Marqués de Valdecilla University Hospital

BACKGROUND: Cetuximab is effective in platinum-resistant recurrent or metastatic squamous-cell carcinoma of the head and neck. We investigated the efficacy of cetuximab plus platinum-based chemotherapy as first-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck. METHODS: We randomly assigned 220 of 442 eligible patients with untreated recurrent or metastatic squamous-cell carcinoma of the head and neck to receive cisplatin (at a dose of 100 mg per square meter of body-surface area on day 1) or carboplatin (at an area under the curve of 5 mg per milliliter per minute, as a 1-hour intravenous infusion on day 1) plus fluorouracil (at a dose of 1000 mg per square meter per day for 4 days) every 3 weeks for a maximum of 6 cycles and 222 patients to receive the same chemotherapy plus cetuximab (at a dose of 400 mg per square meter initially, as a 2-hour intravenous infusion, then 250 mg per square meter, as a 1-hour intravenous infusion per week) for a maximum of 6 cycles. Patients with stable disease who received chemotherapy plus cetuximab continued to receive cetuximab until disease progression or unacceptable toxic effects, whichever occurred first. RESULTS: Adding cetuximab to platinum-based chemotherapy with fluorouracil (platinum-fluorouracil) significantly prolonged the median overall survival from 7.4 months in the chemotherapy-alone group to 10.1 months in the group that received chemotherapy plus cetuximab (hazard ratio for death, 0.80; 95% confidence interval, 0.64 to 0.99; P=0.04). The addition of cetuximab prolonged the median progression-free survival time from 3.3 to 5.6 months (hazard ratio for progression, 0.54; P<0.001) and increased the response rate from 20% to 36% (P<0.001). The most common grade 3 or 4 adverse events in the chemotherapy-alone and cetuximab groups were anemia (19% and 13%, respectively), neutropenia (23% and 22%), and thrombocytopenia (11% in both groups). Sepsis occurred in 9 patients in the cetuximab group and in 1 patient in the chemotherapy-alone group (P=0.02). Of 219 patients receiving cetuximab, 9% had grade 3 skin reactions and 3% had grade 3 or 4 infusion-related reactions. There were no cetuximab-related deaths. CONCLUSIONS: As compared with platinum-based chemotherapy plus fluorouracil alone, cetuximab plus platinum-fluorouracil chemotherapy improved overall survival when given as first-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck. (ClinicalTrials.gov number, NCT00122460.)

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

BACKGROUND: Programmed death 1 (PD-1) blockade has clinical benefit in microsatellite-instability-high (MSI-H) or mismatch-repair-deficient (dMMR) tumors after previous therapy. The efficacy of PD-1 blockade as compared with chemotherapy as first-line therapy for MSI-H-dMMR advanced or metastatic colorectal cancer is unknown. METHODS: In this phase 3, open-label trial, 307 patients with metastatic MSI-H-dMMR colorectal cancer who had not previously received treatment were randomly assigned, in a 1:1 ratio, to receive pembrolizumab at a dose of 200 mg every 3 weeks or chemotherapy (5-fluorouracil-based therapy with or without bevacizumab or cetuximab) every 2 weeks. Patients receiving chemotherapy could cross over to pembrolizumab therapy after disease progression. The two primary end points were progression-free survival and overall survival. RESULTS: At the second interim analysis, after a median follow-up (from randomization to data cutoff) of 32.4 months (range, 24.0 to 48.3), pembrolizumab was superior to chemotherapy with respect to progression-free survival (median, 16.5 vs. 8.2 months; hazard ratio, 0.60; 95% confidence interval [CI], 0.45 to 0.80; P = 0.0002). The estimated restricted mean survival after 24 months of follow-up was 13.7 months (range, 12.0 to 15.4) as compared with 10.8 months (range, 9.4 to 12.2). As of the data cutoff date, 56 patients in the pembrolizumab group and 69 in the chemotherapy group had died. Data on overall survival were still evolving (66% of required events had occurred) and remain blinded until the final analysis. An overall response (complete or partial response), as evaluated with Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, was observed in 43.8% of the patients in the pembrolizumab group and 33.1% in the chemotherapy group. Among patients with an overall response, 83% in the pembrolizumab group, as compared with 35% of patients in the chemotherapy group, had ongoing responses at 24 months. Treatment-related adverse events of grade 3 or higher occurred in 22% of the patients in the pembrolizumab group, as compared with 66% (including one patient who died) in the chemotherapy group. CONCLUSIONS: Pembrolizumab led to significantly longer progression-free survival than chemotherapy when received as first-line therapy for MSI-H-dMMR metastatic colorectal cancer, with fewer treatment-related adverse events. (Funded by Merck Sharp and Dohme and by Stand Up to Cancer; KEYNOTE-177 ClinicalTrials.gov number, NCT02563002.).

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

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

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are increasingly a cause of cirrhosis and hepatocellular carcinoma globally. This burden is expected to increase as epidemics of obesity, diabetes and metabolic syndrome continue to grow. The goal of this analysis was to use a Markov model to forecast NAFLD disease burden using currently available data. METHODS: A model was used to estimate NAFLD and NASH disease progression in eight countries based on data for adult prevalence of obesity and type 2 diabetes mellitus (DM). Published estimates and expert consensus were used to build and validate the model projections. RESULTS: If obesity and DM level off in the future, we project a modest growth in total NAFLD cases (0-30%), between 2016-2030, with the highest growth in China as a result of urbanization and the lowest growth in Japan as a result of a shrinking population. However, at the same time, NASH prevalence will increase 15-56%, while liver mortality and advanced liver disease will more than double as a result of an aging/increasing population. CONCLUSIONS: NAFLD and NASH represent a large and growing public health problem and efforts to understand this epidemic and to mitigate the disease burden are needed. If obesity and DM continue to increase at current and historical rates, both NAFLD and NASH prevalence are expected to increase. Since both are reversible, public health campaigns to increase awareness and diagnosis, and to promote diet and exercise can help manage the growth in future disease burden. LAY SUMMARY: Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis can lead to advanced liver disease. Both conditions are becoming increasingly prevalent as the epidemics of obesity and diabetes continue to increase. A mathematical model was built to understand how the disease burden associated with non-alcoholic fatty liver disease and non-alcoholic steatohepatitis will change over time. Results suggest increasing cases of advanced liver disease and liver-related mortality in the coming years.

PURPOSE: Panitumumab, a fully human anti-epidermal growth factor receptor (EGFR) monoclonal antibody that improves progression-free survival (PFS), is approved as monotherapy for patients with chemotherapy-refractory metastatic colorectal cancer (mCRC). The Panitumumab Randomized Trial in Combination With Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy (PRIME) was designed to evaluate the efficacy and safety of panitumumab plus infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as initial treatment for mCRC. PATIENTS AND METHODS: In this multicenter, phase III trial, patients with no prior chemotherapy for mCRC, Eastern Cooperative Oncology Group performance status of 0 to 2, and available tissue for biomarker testing were randomly assigned 1:1 to receive panitumumab-FOLFOX4 versus FOLFOX4. The primary end point was PFS; overall survival (OS) was a secondary end point. Results were prospectively analyzed on an intent-to-treat basis by tumor KRAS status. RESULTS: KRAS results were available for 93% of the 1,183 patients randomly assigned. In the wild-type (WT) KRAS stratum, panitumumab-FOLFOX4 significantly improved PFS compared with FOLFOX4 (median PFS, 9.6 v 8.0 months, respectively; hazard ratio [HR], 0.80; 95% CI, 0.66 to 0.97; P = .02). A nonsignificant increase in OS was also observed for panitumumab-FOLFOX4 versus FOLFOX4 (median OS, 23.9 v 19.7 months, respectively; HR, 0.83; 95% CI, 0.67 to 1.02; P = .072). In the mutant KRAS stratum, PFS was significantly reduced in the panitumumab-FOLFOX4 arm versus the FOLFOX4 arm (HR, 1.29; 95% CI, 1.04 to 1.62; P = .02), and median OS was 15.5 months versus 19.3 months, respectively (HR, 1.24; 95% CI, 0.98 to 1.57; P = .068). Adverse event rates were generally comparable across arms with the exception of toxicities known to be associated with anti-EGFR therapy. CONCLUSION: This study demonstrated that panitumumab-FOLFOX4 was well tolerated and significantly improved PFS in patients with WT KRAS tumors and underscores the importance of KRAS testing for patients with mCRC.

NOD2, a protein associated with susceptibility to Crohn's disease, confers responsiveness to bacterial preparations of lipopolysaccharide and peptidoglycan, but the precise moiety recognized remains elusive. Biochemical and functional analyses identified muramyl dipeptide (MurNAc-l-Ala-d-isoGln) derived from peptidoglycan as the essential structure in bacteria recognized by NOD2. Replacement of l-Ala for d-Ala ord-isoGln for l-isoGln eliminated the ability of muramyl dipeptide to stimulate NOD2, indicating stereoselective recognition. Muramyl dipeptide was recognized by NOD2 but not by TLR2 or co-expression of TLR2 with TLR1 or TLR6. NOD2 mutants associated with susceptibility to Crohn's disease were deficient in their recognition of muramyl dipeptide. Notably, peripheral blood mononuclear cells from individuals homozygous for the major disease-associated L1007fsinsC NOD2 mutation responded to lipopolysaccharide but not to synthetic muramyl dipeptide. Thus, NOD2 mediates the host response to bacterial muropeptides derived from peptidoglycan, an activity that is important for protection against Crohn's disease. Because muramyl dipeptide is the essential structure of peptidoglycan required for adjuvant activity, these results also have implications for understanding adjuvant function and effective vaccine development. NOD2, a protein associated with susceptibility to Crohn's disease, confers responsiveness to bacterial preparations of lipopolysaccharide and peptidoglycan, but the precise moiety recognized remains elusive. Biochemical and functional analyses identified muramyl dipeptide (MurNAc-l-Ala-d-isoGln) derived from peptidoglycan as the essential structure in bacteria recognized by NOD2. Replacement of l-Ala for d-Ala ord-isoGln for l-isoGln eliminated the ability of muramyl dipeptide to stimulate NOD2, indicating stereoselective recognition. Muramyl dipeptide was recognized by NOD2 but not by TLR2 or co-expression of TLR2 with TLR1 or TLR6. NOD2 mutants associated with susceptibility to Crohn's disease were deficient in their recognition of muramyl dipeptide. Notably, peripheral blood mononuclear cells from individuals homozygous for the major disease-associated L1007fsinsC NOD2 mutation responded to lipopolysaccharide but not to synthetic muramyl dipeptide. Thus, NOD2 mediates the host response to bacterial muropeptides derived from peptidoglycan, an activity that is important for protection against Crohn's disease. Because muramyl dipeptide is the essential structure of peptidoglycan required for adjuvant activity, these results also have implications for understanding adjuvant function and effective vaccine development. Innate immunity recognizes invading microbes and triggers a defense response in the host aimed at clearing the invading pathogen. Toll-like receptors (TLRs) 1The abbreviations used are: TLR, Toll-like receptor; LPS, lipopolysaccharide; MDP, muramyl dipeptide MurNAc-l-Ala-d-isoGln; NF-κB, nuclear factor-κB, PBMNC, peripheral blood mononuclear cells; PGN, peptidoglycan; sBLP, synthetic bacterial lipoprotein; HEK, human embryonic kidney; LRR, leucine-rich repeat; HA, hemagglutinin; IL, interleukin; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; EMSA, electrophoretic mobility shift assay; Mur, muramic acid expressed on the surface of myelomonocytic cells play an important role in the recognition of microbial components and activation of innate immunity (1Takeda K. Akira S. Genes Cells. 2001; 6: 733-742Google Scholar). Each membrane-associated TLR recognizes pathogen-associated molecular patterns that are expressed on infectious agents (1Takeda K. Akira S. Genes Cells. 2001; 6: 733-742Google Scholar). Nods, including NOD1 and NOD2, are members of another family of proteins that have been recently implicated in intracellular recognition of bacterial components (2Inohara N. Ogura T. Nuñez G. Curr. Opin. Microbiol. 2002; 5: 76-80Google Scholar, 3Girardin S.E. Sansonetti P.J. Philpott D.J. Trends Microbiol. 2002; 10: 193-199Google Scholar). NOD2 is composed of two NH2-terminal caspase-recruitment domains, a centrally located nucleotide-binding domain and multiple COOH-terminal leucine-rich repeats (LRRs), and is expressed in myelomonocytic and dendritic cells (4Ogura Y. Inohara N. Benito A. Chen F.F. Yamaoka S. Nuñez G. J. Biol. Chem. 2001; 276: 4812-4818Google Scholar, 5Gutierrez O. Pipaon C. Inohara N. Fontalba A. Ogura Y. Prosper F. Nuñez G. Fernandez-Luna J.L. J. Biol. Chem. 2002; 277: 41701-47705Google Scholar). Three genetic variants within the coding region of NOD2, L1007fsinsC, G908R, and R702W, have been genetically associated with susceptibility to Crohn's disease in European and American populations (6Hugot J.P. Chamaillard M. Zouali H. Lesage S. Cezard J.P. Belaiche J. Almer S. Tysk C. O'Morain C.A. Gassull M. Binder V. Finkel Y. Cortot A. Modigliani R. Laurent-Puig P. Gower-Rousseau C. Macry J. Colombel J.F. Sahbatou M. Thomas G. Nature. 2001; 411: 599-603Google Scholar, 7Ogura Y. Bonen D.K. Inohara N. Nicolae D.L. Chen F.F. Ramos R. Britton H. Moran T. Karaliuskas R. Duerr R.H. Achkar J.P. Brant S.R. Bayless T.M. Kirschner B.S. Hanauer S.B. Nuñez G. Cho J.H. Nature. 2001; 411: 603-606Google Scholar, 8Hampe J. Cuthbert A. Croucher P.J. Mirza M.M. Mascheretti S. Fisher S. Frenzel H. King K. Hasselmeyer A. MacPherson A.J. Bridger S. van Deventer S. Forbes A. Nikolaus S. Lennard-Jones J.E. Foelsch U.R. Krawczak M. Lewis C. Schreiber S. Mathew C.G. Lancet. 2001; 357: 1925-1928Google Scholar, 9Ahmad T. Armuzzi A. Bunce M. Mulcahy-Hawes K. Marshall S.E. Orchard T.R. Crawshaw J. Large O. de Silva A. Cook J.T. Barnardo M. Cullen S. Welsh K.I. Jewell D.P. Gastroenterology. 2002; 122: 854-866Google Scholar). NOD2 has been shown to recognize preparations of lipopolysaccharides (LPS) and peptidoglycan (PGN) through its COOH-terminal LRRs (10Inohara N. Ogura Y. Chen F.F. Muto A. Nuñez G. J. Biol. Chem. 2001; 276: 2551-2554Google Scholar), and this activity is deficient in the disease-associated variants (7Ogura Y. Bonen D.K. Inohara N. Nicolae D.L. Chen F.F. Ramos R. Britton H. Moran T. Karaliuskas R. Duerr R.H. Achkar J.P. Brant S.R. Bayless T.M. Kirschner B.S. Hanauer S.B. Nuñez G. Cho J.H. Nature. 2001; 411: 603-606Google Scholar). However, the precise bacterial structure recognized by NOD2 remains unknown. In this report we identified muramyl dipeptide (MDP) derived from peptidoglycan as the structure in bacteria recognized by NOD2. LPS from Escherichia coli O55:B5 prepared by the phenol extraction method, further purified by gel-filtration chromatography, detoxified LPS, and purified lipid A were obtained from Sigma. LPS from Salmonella typhimurium was obtained from Sigma. PGN from Staphylococcus aureus was from Fluka-Chemie (Buchs, Germany). PGN fromBacillus subtilis was purified as reported (11Hajjar A.M. O'Mahony D.S. Ozinsky A. Underhill D.M. Aderem A. Klebanoff S.J. Wilson C.B. J. Immunol. 2002; 166: 15-19Google Scholar). Pam3CysSerLys4, a synthetic bacterial lipoprotein analog (sBLP), was a gift of A. Zychlinsky (Max Planck Institute for Infection Biology, Berlin, Germany). MDP and their analogs MurNAc-l-alanyl-l-isoglutamine and MurNAc-d-alanyl-d-isoglutamine were obtained from Bachem (Torrance, CA). Molecules with two and four copies of GlcNAc-MurNAc attached to l-Ala-d-isoGln, and their counterparts lacking dipeptide were synthesized as reported (12Onishi M. Kinoshita S. Morikawa Y. Shibuya A. Phillips J. Lanier L.L. Gorman D.M. Nolan G.P. Miyajima A. Kitamura T. Exp. Hematol. 1996; 24: 324-329Google Scholar). Briefly, the disaccharide glucosaminyl-β (1Takeda K. Akira S. Genes Cells. 2001; 6: 733-742Google Scholar, 2Inohara N. Ogura T. Nuñez G. Curr. Opin. Microbiol. 2002; 5: 76-80Google Scholar, 3Girardin S.E. Sansonetti P.J. Philpott D.J. Trends Microbiol. 2002; 10: 193-199Google Scholar, 4Ogura Y. Inohara N. Benito A. Chen F.F. Yamaoka S. Nuñez G. J. Biol. Chem. 2001; 276: 4812-4818Google Scholar)-muramic acid was prepared by stereoselective glycosylation of an N-Troc muramic acid acceptor with N-Troc-glucosaminyl trichloroacetimidate. The disaccharide was converted to both disaccharide acceptor and donor, which was then coupled together by the same glycosylation method to give a tetrasaccharide. Octasaccharide was obtained in a good yield in a similar manner. Introduction of the dipeptide moiety ofl-alanyl-d-isoglutamine to 3-O-lactyl groups was performed by deprotection afforded by the peptidoglycan tetrasaccharide and octasaccharide fragments. The plasmids pcDNA3- NOD2, pcDNA3-TLR4, and pDNA3-MD2 have been described (10Inohara N. Ogura Y. Chen F.F. Muto A. Nuñez G. J. Biol. Chem. 2001; 276: 2551-2554Google Scholar). The plasmids expressing TLR1 and TLR6 have been reported (13Takeuchi O. Hoshino K. Kawai T. Sanjo H. Takada H. Ogawa T. Takeda K. Akira S. Immunity. 1999; 11: 443-451Google Scholar) and were generously provided by Dr. A. Hajjar (University of Washington, Seattle). Expression plasmids producing NH2-terminal HA-tagged NOD2 variants P268S, P268S/R702W, and P268S/G908R were generated by the QuikChange XL site-directed mutagenesis kit (Stratagene, La Jolla, CA). P268S/L1007fsinsC was generated by a PCR method using P268S DNA as a template. The generated PCR products were cloned into the pMX-puro expression plasmid (14Atrih A. Bacher G. Allmaier G. Williamson M.P. Foster S.J. J. Bacteriol. 1999; 181: 3956-3962Google Scholar). The authenticity of the constructs were confirmed by DNA sequencing. Expression of NOD2 proteins in transfected cells was determined by immunoblotting using monoclonal anti-HA antibody (Babco, La Jolla, CA) as described (5Gutierrez O. Pipaon C. Inohara N. Fontalba A. Ogura Y. Prosper F. Nuñez G. Fernandez-Luna J.L. J. Biol. Chem. 2002; 277: 41701-47705Google Scholar). NF-κB activation assays were performed as described (10Inohara N. Ogura Y. Chen F.F. Muto A. Nuñez G. J. Biol. Chem. 2001; 276: 2551-2554Google Scholar). LPS, PGN, and MDP derivaties were added to the cultures in the presence of calcium phosphate to allow their entry into the cells as reported (10Inohara N. Ogura Y. Chen F.F. Muto A. Nuñez G. J. Biol. Chem. 2001; 276: 2551-2554Google Scholar). Results were normalized for transfection efficiency with values obtained with pEF-BOS-βgal. Expression of NOD2 proteins in transfected cells was determined by immunoblotting using monoclonal anti-HA antibody (Babco, La Jolla, CA) as described (4Ogura Y. Inohara N. Benito A. Chen F.F. Yamaoka S. Nuñez G. J. Biol. Chem. 2001; 276: 4812-4818Google Scholar). PGN from B. subtilus (0.4 mg) was digested with mutanolysin (Sigma) for 24 h. After centrifugation at 100,000 × g for 10 min and filtration with a 0.22-μm nitrocellulose filter, digested PGN was fractionated by Superose 12 gel-filtration column chromatography with 10 mm HEPES, 100 mm NaCl, pH 7.4. Purified bovine serum albumine, chicken egg lysozyme, and bovine cytochromec were used as molecular size standards. Peripheral blood was obtained from normal donors and Crohn's disease patients after informed consent according to Guidelines from the Committee for the Protection of Human Subjects at the Hospital Universitario Marques de Valdecilla. DNA was tested for the 3020insC NOD2 mutation using the SNaPshot method (Applied Biosystems, Foster City, CA) based on the dideoxy single-base extension of an unlabeled oligonucleotide primer (5′-GCCCTCCTGCAGGCCC-3′). PBMNC were cultured for 1 h with 1 μg/ml LPS from S. typhimuriumor 10 ng/ml MDP. Then cells were lysed and nuclear extracts were analyzed for the presence of NF-κB binding activity as described previously (5Gutierrez O. Pipaon C. Inohara N. Fontalba A. Ogura Y. Prosper F. Nuñez G. Fernandez-Luna J.L. J. Biol. Chem. 2002; 277: 41701-47705Google Scholar). Total RNA was prepared using TRIZOL reagent (Invitrogen). To assess mRNA expression, a quantitative PCR method was used as described previously (5Gutierrez O. Pipaon C. Inohara N. Fontalba A. Ogura Y. Prosper F. Nuñez G. Fernandez-Luna J.L. J. Biol. Chem. 2002; 277: 41701-47705Google Scholar). The generated cDNA was amplified by using primers for human IL-1β, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (5Gutierrez O. Pipaon C. Inohara N. Fontalba A. Ogura Y. Prosper F. Nuñez G. Fernandez-Luna J.L. J. Biol. Chem. 2002; 277: 41701-47705Google Scholar), and A1 (5′-CGGATGTGGATACCTATAAGG-3′ and 5′-GTCATCCAGCCAGATTTAGG-3′). Quantitative real-time PCR was performed in a 7000 sequence detection system (Applied Biosystems). The ratio of the abundance of IL-1β and A1 transcripts to that of GAPDH transcripts was calculated as described (5Gutierrez O. Pipaon C. Inohara N. Fontalba A. Ogura Y. Prosper F. Nuñez G. Fernandez-Luna J.L. J. Biol. Chem. 2002; 277: 41701-47705Google Scholar). Specificity of the PCR products was determined by melting curve analysis. NOD2 was shown to mediate responsiveness to preparations of LPS and PGN (10Inohara N. Ogura Y. Chen F.F. Muto A. Nuñez G. J. Biol. Chem. 2001; 276: 2551-2554Google Scholar). To further characterize the bacterial moiety recognized by NOD2, we used human embryonic kidney (HEK293T) cells and a NF-κB-dependent luciferase reporter to compare the ability of NOD2 and TLR4 to recognize LPS and PGN. Because NOD2 is an intracellular protein, we assessed NOD2 activity under culture conditions that allow the internalization of the bacterial components into the cells (10Inohara N. Ogura Y. Chen F.F. Muto A. Nuñez G. J. Biol. Chem. 2001; 276: 2551-2554Google Scholar). Expression of NOD2 and TLR4 together with its co-factor MD2 conferred responsiveness to purified LPS prepared by phenol extraction as reported (7Ogura Y. Bonen D.K. Inohara N. Nicolae D.L. Chen F.F. Ramos R. Britton H. Moran T. Karaliuskas R. Duerr R.H. Achkar J.P. Brant S.R. Bayless T.M. Kirschner B.S. Hanauer S.B. Nuñez G. Cho J.H. Nature. 2001; 411: 603-606Google Scholar, 10Inohara N. Ogura Y. Chen F.F. Muto A. Nuñez G. J. Biol. Chem. 2001; 276: 2551-2554Google Scholar), whereas only NOD2 induced the response to PGN (Fig. 1 A). The lipid A moiety of LPS mediates TLR4/MD2 activation (15Glauner B. Höltje J.-V. Schwartz U. J. Biol. Chem. 1988; 263: 10088-10095Google Scholar). Consistent with the latter, NOD2, but not TLR4, did respond to lipid A-depleted detoxified LPS prepared by alkaline treatment (Fig. 1 A), whereas TLR4, but not NOD2, responded to purified lipid A (Fig.1 A). Notably, TLR4, but not NOD2, was stimulated by highly purified LPS prepared by gel-filtration chromatography (Fig.1 A). These results indicate that TLR4 and NOD2 recognize different bacterial components and suggest that PGN present in LPS preparations may contain the moiety recognized by NOD2. To further characterize the bacterial structure recognized by NOD2, we digested purified PGN with the muramidases mutanolysin or Cellosyl, which degrade the glycan chains and result in the generation of muropeptides which are composed of N-acetylglucosamine (GlcNAc) andN-acetylmuramic acid (MurNAc) linked to short peptides (16Inamura S. Fukase K. Kusumoto S. Tetrahedron Lett. 2001; 42: 7613-7619Google Scholar). Digested PGN was fractionated by gel-filtration chromatography. Analysis of each fraction revealed a major peak of NOD2-stimulating activity induced by mutanolysin digestion with a relative molecular mass of less than 12 kDa, consistent with that expected for muropeptides (Fig. 1 B). Similar results were observed when PGN was digested with Cellosyl, which revealed a single peak of NOD2 stimulatory activity of less than 12 kDa. 2N. Inohara, Y. Ogura, and G. Nuñez, unpublished results. PGN-derived muropeptides derived from most bacterial species are composed of GlcNAc-MurNAc linked to short peptides, which include the conserved dipeptide l-Ala and d-isoGln ord-Glu (Fig. 2 A). To determine more directly if muropeptides are recognized by NOD2, we used a panel of synthetic molecules with the structure of GlcNAc-MurNAc linked to l-Ala-d-isoGln, as well as muramyl dipeptide MurNAc-l-Ala-d-isoGln (MDP), which lacks GlcNAc (Fig. 2 A). GlcNAc-MurNAc-l-Ala-d-isoGln stimulated NF-κB in a NOD2-dependent manner, whereas disaccharide GlcNAc-MurNAc in dimeric or tetrameric forms did not (Fig.2 B), indicating that amino acid residues are required for stimulation of NOD2. However, we cannot formally rule out that the lack of NOD2 response to GlcNAc-MurNAc in dimeric or tetrameric forms is due to poor internalization of the synthetic molecules into the cells. MDP induced potent stimulation of NOD2 (Fig. 2 B), indicating that GlcNAc is not essential for stimulatory activity. To determine further the specificity of the recognition of MDP by NOD2, we tested the MDP analogs MurNAc-l-Ala-l-isoGln and MurNAc-d-Ala-d-isoGln. Notably, replacement ofl-Ala for d-Ala or d-isoGln forl-isoGln eliminated the ability of MDP to stimulate NOD2, indicating stereoselective recognition (Fig. 2 C). Thus, the core structure required for recognition of NOD2 is MurNAc attached tol-Ala and d-isoGln. TLR2 has been proposed to act as a surface receptor for PGN and certain bacterial lipoproteins including synthetic bacterial lipopeptide S. B. P. Zychlinsky A. 1999; Scholar, J. Immunol. 2002; Scholar). we tested the ability of TLR2 and NOD2 to respond to MDP and TLR2 a response to but not to MDP (Fig.2 MDP, but not sBLP, stimulated NOD2 activity (Fig. 2 In we tested co-expression of TLR2 with TLR1 TLR6 mediate recognition of MDP. TLR2 in with or did not NF-κB in response to MDP (Fig. 2 Thus, NOD2 and TLR2 recognize different bacterial The NOD2 variants associated with Crohn's disease, R702W, G908R, and L1007fsinsC, on the same which the P268S (6Hugot J.P. Chamaillard M. Zouali H. Lesage S. Cezard J.P. Belaiche J. Almer S. Tysk C. O'Morain C.A. Gassull M. Binder V. Finkel Y. Cortot A. Modigliani R. Laurent-Puig P. Gower-Rousseau C. Macry J. Colombel J.F. Sahbatou M. Thomas G. Nature. 2001; 411: 599-603Google Scholar, 7Ogura Y. Bonen D.K. Inohara N. Nicolae D.L. Chen F.F. Ramos R. Britton H. Moran T. Karaliuskas R. Duerr R.H. Achkar J.P. Brant S.R. Bayless T.M. Kirschner B.S. Hanauer S.B. Nuñez G. Cho J.H. Nature. 2001; 411: 603-606Google Scholar). To compare the ability of normal and NOD2 proteins to NF-κB activity in response to MDP, we expressed the NOD2 proteins in cells and their activity in a functional normal and P268S NOD2 induced similar of NF-κB activation in response to MDP A), which is consistent with the that P268S is not genetically associated with disease (6Hugot J.P. Chamaillard M. Zouali H. Lesage S. Cezard J.P. Belaiche J. Almer S. Tysk C. O'Morain C.A. Gassull M. Binder V. Finkel Y. Cortot A. Modigliani R. Laurent-Puig P. Gower-Rousseau C. Macry J. Colombel J.F. Sahbatou M. Thomas G. Nature. 2001; 411: 599-603Google Scholar, 7Ogura Y. Bonen D.K. Inohara N. Nicolae D.L. Chen F.F. Ramos R. Britton H. Moran T. Karaliuskas R. Duerr R.H. Achkar J.P. Brant S.R. Bayless T.M. Kirschner B.S. Hanauer S.B. Nuñez G. Cho J.H. Nature. 2001; 411: 603-606Google Scholar). In the P268S/R702W, and P268S/L1007fsinsC variants induced of NF-κB activation in response to MDP when with normal NOD2 A). Notably, whereas the and mutants ability to respond to MDP, the protein did not respond at of NOD2 and MDP tested (Fig. A). revealed that the normal and NOD2 mutants were expressed B), indicating that the observed in MDP not by expression of the NOD2 determined the role of NOD2 in the recognition of MDP by cells from normal and Crohn's disease A panel of and Crohn's disease individuals were for the disease-associated NOD2 and two individuals of disease and with Crohn's were homozygous for the L1007fsinsC mutation were The of individuals homozygous for L1007fsinsC is expected in that the of the L1007fsinsC mutation is not (6Hugot J.P. Chamaillard M. Zouali H. Lesage S. Cezard J.P. Belaiche J. Almer S. Tysk C. O'Morain C.A. Gassull M. Binder V. Finkel Y. Cortot A. Modigliani R. Laurent-Puig P. Gower-Rousseau C. Macry J. Colombel J.F. Sahbatou M. Thomas G. Nature. 2001; 411: 599-603Google Scholar, 7Ogura Y. Bonen D.K. Inohara N. Nicolae D.L. Chen F.F. Ramos R. Britton H. Moran T. Karaliuskas R. Duerr R.H. Achkar J.P. Brant S.R. Bayless T.M. Kirschner B.S. Hanauer S.B. Nuñez G. Cho J.H. Nature. 2001; 411: 603-606Google Scholar, 8Hampe J. Cuthbert A. Croucher P.J. Mirza M.M. Mascheretti S. Fisher S. Frenzel H. King K. Hasselmeyer A. MacPherson A.J. Bridger S. van Deventer S. Forbes A. Nikolaus S. Lennard-Jones J.E. Foelsch U.R. Krawczak M. Lewis C. Schreiber S. Mathew C.G. Lancet. 2001; 357: 1925-1928Google Scholar, 9Ahmad T. Armuzzi A. Bunce M. Mulcahy-Hawes K. Marshall S.E. Orchard T.R. Crawshaw J. Large O. de Silva A. Cook J.T. Barnardo M. Cullen S. Welsh K.I. Jewell D.P. Gastroenterology. 2002; 122: 854-866Google Scholar). PBMNC that are to NOD2 were with MDP or LPS, and NF-κB activation was assessed in nuclear extracts by an electrophoretic mobility shift of PBMNC from individuals normal or NOD2 with LPS or MDP in of the (Fig. C). In PBMNC from individuals homozygous for L1007fsinsC did respond to LPS, but not to MDP (Fig. C). The DNA binding induced by MDP was by of the nuclear extracts with an antibody for the of NF-κB indicating that the To further assess NF-κB the mRNA of IL-1β and two NF-κB expressed in PBMNC J.P. M.M. J.P. J. Immunol. Scholar, Chen C. J. C. Genes 1999; Scholar), were by quantitative real-time PCR analysis. IL-1β and A1 mRNA were induced by with LPS and MDP in cells from individuals normal or NOD2 (Fig. and In LPS but not MDP, the of both IL-1β and A1 mRNA in PBMNC from individuals homozygous for L1007fsinsC (Fig. Thus, PBMNC the expression of normal NOD2 for their response to MDP but not to The lack of response to MDP in normal individuals suggest that the presence of certain bacteria in the genetic may required for disease. MDP is the essential structure of bacterial peptidoglycan required for including activity in adjuvant H. S. The and of Scholar). MDP has been shown to through and S. R. S. O. Akira S. S. Takada H. 2001; Scholar, J. Biol. Chem. 2002; 277: Scholar), but the host recognition system for MDP has not been present that NOD2 mediates the recognition of MDP in cells. contain intracellular that bacterial PGN and PGN including J. F. J. Scholar, Scholar). These muropeptides derived from intracellular bacteria as well as PGN bacterial for recognition by NOD2. The synthetic MDP and the muropeptides induced NOD2-dependent activation of Thus, NOD2 is to by muropeptides derived from bacteria in NOD2 mediate the recognition of the is and remains to Because the LRRs are required for muropeptides directly with NOD2 through its LRRs or as to identified Crohn's disease-associated NOD2 variants and PBMNC from individuals homozygous for L1007fsinsC are in their response to muramyl dipeptide. result is consistent with the that for L1007fsinsC is for susceptibility to Crohn's disease (6Hugot J.P. Chamaillard M. Zouali H. Lesage S. Cezard J.P. Belaiche J. Almer S. Tysk C. O'Morain C.A. Gassull M. Binder V. Finkel Y. Cortot A. Modigliani R. Laurent-Puig P. Gower-Rousseau C. Macry J. Colombel J.F. Sahbatou M. Thomas G. Nature. 2001; 411: 599-603Google Scholar, 7Ogura Y. Bonen D.K. Inohara N. Nicolae D.L. Chen F.F. Ramos R. Britton H. Moran T. Karaliuskas R. Duerr R.H. Achkar J.P. Brant S.R. Bayless T.M. Kirschner B.S. Hanauer S.B. Nuñez G. Cho J.H. Nature. 2001; 411: 603-606Google Scholar). Because activation of NF-κB in response to bacterial components mediates protection of the host against susceptibility to disease may by a to a NF-κB in response to a response against certain bacterial products may result in the activation of NF-κB in by The results suggest that the activity against bacterial muropeptides may to Crohn's disease patients NOD2 are to T. for C. for A. Zychlinsky for sBLP, and A. Hajjar for P. for of the

IMPORTANCE: Cerebral amyloid-β aggregation is an early pathological event in Alzheimer disease (AD), starting decades before dementia onset. Estimates of the prevalence of amyloid pathology in persons without dementia are needed to understand the development of AD and to design prevention studies. OBJECTIVE: To use individual participant data meta-analysis to estimate the prevalence of amyloid pathology as measured with biomarkers in participants with normal cognition, subjective cognitive impairment (SCI), or mild cognitive impairment (MCI). DATA SOURCES: Relevant biomarker studies identified by searching studies published before April 2015 using the MEDLINE and Web of Science databases and through personal communication with investigators. STUDY SELECTION: Studies were included if they provided individual participant data for participants without dementia and used an a priori defined cutoff for amyloid positivity. DATA EXTRACTION AND SYNTHESIS: Individual records were provided for 2914 participants with normal cognition, 697 with SCI, and 3972 with MCI aged 18 to 100 years from 55 studies. MAIN OUTCOMES AND MEASURES: Prevalence of amyloid pathology on positron emission tomography or in cerebrospinal fluid according to AD risk factors (age, apolipoprotein E [APOE] genotype, sex, and education) estimated by generalized estimating equations. RESULTS: The prevalence of amyloid pathology increased from age 50 to 90 years from 10% (95% CI, 8%-13%) to 44% (95% CI, 37%-51%) among participants with normal cognition; from 12% (95% CI, 8%-18%) to 43% (95% CI, 32%-55%) among patients with SCI; and from 27% (95% CI, 23%-32%) to 71% (95% CI, 66%-76%) among patients with MCI. APOE-ε4 carriers had 2 to 3 times higher prevalence estimates than noncarriers. The age at which 15% of the participants with normal cognition were amyloid positive was approximately 40 years for APOE ε4ε4 carriers, 50 years for ε2ε4 carriers, 55 years for ε3ε4 carriers, 65 years for ε3ε3 carriers, and 95 years for ε2ε3 carriers. Amyloid positivity was more common in highly educated participants but not associated with sex or biomarker modality. CONCLUSIONS AND RELEVANCE: Among persons without dementia, the prevalence of cerebral amyloid pathology as determined by positron emission tomography or cerebrospinal fluid findings was associated with age, APOE genotype, and presence of cognitive impairment. These findings suggest a 20- to 30-year interval between first development of amyloid positivity and onset of dementia.

BACKGROUND: Mutations in LRRK2, the gene that encodes leucine-rich repeat kinase 2, are a cause of Parkinson's disease (PD). The International LRRK2 Consortium was established to answer three key clinical questions: can LRRK2-associated PD be distinguished from idiopathic PD; which mutations in LRRK2 are pathogenic; and what is the age-specific cumulative risk of PD for individuals who inherit or are at risk of inheriting a deleterious mutation in LRRK2? METHODS: Researchers from 21 centres across the world collaborated on this study. The frequency of the common LRRK2 Gly2019Ser mutation was estimated on the basis of data from 24 populations worldwide, and the penetrance of the mutation was defined in 1045 people with mutations in LRRK2 from 133 families. The LRRK2 phenotype was defined on the basis of 59 motor and non-motor symptoms in 356 patients with LRRK2-associated PD and compared with the symptoms of 543 patients with pathologically proven idiopathic PD. FINDINGS: Six mutations met the consortium's criteria for being proven pathogenic. The frequency of the common LRRK2 Gly2019Ser mutation was 1% of patients with sporadic PD and 4% of patients with hereditary PD; the frequency was highest in the middle east and higher in southern Europe than in northern Europe. The risk of PD for a person who inherits the LRRK2 Gly2019Ser mutation was 28% at age 59 years, 51% at 69 years, and 74% at 79 years. The motor symptoms (eg, disease severity, rate of progression, occurrence of falls, and dyskinesia) and non-motor symptoms (eg, cognition and olfaction) of LRRK2-associated PD were more benign than those of idiopathic PD. INTERPRETATION: Mutations in LRRK2 are a clinically relevant cause of PD that merit testing in patients with hereditary PD and in subgroups of patients with PD. However, this knowledge should be applied with caution in the diagnosis and counselling of patients. FUNDING: UK Medical Research Council; UK Parkinson's Disease Society; UK Brain Research Trust; Internationaal Parkinson Fonds; Volkswagen Foundation; National Institutes of Health: National Institute of Neurological Disorders and Stroke and National Institute of Aging; Udall Parkinson's Disease Centre of Excellence; Pacific Alzheimer Research Foundation Centre; Italian Telethon Foundation; Fondazione Grigioni per il Morbo di Parkinson; Michael J Fox Foundation for Parkinson's Research; Safra Global Genetics Consortium; US Department of Veterans Affairs; French Agence Nationale de la Recherche.

BACKGROUND: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls. PRINCIPAL FINDINGS: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10-6) and 14 (IGHV1-67 p = 7.9×10-8) which indexed novel susceptibility loci. SIGNIFICANCE: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.

The aim of this study was to clarify which cognitive mechanisms underlie Trail Making Test (TMT) direct and derived scores. A comprehensive review of the literature on the topic was carried out to clarify which cognitive factors had been related to TMT performance. Following the review, we explored the relative contribution from working memory, inhibition/interference control, task-switching ability, and visuomotor speed to TMT performance. Forty-one healthy old subjects participated in the study and performed a battery of neuropsychological tests including the TMT, the Digit Symbol subtest [Wechsler Adult Intelligence Scale (Third Version) (WAIS-III)], a Finger Tapping Test, the Digits Forward and Backward subtests (WAIS-III), Stroop Test, and a task-switching paradigm inspired in the Wisconsin Card Sorting Test. Correlation and regression analyses were used in order to clarify the joint and unique contributions from different cognitive factors to the prediction of TMT scores. The results suggest that TMT-A requires mainly visuoperceptual abilities, TMT-B reflects primarily working memory and secondarily task-switching ability, while B-A minimizes visuoperceptual and working memory demands, providing a relatively pure indicator of executive control abilities.

BACKGROUND: alterations. METHODS: alterations. All the patients had a history of disease progression during or after at least one course of chemotherapy or within 12 months after neoadjuvant or adjuvant chemotherapy. Prior immunotherapy was allowed. We initially randomly assigned the patients to receive erdafitinib in either an intermittent or a continuous regimen in the dose-selection phase of the study. On the basis of an interim analysis, the starting dose was set at 8 mg per day in a continuous regimen (selected-regimen group), with provision for a pharmacodynamically guided dose escalation to 9 mg. The primary end point was the objective response rate. Key secondary end points included progression-free survival, duration of response, and overall survival. RESULTS: A total of 99 patients in the selected-regimen group received a median of five cycles of erdafitinib. Of these patients, 43% had received at least two previous courses of treatment, 79% had visceral metastases, and 53% had a creatinine clearance of less than 60 ml per minute. The rate of confirmed response to erdafitinib therapy was 40% (3% with a complete response and 37% with a partial response). Among the 22 patients who had undergone previous immunotherapy, the confirmed response rate was 59%. The median duration of progression-free survival was 5.5 months, and the median duration of overall survival was 13.8 months. Treatment-related adverse events of grade 3 or higher, which were managed mainly by dose adjustments, were reported in 46% of the patients; 13% of the patients discontinued treatment because of adverse events. There were no treatment-related deaths. CONCLUSIONS: alterations. Treatment-related grade 3 or higher adverse events were reported in nearly half the patients. (Funded by Janssen Research and Development; BLC2001 ClinicalTrials.gov number, NCT02365597.).

BACKGROUND AND METHODS: Drowsiness and lack of concentration may contribute to traffic accidents. We conducted a case-control study of the relation between sleep apnea and the risk of traffic accidents. The case patients were 102 drivers who received emergency treatment at hospitals in Burgos or Santander, Spain, after highway traffic accidents between April and December 1995. The controls were 152 patients randomly selected from primary care centers in the same cities and matched with the case patients for age and sex. Respiratory polygraphy was used to screen the patients for sleep apnea at home, and conventional polysomnography was used to confirm the diagnosis. The apnea-hypopnea index (the total number of episodes of apnea and hypopnea divided by the number of hours of sleep) was calculated for each participant. RESULTS: The mean age of the participants was 44 years; 77 percent were men. As compared with those without sleep apnea, patients with an apnea-hypopnea index of 10 or higher had an odds ratio of 6.3 (95 percent confidence interval, 2.4 to 16.2) for having a traffic accident. This relation remained significant after adjustment for potential confounders, such as alcohol consumption, visual-refraction disorders, body-mass index, years of driving, age, history with respect to traffic accidents, use of medications causing drowsiness, and sleep schedule. Among subjects with an apnea-hypopnea index of 10 or more, the risk of an accident was higher among those who had consumed alcohol on the day of the accident than among those who had not. CONCLUSIONS: There is a strong association between sleep apnea, as measured by the apnea-hypopnea index, and the risk of traffic accidents.

BACKGROUND: The cutaneous manifestations of COVID-19 disease are poorly characterized. OBJECTIVES: To describe the cutaneous manifestations of COVID-19 disease and to relate them to other clinical findings. METHODS: We carried out a nationwide case collection survey of images and clinical data. Using a consensus we described five clinical patterns. We later described the association of these patterns with patient demographics, the timing in relation to symptoms of the disease, the severity and the prognosis. RESULTS: The lesions may be classified as acral areas of erythema with vesicles or pustules (pseudo-chilblain) (19%), other vesicular eruptions (9%), urticarial lesions (19%), maculopapular eruptions (47%) and livedo or necrosis (6%). Vesicular eruptions appear early in the course of the disease (15% before other symptoms). The pseudo-chilblain pattern frequently appears late in the evolution of the COVID-19 disease (59% after other symptoms), while the rest tend to appear with other symptoms of COVID-19. The severity of COVID-19 shows a gradient from less severe disease in acral lesions to more severe in the latter groups. The results are similar for confirmed and suspected cases, in terms of both clinical and epidemiological findings. Alternative diagnoses are discussed but seem unlikely for the most specific patterns (pseudo-chilblain and vesicular). CONCLUSIONS: We provide a description of the cutaneous manifestations associated with COVID-19 infection. These may help clinicians approach patients with the disease and recognize cases presenting with few symptoms. What is already known about this topic? Previous descriptions of cutaneous manifestations of COVID-19 were case reports and mostly lacked illustrations. What does this study add? We describe a large, representative sample of patients with unexplained skin manifestations and a diagnosis of COVID-19, using a consensus method to define morphological patterns associated with COVID-19. We describe five clinical patterns associated with different patient demographics, timing and prognosis, and provide illustrations of these patterns to allow for easy recognition.

The profile of brain structural abnormalities in schizophrenia is still not fully understood, despite decades of research using brain scans. To validate a prospective meta-analysis approach to analyzing multicenter neuroimaging data, we analyzed brain MRI scans from 2028 schizophrenia patients and 2540 healthy controls, assessed with standardized methods at 15 centers worldwide. We identified subcortical brain volumes that differentiated patients from controls, and ranked them according to their effect sizes. Compared with healthy controls, patients with schizophrenia had smaller hippocampus (Cohen's d=-0.46), amygdala (d=-0.31), thalamus (d=-0.31), accumbens (d=-0.25) and intracranial volumes (d=-0.12), as well as larger pallidum (d=0.21) and lateral ventricle volumes (d=0.37). Putamen and pallidum volume augmentations were positively associated with duration of illness and hippocampal deficits scaled with the proportion of unmedicated patients. Worldwide cooperative analyses of brain imaging data support a profile of subcortical abnormalities in schizophrenia, which is consistent with that based on traditional meta-analytic approaches. This first ENIGMA Schizophrenia Working Group study validates that collaborative data analyses can readily be used across brain phenotypes and disorders and encourages analysis and data sharing efforts to further our understanding of severe mental illness.

BACKGROUND: Treatment of secondary hyperparathyroidism with vitamin D and calcium in patients receiving dialysis is often complicated by hypercalcemia and hyperphosphatemia, which may contribute to cardiovascular disease and adverse clinical outcomes. Calcimimetics target the calcium-sensing receptor and lower parathyroid hormone levels without increasing calcium and phosphorus levels. We report the results of two identical randomized, double-blind, placebo-controlled trials evaluating the safety and effectiveness of the calcimimetic agent cinacalcet hydrochloride. METHODS: Patients who were receiving hemodialysis and who had inadequately controlled secondary hyperparathyroidism despite standard treatment were randomly assigned to receive cinacalcet (371 patients) or placebo (370 patients) for 26 weeks. Once-daily doses were increased from 30 mg to 180 mg to achieve intact parathyroid hormone levels of 250 pg per milliliter or less. The primary end point was the percentage of patients with values in this range during a 14-week efficacy-assessment phase. RESULTS: Forty-three percent of the cinacalcet group reached the primary end point, as compared with 5 percent of the placebo group (P<0.001). Overall, mean parathyroid hormone values decreased 43 percent in those receiving cinacalcet but increased 9 percent in the placebo group (P<0.001). The serum calcium-phosphorus product declined by 15 percent in the cinacalcet group and remained unchanged in the placebo group (P<0.001). Cinacalcet effectively reduced parathyroid hormone levels independently of disease severity or changes in vitamin D sterol dose. CONCLUSIONS: Cinacalcet lowers parathyroid hormone levels and improves calcium-phosphorus homeostasis in patients receiving hemodialysis who have uncontrolled secondary hyperparathyroidism.

BACKGROUND: The profile of cortical neuroanatomical abnormalities in schizophrenia is not fully understood, despite hundreds of published structural brain imaging studies. This study presents the first meta-analysis of cortical thickness and surface area abnormalities in schizophrenia conducted by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Schizophrenia Working Group. METHODS: The study included data from 4474 individuals with schizophrenia (mean age, 32.3 years; range, 11-78 years; 66% male) and 5098 healthy volunteers (mean age, 32.8 years; range, 10-87 years; 53% male) assessed with standardized methods at 39 centers worldwide. RESULTS: Compared with healthy volunteers, individuals with schizophrenia have widespread thinner cortex (left/right hemisphere: Cohen's d = -0.530/-0.516) and smaller surface area (left/right hemisphere: Cohen's d = -0.251/-0.254), with the largest effect sizes for both in frontal and temporal lobe regions. Regional group differences in cortical thickness remained significant when statistically controlling for global cortical thickness, suggesting regional specificity. In contrast, effects for cortical surface area appear global. Case-control, negative, cortical thickness effect sizes were two to three times larger in individuals receiving antipsychotic medication relative to unmedicated individuals. Negative correlations between age and bilateral temporal pole thickness were stronger in individuals with schizophrenia than in healthy volunteers. Regional cortical thickness showed significant negative correlations with normalized medication dose, symptom severity, and duration of illness and positive correlations with age at onset. CONCLUSIONS: The findings indicate that the ENIGMA meta-analysis approach can achieve robust findings in clinical neuroscience studies; also, medication effects should be taken into account in future genetic association studies of cortical thickness in schizophrenia.

PURPOSE: To determine whether adding cetuximab to irinotecan prolongs survival in patients with metastatic colorectal cancer (mCRC) previously treated with fluoropyrimidine and oxaliplatin. PATIENTS AND METHODS: This multicenter, open-label, phase III study randomly assigned 1,298 patients with epidermal growth factor receptor-expressing mCRC who had experienced first-line fluoropyrimidine and oxaliplatin treatment failure to cetuximab (400 mg/m(2) day 1 followed by 250 mg/m(2) weekly) plus irinotecan (350 mg/m(2) every 3 weeks) or irinotecan alone. Primary end point was overall survival (OS); secondary end points included progression-free survival (PFS), response rate (RR), and quality of life (QOL). RESULTS: Median OS was comparable between treatments: 10.7 months (95% CI, 9.6 to 11.3) with cetuximab/irinotecan and 10.0 months (95% CI, 9.1 to 11.3) with irinotecan alone (hazard ratio [HR], 0.975; 95% CI, 0.854 to 1.114; P = .71). This lack of difference may have been due to post-trial therapy: 46.9% of patients assigned to irinotecan eventually received cetuximab (87.2% of those who did, received it with irinotecan). Cetuximab added to irinotecan significantly improved PFS (median, 4.0 v 2.6 months; HR, 0.692; 95% CI, 0.617 to 0.776; P <or= .0001) and RR (16.4% v 4.2%; P < .0001), and resulted in significantly better scores in the QOL analysis of global health status (P = .047). Cetuximab did not exacerbate toxicity, except for acneform rash, diarrhea, hypomagnesemia, and associated electrolyte imbalances. Neutropenia was the most common severe toxicity across treatment arms. CONCLUSION: Cetuximab and irinotecan improved PFS and RR, and resulted in better QOL versus irinotecan alone. OS was similar between study groups, possibly influenced by the large number of patients in the irinotecan arm who received cetuximab and irinotecan poststudy.

Several molecular subtypes of sporadic Creutzfeldt-Jakob disease have been identified and electroencephalogram and cerebrospinal fluid biomarkers have been reported to support clinical diagnosis but with variable utility according to subtype. In recent years, a series of publications have demonstrated a potentially important role for magnetic resonance imaging in the pre-mortem diagnosis of sporadic Creutzfeldt-Jakob disease. Magnetic resonance imaging signal alterations correlate with distinct sporadic Creutzfeldt-Jakob disease molecular subtypes and thus might contribute to the earlier identification of the whole spectrum of sporadic Creutzfeldt-Jakob disease cases. This multi-centre international study aimed to provide a rationale for the amendment of the clinical diagnostic criteria for sporadic Creutzfeldt-Jakob disease. Patients with sporadic Creutzfeldt-Jakob disease and fluid attenuated inversion recovery or diffusion-weight imaging were recruited from 12 countries. Patients referred as 'suspected sporadic Creutzfeldt-Jakob disease' but with an alternative diagnosis after thorough follow up, were analysed as controls. All magnetic resonance imaging scans were assessed for signal changes according to a standard protocol encompassing seven cortical regions, basal ganglia, thalamus and cerebellum. Magnetic resonance imaging scans were evaluated in 436 sporadic Creutzfeldt-Jakob disease patients and 141 controls. The pattern of high signal intensity with the best sensitivity and specificity in the differential diagnosis of sporadic Creutzfeldt-Jakob disease was identified. The optimum diagnostic accuracy in the differential diagnosis of rapid progressive dementia was obtained when either at least two cortical regions (temporal, parietal or occipital) or both caudate nucleus and putamen displayed a high signal in fluid attenuated inversion recovery or diffusion-weight imaging magnetic resonance imaging. Based on our analyses, magnetic resonance imaging was positive in 83% of cases. In all definite cases, the amended criteria would cover the vast majority of suspected cases, being positive in 98%. Cerebral cortical signal increase and high signal in caudate nucleus and putamen on fluid attenuated inversion recovery or diffusion-weight imaging magnetic resonance imaging are useful in the diagnosis of sporadic Creutzfeldt-Jakob disease. We propose an amendment to the clinical diagnostic criteria for sporadic Creutzfeldt-Jakob disease to include findings from magnetic resonance imaging scans.