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1. Transcriptional regulation of the tumor suppressor FHL2 by p53 in human kidney and liver cells.

Author

Jiaying Xu, Junwei Zhou, Man-Shan Li, Chor-Fung Ng, Yuen-Keng Ng, Paul Bo-San Lai, and Stephen Kwok-Wing Tsui

Subjects
Medicine, Science
Abstract

Four and a Half LIM protein 2 (FHL2) is a LIM domain only protein that is able to form various protein complexes and regulate gene transcription. Recent findings showed that FHL2 is a potential tumor suppressor gene that was down-regulated in hepatocellular carcinoma (HCC). Moreover, FHL2 can bind to and activate the TP53 promoter in hepatic cells. In this study, the activity of the two promoters of FHL2, 1a and 1b, were determined in the human embryonic kidney cell line HEK293 and the activation of these two promoters by p53 was investigated. Our results showed that the 1b promoter has a higher activity than the 1a promoter in HEK 293 cells but the 1a promoter is more responsive to the activation by p53 when compared with the 1b promoter. The regulation of FHL2 by p53 was further confirmed in liver cells by the overexpression of p53 in Hep3B cells and the knockdown of p53 in HepG2 cells. Combining promoter activity results of truncated mutants and predictions by bioinformatics tools, a putative p53 binding site was found in the exon 1a of FHL2 from +213 to +232. The binding between the p53 protein and the putative p53 binding site was then validated by the ChIP assay. Furthermore, the expression of FHL2 and TP53 were down-regulated in majority of HCC tumour samples (n = 41) and significantly correlated (P = 0.026). Finally, we found that the somatic mutation 747 (G→T), a hot spot mutation of the TP53 gene, is potentially associated with a higher expression of FHL2 in HCC tumour samples. Taken together, this is the first in-depth study about the transcriptional regulation of FHL2 by p53.

Published
2014
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2. Differential functions of C- and N-terminal hepatitis B x protein in liver cells treated with doxorubicin in normoxic or hypoxic condition.

Author

Davor Kin-Fan Chau, George Gong Chen, Haitao Zhang, Billy Cheuk Sing Leung, Sukying Chun, and Paul Bo-San Lai

Subjects
Medicine, Science
Abstract

Hepatitis viral B x protein (HBx), a hepatocarcinogen, is frequently mutated. Hypoxia influences the growth of HCC and also the sensitivity of tumor cells to treatments. We aimed to test the role of HBx and acute hypoxia in the efficacy of chemotherapy. In this study, we established 4 Chang liver cell lines with the full-length HBx (HBx), the first 50 amino acids of N-terminal HBx (HBx/50), the last 104 amino acids of C-terminal HBx (HBx/51) and empty vector (CL), respectively. MTT and TNUEL assays were used to assess cell viability and apoptosis respectively. Western blot was used to determine the expression of relevant proteins. Results showed that among 4 cell lines, doxorubicin was most effective in decreasing the viability and enhancing apoptosis in HBx/51 cells, while HBx/50 cells were most resistant to the treatment. Cells in hypoxia were more susceptible to doxorubicin than cells in normoxia. Hypoxia facilitated the Bid cleavage especially in HBx/51 cells via phosphorylating p38 MAPK. p38 MAPK inhibitor significantly reduced the tBid level and increased cell viability. In conclusion, N-terminal HBx and C-terminal HBx function differentially in their ability to regulate cell growth, with the former being promotive but the latter being inhibitory. The acute hypoxia may overcome the HBx-induced resistance and facilitate the chemotherapy.

Published
2012
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3. Carboxyl-terminal truncated HBx regulates a distinct microRNA transcription program in hepatocellular carcinoma development.

Author

Wing-Kit Yip, Alfred Sze-Lok Cheng, Ranxu Zhu, Raymond Wai-Ming Lung, Daisy Pui-Fong Tsang, Suki Shuk-Kei Lau, Yangchao Chen, Jonathan Gabriel Sung, Paul Bo-San Lai, Enders Kai-On Ng, Jun Yu, Nathalie Wong, Ka-Fai To, Vincent Wai-Sun Wong, Joseph Jao-Yiu Sung, and Henry Lik-Yuen Chan

Subjects
Medicine, Science
Abstract

BACKGROUND: The biological pathways and functional properties by which misexpressed microRNAs (miRNAs) contribute to liver carcinogenesis have been intensively investigated. However, little is known about the upstream mechanisms that deregulate miRNA expressions in this process. In hepatocellular carcinoma (HCC), hepatitis B virus (HBV) X protein (HBx), a transcriptional trans-activator, is frequently expressed in truncated form without carboxyl-terminus but its role in miRNA expression and HCC development is unclear. METHODS: Human non-tumorigenic hepatocytes were infected with lentivirus-expressing full-length and carboxyl-terminal truncated HBx (Ct-HBx) for cell growth assay and miRNA profiling. Chromatin immunoprecipitation microarray was performed to identify the miRNA promoters directly associated with HBx. Direct transcriptional control was verified by luciferase reporter assay. The differential miRNA expressions were further validated in a cohort of HBV-associated HCC tissues using real-time PCR. RESULTS: Hepatocytes expressing Ct-HBx grew significantly faster than the full-length HBx counterparts. Ct-HBx decreased while full-length HBx increased the expression of a set of miRNAs with growth-suppressive functions. Interestingly, Ct-HBx bound to and inhibited the transcriptional activity of some of these miRNA promoters. Notably, some of the examined repressed-miRNAs (miR-26a, -29c, -146a and -190) were also significantly down-regulated in a subset of HCC tissues with carboxyl-terminal HBx truncation compared to their matching non-tumor tissues, highlighting the clinical relevance of our data. CONCLUSION: Our results suggest that Ct-HBx directly regulates miRNA transcription and in turn promotes hepatocellular proliferation, thus revealing a viral contribution of miRNA deregulation during hepatocarcinogenesis.

Published
2011
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4. Diagnosis and treatment in chronic pancreatitis: an international survey and case vignette study

Author

Yama Issa, Hjalmar C. van Santvoort, Paul Fockens, Marc G. Besselink, Thomas L. Bollen, Marco J. Bruno, Marja A. Boermeester, Frank G. Moody, Claude Bertrand, Colin Johnson, Aude van Lander, Ross Carter, John B. Conneely, Frederik Berrevoet, Donzília Sousa Silva, Zong-Fang Li, Philippe Lévy, Kofi Oppong, Timothy B. Gardner, C. Mel Wilcox, Jeremy French, Michael Steer, Edward L. Bradley, Peter Layer, Bertrand Napoleon, Jorge Antonio Mosquera, D.J. Gouma, Roland Andersson, Antonio Manzelli, J.M. Klaase, Massimo Falconi, Enrique de-Madaria, Riccardo Casadei, Giuseppe Malleo, Raffaele Pezzilli, Ewa Malecka-Panas, Matthias Lohr, Julia Mayerle, Erik A.J. Rauws, Martin L. Freeman, Affirul Chairil Ariffin, Bhavin Vasavada, Paul Bo-San Lai, Jose Luis Beristain-Hernandez, Álvarez Juan, Haralds Plaudis, Dionisios Vrochides, Vincenzo Neri, Vimalraj Velayutham, Aleksey Andrianov, Joan Figueras, Kjetil Soreide, Aliaksei Shcherba, Mahir Gachabayov, Roger G. Keith, Georgios Tsoulfas, Michael Anthony Fink, Stefano Crippa, Mehrdad Nikfarjam, Dibyajyoti Bora, Rajendra Desai, Marcello Donati, Jan Jin Bong, Emma Martínez Moneo, Gareth Morris-Stiff, Ahmet Coker, Alexandre Prado de Resende, Suryabhan Sakhahari Bhalerao, Sadiq S. Sikora, Dezső Kelemen, László Czakó, Hariharan Ramesh, Oleg Rummo, Aliaksei Fedaruk, Alexey Hlinnik, Madhusudhan Chinthakindi, Traian Dumitrascu, Vyacheslav Egorov, Vincent Bettschart, Michele Molinari, E. Aldana D. Guillermo, Susan L. Orloff, Daniel Vasilev Kostov, Laurent Sulpice, Brett Knowles, Yasutoshi Kimura, Gabriele Marangoni, Rajeev Joshi, Tibor Gyökeres, null Bedin, V. Vladimir, Arpad Ivanecz, Adelmo Antonucci, Jones A.O. Omoshoro-Jones, Richard Nakache, Marco Del Chiaro, Marianne Johnstone, Tomoaki Saito, Gianpaolo Balzano, Serge Chooklin, Piero Boraschi, Walter Park, Pedro Nuno Valente Reis Pereira, Nico Pagano, Pavlos Lykoudis, Lars Ivo Partecke, Aliaksandr Siatkouski, Rosa Jorba Martín, Yasunari Kawabata, Luís Carvalho Lourenço, Carlos Marra-Lopez, Jun Kyu Lee, Nils Habbe, Robert C. Verdonk, Yliya Rabotyagova, Rupjyoti Talukdar, Luca Frulloni, Shamil Galeev, Zoltán Berger, Takeo Yasuda, Thilo Hackert, Ziyovuddin Saatov, Dimitri Aristotle Raptis, Jaume Boadas, Francesco Vitali, Livia Archibugi, Miroslav Ryska, Balazs Tihanyi, Vikesh K. Singh, Atsushi Masamune, Paul Yeaton, Kerrington D. Smith, Shrey Modi, Laura Cosen-Binker, Savio George Barreto, Eugenio Morandi, Sergio Valeri, Cintia Yoko Morioka, Luis F. Lara, Yoshifumi Takeyama, Frank G. Gress, Young-Dong Yu, Ezio Gaia, Sorin Traian Barbu, Ali Tüzün İnce, Akkraporn Deeprasertvit, Yu-Ting Chang, Stephen Olusola Abiola, Sabite Kacar, Peter Muscarella, Henri Braat, Samuel Han, Ali A. Aghdassi, Jean-Louis Frossard, Jill P. Smith, M.P. Schwartz, H.M. van Dullemen, N.G. Venneman, B.W.M. Spanier, Sjoerd Kuiken, Erwin van Geenen, Greg Beilman, Georgios Papachristou, Oscar Chapa Azuela, P. van der Schaar, Nevin Oruc, Marie-Paule Anten, William H. Nealon, Jesús García-Cano, Manol Jovani, Ziad Melki, Mustafa Mohammed Ahmed Ibrahim, M.U. Awajdarip, Mohammad Azam, K.G. Sabu, Igor Ermolaev, Shiran Shetty, Belei Oana, Juris Pokrotnieks, Malgorzata Lazuchiewicz-Kot, Riadh Bouali, Marek Winiarski, Marcus Schmitt, Mihai Rimbas, Alexander Meining, Bories Erwan, Peter N. Meier, Rainer Schoefl, Ahmed Youssef Altonbary, Igor Marsteller, Ingo Wallstabe, Skerdi Prifti, Arnaud Lemmers, M. Horvath, Ajay Kumar, Joseph J. Palermo, Issa, Y., van Santvoort, H. C., Fockens, P., Besselink, M. G., Bollen, T. L., Bruno, M. J., Boermeester, M. A., Moody, F. G., Bertrand, C., Johnson, C., van Lander, A., Carter, R., Conneely, J. B., Berrevoet, F., Sousa Silva, D., Li, Z. -F., Levy, P., Oppong, K., Gardner, T. B., Wilcox, C. M., French, J., Steer, M., Bradley, E. L., Layer, P., Napoleon, B., Mosquera, J. A., Gouma, D. J., Andersson, R., Manzelli, A., Klaase, J. M., Falconi, M., de-Madaria, E., Casadei, R., Malleo, G., Pezzilli, R., Malecka-Panas, E., Lohr, M., Mayerle, J., Rauws, E. A. J., Freeman, M. L., Ariffin, A. C., Vasavada, B., Lai, P. B. -S., Beristain-Hernandez, J. L., Juan, A., Plaudis, H., Vrochides, D., Neri, V., Velayutham, V., Andrianov, A., Figueras, J., Soreide, K., Shcherba, A., Gachabayov, M., Keith, R. G., Tsoulfas, G., Fink, M. A., Crippa, S., Nikfarjam, M., Bora, D., Desai, R., Donati, M., Bong, J. J., Martinez Moneo, E., Morris-Stiff, G., Coker, A., de Resende, A. P., Bhalerao, S. S., Sikora, S. S., Kelemen, D., Czako, L., Ramesh, H., Rummo, O., Fedaruk, A., Hlinnik, A., Chinthakindi, M., Dumitrascu, T., Egorov, V., Bettschart, V., Molinari, M., Guillermo, E. A. D., Orloff, S. L., Kostov, D. V., Sulpice, L., Knowles, B., Kimura, Y., Marangoni, G., Joshi, R., Gyokeres, T., Bedin, Vladimir, V., Ivanecz, A., Antonucci, A., Omoshoro-Jones, J. A. O., Nakache, R., Del Chiaro, M., Johnstone, M., Saito, T., Balzano, G., Chooklin, S., Boraschi, P., Park, W., Pereira, P. N. V. R., Pagano, N., Lykoudis, P., Partecke, L. I., Siatkouski, A., Martin, R. J., Kawabata, Y., Lourenco, L. C., Marra-Lopez, C., Lee, J. K., Habbe, N., Verdonk, R. C., Rabotyagova, Y., Talukdar, R., Frulloni, L., Galeev, S., Berger, Z., Yasuda, T., Hackert, T., Saatov, Z., Raptis, D. A., Boadas, J., Vitali, F., Archibugi, L., Ryska, M., Tihanyi, B., Singh, V. K., Masamune, A., Yeaton, P., Smith, K. D., Modi, S., Cosen-Binker, L., Barreto, S. G., Morandi, E., Valeri, S., Morioka, C. Y., Lara, L. F., Takeyama, Y., Gress, F. G., Yu, Y. -D., Gaia, E., Barbu, S. T., Ince, A. T., Deeprasertvit, A., Chang, Y. -T., Abiola, S. O., Kacar, S., Muscarella, P., Braat, H., Han, S., Aghdassi, A. A., Frossard, J. -L., Smith, J. P., Schwartz, M. P., van Dullemen, H. M., Venneman, N. G., Spanier, B. W. M., Kuiken, S., van Geenen, E., Beilman, G., Papachristou, G., Chapa Azuela, O., van der Schaar, P., Oruc, N., Anten, M. -P., Nealon, W. H., Garcia-Cano, J., Jovani, M., Melki, Z., Ibrahim, M. M. A., Awajdarip, M. U., Azam, M., Sabu, K. G., Ermolaev, I., Shetty, S., Oana, B., Pokrotnieks, J., Lazuchiewicz-Kot, M., Bouali, R., Winiarski, M., Schmitt, M., Rimbas, M., Meining, A., Erwan, B., Meier, P. N., Schoefl, R., Altonbary, A. Y., Marsteller, I., Wallstabe, I., Prifti, S., Lemmers, A., Horvath, M., Kumar, A., Palermo, J. J., Surgery, Amsterdam institute for Infection and Immunity, Amsterdam Gastroenterology Endocrinology Metabolism, Gastroenterology and Hepatology, CCA - Cancer Treatment and Quality of Life, CCA - Imaging and biomarkers, AGEM - Digestive immunity, AGEM - Re-generation and cancer of the digestive system, Cancer Center Amsterdam, APH - Methodology, AII - Infectious diseases, Issa, Yama, van Santvoort, Hjalmar C., Fockens, Paul, Besselink, Marc G., Bollen, Thomas L., Bruno, Marco J., Boermeester, Marja A., Moody, Frank G., Bertrand, Claude, Johnson, Colin, van Lander, Aude, Carter, Ro, Conneely, John B., Berrevoet, Frederik, Sousa Silva, Donzã­lia, Zong-Fang, Li, Lã©vy, Philippe, Oppong, Kofi, Gardner, Timothy B., Wilcox, C. Mel, French, Jeremy, Steer, Michael, Bradley, Edward L., Layer, Peter, Napoleon, Bertrand, Mosquera, Jorge Antonio, Andersson, Roland, Manzelli, Antonio, Falconi, Massimo, de-Madaria, Enrique, Casadei, Riccardo, Malleo, Giuseppe, Pezzilli, Raffaele, Malecka-Panas, Ewa, Lohr, Matthia, Mayerle, Julia, Rauws, Erik A. J., Freeman, Martin L., Ariffin, Affirul Chairil, Vasavada, Bhavin, Lai, Paul Bo-San, Beristain-Hernandez, Jose Lui, Juan, à lvarez, Plaudis, Harald, Vrochides, Dionisio, Neri, Vincenzo, Velayutham, Vimalraj, Andrianov, Aleksey, Figueras, Joan, Soreide, Kjetil, Shcherba, Aliaksei, Gachabayov, Mahir, Keith, Roger G., Tsoulfas, Georgio, Fink, Michael Anthony, Crippa, Stefano, Nikfarjam, Mehrdad, Bora, Dibyajyoti, Desai, Rajendra, Donati, Marcello, Bong, Jan Jin, Martínez Moneo, Emma, Morris-Stiff, Gareth, Coker, Ahmet, de Resende, Alexandre Prado, Bhalerao, Suryabhan Sakhahari, Sikora, Sadiq S., Kelemen, Dezså, Czakã³, Lã¡szlã³, Ramesh, Hariharan, Rummo, Oleg, Fedaruk, Aliaksei, Hlinnik, Alexey, Chinthakindi, Madhusudhan, Dumitrascu, Traian, Egorov, Vyacheslav, Bettschart, Vincent, Molinari, Michele, Guillermo, E. Aldana D., Orloff, Susan L., Kostov, Daniel Vasilev, Sulpice, Laurent, Knowles, Brett, Kimura, Yasutoshi, Marangoni, Gabriele, Joshi, Rajeev, Gyã¶keres, Tibor, Bedin, Null, Ivanecz, Arpad, Antonucci, Adelmo, Omoshoro-Jones, Jones A. O., Nakache, Richard, Del Chiaro, Marco, Johnstone, Marianne, Saito, Tomoaki, Balzano, Gianpaolo, Chooklin, Serge, Boraschi, Piero, Park, Walter, Pereira, Pedro Nuno Valente Rei, Pagano, Nico, Lykoudis, Pavlo, Partecke, Lars Ivo, Siatkouski, Aliaksandr, Martã­n, Rosa Jorba, Kawabata, Yasunari, Lourenã§o, Luís Carvalho, Marra-Lopez, Carlo, Lee, Jun Kyu, Habbe, Nil, Verdonk, Robert C., Rabotyagova, Yliya, Talukdar, Rupjyoti, Frulloni, Luca, Galeev, Shamil, Berger, Zoltã¡n, Yasuda, Takeo, Hackert, Thilo, Saatov, Ziyovuddin, Raptis, Dimitri Aristotle, Boadas, Jaume, Vitali, Francesco, Archibugi, Livia, Ryska, Miroslav, Tihanyi, Balaz, Singh, Vikesh K., Masamune, Atsushi, Yeaton, Paul, Smith, Kerrington D., Modi, Shrey, Cosen-Binker, Laura, Barreto, Savio George, Morandi, Eugenio, Valeri, Sergio, Morioka, Cintia Yoko, Lara, Luis F., Takeyama, Yoshifumi, Gress, Frank G., Young-Dong, Yu, Gaia, Ezio, Barbu, Sorin Traian, Ä°nce, Ali Tüzün, Deeprasertvit, Akkraporn, Chang, Yu-Ting, Abiola, Stephen Olusola, Kacar, Sabite, Muscarella, Peter, Braat, Henri, Han, Samuel, Aghdassi, Ali A., Frossard, Jean-Loui, Smith, Jill P., Kuiken, Sjoerd, van Geenen, Erwin, Beilman, Greg, Papachristou, Georgio, Chapa Azuela, Oscar, Oruc, Nevin, Anten, Marie-Paule, Nealon, William H., García-Cano, Jesãº, Jovani, Manol, Melki, Ziad, Ibrahim, Mustafa Mohammed Ahmed, Azam, Mohammad, Ermolaev, Igor, Shetty, Shiran, Oana, Belei, Pokrotnieks, Juri, Lazuchiewicz-Kot, Malgorzata, Bouali, Riadh, Winiarski, Marek, Schmitt, Marcu, Rimbas, Mihai, Meining, Alexander, Erwan, Borie, Meier, Peter N., Schoefl, Rainer, Altonbary, Ahmed Youssef, Marsteller, Igor, Wallstabe, Ingo, Prifti, Skerdi, Lemmers, Arnaud, Kumar, Ajay, Palermo, Joseph J., and Gastroenterology & Hepatology

Subjects
Endoscopic ultrasound, medicine.medical_treatment, Islets of Langerhans Transplantation, Practice Patterns, Diagnosis, treatment, chronic pancreatitis, survey, Bioinformatics, 0302 clinical medicine, Risk Factors, Lithotripsy, Diagnosis, 03.02. Klinikai orvostan, Endoscopy, Digestive System, Chronic, Practice Patterns, Physicians', Tomography, Digestive System Surgical Procedures, treatment, medicine.diagnostic_test, Gastroenterology, Magnetic Resonance Imaging, X-Ray Computed, Treatment Outcome, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Predictive value of tests, Pancreatectomy, 030211 gastroenterology & hepatology, Autologous, medicine.medical_specialty, Clinical Decision-Making, Transplantation, Autologous, Decision Support Techniques, chronic pancreatitis, 03 medical and health sciences, Predictive Value of Tests, Pancreatitis, Chronic, medicine, Humans, survey, Pancreatic duct, Transplantation, Physicians', Hepatology, business.industry, General surgery, Gastroenterologists, Endoscopy, Magnetic resonance imaging, medicine.disease, Pancreatitis, Health Care Surveys, Tomography, X-Ray Computed, business, Digestive System
Abstract

Background The aim of the study was to evaluate the current opinion and clinical decision-making process of international pancreatologists, and to systematically identify key study questions regarding the diagnosis and treatment of chronic pancreatitis (CP) for future research. Methods An online survey, including questions regarding the diagnosis and treatment of CP and several controversial clinical case vignettes, was send by e-mail to members of various international pancreatic associations: IHPBA, APA, EPC, ESGE and DPSG. Results A total of 288 pancreatologists, 56% surgeons and 44% gastroenterologists, from at least 47 countries, participated in the survey. About half (48%) of the specialists used a classification tool for the diagnosis of CP, including the Mayo Clinic (28%), Mannheim (25%), or Buchler (25%) tools. Overall, CT was the preferred imaging modality for evaluation of an enlarged pancreatic head (59%), pseudocyst (55%), calcifications (75%), and peripancreatic fat infiltration (68%). MRI was preferred for assessment of main pancreatic duct (MPD) abnormalities (60%). Total pancreatectomy with auto-islet transplantation was the preferred treatment in patients with parenchymal calcifications without MPD abnormalities and in patients with refractory pain despite maximal medical, endoscopic, and surgical treatment. In patients with an enlarged pancreatic head, 58% preferred initial surgery (PPPD) versus 42% initial endoscopy. In patients with a dilated MPD and intraductal stones 56% preferred initial endoscopic ± ESWL treatment and 29% preferred initial surgical treatment. Conclusion Worldwide, clinical decision-making in CP is largely based on local expertise, beliefs and disbeliefs. Further development of evidence-based guidelines based on well designed (randomized) studies is strongly encouraged.

Published
2017

5. Integration of albumin-bilirubin (ALBI) score into Barcelona Clinic Liver Cancer (BCLC) system for hepatocellular carcinoma

Author

Ka Fai To, Philip J. Johnson, Anthony W.H. Chan, Hidenori Toyoda, Stephen L. Chan, Takshi Kumada, Winnie Yeo, Anthony T.C. Chan, Frankie Mo, Toshifumi Tada, Charing C N Chong, and Paul Bo-San Lai

Subjects
medicine.medical_specialty, Kappa value, Hepatology, Bilirubin, business.industry, Gastroenterology, medicine.disease, BCLC Stage, Surgery, Clinical trial, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, chemistry, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, Internal medicine, Cohort, medicine, 030211 gastroenterology & hepatology, Liver function, Liver cancer, business
Abstract

Background and Aims The albumin–bilirubin (ALBI) grade is a recently reported, simpler, more objective, and evidence-based alternative to the Child–Pugh (CP) score for hepatocellular carcinoma (HCC). We aimed to study whether ALBI grade could substitute for CP score in Barcelona Clinic Liver Cancer (BCLC) for HCC. Methods An international multicentre cohort (n = 3696) was accrued to compare the prognostic performance of the CP-based and ALBI-based BCLC system, in terms of homogeneity, discriminatory ability, and monotonicity of gradients that were numerically reflected by homogeneity likelihood, linear trend chi-squares, and c-indices, respectively. Results The ALBI grade performed as well as CP score when integrated into the BCLC staging system in terms of predicting clinical outcome of HCC regardless of regions, etiology, and treatment options. CP-based and ALBI-based BCLC systems were highly concordant with weighted kappa value of 0.917. All restaged patients showed significantly different clinical outcomes compared with their original stage classification. In particular, ALBI-based BCLC upstaged 83 (2.2%) patients from lower CP-based BC LC stages to ALBI-based BCLC stage D, whose median overall survival was only 3 months. Conclusions The overall prognostic performance of ALBI-based and CP-based BCLC systems was similar. It also potentially allows more precise patient selection for clinical trials on systemic agents.

Published
2016

6. Abstract 4151: STAT3 regulates chemo-resistance and cancer stemness in hepatocellular carcinoma

Author

Carol Lee, Charing C N Chong, Siu Tim Cheung, Elaine Yee-Ling Or, Linda Wing-Chi Ng, Paul Bo-San Lai, Anthony W.H. Chan, Iris Ming-Jing Xu, Philip Chun Yeung, Tan To Cheung, Marcus H. N. Law, Stephen L. Chan, Peter Tin-Chung Li, and Kelvin K. Ng

Subjects
Cancer Research, Oncology, biology, business.industry, Hepatocellular carcinoma, Cancer research, biology.protein, Medicine, Cancer, business, medicine.disease, STAT3, Chemo resistance
Abstract

Hepatocellular carcinoma (HCC) is a major global health problem and its treatment outcomes are limited by therapeutic resistance. Cancer stem cells are the roots of tumor growth, recurrence, metastasis and treatment resistance. Signal transducer and activator of transcription 3 (STAT3) is a transcription factor well known to promote carcinogenesis in a number of tumors. The present study aims to investigate the role of STAT3 in HCC. Total STAT3 levels were examined by qRT-PCR in patients with primary HCC who underwent curative partial hepatectomy. Elevated STAT3 levels were significantly associated with poor recurrence-free survival and overall survival of HCC patients (log-rank test, P = 0.019 and 0.008, respectively). Immunohistochemistry (IHC) was performed to determine the activation status of STAT3 in HCC. Phosphorylated (p)-Y705 and p-S727 staining was detected in HCC tissues, albeit with varying patterns of expression. To investigate the efficacy of STAT3-targeted therapeutics in HCC, napabucasin, a cancer stemness inhibitor targeting STAT3-driven gene transcription, and the specific small interfering RNA (siRNA) were examined in HCC cell lines Hep3B, HepG2 and Huh7. Both napabucasin and siRNA prominently downregulated RNA and protein levels of total STAT3 and p-STAT3 of HCC cells. Napabucasin reduced viability, induced death, hindered migration, impaired colony and spheroid formation efficiency of HCC cells, as well as lowered expression levels of the cancer stem cell markers granulin-epithelin precursor (GEP) and CD133 in whole genome RNA sequencing analysis. Notably, napabucasin combined with 5-fluorouracil (5-FU) synergistically inhibited cell proliferation and induced apoptosis, suggesting its potential in sensitizing HCC cells to chemotherapeutic agents. In addition, napabucasin diminished the colony and spheroid formation abilities of chemo-resistant HCC cells (acquired resistance to 5-FU with over 10-fold increase) to a similar extent as their parental counterparts, indicating its potency in targeting chemo-resistant HCC cells via cancer stemness inhibition. Furthermore, napabucasin also suppressed HCC tumor growth in vivo, accompanied with reduced total STAT3 and p-STAT3 levels and proliferation (Ki-67). Overall, the present study highlighted the prognostic significance of STAT3 in HCC, and its functional role in the control of chemo-resistance and cancer stemness in HCC through targeted therapeutics. Citation Format: Carol Lee, Elaine Yee-Ling OR, Charing Ching-Ning Chong, Tan To Cheung, Iris Ming-Jing Xu, Linda Wing-Chi Ng, Marcus Hung-Lam Law, Peter Tin-Chung Li, Stephen Lam Chan, Anthony Wing-Hung Chan, Philip Chun Yeung, Kelvin Kwok-Chai Ng, Paul Bo-San Lai, Siu Tim Cheung. STAT3 regulates chemo-resistance and cancer stemness in hepatocellular carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4151.

Published
2020

7. Endoscopic Treatment in Chronic Pancreatitis

Author

Paul Bo-San Lai and Yue Sun Cheung

Subjects
medicine.medical_specialty, business.industry, Pseudocyst drainage, medicine.disease, Resection, Surgery, Stenosis, Upper abdominal pain, medicine, Stone extraction, Pancreatitis, Pancreatic carcinoma, business, Endoscopic treatment
Abstract

Chronic pancreatitis can give rise to relapsing episodic or persistent upper abdominal pain (Frulloni et al., 2010). Apart from the derangement of endocrine and exocrine functions, it can cause local complications such as pancreatic ductal stenosis, formation of intraductal stones and development of pseudocysts (Strobel et al., 2009). Management of these complications can be challenging in some patients. Various surgical drainage and resection procedures had been described with successful results (Strobel et al., 2009) but they were technically demanding and carried significant morbidities (Schnelldorfer et al., 2007). With the advancement in endoscopic treatments and novel techniques, some of the conventional open procedures have been replaced by endoscopic or minimally invasive techniques. In this chapter, we reviewed various endoscopic procedures available in treating patients with chronic pancreatitis, namely endoscopic sphincterotomy, stricture dilatation, stenting, stone extraction, endoscopic ultrasound-guided pseudocyst drainage and celiac plexus block. The indications, techniques and efficacy of endoscopic treatments were discussed in this chapter.

Published
2012

8. Treatment Strategy for Recurrent Hepatocellular Carcinoma

Author

Paul Bo San Lai and Charing C N Chong

Subjects
medicine.medical_specialty, business.industry, medicine.medical_treatment, Gold standard, Cancer, Malignancy, medicine.disease, Gastroenterology, Recurrent Hepatocellular Carcinoma, Internal medicine, Hepatocellular carcinoma, medicine, Treatment strategy, High incidence, Hepatectomy, business
Abstract

Hepatocellular carcinoma is an important malignancy of global significance. It is the seventh commonest cancer and the fourth leading cause of cancer deaths worldwide (GLOBOCAN, 2008). While hepatectomy remains to be the gold standard for treating HCC, long-term prognosis after curative resection remains unsatisfactory with high incidence of recurrence. The reported cumulative 5-year recurrence rate after curative partial hepatectomy averages above 70% in both Eastern and Western centers and the remnant liver is the commonest site of recurrence (Chong et al., 2011; Ercolani et al., 2003; Poon et al., 2001; Yeh et al., 2002).

Published
2012

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