L; P=0.06) in the controls. CONCLUSION: MMF introduction allows a safe CsA taper in HCV-positive liver transplant patients and results in significant improvement of renal function. However, there seems to be a risk of marked progression of HCV-induced allograft injury.

Prevention of early loss of bone mineral density after liver transplantation by prostaglandin E1.

INTRODUCTION: As a result of preexisting chronic liver disease and immunosuppression, the majority of liver transplant patients develop bone mineral density (BMD) loss in the first 3 to 6 months posttransplantation, leading to an increased fracture risk. Using basic prophylaxis and treatment by administration of vitamin D, calcium, and bisphosphonates, BMD loss may be controlled in the long term. In contrast, there is no established medical concept for prevention of early posttransplant BMD loss. MATERIAL AND METHODS: The aim of this trial was to evaluate the effect of prostaglandin E1 on BMD after liver transplantation. Between 1998 and 2004, 29 patients were enrolled in this study. BMD measurement was performed at lumbar spine and femoral neck using dual energy x-ray absorptometry pretransplant, and 3, 6, 12, and 24 months posttransplant. All patients received calcium and vitamin D as basic prophylaxis. In 13 patients, prostaglandin E1 (PGE) was additionally administered for 12 days posttransplant. RESULTS: BMD loss was significantly lower at 3 and 6 months posttransplant in the PGE group (lumbar spine, P < .03; femoral neck, P < .009). Development of BMD loss was comparable between both groups during further follow-up. In the PGE group there was a significantly lower fracture rate compared with the controls (P < .02). CONCLUSION: The application of PGE 1 proved to be beneficial in compensating the early posttransplant BMD loss and in subsequently reducing fracture rate. These positive effects of PGE 1 could be demonstrated in both the femoral neck and lumbar spine.

Impact of mycophenolate mofetil versus azathioprine on early recurrence of hepatitis C after liver transplantation.

The aim of this study was to evaluate the impact of mycophenolate mofetil (MMF) on incidence, delay, severity and clinical course of early recurrent hepatitis C after liver transplantation (LT). A total of 21 hepatitis C virus (HCV)-positive patients after LT were prospectively enrolled in this study. All of them received a quadruple induction cyclosporine A (CsA)-based immunosuppression, augmented by MMF (n=12) or by azathioprine (n=9, AZA). MMF tended to delay recurrent disease (50+/-35 versus 35+/-35 weeks, P=0.5) with significantly lower levels of aminotransferases (P<0.05). Furthermore, patients under MMF revealed less severe allograft fibrosis at disease recurrence (stage of fibrosis: 1.5+/-0.5 versus 2.2+/-1.2; P=0.07). But stage of fibrosis significantly increased in the MMF-group (P<0.05) during 6 months of antiviral treatment. Three patients in the MMF-group and none of the controls suffered from severe fibrosing cholestatic recurrent hepatitis C. Initial post-LT administration of MMF tended to delay recurrent hepatitis C and to limit initial HCV-related biochemical and morphological graft dysfunction. But during clinical follow-up, its immunosuppressive capabilities exceeded possible antiviral properties, finally leading to significant progression of graft fibrosis. Thus, concomitant dose reduction of other basic immunosuppressants might be useful in this clinical setting.

Impact of selective prostaglandin E1 treatment on graft perfusion and function after liver transplantation.

BACKGROUND/AIMS: In several clinical trials, the prophylactic application of prostaglandin E1 did not demonstrate a significant effect on incidence of primary graft nonfunction after liver transplantation. The aim of this study was to evaluate the effect of a selective prostaglandin E1 treatment in liver transplant patients with initially compromised perfusion and thereby depressed early posttransplant graft function. METHODOLOGY: A total of 142 patients were enrolled in this study. In all of them, duplexsonography was performed daily to generally assess patency of allograft vessels and to specifically calculate the resistive index of the hepatic artery. Intravenous therapy with a prostaglandin E1 analogue (Alprostadil, 0.5 microg/kg/h) was initiated in 67 patients after determination of a primarily elevated (>0.75) and posttransplant increasing resistive index of the hepatic artery that was associated with continuously elevating aminotransferases. RESULTS: After initiation of treatment, the arterial resistive index decreased significantly from 0.83+/-0.1 to 0.72+/-0.1 on the first day of application (P<0.05). Primarily elevated serum levels of aspartate aminotransferase (AST: Alprostadil: 890+/-180 IU/L: CONTROL: 375+/-98 IU/L) and alanine aminotransferase (ALT: Alprostadil: 850+/-178 IU/L, CONTROL: 310+/-79 IU/L) decreased significantly and reached values comparable to the control group after three days of therapy (AST: Alprostadil: 190+/-40 IU/L, CONTROL: 150+/-45 IU/L ALT: Alprostadil: 280+/-57 IU/L, CONTROL: 180+/-50 IU/L) (P<0.05). Only 2 grafts with initial compromised perfusion and function (3%) developed primary graft nonfunction. CONCLUSIONS: Prostaglandin E1 seems to be effective in ameliorating ischemia-reperfusion injury to the liver in patients with elevated arterial vascular resistance and early depressed graft function after liver transplantation. Duplexsonography in combination with graft function are useful tools for indicating and monitoring treatment.

[Delayed onset of malignant hyperthermia crisis during a living donor liver transplantation caused by sevoflurane]. / Verzögertes Einsetzen einer Malignen Hyperthermie während einer Leberlebendspende unter Sevoflurananästhesie.

We report on a 25-year old ASA physical status I patient, who developed within 20 minutes a full-blown malignant hyperthermia (MH) in the context of a living donor liver transplantation after 180 minutes of uneventful anaesthesia. The only trigger substance applied was Sevoflurane. The patient had already received a short, uneventful anaesthesia with Isoflurane a couple of years ago. In the context of the special constellation an initial dose of Dantrolene of 10 mg/kg body weight was administered. The patient was stabilised within 30 minutes, and the enzyme levels remained low compared with other case reports. The post-operative in vitro caffeine halothane contracture testing confirmed that son and mother were susceptible to MH, contracture testing in the father was negative. All known triggers may cause life-threatening MH crisis - even after hours and after inconspicuous multiple exposures to known trigger substances. Therefore all trigger substances must be avoided in all patients susceptible to MH.

[Lysis therapy of thrombosis of the superior mesenteric artery]. / Lysetherapie bei arterieller Thrombose der Arteria mesenterica superior.

INTRODUCTION: For surgeons the acute intestinal ischaemia is still a diagnostic and therapeutic challenge. If clinically suspected, the diagnostic procedures such as duplex sonography and arterial angiography should be carried out immediately. Although the diagnosis is often quickly clear, perioperative mortality rate remains high. We report the acute local thrombolytic therapy as an alternative treatment. CASE REPORT: A 80-year-old male patient was referred to our hospital with a complete occlusion of the superior mesenteric artery. Duplex sonography and the arterial angiogram confirmed the clinical diagnosis. Because the patient was assessed to be at high risk we decided to avoid an operation and local thrombolytic therapy using rt-PA and urokinase was carried out. RESULT: The local thrombolytic therapy was successful and led to a complete restoration of the arterial flow within the superior mesenteric artery. The clinical symptoms subsided and no complications were observed. CONCLUSION: Local thrombolytic therapy appears to be a suitable therapeutic option in patients suffering of mesenteric arterial occlusion. Although the duplex sonography often confirms the diagnosis with high accuracy the angiography remains the diagnostic gold standard.

Application of MARS artificial liver support as bridging therapy before split liver retransplantation in a 15-month-old child.

Molecular Adsorbent Recirculating System (MARS) is a blood-filtering system designed to provide biological artificial liver support. We describe its use in a small child to illustrate its effectiveness and practicality in this age group. A 15-month-old male underwent split liver transplantation for acute liver failure following bone marrow transplantation. After development of graft dysfunction we instituted MARS-dialysis. MARS therapy led to a dramatic fall in serum bilirubin and transaminases. Liver synthetic function was not affected. This was accompanied by a stabilization of the patients clinical condition until repeat split liver transplantation was performed 2 weeks after the first graft. MARS-dialysis is practical in the small child. In this case, it did not provide definitive treatment but was an excellent bridging therapy before retransplantation.