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Outcome of elderly patients with diffuse large B-cell lymphoma treated with R-CHOP: results from the UK NCRI R-CHOP14v21 trial with combined analysis of molecular characteristics with the DSHNHL RICOVER-60 trial.
GLA - German Lymphoma Alliance

Abstract (Expand)

Background: There is an on-going debate whether 2- or 3-weekly administration of R-CHOP is the preferred first-line treatment for elderly patients with diffuse large B-cell lymphoma (DLBCL). The UK … NCRI R-CHOP14v21 randomized phase 3 trial did not demonstrate a difference in outcomes between R-CHOP-14 and R-CHOP-21 in newly diagnosed DLBCL patients aged 19-88 years, but data on elderly patients have not been reported in detail so far. Here, we provide a subgroup analysis of patients >/=60 years treated on the R-CHOP14v21 trial with extended follow-up. Patients and methods: Six hundred and four R-CHOP14v21 patients >/=60 years were included in this subgroup analysis, with a median follow-up of 77.7 months. To assess the impact of MYC rearrangements (MYC-R) and double-hit-lymphoma (DHL) on outcome in elderly patients, we performed a joint analysis of cases with available molecular data from the R-CHOP14v21 (N = 217) and RICOVER-60 (N = 204) trials. Results: Elderly DLBCL patients received high dose intensities with median total doses of >/=98% for all agents. Toxicities were similar in both arms with the exception of more grade >/=3 neutropenia (P < 0.0001) and fewer grade >/=3 thrombocytopenia (P = 0.05) in R-CHOP-21 versus R-CHOP-14. The elderly patient population had a favorable 5-year overall survival (OS) of 69% (95% CI: 65-73). We did not identify any subgroup of patients that showed differential response to either regimen. In multivariable analysis including individual factors of the IPI, gender, bulk, B2M and albumin levels, only age and B2M were of independent prognostic significance for OS. Molecular analyses demonstrated a significant impact of MYC-R (HR = 1.96; 95% CI: 1.22-3.16; P = 0.01) and DHL (HR = 2.21; 95% CI: 1.18-4.11; P = 0.01) on OS in the combined trial cohorts, independent of other prognostic factors. Conclusions: Our data support equivalence of both R-CHOP application forms in elderly DLBCL patients. Elderly MYC-R and DHL patients have inferior prognosis and should be considered for alternative treatment approaches. Trial numbers: ISCRTN 16017947 (R-CHOP14v21); NCT00052936 (RICOVER-60).

Authors: A. Kuhnl, D. Cunningham, N. Counsell, E. A. Hawkes, W. Qian, P. Smith, N. Chadwick, A. Lawrie, P. Mouncey, A. Jack, C. Pocock, K. M. Ardeshna, J. Radford, A. McMillan, J. Davies, D. Turner, A. Kruger, P. W. Johnson, J. Gambell, A. Rosenwald, G. Ott, H. Horn, M. Ziepert, M. Pfreundschuh, D. Linch

Date Published: 1st Jul 2017

Publication Type: Not specified

Human Diseases: diffuse large B-cell lymphoma

ASSOCIATION OF HIPPOCAMPAL VOLUMES WITH COGNITIVE TASKS IN A LARGE POPULATION-BASED COHORT
LIFE - Leipzig Research Center for Civilization Diseases

Abstract (Expand)

Background: Hippocampal volume, assessed via high-resolution MRI, is associated with memory and visuospatial performance in humans (Squire, 2004) and specifically prone to develop atrophy with age … (Apostolova,2015). This process has been linked to neurodegenerative diseases, such as Alzheimer’s disease (Apostolova,2015) and a decline of cognitive functions (Bruno,2016). However, due to differences in study-design and characteristics certain heterogeneity in results remains, in particular considering subfieldspecific effects (deFlores,2015). Therefore, we aim to determine the association of volumes of the whole hippocampus and its subfields on cognition in a large population-based cohort. Methods: Subjects: 1956 healthy participants from the Leipzig Research-Center-for-Civilization-Disease, aged 19-82years with MRI and neuropsychological tests (mean-age=57.61,±15.08SD). Exclusion: stroke, major-brain-pathologies, central-nervous-medication. Independent Variables: Volume of hippocampus and its subfields (CornuAmmonis1, 2-3, 4-DentateGyrus,(Pre-)subiculum). Dependent Variables: Verbal word-list learning, verbal-fluency, TrailMakingTask-(TMT)-A&B. Covariates: sex, age, years-of-education, total grey-mattervolume Image Analysis on high-resolution T1-images assessed at 3T. Hippocampal volumes were estimated using automatic segmentation analysis implemented in FreeSurfer (www.freesurfer.net). Statistical Analysis: Independent and dependent variables were first entered into Pearson Correlations. Variables with a correlation coefficient of r>0.1 were entered into multiple linear-regressions and adjusted for potential confounding(forward inclusion-model). Results: According to bivariate correlations, better performance in verbal-learning, verbal-fluency and TMT-A&B correlated moderately with larger whole-hippocampal volume and the volumes of all subfields(all |r|>0.102, all p0.046, all p0.5). Conclusions: Using a large cross-sectional cohort of healthy adults we found that volumes of the whole-hippocampus and subfields covering the CA4/dentate-gyrus region were weakly, yet specifically associated with verbal-learning and spatial processing-speed. Our preliminary results are in line with previous studies presuming a differential involvement of the hippocampus in tasks of verbal-learning and spatial processing (Oosterman,2010). Upcoming analyses implementing parcellation along the anteriorposterior- axis and random-effect-models might help to further disentangle these effects.

Authors: S. Huhn, R. Zhang, Frauke Beyer, L. Lampe, T. Luck, S. G. Riedel-Heller, M. L. Schroeter, Markus Löffler, M. Stumvoll, A. Villringer, A. V. Witte

Date Published: 1st Jul 2017

Publication Type: Not specified

Human Diseases: cognitive disorder, dementia

Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

Importance The clinical management of BRCA1 and BRCA2 mutation carriers requires accurate, prospective cancer risk estimates. Objectives To estimate age-specific risks of breast, ovarian, and contralateral …ral breast cancer for mutation carriers and to evaluate risk modification by family cancer history and mutation location. Design, Setting, and Participants Prospective cohort study of 6036 BRCA1 and 3820 BRCA2 female carriers (5046 unaffected and 4810 with breast or ovarian cancer or both at baseline) recruited in 1997-2011 through the International BRCA1/2 Carrier Cohort Study, the Breast Cancer Family Registry and the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, with ascertainment through family clinics (94%) and population-based studies (6%). The majority were from large national studies in the United Kingdom (EMBRACE), the Netherlands (HEBON), and France (GENEPSO). Follow-up ended December 2013; median follow-up was 5 years. Exposures BRCA1/2 mutations, family cancer history, and mutation location. Main Outcomes and Measures Annual incidences, standardized incidence ratios, and cumulative risks of breast, ovarian, and contralateral breast cancer. Results Among 3886 women (median age, 38 years; interquartile range [IQR], 30-46 years) eligible for the breast cancer analysis, 5066 women (median age, 38 years; IQR, 31-47 years) eligible for the ovarian cancer analysis, and 2213 women (median age, 47 years; IQR, 40-55 years) eligible for the contralateral breast cancer analysis, 426 were diagnosed with breast cancer, 109 with ovarian cancer, and 245 with contralateral breast cancer during follow-up. The cumulative breast cancer risk to age 80 years was 72% (95% CI, 65%-79%) for BRCA1 and 69% (95% CI, 61%-77%) for BRCA2 carriers. Breast cancer incidences increased rapidly in early adulthood until ages 30 to 40 years for BRCA1 and until ages 40 to 50 years for BRCA2 carriers, then remained at a similar, constant incidence (20-30 per 1000 person-years) until age 80 years. The cumulative ovarian cancer risk to age 80 years was 44% (95% CI, 36%-53%) for BRCA1 and 17% (95% CI, 11%-25%) for BRCA2 carriers. For contralateral breast cancer, the cumulative risk 20 years after breast cancer diagnosis was 40% (95% CI, 35%-45%) for BRCA1 and 26% (95% CI, 20%-33%) for BRCA2 carriers (hazard ratio [HR] for comparing BRCA2 vs BRCA1, 0.62; 95% CI, 0.47-0.82; P=.001 for difference). Breast cancer risk increased with increasing number of first- and second-degree relatives diagnosed as having breast cancer for both BRCA1 (HR for \geq2 vs 0 affected relatives, 1.99; 95% CI, 1.41-2.82; P\textless.001 for trend) and BRCA2 carriers (HR, 1.91; 95% CI, 1.08-3.37; P=.02 for trend). Breast cancer risk was higher if mutations were located outside vs within the regions bounded by positions c.2282-c.4071 in BRCA1 (HR, 1.46; 95% CI, 1.11-1.93; P=.007) and c.2831-c.6401 in BRCA2 (HR, 1.93; 95% CI, 1.36-2.74; P\textless.001). Conclusions and Relevance These findings provide estimates of cancer risk based on BRCA1 and BRCA2 mutation carrier status using prospective data collection and demonstrate the potential importance of family history and mutation location in risk assessment.

Authors: Karoline B. Kuchenbaecker, John L. Hopper, Daniel R. Barnes, Kelly-Anne Phillips, Thea M. Mooij, Marie-José Roos-Blom, Sarah Jervis, Flora E. van Leeuwen, Roger L. Milne, Nadine Andrieu, David E. Goldgar, Mary Beth Terry, Matti A. Rookus, Douglas F. Easton, Antonis C. Antoniou, Lesley McGuffog, D. Gareth Evans, Daniel Barrowdale, Debra Frost, Julian Adlard, Kai-Ren Ong, Louise Izatt, Marc Tischkowitz, Ros Eeles, Rosemarie Davidson, Shirley Hodgson, Steve Ellis, Catherine Nogues, Christine Lasset, Dominique Stoppa-Lyonnet, Jean-Pierre Fricker, Laurence Faivre, Pascaline Berthet, Maartje J. Hooning, Lizet E. van der Kolk, Carolien M. Kets, Muriel A. Adank, Esther M. John, Wendy K. Chung, Irene L. Andrulis, Melissa Southey, Mary B. Daly, Saundra S. Buys, Ana Osorio, Christoph Engel, Karin Kast, Rita K. Schmutzler, Trinidad Caldes, Anna Jakubowska, Jacques Simard, Michael L. Friedlander, Sue-Anne McLachlan, Eva Machackova, Lenka Foretova, Yen Y. Tan, Christian F. Singer, Edith Olah, Anne-Marie Gerdes, Brita Arver, Håkan Olsson

Date Published: 20th Jun 2017

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Model-based individual managing of thrombocytopenia during multi-cyclic chemotherapy
HaematoOpt - Individualized model-based managing of the next-cycle thrombopenia of CHOEP/CHOP treated patients based on platelets dynamics during the previous cycles

Abstract (Expand)

Background: Thrombocytopenia is a major side-effect of cytotoxic cancer therapies. The aim of precision medicine is to develop therapy modifications accounting for the individual’s risk. Methodology/Principle … Findings: To solve this task, we develop an individualized bio-mechanistic model of the dynamics of bone marrow thrombopoiesis, circulating platelets and therapy effects thereon. Comprehensive biological knowledge regarding cell differentiation, amplification, apoptosis rates, transition times and corresponding regulations are translated into ordinary differential equations. A model of osteoblast/osteoclast interactions was incorporated to mechanistically describe bone marrow support of quiescent cell stages. Thrombopoietin (TPO) as a major regulator is explicitly modelled including pharmacokinetics and –dynamics of TPO injections. Effects of cytotoxic drugs are modelled by transient depletions of proliferating cells. To calibrate the model, we used population data from the literature and close-meshed individual data of N=135 high-grade non-Hodgkin’s lymphoma patients treated with CHOP-like chemotherapies. To limit the number of free parameters, several parsimony assumptions were derived from biological data and tested via Likelihood methods. Heterogeneity of patients was explained by a few model parameters. The over-fitting issue of individual parameter estimation was successfully dealt with a virtual participation of each patient in population-based experiments. The model qualitatively and quantitatively explains a number of biological observations such as the role of osteoblasts in explaining long-term toxic effects, megakaryocyte-mediated feedback on stem cells, bi-phasic stimulation of thrombopoiesis by TPO, dynamics of megakaryocyte ploidies and non-exponential platelet degradation. Almost all individual time series could be described with high precision. We demonstrated how the model can be used to provide predictions regarding individual therapy adaptations. Conclusions: We propose a mechanistic thrombopoiesis model of unprecedented comprehensiveness in both, biological mechanisms considered and experimental data sets explained. Our innovative method of parameter estimation allows robust determinations of individual parameter settings facilitating the development of individual treatment adaptations during chemotherapy.

Authors: Y. Kheifetz, Markus Scholz, Markus Löffler

Date Published: 9th Jun 2017

Publication Type: Not specified

Human Diseases: thrombocytopenia

Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 … controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.

Authors: Catherine M. Phelan, Karoline B. Kuchenbaecker, Jonathan P. Tyrer, Siddhartha P. Kar, Kate Lawrenson, Stacey J. Winham, Joe Dennis, Ailith Pirie, Marjorie J. Riggan, Ganna Chornokur, Madalene A. Earp, Paulo C. Lyra, Janet M. Lee, Simon Coetzee, Jonathan Beesley, Lesley McGuffog, Penny Soucy, Ed Dicks, Andrew Lee, Daniel Barrowdale, Julie Lecarpentier, Goska Leslie, Cora M. Aalfs, Katja K. H. Aben, Marcia Adams, Julian Adlard, Irene L. Andrulis, Hoda Anton-Culver, Natalia Antonenkova, Gerasimos Aravantinos, Norbert Arnold, Banu K. Arun, Brita Arver, Jacopo Azzollini, Judith Balmaña, Susana N. Banerjee, Laure Barjhoux, Rosa B. Barkardottir, Yukie Bean, Matthias W. Beckmann, Alicia Beeghly-Fadiel, Javier Benitez, Marina Bermisheva, Marcus Q. Bernardini, Michael J. Birrer, Line Bjorge, Amanda Black, Kenneth Blankstein, Marinus J. Blok, Clara Bodelon, Natalia Bogdanova, Anders Bojesen, Bernardo Bonanni, Åke Borg, Angela R. Bradbury, James D. Brenton, Carole Brewer, Louise Brinton, Per Broberg, Angela Brooks-Wilson, Fiona Bruinsma, Joan Brunet, Bruno Buecher, Ralf Butzow, Saundra S. Buys, Trinidad Caldes, Maria A. Caligo, Ian Campbell, Rikki Cannioto, Michael E. Carney, Terence Cescon, Salina B. Chan, Jenny Chang-Claude, Stephen Chanock, Xiao Qing Chen, Yoke-Eng Chiew, Jocelyne Chiquette, Wendy K. Chung, Kathleen B. M. Claes, Thomas Conner, Linda S. Cook, Jackie Cook, Daniel W. Cramer, Julie M. Cunningham, Aimee A. D’Aloisio, Mary B. Daly, Francesca Damiola, Sakaeva Dina Damirovna, Agnieszka Dansonka-Mieszkowska, Fanny Dao, Rosemarie Davidson, Anna deFazio, Capucine Delnatte, Kimberly F. Doheny, Orland Diez, Yuan Chun Ding, Jennifer Anne Doherty, Susan M. Domchek, Cecilia M. Dorfling, Thilo Dörk, Laure Dossus, Mercedes Duran, Matthias Dürst, Bernd Dworniczak, Diana Eccles, Todd Edwards, Ros Eeles, Ursula Eilber, Bent Ejlertsen, Arif B. Ekici, Steve Ellis, Mingajeva Elvira, Kevin H. Eng, Christoph Engel, D. Gareth Evans, Peter A. Fasching, Sarah Ferguson, Sandra Fert Ferrer, James M. Flanagan, Zachary C. Fogarty, Renée T. Fortner, Florentia Fostira, William D. Foulkes, George Fountzilas, Brooke L. Fridley, Tara M. Friebel, Eitan Friedman, Debra Frost, Patricia A. Ganz, Judy Garber, María J. García, Vanesa Garcia-Barberan, Andrea Gehrig, Aleksandra Gentry-Maharaj, Anne-Marie Gerdes, Graham G. Giles, Rosalind Glasspool, Gord Glendon, Andrew K. Godwin, David E. Goldgar, Teodora Goranova, Martin Gore, Mark H. Greene, Jacek Gronwald, Stephen Gruber, Eric Hahnen, Christopher A. Haiman, Niclas Håkansson, Ute Hamann, Thomas v. O. Hansen, Patricia A. Harrington, Holly R. Harris, Jan Hauke, Alexander Hein, Alex Henderson, Michelle A. T. Hildebrandt, Peter Hillemanns, Shirley Hodgson, Claus K. Høgdall, Estrid Høgdall, Frans B. L. Hogervorst, Helene Holland, Maartje J. Hooning, Karen Hosking, Ruea-Yea Huang, Peter J. Hulick, Jillian Hung, David J. Hunter, David G. Huntsman, Tomasz Huzarski, Evgeny N. Imyanitov, Claudine Isaacs, Edwin S. Iversen, Louise Izatt, Angel Izquierdo, Anna Jakubowska, Paul James, Ramunas Janavicius, Mats Jernetz, Allan Jensen, Uffe Birk Jensen, Esther M. John, Sharon Johnatty, Michael E. Jones, Päivi Kannisto, Beth Y. Karlan, Anthony Karnezis, Karin Kast, Catherine J. Kennedy, Elza Khusnutdinova, Lambertus A. Kiemeney, Johanna I. Kiiski, Sung-Won Kim, Susanne K. Kjaer, Martin Köbel, Reidun K. Kopperud, Torben A. Kruse, Jolanta Kupryjanczyk, Ava Kwong, Yael Laitman, Diether Lambrechts, Nerea Larrañaga, Melissa C. Larson, Conxi Lazaro, Nhu D. Le, Loic Le Marchand, Jong Won Lee, Shashikant B. Lele, Arto Leminen, Dominique Leroux, Jenny Lester, Fabienne Lesueur, Douglas A. Levine, Dong Liang, Clemens Liebrich, Jenna Lilyquist, Loren Lipworth, Jolanta Lissowska, Karen H. Lu, Jan Lubinński, Craig Luccarini, Lene Lundvall, Phuong L. Mai, Gustavo Mendoza-Fandiño, Siranoush Manoukian, Leon F. A. G. Massuger, Taymaa May, Sylvie Mazoyer, Jessica N. McAlpine, Valerie McGuire, John R. McLaughlin, Iain McNeish, Hanne Meijers-Heijboer, Alfons Meindl, Usha Menon, Arjen R. Mensenkamp, Melissa A. Merritt, Roger L. Milne, Gillian Mitchell, Francesmary Modugno, Joanna Moes-Sosnowska, Melissa Moffitt, Marco Montagna, Kirsten B. Moysich, Anna Marie Mulligan, Jacob Musinsky, Katherine L. Nathanson, Lotte Nedergaard, Roberta B. Ness, Susan L. Neuhausen, Heli Nevanlinna, Dieter Niederacher, Robert L. Nussbaum, Kunle Odunsi, Edith Olah, Olufunmilayo I. Olopade, Håkan Olsson, Curtis Olswold, David M. O’Malley, Kai-Ren Ong, N. Charlotte Onland-Moret, Nicholas Orr, Sandra Orsulic, Ana Osorio, Domenico Palli, Laura Papi, Tjoung-Won Park-Simon, James Paul, Celeste L. Pearce, Inge Søkilde Pedersen, Petra H. M. Peeters, Bernard Peissel, Ana Peixoto, Tanja Pejovic, Liisa M. Pelttari, Jennifer B. Permuth, Paolo Peterlongo, Lidia Pezzani, Georg Pfeiler, Kelly-Anne Phillips, Marion Piedmonte, Malcolm C. Pike, Anna M. Piskorz, Samantha R. Poblete, Timea Pocza, Elizabeth M. Poole, Bruce Poppe, Mary E. Porteous, Fabienne Prieur, Darya Prokofyeva, Elizabeth Pugh, Miquel Angel Pujana, Pascal Pujol, Paolo Radice, Johanna Rantala, Christine Rappaport-Fuerhauser, Gad Rennert, Kerstin Rhiem, Patricia Rice, Andrea Richardson, Mark Robson, Gustavo C. Rodriguez, Cristina Rodríguez-Antona, Jane Romm, Matti A. Rookus, Mary Anne Rossing, Joseph H. Rothstein, Anja Rudolph, Ingo B. Runnebaum, Helga B. Salvesen, Dale P. Sandler, Minouk J. Schoemaker, Leigha Senter, V. Wendy Setiawan, Gianluca Severi, Priyanka Sharma, Tameka Shelford, Nadeem Siddiqui, Lucy E. Side, Weiva Sieh, Christian F. Singer, Hagay Sobol, Honglin Song, Melissa C. Southey, Amanda B. Spurdle, Zsofia Stadler, Doris Steinemann, Dominique Stoppa-Lyonnet, Lara E. Sucheston-Campbell, Grzegorz Sukiennicki, Rebecca Sutphen, Christian Sutter, Anthony J. Swerdlow, Csilla I. Szabo, Lukasz Szafron, Yen Y. Tan, Jack A. Taylor, Muy-Kheng Tea, Manuel R. Teixeira, Soo-Hwang Teo, Kathryn L. Terry, Pamela J. Thompson, Liv Cecilie Vestrheim Thomsen, Darcy L. Thull, Laima Tihomirova, Anna V. Tinker, Marc Tischkowitz, Silvia Tognazzo, Amanda Ewart Toland, Alicia Tone, Britton Trabert, Ruth C. Travis, Antonia Trichopoulou, Nadine Tung, Shelley S. Tworoger, Anne M. van Altena, David van den Berg, Annemarie H. van der Hout, Rob B. van der Luijt, Mattias van Heetvelde, Els van Nieuwenhuysen, Elizabeth J. van Rensburg, Adriaan Vanderstichele, Raymonda Varon-Mateeva, Ana Vega, Digna Velez Edwards, Ignace Vergote, Robert A. Vierkant, Joseph Vijai, Athanassios Vratimos, Lisa Walker, Christine Walsh, Dorothea Wand, Shan Wang-Gohrke, Barbara Wappenschmidt, Penelope M. Webb, Clarice R. Weinberg, Jeffrey N. Weitzel, Nicolas Wentzensen, Alice S. Whittemore, Juul T. Wijnen, Lynne R. Wilkens, Alicja Wolk, Michelle Woo, Xifeng Wu, Anna H. Wu, Hannah Yang, Drakoulis Yannoukakos, Argyrios Ziogas, Kristin K. Zorn, Steven A. Narod, Douglas F. Easton, Christopher I. Amos, Joellen M. Schildkraut, Susan J. Ramus, Laura Ottini, Marc T. Goodman, Sue K. Park, Linda E. Kelemen, Harvey A. Risch, Mads Thomassen, Kenneth Offit, Jacques Simard, Rita Katharina Schmutzler, Dennis Hazelett, Alvaro N. Monteiro, Fergus J. Couch, Andrew Berchuck, Georgia Chenevix-Trench, Ellen L. Goode, Thomas A. Sellers, Simon A. Gayther, Antonis C. Antoniou, Paul D. P. Pharoah

Date Published: 1st May 2017

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Sex differences in the influence of body mass index on anatomical architecture of brain networks.
LIFE - Leipzig Research Center for Civilization Diseases

Abstract (Expand)

BACKGROUND/OBJECTIVES: The brain has a central role in regulating ingestive behavior in obesity. Analogous to addiction behaviors, an imbalance in the processing of rewarding and salient stimuli results … in maladaptive eating behaviors that override homeostatic needs. We performed network analysis based on graph theory to examine the association between body mass index (BMI) and network measures of integrity, information flow and global communication (centrality) in reward, salience and sensorimotor regions and to identify sex-related differences in these parameters. SUBJECTS/METHODS: Structural and diffusion tensor imaging were obtained in a sample of 124 individuals (61 males and 63 females). Graph theory was applied to calculate anatomical network properties (centrality) for regions of the reward, salience and sensorimotor networks. General linear models with linear contrasts were performed to test for BMI and sex-related differences in measures of centrality, while controlling for age. RESULTS: In both males and females, individuals with high BMI (obese and overweight) had greater anatomical centrality (greater connectivity) of reward (putamen) and salience (anterior insula) network regions. Sex differences were observed both in individuals with normal and elevated BMI. In individuals with high BMI, females compared to males showed greater centrality in reward (amygdala, hippocampus and nucleus accumbens) and salience (anterior mid-cingulate cortex) regions, while males compared to females had greater centrality in reward (putamen) and sensorimotor (posterior insula) regions. CONCLUSIONS: In individuals with increased BMI, reward, salience and sensorimotor network regions are susceptible to topological restructuring in a sex-related manner. These findings highlight the influence of these regions on integrative processing of food-related stimuli and increased ingestive behavior in obesity, or in the influence of hedonic ingestion on brain topological restructuring. The observed sex differences emphasize the importance of considering sex differences in obesity pathophysiology.

Authors: A. Gupta, E. A. Mayer, K. Hamadani, R. Bhatt, C. Fling, M. Alaverdyan, C. Torgerson, C. Ashe-McNalley, J. D. Van Horn, B. Naliboff, K. Tillisch, C. P. Sanmiguel, J. S. Labus

Date Published: 1st Apr 2017

Publication Type: Not specified

Human Diseases: eating disorder

Germline Mutations in Triple-Negative Breast Cancer
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

Triple-negative breast cancer (TNBC) is associated with a poor prognosis and defines a subgroup of patients who do not benefit from endocrine or anti-HER2 therapy. Rather than being a biological entity, … TNBC represents a heterogeneous disease, and further subtyping is necessary to establish targeted therapies. Germline mutational status may serve as a robust biomarker predicting therapy response, especially with respect to compounds challenging the DNA repair machinery. Patients with TNBC usually show an early onset of the disease, as well as a positive family history of breast and/or ovarian cancer in more than one third of all cases, which suggests that TNBC is closely associated with a hereditary disease cause. In unselected TNBC cases, the prevalence of pathogenic germline BRCA1/2 mutations is approximately twice as high as in breast cancer overall. Early age at diagnosis and positive family history are strong predictors for an increased BRCA1/2 mutation probability, which is up to 40% when both risk factors are considered. Apart from BRCA1/2, the rarely mutated breast cancer predisposition genes PALB2 and FANCM have been associated with TNBC. This review summarizes the role of germline mutational status in TNBC pathogenesis. Clinical trials addressing BRCA1/2 mutation carriers are discussed.

Authors: Eric Hahnen, Jan Hauke, Christoph Engel, Guido Neidhardt, Kerstin Rhiem, Rita K. Schmutzler

Date Published: 7th Mar 2017

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

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