Children's Hospital of Los Angeles

The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles ("MISEV") guidelines for the field in 2014. We now update these "MISEV2014" guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points.

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: In a single-center phase 1-2a study, the anti-CD19 chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel produced high rates of complete remission and was associated with serious but mainly reversible toxic effects in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL). METHODS: We conducted a phase 2, single-cohort, 25-center, global study of tisagenlecleucel in pediatric and young adult patients with CD19+ relapsed or refractory B-cell ALL. The primary end point was the overall remission rate (the rate of complete remission or complete remission with incomplete hematologic recovery) within 3 months. RESULTS: For this planned analysis, 75 patients received an infusion of tisagenlecleucel and could be evaluated for efficacy. The overall remission rate within 3 months was 81%, with all patients who had a response to treatment found to be negative for minimal residual disease, as assessed by means of flow cytometry. The rates of event-free survival and overall survival were 73% (95% confidence interval [CI], 60 to 82) and 90% (95% CI, 81 to 95), respectively, at 6 months and 50% (95% CI, 35 to 64) and 76% (95% CI, 63 to 86) at 12 months. The median duration of remission was not reached. Persistence of tisagenlecleucel in the blood was observed for as long as 20 months. Grade 3 or 4 adverse events that were suspected to be related to tisagenlecleucel occurred in 73% of patients. The cytokine release syndrome occurred in 77% of patients, 48% of whom received tocilizumab. Neurologic events occurred in 40% of patients and were managed with supportive care, and no cerebral edema was reported. CONCLUSIONS: In this global study of CAR T-cell therapy, a single infusion of tisagenlecleucel provided durable remission with long-term persistence in pediatric and young adult patients with relapsed or refractory B-cell ALL, with transient high-grade toxic effects. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT02435849 .).

The International League Against Epilepsy (ILAE) Classification of the Epilepsies has been updated to reflect our gain in understanding of the epilepsies and their underlying mechanisms following the major scientific advances that have taken place since the last ratified classification in 1989. As a critical tool for the practicing clinician, epilepsy classification must be relevant and dynamic to changes in thinking, yet robust and translatable to all areas of the globe. Its primary purpose is for diagnosis of patients, but it is also critical for epilepsy research, development of antiepileptic therapies, and communication around the world. The new classification originates from a draft document submitted for public comments in 2013, which was revised to incorporate extensive feedback from the international epilepsy community over several rounds of consultation. It presents three levels, starting with seizure type, where it assumes that the patient is having epileptic seizures as defined by the new 2017 ILAE Seizure Classification. After diagnosis of the seizure type, the next step is diagnosis of epilepsy type, including focal epilepsy, generalized epilepsy, combined generalized, and focal epilepsy, and also an unknown epilepsy group. The third level is that of epilepsy syndrome, where a specific syndromic diagnosis can be made. The new classification incorporates etiology along each stage, emphasizing the need to consider etiology at each step of diagnosis, as it often carries significant treatment implications. Etiology is broken into six subgroups, selected because of their potential therapeutic consequences. New terminology is introduced such as developmental and epileptic encephalopathy. The term benign is replaced by the terms self-limited and pharmacoresponsive, to be used where appropriate. It is hoped that this new framework will assist in improving epilepsy care and research in the 21st century.

The upcoming 5th edition of the World Health Organization (WHO) Classification of Haematolymphoid Tumours is part of an effort to hierarchically catalogue human cancers arising in various organ systems within a single relational database. This paper summarizes the new WHO classification scheme for myeloid and histiocytic/dendritic neoplasms and provides an overview of the principles and rationale underpinning changes from the prior edition. The definition and diagnosis of disease types continues to be based on multiple clinicopathologic parameters, but with refinement of diagnostic criteria and emphasis on therapeutically and/or prognostically actionable biomarkers. While a genetic basis for defining diseases is sought where possible, the classification strives to keep practical worldwide applicability in perspective. The result is an enhanced, contemporary, evidence-based classification of myeloid and histiocytic/dendritic neoplasms, rooted in molecular biology and an organizational structure that permits future scalability as new discoveries continue to inexorably inform future editions.

Abstract We herein present an overview of the upcoming 5 th edition of the World Health Organization Classification of Haematolymphoid Tumours focussing on lymphoid neoplasms. Myeloid and histiocytic neoplasms will be presented in a separate accompanying article. Besides listing the entities of the classification, we highlight and explain changes from the revised 4 th edition. These include reorganization of entities by a hierarchical system as is adopted throughout the 5 th edition of the WHO classification of tumours of all organ systems, modification of nomenclature for some entities, revision of diagnostic criteria or subtypes, deletion of certain entities, and introduction of new entities, as well as inclusion of tumour-like lesions, mesenchymal lesions specific to lymph node and spleen, and germline predisposition syndromes associated with the lymphoid neoplasms.

BACKGROUND: Fusions involving one of three tropomyosin receptor kinases (TRK) occur in diverse cancers in children and adults. We evaluated the efficacy and safety of larotrectinib, a highly selective TRK inhibitor, in adults and children who had tumors with these fusions. METHODS: We enrolled patients with consecutively and prospectively identified TRK fusion-positive cancers, detected by molecular profiling as routinely performed at each site, into one of three protocols: a phase 1 study involving adults, a phase 1-2 study involving children, or a phase 2 study involving adolescents and adults. The primary end point for the combined analysis was the overall response rate according to independent review. Secondary end points included duration of response, progression-free survival, and safety. RESULTS: A total of 55 patients, ranging in age from 4 months to 76 years, were enrolled and treated. Patients had 17 unique TRK fusion-positive tumor types. The overall response rate was 75% (95% confidence interval [CI], 61 to 85) according to independent review and 80% (95% CI, 67 to 90) according to investigator assessment. At 1 year, 71% of the responses were ongoing and 55% of the patients remained progression-free. The median duration of response and progression-free survival had not been reached. At a median follow-up of 9.4 months, 86% of the patients with a response (38 of 44 patients) were continuing treatment or had undergone surgery that was intended to be curative. Adverse events were predominantly of grade 1, and no adverse event of grade 3 or 4 that was considered by the investigators to be related to larotrectinib occurred in more than 5% of patients. No patient discontinued larotrectinib owing to drug-related adverse events. CONCLUSIONS: Larotrectinib had marked and durable antitumor activity in patients with TRK fusion-positive cancer, regardless of the age of the patient or of the tumor type. (Funded by Loxo Oncology and others; ClinicalTrials.gov numbers, NCT02122913 , NCT02637687 , and NCT02576431 .).

The chemokine receptor 5 (CKR5) protein serves as a secondary receptor on CD4(+) T lymphocytes for certain strains of human immunodeficiency virus-type 1 (HIV-1). The CKR5 structural gene was mapped to human chromosome 3p21, and a 32-base pair deletion allele (CKR5Delta32) was identified that is present at a frequency of approximately0.10 in the Caucasian population of the United States. An examination of 1955 patients included among six well-characterized acquired immunodeficiency syndrome (AIDS) cohort studies revealed that 17 deletion homozygotes occurred exclusively among 612 exposed HIV-1 antibody-negative individuals (2.8 percent) and not at all in 1343 HIV-1-infected individuals. The frequency of CKR5 deletion heterozygotes was significantly elevated in groups of individuals that had survived HIV-1 infection for more than 10 years, and, in some risk groups, twice as frequent as their occurrence in rapid progressors to AIDS. Survival analysis clearly shows that disease progression is slower in CKR5 deletion heterozygotes than in individuals homozygous for the normal CKR5 gene. The CKR5Delta32 deletion may act as a recessive restriction gene against HIV-1 infection and may exert a dominant phenotype of delaying progression to AIDS among infected individuals.

Recent studies suggest that one or more genes on chromosome 5q21 are important for the development of colorectal cancers, particularly those associated with familial adenomatous polyposis (FAP). To facilitate the identification of genes from this locus, a portion of the region that is tightly linked to FAP was cloned. Six contiguous stretches of sequence (contigs) containing approximately 5.5 Mb of DNA were isolated. Subclones from these contigs were used to identify and position six genes, all of which were expressed in normal colonic mucosa. Two of these genes (APC and MCC) are likely to contribute to colorectal tumorigenesis. The MCC gene had previously been identified by virtue of its mutation in human colorectal tumors. The APC gene was identified in a contig initiated from the MCC gene and was found to encode an unusually large protein. These two closely spaced genes encode proteins predicted to contain coiled-coil regions. Both genes were also expressed in a wide variety of tissues. Further studies of MCC and APC and their potential interaction should prove useful for understanding colorectal neoplasia.

Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.

The growing worldwide prevalence of type 2 diabetes mellitus in the young, as underlined by an earlier International Diabetes Federation (IDF) Consensus Statement 1, has highlighted a significant shortfall of data on the epidemiology of the disorder and the identification and treatment of children and adolescents at risk of progression to this disease. Urbanization, unhealthy diets, and increasingly sedentary lifestyles have contributed to increase the prevalence of childhood obesity, particularly in developing countries 2. Current treatment initiatives include school-based programs addressing physical activity and diet, which have been conducted with mixed success in reducing adiposity. There are limited safety data supporting the use of drugs for the treatment of obesity and related conditions such as type 2 diabetes in children and adolescents, and non-compliance in this population suggests that pharmacotherapy is unlikely to be effective long term 1. Although criteria have now been developed for bariatric surgery in teenagers 3, there are few evidence-based data available to support the increasing use of this modality in adolescents. Governments and society in general must be made more aware of the problems associated with obesity and the likelihood of progression to the metabolic syndrome in children and adolescents. Obesity, particularly in the central (abdominal) region, has been determined as a key factor in the etiology of type 2 diabetes 2. The prediction of health risks associated with obesity in youth is improved by the additional inclusion of waist circumference (WC) measure to the body mass index (BMI) percentile 4, 5. Such observations reinforce the importance of including WC in the assessment of childhood obesity to identify those at increased metabolic risk as a result of excess abdominal fat 5. The role of obesity can clearly be demonstrated in Japan, where a parallel increase in type 2 diabetes and obesity in children has occurred over the past few decades 6. Central (abdominal) obesity is also a key component in the IDF definition of metabolic syndrome in adults 2. The link between obesity, metabolic syndrome, and type 2 diabetes has already been characterized in adult populations 2. At present, 50–80% of almost 250 million adults worldwide with diabetes 7 are at risk of death from cardiovascular disease. Those with the metabolic syndrome are also at increased risk being twice as likely to die from, and three times as likely to have, cardiovascular complications as compared with those without the syndrome 8, 9. In addition, adults with the metabolic syndrome have a fivefold greater risk of developing type 2 diabetes 10. Already, one-quarter of the world’s adult population have metabolic syndrome 11, 12, and this condition is appearing with increasing frequency in children and adolescents, driven by the growing obesity epidemic in this young population 13-15. In 2004, the World Health Organization (WHO) reported that an estimated 22 million children younger than 5 yr of age and 10% of school-aged children, between 5 and 17 yr, were overweight or obese 16. WHO predicts that the prevalence of childhood obesity in developed and developing countries will continue to increase as has been seen in recent years. For example, from 1985 to 1997, in young Australians, the prevalence of overweight and obesity combined doubled and that of obesity trebled 17. In Thailand, the prevalence of obesity in those aged 5–12 yr increased from 12.2 to 15.6% in just 2 yr 18. In 2003–2004, 17.1% of children aged 2–19 yr in the USA were obese 19. Obesity is associated with an increase in cardiovascular risk factors (also indicators of metabolic syndrome) 20, and the persistence of these indicators from childhood and adolescence to young adulthood has been shown in several studies, including the Quebec Family Study 21, 22. Recently, the IDF released its guidelines for defining and diagnosing the metabolic syndrome in adults 2. The intention was to rationalize the existing multiple definitions of the syndrome and to avoid the confusion that arose as a result of conflicting opinions on the value of each set of criteria. The use of a single unified definition makes it possible to estimate the global prevalence of metabolic syndrome and make valid comparisons between nations. However, to date, there has not been a unified definition that can be used to assess risk in children and adolescents, and existing adult-based definitions of the metabolic syndrome may not be appropriate to address the problem in this age group. A study of adolescents using modified National Cholesterol Education Program (NCEP) [Adult Treatment Panel III (ATP III)] criteria 23 identified that 12% of the study group had the metabolic syndrome 24. When the ≥95th percentile of BMI was used as a cutoff point in the same study group, 31.3% were identified as having the syndrome, more than double of those previously found to be at risk. Duncan et al. 25 studied 991 adolescents (aged 12–19 yr) from National Health and Nutrition Examination Study (NHANES) 1999–2000 and used the ATP III definition modified for age. The overall prevalence of a metabolic syndrome phenotype among US adolescents increased from 4.2% in NHANES III (1988–1992) to 6.4% in NHANES 1999–2000. Based on population-weighted estimates, they estimated that more than 2 million US adolescents currently have a metabolic syndrome phenotype. In a population-based study of a Canadian Qji-Cree community involving 236 children aged 10–19 yr, Retnakaran et al. reported that 18.6% of the children met the criteria for the metabolic syndrome based on a pediatric metabolic syndrome definition based on the ATP III definition, and they used the ATP III definition modified for age and gender 26. Goodman et al. reported on a school-based, cross-sectional study of 1513 black, white, and Hispanic teenagers 27. Overall, the prevalence of ATP III-defined metabolic syndrome was 4.2% and that of the WHO-defined metabolic syndrome was 8.4%. The metabolic syndrome was found almost exclusively among obese teenagers in whom prevalence of the ATP III-defined metabolic syndrome was 19.5% and prevalence of WHO-defined metabolic syndrome 28 was 38.9%. No race or sex differences were present for ATP III definition. However, non-white teenagers were more likely to have metabolic syndrome by WHO criteria, and it was more common among girls if the WHO definition was used. Chi et al. have recently undertaken a literature review on definitions of the metabolic syndrome in children and adolescents published in the past decade 29. They noted that the prevalence of metabolic syndrome in pre-adolescent girls varies widely because of disagreement among proposed definitions of metabolic syndrome in pediatrics. They called for a consensus definition for the metabolic syndrome in children, which would allow researchers to make better temporal, biological, environmental, and social comparisons between data sets. The American College of Endocrinology definition 30 is not ideal in pediatric subjects as WC is rarely measured in children, and nomograms have only recently become available 31 for some ethnic groups but are not available for all. A recent paper has suggested yet another set of criteria with age- and gender-specific cutoff points 32. The variety of cutoff points used for the different components in this paper underlines the need for a single consistent definition with easily measurable components. Therefore, to date, no formal definition for the diagnosis of the metabolic syndrome in children and adolescents has been developed. The rapid increase in obesity highlights the urgency for a definition that could be used to further understand who is at high risk and to distinguish them from those with ‘simple’ uncomplicated obesity. The metabolic syndrome in adults is defined as a cluster of cardiovascular and diabetes risk factors including abdominal obesity, dyslipidemia, glucose intolerance, and hypertension 2. While the danger associated with clustering of components of the metabolic syndrome has been demonstrated in adults, where the presence of three or more components significantly increases the risk for coronary heart disease death/non-fatal myocardial infarction and the onset of new diabetes 33, few, if any, outcome data in children exist. While one definition, although with gender- and ethnicity-specific cutoff points, is suitable for use in the at-risk adult population 2, transposing a single definition to children and adolescents is problematic. Blood pressure, lipid levels, and anthropometric variables change with age and pubertal development. Puberty impacts on fat distribution and is known to cause a decrease both in insulin sensitivity, of approximately 30% with a complementary increase in insulin secretion 34, and in adiponectin levels 35. Therefore, single cutoff points cannot be used to define abnormalities in children. Instead, values above the 90th, 95th, or 97th percentile for gender and age are used. However, there has not been universal agreement as to which level to use for the criteria for the metabolic syndrome. The importance of the early identification of children at risk of developing the metabolic syndrome and subsequently progressing to type 2 diabetes and cardiovascular disease in later life must not be underestimated. From birth and before, circumstances can predispose a child to conditions such as obesity or dysglycemia. The presence of maternal gestational diabetes 36, low birth weight 37, infant feeding practices 38, early adiposity rebound 39, and genetic factors may all contribute to a child’s future level of risk. Being raised in an ‘obesogenic’ environment can also have a strong impact, as can the influence of socioeconomic factors 40, with weight gain often being observed as a positive correlate to affluence in developing countries. Longitudinal outcome studies and further research on the progression and etiology of the metabolic syndrome are urgently required to ascertain the long-term outcomes of abdominal obesity and clustering of the components of metabolic syndrome in at-risk children and to help improve future definitions of the syndrome. This new IDF definition of metabolic syndrome in children and adolescents was developed during a consensus workshop that brought together experts in the field of the metabolic syndrome and pediatrics. The purpose of the new definition of metabolic syndrome in children and adolescents is to expand on the IDF recommendations for managing type 2 diabetes in the young 1 and to provide a useful and unified tool for identifying those at risk. A clinically accessible diagnostic tool, avoiding measurements that may only be available in research settings, is needed to identify the metabolic syndrome in children and adolescents globally. This need has prompted the IDF to develop a definition that has used the limited data available from existing studies in youth. As with the adult criteria, we look on these new criteria as a starting point. As new information emerges, they can be modified. Inspired, in part, by the IDF worldwide definition of metabolic syndrome in adults 2, this new definition builds on previous studies investigating the prevalence of metabolic syndrome in children and adolescents, which have used modified adult criteria with varying cutoff points 12-14, 41, 42 (Table 1). The wide variety of cutoff points used has emphasized the need for a single consistent set of criteria, which is easily measurable and can be used as the basis for future work 29. Because of the developmental challenges presented by the age-related differences in children and adolescents, the new IDF definition of metabolic syndrome has been divided according to the following age groups: 6 to <10, 10 to <16, and ≥16 yr (Table 2). In all the three age groups, abdominal obesity is the ‘sine qua non’. We suggest that below the age of 10 yr, the metabolic syndrome as an entity is not diagnosed, although a strong message for weight reduction will be made for these children. At the age of 10 yr and more, a diagnosis of metabolic syndrome can be made. It requires the presence of abdominal obesity plus the presence of two or more of the other components (elevated triglycerides, low high-density lipoprotein (HDL)-cholesterol, high blood pressure, and elevated plasma glucose). The IDF adult criteria 2 can be used for adolescents aged ≥16 yr, while a modified version of these criteria will be applied to those aged 10 to <16 yr (use 90th percentile cutoff point for waist and <40 mg/dL of HDL for both sexes). On the basis of emerging new data, these criteria may change in the future. In adults, insulin resistance and abdominal obesity are considered to be significant causative factors in the development of the metabolic syndrome 9, 43, 44. The link between obesity, insulin resistance, and the risk of developing the metabolic syndrome has also been described in children 22, 27. With measurement of insulin resistance considered to be impractical for clinical use, abdominal adiposity was positioned as the ‘sine qua non’ in the IDF definition of metabolic syndrome in adults 2 and is recognized to be an independent risk factor for the development of cardiovascular disease in adults 45. Abdominal obesity can be easily assessed using the simple measure of WC, which is known to correlate more strongly with visceral adipose tissue (VAT) than BMI in adults 46 and is a strong predictor of cardiovascular disease risk factors in children 47. The correlation between WC and VAT has also been more recently demonstrated in children 48, further strengthening the existing evidence that WC is an effective measure of abdominal obesity 49 in the youth population. In children and adolescents, a number of studies have demonstrated a similar link between childhood obesity and elevated cardiovascular risk in later life. The Bogalusa Heart study showed that childhood overweight is related to the development of adverse risk factors (BMI, lipids, insulin, diabetes mellitus, and blood pressure) in adulthood and is attributable to the strong persistence of weight status from childhood to adulthood 50. Of the overweight children in the Bogalusa Heart study (BMI ≥95th percentile), 77% remained obese in adulthood. Furthermore, the Muscatine study demonstrated that in young adults, excess weight was the earliest predictor of coronary artery calcification 51. The ATP III definition, applied to a cohort of individuals aged 12–19 yr (NHANES III), identified that 4% of those studied were found to have the metabolic syndrome, with 80% of those meeting the criteria of being overweight 13. Using a modified version of the ATP III definition, metabolic syndrome in adolescents has also been linked to high levels of C-reactive protein, a pro-inflammatory marker. Of the five components of metabolic syndrome, C-reactive protein was higher only among those with abdominal obesity 41. Waist circumference in children is an independent predictor of insulin resistance, lipid levels, and blood pressure 4, 52-54– all components of metabolic syndrome. Moreover, in obese youth with similar BMI, insulin sensitivity is lower in those with high VAT and high waist/hip ratio 53, 54. Furthermore, insulin sensitivity decreases and insulin levels increase with increasing WC percentiles 3. These data, combined with the unequivocal evidence of the dangers of abdominal obesity in adulthood, support the use of abdominal obesity as the ‘sine qua non’ for the diagnosis of metabolic syndrome in children and adolescents. Percentiles rather than absolute values of WC have been used in the new criteria to compensate for varying degrees of development and ethnicity in the youth population. WC percentile data are becoming increasingly available worldwide 31, 55-58. Children with a WC >90th percentile are more likely to have multiple risk factors than those with a WC below this level 59. Several studies attempting to estimate the prevalence of metabolic syndrome in children and adolescents have already used the 90th percentile as a cutoff point for WC 13, 14, 41. We have also chosen to use the 90th percentile as a cutoff point for WC based on this existing evidence and aim to reassess criteria and cutoff points in 5 yr and modify the guidelines, if necessary, based on the new outcome data. Previous studies investigating the metabolic syndrome in children and adolescents have used a range of cutoff points primarily based on ATP III criteria for categorizing additional components of the syndrome, i.e., triglycerides, HDL-cholesterol, blood pressure, and fasting glucose (Table 1) 12-14, 41, 42. Other definitive sources include the National High Blood Pressure Education Program, which recommends blood pressure cutoff points of >90th or >95th percentile adjusted for height, age, and gender to identify ‘high normal’ blood pressure or prehypertension and high blood pressure or hypertension in children and adolescents 60. Cutoff points for impaired fasting glucose have previously followed recommendations by the American Diabetes Association (ADA) [100–125 mg/dL (≥5.6–6.9 mmol/L)] 61 and the NCEP/ATP III in adults [≥110 mg/dL (6.1 mmol/L)] 23, although the latter has recently changed to the lower ADA recommended levels 62. Criteria for defining lipid (triglyceride and HDL-cholesterol) imbalances are even less consistent in the youth population, with recommendations by the NCEP/ATP III (age specific), NHANES III (age and gender specific), and the National Growth and Health Study (age, gender, and ethnic specific), employing either absolute value or percentile cutoff points. In view of this lack of consistency, we believe that use of the adult levels for the present is wise until further information is available. We recommend the following topics as priorities for future research: Develop a better understanding of the relationship between body fat and its distribution in children and adolescents, e.g., dual energy X-ray absorptiometry (DEXA), WC, BMI, and height and weight percentiles; a) Explore whether early growth patterns predict future adiposity and features of the metabolic syndrome, diabetes, and cardiovascular disease and b) explore whether low birth weight predicts future metabolic syndrome, diabetes, and cardiovascular disease; Perform factor analysis in children and adolescents to establish grouping of metabolic characteristics – adiposity, dyslipidemia, hyperinsulinemia, hypoadiponectinemia, and insulin resistance; Investigate how should obesity in children could be better defined, e.g., weight/height, WC etc.; Develop ethnic-specific normal ranges for WC, ideally based on healthy values; Perform ethnic-specific studies of WC etc. vs. abdominal (truncal) fat based on magnetic resonance imaging and DEXA; Support studies of adiponectin, leptin, etc. in children and adolescents to determine if they may be predictors of metabolic syndrome in adulthood; Initiate long-term studies of multi-ethnic cohorts followed into adulthood to determine the natural history and effectiveness of intervention strategies, particularly lifestyle. In conclusion, to combat any conflict that could arise from these multiple interpretations of the metabolic syndrome in children and adolescents, the IDF consensus group has aimed primarily at developing a simple, easy-to-apply definition to begin using in the clinical setting. In the absence of definitive research findings at this time, the proposed IDF definition of the metabolic syndrome in children and adolescents (Table 2) adheres to the absolute values presented in the adult definition 2, with the exception of WC. As described previously, until such time that outcome data from studies in children and adolescents indicate otherwise, WC percentiles are recommended for use. Early detection, followed by treatment in the form of lifestyle intervention and possibly pharmacotherapy, if its safety has been clearly demonstrated, is vital in halting the progression of this syndrome pathway in the adolescent population. It is likely that this will reduce morbidity and mortality in adulthood, as well as minimize the global socioeconomic burden of cardiovascular disease and type 2 diabetes. The workshop was sponsored by an unrestricted educational grant to the IDF Task Force on Epidemiology and Prevention from sanofi-aventis.

BACKGROUND: Children with high-risk neuroblastoma have a poor outcome. In this study, we assessed whether myeloablative therapy in conjunction with transplantation of autologous bone marrow improved event-free survival as compared with chemotherapy alone, and whether subsequent treatment with 13-cis-retinoic acid (isotretinoin) further improves event-free survival. METHODS: All patients were treated with the same initial regimen of chemotherapy, and those without disease progression were then randomly assigned to receive continued treatment with myeloablative chemotherapy, total-body irradiation, and transplantation of autologous bone marrow purged of neuroblastoma cells or to receive three cycles of intensive chemotherapy alone. All patients who completed cytotoxic therapy without disease progression were then randomly assigned to receive no further therapy or treatment with 13-cis-retinoic acid for six months. RESULTS: The mean (+/-SE) event-free survival rate three years after the first randomization was significantly better among the 189 patients who were assigned to undergo transplantation than among the 190 patients assigned to receive continuation chemotherapy (34+/-4 percent vs. 22+/-4 percent, P=0.034). The event-free survival rate three years after the second randomization was significantly better among the 130 patients who were assigned to receive 13-cis-retinoic acid than among the 128 patients assigned to receive no further therapy (46+/-6 percent vs. 29+/-5 percent, P=0.027). CONCLUSIONS: Treatment with myeloablative therapy and autologous bone marrow transplantation improved event-free survival among children with high-risk neuroblastoma. In addition, treatment with 13-cis-retinoic acid was beneficial for patients without progressive disease when it was administered after chemotherapy or transplantation.

BACKGROUND: Preclinical and preliminary clinical data indicate that ch14.18, a monoclonal antibody against the tumor-associated disialoganglioside GD2, has activity against neuroblastoma and that such activity is enhanced when ch14.18 is combined with granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-2. We conducted a study to determine whether adding ch14.18, GM-CSF, and interleukin-2 to standard isotretinoin therapy after intensive multimodal therapy would improve outcomes in high-risk neuroblastoma. METHODS: Patients with high-risk neuroblastoma who had a response to induction therapy and stem-cell transplantation were randomly assigned, in a 1:1 ratio, to receive standard therapy (six cycles of isotretinoin) or immunotherapy (six cycles of isotretinoin and five concomitant cycles of ch14.18 in combination with alternating GM-CSF and interleukin-2). Event-free survival and overall survival were compared between the immunotherapy group and the standard-therapy group, on an intention-to-treat basis. RESULTS: A total of 226 eligible patients were randomly assigned to a treatment group. In the immunotherapy group, a total of 52% of patients had pain of grade 3, 4, or 5, and 23% and 25% of patients had capillary leak syndrome and hypersensitivity reactions, respectively. With 61% of the number of expected events observed, the study met the criteria for early stopping owing to efficacy. The median duration of follow-up was 2.1 years. Immunotherapy was superior to standard therapy with regard to rates of event-free survival (66±5% vs. 46±5% at 2 years, P=0.01) and overall survival (86±4% vs. 75±5% at 2 years, P=0.02 without adjustment for interim analyses). CONCLUSIONS: Immunotherapy with ch14.18, GM-CSF, and interleukin-2 was associated with a significantly improved outcome as compared with standard therapy in patients with high-risk neuroblastoma. (Funded by the National Institutes of Health and the Food and Drug Administration; ClinicalTrials.gov number, NCT00026312.)

Abstract Over the past few decades, neuroimaging has become a ubiquitous tool in basic research and clinical studies of the human brain. However, no reference standards currently exist to quantify individual differences in neuroimaging metrics over time, in contrast to growth charts for anthropometric traits such as height and weight 1 . Here we assemble an interactive open resource to benchmark brain morphology derived from any current or future sample of MRI data ( http://www.brainchart.io/ ). With the goal of basing these reference charts on the largest and most inclusive dataset available, acknowledging limitations due to known biases of MRI studies relative to the diversity of the global population, we aggregated 123,984 MRI scans, across more than 100 primary studies, from 101,457 human participants between 115 days post-conception to 100 years of age. MRI metrics were quantified by centile scores, relative to non-linear trajectories 2 of brain structural changes, and rates of change, over the lifespan. Brain charts identified previously unreported neurodevelopmental milestones 3 , showed high stability of individuals across longitudinal assessments, and demonstrated robustness to technical and methodological differences between primary studies. Centile scores showed increased heritability compared with non-centiled MRI phenotypes, and provided a standardized measure of atypical brain structure that revealed patterns of neuroanatomical variation across neurological and psychiatric disorders. In summary, brain charts are an essential step towards robust quantification of individual variation benchmarked to normative trajectories in multiple, commonly used neuroimaging phenotypes.

OBJECTIVE: The recurrence risk of autism spectrum disorders (ASD) is estimated to be between 3% and 10%, but previous research was limited by small sample sizes and biases related to ascertainment, reporting, and stoppage factors. This study used prospective methods to obtain an updated estimate of sibling recurrence risk for ASD. METHODS: A prospective longitudinal study of infants at risk for ASD was conducted by a multisite international network, the Baby Siblings Research Consortium. Infants (n = 664) with an older biological sibling with ASD were followed from early in life to 36 months, when they were classified as having or not having ASD. An ASD classification required surpassing the cutoff of the Autism Diagnostic Observation Schedule and receiving a clinical diagnosis from an expert clinician. RESULTS: A total of 18.7% of the infants developed ASD. Infant gender and the presence of >1 older affected sibling were significant predictors of ASD outcome, and there was an almost threefold increase in risk for male subjects and an additional twofold increase in risk if there was >1 older affected sibling. The age of the infant at study enrollment, the gender and functioning level of the infant's older sibling, and other demographic factors did not predict ASD outcome. CONCLUSIONS: The sibling recurrence rate of ASD is higher than suggested by previous estimates. The size of the current sample and prospective nature of data collection minimized many limitations of previous studies of sibling recurrence. Clinical implications, including genetic counseling, are discussed.

CONTEXT: The natural history of biochemical recurrence after radical prostatectomy can be long but variable. Better risk assessment models are needed to identify men who are at high risk for prostate cancer death early and who may benefit from aggressive salvage treatment and to identify men who are at low risk for prostate cancer death and can be safely observed. OBJECTIVES: To define risk factors for prostate cancer death following radical prostatectomy and to develop tables to risk stratify for prostate cancer-specific survival. DESIGN, SETTING, AND PATIENTS: Retrospective cohort study of 379 men who had undergone radical prostatectomy at an urban tertiary care hospital between 1982 and 2000 and who had a biochemical recurrence and after biochemical failure had at least 2 prostate-specific antigen (PSA) values at least 3 months apart in order to calculate PSA doubling time (PSADT). The mean (SD) follow-up after surgery was 10.3 (4.7) years and median follow-up was 10 years (range, 1-20 years). MAIN OUTCOME MEASURE: Prostate cancer-specific mortality. RESULTS: Median survival had not been reached after 16 years of follow-up after biochemical recurrence. Prostate-specific doubling time (<3.0 vs 3.0-8.9 vs 9.0-14.9 vs > or =15.0 months), pathological Gleason score (< or =7 vs 8-10), and time from surgery to biochemical recurrence (< or =3 vs >3 years) were all significant risk factors for time to prostate-specific mortality. Using these 3 variables, tables were constructed to estimate the risk of prostate cancer-specific survival at year 15 after biochemical recurrence. CONCLUSION: Clinical parameters (PSADT, pathological Gleason score, and time from surgery to biochemical recurrence) can help risk stratify patients for prostate cancer-specific mortality following biochemical recurrence after radical prostatectomy. These preliminary findings may serve as useful guides to patients and their physicians to identify patients at high risk for prostate cancer-specific mortality following biochemical recurrence after radical prostatectomy to enroll them in early aggressive treatment trials. In addition, these preliminary findings highlight that survival in low-risk patients can be quite prolonged.

BACKGROUND: Ewing's sarcoma and primitive neuroectodermal tumor of bone are closely related, highly malignant tumors of children, adolescents, and young adults. A new drug combination, ifosfamide and etoposide, was highly effective in patients with Ewing's sarcoma or primitive neuroectodermal tumor of bone who had a relapse after standard therapy. We designed a study to test whether the addition of these drugs to a standard regimen would improve the survival of patients with newly diagnosed disease. METHODS: Patients 30 years old or younger with Ewing's sarcoma, primitive neuroectodermal tumor of bone, or primitive sarcoma of bone were eligible. The patients were randomly assigned to receive 49 weeks of standard chemotherapy with doxorubicin, vincristine, cyclophosphamide, and dactinomycin or experimental therapy with these four drugs alternating with courses of ifosfamide and etoposide. RESULTS: A total of 518 patients met the eligibility requirements. Of 120 patients with metastatic disease, 62 were randomly assigned to the standard-therapy group and 58 to the experimental-therapy group. There was no significant difference in five-year event-free survival between the treatment groups (P=0.81). Among the 398 patients with nonmetastatic disease, the mean (+/-SE) five-year event-free survival among the 198 patients in the experimental-therapy group was 69+/-3 percent, as compared with 54+/-4 percent among the 200 patients in the standard-therapy group (P=0.005). Overall survival was also significantly better among patients in the experimental-therapy group (72+/-3.4 percent vs. 61+/-3.6 percent in the standard-therapy group, P=0.01). CONCLUSIONS: The addition of ifosfamide and etoposide to a standard regimen does not affect the outcome for patients with metastatic disease, but it significantly improves the outcome for patients with nonmetastatic Ewing's sarcoma, primitive neuroectodermal tumor of bone, or primitive sarcoma of bone.

During recent years, the American Diabetes Association (ADA) has published detailed guidelines and recommendations for the management of diabetes in the form of technical reviews, position statements, and consensus statements. Recommendations regarding children and adolescents have generally been included as only a minor portion of these documents. For example, the most recent ADA position statement on “Standards of Medical Care for Patients With Diabetes Mellitus” (last revised October 2003) included “special considerations” for children and adolescents (1). Other position statements included age-specific recommendations for screening for nephropathy (2) and retinopathy (3) in children with diabetes. In addition, the ADA has published guidelines pertaining to certain aspects of diabetes that apply exclusively to children and adolescents, including care of children with diabetes at school (4) and camp (5) and a consensus statement on type 2 diabetes in children and adolescents (6). The purpose of this document is to provide a single resource on current standards of care pertaining specifically to children and adolescents with type 1 diabetes. It is not meant to be an exhaustive compendium on all aspects of the management of pediatric diabetes. However, relevant references are provided and current works in progress are indicated as such. The information provided is based on evidence from published studies whenever possible and, when not, supported by expert opinion or consensus (7). Several excellent detailed guidelines and chapters on type 1 diabetes in pediatric endocrinology texts exist, including those by the International Society of Pediatric and Adolescent Diabetes (ISPAD) (8), by the Australian Pediatric Endocrine Group (www.chw.edu/au/prof/services/endocrinology/apeg), in Lifshitz’s Pediatric Endocrinology (9–11), and by Plotnick and colleagues (12,13). Children have characteristics and needs that dictate different standards of care. The management of diabetes in children must take the major differences between children of various ages and …

This meta-analysis addresses whether achievement goal researchers are using different labels for the same constructs or putting the same labels on different constructs. We systematically examined whether conceptual and methodological differences in the measurement of achievement goals moderated achievement goal intercorrelations and relationships with outcomes. We reviewed 243 correlational studies of self-reported achievement goals comprising a total of 91,087 participants. The items used to measure achievement goals were coded as being goal relevant (future-focused, cognitively represented, competence-related end states that the individual approaches or avoids) and were categorized according to the different conceptual definitions found within the literature. The results indicated that achievement goal-outcome and goal-goal correlations differed significantly depending on the goal scale chosen, the individual items used to assess goal strivings, and sociodemographic characteristics of the sample under study. For example, performance-approach goal scales coded as having a majority of normatively referenced items had a positive correlation with performance outcomes (r = .14), whereas scales with a majority of appearance and evaluative items had a negative relationship (r = -.14). Mastery-approach goal scales that contained goal-relevant language were not significantly related to performance outcomes (r = .05), whereas those that did not contain goal-relevant language had a positive relationship with performance outcomes (r = .14). We concluded that achievement goal researchers are using the same label for conceptually different constructs. This discrepancy between conceptual and operational definitions and the absence of goal-relevant language in achievement goal measures may be preventing productive theory testing, research synthesis, and practical application.

BACKGROUND: We evaluated the safety and efficacy of etanercept, a soluble tumor necrosis factor receptor (p75):Fc fusion protein, in children with polyarticular juvenile rheumatoid arthritis who did not tolerate or had an inadequate response to methotrexate. METHODS: Patients 4 to 17 years old received 0.4 mg of etanercept per kilogram of body weight subcutaneously twice weekly for up to three months in the initial, open-label part of a multicenter trial. Those who responded to treatment then entered a double-blind study and were randomly assigned to receive either placebo or etanercept for four months or until a flare of the disease occurred. A response was defined as an improvement of 30 percent or more in at least three of six indicators of disease activity, with no more than one indicator worsening by more than 30 percent. RESULTS: At the end of the open-label study, 51 of the 69 patients (74 percent) had had responses to etanercept treatment. In the double-blind study, 21 of the 26 patients who received placebo (81 percent) withdrew because of disease flare, as compared with 7 of the 25 patients who received etanercept (28 percent) (P=0.003). The median time to disease flare with placebo was 28 days, as compared with more than 116 days with etanercept (P<0.001). In the double-blind study, there were no significant differences between the two treatment groups in the frequency of adverse events. CONCLUSIONS: Treatment with etanercept leads to significant improvement in patients with active polyarticular juvenile rheumatoid arthritis. Etanercept is well tolerated by pediatric patients.