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Activated hepatic stellate cells promote tumorigenicity of hepatocellular carcinoma

CANCER SCIENCE 2009年第4期100卷 646-653页

作者： Amann, Thomas Bataille, Frauke Spruss, Thilo Muehlbauer, Marcus Gaebele, Erwin Schoelmerich, Juergen Kiefer, Paul Bosserhoff, Anja-Katrin Hellerbrand, Claus Univ Regensburg Dept Internal Med 1 D-93053 Regensburg Germany Univ Regensburg Inst Pathol D-93053 Regensburg Germany Univ Regensburg Inst Pharm D-93053 Regensburg Germany Univ Regensburg Inst Clin Chem D-93053 Regensburg Germany

Liver cirrhosis is the main risk factor for the development of hepatocellular carcinoma (HCC). Activated hepatic stellate cells (HSC) are the effector cells of hepatic fibrosis and also infiltrate the HCC stroma where they might play a critical role in HCC progression. Here we aimed to analyze the effects of activated HSC on the proliferation and growth of HCC cell lines in vitro and in vivo. Conditioned media (CM) collected from HSC significantly induced proliferation and migration of HCC cells cultured in monolayers. In a 3-dimensional spheroid coculture system, HSC promoted HCC growth and diminished the extent of central necrosis. In accordance, in vivo simultaneous implantation of HSC and HCC cells into nude mice promoted tumor growth and invasiveness, and inhibited necrosis formation. As potential mechanism of the tumorigenic effects of HSC we identified activation of NFkappaB and extracellular-regulated kinase (ERK) in HCC cells, two signaling cascades that play a crucial role in HCC progression. In summary, our data indicate that stromal HSC promotes HCC progression and suggest the HSC-HCC interaction as an interesting tumor differentiation-independent target for therapy of this highly aggressive cancer. (Cancer Sci 2009;100: 646-653)

关键词： hepatic stellate cell Progression Primary carcinoma of the liver cells progressions Tumorigenicity Hepatocellular Cancer Hepatic Stellate Cells human-centered computing Risk Factors Ito Cells

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Intra-hepatic arterial administration with miriplatin suspended in an oily lymphographic agent inhibits the growth of human hepatoma cells orthotopically implanted in nude rats

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CANCER SCIENCE 2009年第1期100卷 189-194页

作者： Hanada, Mitsuharu Baba, Akemi Tsutsumishita, Yasuyuki Noguchi, Toshihiro Yamaoka, Takashi Dainippon Sumitomo Pharma Co Ltd Pharmacol Res Labs Konohana Ku Osaka 5540022 Japan

Miriplatin is a lipophilic platinum complex which contains myristates as leaving groups and diaminocyclohexane as a carrier ligand. In order to examine in vivo the antitumor activities of miriplatin suspended in an oily lymphographic agent )Lipiodol Ultra-Fluide (R), LPD) against human hepatocellular carcinoma (HCC) after the intra-hepatic arterial administration, we have developed a novel orthotopic model of HCC in which the human hepatoma cell line Li-7 was successively implanted and maintained in the liver of nude rats. Li-7 tumors established in nude rat livers displayed a trabecular structure similar to their original morphology, and were exclusively supplied by the hepatic artery, suggesting that they exhibited in part the conditions of human HCC. Miriplatin suspended in LPD (miriplatin/LPD) administered into the hepatic artery of this model dose-dependently inhibited the growth of Li-7 tumors without markedly enhancing body weight loss and caused a significant reduction in the growth rate at a dose of 400 mu g/head compared to LPD alone. In addition, at the therapeutic dose, miriplatin/LPD as well as cisplatin suspended in LPD )400 mu g/head) was shown to be more active than zinostatin stimalamer suspended in LPD )20 mu g/head) against Li-7 tumors after a single intra-hepatic arterial administration. These results suggest miriplatin to be a suitable candidate for use in transarterial chemoembolization (Cancer Sci 2009;100: 189-194)

关键词： Nude Rats Hepatocellular Cancer LITHIUM 7 Growth rate Hepatic Artery Arteries platinum complex human-centered computing Suspended

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Surgical Resection Versus Laparoscopic Radiofrequency Ablation in Patients With Hepatocellular Carcinoma and Child-Pugh Class A Liver Cirrhosis

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ANNALS OF SURGICAL ONCOLOGY 2009年第12期16卷 3289-3298页

作者： Santambrogio, Roberto Opocher, Enrico Zuin, Massimo Selmi, Carlo Bertolini, Emanuela Costa, Mara Conti, Matteo Montorsi, Marco Milanocuore SpA Osped Classificato San Giuseppe USD Chirurg Epatobiliopancreat Milan Italy Univ Milan Dipartimento Med Chirurg & Odontoiatria Azienda Osped San Paolo UO Chirurg 2 Milan Italy Univ Milan Dipartimento Med Chirurg & Odontoiatria Azienda Osped San Paolo Cattedra Med Interna Milan Italy Univ Milan IRCCS Ist Clin Humanitas Dipartimento Med Interna Milan Italy Univ Milan IRCCS Ist Clin Humanitas Cattedra Chirurg Gen Milan Italy

This study compared two homogeneous groups of patients submitted to either surgical resection (HR) or laparoscopic radiofrequency ablation (LRFA) for the treatment of hepatocellular carcinoma (HCC). When compatible with the liver functional reserve, HR remains the treatment of choice for HCC, while LRFA seems to be a promising, less invasive alternative. We thus compared HR or LRFA for short- and long-term outcomes in patients with a single HCC nodule and Child-Pugh class A liver cirrhosis. We enrolled 152 cirrhotic patients out of 372 cases consecutively evaluated for HCC. Enrolled patients with similar baseline characteristics underwent HR (n = 78) or LRFA (n = 74), in both cases with intraoperative ultrasonography, and they were then followed for similar durations (mean +/- A standard deviation, 36.2 +/- A 23.5 months for HR vs. 38.2 +/- A 28.4 for LRFA). Outcomes included short- and long-term morbidity, HCC recurrence, and overall survival. Short-term morbidity was far higher in the HR group while, during follow-up, HCC recurrence (mainly local) was more frequent in patients treated with LRFA. More importantly, baseline alfa-fetoprotein levels and early HCC recurrence after treatment greatly influenced overall survival, while the use of HR or LRFA did not predict it. On the other hand, HCC recurrence was found to be determined by the surgical approach and ultrasound characteristics of the tumor. Our data were obtained from a large number of HCC cases and support similar survival rates after HR or LRFA for single HCC nodules on Child-Pugh class A liver cirrhosis, despite a marked increase in HCC recurrence rates after LRFA.

关键词： Hepatocellular Cancer radiofrequency ablation ectomy Liver Cirrhosis human-centered computing Heart Rate class A Relapse Patients

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Hepatocellular carcinoma metastatic to skin: diagnostic utility of antihuman hepatocyte antibody in combination with albumin in situ hybridization

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JOURNAL OF CUTANEOUS PATHOLOGY 2009年第2期36卷 262-266页

作者： Wood, Angela J. Lappinga, Paul J. Ahmed, Iftikhar Mayo Clin Dept Lab Med & Pathol Rochester MN 55905 USA Mayo Clin Dept Dermatol Rochester MN 55905 USA

Cutaneous metastases from hepatic neoplasms are rare. Histologic features of hepatocellular carcinoma (HCC) are often poorly differentiated, hindering accurate diagnosis on routine examination by hematoxylin-eosin stain. Antihuman hepatocyte antibody is highly sensitive for HCC but can be strongly expressed in other adenocarcinomas. Albumin in situ hybridization (ISH) is highly specific and sensitive for HCC;in combination with antihuman hepatocyte antibody, it has a diagnostic sensitivity approaching 100%. To our knowledge, the combination of antihuman hepatocyte antibody and albumin ISH has not previously been examined in the context of cutaneous HCC. We present histologic findings and results of ancillary studies for three patients with metastatic HCC. These patients had a poorly differentiated cytokeratin-positive cutaneous neoplasm. All three cases were evaluated with antihuman hepatocyte antibody and albumin ISH. Neoplastic cells were strongly positive for antihuman hepatocyte antibody, and ISH detected albumin messenger RNA in nearly 100% of the neoplastic cells in all three cases. The combination of antihuman hepatocyte antibody and albumin ISH is highly sensitive and specific for HCC metastatic to skin and is useful in the differential diagnosis of a poorly differentiated cytokeratin-positive neoplasm. Wood AJ, Lappinga PJ, Ahmed I. Hepatocellular carcinoma metastatic to skin: diagnostic utility of antihuman hepatocyte antibody in combination with albumin in situ hybridization.J Cutan Pathol 2009;36: 262-266. (C) 2008 Blackwell Munksgaard.

关键词： Aged Albumins Antibodies Neoplasm Carcinoma Hepatocellular Diagnosis Differential 老年人白蛋白类抗体肿瘤癌肝细胞诊断鉴别原位杂交肿瘤转移 Diagnosis Hepatocytes metastasis Neoplasms In Situ Hybridization human-centered computing Liver Neoplasms Differential Carcinoma

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ERK5 is a Target for Gene Amplification at 17p11 and Promotes Cell Growth in Hepatocellular Carcinoma by Regulating Mitotic Entry

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GENES CHROMOSOMES & CANCER 2009年第2期48卷 109-120页

作者： Zen, Keika Yasui, Kohichiroh Nakajima, Tomoaki Zen, Yoh Zen, Kan Gen, Yasuyuki Mitsuyoshi, Hironori Minami, Masahito Mitsufuji, Shoji Tanaka, Shinji Itoh, Yoshito Nakanuma, Yasuni Taniwaki, Masafumi Arii, Shigeki Okanoue, Takeshi Yoshikawa, Toshikazu Kyoto Prefectural Univ Grad Sch Med Sci Kamigyo Ku Kyoto 6028566 Japan Kanazawa Univ Grad Sch Med Dept Human Pathol Kanazawa Ishikawa Japan Omihachiman Community Med Ctr Div Cardiovasc Med Omihachiman Japan Tokyo Med & Dent Univ Dept Hepatobiliary Pancreat Surg Tokyo Japan

Using high-density oligonucleotide microarrays, we investigated DNA copy-number aberrations in cell lines derived from hepatocellular carcinomas (HCCs) and detected a novel amplification at 17p11. To identify the target of amplification at 17p11, we defined the extent of the amplicon and examined HCC cell lines for expression of all seven genes in the 750-kb commonly amplified region. Mitogen-activated protein kinase (MAPK) 7, which encodes extracellular-regulated protein kinase(ERK) 5, was overexpressed in cell lines in which the gene was amplified. An increase in MAPK7 copy number was detected in 35 of 66 primary HCC tumors. Downregulation of MAPK7 by small interfering RNA suppressed the growth of SNU449 cells, the HCC cell line with the greatest amplification and overexpression of MAPK7. ERK5, phosphorylated during the G2/M phases of the cell cycle, regulated entry into mitosis in SNU449 cells. In conclusion, our results suggest that MAPK7 is likely the target of 17p11 amplification and that the ERK5 protein product of NIAPK7 promotes the growth of HCC cells by regulating mitotic entry. (c) 2008 Wiley-Liss, Inc.

关键词： Cell Line Primary carcinoma of the liver cells overexpress growth aspects 细胞系 Gene Amplification Protein Overexpression Hepatocellular Cancer Cell Line S Phase MAPK7 gene human-centered computing Mitosis

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Combination of peritumoral mast cells and T-regulatory cells predicts prognosis of hepatocellular carcinoma

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CANCER SCIENCE 2009年第7期100卷 1267-1274页

作者： Ju, Min-Jie Qiu, Shuang-Jian Gao, Qiang Fan, Jia Cai, Ming-Yan Li, Yi-Wei Tang, Zhao-You Zhongshan Hosp Liver Canc Inst Shanghai Peoples R China Fudan Univ Shanghai Med Sch Key Lab Carcinogenesis & Canc Invas Chinese Minist Educ Shanghai 200433 Peoples R China

The peritumoral inflammatory environment is critical for the progression of intrahepatic recurrence of hepatocellular carcinoma (HCC) after curative resections. Here, we investigated the relevance of peritumoral mast cells (MCs) to HCC outcomes. Peritumoral tryptase(+) MCs in addition to Foxp3(+) T-regulatory cells (Tregs) were evaluated using immunohistochemistry enumeration in tissue microarrays containing 207 randomly selected HCC patients. Clinicopathological factors and postoperative outcomes were compared between high and low subgroups of MCs or Tregs. Compared to low denstiy, higher peritumoral MCs were associated with poorer clinical outcomes, and independently related to elevated 5-year recurrence incidence (54.1% vs 39.2%, P = 0.026). High-dense MCs were especially related to increased probability of early recurrence (within 2 years) (P = 0.004). We also found that peritumoral Tregs were positively correlated with MCs in density (r = 0.353, P < 0.001) and reversely related to HCC outcomes. Notably, MCs in combination with Tregs displayed better prognostic performances than MCs alone (area under curve [AUC](survival) = 0.629 vs 0.589, AUC(recurrence) = 0.632 vs 0.591). Moreover, MCs were positively correlated to alanine aminotransferase, a serum inflammatory marker (P = 0.014). Therefore, peritumoral MCs are promising prognostic parameters for HCC mainly through inflammation response-related mechanisms, and we propose that MCs and Tregs may cooperate with each other and result in poorer prognosis. (Cancer Sci 2009;100: 1267-1274)

关键词： Hepatocellular Cancer Prognosis MCS gene Mast Cells Alanine Transaminase human-centered computing Regulatory T-Lymphocytes Relapse

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Living Donor Liver Transplantation for Hepatocellular Carcinoma: Increased Recurrence but Improved Survival

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LIVER TRANSPLANTATION 2009年第12期15卷 1861-1866页

作者： Vakili, Khashayar Pomposelli, James J. Cheah, Yee Lee Akoad, Mohamed Lewis, W. David Khettry, Urmila Gordon, Fredric Khwaja, Khalid Jenkins, Roger Pomfret, Elizabeth A. Lahey Clin Med Ctr Dept Transplantat Burlington MA 01805 USA Lahey Clin Med Ctr Dept Pathol Burlington MA 01805 USA

In regions with a limited deceased donor pool, living donor adult liver transplantation (LDALT) has become an important treatment modality for patients with hepatocellular carcinoma (HCC) and cirrhosis. Studies have shown higher recurrence rates of HCC after LDALT in comparison with deceased donor liver transplantation (DDLT). The aim of our study was to examine the outcome results and recurrence rates for patients with HCC who underwent LDALT at our center. During an 8-year period, 139 patients underwent LDALT, of whom 28 (20.1%) had HCC in their explanted livers. The median follow-up was 40.8 months. The mean explant tumor size was 3.3 +/- 1.2, and the mean number of tumors was 1.5 +/- 0.8. Twenty-one patients (75%) had tumors within the Milan criteria, 5 patients had tumors outside the Milan criteria but within the University of California San Francisco (UCSF) criteria, and 2 patients were beyond the UCSF criteria. The overall 1- and 5-year patient and graft survival rates were 96% and 81%, respectively. Survival following LDALT was significantly better than survival following DDLT for HCC during the same time period (P = 0.02). Eight patients (28.6%) developed tumor recurrence. Poor differentiation of tumor cells was the most significant determinant of recurrence. Despite high recurrence rates of HCC following LDALT, overall 5-year survival appears to be excellent. Liver Transpl 15:1861-1866, 2009. (C) 2009 AASLD.

关键词： ADULT PATIENTS EXPERIENCE CRITERIA CIRRHOSIS REGISTRY GRAFTS JAPAN SIZE experience Number of tumors Patients Tumours Relapse Japan human-centered computing Registries Neoplastic Cell Repetition rate

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Progression of Hepatocellular Carcinoma Before Liver Transplantation: Dropout or Liver Transplantation?

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TRANSPLANTATION PROCEEDINGS 2009年第4期41卷 1264-1267页

作者： Vitale, A. Boccagni, P. Brolese, A. Neri, D. Srsen, N. Zanus, G. Pagano, D. Pauletto, A. Bonsignore, P. Scopelliti, M. D'Amico, F. E. Ometto, G. Polacco, M. Burra, P. Gambato, M. Feltracco, P. Romano, A. Cillo, U. IRCCS Ist Oncol Veneto Unita Chirurg Oncol San Giovanni Rotondo Italy Univ Padua Azeinda Osped Dipartimento Chirurg Gen & Trapianti Organo Unita Chirurg Epatobiliare & Trapianto Epat I-35100 Padua Italy Univ Padua Dipartimento Sci Chirurg & Gastroenterol Div Gastroenterol I-35100 Padua Italy Univ Padua Dipartimento Farmacol & Anestesiol I-35100 Padua Italy Univ Federico 2 Dipartimento Med Clin & Sperimentale Naples Italy

Background. Tumor progression before liver transplantation (OLT) is the main cause of dropout from the waiting list (WL) of patients with hepatocellular carcinoma (HCC). The aim of this study was to show a correlation between adopted dropout criteria and dropout/intention-to-treat survival rates of WL HCC patients. Methods. The study period was 2000 to 2007. The dropout criteria were macroscopic vascular invasion, metastases, or a poorly differentiated tumor. Adult patients with benign chronic liver disease enlisted for primary OLT in the same period represented the control group. Results. Dropout probability of study (n = 128) versus control group (n = 377) subjects was similar: namely, 12% at 1 year in both groups (P = NS). Intention-to-treat survival curve of the HCC group overlapped that of the benign group (5-year survival rates were 73% and 71%, respectively;P = NS). At the time of listing, 103 study group patients were within the Milan criteria (MC): among these patients, 29 (28%) showed tumor progression beyond MC before OLT. Simulating the dropout of these 29 patients at the time of diagnosis of tumor progression, we compared the dropout probability of the 103 patients within MC with that of the control group. As a result, the 1- and 2-year dropout rates became 37% and 53%, respectively, in the study group, which were significantly higher than those in the controls (P < .01). Conclusion. HCC patients on the WL showed a significantly greater dropout rate than subjects with benign cirrhosis when too restrictive radiologic dropout criteria were used. The adoption of criteria more related to biological aggressiveness of a tumor decreased the dropout risk for HCC patients without impairing their intention-to-treat survival rates.

关键词： Benign Tumor Progression Survival Rate Control Groups Optical Line Terminal human-centered computing WORKING LEVEL Patients

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De Novo Hepatocellular Carcinoma in a Liver Graft with Sustained Hepatitis C Virus Clearance After Living Donor Liver Transplantation

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LIVER TRANSPLANTATION 2009年第11期15卷 1412-1416页

作者： Morita, Kazutoyo Taketomi, Akinobu Soejima, Yuji Ikegami, Toru Fukuhara, Takasuke Iguchi, Tomohiro Nagata, Shigeyuki Sugimachi, Keishi Gion, Tomonobu Shirabe, Ken Maehara, Yoshihiko Kyushu Univ Grad Sch Med Sci Dept Surg & Sci Higashi Ku Fukuoka 8128582 Japan

The occurrence of de novo hepatocellular carcinoma (HCC) after liver transplantation (LT) for advanced HCCs has been extremely limited. In this article, a case of de novo HCC in a liver graft with sustained hepatitis C virus clearance after living donor liver transplantation (LDLT) for multiple HCCs and hepatitis C cirrhosis is reported. The recipient was a 58-year-old female, and the left lobe living donor was the 30-year-old healthy daughter of the recipient. Three years after LDLT, the patient received 48 weeks of interferon treatment for recurrent hepatitis C with advanced fibrosis. The patient has shown successful viral clearance since then. However, an HCC was recognized in the liver graft during a follow-up computed tomography scan performed 6 years after LDLT, and it was surgically resected. To analyze its origin [either from the patient (metastatic) or from the living donor (de novo)], genotyping by microsatellite analysis of tissue and blood samples from the donor and recipient was performed, and it revealed that the HCC originated from the donor. To the best of our knowledge, this is the first report of de novo HCC in a liver graft with sustained hepatitis C virus clearance after LT for advanced HCCs and hepatitis C cirrhosis. Liver Transpl 15:1412-1416, 2009. (C) 2009 AASLD.

关键词： VIROLOGICAL RESPONSE INTERFERON THERAPY CIRRHOSIS ALLOGRAFT EXPERIENCE IMPACT human-centered computing Living Donors Hepatitis C Liver Transplantation interferon therapy

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Beyond Pinch and Flick: Enriching Mobile Gesture Interaction

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COMPUTER 2009年第12期42卷 87-89页

作者： Li, Yang Google Research

An open source toolkit lets developers easily create mobile gesture applications.

关键词： Mobile communication Software Mobile handsets Fingers Data mining Libraries Shape Gesture recognition Invisible computing human-centered computing Mobile Wireless

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