Consorci Institut D'Investigacions Biomediques August Pi I Sunyer

AUTORES: Daniel J Klionsky1745,1749*, Kotb Abdelmohsen840, Akihisa Abe1237, Md Joynal Abedin1762, Hagai Abeliovich425,
\nAbraham Acevedo Arozena789, Hiroaki Adachi1800, Christopher M Adams1669, Peter D Adams57, Khosrow Adeli1981,
\nPeter J Adhihetty1625, Sharon G Adler700, Galila Agam67, Rajesh Agarwal1587, Manish K Aghi1537, Maria Agnello1826,
\nPatrizia Agostinis664, Patricia V Aguilar1960, Julio Aguirre-Ghiso784,786, Edoardo M Airoldi89,422, Slimane Ait-Si-Ali1376,
\nTakahiko Akematsu2010, Emmanuel T Akporiaye1097, Mohamed Al-Rubeai1394, Guillermo M Albaiceta1294,
\nChris Albanese363, Diego Albani561, Matthew L Albert517, Jesus Aldudo128, Hana Alg€ul1164, Mehrdad Alirezaei1198,
\nIraide Alloza642,888, Alexandru Almasan206, Maylin Almonte-Beceril524, Emad S Alnemri1212, Covadonga Alonso544,
\nNihal Altan-Bonnet848, Dario C Altieri1205, Silvia Alvarez1497, Lydia Alvarez-Erviti1395, Sandro Alves107,
\nGiuseppina Amadoro860, Atsuo Amano930, Consuelo Amantini1554, Santiago Ambrosio1458, Ivano Amelio756,
\nAmal O Amer918, Mohamed Amessou2089, Angelika Amon726, Zhenyi An1538, Frank A Anania291, Stig U Andersen6,
\nUsha P Andley2079, Catherine K Andreadi1690, Nathalie Andrieu-Abadie502, Alberto Anel2027, David K Ann58,
\nShailendra Anoopkumar-Dukie388, Manuela Antonioli832,858, Hiroshi Aoki1791, Nadezda Apostolova2007,
\nSaveria Aquila1500, Katia Aquilano1876, Koichi Araki292, Eli Arama2098, Agustin Aranda456, Jun Araya591,
\nAlexandre Arcaro1472, Esperanza Arias26, Hirokazu Arimoto1225, Aileen R Ariosa1749, Jane L Armstrong1930,
\nThierry Arnould1773, Ivica Arsov2120, Katsuhiko Asanuma675, Valerie Askanas1924, Eric Asselin1867, Ryuichiro Atarashi794,
\nSally S Atherton369, Julie D Atkin713, Laura D Attardi1131, Patrick Auberger1787, Georg Auburger379, Laure Aurelian1727,
\nRiccardo Autelli1992, Laura Avagliano1029,1755, Maria Laura Avantaggiati364, Limor Avrahami1166, Suresh Awale1986,
\nNeelam Azad404, Tiziana Bachetti568, Jonathan M Backer28, Dong-Hun Bae1933, Jae-sung Bae677, Ok-Nam Bae409,
\nSoo Han Bae2117, Eric H Baehrecke1729, Seung-Hoon Baek17, Stephen Baghdiguian1368,
\nAgnieszka Bagniewska-Zadworna2, Hua Bai90, Jie Bai667, Xue-Yuan Bai1133, Yannick Bailly884,
\nKithiganahalli Narayanaswamy Balaji473, Walter Balduini2002, Andrea Ballabio316, Rena Balzan1711, Rajkumar Banerjee239,
\nG abor B anhegyi1052, Haijun Bao2109, Benoit Barbeau1363, Maria D Barrachina2007, Esther Barreiro467, Bonnie Bartel997,
\nAlberto Bartolom e222, Diane C Bassham550, Maria Teresa Bassi1046, Robert C Bast Jr1273, Alakananda Basu1798,
\nMaria Teresa Batista1578, Henri Batoko1336, Maurizio Battino970, Kyle Bauckman2085, Bradley L Baumgarner1909,
\nK Ulrich Bayer1594, Rupert Beale1553, Jean-Fran¸cois Beaulieu1360, George R. Beck Jr48,294, Christoph Becker336,
\nJ David Beckham1595, Pierre-Andr e B edard749, Patrick J Bednarski301, Thomas J Begley1135, Christian Behl1419,
\nChristian Behrends757, Georg MN Behrens406, Kevin E Behrns1627, Eloy Bejarano26, Amine Belaid490,
\nFrancesca Belleudi1041, Giovanni B enard497, Guy Berchem706, Daniele Bergamaschi983, Matteo Bergami1401,
\nBen Berkhout1441, Laura Berliocchi714, Am elie Bernard1749, Monique Bernard1354, Francesca Bernassola1880,
\nAnne Bertolotti791, Amanda S Bess272, S ebastien Besteiro1351, Saverio Bettuzzi1828, Savita Bhalla913,
\nShalmoli Bhattacharyya973, Sujit K Bhutia838, Caroline Biagosch1159, Michele Wolfe Bianchi520,1378,1381,
\nMartine Biard-Piechaczyk210, Viktor Billes298, Claudia Bincoletto1314, Baris Bingol350, Sara W Bird1128, Marc Bitoun1112,
\nIvana Bjedov1258, Craig Blackstone843, Lionel Blanc1183, Guillermo A Blanco1496, Heidi Kiil Blomhoff1812,
\nEmilio Boada-Romero1297, Stefan B€ockler1464, Marianne Boes1423, Kathleen Boesze-Battaglia1835, Lawrence H Boise286,287,
\nAlessandra Bolino2063, Andrea Boman693, Paolo Bonaldo1823, Matteo Bordi897, J€urgen Bosch608, Luis M Botana1308,
\nJoelle Botti1375, German Bou1405, Marina Bouch e1038, Marion Bouchecareilh1331, Marie-Jos ee Boucher1901,
\nMichael E Boulton481, Sebastien G Bouret1926, Patricia Boya133, Micha€el Boyer-Guittaut1345, Peter V Bozhkov1141,
\nNathan Brady374, Vania MM Braga469, Claudio Brancolini1997, Gerhard H Braus353, Jos e M Bravo-San Pedro299,393,508,1374,
\nLisa A Brennan322, Emery H Bresnick2022, Patrick Brest490, Dave Bridges1939, Marie-Agn es Bringer124, Marisa Brini1822,
\nGlauber C Brito1311, Bertha Brodin631, Paul S Brookes1872, Eric J Brown352, Karen Brown1690, Hal E Broxmeyer480,
\nAlain Bruhat486,1339, Patricia Chakur Brum1893, John H Brumell446, Nicola Brunetti-Pierri315,1171,
\nRobert J Bryson-Richardson781, Shilpa Buch1777, Alastair M Buchan1819, Hikmet Budak1022, Dmitry V Bulavin118,505,1789,
\nScott J Bultman1792, Geert Bultynck665, Vladimir Bumbasirevic1470, Yan Burelle1356, Robert E Burke216,217,
\nMargit Burmeister1750, Peter B€utikofer1473, Laura Caberlotto1987, Ken Cadwell896, Monika Cahova112, Dongsheng Cai24,
\nJingjing Cai2099, Qian Cai1018, Sara Calatayud2007, Nadine Camougrand1343, Michelangelo Campanella1700,
\nGrant R Campbell1525, Matthew Campbell1249, Silvia Campello556,1876, Robin Candau1769, Isabella Caniggia1983,
\nLavinia Cantoni560, Lizhi Cao116, Allan B Caplan1656, Michele Caraglia1051, Claudio Cardinali1043, Sandra Morais Cardoso1579, Jennifer S Carew208, Laura A Carleton874, Cathleen R Carlin101, Silvia Carloni2002,
\nSven R Carlsson1267, Didac Carmona-Gutierrez1643, Leticia AM Carneiro312, Oliana Carnevali971, Serena Carra1318,
\nAlice Carrier120, Bernadette Carroll900, Caty Casas1324, Josefina Casas1116, Giuliana Cassinelli324, Perrine Castets1462,
\nSusana Castro-Obregon214, Gabriella Cavallini1841, Isabella Ceccherini568, Francesco Cecconi253,555,1884,
\nArthur I Cederbaum459, Valent ın Ce~na199,1281, Simone Cenci1323,2064, Claudia Cerella444, Davide Cervia1996,
\nSilvia Cetrullo1478, Hassan Chaachouay2028, Han-Jung Chae187, Andrei S Chagin634, Chee-Yin Chai626,628,
\nGopal Chakrabarti1502, Georgios Chamilos1601, Edmond YW Chan1142, Matthew TV Chan181, Dhyan Chandra1003,
\nPallavi Chandra548, Chih-Peng Chang818, Raymond Chuen-Chung Chang1653, Ta Yuan Chang345, John C Chatham1434,
\nSaurabh Chatterjee1910, Santosh Chauhan527, Yongsheng Che62, Michael E Cheetham1263, Rajkumar Cheluvappa1783,
\nChun-Jung Chen1153, Gang Chen598,1676, Guang-Chao Chen9, Guoqiang Chen1078, Hongzhuan Chen1077, Jeff W Chen1514,
\nJian-Kang Chen370,371, Min Chen249, Mingzhou Chen2104, Peiwen Chen1823, Qi Chen1674, Quan Chen172,
\nShang-Der Chen138, Si Chen325, Steve S-L Chen10, Wei Chen2125, Wei-Jung Chen829, Wen Qiang Chen979, Wenli Chen1113,
\nXiangmei Chen1133, Yau-Hung Chen1157, Ye-Guang Chen1250, Yin Chen1447, Yingyu Chen953,955, Yongshun Chen2135,
\nYu-Jen Chen712, Yue-Qin Chen1145, Yujie Chen1208, Zhen Chen339, Zhong Chen2123, Alan Cheng1702,
\nChristopher HK Cheng184, Hua Cheng1728, Heesun Cheong814, Sara Cherry1836, Jason Chesney1703,
\nChun Hei Antonio Cheung817, Eric Chevet1359, Hsiang Cheng Chi140, Sung-Gil Chi656, Fulvio Chiacchiera308,
\nHui-Ling Chiang958, Roberto Chiarelli1826, Mario Chiariello235,567,577, Marcello Chieppa835, Lih-Shen Chin290,
\nMario Chiong1285, Gigi NC Chiu878, Dong-Hyung Cho676, Ssang-Goo Cho650, William C Cho982, Yong-Yeon Cho105,
\nYoung-Seok Cho1064, Augustine MK Choi2095, Eui-Ju Choi656, Eun-Kyoung Choi387,400,685, Jayoung Choi1563,
\nMary E Choi2093, Seung-Il Choi2116, Tsui-Fen Chou412, Salem Chouaib395, Divaker Choubey1574, Vinay Choubey1936,
\nKuan-Chih Chow822, Kamal Chowdhury730, Charleen T Chu1856, Tsung-Hsien Chuang827, Taehoon Chun657,
\nHyewon Chung652, Taijoon Chung978, Yuen-Li Chung1194, Yong-Joon Chwae18, Valentina Cianfanelli254,
\nRoberto Ciarcia1775, Iwona A Ciechomska886, Maria Rosa Ciriolo1876, Mara Cirone1042, Sofie Claerhout1694,
\nMichael J Clague1698, Joan Cl aria1457, Peter GH Clarke1687, Robert Clarke361, Emilio Clementi1045,1398, C edric Cleyrat1781,
\nMiriam Cnop1366, Eliana M Coccia574, Tiziana Cocco1459, Patrice Codogno1375, J€orn Coers271, Ezra EW Cohen1533,
\nDavid Colecchia235,567,577, Luisa Coletto25, N uria S Coll123, Emma Colucci-Guyon516, Sergio Comincini1829,
\nMaria Condello578, Katherine L Cook2073, Graham H Coombs1929, Cynthia D Cooper2076, J Mark Cooper1395,
\nIsabelle Coppens601, Maria Tiziana Corasaniti1387, Marco Corazzari485,1884, Ramon Corbalan1566,
\nElisabeth Corcelle-Termeau251, Mario D Cordero1899, Cristina Corral-Ramos1289, Olga Corti507,1109, Andrea Cossarizza1767,
\nPaola Costelli1993, Safia Costes1518, Susan L Cotman721, Ana Coto-Montes946, Sandra Cottet566,1688, Eduardo Couve1301,
\nLori R Covey1015, L Ashley Cowart762, Jeffery S Cox1536, Fraser P Coxon1427, Carolyn B Coyne1846, Mark S Cragg1919,
\nRolf J Craven1679, Tiziana Crepaldi1995, Jose L Crespo1300, Alfredo Criollo1285, Valeria Crippa558, Maria Teresa Cruz1576,
\nAna Maria Cuervo26, Jose M Cuezva1277, Taixing Cui1907, Pedro R Cutillas987, Mark J Czaja27, Maria F Czyzyk-Krzeska1572,
\nRuben K Dagda2068, Uta Dahmen1404, Chunsun Dai800, Wenjie Dai1187, Yun Dai2059, Kevin N Dalby1940,
\nLuisa Dalla Valle1822, Guillaume Dalmasso1340, Marcello D’Amelio557, Markus Damme188, Arlette Darfeuille-Michaud1340,
\nCatherine Dargemont950, Victor M Darley-Usmar1433, Srinivasan Dasarathy205, Biplab Dasgupta202, Srikanta Dash1254,
\nCrispin R Dass242, Hazel Marie Davey8, Lester M Davids1560, David D avila227, Roger J Davis1731, Ted M Dawson604,
\nValina L Dawson606, Paula Daza1898, Jackie de Belleroche470, Paul de Figueiredo1180,1182,
\nRegina Celia Bressan Queiroz de Figueiredo135, Jos e de la Fuente1023, Luisa De Martino1775,
\nAntonella De Matteis1171, Guido RY De Meyer1443, Angelo De Milito631, Mauro De Santi2002,

CLT, Cadaveric liver transplantation; LDLT, live donor liver transplantation; PEI, Percutanoeus ethanol injection; RF, radiofrequency; TACE, Transarterial chemoembolization; PS, Performance Status. These recommendations provide a data-supported approach to the diagnosis, staging and treatment of patients diagnosed with hepatocellular carcinoma (HCC). They are based on the following: (a) formal review and analysis of the recently-published world literature on the topic (Medline search through early 2005); (b) American College of Physicians Manual for Assessing Health Practices and Designing Practice Guidelines.1 (c) guideline policies, including the AASLD Policy on the Development and Use of Practice Guidelines and the AGA Policy Statement on Guidelines2; (d) the experience of the authors in the specified topic. We have also reviewed the guidelines prepared at the time of the Monothematic Conference of the European Association for the Study of the Liver (EASL)3 and the practice of authors experienced in the field. Intended for use by physicians, these recommendations suggest preferred approaches to the diagnostic, therapeutic, and preventive aspects of care. They are intended to be flexible, in contrast to standards of care, which are inflexible policies to be followed in every case. Specific recommendations are based on relevant published information. In an attempt to characterize the quality of evidence supporting recommendations, the Practice Guidelines Committee of the AASLD requires a category to be assigned and reported with each recommendation (Table 1). These recommendations are fully endorsed by the American Association for the Study of Liver Diseases. Over the last 5 to 8 years evidence has been accumulating in different countries that the incidence of hepatocellular carcinoma (HCC) is rising.4-9 Traditionally, the care of patients with HCC has been undertaken by hepatobiliary surgeons, interventional radiologists, and oncologists. Hepatologists in North America are not trained to perform the procedures required to treat HCC, such as alcohol injection, radiofrequency ablation, or hepatic artery catheterization, although hepatologists in Japan and elsewhere may perform many of these procedures. As a result, the role of the hepatologist traditionally has been limited to making the diagnosis and providing care of the underlying liver disease. However, more recently, the role of the hepatologist has changed. First, in many centers the development of multidisciplinary clinics has emphasized the role of the hepatologist in assessing the patient's liver disease status, and carefully managing the liver disease before and during treatment. The hepatologist has also become more actively involved in deciding what form of therapy is most appropriate and whether the patient's liver function would allow that form of therapy to be given. In addition, arising out of caring for patients with end stage liver disease, hepatologists also institute surveillance for HCC and manage the investigation of abnormal results. Finally, hepatologists are involved in the decision whether or not to offer liver transplantation to patients with HCC. There have been many reviews of various aspects of the care of patients with HCC, but only one clinical practice guideline has been published in the Western literature. The European Association for Study of the Liver (EASL) sponsored a single topic conference on HCC in 2000. The proceedings of this conference were published in 2001.3 This document largely reflected practices in Europe, and possibly North America, whereas practices in Japan are somewhat different. Definitions of the terms used in this section are given in Table 2. Surveillance for HCC involves more than simply applying a screening test or tests. Surveillance should be offered in the setting of a program or a process in which screening tests and recall procedures have been standardized and in which quality control procedures are in place. The process of surveillance also involves deciding what level of risk of HCC is high enough to trigger surveillance, what screening tests to apply and how frequently (surveillance interval), and how abnormal results should be dealt with (diagnosis and/or recall). Surveillance for HCC has become widely applied despite, until recently, the absence of evidence of benefit. There is a single randomized controlled trial of surveillance versus no surveillance that has shown a survival benefit to a strategy of 6-monthly surveillance with alphafetoprotein (AFP) and ultrasound.10 This study, which was performed in China, recruited 18,816 patients who had markers of current or prior hepatitis B infection. Adherence to surveillance was suboptimal (less than 60%) but in the subjects in the surveillance arm the HCC related mortality was reduced by 37%. These results probably represent the minimum benefit that can be expected from surveillance, because of poor compliance. In contrast, an earlier study, also conducted in China failed to show benefit, largely because patients who were diagnosed with HCC did not undergo appropriate treatment.11 Ideally, these results should be validated in other geographical areas and therefore, additional randomized controlled trials (RCT) assessing the benefits of surveillance are still considered necessary. Such trials would be difficult to undertake, but are essential to unequivocally determine the benefit of surveillance in reducing HCC mortality. The objective of HCC surveillance must be to decrease mortality from the disease. Fewer people should die from HCC, or if this is not possible, surveillance should at a minimum provide a meaningful improvement in survival duration. Other endpoints, such as stage migration (detecting earlier disease) and 5-year mortality rates are not appropriate surrogate endpoints. This has clearly been shown by analysis of the Surveillance, Epidemiology and End Results (SEER) Program of the National Cancer Institute (NCI), which demonstrated that these endpoints did not correlate with a reduction in disease-specific mortality.12 There are several sources of bias to be considered in assessing reports of surveillance studies, such as lead-time bias and length bias. Only a RCT can eliminate these biases completely. Several studies have shown that surveillance does detect earlier disease (stage migration).13-16 However, as discussed above, this does not correlate well with reduction in disease-specific mortality. Uncontrolled studies, all subject to lead-time bias, have suggested that survival is improved after surveillance.13, 16 Surveillance for HCC is widely practiced and can generally be recommended for certain at-risk groups. HCC detected after the onset of symptoms has a dismal prognosis (0%-10% 5-year survival).17 In contrast, small HCCs can be cured with an appreciable frequency.17-21 Five-year disease-free survival exceeding 50% has been reported for both resection and liver transplantation.17, 22-30 Patients surviving free of disease for this duration must be considered cured. For these patients it is highly likely that surveillance did indeed decrease mortality. Since major advances in our ability to treat HCC are less likely to come from treating late stage disease it is therefore important to find early stage disease. The decision to enter a patient into a surveillance program is determined by the level of risk for HCC. This, in turn, is related to the incidence of HCC, and it is incidence that most people use to assess risk. However, there are no experimental data to indicate what level of risk or what incidence of HCC should trigger surveillance. Instead, decision analysis has been used to provide some guidelines as to the incidence of HCC at which surveillance may become effective. An intervention is considered effective if it provides an increase in longevity of about 100 days, i.e., about 3 months.31 Although the levels were set years ago, and may not be appropriate today, interventions that can be achieved at a cost of less than about $50,000/year of life gained are considered cost-effective.32 There are now several published decision analysis/cost-efficacy models for HCC surveillance. The models differ in the nature of the theoretical population being analyzed, and in the intervention being applied. Nonetheless, these models have several results in common. They all find that surveillance is cost-effective, although in some cases only marginally so, and most find that the efficacy of surveillance is highly dependent on the incidence of HCC. For example, Sarasin et al.33 studied a theoretical cohort of patients with Child–Pugh A cirrhosis and found that if the incidence of HCC was 1.5%/year surveillance resulted in an increase in longevity of about 3 months. However, if the incidence of HCC was 6% the increase in survival was about 9 months. This study did not include transplantation as a treatment option. Arguedas et al.,34 using a similar analysis which did include liver transplantation in a population of hepatitis C patients with cirrhosis and normal liver function, found that surveillance with either CT scanning alone or CT scanning plus ultrasound became cost-effective when the incidence of HCC was more than 1.4%. However, this study has to be interpreted cautiously, because the performance characteristics of CT scanning were derived from diagnostic studies, not surveillance studies (see Surveillance Tests). Lin et al.35 found that surveillance with AFP and ultrasound was cost-effective regardless of HCC incidence. Thus, for patients with cirrhosis of varying etiologies, surveillance should be offered when the risk of HCC is 1.5%/year or greater. Table 3 describes the groups of patients in which these limits are exceeded. These groups of patients are also discussed in more detail below. The above cost-efficacy analyses, which were restricted to cirrhotic populations, cannot be applied to hepatitis B carriers without cirrhosis. These patients, particularly in Asia and Africa, are also at risk for HCC. A cost-efficacy analysis of surveillance of hepatitis B carriers using ultrasound and AFP levels suggested that surveillance became cost-effective once the incidence of HCC exceeded 0.2%/year (Collier J and Sherman M, unpublished observations). The subgroups of hepatitis B carriers in which the incidence of HCC exceeds 0.2%/year are given in Table 3. These groups are discussed in more detail below. Beasley et al., in a prospective controlled study showed that the annual incidence of HCC in hepatitis B carriers was 0.5%.36-38 The annual incidence increased with age, so that at age 70 the incidence was 1%. The incidence in patients with known cirrhosis was 2.5%/year. The relative risk of HCC was about 100, i.e., hepatitis B carriers were 100 times more likely to develop HCC than the uninfected. Sakuma et al.39 found the incidence of HCC in male Japanese railway workers was 0.4%/year. Both these populations were male and Asian, with the hepatitis B infection likely acquired at birth or in early childhood. Uncontrolled prospective cohort studies in North America, where the epidemiology of hepatitis B is different, i.e., hepatitis is acquired later in life, have indicated that the incidence of HCC in HBV carriers varies widely.40-42 Villeneuve et al.40 found no tumors in a cohort infected with HBV and followed for 16 years. McMahon et al.41 reported an incidence of HCC of 0.26%/year in a study of HBV-infected individuals in Alaska. Sherman et al.42 described an incidence of 0.46%/year in their cohort. In Europe HCC in hepatitis B carriers occurs mainly in patients with established cirrhosis.43, 44 Non- Asian chronic carriers who are anti-HBe-positive with long-term inactive viral replication and who do not have cirrhosis seem to have little risk of developing HCC.45-48 Whether surveillance is worthwhile in this population is not clear. This is not true for Asian hepatitis B carriers without cirrhosis, who remain at risk for HCC regardless of replication status.45, 49-51 Similarly, the risk of HCC persists in long-term HBV carriers from Asia who lose HBsAg, and these patients should continue to undergo surveillance.52 In Caucasian hepatitis B carriers who lose surface antigen the risk of HCC seems to decline dramatically.53, 54 The annual incidence of HCC in male hepatitis B carriers from South East Asia only starts to exceed 0.2% at about age 4038 irrespective of presence of cirrhosis or disease activity. In contrast, in Caucasians the risk is related to inflammatory activity and the presence of cirrhosis. Therefore Asian men should undergo surveillance from age 40 onwards. HCC will occur in younger patients, but the efficacy of providing surveillance to all carriers younger than age 40 is likely to be low. The incidence of HCC in women is lower than in men, although age-specific incidence rates are hard to come by. Nonetheless, it seems appropriate to start surveillance at about age 50 in Asian women. All hepatitis B carriers with cirrhosis, regardless of age should be screened for HCC. In the presence of a history of a first degree relative with HCC surveillance should start at a younger age than 40,55 although what that age should be is hard to define. Africans with hepatitis B seem to get HCC at a younger age.56, 57 Expert opinion suggests that surveillance in these populations should also start at a younger age. Whether this is true in Blacks born elsewhere is uncertain. In Caucasian hepatitis B carriers with no cirrhosis and with inactive hepatitis, as determined by a long term normal ALT and low HBV DNA concentration44, 46, 47, 58 the incidence of HCC is probably too low to make surveillance worthwhile. However, there are additional risk factors that have to be taken into account, including older age, persistence of viral replication and co-infection with hepatitis C or HIV, or the presence of other liver diseases. Nevertheless, even in the absence of cirrhosis, adult Caucasian patients with active disease are likely at risk for HCC, and should be screened. The risk of HCC in patients with chronic hepatitis C is highest and has been best studied in patients who have established cirrhosis,59-62 in whom the incidence of HCC is between 2%-8% per year. It should be noted that these data come from clinic-based studies. There is a single prospective population-based study of the risk of HCC in patients with hepatitis C.63 In this study of 12,008 men being anti-HCV-positive conferred a 20-fold increased risk of HCC compared to anti-HCV-negative subjects. The presence or absence of cirrhosis was not evaluated. Hepatitis C infected individuals who do not have cirrhosis have a much lower risk of developing HCC.64 However, the transition from bridging fibrosis to cirrhosis cannot be determined clinically so that the clinician cannot easily determine when these patients start to develop a significant increase in risk of HCC. For this reason the EASL conference3 suggested that surveillance may be offered to patients with hepatitis C and cirrhosis or with bridging fibrosis or transition to cirrhosis. The cost-efficacy of this recommendation has not been evaluated. Based on current knowledge, all patients with hepatitis C and cirrhosis should undergo surveillance. Whether patients with bridging fibrosis should also undergo surveillance remains controversial. There have been several attempts to develop non-invasive markers to predict the stage of fibrosis65-67 and if properly validated, these could be used to determine when to initiate surveillance. Similarly, several other markers may predict a significant risk of HCC. One such marker may be the platelet count. It has been suggested that the incidence of HCC in hepatitis C cirrhosis only increases substantially once the platelet count is less than 100×109/L,62, 68, 69 regardless of liver function. This needs to be validated. Others have attempted to develop predictive indices based on panels of commonly performed serological tests such as alpha 2-macroglobulin, apolipoprotein A1, haptoglobin, bilirubin and gamma-glutamyl-transpeptidase and the AST/ALT ratio.67, 70 However, these indices have still to be validated before entering general use and cannot be recommended at present. Patients who are co-infected with HIV and either hepatitis B or hepatitis C may have more rapidly progressive liver disease71 and when they reach cirrhosis they are also at increased risk of HCC.72 The MORTAVIC study indicated that HCC was responsible for 25% of all liver deaths in the post-HAART era.73, 74 The criteria for entering co-infected patients into programs for HCC screening are the same as for mono-infected patients, i.e., criteria based on the stage and grade of liver disease as described above. The incidence of HCC in cirrhosis caused by diseases other than viral hepatitis is, with some exceptions, not accurately known. Most of the studies of the incidence of HCC in alcoholic cirrhosis date from before the identification of the hepatitis C virus. Given that hepatitis C is relatively frequent in alcoholics75-77 most of the reported HCC incidence rates in earlier studies must be over-estimates. That alcoholic cirrhosis is a risk factor for HCC is clear. In one study alcoholic liver disease accounted for 32% of all HCCs.78 In an Austrian cohort with HCC alcoholic liver disease was the risk factor in 35% of subjects.79 In the United States the approximate hospitalization rate for HCC related to alcoholic cirrhosis is 8-9/100,000/year compared to about 7/100,000/year for hepatitis C.80 This study did not determine the incidence of HCC in alcoholic liver disease, but it does confirm that alcoholic cirrhosis is a significant risk factor for HCC, probably sufficient to warrant surveillance for HCC. With the recognition of steatohepatitis as a cause of cirrhosis, has come the suspicion that this too is a risk factor for HCC. No study to date has followed a sufficiently large group of such patients for long enough to describe an incidence rate for HCC. In one cohort study of patients with HCC81 diabetes was found in 20% as the only risk factor for HCC. Whether or not these patients were cirrhotic was not noted. Non-alcoholic fatty liver disease (NAFLD) has been described in cohorts of patients with HCC.82, 83 Since the incidence of HCC in cirrhosis due to NAFLD is unknown it is not possible to assess whether surveillance might be effective or cost-efficient. No recommendations can be made whether this group should be screened for HCC or not. This does not preclude the possibility that surveillance is beneficial in this group, and future data may change this recommendation. Patients with genetic hemochromatosis (GH) who have established cirrhosis have an increased risk of HCC.84-86 The relative risk of HCC is about 20. The standardized incidence ratio for HCC in cirrhotic GH is 92.9 (95% confidence interval [CI] 25-237.9). The incidence of HCC in cirrhosis due to GH is sufficiently high (about 3%-4%/year) that these patients should be included in surveillance programs. The incidence of HCC in stage 4 primary biliary cirrhosis is about the same as in cirrhosis due to hepatitis C.87 For cirrhosis due to alpha 1-antitrypsin (AAT) or hepatitis there are data from cohort studies to accurately assess HCC incidence. There is as no evidence that treatment of chronic hepatitis B the incidence of HCC. in Europe suggested that therapy for chronic hepatitis B improved survival and reduced the incidence of A study from also indicated that i.e., the development of was with a reduced incidence of However, in these studies the rate was and the were relatively In contrast, a but controlled study from that included a cohort followed for found that the incidence of HCC was not in the A single RCT suggests that treatment of chronic hepatitis B carriers with cirrhosis does the incidence of but whether the risk reduction is sufficient that surveillance is not clear. a patient is a for surveillance before the of it seems to continue to offer surveillance even after or of inflammatory activity. There are a of studies the of treatment of chronic hepatitis C on the incidence of HCC. A single RCT in Japan suggested that the incidence of HCC was reduced in both and to These results could not be in a RCT from The results of these other studies were in a which that the benefit is mainly in who were i.e., had a and even the was A of studies in Japan compared the incidence of HCC in patients with that in These have suggested that there is a reduced incidence of HCC in However, no data that treating or hepatitis C the risk for HCC. it seems that patients with hepatitis C and cirrhosis who have achieved viral on therapy at for continue to undergo surveillance. that patients with or chronic hepatitis B or C may show of fibrosis sufficient to suggest of cirrhosis. The risk of HCC in these patients probably does not decrease with the improvement in There are many about the of HCC in these patients, but one factor seems to be that of and are necessary. The required to initiate the probably occur many years before the disease and so the of HCC remains even if fibrosis fibrosis is not a reason to surveillance. There are a of factors with an increased risk of HCC that are in patients at risk for developing HCC. These include an AFP presence of small and large on to and increased for antigen or of the Although such patients are at more risk of developing HCC they will likely be in surveillance programs because of other risk factors such as cirrhosis or chronic hepatitis The increased does not a change in surveillance Patients at high risk for developing HCC should be into surveillance programs The at-risk groups are in There are several for screening patients on the liver Patients should be screened for HCC to small tumors that might and to patients who develop that exceeds the guidelines for In addition, in the United the current criteria the development of HCC provides liver Thus, it would seem to be in a patient's to have a small HCC diagnosed on the liver One cost-efficacy analysis has suggested that the increase in longevity the cohort of patients is because although there may be an increase in longevity in who develop HCC, it is by the of longevity in other patients on the are so that the patient with HCC can have In contrast, identification of HCC that exceeds and of such patients, is beneficial to other patients on the analysis suggested that there were benefits to treating patients with HCC on the with either resection or The benefit in on the length of the The the the the benefit of In the United States patients to be for liver transplantation with an AFP without of HCC, even in the absence of a on It is important to that AFP is being used for diagnosis, not surveillance. Nonetheless, the performance characteristics of even as a diagnostic test are particularly in the absence of a on (see 2. Patients on the should be screened for HCC because in the the development of HCC increased for and because to for HCC that patients may develop HCC and criteria without the being that is used to determine the presence or absence of a disease must be validated using a of that determine how well the test in the disease no test is The are the and which are For single test and the underlying disease, as the diagnostic of test is related to the of the underlying disease in the population being This is by the and predictive i.e., the rates at which or results are An of the of a test can also be free of the of disease incidence by using the This is a of the and the performance characteristics of a test the of the test results the for diagnosis can be from the a of the of the test results. An important additional is that the history of liver is not the same as for clinical In rates of may be different than rates in clinically may not to clinically in all it cannot be that all found on surveillance will develop into Similarly, the performance characteristics of a test used to disease as a screening are not the same as when the test is used for Therefore one cannot the performance characteristics of a test used in diagnosis CT and the and to the surveillance tests into serological and the serological tests the performance characteristics of AFP have been best analysis of AFP used as a diagnostic test suggests that a of about provides the between and However, at this level the is only i.e., AFP surveillance would of HCC if a of is used as the trigger for This is for general a is used a of HCCs will be the AFP is the to reducing the that more HCCs would be but at the cost of a progressive increase in the This analysis was performed in a control study where the of HCC was set at this the predictive of an AFP of was However, if the HCC rates were more in most liver i.e., about the predictive of an AFP of is only and even at a of the is only In cohorts surveillance the incidence of HCC may be even lower than on the criteria for into surveillance. For example, in hepatitis B carriers infected at birth the incidence of HCC is less than 1%. AFP is an screening AFP still has a role in the diagnosis of HCC, in cirrhotic patients with a in the liver an AFP than has a high predictive for a AFP has been clearly shown to be a risk factor for Thus, the AFP can be used to patients at but to have limited as a screening serological test used to HCC is the also known as by Most reports on the use of have the use of this test in a diagnostic than for surveillance. Although there are reports of use in a surveillance these do not provide sufficient for use of this There are also reports that is a marker for by this would also suggest that is not a screening A screening test should be to early

Liver fibrosis is the excessive accumulation of extracellular matrix proteins including collagen that occurs in most types of chronic liver diseases. Advanced liver fibrosis results in cirrhosis, liver failure, and portal hypertension and often requires liver transplantation. Our knowledge of the cellular and molecular mechanisms of liver fibrosis has greatly advanced. Activated hepatic stellate cells, portal fibroblasts, and myofibroblasts of bone marrow origin have been identified as major collagen-producing cells in the injured liver. These cells are activated by fibrogenic cytokines such as TGF-beta1, angiotensin II, and leptin. Reversibility of advanced liver fibrosis in patients has been recently documented, which has stimulated researchers to develop antifibrotic drugs. Emerging antifibrotic therapies are aimed at inhibiting the accumulation of fibrogenic cells and/or preventing the deposition of extracellular matrix proteins. Although many therapeutic interventions are effective in experimental models of liver fibrosis, their efficacy and safety in humans is unknown. This review summarizes recent progress in the study of the pathogenesis and diagnosis of liver fibrosis and discusses current antifibrotic strategies.

Allergic rhinitis is a symptomatic disorder of the nose\ninduced after allergen exposure by an IgE-mediated\ninflammation of the membranes lining the nose. It is a\nglobal health problem that causes major illness and disability\nworldwide. Over 600 million patients from all\ncountries, all ethnic groups and of all ages suffer from\nallergic rhinitis. It affects social life, sleep, school and\nwork and its economic impact is substantial.\nRisk factors for allergic rhinitis are well identified.\nIndoor and outdoor allergens as well as occupational\nagents cause rhinitis and other allergic diseases.\nThe role of indoor and outdoor pollution is probably\nvery important, but has yet to be fully understood\nboth for the occurrence of the disease and its manifestations.\nIn 1999, during the Allergic Rhinitis and its Impact on\nAsthma (ARIA) WHO workshop, the expert panel\nproposed a new classification for allergic rhinitis which\nwas subdivided into _intermittent_ or _persistent_ disease.\nThis classification is now validated.\nThe diagnosis of allergic rhinitis is often quite easy, but\nin some cases it may cause problems and many patients\nare still under-diagnosed, often because they do not\nperceive the symptoms of rhinitis as a disease impairing\ntheir social life, school and work.\nThe management of allergic rhinitis is well established\nand the ARIA expert panel based its recommendations\non evidence using an extensive review of the literature\navailable up to December 1999. The statements of\nevidence for the development of these guidelines followed\nWHO rules and were based on those of Shekelle et al.\nA large number of papers have been published since 2000\nand are extensively reviewed in the 2008 Update using\nthe same evidence-based system. Recommendations for\nthe management of allergic rhinitis are similar in both the\nARIA workshop report and the 2008 Update. In the\nfuture, the GRADE approach will be used, but is not yet\navailable.\nAnother important aspect of the ARIA guidelines was\nto consider co-morbidities. Both allergic rhinitis and\nasthma are systemic inflammatory conditions and often\nco-exist in the same patients. In the 2008 Update, these\nlinks have been confirmed.\nTheARIAdocument is not intended to be a standard-ofcare\ndocument for individual countries. It is provided as a\nbasis for physicians, health care professionals and\norganizations involved in the treatment of allergic rhinitis\nand asthma in various countries to facilitate the\ndevelopment of relevant local standard-of-care documents\nfor patients.

The classifications of hepatocellular carcinoma (HCC) currently used are based on prognostic factors obtained from studies performed years ago when most tumors were diagnosed at advanced stages and the survival rates were substantially poor. Recent investigations have reviewed the survival of early tumors properly selected to receive radical therapies and the natural outcome of nonsurgical HCC patients. These data enable a new staging system to be proposed, the Barcelona Clinic Liver Cancer (BCLC) staging classification, that comprises four stages that select the best candidates for the best therapies currently available. Early stage (A) includes patients with asymptomatic early tumors suitable for radical therapies--resection, transplantation or percutaneous treatments. Intermediate stage (B) comprises patients with asymptomatic multinodular HCC. Advanced stage (C) includes patients with symptomatic tumors and/or an invasive tumoral pattern (vascular invasion/extrahepatic spread). Stage B and C patients may receive palliative treatments/new agents in the setting of phase II investigations or randomized controlled trials. End-stage disease (D) contain patients with extremely grim prognosis (Okuda stage III or PST 3-4) that should merely receive symptomatic treatment.

Abstract Somatic mutations in cancer genomes are caused by multiple mutational processes, each of which generates a characteristic mutational signature 1 . Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium 2 of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we characterized mutational signatures using 84,729,690 somatic mutations from 4,645 whole-genome and 19,184 exome sequences that encompass most types of cancer. We identified 49 single-base-substitution, 11 doublet-base-substitution, 4 clustered-base-substitution and 17 small insertion-and-deletion signatures. The substantial size of our dataset, compared with previous analyses 3–15 , enabled the discovery of new signatures, the separation of overlapping signatures and the decomposition of signatures into components that may represent associated—but distinct—DNA damage, repair and/or replication mechanisms. By estimating the contribution of each signature to the mutational catalogues of individual cancer genomes, we revealed associations of signatures to exogenous or endogenous exposures, as well as to defective DNA-maintenance processes. However, many signatures are of unknown cause. This analysis provides a systematic perspective on the repertoire of mutational processes that contribute to the development of human cancer.

Promotion of good mental health, prevention, and early intervention before/at the onset of mental disorders improve outcomes. However, the range and peak ages at onset for mental disorders are not fully established. To provide robust, global epidemiological estimates of age at onset for mental disorders, we conducted a PRISMA/MOOSE-compliant systematic review with meta-analysis of birth cohort/cross-sectional/cohort studies, representative of the general population, reporting age at onset for any ICD/DSM-mental disorders, identified in PubMed/Web of Science (up to 16/05/2020) (PROSPERO:CRD42019143015). Co-primary outcomes were the proportion of individuals with onset of mental disorders before age 14, 18, 25, and peak age at onset, for any mental disorder and across International Classification of Diseases 11 diagnostic blocks. Median age at onset of specific disorders was additionally investigated. Across 192 studies (n = 708,561) included, the proportion of individuals with onset of any mental disorders before the ages of 14, 18, 25 were 34.6%, 48.4%, 62.5%, and peak age was 14.5 years (k = 14, median = 18, interquartile range (IQR) = 11-34). For diagnostic blocks, the proportion of individuals with onset of disorder before the age of 14, 18, 25 and peak age were as follows: neurodevelopmental disorders: 61.5%, 83.2%, 95.8%, 5.5 years (k = 21, median=12, IQR = 7-16), anxiety/fear-related disorders: 38.1%, 51.8%, 73.3%, 5.5 years (k = 73, median = 17, IQR = 9-25), obsessive-compulsive/related disorders: 24.6%, 45.1%, 64.0%, 14.5 years (k = 20, median = 19, IQR = 14-29), feeding/eating disorders/problems: 15.8%, 48.1%, 82.4%, 15.5 years (k = 11, median = 18, IQR = 15-23), conditions specifically associated with stress disorders: 16.9%, 27.6%, 43.1%, 15.5 years (k = 16, median = 30, IQR = 17-48), substance use disorders/addictive behaviours: 2.9%, 15.2%, 48.8%, 19.5 years (k = 58, median = 25, IQR = 20-41), schizophrenia-spectrum disorders/primary psychotic states: 3%, 12.3%, 47.8%, 20.5 years (k = 36, median = 25, IQR = 20-34), personality disorders/related traits: 1.9%, 9.6%, 47.7%, 20.5 years (k = 6, median = 25, IQR = 20-33), and mood disorders: 2.5%, 11.5%, 34.5%, 20.5 years (k = 79, median = 31, IQR = 21-46). No significant difference emerged by sex, or definition of age of onset. Median age at onset for specific mental disorders mapped on a time continuum, from phobias/separation anxiety/autism spectrum disorder/attention deficit hyperactivity disorder/social anxiety (8-13 years) to anorexia nervosa/bulimia nervosa/obsessive-compulsive/binge eating/cannabis use disorders (17-22 years), followed by schizophrenia, personality, panic and alcohol use disorders (25-27 years), and finally post-traumatic/depressive/generalized anxiety/bipolar/acute and transient psychotic disorders (30-35 years), with overlap among groups and no significant clustering. These results inform the timing of good mental health promotion/preventive/early intervention, updating the current mental health system structured around a child/adult service schism at age 18.

Abstract Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale 1–3 . Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter 4 ; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation 5,6 ; analyses timings and patterns of tumour evolution 7 ; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity 8,9 ; and evaluates a range of more-specialized features of cancer genomes 8,10–18 .

Standardized criteria for diagnosis and response assessment are needed to interpret and compare clinical trials and for approval of new therapeutic agents by regulatory agencies. Therefore, a National Cancer Institute-sponsored Working Group (NCI-WG) on chronic lymphocytic leukemia (CLL) published guidelines for the design and conduct of clinical trials for patients with CLL in 1988, which were updated in 1996. During the past decade, considerable progress has been achieved in defining new prognostic markers, diagnostic parameters, and treatment options. This prompted the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) to provide updated recommendations for the management of CLL in clinical trials and general practice.

Dementia has been increasingly more recognized to be a common feature in patients with Parkinson's disease (PD), especially in old age. Specific criteria for the clinical diagnosis of dementia associated with PD (PD-D), however, have been lacking. A Task Force, organized by the Movement Disorder Study, was charged with the development of clinical diagnostic criteria for PD-D. The Task Force members were assigned to sub-committees and performed a systematic review of the literature, based on pre-defined selection criteria, in order to identify the epidemiological, clinical, auxillary, and pathological features of PD-D. Clinical diagnostic criteria were then developed based on these findings and group consensus. The incidence of dementia in PD is increased up to six times, point-prevelance is close to 30%, older age and akinetic-rigid form are associated with higher risk. PD-D is characterized by impairment in attention, memory, executive and visuo-spatial functions, behavioral symptoms such as affective changes, hallucinations, and apathy are frequent. There are no specific ancillary investigations for the diagnosis; the main pathological correlate is Lewy body-type degeneration in cerebral cortex and limbic structures. Based on the characteristic features associated with this condition, clinical diagnostic criteria for probable and possible PD-D are proposed.

There is increasing evidence that subjective cognitive decline (SCD) in individuals with unimpaired performance on cognitive tests may represent the first symptomatic manifestation of Alzheimer's disease (AD). The research on SCD in early AD, however, is limited by the absence of common standards. The working group of the Subjective Cognitive Decline Initiative (SCD-I) addressed this deficiency by reaching consensus on terminology and on a conceptual framework for research on SCD in AD. In this publication, research criteria for SCD in pre-mild cognitive impairment (MCI) are presented. In addition, a list of core features proposed for reporting in SCD studies is provided, which will enable comparability of research across different settings. Finally, a set of features is presented, which in accordance with current knowledge, increases the likelihood of the presence of preclinical AD in individuals with SCD. This list is referred to as SCD plus.

The principal limitations of the terms NAFLD and NASH are the reliance on exclusionary confounder terms and the use of potentially stigmatising language. This study set out to determine if content experts and patient advocates were in favor of a change in nomenclature and/or definition. A modified Delphi process was led by three large pan-national liver associations. The consensus was defined a priori as a supermajority (67%) vote. An independent committee of experts external to the nomenclature process made the final recommendation on the acronym and its diagnostic criteria. A total of 236 panelists from 56 countries participated in 4 online surveys and 2 hybrid meetings. Response rates across the 4 survey rounds were 87%, 83%, 83%, and 78%, respectively. Seventy-four percent of respondents felt that the current nomenclature was sufficiently flawed to consider a name change. The terms "nonalcoholic" and "fatty" were felt to be stigmatising by 61% and 66% of respondents, respectively. Steatotic liver disease was chosen as an overarching term to encompass the various aetiologies of steatosis. The term steatohepatitis was felt to be an important pathophysiological concept that should be retained. The name chosen to replace NAFLD was metabolic dysfunction-associated steatotic liver disease. There was consensus to change the definition to include the presence of at least 1 of 5 cardiometabolic risk factors. Those with no metabolic parameters and no known cause were deemed to have cryptogenic steatotic liver disease. A new category, outside pure metabolic dysfunction-associated steatotic liver disease, termed metabolic and alcohol related/associated liver disease (MetALD), was selected to describe those with metabolic dysfunction-associated steatotic liver disease, who consume greater amounts of alcohol per week (140-350 g/wk and 210-420 g/wk for females and males, respectively). The new nomenclature and diagnostic criteria are widely supported and nonstigmatising, and can improve awareness and patient identification.

The principal limitations of the terms NAFLD and NASH are the reliance on exclusionary confounder terms and the use of potentially stigmatising language. This study set out to determine if content experts and patient advocates were in favour of a change in nomenclature and/or definition. A modified Delphi process was led by three large pan-national liver associations. The consensus was defined a priori as a supermajority (67%) vote. An independent committee of experts external to the nomenclature process made the final recommendation on the acronym and its diagnostic criteria. A total of 236 panellists from 56 countries participated in 4 online surveys and 2 hybrid meetings. Response rates across the 4 survey rounds were 87%, 83%, 83%, and 78%, respectively. Seventy-four percent of respondents felt that the current nomenclature was sufficiently flawed to consider a name change. The terms "nonalcoholic" and "fatty" were felt to be stigmatising by 61% and 66% of respondents, respectively. Steatotic liver disease was chosen as an overarching term to encompass the various aetiologies of steatosis. The term steatohepatitis was felt to be an important pathophysiological concept that should be retained. The name chosen to replace NAFLD was metabolic dysfunction-associated steatotic liver disease (MASLD). There was consensus to change the definition to include the presence of at least 1 of 5 cardiometabolic risk factors. Those with no metabolic parameters and no known cause were deemed to have cryptogenic steatotic liver disease. A new category, outside pure metabolic dysfunction-associated steatotic liver disease, termed metabolic and alcohol related/associated liver disease (MetALD), was selected to describe those with metabolic dysfunction-associated steatotic liver disease, who consume greater amounts of alcohol per week (140-350 g/wk and 210-420 g/wk for females and males, respectively). The new nomenclature and diagnostic criteria are widely supported and non-stigmatising, and can improve awareness and patient identification.

autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

BACKGROUND: This study compared bortezomib with high-dose dexamethasone in patients with relapsed multiple myeloma who had received one to three previous therapies. METHODS: We randomly assigned 669 patients with relapsed myeloma to receive either an intravenous bolus of bortezomib (1.3 mg per square meter of body-surface area) on days 1, 4, 8, and 11 for eight three-week cycles, followed by treatment on days 1, 8, 15, and 22 for three five-week cycles, or high-dose dexamethasone (40 mg orally) on days 1 through 4, 9 through 12, and 17 through 20 for four five-week cycles, followed by treatment on days 1 through 4 for five four-week cycles. Patients who were assigned to receive dexamethasone were permitted to cross over to receive bortezomib in a companion study after disease progression. RESULTS: Patients treated with bortezomib had higher response rates, a longer time to progression (the primary end point), and a longer survival than patients treated with dexamethasone. The combined complete and partial response rates were 38 percent for bortezomib and 18 percent for dexamethasone (P<0.001), and the complete response rates were 6 percent and less than 1 percent, respectively (P<0.001). Median times to progression in the bortezomib and dexamethasone groups were 6.22 months (189 days) and 3.49 months (106 days), respectively (hazard ratio, 0.55; P<0.001). The one-year survival rate was 80 percent among patients taking bortezomib and 66 percent among patients taking dexamethasone (P=0.003), and the hazard ratio for overall survival with bortezomib was 0.57 (P=0.001). Grade 3 or 4 adverse events were reported in 75 percent of patients treated with bortezomib and in 60 percent of those treated with dexamethasone. CONCLUSIONS: Bortezomib is superior to high-dose dexamethasone for the treatment of patients with multiple myeloma who have had a relapse after one to three previous therapies.

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.

The European Position Paper on Rhinosinusitis and Nasal Polyps 2012 is the update of similar evidence based position papers published in 2005 and 2007. The document contains chapters on definitions and classification, we now also proposed definitions for difficult to treat rhinosinusitis, control of disease and better definitions for rhinosinusitis in children. More emphasis is placed on the diagnosis and treatment of acute rhinosinusitis. Throughout the document the terms chronic rhinosinusitis without nasal polyps (CRSsNP) and chronic rhinosinusitis with nasal polyps (CRSwNP) are used to further point out differences in pathophysiology and treatment of these two entities. There are extensive chapters on epidemiology and predisposing factors, inflammatory mechanisms, (differential) diagnosis of facial pain, genetics, cystic fibrosis, aspirin exacerbated respiratory disease, immunodeficiencies, allergic fungal rhinosinusitis and the relationship between upper and lower airways. The chapters on paediatric acute and chronic rhinosinusitis are totally rewritten. Last but not least all available evidence for management of acute rhinosinusitis and chronic rhinosinusitis with or without nasal polyps in adults and children is analyzed and presented and management schemes based on the evidence are proposed. This executive summary for otorhinolaryngologists focuses on the most important changes and issues for otorhinolaryngologists. The full document can be downloaded for free on the website of this journal: http://www.rhinologyjournal.com.

BACKGROUND: PSP is a neuropathologically defined disease entity. Clinical diagnostic criteria, published in 1996 by the National Institute of Neurological Disorders and Stroke/Society for PSP, have excellent specificity, but their sensitivity is limited for variant PSP syndromes with presentations other than Richardson's syndrome. OBJECTIVE: We aimed to provide an evidence- and consensus-based revision of the clinical diagnostic criteria for PSP. METHODS: We searched the PubMed, Cochrane, Medline, and PSYCInfo databases for articles published in English since 1996, using postmortem diagnosis or highly specific clinical criteria as the diagnostic standard. Second, we generated retrospective standardized clinical data from patients with autopsy-confirmed PSP and control diseases. On this basis, diagnostic criteria were drafted, optimized in two modified Delphi evaluations, submitted to structured discussions with consensus procedures during a 2-day meeting, and refined in three further Delphi rounds. RESULTS: Defined clinical, imaging, laboratory, and genetic findings serve as mandatory basic features, mandatory exclusion criteria, or context-dependent exclusion criteria. We identified four functional domains (ocular motor dysfunction, postural instability, akinesia, and cognitive dysfunction) as clinical predictors of PSP. Within each of these domains, we propose three clinical features that contribute different levels of diagnostic certainty. Specific combinations of these features define the diagnostic criteria, stratified by three degrees of diagnostic certainty (probable PSP, possible PSP, and suggestive of PSP). Clinical clues and imaging findings represent supportive features. CONCLUSIONS: Here, we present new criteria aimed to optimize early, sensitive, and specific clinical diagnosis of PSP on the basis of currently available evidence. © 2017 International Parkinson and Movement Disorder Society.

OBJECTIVE: To analyze the clinical and immunologic manifestations of antiphospholipid syndrome (APS) in a large cohort of patients and to define patterns of disease expression. METHODS: The clinical and serologic features of APS (Sapporo preliminary criteria) in 1,000 patients from 13 European countries were analyzed using a computerized database. RESULTS: The cohort consisted of 820 female patients (82.0%) and 180 male patients (18.0%) with a mean +/- SD age of 42 +/- 14 years at study entry. "Primary" APS was present in 53.1% of the patients; APS was associated with systemic lupus erythematosus (SLE) in 36.2%, with lupus-like syndrome in 5.0%, and with other diseases in 5.9%. A variety of thrombotic manifestations affecting the majority of organs were recorded. A catastrophic APS occurred in 0.8% of the patients. Patients with APS associated with SLE had more episodes of arthritis and livedo reticularis, and more frequently exhibited thrombocytopenia and leukopenia. Female patients had a higher frequency of arthritis, livedo reticularis, and migraine. Male patients had a higher frequency of myocardial infarction, epilepsy, and arterial thrombosis in the lower legs and feet. In 28 patients (2.8%), disease onset occurred before age 15; these patients had more episodes of chorea and jugular vein thrombosis than the remaining patients. In 127 patients (12.7%), disease onset occurred after age 50; most of these patients were men. These patients had a higher frequency of stroke and angina pectoris, but a lower frequency of livedo reticularis, than the remaining patients. CONCLUSION: APS may affect any organ of the body and display a broad spectrum of manifestations. An association with SLE, the patient's sex, and the patient's age at disease onset can modify the disease expression and define specific subsets of APS.

This guidance provides a data-supported approach to risk stratification, diagnosis, and management of patients with cirrhosis and portal hypertension (PH). A guidance document is different from a guideline. Guidelines are developed by a multidisciplinary panel of experts who rate the quality (level) of the evidence and the strength of each recommendation using the Grading of Recommendations Assessment, Development, and Evaluation system. A guidance document is developed by a panel of experts in the topic, and guidance statements, not recommendations, are put forward to help clinicians understand and implement the most recent evidence. This guidance focuses on PH, varices, and variceal hemorrhage (VH), and statements are based on the following: (1) review of the recent literature using PubMed, giving more weight to large, well-designed, prospective trials and well-performed meta-analyses; (2) several consensus conferences among experts; and (3) the authors' years of experience caring for patients with cirrhosis and varices. Management of ascites and encephalopathy is addressed in other documents. When little or no data exist from well-designed, prospective trials, emphasis is given to results from large series and reports from recognized experts. In this case, clinical studies needed to clarify that management are specified in a section on future research. Practice guidelines for the diagnosis and treatment of gastroesophageal VH were published in 2007, endorsed by the American Association for the Study of Liver Diseases (AASLD), American College of Gastroenterology, American Gastroenterological Association, and American Society of Gastrointestinal Endoscopy (ASGE).1 Since then, a number of randomized, controlled trials (RCTs) have advanced our approach to managing VH. Additionally, four international consensus conferences were held since then, where experts in the field evaluated the changes in pathophysiology, diagnosis, and management of varices and VH. These include two AASLD/European Association for the Study of the Liver single-topic conferences in 2007 (many of the recommendations from this conference were incorporated into the aforementioned guidelines)2 and in 2013, and two Baveno consensus conferences in 20103 and in 2015.4 In this updated practice guidance, recommendations derived from these consensus conferences were also incorporated, particularly those from the latest Baveno conference that took place in Baveno, Italy, in April 2015. Perhaps the most relevant change in these recommendations has been the recognition of the different stages of cirrhosis,5 so that recommendations are now focused on risk stratification and individualizing care for PH. Intended for use by health care providers, this guidance identifies preferred approaches to the diagnostic, therapeutic, and preventive aspects of care of patients with PH. As with other guidance documents, it is not intended to replace clinical judgment, but rather to provide general guidance applicable to the majority of patients. They are intended to be flexible, in contrast to formal treatment recommendations or standards of care, which are inflexible policies designed to be followed in every case. Clinical considerations may justify a course of action that differs from this guidance. Cirrhosis is a chronic condition with a high mortality. It constitutes the fifth-leading cause of adult deaths and ranks eighth in economic cost among the major illnesses.6 Cirrhosis is a heterogeneous disease that cannot be studied or managed as a single entity and is classified in two main prognostic stages: compensated and decompensated cirrhosis.5, 7 This classification depends on the presence or absence of clinically evident decompensating events (specifically ascites, VH, and encephalopathy [HE]), with a median survival in the compensated stage that exceeds 12 years, whereas it is only 1.8 years in patients who develop decompensation.8 The Child-Turcotte-Pugh (CTP) classification has been used to stratify patients with cirrhosis. Patients with cirrhosis belonging to the CTP-A class are compensated, whereas those in the CTP-B/C class are mostly decompensated. PH is the initial and main consequence of cirrhosis and is responsible for the majority of its complications. In fact, it has been shown that portal pressure (PP), determined by the hepatic venous pressure gradient (HVPG), is better than liver biopsy in predicting development of complications of cirrhosis in patients with chronic liver disease (CLD) without cirrhosis on liver biopsy.9 Therefore, a new entity denominated compensated advanced chronic liver disease (cACLD) has been proposed, emphasizing that PH may occur before a formal anatomical diagnosis of cirrhosis is established.4 This entity would encompass patients with cirrhosis and those with advanced liver fibrosis with PH (HVPG > 5 mm Hg). For ease of understanding, in the rest of this guidance, the entity of cACLD will be referred to as compensated cirrhosis (CC), both terms being interchangeable and acceptable by consensus.4 The stage of CC is asymptomatic, and it is the longest stage. Pathophysiological mechanisms are evolving at this stage, and therefore several substages are being recognized. Based on PP, patients with CC can be divided into those with mild PH (HVPG > 5 but < 10 mm Hg) and those with clinically significant portal hypertension (CSPH), defined by an HVPG ≥10 mm Hg. CSPH is associated with an increased risk of developing varices,10 overt clinical decompensation (ascites, VH, and HE),11 postsurgical decompensation,12 and hepatocellular carcinoma (HCC).13 This substaging is not only prognostically important, but, as mentioned below, the mechanisms maintaining PH at these substages are different, and therefore their therapeutic approach will be different. CSPH is present in approximately 50%-60% of patients with CC without gastroesophageal varices (GEV).10 Patients with GEV have, by definition, CSPH, because patients with GEV have an HVPG of at least 10 mm Hg.14, 15 Prognosis is worse in patients with CC with GEV compared to those without GEV.16, 17 Therefore, among patients with CSPH, two substages are recognized based on the absence or presence of GEV. It is important to recognize that although PH and its direct consequences (varices) form the bases of staging in CC, liver insufficiency, even at this stage, plays an important role, given that serum albumin and the Model for End-Stage Liver Disease (MELD) score are also independent predictors of decompensation.11 VH constitutes a decompensating event, but its mortality differs whether it presents as an isolated complication of cirrhosis (20% 5-year mortality) or whether it presents in association with other complications (over 80% 5-year mortality).8 Whereas in the past, emphasis had been placed on managing the direct complications of PH, varices, and VH, it is now clear that these complications cannot be considered in an isolated manner. Rather, they should be considered in the context of advances in the staging of cirrhosis and in the context of other complications of cirrhosis that may occur concomitant or subsequent to development of varices and VH.4 Stages of PH in cirrhosis are depicted in Fig. 1, and goals of therapy at each stage are shown in Table 1. Stages and substages of cirrhosis. The two main stages are the compensated and decompensated stages. The latter is characterized by the presence of clinically overt complications: ascites, VH, or HE. The compensated stage is the longest stage, and it is asymptomatic. There are at least two main substages of compensated cirrhosis with different prognostic and predominant pathophysiological mechanisms: patients with mild PH and those with CSPH. Patients in the latter stage are at risk of developing decompensation, particularly those who have GEV. The decompensated stage is much shorter and can rapidly progress to a stage of further decompensation in which renal failure (HRS) and liver failure (encephalopathy and jaundice) develop, leading to a high mortality. GEV are present in approximately 50% of patients with cirrhosis, but this depends on the clinical stage. In patients with CC, GEV are present in 30%-40%, whereas they can be present in up to 85% of patients with decompensated cirrhosis.18, 19 In patients with CC, varices develop at a rate of 7%-8% per year,10 and progression from small to large varices occurs at a rate of 10%-12% per year, with decompensated cirrhosis being an independent predictor of progression.20 VH occurs at a rate of around 10%-15% per year and depends on the severity of liver disease, size of varices, and presence of red wale marks (areas of thinning of the variceal wall).21, 22 Six-week mortality, which is now recognized as the primary endpoint to assess the impact of therapies for acute VH,4 ranges between 15% and 25%.23-25 Other factors associated with poor outcomes in patients with VH are the presence of bacterial infections and an HVPG >20 mm Hg, which is mostly observed in patients belonging to the CTP-C class.26, 27 If untreated, recurrent VH occurs in 60% of patients, usually within 1-2 years of index hemorrhage.28 Obesity and alcohol use are associated conditions of prognostic relevance in patients with cirrhosis, independent of etiology. Obesity has been shown to predict worsening of liver fibrosis, cirrhosis decompensation, and lack of regression of cirrhosis in patients with viral cirrhosis,29-31 whereas even moderate alcohol intake can lead to worsening PP and has been shown to worsen prognosis of hepatitis C virus (HCV)- and nonalcoholic steatohepatitis (NASH)-related cirrhosis.32, 33 Therefore, although beyond the scope of this guidance, weight loss and alcohol abstinence are important considerations in patients with cirrhosis. PP increases initially as a consequence of an increased intrahepatic resistance to portal flow attributed to structural mechanisms (e.g., fibrous tissue, vascular distortion from regenerative nodules, and microthrombi; Fig. 2). This "structural" component, which explains around 70% of the increased intrahepatic resistance, could be targeted by treating the etiology of cirrhosis, the use of antifibrotic agents, and even anticoagulants.34 However, at least one third of the increased intrahepatic resistance is attributed to an increased intrahepatic vascular tone, which, in turn, is attributed to endothelial dysfunction resulting mostly from reduced nitric oxide (NO) bioavailability.35 This "functional" component is amenable to vasodilators (such as nitrates, alpha-adrenergic antagonists, and angiotensin-2 blockers).36 These drugs should not be used alone, given that they also cause systemic vasodilatation, decrease arterial blood pressure, and may worsen sodium retention. A conceptually more appealing approach to ameliorate the functional component is to use drugs that will reduce PP by improving endothelial dysfunction, such as statins.37 An added advantage of these drugs is that, by causing intrahepatic vasodilatation, they may improve hepatic blood flow and liver function. Statins in particular also have antifibrotic properties.34 Pathogenesis of PH and sites of action of currently recommended therapies to reduce PP or obliterate varices. In cirrhosis, PP increases initially as a consequence of an increased intrahepatic resistance to portal flow attributed to structural mechanisms (e.g., fibrous tissue, regenerative nodules) and an increased intrahepatic vascular tone (functional component). One of the initial consequences of PH is the formation of portosystemic collaterals. Concomitant or even preceding development of collaterals, splanchnic vasodilatation occurs, leading to increased flow into the gut and into the portal venous system. Vasodilation leads to activation of neurohumoral and vasoconstrictive systems, sodium and water retention, increased blood volume, and increased cardiac output; that is, a hyperdynamic circulatory state that further increases portal venous inflow and PP. Additionally, activated vasoconstrictive systems to further contribute to intrahepatic vasoconstriction. Treatment of etiology, by ameliorating fibrosis/inflammation, target the mechanical component of the increased intrahepatic resistance. Vasodilators (like the α-adrenergic blocking effect of carvedilol) target its functional component (this is the site of action of statins). NSBBs (β2-adrenergic blocking effect), SMT, and VP act by causing splanchnic vasoconstriction, thereby reducing portal venous inflow. NSBBs also act by decreasing cardiac output (β1-adrenergic blocking effect). The TIPS connects the hypertensive portal vein with a normotensive hepatic vein, thereby bypassing the site of increased resistance. Varices can be obliterated either endoscopically (EVL or cyanoacrylate injection) or by an endovascular approach (BRTO). One of the initial consequences of PH is the formation of portosystemic collaterals, the most important being those that develop through the coronary and/or short gastric veins and constitute GEV. Although formation of collaterals had been assumed to be the result of dilatation of preexisting vascular channels, research studies have implicated a process of neoangiogenesis.38 Concomitant or even preceding the development of collaterals, splanchnic vasodilatation occurs, leading to increased flow into the gut and into the portal venous system. Therefore, even when portal flow is entirely diverted through collaterals, PH persists.39 Increased splanchnic NO production is the main factor that leads to vasodilatation and increased splanchnic blood flow. Hyperglucagonemia and neoangiogenesis further contribute to the increased splanchnic blood flow that maintains the portal hypertensive state.38 Vasodilation occurs not only in the splanchnic, but also in the systemic circulation (manifested clinically as arterial hypotension), leading to activation of neurohumoral and vasoconstrictive systems, sodium and water retention, increased blood volume, and increased cardiac output, that is, a hyperdynamic circulatory state that further increases portal venous inflow and PP. Additionally, norepinephrine, angiotensin-2, and antidiuretic hormone (activated neurohumoral and vasoconstrictive systems) further contribute to intrahepatic vasoconstriction. Drugs that act by causing splanchnic vasoconstriction, such as non-selective beta-blockers (NSBBs; propranolol, nadolol, and carvedilol), vasopressin (VP), and its analogue, terlipressin, and somatostatin (SMT) and its analogues (octreotide, vapreotide) are known to reduce PP and constitute the current mainstay in the treatment of varices and VH. Given that these drugs act by decreasing flow to the splanchnic circulation and liver, an improvement in liver function would not be expected. β-1 adrenergic blockade decreases portal flow through a decrease in cardiac output, and β-2 blockade decreases portal flow through splanchnic vasoconstriction by unopposed α-adrenergic activity. Therefore, it is essential that beta-blockers used in the treatment of PH be nonselective. Importantly, the effect of NSBBs in decreasing flow is more related to their β-2 blocking effect rather than to their β-1 effect40 and explains the lack of correlation between decreases in PP and decreases in heart rate.41 Carvedilol, an NSBB with anti-α1 adrenergic (vasodilator) activity, acts as an NSBB decreasing portal flow, but also acts as a vasodilator (intrahepatic circulation). HVPG response is greater with carvedilol than with propranolol or nadolol, but, given its vasodilatory properties, carvedilol is associated with a greater decrease in mean arterial pressure (MAP).42 It has been recently shown that patients with mild PH (HVPG > 5 but < 10 mm Hg) have a normal cardiac index (i.e., they have not yet developed the hyperdynamic circulatory state), whereas those with CSPH, especially if varices are present, have already developed a hyperdynamic state. Accordingly, response to NSBB in patients with mild PH is suboptimal compared to that of those with CSPH,43 indicating that there is no role for NSBB in the setting of mild PH. Endoscopic variceal ligation (EVL) is a local therapy that consists of placing rubber bands around esophageal varices (EV) in repeated sessions until they become obliterated. Because it is a local therapy that has no effect on PH, recurrence of varices is the rule, and patients require indefinite endoscopic monitoring. Local therapies for management of gastric (mostly cardiofundal) varices consist of the (1) transendoscopic obturation by injection of cyanoacrylate glue into the varices or (2) transvenous obliteration by instillment of sclerosants and/or liquid embolic agents into a gastro-/splenorenal collateral through the left renal vein aided by balloon occlusion, that is, balloon occluded retrograde transvenous obliteration (BRTO).44 In patients with decompensated cirrhosis, placement of the transjugular intrahepatic portosystemic shunt (TIPS) by interventional radiological techniques that consist of connecting the hypertensive portal vein with a normotensive hepatic vein by a coated stent causes a significant decrease, and even normalization, of PP. Therefore, in patients with functional TIPS stents, there is no need for other therapies for PH (e.g., NSBB, EVL). PH is defined as a portal pressure gradient (the difference in pressure between the portal vein and the hepatic veins) greater than 5 mm Hg. The best method to assess PP is through the catheterization of the hepatic vein with determination, through a balloon catheter, of the HVPG, which is the difference between the wedged (or occluded) hepatic venous pressure and the free hepatic venous pressure.45 Normal HVPG is 3-5 mm Hg. It should be underlined that the wedged (occluded) pressure (and, consequently, the HVPG) is a measure of sinusoidal pressure and does not provide useful data in prehepatic or presinusoidal PH (Table 2). An HVPG over 5 mm Hg identifies patients with cACLD/CC secondary to conditions associated with sinusoidal hypertension (Table 2). As mentioned above, PH is further defined as mild PH (HVPG > 5 but < 10 mm Hg) and as CSPH (HVPG ≥ 10 mm Hg). Above this threshold of 10 mm Hg, all the complications of PH are more likely to appear (varices, clinical decompensation). In patients with GEV (who, by definition, have CSPH), an HVPG > 12 mm Hg identifies bleeding risk, mostly because there is clear evidence that shows that reducing the HVPG to levels of 12 mm Hg or below is associated with protection from variceal hemorrhage (VH).28 An HVPG > 16 mm Hg indicates a higher risk of death.46 As mentioned previously, an HVPG ≥20 mm Hg predicts failure to control bleeding, early rebleeding, and death during acute VH,27, 47 and in patients with cirrhosis awaiting liver transplantation, each 1-mm-Hg increase in HVPG predicts a 3% increase in the risk of death in a median follow-up of 19 months.48 Despite the crucial role of HVPG in the determination of CSPH and other outcomes, HVPG measurements require specific expertise, are invasive, relatively expensive, and not available in all centers. Therefore, HVPG measurements are not considered standard of care for every patient with cirrhosis, particularly because noninvasive or surrogate indicators are increasingly utilized at most centers. In a step-wise diagnostic approach, specific signs of PH should be first looked for on physical examination. They include spider nevi or visible abdominal portosystemic collaterals. The absence of physical signs cannot be used to rule out CSPH. Among laboratory data, a low platelet count is the most common laboratory sign of PH; it correlates slightly with HVPG and with the presence of GEV. However, taken alone, it is not to either or CSPH or GEV. the other the of platelet count with other noninvasive the noninvasive diagnosis of provides and evidence of associated with cirrhosis and PH. The presence of circulation on or vein, and left and short gastric veins) or the of a of flow within the portal is specific for and is to CSPH. other signs of PH have been such as dilatation of portal vein and the of portal vein (or their as index of the portal Although taken is a but sign of PH, the size of the should be when with platelet count and liver it provides data on the presence of The to assess liver a physical of liver by the of liver fibrosis has a major in this by has for patients with and without CSPH, with a mean the of in a recent on studies and can be currently considered the of the noninvasive diagnosis of PH. However, most of the data have been in patients with viral cirrhosis and cirrhosis. other and data in patients who have require further studies have shown that the best to CSPH is with a diagnostic over In a prospective HVPG ≥10 mm Hg and were in predicting In a large an size count > specific in in CSPH with a of Importantly, these have to be considered in the context of clinical In this a recent prospective a based on measurements in the context of the presence of and/or a platelet count and the of patients with CC in CSPH would be more by has been recently as a more related to PH, with In fact, > better than and to HVPG in predicting first clinical decompensation in one However, cannot be by without a and cannot be if the is not Therefore, measurements by cannot be recommended in clinical direct of the liver and is but and results with higher and in the of CSPH. is an that provides data on and of much of the liver and compared to Although has been shown to be in the staging of liver data its diagnostic in the diagnosis of CSPH are with one that determined by of clinical decompensation in patients with studies are needed in this the presence and size of varices and presence of red wale marks an and that is not free of studies have looked for noninvasive of the presence of varices varices, those so as to the need for The of in predicting the presence of GEV is between and and the use of to GEV is not However, are to rule out varices in patients with In with platelet count identifies patients at low risk of These data have been mostly from patients with viral cirrhosis. in patients with cirrhosis, liver disease, and in those with cirrhosis response are consensus among and review of the it that patients with CC with by and a platelet count were to have varices and could be in studies have these and that of can be In patients with cirrhosis secondary to hepatitis an size count < in out this can be to patients with cirrhosis attributed to other to be Because measurements of are more with of this is a in and out varices and to other in data in and American patients are Patients without evidence of CSPH should be to of the if data on this specific are data from published that and platelet count could be The of new portosystemic collaterals during follow-up has been shown to be associated with variceal formation and as is Therefore, when for evidence of worsening PH should be Patients without varices on constitute an of given that their has not yet been particularly with the of therapies that the that if liver is (e.g., in and lack of in and/or of disease are present (e.g., should be repeated at in the absence of are considered Although there are no data to if several of are for varices. In patients with small varices on who are not for primary is It has been that if the liver is (e.g., in and lack of in and/or of disease are present (e.g., should be repeated at in the absence of are considered Because development of decompensation could worsening of PH and liver dysfunction with a higher of cirrhosis, patients with no or small varices on should have a when and if decompensation in HVPG, or during have been shown to be of In patients with a of VH, a decrease in HVPG to than 12 mm Hg or a decrease greater than from the risk of recurrent ascites, and In patients with CC, in HVPG from have been associated with a in development of varices,10 first VH, and studies that the need for HVPG to assess response to therapy can be by the acute response to propranolol during a single but this further there have been no (e.g., that with changes in As mentioned above, therapy of varices and VH should be to the different clinical stages of cirrhosis and PH that are shown in Table 1. The of therapy for patients at an early stage is to the development of stages. Varices and VH should be managed in the context of the presence (or of other complications of (e.g., ascites, and therefore the or of the patient with should be considered in the of the different In the compensated the is to that is, the is not only to varices or VH, but also to the other complications of cirrhosis. In to specific therapies that will be below, in the compensated every should be taken to the and to associated such as and liver given that these in can decrease portal pressure and reduce the risk of This stage is defined by an HVPG but < 10 mm Hg. Patients in this stage not have varices or