Hôpital Européen

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,

BACKGROUND: Since sunitinib malate has shown activity in two uncontrolled studies in patients with metastatic renal-cell carcinoma, a comparison of the drug with interferon alfa in a phase 3 trial is warranted. METHODS: We enrolled 750 patients with previously untreated, metastatic renal-cell carcinoma in a multicenter, randomized, phase 3 trial to receive either repeated 6-week cycles of sunitinib (at a dose of 50 mg given orally once daily for 4 weeks, followed by 2 weeks without treatment) or interferon alfa (at a dose of 9 MU given subcutaneously three times weekly). The primary end point was progression-free survival. Secondary end points included the objective response rate, overall survival, patient-reported outcomes, and safety. RESULTS: The median progression-free survival was significantly longer in the sunitinib group (11 months) than in the interferon alfa group (5 months), corresponding to a hazard ratio of 0.42 (95% confidence interval, 0.32 to 0.54; P<0.001). Sunitinib was also associated with a higher objective response rate than was interferon alfa (31% vs. 6%, P<0.001). The proportion of patients with grade 3 or 4 treatment-related fatigue was significantly higher in the group treated with interferon alfa, whereas diarrhea was more frequent in the sunitinib group (P<0.05). Patients in the sunitinib group reported a significantly better quality of life than did patients in the interferon alfa group (P<0.001). CONCLUSIONS: Progression-free survival was longer and response rates were higher in patients with metastatic renal-cell cancer who received sunitinib than in those receiving interferon alfa (ClinicalTrials.gov numbers, NCT00098657 and NCT00083889 [ClinicalTrials.gov]).

BACKGROUND: Mitoxantrone plus prednisone reduces pain and improves the quality of life in men with advanced, hormone-refractory prostate cancer, but it does not improve survival. We compared such treatment with docetaxel plus prednisone in men with this disease. METHODS: From March 2000 through June 2002, 1006 men with metastatic hormone-refractory prostate cancer received 5 mg of prednisone twice daily and were randomly assigned to receive 12 mg of mitoxantrone per square meter of body-surface area every three weeks, 75 mg of docetaxel per square meter every three weeks, or 30 mg of docetaxel per square meter weekly for five of every six weeks. The primary end point was overall survival. Secondary end points were pain, prostate-specific antigen (PSA) levels, and the quality of life. All statistical comparisons were against mitoxantrone. RESULTS: As compared with the men in the mitoxantrone group, men in the group given docetaxel every three weeks had a hazard ratio for death of 0.76 (95 percent confidence interval, 0.62 to 0.94; P=0.009 by the stratified log-rank test) and those given weekly docetaxel had a hazard ratio for death of 0.91 (95 percent confidence interval, 0.75 to 1.11; P=0.36). The median survival was 16.5 months in the mitoxantrone group, 18.9 months in the group given docetaxel every 3 weeks, and 17.4 months in the group given weekly docetaxel. Among these three groups, 32 percent, 45 percent, and 48 percent of men, respectively, had at least a 50 percent decrease in the serum PSA level (P<0.001 for both comparisons with mitoxantrone); 22 percent, 35 percent (P=0.01), and 31 percent (P=0.08) had predefined reductions in pain; and 13 percent, 22 percent (P=0.009), and 23 percent (P=0.005) had improvements in the quality of life. Adverse events were also more common in the groups that received docetaxel. CONCLUSIONS: When given with prednisone, treatment with docetaxel every three weeks led to superior survival and improved rates of response in terms of pain, serum PSA level, and quality of life, as compared with mitoxantrone plus prednisone.

BACKGROUND: We conducted a phase 3, randomized, double-blind, placebo-controlled trial of sorafenib, a multikinase inhibitor of tumor-cell proliferation and angiogenesis, in patients with advanced clear-cell renal-cell carcinoma. METHODS: From November 2003 to March 2005, we randomly assigned 903 patients with renal-cell carcinoma that was resistant to standard therapy to receive either continuous treatment with oral sorafenib (at a dose of 400 mg twice daily) or placebo; 451 patients received sorafenib and 452 received placebo. The primary end point was overall survival. A single planned analysis of progression-free survival in January 2005 showed a statistically significant benefit of sorafenib over placebo. Consequently, crossover was permitted from placebo to sorafenib, beginning in May 2005. RESULTS: At the January 2005 cutoff, the median progression-free survival was 5.5 months in the sorafenib group and 2.8 months in the placebo group (hazard ratio for disease progression in the sorafenib group, 0.44; 95% confidence interval [CI], 0.35 to 0.55; P<0.01). The first interim analysis of overall survival in May 2005 showed that sorafenib reduced the risk of death, as compared with placebo (hazard ratio, 0.72; 95% CI, 0.54 to 0.94; P=0.02), although this benefit was not statistically significant according to the O'Brien-Fleming threshold. Partial responses were reported as the best response in 10% of patients receiving sorafenib and in 2% of those receiving placebo (P<0.001). Diarrhea, rash, fatigue, and hand-foot skin reactions were the most common adverse events associated with sorafenib. Hypertension and cardiac ischemia were rare serious adverse events that were more common in patients receiving sorafenib than in those receiving placebo. CONCLUSIONS: As compared with placebo, treatment with sorafenib prolongs progression-free survival in patients with advanced clear-cell renal-cell carcinoma in whom previous therapy has failed; however, treatment is associated with increased toxic effects. (ClinicalTrials.gov number, NCT00073307 [ClinicalTrials.gov].).

Cell death can be executed through different subroutines. Since the description of ferroptosis as an iron-dependent form of non-apoptotic cell death in 2012, there has been mounting interest in the process and function of ferroptosis. Ferroptosis can occur through two major pathways, the extrinsic or transporter-dependent pathway and the intrinsic or enzyme-regulated pathway. Ferroptosis is caused by a redox imbalance between the production of oxidants and antioxidants, which is driven by the abnormal expression and activity of multiple redox-active enzymes that produce or detoxify free radicals and lipid oxidation products. Accordingly, ferroptosis is precisely regulated at multiple levels, including epigenetic, transcriptional, posttranscriptional and posttranslational layers. The transcription factor NFE2L2 plays a central role in upregulating anti-ferroptotic defense, whereas selective autophagy may promote ferroptotic death. Here, we review current knowledge on the integrated molecular machinery of ferroptosis and describe how dysregulated ferroptosis is involved in cancer, neurodegeneration, tissue injury, inflammation, and infection.

Antibodies targeting CTLA-4 have been successfully used as cancer immunotherapy. We find that the antitumor effects of CTLA-4 blockade depend on distinct Bacteroides species. In mice and patients, T cell responses specific for B. thetaiotaomicron or B. fragilis were associated with the efficacy of CTLA-4 blockade. Tumors in antibiotic-treated or germ-free mice did not respond to CTLA blockade. This defect was overcome by gavage with B. fragilis, by immunization with B. fragilis polysaccharides, or by adoptive transfer of B. fragilis-specific T cells. Fecal microbial transplantation from humans to mice confirmed that treatment of melanoma patients with antibodies against CTLA-4 favored the outgrowth of B. fragilis with anticancer properties. This study reveals a key role for Bacteroidales in the immunostimulatory effects of CTLA-4 blockade.

Depending on the initiating stimulus, cancer cell death can be immunogenic or nonimmunogenic. Immunogenic cell death (ICD) involves changes in the composition of the cell surface as well as the release of soluble mediators, occurring in a defined temporal sequence. Such signals operate on a series of receptors expressed by dendritic cells to stimulate the presentation of tumor antigens to T cells. We postulate that ICD constitutes a prominent pathway for the activation of the immune system against cancer, which in turn determines the long-term success of anticancer therapies. Hence, suboptimal regimens (failing to induce ICD), selective alterations in cancer cells (preventing the emission of immunogenic signals during ICD), or defects in immune effectors (abolishing the perception of ICD by the immune system) can all contribute to therapeutic failure. We surmise that ICD and its subversion by pathogens also play major roles in antiviral immune responses.

Interferons interfere with lung repair Interferons (IFNs) are central to antiviral immunity. Viral recognition elicits IFN production, which in turn triggers the transcription of IFN-stimulated genes (ISGs), which engage in various antiviral functions. Type I IFNs (IFN-α and IFN-β) are widely expressed and can result in immunopathology during viral infections. By contrast, type III IFN (IFN-λ) responses are primarily restricted to mucosal surfaces and are thought to confer antiviral protection without driving damaging proinflammatory responses. Accordingly, IFN-λ has been proposed as a therapeutic in coronavirus disease 2019 (COVID-19) and other such viral respiratory diseases (see the Perspective by Grajales-Reyes and Colonna). Broggi et al. report that COVID-19 patient morbidity correlates with the high expression of type I and III IFNs in the lung. Furthermore, IFN-λ secreted by dendritic cells in the lungs of mice exposed to synthetic viral RNA causes damage to the lung epithelium, which increases susceptibility to lethal bacterial superinfections. Similarly, using a mouse model of influenza infection, Major et al. found that IFN signaling (especially IFN-λ) hampers lung repair by inducing p53 and inhibiting epithelial proliferation and differentiation. Complicating this picture, Hadjadj et al. observed that peripheral blood immune cells from severe and critical COVID-19 patients have diminished type I IFN and enhanced proinflammatory interleukin-6– and tumor necrosis factor-α–fueled responses. This suggests that in contrast to local production, systemic production of IFNs may be beneficial. The results of this trio of studies suggest that the location, timing, and duration of IFN exposure are critical parameters underlying the success or failure of therapeutics for viral respiratory infections. Science , this issue p. 706 , p. 712 , p. 718 ; see also p. 626

Ventilator-associated pneumonia (VAP) continues to complicate the course of 8 to 28% of patients receiving mechanical ventilation (MV). In contrast to infections of more frequently involved organs (e.g., urinary tract and skin), for which mortality is low, ranging from 1 to 4%, the mortality rate for VAP ranges from 24 to 50% and can reach 76% in some specific settings or when lung infection is caused by high-risk pathogens. The predominant organisms responsible for infection are Staphylococcus aureus, Pseudomonas aeruginosa, and Enterobacteriaceae, but etiologic agents widely differ according to the population of patients in an intensive care unit, duration of hospital stay, and prior antimicrobial therapy. Because appropriate antimicrobial treatment of patients with VAP significantly improves outcome, more rapid identification of infected patients and accurate selection of antimicrobial agents represent important clinical goals. Our personal bias is that using bronchoscopic techniques to obtain protected brush and bronchoalveolar lavage specimens from the affected area in the lung permits physicians to devise a therapeutic strategy that is superior to one based only on clinical evaluation. When fiberoptic bronchoscopy is not available to physicians treating patients clinically suspected of having VAP, we recommend using either a simplified nonbronchoscopic diagnostic procedure or following a strategy in which decisions regarding antibiotic therapy are based on a clinical score constructed from seven variables. Selection of the initial antimicrobial therapy should be based on predominant flora responsible for VAP at each institution, clinical setting, information provided by direct examination of pulmonary secretions, and intrinsic antibacterial activities of antimicrobial agents and their pharmacokinetic characteristics. Further trials will be needed to clarify the optimal duration of treatment and the circumstances in which monotherapy can be safely used.

: Document reviewers: Guy De Backer (ESC Review Co-ordinator) (Belgium), Anthony M. Heagerty (ESH Review Co-ordinator) (UK), Stefan Agewall (Norway), Murielle Bochud (Switzerland), Claudio Borghi (Italy), Pierre Boutouyrie (France), Jana Brguljan (Slovenia), Héctor Bueno (Spain), Enrico G. Caiani (Italy), Bo Carlberg (Sweden), Neil Chapman (UK), Renata Cifkova (Czech Republic), John G. F. Cleland (UK), Jean-Philippe Collet (France), Ioan Mircea Coman (Romania), Peter W. de Leeuw (The Netherlands), Victoria Delgado (The Netherlands), Paul Dendale (Belgium), Hans-Christoph Diener (Germany), Maria Dorobantu (Romania), Robert Fagard (Belgium), Csaba Farsang (Hungary), Marc Ferrini (France), Ian M. Graham (Ireland), Guido Grassi (Italy), Hermann Haller (Germany), F. D. Richard Hobbs (UK), Bojan Jelakovic (Croatia), Catriona Jennings (UK), Hugo A. Katus (Germany), Abraham A. Kroon (The Netherlands), Christophe Leclercq (France), Dragan Lovic (Serbia), Empar Lurbe (Spain), Athanasios J. Manolis (Greece), Theresa A. McDonagh (UK), Franz Messerli (Switzerland), Maria Lorenza Muiesan (Italy), Uwe Nixdorff (Germany), Michael Hecht Olsen (Denmark), Gianfranco Parati (Italy), Joep Perk (Sweden), Massimo Francesco Piepoli (Italy), Jorge Polonia (Portugal), Piotr Ponikowski (Poland), Dimitrios J. Richter (Greece), Stefano F. Rimoldi (Switzerland), Marco Roffi (Switzerland), Naveed Sattar (UK), Petar M. Seferovic (Serbia), Iain A. Simpson (UK), Miguel Sousa-Uva (Portugal), Alice V. Stanton (Ireland), Philippe van de Borne (Belgium), Panos Vardas (Greece), Massimo Volpe (Italy), Sven Wassmann (Germany), Stephan Windecker (Switzerland), Jose Luis Zamorano (Spain).The disclosure forms of all experts involved in the development of these Guidelines are available on the ESC website www.escardio.org/guidelines.

OBJECTIVE: The aim was to formulate clinical practice guidelines for pheochromocytoma and paraganglioma (PPGL). PARTICIPANTS: The Task Force included a chair selected by the Endocrine Society Clinical Guidelines Subcommittee (CGS), seven experts in the field, and a methodologist. The authors received no corporate funding or remuneration. EVIDENCE: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence. The Task Force reviewed primary evidence and commissioned two additional systematic reviews. CONSENSUS PROCESS: One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of the Endocrine Society, European Society of Endocrinology, and Americal Association for Clinical Chemistry reviewed drafts of the guidelines. CONCLUSIONS: The Task Force recommends that initial biochemical testing for PPGLs should include measurements of plasma free or urinary fractionated metanephrines. Consideration should be given to preanalytical factors leading to false-positive or false-negative results. All positive results require follow-up. Computed tomography is suggested for initial imaging, but magnetic resonance is a better option in patients with metastatic disease or when radiation exposure must be limited. (123)I-metaiodobenzylguanidine scintigraphy is a useful imaging modality for metastatic PPGLs. We recommend consideration of genetic testing in all patients, with testing by accredited laboratories. Patients with paraganglioma should be tested for SDHx mutations, and those with metastatic disease for SDHB mutations. All patients with functional PPGLs should undergo preoperative blockade to prevent perioperative complications. Preparation should include a high-sodium diet and fluid intake to prevent postoperative hypotension. We recommend minimally invasive adrenalectomy for most pheochromocytomas with open resection for most paragangliomas. Partial adrenalectomy is an option for selected patients. Lifelong follow-up is suggested to detect recurrent or metastatic disease. We suggest personalized management with evaluation and treatment by multidisciplinary teams with appropriate expertise to ensure favorable outcomes.

The anti-epidermal growth factor receptor (anti-EGFR) cetuximab has been proven to be efficient in metastatic colorectal cancer. The molecular mechanisms underlying the clinical response to this drug remain unknown. Genetic alterations of the intracellular effectors involved in EGFR-related signaling pathways may have an effect on response to this targeted therapy. In this study, tumors from 30 metastatic colorectal cancer patients treated by cetuximab were screened for KRAS, BRAF, and PIK3CA mutation by direct sequencing and for EGFR copy number by chromogenic in situ hybridization. Eleven of the 30 patients (37%) responded to cetuximab. A KRAS mutation was found in 13 tumors (43%) and was significantly associated with the absence of response to cetuximab (KRAS mutation in 0% of the 11 responder patients versus 68.4% of the 19 nonresponder patients; P = 0.0003). The overall survival of patients without KRAS mutation in their tumor was significantly higher compared with those patients with a mutated tumor (P = 0.016; median, 16.3 versus 6.9 months). An increased EGFR copy number was found in 3 patients (10%) and was significantly associated with an objective tumor response to cetuximab (P = 0.04). In conclusion, in this study, KRAS mutations are a predictor of resistance to cetuximab therapy and are associated with a worse prognosis. The EGFR amplification, which is not as frequent as initially reported, is also associated with response to this treatment.

Cyclophosphamide is one of several clinically important cancer drugs whose therapeutic efficacy is due in part to their ability to stimulate antitumor immune responses. Studying mouse models, we demonstrate that cyclophosphamide alters the composition of microbiota in the small intestine and induces the translocation of selected species of Gram-positive bacteria into secondary lymphoid organs. There, these bacteria stimulate the generation of a specific subset of "pathogenic" T helper 17 (pT(H)17) cells and memory T(H)1 immune responses. Tumor-bearing mice that were germ-free or that had been treated with antibiotics to kill Gram-positive bacteria showed a reduction in pT(H)17 responses, and their tumors were resistant to cyclophosphamide. Adoptive transfer of pT(H)17 cells partially restored the antitumor efficacy of cyclophosphamide. These results suggest that the gut microbiota help shape the anticancer immune response.

The currently used classification reflects our understanding of the pathogenesis of the various forms of lupus nephritis, but clinicopathologic studies have revealed the need for improved categorization and terminology. Based on the 1982 classification published under the auspices of the World Health Organization (WHO) and subsequent clinicopathologic data, we propose that class I and II be used for purely mesangial involvement (I, mesangial immune deposits without mesangial hypercellularity; II, mesangial immune deposits with mesangial hypercellularity); class III for focal glomerulonephritis (involving <50% of total number of glomeruli) with subdivisions for active and sclerotic lesions; class IV for diffuse glomerulonephritis (involving > or = 50% of total number of glomeruli) either with segmental (class IV-S) or global (class IV-G) involvement, and also with subdivisions for active and sclerotic lesions; class V for membranous lupus nephritis; and class VI for advanced sclerosing lesions]. Combinations of membranous and proliferative glomerulonephritis (i.e., class III and V or class IV and V) should be reported individually in the diagnostic line. The diagnosis should also include entries for any concomitant vascular or tubulointerstitial lesions. One of the main advantages of the current revised classification is that it provides a clear and unequivocal description of the various lesions and classes of lupus nephritis, allowing a better standardization and lending a basis for further clinicopathologic studies. We hope that this revision, which evolved under the auspices of the International Society of Nephrology and the Renal Pathology Society, will contribute to further advancement of the WHO classification.

These practice guidelines on the management of arterial hypertension are a concise summary of the more extensive ones prepared by a Task Force jointly appointed by the European Society of Hypertension and the European Society of Cardiology. These guidelines have been prepared on the basis of the best available evidence on all issues deserving recommendations; their role must be educational and not prescriptive or coercive for the management of individual subjects who may differ widely in their personal, medical and cultural characteristics. The members of the Task Force have participated independently in the preparation of these guidelines, drawing on their academic and clinical experience and by objective examination and interpretation of all available literature. A disclosure of their potential con?ict of interest is reported on the websites of the ESH and the ESC

BACKGROUND: In patients who have chronic heart failure with reduced left ventricular ejection fraction, severe secondary mitral-valve regurgitation is associated with a poor prognosis. Whether percutaneous mitral-valve repair improves clinical outcomes in this patient population is unknown. METHODS: or a regurgitant volume of >30 ml per beat), a left ventricular ejection fraction between 15 and 40%, and symptomatic heart failure, in a 1:1 ratio, to undergo percutaneous mitral-valve repair in addition to receiving medical therapy (intervention group; 152 patients) or to receive medical therapy alone (control group; 152 patients). The primary efficacy outcome was a composite of death from any cause or unplanned hospitalization for heart failure at 12 months. RESULTS: At 12 months, the rate of the primary outcome was 54.6% (83 of 152 patients) in the intervention group and 51.3% (78 of 152 patients) in the control group (odds ratio, 1.16; 95% confidence interval [CI], 0.73 to 1.84; P=0.53). The rate of death from any cause was 24.3% (37 of 152 patients) in the intervention group and 22.4% (34 of 152 patients) in the control group (hazard ratio, 1.11; 95% CI, 0.69 to 1.77). The rate of unplanned hospitalization for heart failure was 48.7% (74 of 152 patients) in the intervention group and 47.4% (72 of 152 patients) in the control group (hazard ratio, 1.13; 95% CI, 0.81 to 1.56). CONCLUSIONS: Among patients with severe secondary mitral regurgitation, the rate of death or unplanned hospitalization for heart failure at 1 year did not differ significantly between patients who underwent percutaneous mitral-valve repair in addition to receiving medical therapy and those who received medical therapy alone. (Funded by the French Ministry of Health and Research National Program and Abbott Vascular; MITRA-FR ClinicalTrials.gov number, NCT01920698 .).

Abbreviations ACE: angiotensin-converting enzyme; BP: blood pressure; DBP: diastolic blood pressure; eGFR: estimated glomerular filtration rate; ESC: European Society of Cardiology; ESH: European Society of Hypertension; ET: endothelin; IMT: carotid intima-media thickness; JNC: Joint National Committee; LVH: left ventricular hypertrophy; LVM: left ventricular mass; PDE-5: phosphodiesterase-5; PPAR-γ: peroxisome proliferators-activated receptor-γ; PWV: pulse wave velocity; SBP: systolic blood pressure; WHO: World Health Organization. Introduction In the 2 years since the publication of the 2007 guidelines for the management of arterial hypertension of the European Society of Hypertension (ESH) and the European Society of Cardiology (ESC) [1], research on hypertension has actively been pursued and the results of new important studies (including several large randomized trials of antihypertensive therapy) have been published. Some of these studies have reinforced the evidence on which the recommendations of the 2007 ESH/ESC guidelines were based. However, other studies have widened the information available in 2007, modifying some of the previous concepts, and suggesting that new evidence-based recommendations could be appropriate. The aim of this document of the ESH is to address a number of studies on hypertension published in the last 2 years in order to assess their contribution to our expanding knowledge of hypertension. Furthermore, some critical appraisal of the current recommendations of the ESH/ESC, as well as of other guidelines, might be a useful step toward the preparation of a third version of the European guidelines in the future. The most important conclusions are summarized in boxes. The points that will be discussed are reported in Box 1.Box. 1Assessment of subclinical organ damage for stratification of total cardiovascular risk The 2007 ESH/ESC guidelines recommend total cardiovascular risk be evaluated in each patient to decide about important aspects of treatment: the blood pressure (BP) threshold at which to commence drug administration, the target BP to be reached by treatment, the use of two-drug combinations as the initial treatment step, and the possible addition to the antihypertensive treatment regimen of lipid-lowering and antiplatelet agents [1]. Among the criteria to assess total cardiovascular risk, the European guidelines consider subclinical organ damage to be a very important component, because asymptomatic alterations of the cardiovascular system and the kidney are crucial intermediate stages in the disease continuum that links risk factors such as hypertension to cardiovascular events and death. On the basis of a number of criteria (prognostic importance, prevalence in the population, availability and cost of the assessment procedures, etc.), the 2007 European guidelines considered detection of organ damage as important for the diagnostic and prognostic evaluation of hypertensive patients. They further subdivided the different types of organ damage into (1) those that can be identified by relatively simple and cheap procedures [electrocardiogram, serum creatinine, estimated glomerular filtration rate (eGFR), and measurement of urinary protein excretion in order to detect microalbuminuria or proteinuria], which were thus regarded as suitable for routine search in the whole hypertensive population, and (2) those that require more complex procedures or instrumentations (echocardiogram, carotid ultrasonography, pulse wave velocity), which were for this reason only recommended for a more in-depth characterization of the hypertensive patient. Since then, other studies have added useful information on the importance of detecting subclinical organ damage in the hypertensive population, strengthening the recommendation to use the most easily available and the least costly procedures in the routine examination of individuals with hypertension. Heart A few recent papers have revived interest in the power of the electrocardiogram to predict the risk of cardiovascular events. In a prospective survey including 7495 American adults, a new indicator of left ventricular hypertrophy (LVH), the Novacode estimate of left ventricular mass index that is based on both voltage and strain pattern criteria, has been reported to be significantly related to 10-year cardiovascular mortality [2]. The relation remained significant after adjusting for age, SBP, smoking, cholesterol, and diabetes. Furthermore, in the LIFE trial, the investigators have reported that in hypertensive patients with electrocardiographic LVH, left bundle branch block identifies individuals at increased risk of cardiovascular mortality (hazard ratio 1.6), sudden cardiovascular death (hazard ratio 3.5), and hospitalization for heart failure (hazard ratio 1.7) [3]. Finally, a very recent prospective study [4] focused on the R-wave voltage in lead aVL as being rather closely associated with left ventricular mass (LVM), and additionally predictive of incident cardiovascular events even when hypertension is not accompanied by electrocardiographic LVH (9% higher risk for each 0.1 mV higher R-wave). Additional evidence is also available on the predictive power of cardiac abnormalities, as detected by echocardiography, an approach of continuing interest because of its ability to more directly and precisely quantify LVM and geometric LVH patterns. A retrospective study has recently updated information from more than 35 000 normotensive and hypertensive participants with normal left ventricular ejection fraction [5]. Despite normal left ventricular function, an abnormal left ventricular geometric pattern was found in 46% of the patients (35% left ventricular concentric remodeling and 11% LVH), and the associated risk of all-cause mortality was twice as large as that of patients with normal left ventricular geometry. Although in another study on an African–American population, the relationship between left ventricular geometric patterns and all-cause mortality was markedly attenuated after adjusting for baseline variables, and remained significant only in men [6], the increased risk associated with LVH has been confirmed by other observations. In a prospective study on a cohort of 1652 Greek hypertensive patients followed up for 6 years, echocardiographic LVH was significantly associated with either a composite of all-cause mortality and cardiovascular events (hazard ratio 1.53) and with stroke (hazard ratio 2.01), after adjustment for major cardiovascular risk factors [7]. Furthermore, a retrospective analysis of 1447 Japanese hypertensive patients who participated in the CASE-J trial showed that cardiovascular events occurred about 2.6 times more frequently in patients with a LVM index 125 g/m2 or more compared with those with a LVM index below this value [8]. Finally, in the PAMELA population, echocardiographic LVH was associated with a four-fold to five-fold significant increase in cardiovascular morbidity and mortality when data were adjusted for a large number of potential confounders, including office, home, and ambulatory BP values. A 10% increase in LVM increased the risk more markedly when baseline LVM was already abnormal, but an increasing risk was evident also when calculated from LVM values within the normal range [9]. Blood vessels The relationship of carotid intima–media thickness (IMT) and plaques with subsequent cardiovascular events, already discussed in the 2007 guidelines, has been further strengthened by data from ELSA [10], which have shown that baseline carotid IMT predicts cardiovascular events independent of BP (clinic and ambulatory) and this occurs both for the IMT value at the carotid bifurcations and for the IMT value at the level of the common carotid artery. This suggests that both atherosclerosis (reflected by the IMT value at the bifurcations) and vascular hypertrophy (reflected by the common carotid IMT) exert an adverse prognostic effect in addition to that of high BP. An adverse prognostic significance of carotid plaques (hazard ratio 2.3) has also been reported in a sample of residents of the Copenhagen County free of overt cardiovascular disease, which was prospectively followed for about 13 years [11]. Evidence has also accrued on the adverse prognostic value of arterial stiffening. In the Copenhagen County population, an increased pulse wave velocity (PWV >12 m/s) was associated with a 50% increase in the risk of a cardiovascular event [11]. Furthermore, an independent predictive value of PWV for cardiovascular events has been shown in Japanese men followed for 8.2 years [12]. Finally, indirect indices of aortic stiffness and wave reflection, such as central BP and augmentation index, have been confirmed as independent predictors of cardiovascular events in two recent studies [13,14]. In particular, in one of these studies of 1272 normotensive and untreated hypertensive patients, only central SBP consistently and independently predicted cardiovascular mortality after adjustment for various cardiovascular risk factors, including LVM and carotid IMT [14]. However, it should be emphasized that in most available studies, the additive predictive value of central BP beyond brachial pressure appears limited, which leaves the question whether central BP measurements should be regularly considered in the clinical profiling of hypertensive patients in need of further investigation. Kidney Several new data [15] reinforce the already solid evidence on the prognostic value of eGFR that was available at the time of the 2007 guidelines [1]. In the population of Gubbio (Italy), an eGFR in the lowest decile was associated with a significantly higher incidence of cardiovascular events (hazard ratio 2.14) [16], and in the above-mentioned Greek study [7], an eGFR between 15 and 59 ml/min per 1.73 m2 was associated with a 66% increase in the composite endpoint of all cause mortality and cardiovascular events after adjustment for baseline cardiovascular risk and independent of LVH [7]. Likewise, in a post hoc analysis of data from the VALUE trial [17], eGFR according to the MDRD formula was significantly predictive of all outcomes except stroke (with hazard ratios between 1.23 and 1.70 according to the different outcomes) and was more sensitive than calculation of the creatinine clearance value according to the Cockroft–Gault formula, which was only predictive of all-cause mortality. The baseline eGFR by the MDRD formula turned out to be importantly predictive of both renal and cardiovascular events also in the large number (n = 11 140) of type 2 diabetic patients included in the ADVANCE trial, even when data were adjusted for many potential confounders, including the concomitant urinary protein excretion value. For every 50% reduction of baseline eGFR the risk of cardiovascular events significantly increased 2.2-fold, the concomitant increase in the risk of cardiovascular death and renal events being 3.6-fold and 63.6-fold, respectively [18]. New evidence is also available to support the already large amount of data in favor of the prognostic value of the moderate increase in urinary protein excretion, defined as microalbuminuria [19,20]. In two population studies, the Gubbio study [16] and the Copenhagen County study [11], microalbuminuria was confirmed as an important predictor of cardiovascular outcome, the adjusted hazard ratio being, respectively, 2.15-fold and 3.10-fold greater in patients with microalbuminuria compared with those without. In the Gubbio study, the association of microalbuminuria with low eGFR had a multiplicative effect (hazard ratio 5.93). In the ADVANCE trial [18], a change from one clinical stage of albuminuria to the next was associated with a 1.6-fold, 2.0-fold, and 3.3-fold increase in the multivariate-adjusted risk of cardiovascular events, cardiovascular death, and renal events, respectively, this being the case also when the change from normoalbuminuria to microalbuminuria was involved. The effects of higher baseline urinary protein excretion and reduced eGFR were independent of each other and the association of microalbuminuria and an eGFR value less than 60 ml/min per 1.73 m2 brought about an additional increase in risk: 3.2-fold for cardiovascular events, 5.9-fold for cardiovascular mortality, and 22.2-fold for renal events. Additional measures of organ damage The 2007 European guidelines mention a number of additional measures of organ damage for which evidence of prognostic relevance was available, but no use in the clinical practice could be foreseen because of drawbacks of practical relevance, such as the high cost and low availability of the devices involved, the complexity and time consumption inherent in the procedures, and in several instances the lack of standardization of the values obtained between laboratories and across countries. Based on the evidence available in the last 2 years, no addition to the measures of organ damage included in the 2007 guidelines can be supported, although the growing availability of more sophisticated techniques and the reduced cost of their use brought about by technological progress, makes future additions likely. In this context, the use of nuclear magnetic resonance deserves special mention. Although not prospective in nature, a very recent study systematically employing nuclear magnetic resonance imaging in a group of 142 hypertensive patients without overt cardiovascular disease has provided the interesting information that silent cerebrovascular lesions are even more prevalent (44%) than cardiac (21%) and renal (26%) subclinical damage, and do frequently occur in the absence of other signs of organ damage [21]. Increasing evidence also relates these lesions to cognitive dysfunction [22,23], a problem of primary importance because of the senescence of the population [24]. With magnetic resonance imaging becoming more and more frequently employed in diagnostic procedures, silent cerebrovascular disease is likely to become more frequently investigated in prognostic and therapeutic studies in hypertension. The prognostic value of structural alterations in small subcutaneous arteries has recently been confirmed by two independent studies [25,26]. However, the invasive nature of this measurement prevents larger scale application of this method. A new noninvasive method for assessing the media–lumen ratio of small retinal arteries seems promising for large-scale evaluation [27], although its predictive value remains to be investigated. Evidence remains inconclusive on a marker of a vascular alteration that has been actively investigated in the past decade, namely endothelial dysfunction. In a population sample of individuals without overt cardiovascular disease (67% with hypertension and 22% with diabetes mellitus) from the Northern Manhattan study, measures of flow-mediated vasodilatation predicted the incidence of cardiovascular events, but this effect was not independent of traditional cardiovascular risk factors [28]. Likewise, in the large cohort of elderly patients of the Cardiovascular Health Study, flow-mediated vasodilatation added very little to the prognostic accuracy of traditional risk factors [29]. On the contrary, Muiesan et al.[30] have recently reported that in a small cohort (n = 172) of uncomplicated hypertensive persons followed for about 8 years, flow-mediated vasodilatation of the brachial artery below the median value was significantly associated with a 2.7-fold increase in incident cardiovascular events even after adjusting for all major cardiovascular risk factors. However, the same group of investigators also have reported that endothelial dysfunction in the subcutaneous vessels of hypertensive patients was not predictive of cardiovascular events [31], possibly because endothelial dysfunction in different vascular beds may have a different prognostic significance. Clearly, the prognostic value of endothelial dysfunction in hypertension remains to be further elucidated. It should be emphasized that the addition of new measures of organ damage to the assessment of total cardiovascular risk requires not only the demonstration of their prognostic importance, but it has to improve the power to predict the incidence of cardiovascular events. This is by no means easy to be documented, and indeed data are available that in some instances new risk factors of individual prognostic significance do not improve, when added to the others, the accuracy by which cardiovascular risk can be quantified, thus only making the diagnostic procedures more complex, time consuming, and costly. This is exemplified by the recent results of the Framingham study, which showed that inclusion of inflammatory markers did not lead to any substantial improvement in the accuracy (sensitivity and specificity) by which total cardiovascular risk was assessed [32]. Subclinical organ damage as a marker of high cardiovascular risk Although subclinical organ damage undoubtedly increases the level of cardiovascular risk, the question arises whether it always brings the patient into the high-risk category, that is, an absolute risk of at least 20 cardiovascular events in 10 years per 100 patients. The 2007 European guidelines classify hypertensive patients with subclinical organ damage among those with a high total cardiovascular risk. This is further supported by more recent evidence on the contribution of subclinical cardiac, vascular, and renal damage to the total cardiovascular risk. As regards to subclinical cardiac damage, analysis of the data provided by some of the major prospective studies indicates that in hypertensive patients, echocardiographic LVH, particularly if of the concentric variety, is associated with an incidence of cardiovascular events equal to or above 20% in 10 years [5,7,33]. An incidence greater than 20% in 10 years has also been reported for men, but not for women, with echocardiographic LVH in the Framingham population study [34]. Finally, in the hypertensive patients of the CASE-J trial, echocardiographic LVH was associated with a 10-year incidence of cardiovascular events of 24% compared with the 10% incidence seen in patients without LVH [8]. Similar evidence exists for vascular damage. In the elderly patients of the Cardiovascular Health Study [35], the 10-year incidence of major cardiovascular events was higher than 20% when the common carotid IMT was 1.06 mm or more (fourth and fifth quintiles) and below 10% in those with an IMT in the first quintile (<0.87 mm). In the hypertensive patients of the ELSA study [10], the incidence of all (major and minor) cardiovascular events was greater than 20% in 10 years when IMT (common carotid plus bifurcation) was in the third and fourth quartiles (≥1.16 mm) or when at least one plaque had been detected. In contrast, patients with IMT in the first or the smallest IMT quartile (<0.98 mm) had incident cardiovascular events below 10% in 10 years. In hypertensive patients, the 10-year incidence of major cardiovascular events was higher than 20% when carotid-femoral PWV (aortic stiffness) was 16.3 m/s or more (fifth quintile) and below 10% in those with an aortic stiffness in the first and second quintiles [36]. Furthermore, even asymptomatic peripheral vascular disease as detected by a positive ankle-brachial index has prospectively been found to be associated in men with an incidence of cardiovascular events approaching 20% in 10 years [37,38]. Finally, old and recent evidence leaves little doubt that in hypertensive individuals, renal subclinical organ damage is associated with a 10-year risk of cardiovascular events of 20% or more. It has already been reported some years ago that reduced renal function, defined by a serum creatinine more than 1.5 mg/dl is associated with a 10-year incidence of cardiovascular events 20% or more [39,40]. In the recent prospective cohort of Greek hypertensive patients [7], a low eGFR was associated with incident cardiovascular events of about 20% in 10 years, an even higher incidence being observed when low eGFR occurred together with LVH. Furthermore, in the hypertensive patients prospectively studied by Jensen et al.[41], the incidence of ischemic heart disease was 20% in 10 years in the presence of microalbuminuria and of only 5% in its absence. Also, in the Gubbio population study, the incidence of cardiovascular events was greater than 20% in 10 years, but only in those individuals in whom microalbuminuria in the highest decile was associated with eGFR in the lowest decile [16]. Over 78% of these patients had hypertension. The 2007 European guidelines classify patients with subclinical organ damage as being at high risk also when BP is in the high normal range, but admittedly evidence that this is invariably the case is less clear. In the general population of the Framingham study, no information was made available on the prognostic value of echographic LVH, separately in the normotensive and hypertensive population [34]. Furthermore, in the same population, the association of renal dysfunction with cardiovascular events was lost after adjustment for cardiovascular risk factors, including BP [42]. In the PREVEND population study [43], microalbuminuria (20–200 mg/l) was associated with only a 4.7% cardiovascular mortality in 10 years, that is, a moderate absolute risk according to the SCORE classification [44], and in the nonhypertensive, nondiabetic individuals of the Framingham study, a microalbuminuria above the median value was associated with a rate of incident cardiovascular events of only 8.8% in 10 years compared with a 2.9% rate in individuals with microalbuminuria below the median value [45]. Prognostic value of treatment-induced modifications of subclinical organ damage The 2007 European guidelines have emphasized that treatment-induced changes of organ damage affect the incidence of cardiovascular events, thereby recommending that organ damage be measured also during treatment. Reference was made to the data obtained in the LIFE study [46], in which hypertensive patients in whom treatment was accompanied by regression of echocardiographic LVH or a delayed increase in LVM had less incident cardiovascular events, including sudden death, than those in whom no regression from or earlier progression to LVH occurred. It was also mentioned that both in LIFE [47] and in other studies [48], a similar relationship was found between treatment-induced changes in and renal or cardiovascular events. This means compared with patients in whom treatment had little or no reduction in was associated with a reduced incidence of cardiovascular events and less progression to renal Since 2007, data on the relationship between treatment-induced changes in cardiac damage and cardiovascular have been by further of the LIFE study, which have shown that also treatment-induced changes in left left ventricular and in electrocardiographic signs of LVH with incident cardiovascular event rate Furthermore, have been that in changes in LVM during treatment affect cardiovascular Finally, the predictive power of treatment-induced IMT changes in the carotid arteries has for the first time been investigated in a recent analysis of ELSA trial This analysis to a predictive of IMT but the of these changes compared with the large individual in baseline IMT makes it to conclusions The of treatment-induced changes in with cardiovascular event incidence has been by some of the In this trial on a large number of high or very high cardiovascular risk patients, the group with a of an angiotensin-converting and an the study less increase in than the group on with one or the other but this effect was not accompanied by a reduction in cardiovascular events and was even associated with an increase in renal events However, these results do not the important that treatment-induced changes in can be a marker of the more or less effects of treatment because for the results are For in most patients had a normal renal and few overt which in a very number of the endpoint that for renal that is, renal Furthermore, in the very high cardiovascular risk population the of the system provided by the and might have an adverse effect of its that and the associated with a reduction in In favor of this are some recent of the ADVANCE study in patients with type 2 diabetes. In these patients, values of showed a independent association with both renal and cardiovascular events, the contribution of being to the concomitant values of eGFR [18]. Evidence on the important prognostic of subclinical organ damage to In both hypertensive patients and the general population, the presence of electrocardiographic and echocardiographic LVH, a carotid plaque or an increased arterial a reduced eGFR by the MDRD or microalbuminuria or increases the total cardiovascular risk, hypertensive patients into the high absolute risk The changes in or detected LVH by treatment the effects on cardiovascular events, thereby information on whether patients are more or less by the treatment Despite some recent results solid evidence suggests that this is the case also for treatment-induced changes in urinary protein excretion, although the problem remains for treatment-induced vascular assessing the presence of subclinical organ damage is of crucial importance in the hypertensive This assessment can use of simple and cheap procedures that can routine information and at various times during treatment. It can also on more sophisticated that can further cardiac and vascular In all organ damage assessment is useful because of the evidence that in the presence of two signs of organ damage when inherent to the same cardiovascular risk may be more markedly with an to the high cardiovascular risk It is not from published data whether subclinical organ damage can total cardiovascular risk to the high range also in patients with high normal BP. However, organ damage when it is particularly or or is accompanied by risk factors, is associated with a or increase in risk also in normotensive individuals and the 2007 guidelines recommend risk as a for the need of treatment in and patients. In this context, it is also important to that the of organ damage in patients that decide to the of several studies that the incidence of cardiovascular events is higher in than in untreated hypertensive patients even after adjustment for cardiovascular risk factors and past clinical This is with the that antihypertensive treatment even if a high total risk to a the that in treatment is organ damage when is not use of organ damage assessment may thus to a more about the of treatment and thus favor its greater Some of the discussed in of subclinical organ damage for stratification of total cardiovascular risk are summarized in Box approach guidelines on the management of hypertension recommend the of antihypertensive in all patients with a SBP or more a or and to the treatment in order for the patients to be below these values. They further recommend drug treatment to be within a BP range, that is, a SBP between and and a between and in patients with diabetes or a of cardiovascular or renal disease, at values The 2007 ESH/ESC guidelines have accompanied these recommendations with information on the evidence are based and a critical of this has recently been by of the in the of further information provided by recent The of the ESH document is to the and the type of evidence on which these recommendations are and thus the and

BACKGROUND: Low-molecular-weight heparin is the standard treatment for cancer-associated venous thromboembolism. The role of treatment with direct oral anticoagulant agents is unclear. METHODS: In this open-label, noninferiority trial, we randomly assigned patients with cancer who had acute symptomatic or incidental venous thromboembolism to receive either low-molecular-weight heparin for at least 5 days followed by oral edoxaban at a dose of 60 mg once daily (edoxaban group) or subcutaneous dalteparin at a dose of 200 IU per kilogram of body weight once daily for 1 month followed by dalteparin at a dose of 150 IU per kilogram once daily (dalteparin group). Treatment was given for at least 6 months and up to 12 months. The primary outcome was a composite of recurrent venous thromboembolism or major bleeding during the 12 months after randomization, regardless of treatment duration. RESULTS: Of the 1050 patients who underwent randomization, 1046 were included in the modified intention-to-treat analysis. A primary-outcome event occurred in 67 of the 522 patients (12.8%) in the edoxaban group as compared with 71 of the 524 patients (13.5%) in the dalteparin group (hazard ratio, 0.97; 95% confidence interval [CI], 0.70 to 1.36; P=0.006 for noninferiority; P=0.87 for superiority). Recurrent venous thromboembolism occurred in 41 patients (7.9%) in the edoxaban group and in 59 patients (11.3%) in the dalteparin group (difference in risk, -3.4 percentage points; 95% CI, -7.0 to 0.2). Major bleeding occurred in 36 patients (6.9%) in the edoxaban group and in 21 patients (4.0%) in the dalteparin group (difference in risk, 2.9 percentage points; 95% CI, 0.1 to 5.6). CONCLUSIONS: Oral edoxaban was noninferior to subcutaneous dalteparin with respect to the composite outcome of recurrent venous thromboembolism or major bleeding. The rate of recurrent venous thromboembolism was lower but the rate of major bleeding was higher with edoxaban than with dalteparin. (Funded by Daiichi Sankyo; Hokusai VTE Cancer ClinicalTrials.gov number, NCT02073682 .).

Supplementary data with additional supplementary tables complementing the full text, as well as section 11 on non-thrombotic PE, are available from erj.ersjournals

Complement is a complex innate immune surveillance system, playing a key role in defense against pathogens and in host homeostasis. The complement system is initiated by conformational changes in recognition molecular complexes upon sensing danger signals. The subsequent cascade of enzymatic reactions is tightly regulated to assure that complement is activated only at specific locations requiring defense against pathogens, thus avoiding host tissue damage. Here, we discuss the recent advances describing the molecular and structural basis of activation and regulation of the complement pathways and their implication on physiology and pathology. This article will review the mechanisms of activation of alternative, classical, and lectin pathways, the formation of C3 and C5 convertases, the action of anaphylatoxins, and the membrane-attack-complex. We will also discuss the importance of structure-function relationships using the example of atypical hemolytic uremic syndrome. Lastly, we will discuss the development and benefits of therapies using complement inhibitors.