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World Journal of Gastroenterology 2018年第20期24卷 2152-2162页

作者： Ashley Kieran Clift andrea frilling Department of Surgery and Cancer Imperial College London

Orthotopic liver transplantation(OLT) represents a generally accepted albeit somewhat controversially discussed therapeutic strategy in highly selected patients with non-resectable hepatic metastases from neuroendocrine tumours(NET). Whilst there are some exclusion criteria, these are not universally followed, and the optimal set of inclusion parameters for deeming patients eligible has not yet been elucidated. This is due to heterogeneity in the study populations, as well differing approaches employed and also divergences in selection criteria between centres. Recent data have suggested that OLT may represent the most efficacious approach in terms of overall and disease-free survival to the management of NET metastatic to the liver when conducted in accordance with the modified Milan criteria. Therefore, a consensus set of selection criteria requires definition to facilitate stringent and fair allocation of deceased-donor organs, as well as consideration for living-donor organs. In the context of classically non-resectable metastatic tumour bulk, multivisceral transplantation with or without the liver may also be indicated, yet experience is very limited. In this review, we discuss the diagnostic work-up of patients in whom the aforementioned transplantation approaches are being considered, critically analyse the published experience and also anticipate future developments in this field, including a discussion of immediate and longer-term research priorities.

关键词： neuroendocrine transplantation metastases liver multivisceral

Identification of osteopontin as the most consistently over-expressed gene in intrahepatic cholangiocarcinoma: Detection by oligonucleotide microarray and real-time PCR analysis

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World Journal of Gastroenterology 2008年第16期14卷 2501-2510页

作者： Holger G Hass Oliver Nehls Juergen Jobst andrea frilling Ulrich Vogel Stephan Kaiser Department of Oncology Hematology and Palliative Care Marien Hospital Stuttgart Department of Hematology Oncology and Rheumatology University of Tuebingen Matrigene GmbH Company Reutlingen Department of Abdominal and Transplant Surgery University of Essen Department of Pathology University of Tuebingen Department of Gastroenterology Hepatology and Infectious Diseases University of Tuebingen

AIM: To investigate the molecular pathways involved in human cholangiocarcinogenesis by gene expression profiling. METHODS: Oligonucleotide arrays (Affymetrix U133A) were used to establish a specific gene expression profile of intrahepatic CCC in comparison to corresponding non- malignant liver tissue. To validate the expression values of the most overexpressed genes, RT-PCR experiments were performed. RESULTS: Five hundred and fifty-two statistically differentially expressed genes/ESTs (221 probes significantly up-regulated, 331 probes down-regulated; P 2; ≥ 70%) were identified. Using these data and two-dimensional cluster analysis,a specific gene expression profile was obtained allowing fast and reproducible differentiation of CCC, which was confirmed by supervised neuronal network modelling. The most consistently overexpressed gene (median fold change 33.5, significantly overexpressed in 100%) encoded osteopontin. Furthermore, an association of various genes with the histopathological grading could be demonstrated. CONCLUSION: A highly specific gene expression profile for intrahepatic CCC was identified, allowing for its fast and reproducible discrimination against non- malignant liver tissue and other liver masses. The most overexpressed gene in intrahepatic CCC was the gene encoding osteopontin. These data may lead to a better understanding of human cholangiocarcinogenesis.

关键词： Cholangiocarcinoma Oligonucleotide arrays Osteopontin Cell cycle regulation Gene expression

Cyclosporine A, FK-506, 40-0-[2-hydroxyethyl]rapamycin and mycophenolate mofetil inhibit proliferation of human intrahepatic biliary epithelial cells in vitro

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World Journal of Gastroenterology 2005年第48期11卷 7602-7606页

作者： Chao Liu Thomas Schreiter andrea frilling Uta Dahmen Christoph E Broelsch Guido Gerken Ulrich Treichel Department of Gastroenterology and Hepatology University Hospital Essen Germany Department of General Surgery and Transplantation University Hospital Essen Germany

AIM： To investigate the effect of cyclosporine A （CsA）, FK-506, and mycophenolate mofetil （MMF） and 40-0-[2- hydroxyethyl]rapamycin （RAD） on proliferation of human intrahepatic biliary epithelial cells （BECs） in ***： BECs were isolated from six human liver tissuespecimens with the immunomagnetic separation method and treated with different concentrations of CsA, FK-S06, RAD, and MMF in vitro. Proliferation of the cells was measured by MTT assay at 24 and 48 h after treatment, respectively. One-way analysis of variance was used to analyze the results. Expression of CK 19 in BECs was monitored by flow cytometry and Western ***： Six lines of BECs were established. They survived for 4-18 wk in vitro. Flow cytometry analysis showed that these cells always expressed CK19. CsA, FK-506, RAD, and MMF inhibited proliferation of BECs in a dose-dependent manner. The lowest concentration of CsA, FK-506, RAD, and MMF to inhibit proliferation of BECs （P〈0.05） was 500, 100, 0.25, and 100 pg/L, respectively. However, the expression of CK19 by BECs was not ***： CsA, FK-506, RAD, and MMF have an antiproliferative effect on human intrahepatic BECs in vitro, while RAD has the strongest growth-inhibitory effect. Their possible effects on liver regeneration and bile duct injury in transplant patients should be further investigated.

关键词： Cyclosporine A FK-506, Rapamycin Mycophenolate mofetil Biliary epithelial cells

Successful photodynamic therapy for biliary papillomatosis:A case report

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World Journal of Gastroenterology 2008年第26期14卷 4234-4237页

作者： Lars P Bechmann Philip Hilgard andrea frilling Brigitte Schumacher Hideo A Baba Guido Gerken Thomas Zoepf Department of Gastroenterology and Hepatology University Hospital EssenEssen D-45122Germany Department of General- Visceral- and Transplant Surgery University Hospital EssenEssen D-45122Germany Department of Internal Medicine Evangelisches KrankenhausDuesseldorf D-40217Germany Department of Pathology University Hospital EssenEssen D-45122Germany

Papillomatosis of the bile duct is a rare disease with a high risk of malignant transformation. Therapeutical options include partial hepatectomy and liver trans- plantation. A previously healthy 65-years old male developed jaundice and right upper abdominal quadrant pain in 1996. A villous adenoma of the distal bile duct was diagnosed. A Whipple procedure was performed. In 2002 the patient turned symptomatic again. An- other adenoma was found in the right hepatic duct resulting in a right hepatectomy. Two years later the patient again developed cholestasis. Alter drainage of the left hepatic duct with a percutaneous transhepatic cholangial drainage （PTCD） catheter, a recurrent biliary adenomatosis was diagnosed by cholangioscopy. As there was no surgical option left, the patient received photodynamic therapy （PDT） for the recurrent biliary papillomatosis. Three mo alter he received further photodynamic therapies, the bile duct epithelium appeared normal and the patient had no signs of adenomatosis, both macroscopically and histologically. The follow-up cholangioscopy in late 2005 revealed only a small papil-loma without the need for intervention. In early 2006, the patient died of multi organ failure without signs of extrahepatic cholestasis or cholangitis at the age of 75, 10 years after the diagnosis of biliary papillomatosis was established. The patient exceeded the average life expectancy of patients with biliary papillomatosis by far. Thus, PDT might be a sufficient therapeutic option for recurrent papillomatosis patients with no significant side effects.

关键词： Biliary papillomatosis Cholangioscopy Photodynamic therapy

Glucagon receptor gene mutations with hyperglucagonemia but without the glucagonoma syndrome

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World Journal of Gastrointestinal Surgery 2015年第4期7卷 60-66页

作者： Helen C Miller Mark Kidd Irvin M Modlin Patrizia Cohen Roberto Dina Panagiotis Drymousis Panagiotis Vlavianos Günter Klöppel andrea frilling Department of Surgery and Cancer Imperial College LondonLondon W12 0HSUnited Kingdom Department of Surgery Yale UniversityNew HavenCT 06510United States Emeritus Yale University School of MedicineNew HavenCT 06510United States Department of Histopathology Imperial College LondonLondon W12 0HSUnited Kingdom Department of Gastroenterology Imperial College LondonLondon W12 0HSUnited Kingdom Department of Pathology Technical University of Munich81675 MunichGermany

Pancreatic neoplasms producing exclusively glucagon associated with glucagon cell hyperplasia of the islets and not related to hereditary endocrine syndromes have been recently described. They represent a novel entity within the panel of non-syndromic disorders associated with hyperglucagonemia. This case report describes a 36-year-old female with a 10 years history of nonspecific abdominal pain. No underlying cause was evident despite extensive diagnostic work-up. More recently she was diagnosed with gall bladder stones. Abdominal ultrasound, computerised tomography and magnetic resonance imaging revealed no pathologic findings apart from cholelithiasis. Endoscopic ultrasound revealed a 5.5 mm pancreatic lesion. Fine needle aspiration showed cells focally expressing chromogranin, suggestive but not diagnostic of a low grade neuroendocrine tumor. Octreo Scan was negative. Serum glucagon was elevated to 66 pmol/L(normal: 0-50 pmol/L). Other gut hormones, chromogranin A and chromogranin B were normal. Cholecystectomy and enucleation of the pancreatic lesion were undertaken. Postoperatively, abdominal symptoms resolved and serum glucagon dropped to 7 pmol/L. Although H and E staining confirmed normal pancreatic tissue, immunohistochemistry was initially thought to be suggestive of alpha cell hyperplasia. A count of glucagon positive cells from 5 islets, compared to 5 islets from 5 normal pancreata indicated that islet size and glucagon cell ratios were increased, however still within the wide range of normal physiological findings. Glucagon receptor gene(GCGR) sequencing revealed a heterozygous deletion,K349_G359del and 4 missense mutations. This case may potentially represent a progenitor stage of glucagon cell adenomatosis with hyperglucagonemia in the absence of glucagonoma syndrome. The identification of novel GCGR mutations suggests that these may represent the underlying cause of this condition.

关键词： Hyperglucagonemia Glucagon receptorgene Mutation Adenomatosis Pancreas