rubrica

Registri di patologia

  • Emanuele Crocetti1

  1. UO Epidemiologia clinica e descrittiva, ISPO Firenze
Emanuele Crocetti -

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Ricerca bibliografica periodo dal 16 settembre 2014 – 01 dicembre 2014

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Stringa: (("registries"[MeSH Terms] OR "registries"[All Fields] OR "registry"[All Fields]) OR ("registries"[MeSH Terms] OR "registries"[All Fields])) AND (("italy"[MeSH Terms] OR "italy"[All Fields]) OR italian[All Fields]) AND "humans"[MeSH Terms] AND ("2014/09/16"[PDat] : "2014/12/01"[PDat])
1. Virgili G(1), Parravano M, Menchini F, Evans JR. Anti-vascular endothelial growth factor for diabetic macular oedema. Cochrane Database Syst Rev. 2014 Oct 24;10:CD007419. doi: 10.1002/14651858.CD007419.pub4.
Author information: (1)Department of Translational Surgery and Medicine, Eye Clinic, University of Florence, Largo Brambilla, 3, Florence, Italy, 50134. Update of Cochrane Database Syst Rev. 2012;12:CD007419.

Abstract BACKGROUND: Diabetic macular oedema (DMO) is a common complication of diabetic retinopathy. Although grid or focal laser photocoagulation has been shown to reduce the risk of visual loss in DMO, or clinically significant macular oedema (CSMO), vision is rarely improved. Antiangiogenic therapy with anti-vascular endothelial growth factor (anti-VEGF) modalities is used to try to improve vision in people with DMO. OBJECTIVES: To investigate the effects in preserving and improving vision and acceptability, including the safety, compliance with therapy and quality of life, of antiangiogenic therapy with anti-VEGF modalities for the treatment of DMO. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (2014, Issue 3), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to April 2014), EMBASE (January 1980 to April 2014), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to April 2014), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 28 April 2014. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing any antiangiogenic drugs with an anti-VEGF mechanism of action versus another treatment, sham treatment or no treatment in people with DMO. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by The Cochrane Collaboration. The risk ratios (RR) for visual loss and visual gain of three or more lines of logMAR visual acuity were estimated at one year of follow-up (plus or minus six months) after treatment initiation. MAIN RESULTS: Eighteen studies provided data on four comparisons of interest in this review. Participants in the trials had central DMO and moderate vision loss.Compared with grid laser photocoagulation, people treated with antiangiogenic therapy were more likely to gain 3 or more lines of vision at one year (RR 3.6, 95% confidence interval (CI) 2.7 to 4.8, 10 studies, 1333 cases, high quality evidence) and less likely to lose 3 or more lines of vision (RR 0.11, 95% CI 0.05 to 0.24, 7 studies, 1086 cases, high quality evidence). In meta-analyses, no significant subgroup difference was demonstrated between bevacizumab, ranibizumab and aflibercept for the two primary outcomes, but there was little power to detect a difference. The quality of the evidence was judged to be high, because the effect was large, precisely measured and did not vary across studies, although some studies were at high or unclear risk of bias for one or more domains. Regarding absolute benefit, we estimated that 8 out of 100 participants with DMO may gain 3 or more lines of visual acuity using photocoagulation whereas 28 would do so with antiangiogenic therapy, meaning that 100 participants need to be treated with antiangiogenic therapy to allow 20 more people (95% CI 13 to 29) to markedly improve their vision after one year. People treated with anti-VEGF on average had 1.6 lines better vision (95% CI 1.4 to 1.8) after one year compared to laser photocoagulation (9 studies, 1292 cases, high quality evidence). To achieve this result, seven to nine injections were delivered in the first year and three or four in the second, in larger studies adopting either as needed regimens with monthly monitoring or fixed regimens.In other analyses antiangiogenic therapy was more effective than sham (3 studies on 497 analysed participants, high quality evidence) and ranibizumab associated with laser was more effective than laser alone (4 studies on 919 participants, high quality evidence).Ocular severe adverse events, such as endophthalmitis, were rare in the included studies. Meta-analyses conducted for all antiangiogenic drugs compared with either sham or photocoagulation did not show a significant difference regarding serious systemic adverse events (15 studies, 441 events in 2985 participants, RR 0.98, 95% CI 0.83 to 1.17), arterial thromboembolic events (14 studies, 129 events in 3034 participants, RR 0.89, 95% CI 0.63 to 1.25) and overall mortality (63 events in 3562 participants, RR 0.88, 95% CI 0.52 to 1.47). We judged the quality of the evidence on adverse effects as moderate due to partial reporting of safety data and the exclusion of participants with previous cardiovascular events in some studies. AUTHORS' CONCLUSIONS: There is high quality evidence that antiangiogenic drugs provide a benefit compared to current therapeutic options for DMO, that is grid laser photocoagulation, in clinical trial populations at one or two years. Future research should investigate differences between drugs, effectiveness under real-world monitoring and treatment conditions, and safety in high-risk populations, particularly regarding cardiovascular risk.

2. Fu YP(1), Kohaar I(1), Moore LE(2), Lenz P(3), Figueroa JD(2), Tang W(1), Porter-Gill P(1), Chatterjee N(2), Scott-Johnson A(1), Garcia-Closas M(4), Muchmore B(1), Baris D(2), Paquin A(1), Ylaya K(5), Schwenn M(6), Apolo AB(7), Karagas MR(8), Tarway M(1), Johnson A(9), Mumy A(1), Schned A(8), Guedez L(10), Jones MA(11), Kida M(12), Hosain GM(13), Malats N(14), Kogevinas M(15), Tardon A(16), Serra C(17), Carrato A(18), Garcia-Closas R(19), Lloreta J(20), Wu X(21), Purdue M(2), Andriole GL Jr(22), Grubb RL 3rd(22), Black A(2), Landi MT(2), Caporaso NE(2), Vineis P(23), Siddiq A(24), Bueno-de-Mesquita HB(25), Trichopoulos D(26), Ljungberg B(27), Severi G(28), Weiderpass E(29), Krogh V(30), Dorronsoro M(31), Travis RC(32), Tjønneland A(33), Brennan P(34), Chang-Claude J(35), Riboli E(24), Prescott J(36), Chen C(37), De Vivo I(36), Govannucci E(38), Hunter D(37), Kraft P(37), Lindstrom S(37), Gapstur SM(39), Jacobs EJ(39), Diver WR(39), Albanes D(2), Weinstein SJ(2), Virtamo J(40), Kooperberg C(41), Hohensee C(41), Rodabough RJ(41), Cortessis VK(42), Conti DV(43), Gago-Dominguez M(44), Stern MC(43), Pike MC(45), Van Den Berg D(43), Yuan JM(46), Haiman CA(43), Cussenot O(47), Cancel-Tassin G(48), Roupret M(49), Comperat E(49), Porru S(50), Carta A(50), Pavanello S(51), Arici C(50), Mastrangelo G(51), Grossman HB(52), Wang Z(53), Deng X(53), Chung CC(53), Hutchinson A(53), Burdette L(53), Wheeler W(54), Fraumeni J Jr(2), Chanock SJ(2), Hewitt SM(5), Silverman DT(2), Rothman N(2), Prokunina-Olsson L(55). The 19q12 bladder cancer GWAS signal: association with cyclin E function and aggressive disease. Cancer Res. 2014 Oct 15;74(20):5808-18. doi: 10.1158/0008-5472.CAN-14-1531.
Author information: (1)Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. (2)Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. (3)Clinical Research Directorate/Clinical Monitoring Research Program, SAIC-Frederick, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland. (4)Division of Genetics and Epidemiology, Institute of Cancer Research, London, United Kingdom. (5)Laboratory of Pathology, Center of Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. (6)Maine Cancer Registry, Augusta, Maine. (7)Genitourinary Malignancy Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland. (8)Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire. (9)Vermont Cancer Registry, Burlington, Vermont. (10)Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. (11)Department of Pathology and Laboratory Medicine, Maine Medical Center, Portland, Maine. (12)Department of Pathology, University of Vermont College of Medicine, Burlington, Vermont. (13)New Hampshire State Cancer Registry, Concord, New Hampshire. (14)Spanish National Cancer Research Centre, Madrid, Spain. (15)Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain. Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain. National School of Public Health, Athens, Greece. CIBER Epidemiologia y Salud Pública (CIBERESP), Barcelona, Spain. (16)CIBER Epidemiologia y Salud Pública (CIBERESP), Barcelona, Spain. Instituto Universitario de Oncología, Universidad de Oviedo, Oviedo, Spain. (17)CIBER Epidemiologia y Salud Pública (CIBERESP), Barcelona, Spain. Universitat Pompeu Fabra, Barcelona, Spain. (18)Ramón y Cajal Hospital, Madrid, Spain. (19)Unidad de Investigación, Hospital Universitario de Canarias, La Laguna, Spain. (20)Hospital del Mar-IMIM, Univesitat Pompeu Fabra, Barcelona, Spain. (21)Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. (22)Division of Urologic Surgery, Washington University School of Medicine, St. Louis, Missouri. (23)School of Public Health, Imperial College London, London, United Kingdom. Human Genetics Foundation (HuGeF), Torino, Italy. (24)School of Public Health, Imperial College London, London, United Kingdom. (25)National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands. Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, the Netherlands. Department of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, London, United Kingdom. Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia. (26)Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts. Bureau of Epidemiologic Research, Academy of Athens, Athens, Greece. Hellenic Health Foundation, Athens, Greece. (27)Department of Surgical and Perioperative Sciences, Urology and Andrology, Umeå University, Umeå, Sweden. (28)Human Genetics Foundation (HuGeF), Torino, Italy. Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia. Centre for Epidemiology and Biostatistics, University of Melbourne, Australia. (29)Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, Tromsø, Norway. Department of Research, Cancer Registry of Norway, Oslo, Norway. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. Samfundet Folkhälsan, Helsinki, Finland. (30)Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy. (31)Public Health Division of Gipuzkoa, Basque Regional Health Department and Ciberesp-Biodonostia, San Sebastian, Spain. (32)Cancer Epidemiology Unit, University of Oxford, Oxford, United Kingdom. (33)Danish Cancer Society Research Center, Copenhagen, Denmark. (34)International Agency for Research on Cancer, Lyon, France. (35)Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. (36)Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts. (37)Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts. (38)Department of Nutrition and Epidemiology, Harvard School of Public Health, Boston, Massachusetts. (39)Epidemiology Research Program, American Cancer Society, Atlanta, Georgia. (40)National Institute for Health and Welfare, Helsinki, Finland. (41)Fred Hutchinson Cancer Research Center, Division of Public Health Sciences, Seattle, Washington. (42)Department of Obstetrics and Gynecology, Keck School of Medicine of USC, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California. Department of Preventive Medicine, Keck School of Medicine of USC, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California. (43)Department of Preventive Medicine, Keck School of Medicine of USC, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California. (44)Genomic Medicine Group, Galician Foundation of Genomic Medicine, Complejo Hospitalario Universitario de Santiago, Servicio Galego de Saude (SERGAS), Instituto de Investigación Sanitaria de Santiago (IDIS), Santiago de Compostela, Spain. (45)Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York. (46)University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. (47)AP-HP, Hopital Tenon, GHU-Est, Department of Urology, Paris, France. Centre de Recherche sur les Pathologies Prostatiques, Paris, France. UPMC Univ Paris 06, ONCOTYPE-URO, Paris, France. (48)Centre de Recherche sur les Pathologies Prostatiques, Paris, France. UPMC Univ Paris 06, ONCOTYPE-URO, Paris, France. (49)Centre de Recherche sur les Pathologies Prostatiques, Paris, France. UPMC Univ Paris 06, ONCOTYPE-URO, Paris, France. AP-HP, Hopital Pitie-Salpetriere, GHU-Est, Departments of Urology and Pathology, Paris, France. (50)Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy. (51)Department of Cardiac, Thoracic and Vascular Sciences, University of Padova, Padua, Italy. (52)Department of Urology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. (53)Cancer Genomics Research Laboratory, SAIC-Frederick, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland. (54)Information Management Services, Rockville, Maryland. (55)Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. prokuninal@mail.nih.gov.

Abstract A genome-wide association study (GWAS) of bladder cancer identified a genetic marker rs8102137 within the 19q12 region as a novel susceptibility variant. This marker is located upstream of the CCNE1 gene, which encodes cyclin E, a cell-cycle protein. We performed genetic fine-mapping analysis of the CCNE1 region using data from two bladder cancer GWAS (5,942 cases and 10,857 controls). We found that the original GWAS marker rs8102137 represents a group of 47 linked SNPs (with r(2) ≥ 0.7) associated with increased bladder cancer risk. From this group, we selected a functional promoter variant rs7257330, which showed strong allele-specific binding of nuclear proteins in several cell lines. In both GWASs, rs7257330 was associated only with aggressive bladder cancer, with a combined per-allele OR = 1.18 [95% confidence interval (CI), 1.09-1.27, P = 4.67 × 10(-5)] versus OR = 1.01 (95% CI, 0.93-1.10, P = 0.79) for nonaggressive disease, with P = 0.0015 for case-only analysis. Cyclin E protein expression analyzed in 265 bladder tumors was increased in aggressive tumors (P = 0.013) and, independently, with each rs7257330-A risk allele (P(trend) = 0.024). Overexpression of recombinant cyclin E in cell lines caused significant acceleration of cell cycle. In conclusion, we defined the 19q12 signal as the first GWAS signal specific for aggressive bladder cancer. Molecular mechanisms of this genetic association may be related to cyclin E overexpression and alteration of cell cycle in carriers of CCNE1 risk variants. In combination with established bladder cancer risk factors and other somatic and germline genetic markers, the CCNE1 variants could be useful for inclusion into bladder cancer risk prediction models.

3. La Rosa F(1), Liso A(2), Bianconi F(1), Duca E(3), Stracci F(1). Seasonal variation in the month of birth in patients with skin cancer. Br J Cancer. 2014 Oct 28;111(9):1810-3. doi: 10.1038/bjc.2014.522. Epub 2014 Oct 7.
Author information: (1)Department of Experimental Medicine, Public Health Section, University of Perugia, 06126 Perugia, Italy. (2)Department of Medicine and Surgery, University of Foggia, 71122 Foggia, Italy. (3)Department of Health, Regional Government of Umbria, 06124 Perugia, Italy.

Abstract BACKGROUND: Month of birth influences the risk of developing several diseases. We investigated the influence of date of birth on melanoma skin cancer (MSC) and non-melanoma skin cancer (NMSC) incidence. METHODS: Enhanced cancer registry data were analysed including 1751 MSC and 15 200 NMSC. RESULTS: People born in February to April showed significantly elevated risks of NMSC compared with those born in summertime. CONCLUSIONS: We demonstrated seasonality by date of birth for skin cancer incidence. Neonatal UV exposure may explain this finding.

4. Skibola CF(1), Berndt SI(2), Vijai J(3), Conde L(4), Wang Z(5), Yeager M(5), de Bakker PI(6), Birmann BM(7), Vajdic CM(8), Foo JN(9), Bracci PM(10), Vermeulen RC(11), Slager SL(12), de Sanjose S(13), Wang SS(14), Linet MS(2), Salles G(15), Lan Q(2), Severi G(16), Hjalgrim H(17), Lightfoot T(18), Melbye M(19), Gu J(20), Ghesquières H(21), Link BK(22), Morton LM(2), Holly EA(10), Smith A(18), Tinker LF(23), Teras LR(24), Kricker A(25), Becker N(26), Purdue MP(2), Spinelli JJ(27), Zhang Y(28), Giles GG(29), Vineis P(30), Monnereau A(31), Bertrand KA(32), Albanes D(2), Zeleniuch-Jacquotte A(33), Gabbas A(34), Chung CC(2), Burdett L(5), Hutchinson A(5), Lawrence C(35), Montalvan R(35), Liang L(36), Huang J(37), Ma B(38), Liu J(9), Adami HO(39), Glimelius B(40), Ye Y(20), Nowakowski GS(12), Dogan A(41), Thompson CA(42), Habermann TM(42), Novak AJ(42), Liebow M(42), Witzig TE(42), Weiner GJ(22), Schenk M(43), Hartge P(2), De Roos AJ(44), Cozen W(45), Zhi D(46), Akers NK(47), Riby J(4), Smith MT(47), Lacher M(3), Villano DJ(3), Maria A(3), Roman E(18), Kane E(18), Jackson RD(48), North KE(49), Diver WR(24), Turner J(50), Armstrong BK(25), Benavente Y(13), Boffetta P(51), Brennan P(52), Foretova L(53), Maynadie M(54), Staines A(55), McKay J(56), Brooks-Wilson AR(57), Zheng T(28), Holford TR(58), Chamosa S(59), Kaaks R(26), Kelly RS(60), Ohlsson B(61), Travis RC(62), Weiderpass E(63), Clavel J(64), Giovannucci E(65), Kraft P(36), Virtamo J(66), Mazza P(67), Cocco P(34), Ennas MG(68), Chiu BC(69), Fraumeni JF Jr(2), Nieters A(70), Offit K(3), Wu X(20), Cerhan JR(12), Smedby KE(71), Chanock SJ(2), Rothman N(2). Genome-wide association study identifies five susceptibility loci for follicular lymphoma outside the HLA region. Am J Hum Genet. 2014 Oct 2;95(4):462-71. doi: 10.1016/j.ajhg.2014.09.004.
Author information: (1)Department of Epidemiology, School of Public Health and Comprehensive Cancer Center, Birmingham, AL 35233, USA; Division of Environmental Health Sciences, University of California Berkeley School of Public Health, Berkeley, CA 94720, USA. Electronic address: cskibola@uab.edu. (2)Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD 20892, USA. (3)Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (4)Department of Epidemiology, School of Public Health and Comprehensive Cancer Center, Birmingham, AL 35233, USA; Division of Environmental Health Sciences, University of California Berkeley School of Public Health, Berkeley, CA 94720, USA. (5)Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Gaithersburg, MD 20877, USA. (6)Department of Medical Genetics and of Epidemiology, University Medical Center Utrecht, Utrecht 3584 CG, the Netherlands; Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht 3584 CX, the Netherlands. (7)Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. (8)Prince of Wales Clinical School, University of New South Wales, Sydney, NSW 2052, Australia. (9)Human Genetics, Genome Institute of Singapore, Singapore 138672, Singapore. (10)Department of Epidemiology & Biostatistics, University of California, San Francisco, San Francisco, CA 94118, USA. (11)Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht 3584 CX, the Netherlands; Institute for Risk Assessment Sciences, Utrecht University, Utrecht 3508 TD, the Netherlands. (12)Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA. (13)Unit of Infections and Cancer (UNIC), Cancer Epidemiology Research Programme, Institut Catala d'Oncologia, IDIBELL, Barcelona 8907, Spain; Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Barcelona 8036, Spain. (14)Department of Cancer Etiology, City of Hope Beckman Research Institute, Duarte, CA 91030, USA. (15)Department of Hematology, Hospices Civils de Lyon, Pierre benite Cedex 69495, France; Department of Hematology, Université Lyon-1, Pierre benite Cedex 69495, France; Laboratoire de Biologie Moléculaire de la Cellule UMR 5239, Centre National de la Recherche Scientifique, Pierre benite Cedex 69495, France. (16)Human Genetics Foundation, Turin 10126, Italy; Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, VIC 3053, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Carlton, VIC 3010, Australia. (17)Department of Epidemiology Research, Division of Health Surveillance and Research, Statens Serum Institut, Copenhagen 2300, Denmark. (18)Department of Health Sciences, University of York, York YO10 5DD, UK. (19)Department of Epidemiology Research, Division of Health Surveillance and Research, Statens Serum Institut, Copenhagen 2300, Denmark; Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. (20)Department of Epidemiology, M.D. Anderson Cancer Center, Houston, TX 77030, USA. (21)Laboratoire de Biologie Moléculaire de la Cellule UMR 5239, Centre National de la Recherche Scientifique, Pierre benite Cedex 69495, France; Department of Hematology, Centre Léon Bérard, Lyon 69008, France. (22)Department of Internal Medicine, Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USA. (23)Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98117, USA. (24)Epidemiology Research Program, American Cancer Society, Atlanta, GA 30303, USA. (25)Sydney School of Public Health, The University of Sydney, Sydney, NSW 2006, Australia. (26)Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Baden-Württemberg 69120, Germany. (27)Cancer Control Research, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada; School of Population and Public Health, University of British Columbia, Vancouver, BC V6T 1Z3, Canada. (28)Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT 06520, USA. (29)Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, VIC 3053, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Carlton, VIC 3010, Australia. (30)Human Genetics Foundation, Turin 10126, Italy; MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London W2 1PG, UK. (31)Environmental Epidemiology of Cancer Group, Inserm, Centre for Research in Epidemiology and Population Health (CESP), U1018, Villejuif Cedex 94807, France; UMRS 1018, Université Paris Sud, Villejuif Cedex 94807, France; Registre des hémopathies malignes de la Gironde, Institut Bergonié, Bordeaux Cedex 33076, France. (32)Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA. (33)Department of Population Health, New York University School of Medicine, New York, NY 10016, USA; Cancer Institute, New York University School of Medicine, New York, NY 10016, USA. (34)Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Monserrato, Cagliari 09042, Italy. (35)Health Studies Sector, Westat, Rockville, MD 20850, USA. (36)Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA; Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, USA. (37)Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA. (38)Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA; College of Information Science and Technology, Dalian Maritime University, Dalian, Liaoning Province 116026, China. (39)Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 17177, Sweden. (40)Department of Oncology and Pathology, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm 17176, Sweden; Department of Radiology, Oncology and Radiation Science, Uppsala University, Uppsala 75105, Sweden. (41)Departments of Laboratory Medicine and Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (42)Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA. (43)Department of Family Medicine and Public Health Sciences, Wayne State University, Detroit, MI 48201, USA. (44)Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98117, USA; Department of Environmental and Occupational Health, Drexel University School of Public Health, Philadelphia, PA 19104, USA. (45)Department of Preventive Medicine, USC Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Norris Comprehensive Cancer Center, USC Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA. (46)Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL 35233, USA. (47)Division of Environmental Health Sciences, University of California Berkeley School of Public Health, Berkeley, CA 94720, USA. (48)Division of Endocrinology, Diabetes and Metabolism, The Ohio State University, Columbus, OH 43210, USA. (49)Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Carolina Center for Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. (50)Department of Anatomical Pathology, Australian School of Advanced Medicine, Macquarie University, Sydney, NSW 2109, Australia; Department of Histopathology, Douglass Hanly Moir Pathology, Macquarie Park, NSW 2113, Australia. (51)The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (52)Group of Genetic Epidemiology, Section of Genetics, International Agency for Research on Cancer, Lyon 69372, France. (53)Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute and MF MU, Brno 656 53, Czech Republic. (54)EA 4184, Registre des Hémopathies Malignes de Côte d'Or, University of Burgundy and Dijon University Hospital, Dijon 21070, France. (55)School of Nursing and Human Sciences, Dublin City University, Dublin 9, Ireland. (56)Genetic Cancer Susceptibility Group, Section of Genetics, International Agency for Research on Cancer, Lyon 69372, France. (57)Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada; Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC V5A 1S6, Canada. (58)Department of Biostatistics, Yale School of Public Health, New Haven, CT 06520, USA. (59)Health Department, BioDonostia Research Institute, Basque Region 20014, Spain. (60)MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London W2 1PG, UK; Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA. (61)Department of Clinical Sciences, Division of Internal Medicine, Skåne University Hospital, Lund University, Malmö 205 02, Sweden. (62)Cancer Epidemiology Unit, University of Oxford, Oxford OX3 7LF, UK. (63)Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 17177, Sweden; Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, Breivika 9037, Norway; Cancer Registry of Norway, Oslo 0304, Norway; Department of Genetic Epidemiology, Folkhalsan Research Center, Helsinki 00250, Finland. (64)Environmental Epidemiology of Cancer Group, Inserm, Centre for Research in Epidemiology and Population Health (CESP), U1018, Villejuif Cedex 94807, France; UMRS 1018, Université Paris Sud, Villejuif Cedex 94807, France. (65)Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA; Department of Nutrition, Harvard School of Public Health, Boston, MA 02115, USA. (66)Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki 00271, Finland. (67)Department of Hematology, Ospedale Nord, Taranto 74100, Italy. (68)Department of Biomedical Science, University of Cagliari, Monserrato, Cagliari 09042, Italy. (69)Department of Health Studies, University of Chicago, Chicago, IL 60637, USA. (70)Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Baden-Württemberg 79108, Germany. (71)Department of Medicine Solna, Karolinska Institutet, Stockholm 17176, Sweden.

Abstract Genome-wide association studies (GWASs) of follicular lymphoma (FL) have previously identified human leukocyte antigen (HLA) gene variants. To identify additional FL susceptibility loci, we conducted a large-scale two-stage GWAS in 4,523 case subjects and 13,344 control subjects of European ancestry. Five non-HLA loci were associated with FL risk: 11q23.3 (rs4938573, p = 5.79 × 10(-20)) near CXCR5; 11q24.3 (rs4937362, p = 6.76 × 10(-11)) near ETS1; 3q28 (rs6444305, p = 1.10 × 10(-10)) in LPP; 18q21.33 (rs17749561, p = 8.28 × 10(-10)) near BCL2; and 8q24.21 (rs13254990, p = 1.06 × 10(-8)) near PVT1. In an analysis of the HLA region, we identified four linked HLA-DRβ1 multiallelic amino acids at positions 11, 13, 28, and 30 that were associated with FL risk (pomnibus = 4.20 × 10(-67) to 2.67 × 10(-70)). Additional independent signals included rs17203612 in HLA class II (odds ratio [OR(per-allele)] = 1.44; p = 4.59 × 10(-16)) and rs3130437 in HLA class I (OR(per-allele) = 1.23; p = 8.23 × 10(-9)). Our findings further expand the number of loci associated with FL and provide evidence that multiple common variants outside the HLA region make a significant contribution to FL risk.

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Collaborators: Cousminer DL, Stergiakouli E, Berry DJ, Ang W, Groen-Blokhuis MM, Körner A, Siitonen N, Ntalla I, Marinelli M, Perry JR, Kettunen J, Jansen R, Surakka I, Timpson NJ, Ring S, McMahon G, Power C, Wang C, Kähönen M, Viikari J, Lehtimäki T, Middeldorp CM, Hulshoff HE, Neef M, Weise S, Pahkala K, Niinikoski H, Zeggini E, Panoutsopoulou K, Bustamante M, Penninx BW, Murabito J, Torrent M, Dedoussis GV, Kiess W, Boomsma DI, Pennell CE, Raitakari OT, Hyppönen E, Davey Smith G, Ripatti S, McCarthy MI, Widén E, Alizadeh BZ, de Boer RA, Boezen HM, Bruinenberg M, Franke L, van der Harst P, Hillege HL, van der Klauw MM, Navis G, Ormel J, Postma D, Rosmalen JG, Slaets JP, Snieder H, Stolk RP, Wolffenbuttel BH, Wijmenga C, Forouhi N, Kerrison ND, Langenberg C, Scott RA, Sharp SJ, Sims M, Barroso I, Deloukas P, McCarthy MI, Arriola L, Balkau B, Barricarte A, Boeing H, Franks PW, Gonzalez C, Grioni S, Kaaks R, Key TJ, Navarro C, Nilsson PM, Overvad K, Palli D, Panico S, Quirós J, Rolandsson O, Sacerdote C, Sánchez MJ, Slimani N, Tjonneland A, Tumino R, van der A DL, van der Schouw YT, Riboli E, Wareham NJ, Bowtell DD, Green A, Chenevix-Trench G, deFazio A, Gertig D, Webb PM, Brauch H, Justenhoven C, Hamann U, Ko YD, Baisch C, Fischer HP, Pesch B, Rabstein S, Spickenheuer A, Harth V, Aghmesheh M, Amor D, Andrews L, Antill Y, Armitage S, Arnold L, Balleine R, Bankier A, Bastick P, Beesley J, Beilby J, Bennett I, Bennett B, Berry G, Blackburn A, Bogwitz M, Brennan M, Brown M, Buckley M, Burgess M, Burke J, Butow P, Byron K, Callen D, Campbell I, Chauhan D, Chenevix-Trench G, Christian A, Clarke C, Colley A, Cotton D, Crook A, Cui J, Culling B, Cummings M, Dawson SJ, deFazio A, Delatycki M, Dickson R, Dixon J, Dobrovic A, Dudding T, Edkins T, Edwards S, Eisenbruch M, Farshid G, Fawcett S, Fellows A, Fenton G, Field M, Firgaira F, Flanagan J, Fleming J, Fong P, Forbes J, Fox S, French J, Friedlander M, Gaff C, Gardner M, Gattas M, George P, Giles G, Gill G, Goldblatt J, Greening S, Grist S, Eric H, Hardie K, Harris M, Hart S, Hayward N, Healey S, Heiniger L, Hopper J, Humphrey E, Hunt C, James P, Jenkins M, Jones A, Kefford R, Kidd A, Kiely B, Kirk J, Koehler J, Kollias J, Kovalenko S, Lakhani S, Leaming A, Leary J, Lim J, Lindeman G, Lipton L, Lobb L, Mann G, Marsh D, McLachlan SA, Meiser B, Meldrum C, Milne R, Mitchell G, Newman B, O'Connell S, O'Loughlin I, Osborne R, Pachter N, Patterson B, Peters L, Phillips K, Price M, Purser L, Reeve J, Reeve T, Richards R, Rickard E, Robinson B, Rudzki B, Saleh M, Salisbury E, Sambrook J, Saunders C, Saunus J, Sayer R, Scott E, Scott R, Scott C, Seshadri R, Sexton A, Sharma R, Shelling A, Simpson P, Southey M, Spurdle A, Suthers G, Sykes P, Taylor D, Taylor J, Thierry B, Thompson E, Thorne H, Townshend S, Trainer A, Tran L, Tucker K, Tyler J, Visvader J, Walker L, Walpole I, Waring P, Warner B, Warren G, Williams R, Wilson J, Winship I, Wu K, Young MA. Author information: (1)1] MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Box 285 Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK. [2] University of Exeter Medical School, University of Exeter, Exeter EX1 2LU, UK. [3] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK. [4] Department of Twin Research and Genetic Epidemiology, King's College London, London SE1 7EH, UK. [5]. (2)1] MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Box 285 Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK. [2]. (3)1] deCODE Genetics, Reykjavik IS-101, Iceland. [2]. (4)Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK. (5)Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK. (6)1] Department of Epidemiology, Indiana University Richard M Fairbanks School of Public Health, Indianapolis, Indiana 46202, USA. [2] Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana 46202, USA. (7)1] Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02215, USA. [2] Harvard Medical School, Boston, Massachusetts 02115, USA. (8)1] Estonian Genome Center, University of Tartu, Tartu, 51010, Estonia. [2] Divisions of Endocrinology and Genetics and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, Massachusetts 02115, USA. [3] Broad Institute of the Massachusetts Institute of Technology and Harvard University, 140 Cambridge, Massachusetts 02142, USA. [4] Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA. (9)deCODE Genetics, Reykjavik IS-101, Iceland. (10)Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, D-85764 Neuherberg, Germany. (11)School of Women's and Infants' Health, The University of Western Australia, WA-6009, Australia. (12)1] Department of Medical Genetics, University of Lausanne, CH-1005 Lausanne, Switzerland. [2] Swiss Institute of Bioinformatics, CH-1015 Lausanne, Switzerland. (13)Institute for Molecular Medicine Finland (FIMM), University of Helsinki, FI-00014, Finland. (14)Department of Epidemiology Research, Statens Serum Institut, DK-2300 Copenhagen, Denmark. (15)Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina 27599-7400, USA. (16)Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 17177 Stockholm, Sweden. (17)NHLBI's and Boston University's Framingham Heart Study, Framingham, Massachusetts 01702-5827, USA. (18)Science for Life Laboratory, Karolinska Institutet, Stockholm, Box 1031, 17121 Solna, Sweden. (19)1] NHLBI's and Boston University's Framingham Heart Study, Framingham, Massachusetts 01702-5827, USA. [2] Boston University School of Public Health, Department of Biostatistics, Boston, Massachusetts 02118, USA. (20)1] MRC Integrative Epidemiology Unit, University of Bristol, Bristol BS8 2BN, UK. [2] School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK. (21)Department of Epidemiology, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, The Netherlands. (22)MRC Integrative Epidemiology Unit, University of Bristol, Bristol BS8 2BN, UK. (23)1] Institute of Genetics and Biomedical Research, National Research Council, Cagliari, 09042 Sardinia, Italy. [2] University of Sassari, Department of Biomedical Sciences, 07100 Sassari, Italy. (24)1] Icelandic Heart Association, IS-201 Kopavogur, Iceland. [2] University of Iceland, IS-101 Reykjavik, Iceland. (25)1] Department of Internal Medicine, Erasmus MC, 3015 GE Rotterdam, the Netherlands. [2] Netherlands Consortium on Health Aging and National Genomics Initiative, 2300 RC Leiden, the Netherlands. (26)Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, D-17475 Greifswald, Germany. (27)1] Estonian Genome Center, University of Tartu, Tartu, 51010, Estonia. [2] Department of Biotechnology, University of Tartu, 51010 Tartu, Estonia. (28)1] Institute for Molecular Medicine Finland (FIMM), University of Helsinki, FI-00014, Finland. [2] Hjelt Institute, University of Helsinki, FI-00014, Finland. (29)Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", 34137 Trieste, Italy. (30)Genetic Epidemiology Unit Department of Epidemiology, Erasmus MC, 3015 GE, Rotterdam, the Netherlands. (31)Department of Psychiatry, Washington University, St Louis, Missouri 63110, USA. (32)1] The University of Queensland, Queensland Brain Institute, St Lucia, Queensland 4072, Australia. [2] QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia. (33)Department of Biological Psychology, VU University Amsterdam, van der Boechorststraat 1, 1081 BT, Amsterdam, The Netherlands. (34)Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202-3082, USA. (35)Department of Twin Research and Genetic Epidemiology, King's College London, London SE1 7EH, UK. (36)1] Divisions of Endocrinology and Genetics and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, Massachusetts 02115, USA. [2] Broad Institute of the Massachusetts Institute of Technology and Harvard University, 140 Cambridge, Massachusetts 02142, USA. [3] Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts 02142, USA. [4] Center for Biological Sequence Analysis, Department of Systems Biology, Technical 142 University of Denmark, DK-2800 Lyngby, Denmark. (37)Program in Personalized and Genomic Medicine, and Department of Medicine, Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA. (38)MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Box 285 Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK. (39)1] Ontario Cancer Genetics Network, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada. [2] Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada. (40)Department of Epidemiology, University of California Irvine, Irvine, California 92697-7550, USA. (41)Sanquin Research, 6525 GA Nijmegen, The Netherlands. (42)1] Tuscany Regional Health Agency, Florence, Italy, I.O.T. and Department of Medical and Surgical Critical Care, University of Florence, 50134 Florence, Italy. [2] Geriatric Unit, Azienda Sanitaria di Firenze, 50122 Florence, Italy. (43)University Breast Center Franconia, Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, D-91054 Erlangen, Germany. (44)1] Human Genetics Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), E-28029 Madrid, Spain. [2] Centro de Investigación en Red de Enfermedades Raras (CIBERER), E-46010 Valencia, Spain. (45)Department of Oncology, University of Helsinki and Helsinki University Central Hospital, FI-00100 Helsinki, Finland. (46)1] Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, University of Copenhagen, DK-2100 Copenhagen, Denmark. [2] Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, University of Copenhagen, DK-2100 Copenhagen, Denmark. (47)Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia (IEO), 20139 Milan, Italy. (48)1] DrMargarete Fischer-Bosch-Institute of Clinical Pharmacology, D-70376 Stuttgart, Germany. [2] University of Tübingen, D-72074 Tübingen, Germany. (49)1] Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany. [2] German Cancer Consortium (DKTK), D-69120 Heidelberg, Germany. (50)Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany. (51)Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland 20892, USA. (52)1] Departments of Anatomy and Neurological Surgery, Indiana University school of Medicine, Indianapolis, Indiana 46202, USA. [2] Stark Neuroscience Research Center, Indiana University school of Medicine, Indianapolis, Indiana 46202, USA. (53)Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006 Australia. (54)Department of Clinical Genetics, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands. (55)Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota 55905, USA. (56)Department of Biostatistics, University of North Carolina, Chapel Hill, North Carolina 27599-7420, USA. (57)Boston University School of Medicine, Department of Medicine, Sections of Preventive Medicine and Endocrinology, Boston, Massachusetts 02118, USA. (58)Sheffield Cancer Research Centre, Department of Oncology, University of Sheffield, Sheffield S10 2RX, UK. (59)1] Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", 34137 Trieste, Italy. [2] Department of Clinical Medical Sciences, Surgical and Health, University of Trieste, 34149 Trieste, Italy. (60)1] Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts 02115, USA. [2] Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA. (61)Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota 55455, USA. (62)Department of Human Genetics &Department of Pathology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands. (63)Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge CB1 8RN, UK. (64)Icelandic Heart Association, IS-201 Kopavogur, Iceland. (65)1] National Institute for Health and Welfare, P.O. Box 30, FI-00271 Helsinki, Finland. [2] Department of General Practice and Primary health Care, University of Helsinki, FI-00014 Helsinki, Finland. [3] Helsinki University Central Hospital, Unit of General Practice, FI-00029 HUS Helsinki, Finland. [4] Folkhalsan Research Centre, FI-00290 Helsinki, Finland. (66)Longitudinal Studies Section, Clinical Research Branch, Gerontology Research Center, National Institute on Aging, Baltimore, Maryland 20892, USA. (67)Department of Cancer Epidemiology/Clinical Cancer Registry and Institute for Medical Biometrics and Epidemiology, University Clinic Hamburg-Eppendorf, D-20246 Hamburg, Germany. (68)Department of Breast Surgery, Herlev Hospital, Copenhagen University Hospital, DK-2100 Copenhagen, Denmark. (69)Department of Genetics, University of Groningen, University Medical Centre Groningen, P.O. Box 72, 9700 AB Groningen, The Netherlands. (70)National Insitute on Aging, National Institutes of Health, Baltimore, Maryland 20892, USA. (71)1] Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK. [2] Breakthrough Breast Cancer Research Centre, Division of Breast Cancer Research, The Institute of Cancer Research, London SW3 6JB, UK. (72)1] Department of Biological Psychology, VU University Amsterdam, van der Boechorststraat 1, 1081 BT, Amsterdam, The Netherlands. [2] EMGO + Institute for Health and Care Research, VU University Medical Centre, Van der Boechorststraat 7, 1081 Bt, Amsterdam, The Netherlands. (73)1] Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria 3004, Australia. [2] Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria 3010, Australia. (74)1] deCODE Genetics, Reykjavik IS-101, Iceland. [2] Faculty of Medicine, University of Iceland, IS-101 Reykjavik, Iceland. (75)1] Inserm (National Institute of Health and Medical Research), CESP (Center for Research in Epidemiology and Population Health), U1018, Environmental Epidemiology of Cancer, F-94807 Villejuif, France. [2] University Paris-Sud, UMRS 1018, F-94807 Villejuif, France. (76)Department of Obstetrics and Gynecology, Southern Medical University, 510515 Guangzhou, China. (77)Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum (DKFZ), D-69120 Heidelberg, Germany. (78)Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, D-17475 Greifswald, Germany. (79)Department of Psychiatry, University of Groningen, University Medical Center Groningen, P.O. Box 72, 9700 AB Groningen, The Netherlands. (80)Washington University, Department of Psychiatry, St Louis, Missouri 63110, USA. (81)Department of Epidemiology, Erasmus MC, PO Box 2040, 3000 CA Rotterdam, the Netherlands. (82)Department of Medical Oncology, Erasmus University Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands. (83)Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria 3010, Australia. (84)1] Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts 02115, USA. [2] Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA. [3] Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts 02115, USA. (85)1] Broad Institute of the Massachusetts Institute of Technology and Harvard University, 140 Cambridge, Massachusetts 02142, USA. [2] Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts 02115, USA. [3] Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA. (86)1] Harvard Medical School, Boston, Massachusetts 02115, USA. [2] Hebrew SeniorLife Institute for Aging Research, Boston, Massachusetts 02131, USA. (87)1] Hebrew SeniorLife Institute for Aging Research, Boston, Massachusetts 02131, USA. [2] Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02115, USA. (88)1] Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada. [2] Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario M5T 3M7, Canada. (89)1] School of Medicine, Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland. [2] Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, P.O. Box 100, FI-70029 Kuopio, Finland. (90)Institute of Genetics and Biomedical Research, National Research Council, Cagliari, 09042 Sardinia, Italy. (91)1] Vesalius Research Center (VRC), VIB, 3000 Leuven, Belgium. [2] Laboratory for Translational Genetics, Department of Oncology, University of Leuven, 3000 Leuven, Belgium. (92)Department of Molecular Medicine and Surgery, Karolinska Institutet, SE-171 77 Stockholm, Sweden. (93)Estonian Genome Center, University of Tartu, Tartu, 51010, Estonia. (94)School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK. (95)1] Department of Epidemiology Research, Statens Serum Institut, DK-2300 Copenhagen, Denmark. [2] Department of Medicine, Stanford School of Medicine, Stanford, California 94305-5101, USA. (96)Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, P.O. Box 100, FI-00029 HUS Helsinki, Finland. (97)KULeuven (University of Leuven), Department of Oncology, Multidisciplinary Breast Center, University Hospitals Leuven, 3000 Leuven, Belgium. (98)Research Unit of Obstetrics &Gynecology, Institute of Clinical Research, University of Southern Denmark, DK-5000 Odense C, Denmark. (99)Interdisciplinary Center Psychopathology and Emotion Regulation, University of Groningen, University Medical Center Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands. (100)1] Institute for Molecular Medicine Finland (FIMM), University of Helsinki, FI-00014, Finland. [2] Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. [3] Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts 02142, USA. [4] Psychiatric &Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. (101)Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA. (102)IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, 20139 Milan, Italy. (103)Non-communicable Disease Epidemiology Department, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK. (104)University Groningen, University Medical Center Groningen, Department Pulmonary Medicine and Tuberculosis, GRIAC Research Institute, P.O. Box 30.001, NL-9700 RB Groningen, The Netherlands. (105)1] National Institute for Health and Welfare, P.O. Box 30, FI-00271 Helsinki, Finland. [2] Department of Obstetrics and Gynecology, Oulu University Hospital, P.O. Box 10, FI-90029 OYS Oulu, Finland. (106)Laboratory of Cancer Genetics and Tumor Biology, Department of Clinical Chemistry and Biocenter Oulu, University of Oulu, Oulu University Hospital/NordLab Oulu, P.O. Box 3000, FI-90014 Oulu, Finland. (107)Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), 20133 Milan, Italy. (108)1] Department of Internal Medicine, Erasmus MC, 3015 GE Rotterdam, the Netherlands. [2] Netherlands Consortium on Health Aging and National Genomics Initiative, 2300 RC Leiden, the Netherlands. [3] Department of Epidemiology, Erasmus MC, PO Box 2040, 3000 CA Rotterdam, the Netherlands. (109)Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02215, USA. (110)National Institute for Health and Welfare, P.O. Box 30, FI-00271 Helsinki, Finland. (111)National Institute on Aging, Intramural Research Program, Baltimore, Maryland 21224-6825, USA. (112)Netherlands Cancer Institute, Antoni van Leeuwenhoek hospital, Postbus 90203, 1006 BE Amsterdam, The Netherlands. (113)Department of Pathology, The University of Melbourne, Melbourne, Victoria 3010, Australia. (114)1] Department of Epidemiology and Biostatistics, MRC Health Protection Agency (HPA) Centre for Environment and Health, School of Public Health, Imperial College London, London W2 1PG, UK. [2] Department of Obstetrics and Gynaecology, University of Cambridge, Cambridge CB2 0SW, UK. (115)1] Institute of Epidemiology II, Helmholtz Zentrum München - German Research Center for Environmental Health, D-8576 Neuherberg, Germany. [2] Department of Obstetrics and Gynaecology, Campus Grosshadern, Ludwig-Maximilians-University, D-81377 Munich, Germany. (116)Department of Internal Medicine, Erasmus MC, 3015 GE Rotterdam, the Netherlands. (117)Department of Internal Medicine, Lausanne University Hospital, CH-1015 Lausanne, Switzerland. (118)1] Institute for Community Medicine, University Medicine Greifswald, D-17475 Greifswald, Germany. [2] DZHK (German Centre for Cardiovascular Research), partner site Greifswald, D-17475 Greifswald, Germany. (119)Research Unit of Molecular Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, D-8576 Neuherberg, Germany. (120)1] Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, D-17475 Greifswald, Germany. [2] DZHK (German Centre for Cardiovascular Research), partner site Greifswald, D-17475 Greifswald, Germany. (121)Department of Endocrinology, University of Groningen, University Medical Centre Groningen, P.O. Box 72, 9700 AB Groningen, The Netherlands. (122)Queensland Insitute of Medical Research, Brisbane, Queensland 4029, Australia. (123)1] Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202-3082, USA. [2] Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA. (124)Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge, Cambridge CB2 0QQ, UK. (125)1] MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Box 285 Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK. [2] Genetics of Obesity and Related Metabolic Traits Program, The Charles Bronfman Institute for Personalized Medicine, The Mindich Child Health and Development Institute, Department of Preventive Medicine, Icahn School of Medicine at Mount Sinai, 1 Gustave L Levy Place, Box 1003, New York, New York 10029, USA. (126)1] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK. [2] NIHR Oxford Biomedical Research Centre, Churchill Hospital, Oxford OX3 7LE, UK. [3] Oxford Centre for Diabetes, Endocrinology, &Metabolism, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK. (127)1] Program in Personalized and Genomic Medicine, and Department of Medicine, Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA. [2] Geriatric Research and Education Clinical Center (GRECC) - Veterans Administration Medical Center, Baltimore, Maryland 21201, USA. (128)1] Netherlands Consortium on Health Aging and National Genomics Initiative, 2300 RC Leiden, the Netherlands. [2] Genetic Epidemiology Unit Department of Epidemiology, Erasmus MC, 3015 GE, Rotterdam, the Netherlands. [3] Centre of Medical Systems Biology, PO Box 9600, 2300 RC Leiden, the Netherlands. (129)Human Genetics Center and Divof Epidemiology, University of Houston, P.O. Box 20186, Texas 77025 USA. (130)Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Box 256, 751 05 Uppsala, Sweden. (131)1] Department of Epidemiology and Biostatistics, MRC Health Protection Agency (HPA) Centre for Environment and Health, School of Public Health, Imperial College London, London W2 1PG, UK. [2] Institute of Health Sciences, University of Oulu, P.O. Box 5000, FI-90014 Oulu, Finland. [3] Biocenter Oulu, University of Oulu, P.O. Box 5000, Aapistie 5A, FI-90014 Oulu, Finland. [4] Department of Children and Young People and Families, National Institute for Health and Welfare, Aapistie 1, Box 310, FI-90101 Oulu, Finland. [5] Unit of Primary Care, Oulu University Hospital, Kajaanintie 50, P.O. Box 20, FI-90220 Oulu, 90029 OYS, Finland. (132)1] Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts 02115, USA. [2] Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts 02115, USA. (133)1] Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200, Denmark. [2] Institute of Preventive Medicine, Bispebjerg and Frederiksberg Hospitals, The Capital Region, Copenhagen, DK-2000 Frederiksberg, Denmark. (134)Division of Population Health Sciences and Education, St George's, University of London, Cranmer Terrace, London SW17 0RE, UK. (135)Department of Obstetrics and Gynecology, University Medicine Greifswald, D-17475 Greifswald, Germany. (136)University of Exeter Medical School, University of Exeter, Exeter EX1 2LU, UK. (137)1] deCODE Genetics, Reykjavik IS-101, Iceland. [2] Faculty of Medicine, University of Iceland, IS-101 Reykjavik, Iceland. [3]. (138)1] NHLBI's and Boston University's Framingham Heart Study, Framingham, Massachusetts 01702-5827, USA. [2] Boston University School of Medicine, Department of Medicine, Section of General Internal Medicine, Boston, Massachusetts 02118, USA. [3]. (139)1] MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Box 285 Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK. [2] Department of Paediatrics, University of Cambridge, Cambridge CB2 0QQ, UK. [3].

Abstract Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.

6. Al Olama AA(1), Kote-Jarai Z(2), Berndt SI(3), Conti DV(4), Schumacher F(4), Han Y(5), Benlloch S(6), Hazelett DJ(4), Wang Z(7), Saunders E(8), Leongamornlert D(8), Lindstrom S(9), Jugurnauth-Little S(8), Dadaev T(8), Tymrakiewicz M(8), Stram DO(4), Rand K(5), Wan P(5), Stram A(5), Sheng X(5), Pooler LC(5), Park K(5), Xia L(5), Tyrer J(6), Kolonel LN(10), Le Marchand L(10), Hoover RN(3), Machiela MJ(3), Yeager M(3), Burdette L(3), Chung CC(3), Hutchinson A(3), Yu K(3), Goh C(8), Ahmed M(8), Govindasami K(8), Guy M(8), Tammela TL(11), Auvinen A(12), Wahlfors T(13), Schleutker J(14), Visakorpi T(15), Leinonen KA(15), Xu J(16), Aly M(17), Donovan J(18), Travis RC(19), Key TJ(19), Siddiq A(20), Canzian F(21), Khaw KT(22), Takahashi A(23), Kubo M(24), Pharoah P(25), Pashayan N(25), Weischer M(26), Nordestgaard BG(27), Nielsen SF(27), Klarskov P(28), Røder MA(29), Iversen P(29), Thibodeau SN(30), McDonnell SK(30), Schaid DJ(30), Stanford JL(31), Kolb S(32), Holt S(33), Knudsen B(34), Coll AH(35), Gapstur SM(36), Diver WR(36), Stevens VL(36), Maier C(37), Luedeke M(37), Herkommer K(38), Rinckleb AE(37), Strom SS(39), Pettaway C(40), Yeboah ED(41), Tettey Y(41), Biritwum RB(41), Adjei AA(41), Tay E(41), Truelove A(42), Niwa S(42), Chokkalingam AP(43), Cannon-Albright L(44), Cybulski C(45), Wokołorczyk D(45), Kluźniak W(45), Park J(46), Sellers T(46), Lin HY(47), Isaacs WB(48), Partin AW(48), Brenner H(49), Dieffenbach AK(49), Stegmaier C(50), Chen C(9), Giovannucci EL(51), Ma J(52), Stampfer M(53), Penney KL(54), Mucci L(54), John EM(55), Ingles SA(4), Kittles RA(56), Murphy AB(57), Pandha H(58), Michael A(58), Kierzek AM(58), Blot W(59), Signorello LB(54), Zheng W(60), Albanes D(61), Virtamo J(62), Weinstein S(61), Nemesure B(63), Carpten J(64), Leske C(63), Wu SY(63), Hennis A(65), Kibel AS(66), Rybicki BA(67), Neslund-Dudas C(67), Hsing AW(55), Chu L(55), Goodman PJ(68), Klein EA(69), Zheng SL(16), Batra J(70), Clements J(70), Spurdle A(71), Teixeira MR(72), Paulo P(73), Maia S(73), Slavov C(74), Kaneva R(75), Mitev V(75), Witte JS(76), Casey G(4), Gillanders EM(77), Seminara D(77), Riboli E(78), Hamdy FC(79), Coetzee GA(4), Li Q(80), Freedman ML(80), Hunter DJ(9), Muir K(81), Gronberg H(82), Neal DE(83), Southey M(84), Giles GG(85), Severi G(86); Breast and Prostate Cancer Cohort Consortium (BPC3); PRACTICAL (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome) Consortium; COGS (Collaborative Oncological Gene-environment Study) Consortium; GAME-ON/ELLIPSE Consortium, Cook MB(87), Nakagawa H(88), Wiklund F(89), Kraft P(90), Chanock SJ(87), Henderson BE(91), Easton DF(1), Eeles RA(92), Haiman CA(91). A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer. Nat Genet. 2014 Oct;46(10):1103-9. doi: 10.1038/ng.3094. Epub 2014 Sep 14.
Author information: (1)1] Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. [2]. (2)1] Institute of Cancer Research, London, UK. [2]. (3)Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institute of Health, Bethesda, Maryland, USA. (4)1] Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA. [2] Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, USA. (5)Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA. (6)Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. (7)1] Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institute of Health, Bethesda, Maryland, USA. [2] Cancer Genomics Research Laboratory, National Cancer Institute, Division of Cancer Epidemiology and Genetics, SAIC-Frederick, Inc., Frederick, Maryland, USA. (8)Institute of Cancer Research, London, UK. (9)Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA. (10)Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA. (11)Department of Urology, Tampere University Hospital and Medical School, University of Tampere, Tampere, Finland. (12)Department of Epidemiology, School of Health Sciences, University of Tampere, Tampere, Finland. (13)BioMediTech, University of Tampere and FimLab Laboratories, Tampere, Finland. (14)1] BioMediTech, University of Tampere and FimLab Laboratories, Tampere, Finland. [2] Department of Medical Biochemistry, Institute of Biomedicine, University of Turku, Turku, Finland. (15)Institute of Biomedical Technology/BioMediTech, University of Tampere and Tampere University Hospital, Tampere, Finland. (16)Center for Cancer Genomics, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA. (17)1] Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden. [2] Department of Clinical Sciences at Danderyds Hospital, Stockholm, Sweden. (18)School of Social and Community Medicine, University of Bristol, Bristol, UK. (19)Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK. (20)Department of Genomics of Common Disease, School of Public Health, Imperial College London, London, UK. (21)Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany. (22)Clinical Gerontology Unit, University of Cambridge, Cambridge, UK. (23)Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. (24)Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. (25)Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK. (26)Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark. (27)1] Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark. [2] Faculty of Healthy and Medical Sciences, University of Copenhagen, Herlev, Denmark. (28)Department of Urology, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark. (29)Copenhagen Prostate Cancer Center, Department of Urology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. (30)Mayo Clinic, Rochester, Minnesota, USA. (31)1] Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. [2] Department of Epidemiology, School of Public Health, University of Washington, Seattle, Washington, USA. (32)Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. (33)Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. (34)Translational Pathology, Cedars-Sinai, Los Angeles, California, USA. (35)Prostate Center, Vancouver, British Columbia, Canada. (36)Epidemiology Research Program, American Cancer Society, Atlanta, Georgia, USA. (37)Department of Urology, University Hospital Ulm, Ulm, Germany. (38)Department of Urology, Klinikum Rechts der Isar der Technischen Universität München, Munich, Germany. (39)Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA. (40)Department of Urology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA. (41)1] University of Ghana Medical School, Accra, Ghana. [2] Korle Bu Teaching Hospital, Accra, Ghana. (42)Westat, Rockville, Maryland, USA. (43)School of Public Health, University of California, Berkeley, Berkeley, California, USA. (44)1] Division of Genetic Epidemiology, Department of Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA. [2] George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, Utah, USA. (45)International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland. (46)Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida, USA. (47)Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, Florida, USA. (48)James Buchanan Brady Urological Institute, Johns Hopkins Hospital and Medical Institution, Baltimore, Maryland, USA. (49)1] Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany. [2] German Cancer Consortium, Heidelberg, Germany. (50)Saarland Cancer Registry, Saarbrücken, Germany. (51)1] Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA. [2] Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA. (52)Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. (53)1] Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA. [2] Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA. [3] Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. (54)1] Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA. [2] Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. (55)1] Cancer Prevention Institute of California, Fremont, California, USA. [2] Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California, USA. (56)Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA. (57)Department of Urology, Northwestern University, Chicago, Illinois, USA. (58)Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK. (59)1] International Epidemiology Institute, Rockville, Maryland, USA. [2] Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA. (60)Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA. (61)Nutritional Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institute of Health, Bethesda, Maryland, USA. (62)Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland. (63)Department of Preventive Medicine, Stony Brook University, Stony Brook, New York, USA. (64)Translational Genomics Research Institute, Phoenix, Arizona, USA. (65)1] Department of Preventive Medicine, Stony Brook University, Stony Brook, New York, USA. [2] Chronic Disease Research Centre, University of the West Indies, Bridgetown, Barbados. (66)Division of Urologic Surgery, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. (67)Department of Public Health Sciences, Henry Ford Hospital, Detroit, Michigan, USA. (68)Southwest Oncology Group Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. (69)Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio, USA. (70)Australian Prostate Cancer Research Centre-Queensland, Institute of Health and Biomedical Innovation and School of Biomedical Science, Queensland University of Technology, Translational Research Institute, Brisbane, Queensland, Australia. (71)Molecular Cancer Epidemiology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. (72)1] Department of Genetics, Portuguese Oncology Institute, Porto, Portugal. [2] Biomedical Sciences Institute, University of Porto, Porto, Portugal. (73)Department of Genetics, Portuguese Oncology Institute, Porto, Portugal. (74)Department of Urology, Medical University-Sofia, Sofia, Bulgaria. (75)Department of Medical Chemistry and Biochemistry, Molecular Medicine Center, Medical University-Sofia, Sofia, Bulgaria. (76)1] Institute for Human Genetics, University of California, San Francisco, San Francisco, California, USA. [2] Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, USA. (77)Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, Maryland, USA. (78)Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK. (79)Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK. (80)Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. (81)1] Institute of Population Health, University of Manchester, Manchester, UK. [2] Warwick Medical School, University of Warwick, Coventry, UK. (82)Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden. (83)1] Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Cambridge, UK. [2] Department of Oncology, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK. (84)Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne, Parkville, Victoria, Australia. (85)1] Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia. [2] Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia. (86)1] Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia. [2] Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia. [3] Human Genetics Foundation, Torino, Italy. (87)1] Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institute of Health, Bethesda, Maryland, USA. [2]. (88)1] Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan. [2]. (89)1] Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden. [2]. (90)1] Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA. [2] Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA. [3]. (91)1] Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA. [2] Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, USA. [3]. (92)1] Institute of Cancer Research, London, UK. [2] Royal Marsden National Health Service (NHS) Foundation Trust, London and Sutton, UK. [3].

Abstract Genome-wide association studies (GWAS) have identified 76 variants associated with prostate cancer risk predominantly in populations of European ancestry. To identify additional susceptibility loci for this common cancer, we conducted a meta-analysis of > 10 million SNPs in 43,303 prostate cancer cases and 43,737 controls from studies in populations of European, African, Japanese and Latino ancestry. Twenty-three new susceptibility loci were identified at association P < 5 × 10(-8); 15 variants were identified among men of European ancestry, 7 were identified in multi-ancestry analyses and 1 was associated with early-onset prostate cancer. These 23 variants, in combination with known prostate cancer risk variants, explain 33% of the familial risk for this disease in European-ancestry populations. These findings provide new regions for investigation into the pathogenesis of prostate cancer and demonstrate the usefulness of combining ancestrally diverse populations to discover risk loci for disease.

7. Ponti A(1), Lynge E(2), James T(3), Májek O(4), von Euler-Chelpin M(2), Anttila A(5), Fitzpatrick P(6), Mano MP(7), Kawai M(8), Scharpantgen A(9), Fracheboud J(10), Hofvind S(11), Vidal C(12), Ascunce N(13), Salas D(14), Bulliard JL(15), Segnan N(7), Kerlikowske K(16), Taplin S(17); ICSN DCIS Working group. International variation in management of screen-detected ductal carcinoma in situ of the breast. Eur J Cancer. 2014 Oct;50(15):2695-704. doi: 10.1016/j.ejca.2014.07.019. Epub 2014 Aug 19.
Collaborators: Broeders M, Danes J, Ederra M, Filliez B, Hakama M, Munoz C, Martinez MG, Mantellini P, Miranda J, Mooney T, Ohuchi N, Robert I, Saito H, Falk RS, Taskinen A, Timmers J, Ventura L, Wagnon MC. Author information: (1)CPO Piemonte, AOU Città della Salute e della Scienza, Torino, Italy. Electronic address: antonio.ponti@cpo.it. (2)Department of Public Health, University of Copenhagen, Copenhagen, Denmark. (3)Department of Surgery, University of Vermont, Burlington, VT, USA. (4)Institute of Biostatistics and Analyses, Masaryk University, Brno, Czech Republic. (5)Mass Screening Registry, Finnish Cancer Registry, Helsinki, Finland. (6)National Cancer Screening Service, Dublin, Ireland. (7)CPO Piemonte, AOU Città della Salute e della Scienza, Torino, Italy. (8)Department of Surgical Oncology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan. (9)Programme Mammographie, Direction de la Santé, Luxembourg. (10)Erasmus Medical Centre, Rotterdam, The Netherlands. (11)The Cancer Registry of Norway, Oslo, Norway. (12)Cancer Detection and Control Programme, Catalan Institute of Oncology, Barcelona, Spain. (13)Breast Cancer Screening Programme, Instituto de Salud Pública, Navarra, Spain. (14)General Directorate Research and Public Health and Centre for Public Health Research, Valencia, Spain. (15)Lausanne University Hospital, Lausanne, Switzerland. (16)Department of Medicine, University of California San Francisco, San Francisco, CA, USA; Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA. (17)Behavioral Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, MD, USA.

Abstract BACKGROUND: Ductal carcinoma in situ (DCIS) incidence has grown with the implementation of screening and its detection varies across International Cancer Screening Network (ICSN) countries. The aim of this survey is to describe the management of screen-detected DCIS in ICSN countries and to evaluate the potential for treatment related morbidity. METHODS: We sought screen-detected DCIS data from the ICSN countries identified during 2004-2008. We adopted standardised data collection forms and analysis and explored DCIS diagnosis and treatment processes ranging from pre-operative diagnosis to type of surgery and radiotherapy. RESULTS: Twelve countries contributed data from a total of 15 screening programmes, all from Europe except the United States of America and Japan. Among women aged 50-69 years, 7,176,050 screening tests and 5324 screen-detected DCIS were reported. From 21% to 93% of DCIS had a pre-operative diagnosis (PO); 67-90% of DCIS received breast conservation surgery (BCS), and in 41-100% of the cases this was followed by radiotherapy; 6.4-59% received sentinel lymph node biopsy (SLNB) only and 0.8-49% axillary dissection (ALND) with 0.6% (range by programmes 0-8.1%) being node positive. Among BCS patients 35% received SLNB only and 4.8% received ALND. Starting in 2006, PO and SLNB use increased while ALND remained stable. SLNB and ALND were associated with larger size and higher grade DCIS lesions. CONCLUSIONS: Variation in DCIS management among screened women is wide and includes lymph node surgery beyond what is currently recommended. This indicates the presence of varying levels of overtreatment and the potential for its reduction.

8. Cervellin G(1), Bonfanti L(1), Picanza A(1), Lippi G(1). Relation of D-dimer and troponin I in patients with new-onset atrial fibrillation. Am J Cardiol. 2014 Oct 1;114(7):1129-30. doi: 10.1016/j.amjcard.2014.07.029. Epub 2014 Jul 29.
Author information: (1)Parma, Italy. Comment on Am J Cardiol. 2013 Nov 1;112(9):1390-5.
9. Zamora-Ros R(1), Sacerdote C(2), Ricceri F(2), Weiderpass E(3), Roswall N(4), Buckland G(5), St-Jules DE(6), Overvad K(7), Kyrø C(4), Fagherazzi G(8), Kvaskoff M(8), Severi G(9), Chang-Claude J(10), Kaaks R(10), Nöthlings U(11), Trichopoulou A(12), Naska A(13), Trichopoulos D(14), Palli D(15), Grioni S(16), Mattiello A(17), Tumino R(18), Gram IT(19), Engeset D(19), Huerta JM(20), Molina-Montes E(21), Argüelles M(22), Amiano P(23), Ardanaz E(24), Ericson U(25), Lindkvist B(26), Nilsson LM(27), Kiemeney LA(28), Ros M(29), Bueno-de-Mesquita HB(30), Peeters PH(31), Khaw KT(32), Wareham NJ(33), Knaze V(34), Romieu I(34), Scalbert A(34), Brennan P(35), Wark P(36), Vineis P(36), Riboli E(36), González CA(5). Flavonoid and lignan intake in relation to bladder cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Br J Cancer. 2014 Oct 28;111(9):1870-80. doi: 10.1038/bjc.2014.459. Epub 2014 Aug 14. Author information: (1)1] Unit of Nutrition, Environment and Cancer, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain [2] Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC), Lyon, France. (2)Center for Cancer Prevention (CPO-Piemonte), and Human Genetic Foundation (HuGeF), Torino, Italy. (3)1] Department of Community Medicine, University of Tromsø, The Arctic University of Norway, Tromsø, Norway [2] Cancer Registry of Norway, Oslo, Norway [3] Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden [4] Samfundet Folkhälsan, Helsinki, Finland. (4)Danish Cancer Society Research Center, Copenhagen, Denmark. (5)Unit of Nutrition, Environment and Cancer, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain. (6)Department of Nutrition, Harvard School of Public Health, Boston, MA, USA. (7)Department of Public Health, Section for Epidemiology, Aarhus University, Aarhus, Denmark. (8)1] Inserm, Centre for research in Epidemiology and Population Health (CESP), U1018, Nutrition, Hormones and Women's Health team, Villejuif, France [2] Paris South University, UMRS 1018, Villejuif, France [3] IGR, F-94805, Villejuif, France. (9)1] Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia [2] Centre for Molecular, Environmental, Genetic, and Analytic Epidemiology, The University of Melbourne, Melbourne, Victoria, Australia. (10)Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany. (11)Department of Nutrition and Food Sciences, Nutritional Epidemiology, University of Bonn, Bonn, Germany. (12)1] Hellenic Health Foundation, Athens, Greece [2] Bureau of Epidemiologic Research, Academy of Athens, Athens, Greece. (13)Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Athens, Greece. (14)1] Hellenic Health Foundation, Athens, Greece [2] Bureau of Epidemiologic Research, Academy of Athens, Athens, Greece [3] Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA. (15)Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute-ISPO, Florence, Italy. (16)Nutritional Epidemiology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. (17)Dipartimento di Medicina Clinica e Chirurgia, Federico II University, Naples, Italy. (18)Cancer Registry and Histopathology Unit, 'Civic MP Arezzo' Hospital, ASP Ragusa, Italy. (19)Department of Community Medicine, University of Tromsø, The Arctic University of Norway, Tromsø, Norway. (20)1] Department of Epidemiology, Murcia Regional Health Council, Murcia, Spain [2] CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain. (21)1] CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain [2] Andalusian School of Public Health, Granada, Spain. (22)Public Health Directorate, Asturias, Spain. (23)1] CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain [2] Public Health Department of Gipuzkoa, BioDonostia Research Institute, Health Department of Basque Region, San Sebastián, Spain. (24)1] CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain [2] Public Health Institute of Navarra, Pamplona, Spain. (25)Diabetes and Cardiovascular disease, Genetic Epidemiology, Department of Clinical Sciences, Lund University, Malmö, Sweden. (26)Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. (27)1] Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden [2] Arcum, Arctic Research Centre at Umeå University, Umeå, Sweden. (28)Department for Health Evidence and Department of Urology, Radboud University Medical Center, Nijmegen, The Netherlands. (29)1] National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands [2] Department of Epidemiology, Biostatistics and HTA, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. (30)1] National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands [2] Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, The Netherlands [3] School of Public Health, Imperial College, London, UK. (31)1] School of Public Health, Imperial College, London, UK [2] Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands. (32)Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. (33)MRC Epidemiology Unit, Cambridge University, Institute of Metabolic Science, Cambridge, UK. (34)Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC), Lyon, France. (35)Genetic Epidemiology Group, Section of Genetics, International Agency for Research on Cancer (IARC), Lyon, France. (36)School of Public Health, Imperial College, London, UK.

Abstract BACKGROUND: There is growing evidence of the protective role of dietary intake of flavonoids and lignans on cancer, but the association with bladder cancer has not been thoroughly investigated in epidemiological studies. We evaluated the association between dietary intakes of total and subclasses of flavonoids and lignans and risk of bladder cancer and its main morphological type, urothelial cell carcinoma (UCC), within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. METHODS: A cohort of 477 312 men and women mostly aged 35-70 years, were recruited in 10 European countries. At baseline, dietary flavonoid and lignan intakes were estimated using centre-specific validated questionnaires and a food composition database based on the Phenol-Explorer, the UK Food Standards Agency and the US Department of Agriculture databases. RESULTS: During an average of 11 years of follow-up, 1575 new cases of primary bladder cancer were identified, of which 1425 were UCC (classified into aggressive (n=430) and non-aggressive (n=413) UCC). No association was found between total flavonoid intake and bladder cancer risk. Among flavonoid subclasses, significant inverse associations with bladder cancer risk were found for intakes of flavonol (hazard ratio comparing fifth with first quintile (HRQ5-Q1) 0.74, 95% confidence interval (CI): 0.61-0.91; P-trend=0.009) and lignans (HRQ5-Q1 0.78, 95% CI: 0.62-0.96; P-trend=0.046). Similar results were observed for overall UCC and aggressive UCC, but not for non-aggressive UCC. CONCLUSIONS: Our study suggests an inverse association between the dietary intakes of flavonols and lignans and risk of bladder cancer, particularly aggressive UCC.

10. Nuti F(1), Civitelli F, Cucchiara S. Long-term safety of immunomodulators in pediatric inflammatory diseases. Paediatr Drugs. 2014 Oct;16(5):343-52. doi: 10.1007/s40272-014-0084-2.
Author information: (1)Department of Pediatrics and Pediatric Neuropsychiatry, Pediatric Gastroenterology and Liver Unit, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy. The medical management of chronic inflammatory disorders in children, including mainly inflammatory bowel diseases and rheumatic diseases, has evolved dramatically over recent years with the advent of disease-modifying drugs such as immunomodulators and biological agents capable of interrupting the inflammatory cascade underlying these disorders. These agents are generally administered in patients who are refractory to conventional therapies. However, there is growing support that their use in the initial phases of these disorders, especially in pediatric patients, could interrupt and cease the inflammatory process. Thus, the aims of therapy have transitioned from symptomatic control to the achievement of deeper remission, including the healing of the inflammatory lesions combined with symptomatic remission. Therefore, more patients are currently receiving immunomodulators or biologics, frequently in addition to corticosteroids. Immunosuppression due to these therapies increases safety concerns, particularly regarding the risk of infections and malignancies. The available literature highlights how the combination of more than one of these therapies, especially if the combination includes corticosteroids, amplifies the risk of severe opportunistic infections. Otherwise, the infections described are mainly mild. Regarding malignancies, the overall risk associated with treatment appears non-significant in pediatric populations, but an appropriate benefit/risk assessment is recommended prior to the introduction of aggressive treatments such as immunomodulants and biologics. The background cancer risk related to the disease itself remains an issue. Protracted follow-up programs are needed, and the results from international multicenter registries are awaited to better understand the true risk related to therapy of these pediatric populations.
11. Russo R(1), Gambale A, Langella C, Andolfo I, Unal S, Iolascon A. Retrospective cohort study of 205 cases with congenital dyserythropoietic anemia type II: definition of clinical and molecular spectrum and identification of new diagnostic scores. Am J Hematol. 2014 Oct;89(10):E169-75. doi: 10.1002/ajh.23800. Epub 2014 Jul 22.
Author information: (1)Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Napoli, Italy; CEINGE Biotecnologie Avanzate, Napoli, Italy.

Abstract Congenital Dyserythropoietic Anemia II (CDA II) is a rare hyporegenerative anemia of variable degree, whose causative gene is SEC23B. More than 60 causative mutations in 142 independent pedigrees have been described so far. However, the prevalence of the CDA II is probably underestimated, since its clinical spectrum was not yet well-defined and thus it is often misdiagnosed with more frequent clinically-related anemias. This study represents the first meta-analysis on clinical and molecular spectrum of CDA II from the largest cohort of cases ever described. We characterized 41 new cases and 18 mutations not yet associated to CDA II, thus expanding the global series to 205 cases (172 unrelated) and the total number of causative variants to 84. The 68.3% of patients are included in our International Registry of CDA II (Napoli, Italy). A genotype-phenotype correlation in three genotypic groups of patients was assessed. To quantify the degree of severity in each patient, a method based on ranking score was performed. We introduced a clinical index to easily discriminate patients with a well-compensated hemolytic anemia from those with ineffective erythropoiesis. Finally, the worldwide geographical distribution of SEC23B alleles highlighted the presence of multiple founder effects in different areas of the world.

14. Cipriani C(1), Carnevale V(2), Biamonte F(2), Piemonte S(2), Pepe J(2), Nieddu L(2), Bilezikian JP(2), Minisola S(2). Hospital care for primary hyperparathyroidism in Italy: a 6-year register-based study. Eur J Endocrinol. 2014 Oct;171(4):481-7. doi: 10.1530/EJE-14-0493. Epub 2014 Jul 11.
Author information: (1)Department of Internal Medicine and Medical Disciplines'Sapienza' University of Rome, Viale del Policlinico 155, 00161 Rome, ItalyUnit of Internal Medicine'Casa Sollievo della Sofferenza' Hospital, IRCCS, Viale dei Cappuccini snc, 71013 San Giovanni Rotondo, Foggia, ItalyFaculty of Economics (L.N.)LUSPIO University, Via delle Sette Chiese 139, 00145 Rome, ItalyMetabolic Bone Diseases UnitDivision of Endocrinology, Department of Medicine, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, New York 10032, USA cristianac@alice.it. (2)Department of Internal Medicine and Medical Disciplines'Sapienza' University of Rome, Viale del Policlinico 155, 00161 Rome, ItalyUnit of Internal Medicine'Casa Sollievo della Sofferenza' Hospital, IRCCS, Viale dei Cappuccini snc, 71013 San Giovanni Rotondo, Foggia, ItalyFaculty of Economics (L.N.)LUSPIO University, Via delle Sette Chiese 139, 00145 Rome, ItalyMetabolic Bone Diseases UnitDivision of Endocrinology, Department of Medicine, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, New York 10032, USA.

Abstract OBJECTIVE: Primary hyperparathyroidism (PHPT) is one of the most frequently diagnosed endocrine disorders, but few studies have focused on hospital management of the disease in Europe. We investigated the frequency of hospital admission for diagnosis and surgical treatment of PHPT in Italy. DESIGN: A retrospective study was conducted for investigating the hospital care for PHPT in Italy. METHODS: We retrieved data from the 'Record of Hospital Discharge' of the Italian Health Ministry, from 2006 to 2011, and analyzed the codes corresponding to PHPT-related diagnoses and surgical procedures. RESULTS: Overall, 46 275 hospitalization episodes for PHPT were identified during the entire period (69% in women and 31% in men; mean age 63.3±39.8 years). Patients' mean age significantly increased during the years (P<0.001). The mean length of stay was 8.2±10.5 days (28% of the episodes requiring <3 days of stay). Admissions for surgical procedures were 12 457 accounting for 26.9% of the total hospitalizations. There was a trend to a significant increase in the percentage of surgery (P<0.05). The mean hospitalization rate for PHPT was 12.9/100 000 inhabitants per year and the trend showed a significant decrease during the period of 2006-2011 (P<0.0001). The mean hospitalization rate for PHPT surgery was 3.65/100 000 per year, which significantly increased over time (P<0.001). CONCLUSIONS: PHPT considerably influences the Italian Hospital healthcare system. We observed a tendency to a decrease in the frequency of hospitalization during the period of 2006-2011, most probably because of economic issues, a concomitant increased age of patients, and, interestingly, also a progressive increase in the percentage of surgical treatment among patients admitted for PHPT.

Breve commento a cura di E. Crocetti
Questo articolo descrive l’utilizzo dell’archivio delle Schede di dimissione ospedaliera del Ministero della salute, al fine di valutare l’ospedalizzazione per diagnosi e trattamenti collegati all’iperparatiroidismo primario (PHP). La valutazione è stata condotta sulle SDO degli anni 2006-1011 utilizzando un algoritmo basato su una serie di codici di diagnosi di dimissione (in tutte le posizioni) e di trattamenti. E’ stata valutata anche la concomitanza di alcune tipiche complicazioni e il costo del ricovero sulla base di una serie di codici DRG (diagnosis-related groups). La patologia viene definita di diagnosi complessa per la presenza di varianti asintomatiche ed anche normocalcemiche. L’epidemiologia del PHP, in termini di frequenza di nuove diagnosi, è stata fortemente influenzata nel tempo dall’introduzione nelle routine analitiche della misura della calcemia e, più recentemente, anche dalla diffusione di esami per la valutazione dell’osteoporosi, soprattutto in donne in menopausa. La standardizzazione per età degli indicatori di ospedalizzazione avrebbe permesso un confronto nel tempo e con altri dati Europei, anche se i criteri di definizione degli episodi di ospedalizzazione possono non essere uguali in tutti gli studi citati. D’altra parte le scelte metodologiche, come sempre accade, condizionano fortemente i risultati (ad esempio considerare ricoveri e non ricoverati, ecc) e possono spiegare almeno in parte le differenze geografiche riportate. Senza entrare nel merito dei risultati e soprattutto dell’analisi statistica, l’articolo è interessante come esempio dell’utilizzo di un flusso informativo sanitario routinario (SDO) ufficiale e disponibile, allo scopo di quantificare il peso ospedaliero di una patologia relativamente rara e complessa, per la quale non sembrano esserci altri strumenti di valutazione epidemiologica. Nel sito del Ministero della Salute è spiegata la modalità di richiesta dei dati SDO (modulo, variabili, ecc) (http://www.salute.gov.it/portale/temi/p2_6.jsp?lingua=italiano&id=3118/&... Ospedalieri&menu=vuoto) e questo articolo è un esempio del loro utilizzo.

13. Borgna-Pignatti C(1), Garani MC, Forni GL, Cappellini MD, Cassinerio E, Fidone C, Spadola V, Maggio A, Restivo Pantalone G, Piga A, Longo F, Gamberini MR, Ricchi P, Costantini S, D'Ascola D, Cianciulli P, Lai ME, Carta MP, Ciancio A, Cavalli P, Putti MC, Barella S, Amendola G, Campisi S, Capra M, Caruso V, Colletta G, Volpato S. Hepatocellular carcinoma in thalassaemia: an update of the Italian Registry. Br J Haematol. 2014 Oct;167(1):121-6. doi: 10.1111/bjh.13009. Epub 2014 Jul 3.
Author information: (1)Dipartimento di Scienze Mediche-Pediatria, Università di Ferrara, Ferrara, Italy.

Abstract The risk of developing hepatocellular carcinoma (HCC) in patients with thalassaemia is increased by transfusion-transmitted infections and haemosiderosis. All Italian Thalassaemia Centres use an ad hoc form to report all diagnoses of HCC to the Italian Registry. Since our last report, in 2002, up to December 2012, 62 new cases were identified, 52% of whom were affected by thalassaemia major (TM) and 45% by thalassaemia intermedia (TI). Two had sickle-thalassaemia (ST). The incidence of the tumour is increasing, possibly because of the longer survival of patients and consequent longer exposure to the noxious effects of the hepatotropic viruses and iron. Three patients were hepatitis B surface antigen-positive, 36 patients showed evidence of past infection with hepatitis B virus (HBV). Fifty-four patients had antibodies against hepatitis C virus (HCV), 43 of whom were HCV RNA positive. Only 4 had no evidence of exposure either to HCV or HBV. The mean liver iron concentration was 8 mg/g dry weight. Therapy included chemoembolization, thermoablation with radiofrequency and surgical excision. Three patients underwent liver transplant, 21 received palliative therapy. As of December 2012, 41 patients had died. The average survival time from HCC detection to death was 11•5 months (1•4-107•2 months). Ultrasonography is recommended every 6 months to enable early diagnosis of HCC, which is crucial to decrease mortality.

14. Di Bari M(1), Balzi D(2), Fracchia S(1), Barchielli A(2), Orso F(1), Sori A(3), Spini S(4), Carrabba N(5), Santoro GM(6), Gensini GF(7), Marchionni N(1); Acute Myocardial Infarction in Florence 2 (AMI Florence-2) Working Group. Decreased usage and increased effectiveness of percutaneous coronary intervention in complex older patients with acute coronary syndromes. Heart. 2014 Oct;100(19):1537-42. doi: 10.1136/heartjnl-2013-305445. Epub 2014 May 26.
Author information: (1)Department of Experimental and Clinical Medicine, Research Unit of Medicine of Aging, University of Florence and Azienda Ospedaliero-Universitaria Careggi, Florence, Italy. (2)Epidemiology Unit, Local Health Unit 10, Florence, Italy. (3)Department of Cardiovascular Medicine, Unit of Internal Medicine and Cardiology, University of Florence and Azienda Ospedaliero-Universitaria Careggi, Florence, Italy. (4)Cardiology Unit, Santa Maria Nuova Hospital, Local Health Unit 10, Florence, Italy. (5)Department of Cardiovascular Medicine, Cardiology Unit 1, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy. (6)Cardiology Unit, Nuovo San Giovanni di Dio Hospital, Local Health Unit 10, Florence, Italy. (7)Department of Experimental and Clinical Medicine, University of Florence, Azienda Ospedaliero-Universitaria Careggi, Fondazione Don Carlo Gnocchi IRCCS, Florence Italy.

Abstract BACKGROUND: Application of percutaneous coronary intervention (PCI) in patients with acute coronary syndromes (ACS) is suboptimal in older frail individuals. This study was conducted to verify if background risk is a risk factor for underuse and diminished effectiveness of PCI in older patients. METHODS: An observational cohort study was conducted using data from the Acute Myocardial Infarction in Florence 2 registry, including all ACS hospitalised in 1 year in the area of Florence, Italy. Patients aged 75+ years were selected, whose background risk was stratified with the Silver Code (SC), a validated tool predicting mortality based upon administrative data. Multivariable OR for PCI application and HR for 1-year mortality by PCI usage were calculated. RESULTS: In 698 patients (358 women, mean age 83 years), of whom 176 had ST-segment elevation myocardial infarction (STEMI), for each point increase in SC score the odds for application of PCI decreased by 11%, whereas the hazard of 1-year mortality increased by 10%, adjusting for positive and negative predictors. PCI reduced 1-year mortality progressively more with increasing SC, with HR (95% CI) of 0.8 (0.19 to 1.21), 0.41 (0.18 to 0.45), 0.41 (0.23 to 0.74) and 0.26 (0.14 to 0.48) for SC of 0-3, 4-6, 7-10 and 11+. CONCLUSIONS: Application of PCI in older ACS patients decreased with increasing background risk. This therapeutic attitude could not be justified by decreasing effectiveness of PCI in more compromised patients: conversely, application of PCI was associated with a long-term survival advantage that increased progressively with background risk, as expressed by SC.

15. Lachmann HJ(1), Papa R(2), Gerhold K(3), Obici L(4), Touitou I(5), Cantarini L(6), Frenkel J(7), Anton J(8), Kone-Paut I(9), Cattalini M(10), Bader-Meunier B(11), Insalaco A(12), Hentgen V(13), Merino R(14), Modesto C(15), Toplak N(16), Berendes R(17), Ozen S(18), Cimaz R(19), Jansson A(20), Brogan PA(21), Hawkins PN(1), Ruperto N(2), Martini A(22), Woo P(21), Gattorno M(2); Paediatric Rheumatology International Trials Organisation (PRINTO), the EUROTRAPS and the Eurofever Project. The phenotype of TNF receptor-associated autoinflammatory syndrome (TRAPS) at presentation: a series of 158 cases from the Eurofever/EUROTRAPS international registry. Ann Rheum Dis. 2014 Dec;73(12):2160-7. doi: 10.1136/annrheumdis-2013-204184. Epub 2013 Aug 21.
Author information: (1)National Amyloidosis Centre, Royal Free Campus, University College Medical School, London, UK. (2)Pediatria II, Istituto Giannina Gaslini, Genova, Italy. (3)Pediatric Pneumology and Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany. (4)Biotechnology Research Laboratories, Amyloid Centre, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. (5)Unit of Autoinflammatory Diseases, CHU Montpellier, UM1, INSERM U844, Montpellier, France. (6)Rheumatology Unit, Policlinico le Scotte, University of Siena, Siena, Italy. (7)Department of Paediatrics, University Medical Center Utrecht, Utrecht, Netherlands. (8)Hospital Sant Joan de Déu, Universitat de Barcelona, Esplugues (Barcelona), Spain. (9)Centre de référence national des maladies auto-inflammatoires, CEREMAI, rhumatologie pediatrique, CHU Le Kremlin Bicetre (University of Paris SUD, APHP), Le kremlin Bicetre (Paris), France. (10)Dipartimento di Pediatria, Unità di Immunologia e Reumatologia Pediatrica, Clinica Pediatrica dell'Università di Brescia, Spedali Civili, Brescia, Italy. (11)Unité d'Immunologie, Hématologie et Rhumatologie Pediatrique, Université Paris-Descartes, Hôpital Necker-Enfants Malades, Centre de référence national pour les Arthrites Juveniles, APHP, IHU Imagine, Paris, France. (12)Reumatologia, Ospedale Pediatrico Bambin Gesù, Roma, Italy. (13)Service de pediatrie generale, Hopital A Mignot, Centre de référence national des maladies auto-inflammatoires, Le Chesnay (Paris), France. (14)Unidad De Reumatologia Pediatrica, Hospital Universitario La Paz, Madrid, Spain. (15)Reumatologia, Hospital Valle de Hebron, Barcelona, Spain. (16)Department of Allergology, Rheumatology and Clinical Immunology, University Children's Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia. (17)Kinderkrankenhaus St. Marien, Landshut, Germany. (18)Department of Pediatric Nephrology and Rheumatology, Hacettepe University, Ankara, Turkey. (19)Dept di Pediatria, Ospedale A Meyer, Firenze, Italy. (20)Rheumatology & Immunology, Dr von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Munich, Germany. (21)Center of Paediatric and Adolescent Rheumatology-UCL, Institute of Child Health and Great Ormond Street Hospital NHS Foundation Trust, London, UK. (22)Istituto Giannina Gaslini, Pediatria II and Università degli Studi di Genova, Genova, Italy.

Abstract OBJECTIVE: To evaluate the genetic findings, demographic features and clinical presentation of tumour necrosis factor receptor-associated autoinflammatory syndrome (TRAPS) in patients from the Eurofever/EUROTRAPS international registry. METHODS: A web-based registry collected retrospective data on patients with TNFRSF1A sequence variants and inflammatory symptoms. Participating hospitals included paediatric rheumatology centres and adult centres with a specific interest in autoinflammatory diseases. Cases were independently validated by experts in the disease. RESULTS: Complete information on 158 validated patients was available. The most common TNFRSF1A variant was R92Q (34% of cases), followed by T50M (10%). Cysteine residues were disrupted in 27% of cases, accounting for 39% of sequence variants. A family history was present in 19% of patients with R92Q and 64% of those with other variants. The median age at which symptoms began was 4.3 years but 9.1% of patients presented after 30 years of age. Attacks were recurrent in 88% and the commonest features associated with the pathogenic variants were fever (88%), limb pain (85%), abdominal pain (74%), rash (63%) and eye manifestations (45%). Disease associated with R92Q presented slightly later at a median of 5.7 years with significantly less rash or eye signs and more headaches. Children were more likely than adults to present with lymphadenopathy, periorbital oedema and abdominal pains. AA amyloidosis has developed in 16 (10%) patients at a median age of 43 years. CONCLUSIONS: In this, the largest reported case series to date, the genetic heterogeneity of TRAPS is accompanied by a variable phenotype at presentation. Patients had a median 70 symptomatic days a year, with fever, limb and abdominal pain and rash the commonest symptoms. Overall, there is little evidence of a significant effect of age or genotype on disease features at presentation.

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