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14 results on '"Malecka-Panas, E."'

1. Common variants in glyoxalase I do not inease chronic pancreatitis risk

Author

Kaune T., Hollenbach M., Keil B., Chen J. -M., Masson E., Becker C., Damm M., Ruffert C., Grutzmann R., Hoffmeister A., Te Morsche R. H. M., Cavestro G. M., Zuppardo R. A., Saftoiu A., Malecka-Panas E., Gluszek S., Bugert P., Lerch M. M., Weiss F. U., Zou W. -B., Liao Z., Hegyi P., Drenth J. P. H., Riedel J., Ferec C., Scholz M., Kirsten H., Toth A., Ewers M., Witt H., Griesmann H., Michl P., Rosendahl J., Kaune, T., Hollenbach, M., Keil, B., Chen, J. -M., Masson, E., Becker, C., Damm, M., Ruffert, C., Grutzmann, R., Hoffmeister, A., Te Morsche, R. H. M., Cavestro, G. M., Zuppardo, R. A., Saftoiu, A., Malecka-Panas, E., Gluszek, S., Bugert, P., Lerch, M. M., Weiss, F. U., Zou, W. -B., Liao, Z., Hegyi, P., Drenth, J. P. H., Riedel, J., Ferec, C., Scholz, M., Kirsten, H., Toth, A., Ewers, M., Witt, H., Griesmann, H., Michl, P., and Rosendahl, J.

Subjects
Glycation End Products, Advanced, Male, Genotype, Pancreatitis, Alcoholic, Lactoylglutathione Lyase, Middle Aged, Pyruvaldehyde, Polymorphism, Single Nucleotide, Oxidative Stress, Risk Factors, Pancreatitis, Chronic, Humans, Female, Genetic Predisposition to Disease, Reactive Oxygen Species, Genetic Association Studies
Abstract

Introduction Chronic pancreatitis (CP) may be caused by oxidative stress. An important source of reactive oxygen species (ROS) is the methylglyoxal-derived formation of advanced glycation endproducts (AGE). Methylglyoxal is detoxified by Glyoxalase I (GLO1). A reduction in GLO1 activity results in increased ROS. Single nucleotide polymorphisms (SNPs) of GLO1 have been linked to various inflammatory diseases. Here, we analyzed whether common GLO1 variants are associated with alcoholic (ACP) and non-alcoholic CP (NACP). Methods Using melting curve analysis, we genotyped a screening cohort of 223 ACP, 218 NACP patients, and 328 controls for 11 tagging SNPs defined by the SNPinfo LD TAG SNP Selection tool and the functionally relevant variant rs4746. For selected variants the cohorts were extended to up to 1,441 patient samples. Results In the ACP cohort, comparison of genotypes for rs1937780 between patients and controls displayed an ambiguous result in the screening cohort (p = 0.08). However, in the extended cohort of 1,441 patients no statistically significant association was found for the comparison of genotypes (p = 0.11), nor in logistic regression analysis (p = 0.214, OR 1.072, 95% CI 0.961-1.196). In the NACP screening cohort SNPs rs937662, rs1699012, and rs4746 displayed an ambiguous result when patients were compared to controls in the recessive or dominant model (p = 0.08, 0.08, and 0.07, respectively). Again, these associations were not confirmed in the extended cohorts (rs937662, dominant model: P = 0.07, logistic regression: P = 0.07, OR 1.207, 95% CI 0.985-1.480) or in the replication cohorts for rs4746 (Germany, p = 0.42, OR 1.080, 95% CI 0.673-1.124; France, p = 0.19, OR 0.90, 95% CI 0.76-1.06; China, p = 0.24, OR 1.18, 95% CI 0.90-1.54) and rs1699012 (Germany, Munich; p = 0.279, OR 0.903, 95% CI 0.750-1.087). Conclusions Common GLO1 variants do not increase chronic pancreatitis risk.

Published
2019

2. Germline BRCA2 K3326X and CHEK2 I157T mutations increase risk for sporadic pancreatic ductal adenocarcinoma

Author

Obazee, O., Archibugi, L., Andriulli, A., Soucek, P., Malecka-Panas, E., Ivanauskas, A., Johnson, T., Gazouli, M., Pausch, T., Lawlor, R. T., Cavestro, G. M., Milanetto, A. C., Di Leo, M., Pasquali, C., Hegyi, P., Szentesi, A., Radu, C. E., Gheorghe, C., Theodoropoulos, G. E., Bergmann, F., Brenner, H., Vodickova, L., Katzke, V., Campa, D., Strobel, O., Kaiser, J., Pezzilli, R., Federici, F., Mohelnikova-Duchonova, B., Boggi, U., Lemstrova, R., Johansen, J. S., Bojesen, S. E., Chen, I., Jensen, B. V., Capurso, G., Pazienza, V., Dervenis, C., Sperti, C., Mambrini, A., Hackert, T., Kaaks, R., Basso, D., Talar-Wojnarowska, R., Maiello, E., Izbicki, J. R., Cuk, K., Saum, K. U., Cantore, M., Kupcinskas, J., Palmieri, O., Delle Fave, G., Landi, S., Salvia, R., Fogar, P., Vashist, Y. K., Scarpa, A., Vodicka, P., Tjaden, C., Iskierka-Jazdzewska, E., Canzian, F., Obazee, O., Archibugi, L., Andriulli, A., Soucek, P., Malecka-Panas, E., Ivanauskas, A., Johnson, T., Gazouli, M., Pausch, T., Lawlor, R. T., Cavestro, G. M., Milanetto, A. C., Di Leo, M., Pasquali, C., Hegyi, P., Szentesi, A., Radu, C. E., Gheorghe, C., Theodoropoulos, G. E., Bergmann, F., Brenner, H., Vodickova, L., Katzke, V., Campa, D., Strobel, O., Kaiser, J., Pezzilli, R., Federici, F., Mohelnikova-Duchonova, B., Boggi, U., Lemstrova, R., Johansen, J. S., Bojesen, S. E., Chen, I., Jensen, B. V., Capurso, G., Pazienza, V., Dervenis, C., Sperti, C., Mambrini, A., Hackert, T., Kaaks, R., Basso, D., Talar-Wojnarowska, R., Maiello, E., Izbicki, J. R., Cuk, K., Saum, K. U., Cantore, M., Kupcinskas, J., Palmieri, O., Delle Fave, G., Landi, S., Salvia, R., Fogar, P., Vashist, Y. K., Scarpa, A., Vodicka, P., Tjaden, C., Iskierka-Jazdzewska, E., and Canzian, F.

Subjects
Male, Cancer Research, pancreatic cancer, Genes, BRCA2, I157T, Polymorphism, Single Nucleotide, Humans, Genetic Predisposition to Disease, Germ-Line Mutation, Aged, BRCA2 Protein, K3326X, PANDoRA consortium, rs11571833, rs17879961, Oncology, Pancreatic cancer, Middle Aged, Pancreatic Neoplasms, Checkpoint Kinase 2, Case-Control Studies, Female, Carcinoma, Pancreatic Ductal
Abstract

Rare truncating BRCA2 K3326X (rs11571833) and pathogenic CHEK2 I157T (rs17879961) variants have previously been implicated in familial pancreatic ductal adenocarcinoma (PDAC), but not in sporadic cases. The effect of both mutations in important DNA repair genes on sporadic PDAC risk may shed light on the genetic architecture of this disease. Both mutations were genotyped in germline DNA from 2,935 sporadic PDAC cases and 5,626 control subjects within the PANcreatic Disease ReseArch (PANDoRA) consortium. Risk estimates were evaluated using multivariate unconditional logistic regression with adjustment for possible confounders such as sex, age and country of origin. Statistical analyses were two-sided with p values

Published
2018

3. Ustekinumab as Induction and Maintenance Therapy for Ulcerative Colitis

Author

Sands, B. E., Sandborn, W. J., Panaccione, R., O'Brien, C. D., Zhang, H., Johanns, J., Adedokun, O. J., Li, K., Peyrin-Biroulet, L., Van Assche, G., Danese, S., Targan, S., Abreu, M. T., Hisamatsu, T., Szapary, P., Brown S, Marano C., Connor, S, De Cruz, P, Ding, Nj, Florin, T, Hendy, P, Leong, R, Moore, G, Pavli, P, Sparrow, M, Gassner, S, Vogelsang, H, Baert, F, Colard, A, De Vos, M, D'Heygere, F, Ferrante, M, Louis, E, Staessen, D, Berova, T, Churchev, J, Draganova, R, Gancheva, D, Ivanova, N, Marinova, I, Markov, M, Nikolov, R, Tsonev, N, Vassileva, G, Afif, W, Berstein, C, Bressler, B, Jairath, V, Lachance, Jr, Singh, R, Tilbe, K, Komarek, V, Kozeluhova, J, Lukas, M, Volfova, M, Dahlerup, J, Altwegg, R, Beorchia, S, Bouguen, G, Cadiot, G, Dupas, Jl, Desreumaux, P, Flourie, B, Grimaud, Jc, Guillaud, O, Moreau, J, Roblin, X, Zerbib, F, Baumgart, D, Beckebaum, S, Bokemeyer, B, Ebert, M, Hasselblatt, P, Lügering, A, Maaser, C, Schiefke, I, Schreiber, S, Seidler, U, Altorjay, I, Kiss, Gg, Literati-Nagy, B, Patai, A, Pecsi, G, Salamon, A, Schnabel, R, Székely, A, Tulassay, Z, Varga, M, Fich, A, Fishman, S, Konikoff, F, Lichtenstein, L, Rainis, T, Sbeit, W, Schwartz, D, Annese, V, Biancone, L, Bossa, F, Costintino, R, Danese, S, Fries, W, Gasbarrini, A, Guidi, L, Kohn, A, Maconi, G, Rocca, R, Rogai, F, Villa, E, Zoli, G, Akiho, H, Aoyama, N, Arisawa, T, Hidaka, H, Hisamatsu, T, Horiki, N, Inaba, T, Inoue, S, Ishida, T, Ishida, H, Ishiguro, Y, Ishihara, S, Iwabuchi, M, Kato, J, Katsushima, S, Kobayashi, T, Kojima, Y, Kurihara, H, Masuo, T, Matsui, T, Matsumoto, T, Matsuoka, K, Mitsuyama, K, Motoya, S, Nakagawa, T, Nakai, K, Nakamura, S, Niihara, T, Ohnishi, Y, Ohta, A, Osada, T, Ryuichi, I, Sakai, Y, Sakata, Y, Sameshima, Y, Sano, K, Shibatoge, M, Shibuya, T, Suzuki, Y, Takeshima, F, Tanaka, S, Taruishi, M, Tokito, S, Ueo, T, Watanabe, K, Yamagami, H, Cheon, Jh, Cho, Kb, Knowles, Kim, Kim, Hj, Kim, Y, Lee, Km, Yang, Sk, D'Haens, G, Pierik, M, Gearry, R, Inns, S, Rowbotham, D, Schultz, M, Bochenek, A, Gawdis-Wojnarska, B, Kleczkowski, D, Leszczyszyn, J, Malecka-Panas, E, Mamos, A, Petryka, R, Regula, J, Rozciecha, J, Stefanuik, P, Wozniak-Stolarska, B, Cimpoeru, N, Craciun, E, Ovidiu, Cf, Goldis, E, Ionita-Radu, F, Lazar, D, Suciu, I, Abdulkhakov, R, Alikhanov, B, Apartsin, K, Bakulin, I, Belousova, E, Gofman, A, Grinevich, V, Kulyapin, A, Nizov, A, Osipenko, M, Simanenkov, V, Tkachev, A, Uspenskiy, Y, Valuyskikh, E, Jovanovic, I, Nagorni, A, Svorcan, P, Zdravkovic, N, Bunganic, I, Abrahamovych, O, Bilianskyi, L, Datsenko, O, Golovchenko, O, Kharchenko, N, Klymenko, V, Levchenko, O, Lozynskyy, Y, Murenets, N, Oliinyk, O, Prystupa, L, Pyrogovskyi, V, Reznikova, V, Rishko, I, Stanislavchuk, M, Vizir, V, Yatsyshyn, R, Arasaradnam, R, Bloom, S, Cummings, F, Iqbal, T, Irving, P, Kaser, A, Shonde, A, Subramanian, S, Aberra, F, Aguilar, H, Araya, V, Bakken, A, Beaulieu, D, Cappa, Ja, Chiorean, M, Cohen, N, Dryden, G, Duvall, G, Ehrlich, A, Eisner, M, Ertan, A, Fogel, R, Friedenberg, K, Gatof, D, Glover, S, Grosman, I, Gunaratnam, N, Gupta, N, Haynes, P, Hemaidan, A, Higgins, P, Hou, J, Hudesman, D, Iskandar, H, Jazrawi, S, Jones, M, Karnam, U, Khurana, S, Killpack, M, Kreines, M, Lawlor, G, Lee, S, Loftus, E, Lukin, Dj, Marcet, J, Mattar, M, Melmed, G, Minor, T, Mirkin, K, Mutlu, E, Nichols, M, Nudell, J, Rai, R, Ramos, C, Mcleod, Randall, Rausher, D, Ritter, T, Singh Saini, S, Salzberg, B, Saubermann, L, Scherl, E, Sedghi, S, Sellin, J, Shafran, I, Sorrentino, D, Suiter, D, Swaminath, A, Tiongco, F, Vrabie, R, Walp, K, Warner, N, Winstead, N, Wolf, Dc, Woods, J, Yen, E, Younes, Z., Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Humanitas Clinical and Research Center [Rozzano, Milan, Italy], RS: NUTRIM - R2 - Liver and digestive health, MUMC+: MA Maag Darm Lever (9), Interne Geneeskunde, Sands, Be, Sandborn, Wj, Panaccione, R, O'Brien, Cd, Zhang, H, Johanns, J, Adedokun, Oj, Li, K, Peyrin-Biroulet, L, Van Assche, G, Danese, S, Targan, S, Abreu, Mt, Hisamatsu, T, Szapary, P, and Marano, C

Subjects
Adult, Male, Infusions, [SDV]Life Sciences [q-bio], Injections, Subcutaneous, Anti-Inflammatory Agents, Ulcerative, Klinikai orvostudományok, Article, Injections, Maintenance Chemotherapy, Dose-Response Relationship, 03 medical and health sciences, 0302 clinical medicine, Double-Blind Method, INFLIXIMAB, Colitis, Ulcerative, Dose-Response Relationship, Drug, Female, Humans, Induction Chemotherapy, Infusions, Intravenous, Patient Acuity, Remission Induction, Ustekinumab, ComputingMilieux_MISCELLANEOUS, ACTIVITY INDEXES, Subcutaneous, Orvostudományok, General Medicine, EFFICACY, Colitis, 3. Good health, INFECTIONS, 030220 oncology & carcinogenesis, 030211 gastroenterology & hepatology, Drug, Intravenous
Abstract

The efficacy of ustekinumab, an antagonist of the p40 subunit of interleukin-12 and interleukin-23, as induction and maintenance therapy in patients with ulcerative colitis is unknown.We evaluated ustekinumab as 8-week induction therapy and 44-week maintenance therapy in patients with moderate-to-severe ulcerative colitis. A total of 961 patients were randomly assigned to receive an intravenous induction dose of ustekinumab (either 130 mg [320 patients] or a weight-range-based dose that approximated 6 mg per kilogram of body weight [322]) or placebo (319). Patients who had a response to induction therapy 8 weeks after administration of intravenous ustekinumab were randomly assigned again to receive subcutaneous maintenance injections of 90 mg of ustekinumab (either every 12 weeks [172 patients] or every 8 weeks [176]) or placebo (175). The primary end point in the induction trial (week 8) and the maintenance trial (week 44) was clinical remission (defined as a total score of ≤2 on the Mayo scale [range, 0 to 12, with higher scores indicating more severe disease] and no subscore1 [range, 0 to 3] on any of the four Mayo scale components).The percentage of patients who had clinical remission at week 8 among patients who received intravenous ustekinumab at a dose of 130 mg (15.6%) or 6 mg per kilogram (15.5%) was significantly higher than that among patients who received placebo (5.3%) (P0.001 for both comparisons). Among patients who had a response to induction therapy with ustekinumab and underwent a second randomization, the percentage of patients who had clinical remission at week 44 was significantly higher among patients assigned to 90 mg of subcutaneous ustekinumab every 12 weeks (38.4%) or every 8 weeks (43.8%) than among those assigned to placebo (24.0%) (P = 0.002 and P0.001, respectively). The incidence of serious adverse events with ustekinumab was similar to that with placebo. Through 52 weeks of exposure, there were two deaths (one each from acute respiratory distress syndrome and hemorrhage from esophageal varices) and seven cases of cancer (one each of prostate, colon, renal papillary, and rectal cancer and three nonmelanoma skin cancers) among 825 patients who received ustekinumab and no deaths and one case of cancer (testicular cancer) among 319 patients who received placebo.Ustekinumab was more effective than placebo for inducing and maintaining remission in patients with moderate-to-severe ulcerative colitis. (Funded by Janssen Research and Development; UNIFI ClinicalTrials.gov number, NCT02407236.).

Published
2019

4. Do pancreatic cancer and chronic pancreatitis share the same genetic risk factors? A PANcreatic Disease ReseArch (PANDoRA) consortium investigation

Author

Campa, D, Pastore, M, Capurso, G, Hackert, T, Di Leo, M, Izbicki, JR, Khaw, K-T, Gioffreda, D, Kupcinskas, J, Pasquali, C, Macinga, P, Kaaks, R, Stigliano, S, Peeters, PH, Key, TJ, Talar-Wojnarowska, R, Vodicka, P, Valente, R, Vashist, YK, Salvia, R, Papaconstantinou, I, Shimizu, Y, Valsuani, C, Zambon, CF, Gazouli, M, Valantiene, I, Niesen, W, Mohelnikova-Duchonova, B, Hara, K, Soucek, P, Malecka-Panas, E, Bueno-de-Mesquita, HBA, Johnson, T, Brenner, H, Tavano, F, Fogar, P, Ito, H, Sperti, C, Butterbach, K, Latiano, A, Andriulli, A, Cavestro, GM, Busch, ORC, Dijk, F, Greenhalf, W, Matsuo, K, Lombardo, C, Strobel, O, König, A-K, Cuk, K, Strothmann, H, Katzke, V, Cantore, M, Mambrini, A, Oliverius, M, Pezzilli, R, Landi, S, Canzian, F, Other departments, CCA - Imaging and biomarkers, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Campa, Daniele, Pastore, Manuela, Capurso, Gabriele, Hackert, Thilo, Di Leo, Milena, Izbicki, Jakob R, Khaw, Kay tee, Gioffreda, Domenica, Kupcinskas, Juoza, Pasquali, Claudio, Macinga, Peter, Kaaks, Rudolf, Stigliano, Serena, Peeters, Petra H, Key, Timothy J, Talar wojnarowska, Renata, Vodicka, Pavel, Valente, Roberto, Vashist, Yogesh K, Salvia, Roberto, Papaconstantinou, Ioanni, Shimizu, Yasuhiro, Valsuani, Chiara, Zambon, Carlo Federico, Gazouli, Maria, Valantiene, Irena, Niesen, Willem, Mohelnikova duchonova, Beatrice, Hara, Kazuo, Soucek, Pavel, Malecka panas, Ewa, Bueno de mesquita, H. Ba, Johnson, Theron, Brenner, Herman, Tavano, Francesca, Fogar, Paola, Ito, Hidemi, Sperti, Cosimo, Butterbach, Katja, Latiano, Anna, Andriulli, Angelo, Cavestro, GIULIA MARTINA, Busch, Olivier R. C, Dijk, Frederike, Greenhalf, William, Matsuo, Keitaro, Lombardo, Carlo, Strobel, Oliver, König, Anna katharina, Cuk, Katarina, Strothmann, Hendrik, Katzke, Verena, Cantore, Maurizio, Mambrini, Andrea, Oliverius, Martin, Pezzilli, Raffaele, Landi, Stefano, and Canzian, Federico

Subjects
Adult, Male, Cancer Research, endocrine system diseases, Chronic pancreatiti, pancreatic ductal adenocarcinoma, Adenocarcinoma, Polymorphism, Single Nucleotide, genetic polymorphisms, Risk Factors, Pancreatitis, Chronic, Biomarkers, Tumor, genetic polymorphism, Humans, Trypsin, Chronic, Polymorphism, Aged, Retrospective Studies, Tumor, Carcinoma, association, Nuclear Proteins, Single Nucleotide, Middle Aged, ACUTE PANCREATITIS, Prognosis, digestive system diseases, PANCREATIC CANCER, Pancreatic Neoplasms, Pancreatitis, Oncology, Pancreatic Ductal, Case-Control Studies, Chronic pancreatitis, Carcinoma, Pancreatic Ductal, Female, Follow-Up Studies, Trypsinogen, Biomarkers
Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive tumor with a five-year survival of less than 6%. Chronic pancreatitis (CP), an inflammatory process in of the pancreas, is a strong risk factor for PDAC. Several genetic polymorphisms have been discovered as susceptibility loci for both CP and PDAC. Since CP and PDAC share consistent number of epidemiologic risk factors, the aim of this study was to investigate whether specific CP risk loci also contribute to PDAC susceptibility. We selected five common SNPs (rs11988997, rs379742, rs10273639 rs2995271 and rs12688220) that were identified as susceptibility markers for CP and analyzed them in 2,914 PDAC cases, 356 CP cases and 5,596 controls retrospectively collected in the context of the international PANDoRA consortium. We found a weak association between the minor allele of the PRSS1-PRSS2-rs10273639 and an increased risk of developing PDAC (ORhomozygous =1.19, 95% CI 1.02-1.38, p=0.023). Additionally all the SNPs confirmed statistically significant associations with risk of developing CP, the strongest being PRSS1-PRSS2-rs10273639 (ORheterozygous =0.51, 95% CI 0.39-0.67, p=1.10x10(-6) ) and MORC4-rs 12837024 (ORhomozygous =2.07 (1.55-2.77, ptrend =0.7x10(-11) ). Taken together, the results from our study do not support variants rs11988997, rs379742, rs10273639 rs2995271 and rs12688220 as strong predictors of PDAC risk, but further support the role of these SNPs in CP susceptibility. Our study suggests that CP and PDAC probably do not share genetic susceptibility, at least in terms of high frequency variants. This article is protected by copyright. All rights reserved.

Published
2017

5. Ustekinumab as induction and maintenance therapy for Crohn's disease

Author

Feagan, Bg, Sandborn, Wj, Gasink, C, Jacobstein, D, Lang, Y, Friedman, Jr, Blank, Ma, Johanns, J, Gao, Ll, Miao, Y, Adedokun, Oj, Sands, Be, Hanauer, Sb, Vermeire, S, Targan, S, Ghosh, S, de Villiers WJ, Colombel, Jf, Tulassay, Z, Seidler, U, Salzberg, Ba, Desreumaux, P, Lee, Sd, Loftus EV Jr, Dieleman, La, Katz, S, Rutgeerts, P, Bampton, P, Chung, A, Connor, S, Debinski, H, Leong, R, Macrae, F, Pavli, P, Sorrentino, D, van den Bogaerde, J, Vogel, W, Vogelsang, H, Louis, E, Mana, F, Zaltman, C, Aumais, G, Bernstein, C, Bressler, B, Dhalla, S, Dieleman, L, Feagan, B, Marshall, J, Panaccione, R, Ropeleski, M, Stehlik, J, Volfova, M, Brynskov, J, Glerup, H, Abitbol-Selinger, V, Allez, M, Beaugerie, L, Bourreille, A, Cadiot, G, Dupas, J, Grimaud, J, Laharie, D, Lerebours, E, Moreau, J, Baumgart, D, Brand, S, Ebert, M, Ehehalt, R, Hasselblatt, P, Howaldt, S, Klaus, J, Krummenerl, P, Kucharzik, T, Lügering, A, Mudter, J, Preiss, J, Schreiber, S, Stallmach, A, Stein, J, Strauch, U, Salamon, A, Patchett, S, Lahat-Zok, A, Rachmilewitz, D, Annese, V, Bossa, F, Guidi, L, Kohn, A, Rocca, R, Ando, A, Ashida, T, Hanai, H, Ishida, T, Ito, H, Matsumoto, T, Motoya, S, Nakamura, S, Sameshima, Y, Suzuki, Y, Watanabe, K, Yamagami, H, Yamamoto, T, Yao, K, Kim, H, Kim, Y, D'Haens, G, Pierik, M, van Bodegraven, A, van der Woude CJ, Gearry, R, Ciecko-Michalska, I, Malecka-Panas, E, Jojic, N, Aboo, N, Wright, J, Arranz, M, Viso, L, Ahmad, T, Bloom, S, Campbell, S, Creed, T, Cummings, F, Hawthorne, B, Iqbal, T, Ireland, A, Parkes, M, Pollok, R, Shaw, I, Shonde, A, Smith, M, Steel, A, Subramanian, S, Travis, S, Tremelling, M, Aberra, F, Abraham, B, Barish, C, Behm, B, Birbara, C, Bochner, R, Bologna, S, Brant, S, Charles, R, Cohen, N, de Villers, W, Dryden, G, Duvall, A, Flasar, M, Fleisher, M, Florez, D, Fogel, R, Gagneja, H, Gross, C, Hamilton, J, Hanauer, S, Hanson, J, Hardi, R, Higgins, P, Isaacs, K, Katz, J, Kaur, N, Khan, N, Lee, S, Leman, B, Levenson, S, Lichtiger, S, Loftus, E, Malik, P, Mcnair, A, Melmed, G, Miner, P, Nichols, M, Noar, M, Oikonomou, I, Oubre, B, Peterson, K, Pruitt, R, Quirk, D, Safdi, A, Safdi, M, Salzberg, B, Sandborn, W, Saubermann, L, Scherl, E, Schwartz, D, Schwarz, R, Sedghi, S, Selby, L, Shafran, I, Siegel, C, Sninsky, C, Stern, M, Stockwell, D, Stone, C, Swaminath, A, Swoger, J, Taormina, M, Williams, E, Winstead, N, Wolf, D, Wolosin, J, Yacyshyn, B, Yajnik, V, Yen, E, Hetzel, D, Muls, V, Bafutto, M, Francesconi, C, Sipahi, A, Steinwurz, F, Churchev, J, Kotzev, I, Marinova, I, Penchev, P, Spassova, Z, Stoinov, S, Takov, D, Vassileva, G, Fowler, S, Greenberg, G, Jones, J, Saibil, F, Salh, B, Banić, M, Duvnjak, M, Stimac, D, Goujon, G, Pelletier, A, Peyrin-Biroulet, L, Aldinger, V, Bokemeyer, B, Büning, C, Konturek, J, Krummenerl, T, Ochsenkuehn, T, Altorjay, I, Kis, J, Pecsi, G, Székely, A, Varga, M, Vincze, A, Wacha, J, Oddsson, E, Orvar, K, Avni-Biron, I, Fishman, S, Fraser, G, Konikoff, F, Melzer, E, Oren, R, Shirin, H, Danese, S, Marino, M, Sturniolo, Gc, Horiki, N, Iijima, H, Iwabuchi, M, Kanai, T, Kunisaki, R, Maemoto, A, Matsuoka, K, Osada, T, Sugimoto, K, Tanaka, S, Cheon, Jh, Han, Ds, Jang, Bi, Kim, Hj, Kim, Js, Kim, Yh, Park, Sj, Yang, Sk, Arnold, M, Claydon, A, Haines, M, Hill, J, Rowbotham, D, Schultz, M, Wallace, I, Bochenek, A, Niezgoda, K, Szura, M, Arutyunov, G, Baranovsky, A, Khalif, I, Osipenko, M, Milinic, N, Bloch, H, Kruger, Fc, Prins, M, Watermeyer, G, Ziady, C, Calvo, Xc, Domínguez-Muñoz, Je, Gisbert, Jp, Arsenescu, R, Beaulieu, D, Bedford, R, Behrend, C, Cleavinger, P, Cohen, J, Ertan, A, Freilich, B, Friedenberg, K, Glover, S, Gordon, G, Gunaratnam, N, Gupta, N, Holbrook, R, Jones, M, Kaufman, B, Khan, Nh, Khurana, S, Legnani, P, Mutlu, E, Phillips, R, Rai, R, Reichelderfer, M, Ritter, T, Safdi, Ma, Sands, B, Schulman, M, Smith, J, Suiter, D, Taylor, D, Vasudeva, R, Winstead, T, Zwick, A, Savoye, G, Atreya, R, Ochsenkuhn, T, Ott, C, Goldin, E, Motohiro, E, Takanori, K, Park, S, James, B, Cummings, J, Tariq, A, Willert, R, Allan, M, Bulat, R, Devilliers, W, Eaker, E, Hou, J, Mendu, S, Nicols, M, Proctor, D, Thosani, N, Zhang, C, and UNITI-IM-UNITI Study Group

Subjects
030203 arthritis & rheumatology, Adult, Male, Infusions, Medicine (all), Remission Induction, Crohn Disease, Female, Humans, Induction Chemotherapy, Infusions, Intravenous, Maintenance Chemotherapy, Middle Aged, Ustekinumab, General Medicine, Orvostudományok, Klinikai orvostudományok, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, Intravenous
Abstract

Ustekinumab, a monoclonal antibody to the p40 subunit of interleukin-12 and interleukin-23, was evaluated as an intravenous induction therapy in two populations with moderately to severely active Crohn's disease. Ustekinumab was also evaluated as subcutaneous maintenance therapy.We randomly assigned patients to receive a single intravenous dose of ustekinumab (either 130 mg or approximately 6 mg per kilogram of body weight) or placebo in two induction trials. The UNITI-1 trial included 741 patients who met the criteria for primary or secondary nonresponse to tumor necrosis factor (TNF) antagonists or had unacceptable side effects. The UNITI-2 trial included 628 patients in whom conventional therapy failed or unacceptable side effects occurred. Patients who completed these induction trials then participated in IM-UNITI, in which the 397 patients who had a response to ustekinumab were randomly assigned to receive subcutaneous maintenance injections of 90 mg of ustekinumab (either every 8 weeks or every 12 weeks) or placebo. The primary end point for the induction trials was a clinical response at week 6 (defined as a decrease from baseline in the Crohn's Disease Activity Index [CDAI] score of ≥100 points or a CDAI score150). The primary end point for the maintenance trial was remission at week 44 (CDAI score150).The rates of response at week 6 among patients receiving intravenous ustekinumab at a dose of either 130 mg or approximately 6 mg per kilogram were significantly higher than the rates among patients receiving placebo (in UNITI-1, 34.3%, 33.7%, and 21.5%, respectively, with P≤0.003 for both comparisons with placebo; in UNITI-2, 51.7%, 55.5%, and 28.7%, respectively, with P0.001 for both doses). In the groups receiving maintenance doses of ustekinumab every 8 weeks or every 12 weeks, 53.1% and 48.8%, respectively, were in remission at week 44, as compared with 35.9% of those receiving placebo (P=0.005 and P=0.04, respectively). Within each trial, adverse-event rates were similar among treatment groups.Among patients with moderately to severely active Crohn's disease, those receiving intravenous ustekinumab had a significantly higher rate of response than did those receiving placebo. Subcutaneous ustekinumab maintained remission in patients who had a clinical response to induction therapy. (Funded by Janssen Research and Development; ClinicalTrials.gov numbers, NCT01369329 , NCT01369342 , and NCT01369355 .).

Published
2016

6. Randomised clinical trial: the efficacy and safety of propionyl-L-carnitine therapy in patients with ulcerative colitis receiving stable oral treatment

Author

Mikhailova TL, Sishkova E, Poniewierka E, Zhidkov KP, Bakulin IG, Kupcinskas L, Lesniakowski K, Grinevich VB, Malecka Panas E, Ardizzone S, Valpiani D, Koch M, Denapiene G, Vago G, Fociani P, Zerbi P, Ceracchi M, Camerini R, Gasbarrini G., D'ARIENZO, AGESILAO, Mikhailova, Tl, Sishkova, E, Poniewierka, E, Zhidkov, Kp, Bakulin, Ig, Kupcinskas, L, Lesniakowski, K, Grinevich, Vb, Malecka Panas, E, Ardizzone, S, D'Arienzo, Agesilao, Valpiani, D, Koch, M, Denapiene, G, Vago, G, Fociani, P, Zerbi, P, Ceracchi, M, Camerini, R, and Gasbarrini, G.

Subjects
Adult, Male, Dose-Response Relationship, Drug, Anti-Inflammatory Agents, Non-Steroidal, Administration, Oral, Middle Aged, Severity of Illness Index, ulcerative coliti, randomised clinical trial, Cohort Studies, Young Adult, propionyl-L-carnitine, Treatment Outcome, Double-Blind Method, Carnitine, Humans, Colitis, Ulcerative, Female
Abstract

Ulcerative colitis (UC) is characterised by impaired fatty-acid oxidation; l-carnitine has a key role in fatty-acid metabolism and short-chain fatty acids such as butyrate and propionate are important energy source for intestinal epithelial cells.To evaluate efficacy and safety of colon-release propionyl-L-carnitine (PLC) in patients with mild-to-moderate UC receiving stable oral aminosalicylate or thiopurine therapy.In a multicentre, phase II, double-blind, parallel-group trial, patients were randomised to receive PLC 1 g/day, PLC 2 g/day or placebo. Main inclusion criteria were as follows: age 18-75; disease activity index (DAI) score 3-10 inclusive, be under oral stable treatment with aminosalicylate or thiopurine. The primary endpoint was clinical/endoscopic response, defined as a decrease in DAI score ≥ 3 points or remission, defined as a DAI score ≤ 2 with no individual sub-score1.Of 121 patients who were randomised, 57 of 79 (72%) patients receiving PLC (combined 1 g and 2 g cohort) had a clinical/endoscopic response vs. 20 of 40 (50%) receiving placebo (P = 0.02). Specifically, in PLC 1 g/day group, 30 of 40 (75%) patients had clinical/endoscopic response (P = 0.02 vs. placebo) and 27 of 39 (69%) in the PLC 2 g/day group (P = 0.08 vs. placebo). Rates of remission were 22/40 (55%), 19/39 (49%), 14/40 (35%) in the PLC 1 g, PLC 2 g, and placebo groups, respectively. PLC had a similar safety profile to placebo; the most common adverse events were gastrointestinal.Propionyl-L-carnitine 1 g/day should be investigated further as a co-treatment for mild-to-moderate ulcerative colitis (NCT-01026857).

Published
2011

7. Adiponectin and leptin receptors expression in Barrett's esophagus and normal squamous epithelium in relation to central obesity status

Author

Mokrowiecka A, Sokolowska M, Luczak E, Dudojc M, Wieczfinska J, Kacprzak D, Wierzchniewska-Lawska A, Rafał Pawliczak, and Malecka-Panas E

Subjects
Adult, Leptin, Male, Esophageal Neoplasms, Adenocarcinoma, Middle Aged, Epithelium, Barrett Esophagus, Obesity, Abdominal, Humans, Receptors, Leptin, Female, Adiponectin, Receptors, Adiponectin, Aged
Abstract

Esophageal adenocarcinoma incidence is rapidly increasing which may be due to the growing incidence of Barrett's esophagus (BE) and obesity. The mechanisms linking obesity and progression of Barrett's carcinogenesis is poorly understood. The aim of the study was to evaluate the expression of adipokines receptors in BE and in normal squamous epithelium in the same patients in correlation with obesity parameters.Expression of adiponectin receptors 1 and 2 protein (AdipoR1, AdipoR2) as well as leptin receptor protein (ObR) in biopsies from 27 BE and normal squamous epithelium (N) in the same patients as well as in obese and normal controls were assessed with Western-blot analysis. These correlations were confirmed with the quantitative RT-PCR (qRT-PCR). AdipoR1 and ObR protein levels were similar in BE mucosa and squamous epithelium in the same patients in Western-blot analysis (2303 vs. 2448 OB units; 106927 vs. 103390, respectively; p0.05). RT-PCR analysis confirmed this observation for AdipoR1, R2 and ObR genes expression (0.11±0.08 vs. 0.19±0.24, p=0.78; 0.24±0.36 vs. 0.33±0.49, p=0.5375; 0.71±0.8 vs. 1.33±2.95, p=1.0; respectively). Using linear correlation analysis we found the positive correlation between AdipoR1 expression in Barrett's epithelium compared to squamous epithelium in the same patients (N) (r=0.5; p=0.008) and between ObR expression in BE and N (r=0.8; p0.001). The AdipoR1 and ObR protein levels were significantly higher in BE patients compared to controls and obese controls (2303 vs. 895 vs. 1674 and OD units, p0.05).in opposite to the prior hypothesis adiponectin and leptin receptors activation in BE may be not caused by obesity.

8. Analysis of GPRC6A variants in different pancreatitis etiologies

Author

Markus M. Lerch, Emmanuelle Masson, Joost P.H. Drenth, Peter Bugert, Jian-Min Chen, Wen Bin Zou, Marko Damm, Matthias Sendler, Jonas Rosendahl, Heidi Griesmann, Holger Kirsten, Claudia Ruffert, Ewa Małecka-Panas, Markus Scholz, Nico Hesselbarth, Tom Kaune, Rene H. M. te Morsche, Péter Hegyi, Stanisław Głuszek, Zhuan Liao, Julian Cardinal von Widdern, Heiko Witt, Raffaella Alessia Zuppardo, Robert Grützmann, Louis Buscail, Sebastian Krug, Shun Jiang Deng, Frank Ulrich Weiss, Vinciane Rebours, Giulia Martina Cavestro, Claude Férec, Adrian Saftoiu, Patrick Michl, Kaune, T., Ruffert, C., Hesselbarth, N., Damm, M., Krug, S., Cardinal von Widdern, J., Masson, E., Chen, J. -M., Rebours, V., Buscail, L., Ferec, C., Grutzmann, R., te Morsche, R. H. M., Drenth, J. P., Cavestro, G. M., Zuppardo, R. A., Saftoiu, A., Malecka-Panas, E., Gluszek, S., Bugert, P., Lerch, M. M., Sendler, M., Weiss, F. U., Zou, W. -B., Deng, S. -J., Liao, Z., Scholz, M., Kirsten, H., Hegyi, P., Witt, H., Michl, P., Griesmann, H., and Rosendahl, J.

Subjects
Adult, Male, Candidate gene, Pancreatitis, Alcoholic, Endocrinology, Diabetes and Metabolism, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, White People, Receptors, G-Protein-Coupled, 03 medical and health sciences, 0302 clinical medicine, Asian People, Risk Factors, Genetics, Humans, Medicine, SNP, Genetic Predisposition to Disease, Aged, Inflammation, Hepatology, G-Protein coupled receptor, business.industry, Gastroenterology, Genetic Variation, Inflammasome, DNA, Odds ratio, Middle Aged, Tag SNP, medicine.disease, Europe, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], Pancreatitis, 030220 oncology & carcinogenesis, Cohort, Immunology, Female, Calcium, 030211 gastroenterology & hepatology, business, Receptors, Calcium-Sensing, Genome-Wide Association Study, Signal Transduction, medicine.drug
Abstract

Contains fulltext : 229360.pdf (Publisher’s version ) (Closed access) BACKGROUND: The G-protein-coupled receptor Class C Group 6 Member A (GPRC6A) is activated by multiple ligands and is important for the regulation of calcium homeostasis. Extracellular calcium is capable to increase NLRP3 inflammasome activity of the innate immune system and deletion of this proinflammatory pathway mitigated pancreatitis severity in vivo. As such this pathway and the GPRC6A receptor is a reasonable candidate gene for pancreatitis. Here we investigated the prevalence of sequence variants in the GPRC6A locus in different pancreatitis aetiologies. METHODS: We selected 6 tagging SNPs with the SNPinfo LD TAG SNP Selection tool and the functional relevant SNP rs6907580 for genotyping. Cohorts from Germany, further European countries and China with up to 1,124 patients and 1,999 controls were screened for single SNPs with melting curve analysis. RESULTS: We identified an association of rs1606365(G) with alcoholic chronic pancreatitis in a German (odds ratio (OR) 0.76, 95% confidence interval (CI) 0.65-0.89, p = 8 × 10(-5)) and a Chinese cohort (OR 0.78, 95% CI 0.64-0.96, p = 0.02). However, this association was not replicated in a combined cohort of European patients (OR 1.18, 95% CI 0.99-1.41, p = 0.07). Finally, no association was found with acute and non-alcoholic chronic pancreatitis. CONCLUSIONS: Our results support a potential role of calcium sensing receptors and inflammasome activation in alcoholic chronic pancreatitis development. As the functional consequence of the associated variant is unclear, further investigations might elucidate the relevant mechanisms.

Published
2020

9. Genome-wide scan of long noncoding RNA single nucleotide polymorphisms and pancreatic cancer susceptibility

Author

Ewa Małecka-Panas, Jakob R. Izbicki, Krzysztof Jamroziak, Claudio Pasquali, Sabrina Gloria Giulia Testoni, Silvia Carrara, Livia Archibugi, Domenica Gioffreda, Francesca Tavano, Matteo Giaccherini, Gregorio Di Franco, Niccolò Napoli, Viktor Hlavac, Yogesh K. Vashist, Oliver Strobel, Martin Lovecek, Paolo Giorgio Arcidiacono, Thilo Hackert, Klara Cervena, Stefano Landi, Claudio Luchini, Andrea Szentesi, Maria Gazouli, Giulia Martina Cavestro, Daniele Campa, Gabriele Capurso, Rita T. Lawlor, Martin Oliverius, Edita Kreivenaite, Audrius Ivanauskas, Luca Morelli, Raffaele Pezzilli, Maria Chiara Petrone, Chiara Corradi, Stefania Moz, George Theodoropoulos, Michael F. Nentwich, Pavel Vodicka, Giuseppe Vanella, Hermann Brenner, Manuel Gentiluomo, John P. Neoptolemos, Cosimo Sperti, Angelo Andriulli, Ye Lu, Péter Hegyi, Cristian Gheorghe, Anna Caterina Milanetto, Pavel Soucek, László Gajdán, Erika Darvasi, Juozas Kupcinskas, Federico Canzian, Raffaella Alessia Zuppardo, Corradi, C., Gentiluomo, M., Gajdan, L., Cavestro, G. M., Kreivenaite, E., Di Franco, G., Sperti, C., Giaccherini, M., Petrone, M. C., Tavano, F., Gioffreda, D., Morelli, L., Soucek, P., Andriulli, A., Izbicki, J. R., Napoli, N., Malecka-Panas, E., Hegyi, P., Neoptolemos, J. P., Landi, S., Vashist, Y., Pasquali, C., Lu, Y., Cervena, K., Theodoropoulos, G. E., Moz, S., Capurso, G., Strobel, O., Carrara, S., Hackert, T., Hlavac, V., Archibugi, L., Oliverius, M., Vanella, G., Vodicka, P., Arcidiacono, P. G., Pezzilli, R., Milanetto, A. C., Lawlor, R. T., Ivanauskas, A., Szentesi, A., Kupcinskas, J., Testoni, S. G. G., Lovecek, M., Nentwich, M., Gazouli, M., Luchini, C., Zuppardo, R. A., Darvasi, E., Brenner, H., Gheorghe, C., Jamroziak, K., Canzian, F., and Campa, D.

Subjects
Male, Cancer Research, association study, long noncoding RNA, pancreatic cancer, single nucleotide polymorphism, Aged, Carcinoma, Pancreatic Ductal, Case-Control Studies, Computational Biology, Cyclin-Dependent Kinase Inhibitor p15, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, MicroRNAs, Middle Aged, Pancreatic Neoplasms, RNA, Long Noncoding, Polymorphism, Single Nucleotide, Single-nucleotide polymorphism, Locus (genetics), Genome-wide association study, Biology, Genome, 03 medical and health sciences, 0302 clinical medicine, SNP, Genetic variability, Polymorphism, Gene, Genetics, Carcinoma, Single Nucleotide, Long non-coding RNA, Oncology, Pancreatic Ductal, 030220 oncology & carcinogenesis, RNA, Long Noncoding
Abstract

Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second cancer-related cause of death by 2030. Identifying novel risk factors, including genetic risk loci, could be instrumental in risk stratification and implementation of prevention strategies. Long noncoding RNAs (lncRNAs) are involved in regulation of key biological processes, and the possible role of their genetic variability has been unexplored so far. Combining genome wide association studies and functional data, we investigated the genetic variability in all lncRNAs. We analyzed 9893 PDAC cases and 9969 controls and identified a genome-wide significant association between the rs7046076 SNP and risk of developing PDAC (P = 9.73 × 10-9 ). This SNP is located in the NONHSAG053086.2 (lnc-SMC2-1) gene and the risk allele is predicted to disrupt the binding of the lncRNA with the micro-RNA (miRNA) hsa-mir-1256 that regulates several genes involved in cell cycle, such as CDKN2B. The CDKN2B region is pleiotropic and its genetic variants have been associated with several human diseases, possibly though an imperfect interaction between lncRNA and miRNA. We present a novel PDAC risk locus, supported by a genome-wide statistical significance and a plausible biological mechanism.

Published
2021

10. Polygenic and multifactorial scores for pancreatic ductal adenocarcinoma risk prediction

Author

John P. Neoptolemos, Markus W. Büchler, Jakob R. Izbicki, Ben Schöttker, Cosmeri Rizzato, Cornelia Schroeder, Salvatore Paiella, Hanneke W. M. van Laarhoven, William Greenhalf, Simona Bursi, Renata Talar-Wojnarowska, Christos Dervenis, Ludmila Vodickova, Francesca Tavano, Giulia Martina Cavestro, Thilo Hackert, Claudio Pasquali, Ewa Małecka-Panas, Gabriele Capurso, Andrea Mambrini, Daniele Campa, Andrea Padoan, Ioannis S. Papanikolaou, Raffaele Pezzilli, Péter Hegyi, Beatrice Mohelnikova-Duchonova, Federica Gemignani, Michael F. Nentwich, Pavel Vodicka, Stefano Landi, Richárd Szmola, Anna Caterina Milanetto, Eithne Costello, Rudolf Kaaks, Laura Ginocchi, Bernd Holleczek, Erika Darvasi, Verena Katzke, Evaristo Maiello, Manuel Gentiluomo, Ondrej Strouhal, Orazio Palmieri, Juozas Kupcinskas, Alice Alessandra Galeotti, Viktor Hlavac, George Theodoropoulos, Audrius Ivanauskas, Maria Gazouli, Ferenc Izbéki, Federico Canzian, Oliver Strobel, Ofure Obazee, Martin Lovecek, Timothy J. Key, Domenica Gioffreda, Pavel Soucek, Ugo Boggi, Krzysztof Jamroziak, Cosimo Sperti, Maarten F. Bijlsma, Yogesh K. Vashist, Andrea Szentesi, Hermann Brenner, Livia Archibugi, Giuseppe Vanella, Daniela Basso, Radiotherapy, Center of Experimental and Molecular Medicine, CCA - Cancer Treatment and Quality of Life, Oncology, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Galeotti, A. A., Gentiluomo, M., Rizzato, C., Obazee, O., Neoptolemos, J. P., Pasquali, C., Nentwich, M., Cavestro, G. M., Pezzilli, R., Greenhalf, W., Holleczek, B., Schroeder, C., Schottker, B., Ivanauskas, A., Ginocchi, L., Key, T. J., Hegyi, P., Archibugi, L., Darvasi, E., Basso, D., Sperti, C., Bijlsma, M. F., Palmieri, O., Hlavac, V., Talar-Wojnarowska, R., Mohelnikova-Duchonova, B., Hackert, T., Vashist, Y., Strouhal, O., Van Laarhoven, H., Tavano, F., Lovecek, M., Dervenis, C., Izbeki, F., Padoan, A., Malecka-Panas, E., Maiello, E., Vanella, G., Capurso, G., Izbicki, J. R., Theodoropoulos, G. E., Jamroziak, K., Katzke, V., Kaaks, R., Mambrini, A., Papanikolaou, I. S., Szmola, R., Szentesi, A., Kupcinskas, J., Bursi, S., Costello, E., Boggi, U., Milanetto, A. C., Landi, S., Gazouli, M., Vodickova, L., Soucek, P., Gioffreda, D., Gemignani, F., Brenner, H., Strobel, O., Buchler, M., Vodicka, P., Paiella, S., Canzian, F., and Campa, D.

Subjects
0301 basic medicine, Oncology, Male, medicine.medical_specialty, Multifactorial Inheritance, Pancreatic disease, genetic epidemiology, Population, Single-nucleotide polymorphism, Disease, pancreas and biliary tract, Polymorphism, Single Nucleotide, Risk Assessment, ABO Blood-Group System, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, Pancreatic cancer, Internal medicine, Genetics, medicine, oncology, Humans, education, Genetics (clinical), Alleles, Early Detection of Cancer, Genetic association, education.field_of_study, business.industry, medicine.disease, Pancreatic Neoplasms, 030104 developmental biology, Genetic epidemiology, 030220 oncology & carcinogenesis, Cohort, Female, business, Carcinoma, Pancreatic Ductal
Abstract

BackgroundMost cases of pancreatic ductal adenocarcinoma (PDAC) are asymptomatic in early stages, and the disease is typically diagnosed in advanced phases, resulting in very high mortality. Tools to identify individuals at high risk of developing PDAC would be useful to improve chances of early detection.ObjectiveWe generated a polygenic risk score (PRS) for PDAC risk prediction, combining the effect of known risk SNPs, and carried out an exploratory analysis of a multifactorial score.MethodsWe tested the associations of the individual known risk SNPs on up to 2851 PDAC cases and 4810 controls of European origin from the PANcreatic Disease ReseArch (PANDoRA) consortium. Thirty risk SNPs were included in a PRS, which was computed on the subset of subjects that had 100% call rate, consisting of 839 cases and 2040 controls in PANDoRA and 6420 cases and 4889 controls from the previously published Pancreatic Cancer Cohort Consortium I–III and Pancreatic Cancer Case-Control Consortium genome-wide association studies. Additional exploratory multifactorial scores were constructed by complementing the genetic score with smoking and diabetes.ResultsThe scores were associated with increased PDAC risk and reached high statistical significance (OR=2.70, 95% CI 1.99 to 3.68, p=2.54×10−10 highest vs lowest quintile of the weighted PRS, and OR=14.37, 95% CI 5.57 to 37.09, p=3.64×10−8, highest vs lowest quintile of the weighted multifactorial score).ConclusionWe found a highly significant association between a PRS and PDAC risk, which explains more than individual SNPs and is a step forward in the direction of the construction of a tool for risk stratification in the population.

Published
2020

11. Genome-wide association study identifies an early onset pancreatic cancer risk locus

Author

Verena Katzke, Jakob R. Izbicki, Francesca Tavano, Rita T. Lawlor, Thilo Hackert, Raffaella Alessia Zuppardo, Giulia Martina Cavestro, Federico Canzian, Frederike Dijk, Martin Oliverius, George Theodoropoulos, Pavel Soucek, Manuel Gentiluomo, Rudolf Kaaks, Erika Darvasi, Yogesh K. Vashist, Bill Greenhalf, Juozas Kupcinskas, Maurizio Lucchesi, Borislav Rusev, Andrea Szentesi, Gabriele Capurso, Ewa Małecka-Panas, Lucia Moletta, Beatrice Mohelnikova-Duchonova, Franco Bambi, Ugo Boggi, Alba Ballerini, Krzysztof Jamroziak, Ben Schöttker, Simona Bursi, Raffaele Pezzilli, Gyula Farkas, Dania Bozzato, Áron Vincze, Stefano Landi, Anna Caterina Milanetto, Péter Hegyi, Michael F. Nentwich, Laura Ginocchi, Pavel Vodicka, Stefania Moz, Ludmila Vodickova, Hermann Brenner, Olivier R. Busch, Viktor Hlavac, Audrius Ivanauskas, John P. Neoptolemos, Domenica Gioffreda, Ofure Obazee, Livia Archibugi, Nathalia A. Giese, Giuseppe Vanella, Xin Gao, Renata Talar-Wojnarowska, Angelo Andriulli, Oliver Strobel, Daniele Campa, Maria Gazouli, Pathology, CCA - Cancer biology and immunology, Surgery, AGEM - Digestive immunity, AGEM - Endocrinology, metabolism and nutrition, AGEM - Re-generation and cancer of the digestive system, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Campa, D., Gentiluomo, M., Obazee, O., Ballerini, A., Vodickova, L., Hegyi, P., Soucek, P., Brenner, H., Milanetto, A. C., Landi, S., Gao, X., Bozzato, D., Capurso, G., Tavano, F., Vashist, Y., Hackert, T., Bambi, F., Bursi, S., Oliverius, M., Gioffreda, D., Schottker, B., Ivanauskas, A., Mohelnikova-Duchonova, B., Darvasi, E., Pezzilli, R., Malecka-Panas, E., Strobel, O., Gazouli, M., Katzke, V., Szentesi, A., Cavestro, G. M., Farkas, G., Izbicki, J. R., Moz, S., Archibugi, L., Hlavac, V., Vincze, A., Talar-Wojnarowska, R., Rusev, B., Kupcinskas, J., Greenhalf, B., Dijk, F., Giese, N., Boggi, U., Andriulli, A., Busch, O. R., Vanella, G., Vodicka, P., Nentwich, M., Lawlor, R. T., Theodoropoulos, G. E., Jamroziak, K., Zuppardo, R. A., Moletta, L., Ginocchi, L., Kaaks, R., Neoptolemos, J. P., Lucchesi, M., and Canzian, F.

Subjects
Oncology, Male, Cancer Research, medicine.medical_specialty, Pancreatic disease, pancreatic cancer, early onset, Single-nucleotide polymorphism, Genome-wide association study, very early onset pancreatic cancer, Polymorphism, Single Nucleotide, 03 medical and health sciences, single nucleotide polymorphisms, 0302 clinical medicine, Risk Factors, Pancreatic cancer, Internal medicine, Genetic predisposition, Medicine, Humans, Genetic Predisposition to Disease, Genetic variability, Pancreas, Genetic association, genome-wide association study, business.industry, Middle Aged, medicine.disease, Pancreatic Neoplasms, 030220 oncology & carcinogenesis, Case-Control Studies, Female, Age of onset, business, Carcinoma, Pancreatic Ductal
Abstract

Early onset pancreatic cancer (EOPC) is a rare disease with a very high mortality rate. Almost nothing is known on the genetic susceptibility of EOPC, therefore we performed a genome-wide association study (GWAS) to identify novel genetic variants specific for patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) at younger ages. In the first phase, conducted on 821 cases with age of onset ≤60 years, of whom 198 with age of onset ≤50, and 3227 controls from PanScan I-II, we observed four SNPs (rs7155613, rs2328991, rs4891017 and rs12610094) showing an association with EOPC risk (P < 1x10-4 ). We replicated these SNPs in the PANcreatic Disease ReseArch (PANDoRA) consortium and used additional in silico data from PanScan III and PanC4. Among these four variants rs2328991 was significant in an independent set of 855 cases with age of onset ≤60 years, of whom 265 with age of onset≤50, and 4142 controls from the PANDoRA consortium while in the in silico data we observed no statistically significant association. However, the resulting meta-analysis supported the association (P = 1.15x10-4 ). In conclusion we propose a novel variant rs2328991 to be involved in EOPC risk. Even though it was not possible to find a mechanistic link between the variant and the function, the association is supported by a solid statistical significance obtained in the largest study on EOPC genetics present so far in the literature. This article is protected by copyright. All rights reserved.

Published
2020

12. Acid suppression therapy, gastrointestinal bleeding and infection in acute pancreatitis - An international cohort study

Author

Péter Jenő Hegyi, Áron Vincze, Alexandra Demcsák, László Gajdán, Andrey Litvin, Andra Iulia Suceveanu, Eva Pijoan Comas, Riccardo Casadei, George I Papachristou, Vincenzo Cennamo, Yu-Ting Chang, Péter Hegyi, Ionut Negoi, Carlo Ingaldi, Vitor Nunes, Adriano Quiroga Castiñeira, Lihui Deng, Orestis Ioannidis, Ernő Bóna, Milene Raquel Ramos Moreira e Sá, Juan Armando Rodriguez-Oballe, Andrea Jardi Cuadrado, József Hamvas, Judit Bajor, Alexander Schneider, Tiago Cúrdia Gonçalves, Haluk Tarik Kani, Alexandra Soós, Serge Chooklin, Marcus Hollenbach, Claudio Ricci, Marta Freitas, Isabel Miguel Salas, Michael Hirth, Cristina Tocia, Dóra Illés, Daniel de la Iglesia Garcia, Amir Gougol, Patrícia Sarlós, Marco Marino, Emőke Miklós, Qing Xia, Valentina Negoita, Mihailo Bezmarevic, Radislav Nakov, Erika Darvasi, Deniz Güney Duman, Péter Kanizsai, Laura Mastrangelo, Vasile Sandru, Andrea Párniczky, Hubert Zatorski, Andrea Szentesi, Mária Papp, Mario Pelaez-Luna, Marcel Tantau, Yliya Rabotyagova, Ferenc Izbéki, Natalia V Shirinskaya, Cristian Gheorghe, Ewa Małecka-Panas, Giedrius Barauskas, Engin Altintaş, Wei Huang, Ali Kchaou, Povilas Ignatavicius, Cezar Ciubotaru, Stefania Bunduc, Jorge Paulino Pereira, Dong Wu, Sabite Kacar, Alina Tantau, António Pedro Gomes, Svetlana Turcan, Bálint Erőss, Sorin T. Barbu, Adriana Gherbon, Georgi Minkov, Júlio Constantino, Márk Félix Juhász, Jimin Han, Serhii Chuklin, Klementina Ocskay, Mila Kovacheva-Slavova, Eugen Tcaciuc, Elio Jovine, Lilla Barbara Kincses, Ines Capunge, Gabriel Constantinescu, Bogdan Mateescu, Eugen Dumitru, Ming-Chu Chang, Andrea Soriano Rios, Márta Varga, László Czakó, Volkan Gökbulut, Alexandra Mikó, Szilárd Váncsa, Ahmed Tlili, Demcsak, Alexandra, Soos, Alexandra, Kincses, Lilla, Capunge, Ines, Minkov, Georgi, Kovacheva-Slavova, Mila, Nakov, Radislav, Wu, Dong, Huang, Wei, Xia, Qing, Deng, Lihui, Hollenbach, Marcus, Schneider, Alexander, Hirth, Michael, Ioannidis, Orestis, Vincze, Aron, Bajor, Judit, Sarlos, Patricia, Czako, Laszlo, Illes, Dora, Izbeki, Ferenc, Gajdan, Laszlo, Papp, Maria, Hamvas, Jozsef, Varga, Marta, Kanizsai, Peter, Bona, Erno, Miko, Alexandra, Vancsa, Szilard, Juhasz, Mark Felix, Ocskay, Klementina, Darvasi, Erika, Miklos, Emoke, Eross, Balint, Szentesi, Andrea, Parniczky, Andrea, Casadei, Riccardo, Ricci, Claudio, Ingaldi, Carlo, Mastrangelo, Laura, Jovine, Elio, Cennamo, Vincenzo, Marino, Marco V., Barauskas, Giedrius, Ignatavicius, Povilas, Pelaez-Luna, Mario, Rios, Andrea Soriano, Turcan, Svetlana, Tcaciuc, Eugen, Malecka-Panas, Ewa, Zatorski, Hubert, Nunes, Vitor, Gomes, Antonio, Goncalves, Tiago Curdia, Freitas, Marta, Constantino, Julio, Sa, Milene, Pereira, Jorge, Mateescu, Bogdan, Constantinescu, Gabriel, Sandru, Vasile, Negoi, Ionut, Ciubotaru, Cezar, Negoita, Valentina, Bunduc, Stefania, Gheorghe, Cristian, Barbu, Sorin, Tantau, Alina, Tantau, Marcel, Dumitru, Eugen, Suceveanu, Andra Iulia, Tocia, Cristina, Gherbon, Adriana, Litvin, Andrey, Shirinskaya, Natalia, Rabotyagova, Yliya, Bezmarevic, Mihailo, Hegyi, Peter Jeno, Han, Jimin, Rodriguez-Oballe, Juan Armando, Salas, Isabel Miguel, Comas, Eva Pijoan, de la Iglesia Garcia, Daniel, Cuadrado, Andrea Jardi, Castineira, Adriano Quiroga, Chang, Yu-Ting, Chang, Ming-Chu, Kchaou, Ali, Tlili, Ahmed, Kacar, Sabite, Gokbulut, Volkan, Duman, Deniz, Kani, Haluk Tarik, Altintas, Engin, Chooklin, Serge, Chuklin, Serhii, Gougol, Amir, Papachristou, George, Hegyi, Peter, Demcsak A., Soos A., Kincses L., Capunge I., Minkov G., Kovacheva-Slavova M., Nakov R., Wu D., Huang W., Xia Q., Deng L., Hollenbach M., Schneider A., Hirth M., Ioannidis O., Vincze A., Bajor J., Sarlos P., Czako L., Illes D., Izbeki F., Gajdan L., Papp M., Hamvas J., Varga M., Kanizsai P., Bona E., Miko A., Vancsa S., Juhasz M.F., Ocskay K., Darvasi E., Miklos E., Eross B., Szentesi A., Parniczky A., Casadei R., Ricci C., Ingaldi C., Mastrangelo L., Jovine E., Cennamo V., Marino M.V., Barauskas G., Ignatavicius P., Pelaez-Luna M., Rios A.S., Turcan S., Tcaciuc E., Malecka-Panas E., Zatorski H., Nunes V., Gomes A., Goncalves T.C., Freitas M., Constantino J., Sa M., Pereira J., Mateescu B., Constantinescu G., Sandru V., Negoi I., Ciubotaru C., Negoita V., Bunduc S., Gheorghe C., Barbu S., Tantau A., Tantau M., Dumitru E., Suceveanu A.I., Tocia C., Gherbon A., Litvin A., Shirinskaya N., Rabotyagova Y., Bezmarevic M., Hegyi P.J., Han J., Rodriguez-Oballe J.A., Salas I.M., Comas E.P., Garcia D.D.L.I., Cuadrado A.J., Castineira A.Q., Chang Y.-T., Chang M.-C., Kchaou A., Tlili A., Kacar S., Gokbulut V., Duman D., Kani H.T., Altintas E., Chooklin S., Chuklin S., Gougol A., Papachristou G., and Hegyi P.

Subjects
Male, Endocrinology, Diabetes and Metabolism, Gastroenterology, Cohort Studies, Feces, 0302 clinical medicine, Risk Factors, Surveys and Questionnaires, Acid suppressing drug, Acute pancreatitis, Gastrointestinal bleeding, Gastrointestinal infection, Proton pump inhibitor, Enterocolitis, Pseudomembranous, Aged, 80 and over, RISK, ASSOCIATION, Middle Aged, Clostridium difficile, CANCER, 3. Good health, Hospitalization, Treatment Outcome, 030220 oncology & carcinogenesis, Acute Disease, Female, 030211 gastroenterology & hepatology, Gastrointestinal Hemorrhage, Cohort study, Adult, medicine.medical_specialty, GI bleeding, medicine.drug_class, Proton-pump inhibitor, Infections, PROTON-PUMP INHIBITORS, 03 medical and health sciences, Internal medicine, mental disorders, medicine, MANAGEMENT, Humans, DRUGS, Acute pancreatiti, Aged, Retrospective Studies, Hepatology, Clostridioides difficile, business.industry, Proton Pump Inhibitors, medicine.disease, Pancreatitis, Acid suppression, business
Abstract

Background: Acid suppressing drugs (ASD) are generally used in acute pancreatitis (AP); however, large cohorts are not available to understand their efficiency and safety. Therefore, our aims were to evaluate the association between the administration of ASDs, the outcome of AP, the frequency of gastrointestinal (GI) bleeding and GI infection in patients with AP. Methods: We initiated an international survey and performed retrospective data analysis on AP patients hospitalized between January 2013 and December 2018. Results: Data of 17,422 adult patients with AP were collected from 59 centers of 23 countries. We found that 23.3% of patients received ASDs before and 86.6% during the course of AP. ASDs were prescribed to 57.6% of patients at discharge. ASD administration was associated with more severe AP and higher mortality. GI bleeding was reported in 4.7% of patients, and it was associated with pancreatitis severity, mortality and ASD therapy. Stool culture test was performed in 6.3% of the patients with 28.4% positive results. Clostridium difficile was the cause of GI infection in 60.5% of cases. Among the patients with GI infections, 28.9% received ASDs, whereas 24.1% were without any acid suppression treatment. GI infection was associated with more severe pancreatitis and higher mortality. Conclusions: Although ASD therapy is widely used, it is unlikely to have beneficial effects either on the outcome of AP or on the prevention of GI bleeding during AP. Therefore, ASD therapy should be substantially decreased in the therapeutic management of AP. (C) 2020 IAP and EPC. Published by Elsevier B.V.

Published
2020

13. Infliximab Reduces Endoscopic, but Not Clinical, Recurrence of Crohn’s Disease After Ileocolonic Resection

Author

Silvio Danese, V. Yajnik, P. Gionchetti, Brian G. Feagan, Richard N. Fedorak, O. Dewit, D. Sorrentino, V. F. Annese, W J Sandborn, Michael Chiorean, G. Radford-Smith, S Plevy, I. Lawrance, Jane E. Onken, Simon Campbell, Jewel Johanns, Peter L. Lakatos, G R D’Haens, Denis Franchimont, J. C. Preiss, Giovanni Terrosu, Áron Vincze, Torsten Kucharzik, Charles Randall, I. Stein, Edward V. Loftus, L. Sauberman, X. Li, I. Oikonomou, Frank Zerbib, H. G. Lamprecht, R. Kottoor, J. Vecchio, Severine Vermeire, Daniel Rachmilewitz, J. R. Lachance, J.L. Dupas, W. H. Holderman, Michael Safdi, T. Haas, J.-F. Colombel, Richard B. Gearry, Russell S. Walmsley, R. P. Phillips, Miguel Regueiro, A. B. Hawthorne, David T. Rubin, J. W. Hamilton, G. D'Haens, M Parkes, Jean-Marie Reimund, Fabrizio Bossa, Walter Reinisch, K. A. Peterson, M. Ropeleski, S. Fishman, Marc Chevrier, Hans H Herfarth, Stephen B. Hanauer, Timothy H. Florin, Walter Fries, D. J. Hetzel, D. E. Elliott, János Banai, B. W. Behm, S. Sedghi, Remo Panaccione, Peter D.R. Higgins, Jean-Paul Achkar, Ziad Younes, Raja Atreya, Harald Vogelsang, M. Noar, S. S. Dhalla, U. Boecker, Raymond Bourdages, Ellen Scherl, Eran Goldin, T. Ritter, S. Gassner, Stefanie Howaldt, M. Ricci, Paolo Gionchetti, B. I. Leman, Marion Blank, D. Grunkmeier, Livia Biancone, J. Mudter, N. Chiba, Paolo Usai, R. Hardi, I. P. Beales, István Altorjay, W. J S Devilliers, J. Hill, Daniel C. Baumgart, Jason M. Swoger, Charles A. Sninsky, B. Singh Salh, L. D. Wruble, G. Bramkamp, Dario Sorrentino, Paul Rutgeerts, Stephen J. Bickston, S. Schreiber, D. J. Helper, Eric Lerebours, Jaroslaw Regula, M. D. Kreines, M. Strasser, C. Antoni, Giovanni Maconi, Freddy Cornillie, Laurent Peyrin-Biroulet, J. S. Hanson, Ewa Małecka-Panas, David Rowbotham, Jean-Charles Grimaud, Gerald Fraser, Ursula Seidler, C. Bünning, C. Berg, G. Reicht, Martin Lukas, John W. Popp, Edouard Louis, D. Laharie, Xavier Hébuterne, K. J. Brown, Márta Varga, L. Paradowski, Robert Ehehalt, Sandro Ardizzone, Stephanie Viennot, S. B. Hanauer, Charles N. Bernstein, Milan Lukas, H. Debinski, R. P. Schwarz, Simon Travis, D. I. Weinberg, D. Wallace, R. S. Stubbs, Bin Zou, A. Sloss, John Wyeth, Irit Avni-Biron, Peter Bossuyt, Ira Shafran, Matthieu Allez, Pierre Desreumaux, Michael Schultz, W. Reinisch, William J. Sandborn, APH - Amsterdam Public Health, 10 Public Health & Methodologie, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Gastroenterology and Hepatology, AII - Amsterdam institute for Infection and Immunity, Intensive Care Medicine, UCL - SSS/IREC-Institut de recherche expérimentale et clinique, UCL - SSS/IREC/GAEN-Pôle d'Hépato-gastro-entérologie, UCL - (SLuc) Service de gastro-entérologie, Regueiro, M, Feagan, Bg, Zou, B, Johanns, J, Blank, Ma, Chevrier, M, Plevy, S, Popp, J, Cornillie, Fj, Lukas, M, Danese, S, Gionchetti, P, Hanauer, Sb, Reinisch, W, Sandborn, Wj, Sorrentino, D, Rutgeerts, P, Regueiro, Miguel, Feagan, Brian G., Zou, Bin, Johanns, Jewel, Blank, Marion A., Chevrier, Marc, Plevy, Scott, Popp, John, Cornillie, Freddy J., Lukas, Milan, Danese, Silvio, Gionchetti, Paolo, Hanauer, Stephen B., Reinisch, Walter, Sandborn, William J., Sorrentino, Dario, Rutgeerts, Paul, Debinski, H., Florin, T., Hetzel, D., Lawrance, I., Radford Smith, G., Sloss, A., Sorrentino, D., Gassner, S., Haas, T., Reicht, G., Reinisch, W., Strasser, M., Vogelsang, H., Bossuyt, P., Dewit, O., D'Haens, G., Franchimont, D., Louis, E., Vermeire, S., Bernstein, C. N., Bourdages, R., Chiba, N., Dhalla, S. S., Feagan, B. G., Fedorak, R. N., Lachance, J. R., Panaccione, R., Ropeleski, M., Singh Salh, B., Lukas, M., Colombel, J. F., Allez, M., Desreumaux, P., Dupas, J. L., Grimaud, J. C., Hebuterne, X., Laharie, D., Lerebours, E., Peyrin Biroulet, L., Reimund, J. M., Viennot, S., Zerbib, F., Antoni, C., Atreya, R., Baumgart, D. C., Berg, C., Boecker, U., Bramkamp, G., Bünning, C., Ehehalt, R., Howaldt, S., Kucharzik, T., Lamprecht, H. G., Mudter, J., Preiss, J. C., Schreiber, S., Seidler, U., Altorjay, I., Banai, J., Lakatos, P. L., Varga, M., Vincze, A., Avni Biron, I., Fishman, S., Fraser, G. M., Goldin, E., Rachmilewitz, D., Annese, V., Ardizzone, S., Biancone, L., Bossa, F., Danese, S., Fries, W., Gionchetti, P., Maconi, G., Terrosu, G., Usai, P., D'Haens, G. R., Gearry, R. B., Hill, J., Rowbotham, D. S., Schultz, M., Stubbs, R. S., Wallace, D., Walmsley, R. S., Wyeth, J., Malecka Panas, E., Paradowski, L., Regula, J., Beales, I. P., Campbell, S., Hawthorne, A. B., Parkes, M., Travis, S. P., Achkar, J. P., Behm, B. W., Bickston, S. J., Brown, K. J., Chiorean, M. V., Devilliers, W. J. S., Elliott, D. E., Grunkmeier, D., Hamilton, J. W., Hanauer, S. B., Hanson, J. S., Hardi, R., Helper, D. J., Herfarth, H., Higgins, P. D. R., Holderman, W. H., Kottoor, R., Kreines, M. D., Leman, B. I., Li, X., Loftus, E. V., Noar, M., Oikonomou, I., Onken, J., Peterson, K. A., Phillips, R. P., Randall, C. W., Ricci, M., Ritter, T., Rubin, D. T., Safdi, M., Sandborn, W. J., Sauberman, L., Scherl, E., Schwarz, R. P., Sedghi, S., Shafran, I., Sninsky, C. A., Stein, I., Swoger, J., Vecchio, J., Weinberg, D. I., Wruble, L. D., Yajnik, V., and Younes, Z.

Subjects
Adult, Male, musculoskeletal diseases, medicine.medical_specialty, Colon, medicine.medical_treatment, Colonoscopy, Klinikai orvostudományok, Placebo, law.invention, Anti-TNF, 03 medical and health sciences, 0302 clinical medicine, Crohn Disease, Double-Blind Method, Gastrointestinal Agents, Randomized controlled trial, Ileum, Recurrence, law, CDAI, Inflammatory Bowel Disease, PREVENT, Gastroenterology, Secondary Prevention, medicine, Clinical endpoint, Humans, Postoperative Period, Colectomy, Gastrointestinal agent, Hepatology, medicine.diagnostic_test, business.industry, Orvostudományok, Middle Aged, Crohn's Disease Activity Index, Infliximab, Surgery, Treatment Outcome, 030220 oncology & carcinogenesis, Female, 030211 gastroenterology & hepatology, business, medicine.drug
Abstract

Background & Aims Most patients with Crohn's disease (CD) eventually require an intestinal resection. However, CD frequently recurs after resection. We performed a randomized trial to compare the ability of infliximab vs placebo to prevent CD recurrence. Methods We evaluated the efficacy of infliximab in preventing postoperative recurrence of CD in 297 patients at 104 sites worldwide from November 2010 through May 2012. All study patients had undergone ileocolonic resection within 45 days before randomization. Patients were randomly assigned (1:1) to groups given infliximab (5 mg/kg) or placebo every 8 weeks for 200 weeks. The primary end point was clinical recurrence, defined as a composite outcome consisting of a CD Activity Index score >200 and a ≥70-point increase from baseline, and endoscopic recurrence (Rutgeerts score ≥i2, determined by a central reader) or development of a new or re-draining fistula or abscess, before or at week 76. Endoscopic recurrence was a major secondary end point. Results A smaller proportion of patients in the infliximab group had a clinical recurrence before or at week 76 compared with the placebo group, but this difference was not statistically significant (12.9% vs 20.0%; absolute risk reduction [ARR] with infliximab, 7.1%; 95% confidence interval: -1.3% to 15.5%; P =.097). A significantly smaller proportion of patients in the infliximab group had endoscopic recurrence compared with the placebo group (30.6% vs 60.0%; ARR with infliximab, 29.4%; 95% confidence interval: 18.6% to 40.2%; P

Published
2016

14. Common variation at 2p13.3, 3q29, 7p13 and 17q25.1 associated with susceptibility to pancreatic cancer

Author

Herbert Yu, Gabriele Capurso, Robert N. Hoover, Beatrice Mohelnikova-Duchonova, Amanda L. Blackford, Harvey A. Risch, H. Bas Bueno-de-Mesquita, Timothy J. Key, Stephen J. Chanock, Ann L. Oberg, Federico Canzian, Lingeng Lu, Maria Gazouli, Michelle Cotterchio, Daniele Campa, John P. Neoptolemos, Claudio Pasquali, Rachel E. Neale, Rayjean J. Hung, William R. Bamlet, Raffaele Pezzilli, Stefano Landi, Juozas Kupcinskas, Joseph M. Herman, Erica J. Childs, Ivana Holcatova, Steven Gallinger, Manal M. Hassan, Ewa Małecka-Panas, Pavel Vodicka, Donghui Li, Maarten F. Bijlsma, Irene Orlow, Lenka Foretova, Robert C. Kurtz, Yogesh K. Vashist, Francesca Tavano, Evelina Mocci, Amethyst Saldia, Michael Borges, Sean P. Cleary, Gloria M. Petersen, Brian M. Wolpin, Sara H. Olson, Kari G. Chaffee, Aldo Scarpa, Vladimir Janout, Elizabeth A. Holly, Niccola Funel, Hermann Brenner, Ghislaine Scelo, Laufey T. Amundadottir, Rachael Z. Stolzenberg-Solomon, Paige M. Bracci, Charles S. Fuchs, Paul Brennan, Oliver Strobel, Michael Goggins, Giulia Martina Cavestro, Cosmeri Rizzato, Andrea Mambrini, Alison P. Klein, CCA -Cancer Center Amsterdam, Radiotherapy, Childs, Ej, Mocci, E, Campa, D, Bracci, Pm, Gallinger, S, Goggins, M, Li, D, Neale, Re, Olson, Sh, Scelo, G, Amundadottir, Lt, Bamlet, Wr, Bijlsma, Mf, Blackford, A, Borges, M, Brennan, P, Brenner, H, Bueno de Mesquita, Hb, Canzian, F, Capurso, G, Cavestro, GIULIA MARTINA, Chaffee, Kg, Chanock, Sj, Cleary, Sp, Cotterchio, M, Foretova, L, Fuchs, C, Funel, N, Gazouli, M, Hassan, M, Herman, Jm, Holcatova, I, Holly, Ea, Hoover, Rn, Hung, Rj, Janout, V, Key, Tj, Kupcinskas, J, Kurtz, Rc, Landi, S, Lu, L, Malecka Panas, E, Mambrini, A, Mohelnikova Duchonova, B, Neoptolemos, Jp, Oberg, Al, Orlow, I, Pasquali, C, Pezzilli, R, Rizzato, C, Saldia, A, Scarpa, A, Stolzenberg Solomon, Rz, Strobel, O, Tavano, F, Vashist, Yk, Vodicka, P, Wolpin, Bm, Yu, H, Petersen, Gm, Risch, Ha, and Klein, A. P.

Subjects
Male, pancreatic cancer, Genome-wide association study, Gastroenterology, Aged, Australia, Chromosomes, Human, Pair 17, Chromosomes, Human, Pair 2, Chromosomes, Human, Pair 3, Chromosomes, Human, Pair 7, Europe, Female, Gene Frequency, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Middle Aged, North America, Pancreatic Neoplasms, Risk Factors, Polymorphism, Single Nucleotide, Genetics, Medicine (all), 0302 clinical medicine, CDKN2A, 0303 health sciences, Single Nucleotide, 3. Good health, 030220 oncology & carcinogenesis, Pair 3, Pair 2, Pair 7, Human, medicine.medical_specialty, PALB2, Biology, Article, Chromosomes, 03 medical and health sciences, Internal medicine, ABO blood group system, Pancreatic cancer, medicine, Polymorphism, 030304 developmental biology, Pair 17, Odds ratio, medicine.disease, Confidence interval, pancreatic cancer, genome-wide association study
Abstract

Pancreatic cancer is the fourth leading cause of cancer death in the developed world. Both inherited high-penetrance mutations in BRCA2 (ref. 2), ATM, PALB2 (ref. 4), BRCA1 (ref. 5), STK11 (ref. 6), CDKN2A and mismatch-repair genes and low-penetrance loci are associated with increased risk. To identify new risk loci, we performed a genome-wide association study on 9,925 pancreatic cancer cases and 11,569 controls, including 4,164 newly genotyped cases and 3,792 controls in 9 studies from North America, Central Europe and Australia. We identified three newly associated regions: 17q25.1 (LINC00673, rs11655237, odds ratio (OR) = 1.26, 95% confidence interval (CI) = 1.19-1.34, P = 1.42 × 10(-14)), 7p13 (SUGCT, rs17688601, OR = 0.88, 95% CI = 0.84-0.92, P = 1.41 × 10(-8)) and 3q29 (TP63, rs9854771, OR = 0.89, 95% CI = 0.85-0.93, P = 2.35 × 10(-8)). We detected significant association at 2p13.3 (ETAA1, rs1486134, OR = 1.14, 95% CI = 1.09-1.19, P = 3.36 × 10(-9)), a region with previous suggestive evidence in Han Chinese. We replicated previously reported associations at 9q34.2 (ABO), 13q22.1 (KLF5), 5p15.33 (TERT and CLPTM1), 13q12.2 (PDX1), 1q32.1 (NR5A2), 7q32.3 (LINC-PINT), 16q23.1 (BCAR1) and 22q12.1 (ZNRF3). Our study identifies new loci associated with pancreatic cancer risk.

Published
2015

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