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author:("schneweis, S")
1.  rDNA Loci Evolution in the Genus Glechoma (Lamiaceae) 
PLoS ONE  2016;11(11):e0167177.
Glechoma L. (Lamiaceae) is distributed in eastern Asia and Europe. Understanding chromosome evolution in Glechoma has been strongly hampered by its small chromosomes, constant karyotype and polyploidy. Here phylogenetic patterns and chromosomal variation in Glechoma species are considered, using genome sizes, chromosome mapping of 5S and 35S rDNAs by fluorescence in situ hybridisation (FISH), and phylogenetic analyses of internal transcribed spacers (nrITS) of 35S rDNA and 5S rDNA NTS sequences. Species and populations of Glechoma are tetraploid (2n = 36) with base chromosome number of x = 9. Four chromosomes carry pericentric 5S rDNA sites in their short arms in all the species. Two to four of these chromosomes also carry 35S rDNA in subterminal regions of the same arms. Two to four other chromosomes have 35S rDNA sites, all located subterminally within short arms; one individual possessed additional weak pericentric 35S rDNA signals on three other chromosomes. Five types of rDNA locus distribution have been defined on the basis of 35S rDNA variation, but none is species-specific, and most species have more than one type. Glechoma hederacea has four types. Genome size in Glechoma ranges from 0.80 to 0.94 pg (1C), with low levels of intrapopulational variation in all species. Phylogenetic analyses of ITS and NTS sequences distinguish three main clades coinciding with geographical distribution: European (G. hederacea–G. hirsuta), Chinese and Korean (G. longituba), and Japanese (G. grandis). The paper presents the first comparative cytogenetic analyses of Glechoma species including karyotype structure, rDNA location and number, and genome size interpreted in a phylogenetic context. The observed variation suggests that the genus is still in genomic flux. Genome size, but not rDNA loci number and distribution, provides a character for species delimitation which allows better inferences of interspecific relationships to be made, in the absence of well-defined morphological differentiation.
doi:10.1371/journal.pone.0167177
PMCID: PMC5117774  PMID: 27870903
2.  The Impact of Reconstruction Methods, Phylogenetic Uncertainty and Branch Lengths on Inference of Chromosome Number Evolution in American Daisies (Melampodium, Asteraceae)  
PLoS ONE  2016;11(9):e0162299.
Chromosome number change (polyploidy and dysploidy) plays an important role in plant diversification and speciation. Investigating chromosome number evolution commonly entails ancestral state reconstruction performed within a phylogenetic framework, which is, however, prone to uncertainty, whose effects on evolutionary inferences are insufficiently understood. Using the chromosomally diverse plant genus Melampodium (Asteraceae) as model group, we assess the impact of reconstruction method (maximum parsimony, maximum likelihood, Bayesian methods), branch length model (phylograms versus chronograms) and phylogenetic uncertainty (topological and branch length uncertainty) on the inference of chromosome number evolution. We also address the suitability of the maximum clade credibility (MCC) tree as single representative topology for chromosome number reconstruction. Each of the listed factors causes considerable incongruence among chromosome number reconstructions. Discrepancies between inferences on the MCC tree from those made by integrating over a set of trees are moderate for ancestral chromosome numbers, but severe for the difference of chromosome gains and losses, a measure of the directionality of dysploidy. Therefore, reliance on single trees, such as the MCC tree, is strongly discouraged and model averaging, taking both phylogenetic and model uncertainty into account, is recommended. For studying chromosome number evolution, dedicated models implemented in the program ChromEvol and ordered maximum parsimony may be most appropriate. Chromosome number evolution in Melampodium follows a pattern of bidirectional dysploidy (starting from x = 11 to x = 9 and x = 14, respectively) with no prevailing direction.
doi:10.1371/journal.pone.0162299
PMCID: PMC5017664  PMID: 27611687
3.  Molecular phylogenetic analyses of nuclear and plastid DNA sequences support dysploid and polyploid chromosome number changes and reticulate evolution in the diversification of Melampodium (Millerieae, Asteraceae) 
Chromosome evolution (including polyploidy, dysploidy, and structural changes) as well as hybridization and introgression are recognized as important aspects in plant speciation. A suitable group for investigating the evolutionary role of chromosome number changes and reticulation is the medium-sized genus Melampodium (Millerieae, Asteraceae), which contains several chromosome base numbers (x = 9, 10, 11, 12, 14) and a number of polyploid species, including putative allopolyploids. A molecular phylogenetic analysis employing both nuclear (ITS) and plastid (matK) DNA sequences, and including all species of the genus, suggests that chromosome base numbers are predictive of evolutionary lineages within Melampodium. Dysploidy, therefore, has clearly been important during evolution of the group. Reticulate evolution is evident with allopolyploids, which prevail over autopolyploids and several of which are confirmed here for the first time, and also (but less often) on the diploid level. Within sect. Melampodium, the complex pattern of bifurcating phylogenetic structure among diploid taxa overlain by reticulate relationships from allopolyploids has non-trivial implications for intrasectional classification.
doi:10.1016/j.ympev.2009.02.021
PMCID: PMC4268500  PMID: 19272456
Asteraceae; Dysploidy; ITS; matK; Melampodium; Phylogeny; Polyploidy; Reticulate evolution
4.  The Evolutionary History Of The White-Rayed Species Of Melampodium (Asteraceae) Involved Multiple Cycles Of Hybridization And Polyploidization1 
American journal of botany  2012;99(6):1043-1057.
Premise of the study
Polyploidy plays an important role in race differentiation and eventually speciation. Underlying mechanisms include chromosomal and genomic changes facilitating reproductive isolation and/or stabilization of hybrids. A prerequisite for studying these processes is a sound knowledge on the origin of polyploids. A well-suited group for studying polyploid evolution consists of the three species of Melampodium ser. Leucantha (Asteraceae): M. argophyllum, M. cinereum, and M. leucanthum.
Methods
The origin of polyploids was inferred using network and tree-based phylogenetic analyses of several plastid and nuclear DNA sequences and of fingerprint data (AFLP). Genome evolution was assessed via genome size measurements, karyotype analysis, and in situ hybridization of ribosomal DNA.
Key results
Tetraploid cytotypes of the phylogenetically distinct M. cinereum and M. leucanthum had, compared to the diploid cytotypes, doubled genome sizes and no evidence of gross chromosomal rearrangements. Hexaploid M. argophyllum constituted a separate lineage with limited intermixing with the other species, except in analyses from nuclear ITS. Its genome size was lower than expected if M. cinereum and/or M. leucanthum were involved in its origin, and no chromosomal rearrangements were evident.
Conclusions
Polyploids in M. cinereum and M. leucanthum are of recent autopolyploid origin in line with the lack of significant genomic changes. Hexaploid M. argophyllum also appears to be of autopolyploid origin against the previous hypothesis of an allopolyploid origin involving the other two species, but some gene flow with the other species in early phases of differentiation cannot be excluded.
doi:10.3732/ajb.1100539
PMCID: PMC4268502  PMID: 22645096
allopolyploidy; Asteraceae; autopolyploidy; genome size; hybridization; Melampodium; polyploid evolution; rDNA
5.  Evolutionary Consequences, Constraints and Potential of Polyploidy in Plants 
Cytogenetic and genome research  2013;140(0):10.1159/000351727.
Polyploidy, the possession of more than 2 complete genomes, is a major force in plant evolution known to affect the genetic and genomic constitution and the phenotype of an organism, which will have consequences for its ecology and geography as well as for lineage diversification and speciation. In this review, we discuss phylogenetic patterns in the incidence of polyploidy including possible underlying causes, the role of polyploidy for diversification, the effects of polyploidy on geographical and ecological patterns, and putative underlying mechanisms as well as chromosome evolution and evolution of repetitive DNA following polyploidization. Spurred by technological advances, a lot has been learned about these aspects both in model and increasingly also in nonmodel species. Despite this enormous progress, long-standing questions about polyploidy still cannot be unambiguously answered, due to frequently idiosyncratic outcomes and insufficient integration of different organizational levels (from genes to ecology), but likely this will change in the near future. See also the sister article focusing on animals by Choleva and Janko in this themed issue.
doi:10.1159/000351727
PMCID: PMC3859924  PMID: 23796571
Chromosome evolution; Diversification; Ecogeography; Polyploidy; Repetitive DNA
6.  Karyotype Diversification and Evolution in Diploid and Polyploid South American Hypochaeris (Asteraceae) Inferred from rDNA Localization and Genetic Fingerprint Data 
Annals of Botany  2008;101(7):909-918.
Background and Aims
Changes in chromosome structure and number play an important role in plant evolution. A system well-suited to studying different modes of chromosome evolution is the genus Hypochaeris (Asteraceae) with its centre of species' diversity in South America. All South American species uniformly have a chromosome base number of x = 4 combined with variation in rDNA number and distribution, and a high frequency of polyploidy. The aim of this paper is to assess directions and mechanisms of karyotype evolution in South American species by interpreting both newly obtained and previous data concerning rDNA localization in a phylogenetic context.
Methods
Eleven Hypochaeris species from 18 populations were studied using fluorescence in situ hybridization (FISH) with 35S and 5S rDNA probes. A phylogenetic framework was established from neighbour-net analysis of amplified fragment length polymorphism (AFLP) fingerprint data.
Key Results
A single 5S rDNA locus is invariably found on the short arm of chromosome 2. Using 35S rDNA loci, based on number (one or two) and localization (interstitial on the long arm of chromosome 2, but sometimes lacking, and terminal or interstitial on the short arm of chromosome 3, only very rarely lacking), seven karyotype groups can be distinguished; five of these include polyploids. Karyotype groups with more than one species do not form monophyletic groups.
Conclusions
Early evolution of Hypochaeris in South America was characterized by considerable karyotype differentiation resulting from independent derivations from an ancestral karyotype. There was marked diversification with respect to the position and evolution of the 35S rDNA locus on chromosome 3, probably involving inversions and/or transpositions, and on chromosome 2 (rarely 3) concerning inactivation and loss. Among these different karyotype assemblages, the apargioides group and its derivatives constitute by far the majority of species.
doi:10.1093/aob/mcn023
PMCID: PMC2710225  PMID: 18285356
Asteraceae; fluorescence in situ hybridization; Hypochaeris; karyotype evolution; polyploidy; rDNA; South America
7.  Initiation patterns of statin therapy among adult patients undergoing intermediate to high risk non-cardiac surgery 
Background
A growing body of literature has been produced on the potential role of statins in reducing perioperative cardiac events in patients undergoing non-cardiac surgery. However, evidence remains inconsistent and little is known about the patterns of perioperative statin use in routine care.
Objectives
To examine patterns of perioperative statin initiation among adults undergoing non-cardiac elective surgery in the US.
Methods
Using data from a large US healthcare insurer, we identified patients ≥18 years who underwent moderate- to high-risk non-cardiac elective surgery between 2003-2012 and initiated statins within 30 days before surgery. We evaluated temporal trends of statin initiation and patient characteristics. In a matched analysis, we assessed the effect of temporal proximity to surgery on the likelihood of statin initiation.
Results
Of 460,154 patients undergoing surgery, 5,628 (12 per 1000 patients) initiated a statin within 30 days before surgery. Statin initiation increased from 8 per 1000 patients in 2003 to 15 in 2012 (p = .0022). The increase was more pronounced among patients undergoing vascular surgery (149 initiators per 1000 patients by the end of 2012) and with revised cardiac risk index (RCRI) score ≥2 (72 per 1000 patients). Proximity to surgery, in particular vascular surgery, was predictive of statin initiation.
Conclusions
Despite the lack of robust evidence, perioperative statin initiation progressively increased from 2003 to 2012, particularly among patients undergoing major vascular surgery and with higher RCRI score. These trends were largely attributable to the initiation of statins in anticipation of non-cardiac surgery rather than routine dyslipidemia treatment.
doi:10.1002/pds.3892
PMCID: PMC4843110  PMID: 26494361
8.  In silico SNP analysis of the breast cancer antigen NY-BR-1 
BMC Cancer  2016;16:901.
Background
Breast cancer is one of the most common malignancies with increasing incidences every year and a leading cause of death among women. Although early stage breast cancer can be effectively treated, there are limited numbers of treatment options available for patients with advanced and metastatic disease. The novel breast cancer associated antigen NY-BR-1 was identified by SEREX analysis and is expressed in the majority (>70%) of breast tumors as well as metastases, in normal breast tissue, in testis and occasionally in prostate tissue. The biological function and regulation of NY-BR-1 is up to date unknown.
Methods
We performed an in silico analysis on the genetic variations of the NY-BR-1 gene using data available in public SNP databases and the tools SIFT, Polyphen and Provean to find possible functional SNPs. Additionally, we considered the allele frequency of the found damaging SNPs and also analyzed data from an in-house sequencing project of 55 breast cancer samples for recurring SNPs, recorded in dbSNP.
Results
Over 2800 SNPs are recorded in the dbSNP and NHLBI ESP databases for the NY-BR-1 gene. Of these, 65 (2.07%) are synonymous SNPs, 191 (6.09%) are non-synoymous SNPs, and 2430 (77.48%) are noncoding intronic SNPs. As a result, 69 non-synoymous SNPs were predicted to be damaging by at least two, and 16 SNPs were predicted as damaging by all three of the used tools. The SNPs rs200639888, rs367841401 and rs377750885 were categorized as highly damaging by all three tools. Eight damaging SNPs are located in the ankyrin repeat domain (ANK), a domain known for its frequent involvement in protein-protein interactions. No distinctive features could be observed in the allele frequency of the analyzed SNPs.
Conclusion
Considering these results we expect to gain more insights into the variations of the NY-BR-1 gene and their possible impact on giving rise to splice variants and therefore influence the function of NY-BR-1 in healthy tissue as well as in breast cancer.
doi:10.1186/s12885-016-2924-7
PMCID: PMC5116164  PMID: 27863482
NY-BR-1; Breast cancer; Antigen; SNPs; In silico
9.  rs2735383, located at a microRNA binding site in the 3’UTR of NBS1, is not associated with breast cancer risk 
Liu, Jingjing | Lončar, Ivona | Collée, J. Margriet | Bolla, Manjeet K. | Dennis, Joe | Michailidou, Kyriaki | Wang, Qin | Andrulis, Irene L. | Barile, Monica | Beckmann, Matthias W. | Behrens, Sabine | Benitez, Javier | Blomqvist, Carl | Boeckx, Bram | Bogdanova, Natalia V. | Bojesen, Stig E. | Brauch, Hiltrud | Brennan, Paul | Brenner, Hermann | Broeks, Annegien | Burwinkel, Barbara | Chang-Claude, Jenny | Chen, Shou-Tung | Chenevix-Trench, Georgia | Cheng, Ching Y. | Choi, Ji-Yeob | Couch, Fergus J. | Cox, Angela | Cross, Simon S. | Cuk, Katarina | Czene, Kamila | Dörk, Thilo | dos-Santos-Silva, Isabel | Fasching, Peter A. | Figueroa, Jonine | Flyger, Henrik | García-Closas, Montserrat | Giles, Graham G. | Glendon, Gord | Goldberg, Mark S. | González-Neira, Anna | Guénel, Pascal | Haiman, Christopher A. | Hamann, Ute | Hart, Steven N. | Hartman, Mikael | Hatse, Sigrid | Hopper, John L. | Ito, Hidemi | Jakubowska, Anna | Kabisch, Maria | Kang, Daehee | Kosma, Veli-Matti | Kristensen, Vessela N. | Le Marchand, Loic | Lee, Eunjung | Li, Jingmei | Lophatananon, Artitaya | Jan Lubinski,  | Mannermaa, Arto | Matsuo, Keitaro | Milne, Roger L. | Neuhausen, Susan L. | Nevanlinna, Heli | Orr, Nick | Perez, Jose I. A. | Peto, Julian | Putti, Thomas C. | Pylkäs, Katri | Radice, Paolo | Sangrajrang, Suleeporn | Sawyer, Elinor J. | Schmidt, Marjanka K. | Schneeweiss, Andreas | Shen, Chen-Yang | Shrubsole, Martha J. | Shu, Xiao-Ou | Simard, Jacques | Southey, Melissa C. | Swerdlow, Anthony | Teo, Soo H. | Tessier, Daniel C. | Thanasitthichai, Somchai | Tomlinson, Ian | Torres, Diana | Truong, Thérèse | Tseng, Chiu-Chen | Vachon, Celine | Winqvist, Robert | Wu, Anna H. | Yannoukakos, Drakoulis | Zheng, Wei | Hall, Per | Dunning, Alison M. | Easton, Douglas F. | Hooning, Maartje J. | van den Ouweland, Ans M. W. | Martens, John W. M. | Hollestelle, Antoinette
Scientific Reports  2016;6:36874.
NBS1, also known as NBN, plays an important role in maintaining genomic stability. Interestingly, rs2735383 G > C, located in a microRNA binding site in the 3′-untranslated region (UTR) of NBS1, was shown to be associated with increased susceptibility to lung and colorectal cancer. However, the relation between rs2735383 and susceptibility to breast cancer is not yet clear. Therefore, we genotyped rs2735383 in 1,170 familial non-BRCA1/2 breast cancer cases and 1,077 controls using PCR-based restriction fragment length polymorphism (RFLP-PCR) analysis, but found no association between rs2735383CC and breast cancer risk (OR = 1.214, 95% CI = 0.936–1.574, P = 0.144). Because we could not exclude a small effect size due to a limited sample size, we further analyzed imputed rs2735383 genotypes (r2 > 0.999) of 47,640 breast cancer cases and 46,656 controls from the Breast Cancer Association Consortium (BCAC). However, rs2735383CC was not associated with overall breast cancer risk in European (OR = 1.014, 95% CI = 0.969–1.060, P = 0.556) nor in Asian women (OR = 0.998, 95% CI = 0.905–1.100, P = 0.961). Subgroup analyses by age, age at menarche, age at menopause, menopausal status, number of pregnancies, breast feeding, family history and receptor status also did not reveal a significant association. This study therefore does not support the involvement of the genotype at NBS1 rs2735383 in breast cancer susceptibility.
doi:10.1038/srep36874
PMCID: PMC5109293  PMID: 27845421
10.  Dipeptidyl peptidase-4 inhibitors in type 2 diabetes may reduce the risk of autoimmune diseases: a population-based cohort study 
Annals of the rheumatic diseases  2014;74(11):1968-1975.
Objective
Dipeptidyl peptidase-4 (DPP4), also known as CD26, is a transmembrane glycoprotein which has a co-stimulatory function in the immune response. DPP4 inhibitors (DPP4i) are oral glucose-lowering drugs for type 2 diabetes mellitus (T2DM). This study evaluated the risk of incident rheumatoid arthritis (RA) and other autoimmune diseases (AD) such as systemic lupus erythematosus, psoriasis, multiple sclerosis, and inflammatory bowel disease, associated with DPP4i in patients with T2DM.
Methods
Using U.S. insurance claims data (2005–2012), we conducted a population-based cohort study that included initiators of combination therapy with DPP4i (DPP4i plus metformin) and non-DPP4i (non-DPP4i plus metformin). RA and other AD were identified with ≥2 diagnoses and ≥1 dispensing for AD-specific immunomodulating drugs or steroids. Composite AD includes RA or other AD. Propensity score (PS)-stratified Cox proportional hazards models compared the risk of AD in DPP4i initiators vs. non-DPP4i, controlling for potential confounders.
Results
After asymmetric trimming on the PS, 73,928 patients with T2DM starting DPP4i combination therapy and 163,062 starting non-DPP4i combination therapy were selected. Risks of incident RA and composite AD were lower in the DPP4i group vs. non-DPP4i with the PS-stratified hazard ratio of 0.66 (95% CI 0.44–0.99) for RA, 0.73 (0.51–1.03) for other AD, and 0.68 (95% CI 0.52–0.89) for composite AD.
Conclusions
In this large cohort of diabetic patients, those initiating DPP4i combination therapy appear to have a decreased risk of incident AD including RA compared to those initiating non-DPP4i combination therapy. These results may suggest possible pharmacologic pathways for prevention or treatment of AD.
doi:10.1136/annrheumdis-2014-205216
PMCID: PMC4263684  PMID: 24919467
dipeptidyl peptidase-4 inhibitors; autoimmune disease; rheumatoid arthritis; inflammatory bowel disease; psoriasis; multiple sclerosis; systemic lupus erythematosus; type 2 diabetes
11.  “Threshold‐crossing”: A Useful Way to Establish the Counterfactual in Clinical Trials? 
A central question in the assessment of benefit/harm of new treatments is: how does the average outcome on the new treatment (the factual) compare to the average outcome had patients received no treatment or a different treatment known to be effective (the counterfactual)? Randomized controlled trials (RCTs) are the standard for comparing the factual with the counterfactual. Recent developments necessitate and enable a new way of determining the counterfactual for some new medicines. For select situations, we propose a new framework for evidence generation, which we call “threshold‐crossing.” This framework leverages the wealth of information that is becoming available from completed RCTs and from real world data sources. Relying on formalized procedures, information gleaned from these data is used to estimate the counterfactual, enabling efficacy assessment of new drugs. We propose future (research) activities to enable “threshold‐crossing” for carefully selected products and indications in which RCTs are not feasible.
doi:10.1002/cpt.515
PMCID: PMC5114686  PMID: 27650716
12.  Changes in chemotherapy usage and outcome of early breast cancer patients in the last decade 
Background
During the last decade, neoadjuvant chemotherapy (NACT) of early breast cancer (EBC) evolved from a therapy intended to enable operability to a standard treatment option aiming for increasing cure rates equivalent to adjuvant chemotherapy (ACT). In parallel, improvements in the quality control of breast cancer care have been established in specialized breast care units.
Patients and methods
This study analyzed chemotherapy usage in patients with EBC treated at the Heidelberg University Breast Unit between January 2003 and December 2014.
Results
Overall, 5703 patients were included in the analysis of whom 2222 (39 %) received chemotherapy, 817 (37 %) as NACT, and 1405 (63 %) as ACT. The chemotherapy usage declined from 48 % in 2003 to 34 % in 2014 of the cohort. Further, the proportion of NACT raised from 42 to 65 % irrespective of tumor subtype. In addition, frequency of pathologic complete response (pCR) defined as no tumor residues in breast and axilla (ypT0 ypN0) at surgery following NACT increased from 12 % in 2003 to 35 % in 2014. The greatest effect was observed in HER2+ breast cancer with an increase in patients achieving pCR from 24 to 68 %.
Conclusions
The results mirror the refined indication for chemotherapy in EBC and its preferred usage as NACT in Germany. The increase in pCR rate over time suggests improvement in outcome accomplished by a multidisciplinary decision-making process and stringent measures for quality control.
Electronic supplementary material
The online version of this article (doi:10.1007/s10549-016-4016-4) contains supplementary material, which is available to authorized users.
doi:10.1007/s10549-016-4016-4
PMCID: PMC5090013  PMID: 27744486
Early breast cancer; Pathologic complete response; Neoadjuvant chemotherapy; Adjuvant chemotherapy; Certified breast cancer unit
13.  Concussion and its management: What do parents know? 
Paediatrics & Child Health  2016;21(3):e22-e26.
OBJECTIVES:
To determine the sensitivity of parental suspicion of concussion relative to paediatric emergency physicians in children who presented to an emergency department (ED) with a head injury. A secondary objective was to examine the variables associated with parental suspicion of concussion concordant with that of a physician.
METHODS:
Parents of children five to 18 years of age presenting to an urban paediatric ED with a nonstructural head injury completed a 24-item questionnaire.
RESULTS:
Of the 577 eligible parents, 495 (85.8%) consented to participate. The sensitivity of parental suspicion for concussion was 40.0% (95% CI 33.2% to 47.2%), while the specificity was 58.3% (95% CI 52.4% to 64.0%). The variable of child age ≥10 years was associated with an increased odds (OR 3.0) of a parental suspicion of concussion concordant with that of a physician; parent age, parent sex, mechanism of head injury and history of concussion in the child were not. Although 453 (91.5%) parents would stop activity if they believed their child sustained a concussion, only 159 (32.1%) were familiar with return-to-play guidelines.
CONCLUSIONS:
Parents often did not suspect a concussion when it was ultimately diagnosed by a paediatric emergency physician, although they were more likely to do so in older children. Only approximately one-third were aware of return-to-play guidelines. To enhance the potential for parent-driven advocacy in the recognition and management of concussion, these data support the need for increased parental education on this injury.
PMCID: PMC4933083  PMID: 27398059
Concussion; Paediatrics; Parents; Surveys
14.  ESICM LIVES 2016: part two 
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C. | Schneeweiss, B. | Fuhrmann, V. | Sabetian, G. | Pooresmaeel, F. | Zand, F. | Ghaffaripour, S. | Farbod, A. | Tabei, H. | Taheri, L. | Anandanadesan, R. | Metaxa, V. | Teixeira, C. | Pereira, S. M. | Hernández-Marrero, P. | Carvalho, A. S. | Beckmann, M. | Hartog, C. S. | Schwarzkopf, D. | Raadts, A. | Robertsen, A. | Førde, R. | Skaga, N. O. | Helseth, E. | Honeybul, S. | Ho, K. | Lopez, P. Martinez | Gonzalez, M. Nieto | Ortega, P. Nuevo | Sola, E. Camara | Spasova, T. | de la Torre-Prados, M. V. | Kopecky, O. | Rusinova, K. | Waldauf, P. | Cepeplikova, Z. | Balik, M. | Domínguez, J. Palamidessi | Almudevar, P. Matia | Carmona, S. Alcántara | Muñoz, J. J. Rubio | Castañeda, D. Palacios | Abellán, A. Naharro | Villamizar, P. Rodríguez | Ramos, J. Veganzones | Pérez, L. Pérez | Lucendo, A. Pérez | Ejarque, M. Camós | Estella, A. | Camps, V. Lopez | Martín, M. C. | Masnou, N. | Barbosa, S. | Varela, A. | Palma, I. | Cristina, L. | Nunes, E. | Pereira, I. | Campello, G. | Granja, C. | Pande, R. | Pandey, M. | Varghese, S. | Chanu, M. | Van Dam, M. J. | Ter Braak, E. W. M. T. | Estella, A. | Gracia, M. | Viciana, R. | Recuerda, M. | Fontaiña, L. Perez | Tharmalingam, B. | Kovari, F. | Rose, L. | Mcginlay, M. | Amin, R. | Burns, K. | Connolly, B. | Hart, N. | Jouvet, P. | Katz, S. | Leasa, D. | Mawdsley, C. | Mcauley, D. | Schultz, M. | Blackwood, B. | Denham, S. | Worrall, R. | Arshad, M. | Isherwood, P. | Khadjibaev, A. | Sabirov, D. | Rosstalnaya, A. | Parpibaev, F. | Sharipova, V. | Blanco, G. A. Galvez | Guzman, C. I. Olvera | Sánchez, J. S. Aguirre | Granillo, J. Franco | Gupta, S. | Govil, D. | Srinivasan, S. | Patel, S. J. | N, J. K. | Gupta, A. | Shafi, M. | Tomar, D. S. | Harne, R. | Arora, D. P. | Talwar, N. | Mazumdar, S. | Cha, Y. S. | Lee, S. J. | Tyagi, N. | Rajput, R. K. | Taneja, S. | Singh, V. K. | Sharma, S. C. | Mittal, S. | Rao, B. K. | Ayachi, J. | Fraj, N. | Romdhani, S. | Khedher, A. | Meddeb, K. | Sma, N. | Azouzi, A. | Bouneb, R. | Chouchene, I. | El Ghardallou, M. | Boussarsar, M. | Jennings, R. | Walter, E. | Ribeiro, J. M. | Moniz, I. | Marçal, R. | Santos, A. C. | Candeias, C. | e Silva, Z. Costa | Gomez, S. E. Zamora | Nieto, O. R. Perez | Gonzalez, J. A. Castanon | Cuellar, A. I. Vasquez | Mildh, H. | Pettilä, V. | Korhonen, A. M. | Karlsson, S. | Ala-Kokko, T. | Reinikainen, M. | Vaara, S. T. | Zaleska-Kociecka, M. | Grabowski, M. | Dąbrowski, M. | Wozniak, S. | Piotrowska, K. | Banaszewski, M. | Imiela, J. | Stepinska, J. | Pérez, A. González
doi:10.1186/s40635-016-0099-9
PMCID: PMC5042923
15.  Prognosis of breast cancer molecular subtypes in routine clinical care: A large prospective cohort study 
BMC Cancer  2016;16:734.
Background
In Germany, most breast cancer patients are treated in specialized breast cancer units (BCU), which are certified, and routinely monitored. Herein, we evaluate up-to-date oncological outcome of breast cancer (BC) molecular subtypes in routine clinical care of a specialized BCU.
Methods
The study was a prospectively single-center cohort study of 4102 female cases with primary, unilateral, non-metastatic breast cancer treated between 01 January 2003 and 31 December 2012. The five routinely used molecular subtypes (Luminal A-like, Luminal B/HER2 negative-like, Luminal B/HER2 positive-like, HER2-type, Triple negative) were analyzed. The median follow-up time of the whole cohort was 55 months. We calculated estimates for local control rate (LCR), disease-free survival (DFS), distant disease-free survival (DDFS), overall survival (OS), and relative overall survival (ROS).
Results
Luminal A-like tumors were the most frequent (44.7 %) and showed the best outcome with LCR of 99.1 % (95 % CI 98.5; 99.7), OS of 95.1 % (95 % CI 93.7; 96.5), and ROS of 100.0 % (95 % CI 98.5; 101.5). Triple negative tumors (12.3 %) presented the poorest outcome with LCR of 89.6 % (95 % CI 85.8; 93.4), OS of 78.5 % (95 % CI 73.8; 83.3), and ROS of 80.1 % (95 % CI 73.8; 83.2).
Conclusions
Patients with a favorable subtype can expect an OS above 95 % and an LCR of almost 100 % over 5 years. On the other hand the outcome of patients with HER2 and Triple negative subtypes remains poor, thus necessitating more intensified research and care.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-016-2766-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s12885-016-2766-3
PMCID: PMC5024419  PMID: 27634735
Breast cancer; Molecular subtypes; Outcome; Breast care unit
16.  Mediators of first- versus second-generation antipsychotic-related mortality in older adults 
Epidemiology (Cambridge, Mass.)  2015;26(5):700-709.
Background
Observational studies of older adults showed higher mortality for first-generation antipsychotics than their second-generation counterparts which led to FDA warnings, but the actual mechanisms involved remain unclear.
Methods
A cohort of 9,060 initiators of first-generation antipsychotics and 17,137 of second-generation antipsychotics enrolled in New Jersey and Pennsylvania Medicare were followed for 180 days. Medical events were assessed using diagnostic and procedure codes on inpatient billing claims. For the individual and joint set of medical events (mediators), we estimated the total, direct, and indirect effects of antipsychotic type (first versus second generation) on mortality on the risk ratio scale (RR) and the proportion mediated on the risk difference scale, obtaining 95% confidence intervals (CI) through bootstrapping. We performed bias analyses for false negative mediator misclassification in claims data, with sensitivity ranging from 0.25 to 0.75.
Results
There were 3,199 deaths (outcomes), 862 cardiovascular events, 675 infectious events, and 491 hip fractures (potential mediators). Mortality was higher for first-than second-generation antipsychotic initiators (adjusted RR 1.14; 95%CI 1.06-1.22). In naïve analyses that ignored potential misclassification, less than 4% of this difference was explained by any particular medical event. In bias analyses the proportion mediated ranged from 6% to 16% for stroke, 3% to 9% for ventricular arrhythmia, 3% to 11% for myocardial infarction, 0% venous thromboembolism, 3% to 9% for pneumonia, 0% to 1% for other bacterial infection, and 1% to 3% for hip fracture.
Conclusions
Acute cardiovascular events and pneumonia may explain part of the mortality difference between first- and second-generation antipsychotic initiators in this analysis.
doi:10.1097/EDE.0000000000000321
PMCID: PMC4720122  PMID: 26035686
17.  Structural polymorphisms and distinct genomic composition suggest recurrent origin and ongoing evolution of B chromosomes in the Prospero autumnale complex (Hyacinthaceae) 
The New Phytologist  2015;210(2):669-679.
Summary
Supernumerary B chromosomes (Bs) are genomic parasitic components, originating from the A complement via chromosomal rearrangements, which follow their own evolutionary trajectories. They often contain repetitive DNAs, some shared with regular chromosomes and some newly evolved. Genomic composition, origin and evolution of Bs have been analysed in the chromosomally variable Prospero autumnale complex.Two rDNAs and a satellite DNA (PaB6) from regular chromosomes were mapped to Bs of 26 plants from three diploid cytotypes, their hybrids and polyploid derivatives. In homoploid diploid hybrids, genomic in situ hybridization (GISH) allowed B painting with the parental DNAs.Bs were structurally variable and highly enriched in 5S rDNA and satDNA PaB6, and rarely in 35S rDNA. Eleven combinations of rDNA and PaB6 localization were observed. The quantities of PaB6 in Bs and regular chromosomes were not correlated, suggesting amplification mechanisms other than recombination. PaB6 and 5S rDNA amounts increased with increasing ploidy level. GISH revealed two independent origins of Bs.The structural variation, repeat content, repeat‐type fluctuations and differing genomic affinities of Bs in different cytotypes suggest that they represent young proto‐B chromosomes. Bs in P. autumnale probably form recurrently as by‐products of the extensive genome restructuring within this chromosomally variable species complex.
doi:10.1111/nph.13778
PMCID: PMC4949986  PMID: 26643365
B‐chromosome evolution; B‐chromosome painting; fluorescence in situ hybridization (FISH); genomic in situ hybridization (GISH); polyploids; Prospero autumnale complex; rDNA (5S and 35S rDNA); satellite DNA PaB6
18.  Intravenous pamidronate versus oral and intravenous clodronate in bone metastatic breast cancer: a randomized, open-label, non-inferiority Phase III trial 
OncoTargets and therapy  2016;9:4173-4180.
Purpose
Patients with metastasized breast cancer often suffer from discomfort caused by metastatic bone disease. Thus, osteoprotection is an important part of therapy in breast cancer metastasized to bone, and bisphosphonates (BPs) are a major therapeutic option. In this study, our objectives were to compare the side effects of oral versus intravenous BP treatment and to assess their clinical effectiveness.
Patients and methods
In this prospective randomized, open-label, non-inferiority trial, we enrolled breast cancer patients with at least one bone metastasis and an Eastern Cooperative Oncology Group performance status of 0–2. Patients were randomly assigned to one of the three treatment groups: A, 60 mg pamidronate intravenously q3w; B-iv, 900 mg clodronate intravenously q3w; and B-o, 2,400 mg oral clodronate daily. Assessments were performed at baseline and every 3 months thereafter.
Results
Between 1995 and 1999, 321 patients with confirmed bone metastases from breast cancer were included in the study. At first follow-up, gastrointestinal (GI) tract side effects were most common, and adverse effects on the GI tract were more frequent in the oral treatment group (P=0.002 and P<0.001, respectively). There were no statistically significant differences among the treatment cohorts for other documented side effects (skin, serum electrolytes, urinary tract, immune system, and others). No significant differences in clinical effectiveness of BP treatment, as assessed by pain score, were detected among the groups; however, pathologic fractures were more effectively prevented by intravenous than oral BP administration (P=0.03). Noncompliance rates were similar among the study cohorts.
Conclusion
We conclude that oral BP treatment is significantly associated with higher rates of adverse GI side effects. Additionally, our data indicate that intravenous BP administration is more effective than oral treatment in prevention of pathologic fractures; hence, oral administration should be considered with caution.
doi:10.2147/OTT.S103130
PMCID: PMC4944913  PMID: 27468239
metastatic bone disease; bisphosphonates; adverse effects; clinical effectiveness
19.  Detection of circulating tumor cells using manually performed immunocytochemistry (MICC) does not correlate with outcome in patients with early breast cancer – Results of the German SUCCESS-A- trial 
BMC Cancer  2016;16:401.
Background
Recently, the prognostic significance of circulating tumor cells (CTCs) in primary breast cancer as assessed using the Food-and-Drug-Administration-approved CellSearch® system has been demonstrated. Here, we evaluated the prognostic relevance of CTCs, as determined using manually performed immunocytochemistry (MICC) in peripheral blood at primary diagnosis, in patients from the prospectively randomized multicenter SUCCESS-A trial (EudraCT2005000490-21).
Methods
We analyzed 23 ml of blood from 1221 patients with node-positive or high risk node-negative breast cancer before adjuvant taxane-based chemotherapy. Cells were separated using a density gradient followed by epithelial cell labeling with the anti-cytokeratin-antibody A45-B/B3, immunohistochemical staining with new fuchsin, and cytospin preparation. All cytospins were screened for CTCs, and the cutoff for positivity was at least one CTC. The prognostic value of CTCs with regard to disease-free survival (DFS), distant disease-free survival (DDFS), breast-cancer-specific survival (BCSS), and overall survival (OS) was assessed using both univariate analyses applying the Kaplan–Meier method and log-rank tests, and using multivariate Cox regressions adjusted for other predictive factors.
Results
In 20.6 % of all patients (n = 251) a median of 1 (range, 1–256) CTC was detected, while 79.4 % of the patients (n = 970) were negative for CTCs before adjuvant chemotherapy. A pT1 tumor was present in 40.0 % of patients, 4.8 % had G1 grading and 34.6 % were node-negative. There was no association between CTC positivity and tumor stage, nodal status, grading, histological type, hormone receptor status, Her2 status, menopausal status or treatment. Univariate survival analyses based on a median follow-up of 64 months revealed no significant differences between CTC-positive and CTC-negative patients with regard to DFS, DDFS, BCSS, or OS. This was confirmed by fully adjusted multivariate Cox regressions, showing that the presence of CTCs (yes/no) as assessed by MICC did not predict DFS, DDFS, BCSS or OS.
Conclusions
We could not demonstrate prognostic relevance regarding CTCs that were quantified using the MICC method at the time of primary diagnosis in our cohort of early breast cancer patients. Further studies are necessary to evaluate if the presence of CTCs assessed using MICC has prognostic relevance, or can be used for risk stratification and treatment monitoring in adjuvant breast cancer.
Trial registration
The ClinicalTrial.gov registration ID of this prospectively randomized trial is NCT02181101; the (retrospective) registration date was June 2014 (study start date September 2005).
doi:10.1186/s12885-016-2454-3
PMCID: PMC4936301  PMID: 27387743
Breast cancer; Circulating tumor cells; Manual immunocytochemistry; Disease-free survival; Overall survival; Neoplasm; Neoplasm recurrence; Translational research; Detection method
20.  Risk of high-grade cervical dysplasia and cervical cancer in women with systemic inflammatory diseases: a population-based cohort study 
Annals of the rheumatic diseases  2014;74(7):1360-1367.
Objectives
Prior studies have suggested a potential risk of cervical cancer in patients with systemic inflammatory diseases (SID) such as inflammatory bowel disease (IBD) and systemic lupus erythematosus (SLE). The objective of this study was to assess the risk of high-grade cervical dysplasia, a surrogate endpoint for cervical cancer, and cervical cancer in women with SID including IBD, psoriasis, rheumatoid arthritis (RA), or SLE versus non-SID.
Methods
Using U.S. insurance data (2001-2012), we conducted a cohort study that included 133,333 women with SID based on ≥2 diagnoses and ≥1 dispensing for disease-specific treatment and 533,332 women without SID. High-grade cervical dysplasia and cervical cancer was defined by a validated algorithm with a positive predictive value of ≥81%.
Results
Over the mean follow-up of 2.1 years, the crude incidence rate of high-grade cervical dysplasia and cervical cancer per 100,000 person-years was the highest at 141.1 in SLE and the lowest at 82.2 in psoriasis among women with SID, and 73.4 in non-SID women. The multivariable hazard ratio adjusted for potential confounders was 1.07 (95%CI 0.79-1.45) in IBD, 0.96 (95%CI 0.73-1.27) in psoriasis, 1.49 (95%CI 1.11-2.01) in RA, and 1.53 (95%CI 1.07-2.19) in SLE. Multivariable hazard ratios were increased, not statistically significant, in IBD, RA and SLE with baseline use of systemic immunosuppressive drugs or steroids.
Conclusions
The risk of high-grade cervical dysplasia and cervical cancer was 1.5 times higher in RA and SLE compared to non-SID. The risk may be increased in IBD with of systemic immunosuppressive drugs or steroids.
doi:10.1136/annrheumdis-2013-204993
PMCID: PMC4161656  PMID: 24618265
cervical dysplasia; systemic inflammatory disease; rheumatoid arthritis; systemic lupus erythematosus; inflammatory bowel disease
21.  Targeted Therapies in Triple-Negative Breast Cancer 
Breast Care  2015;10(3):159-166.
Summary
Triple-negative breast cancer (TNBC) is a heterogeneous disease comprised of several biologically distinct subtypes. However, treatment is currently mainly relying on chemotherapy as there are no targeted therapies specifically approved for TNBC. Despite initial responses to chemotherapy, resistance frequently and rapidly develops and metastatic TNBC has a poor prognosis. New targeted approaches are, therefore, urgently needed. Currently, bevacizumab, a monoclonal anti-vascular endothelial growth factor (VEGF)-A antibody, is the only targeted agent with an approval for the therapy of metastatic breast cancer, but does not provide a specific benefit in the TNBC subtype. This review discusses the current clinical developments in targeted approaches for TNBC, including anti-angiogenic therapies, epidermal growth factor receptor (EGFR)-targeted therapies, poly(ADP-ribose) polymerase (PARP) inhibitors and platinum salts, as well as novel strategies using immune-checkpoint inhibitors, which have recently demonstrated first promising results. Strategies focusing on specific subtypes of TNBC like anti-androgenic therapies for the luminal androgen receptor subtype (LAR) and others are also discussed.
doi:10.1159/000433622
PMCID: PMC4569194  PMID: 26557820
Triple-negative breast cancer; Subtypes; PARP inhibitors; Immune-checkpoint inhibitors; Targeted therapy; Bevacizumab
22.  14th St. Gallen International Breast Cancer Conference 2015: Evidence, Controversies, Consensus – Primary Therapy of Early Breast Cancer: Opinions Expressed by German Experts 
Breast Care  2015;10(3):211-219.
Summary
The key topics of this year's 14th St. Gallen Consensus Conference on the diagnosis and therapy of primary breast cancer were again questions about breast surgery and axillary surgery, radio-oncology and systemic therapy options in consideration of tumor biology, and the clinical application of multigene assays. This year, the consensus conference took place in Vienna. From a German perspective, it makes sense to substantiate the results of the vote of the international panel representing 19 countries in light of the updated national therapy recommendations of the AGO (Arbeitsgemeinschaft Gynäkologische Onkologie). Therefore, 14 German breast cancer experts, 3 of whom are members of the International St. Gallen Panel, have commented on the voting results of the St. Gallen Consensus Conference 2015 in relation to clinical routine in Germany.
doi:10.1159/000433590
PMCID: PMC4569213  PMID: 26557827
St. Gallen Consensus 2015; Systemic therapy; Local therapy; Sentinel node biopsy; Endocrine therapy; Targeted substances; Multigene assay
23.  Non-pegylated liposomal doxorubicin for patients with recurrent ovarian cancer: A multicentric phase II trial 
Oncology Letters  2016;12(2):1211-1215.
Patients with non-platinum-sensitive recurrent ovarian cancer have a poor prognosis. Non-pegylated liposomal doxorubicin (Myocet®) is a promising drug that may be able to improve treatment for such patients. In the current study, patients with recurrent ovarian cancer relapsing within 12 months after primary treatment received non-pegylated liposomal doxorubicin at 75 mg/m2 d1q22 and 60 mg/m2 d1q22 after study dose modification, respectively. There were 29 patients enrolled in the trial, and 124 cycles of non-pegylated liposomal doxorubicin were administered in total. All 29 patients were evaluable for toxicity. The clinical benefit rate (defined as the proportion of patients with either complete remission or partial remission, or with stable disease for >6 months) was 50%. The predominant non-hematological toxicity was nausea and vomiting (18 patients, grade I/II), whilst no palmar plantar erythrodysesthesia was observed. In 3 patients, a grade III hematological toxicity occurred, and the treatment schedule was consequently modified to 60 mg/m2 d1q22. The findings suggest that non-pegylated liposomal doxorubicin administered in a schedule of 60 mg/m2 d1q22 is well-manageable and is associated with tolerable non-hematological toxicities (predominantly nausea).
doi:10.3892/ol.2016.4740
PMCID: PMC4950884  PMID: 27446420
epithelial ovarian cancer; platinum-resistant recurrence; non-pegylated liposomal doxorubicin
24.  Mucin 1-specific B cell immune responses and their impact on overall survival in breast cancer patients 
Oncoimmunology  2015;5(1):e1057387.
Considering the diverse functions of B cells, responses to tumor-associated antigens (TAA) have been thought to be the main source of B cell-mediated antitumor immunity. Polymorphic epithelial mucin (MUC1) is considered one of the most specific TAA in patients with breast cancer. The present study aims to dissect the level and subclasses of naturally occurring anti-MUC1 antibodies in regard to tumor biologic parameters, clinical characteristics and overall survival. In 288 primary, non-metastatic breast cancer patients, pretreatment serum levels of anti-MUC1 immunoglobulin G (IgG) and its subclasses G1–4 as well as immunoglobulin M (IgM) were analyzed via ELISA. With respect to overall survival (Kaplan–Meier analysis), tumor biologic parameters as hormone receptor status, human epidermal growth factor receptor 2 (Her2), Ki-67 expression and tumor grading have been correlated as well as clinical characteristics as nodal involvement, tumor stage and patients' age at the time of diagnosis. Median follow-up time was 148 mo (IQR: 73.1–158.5 mo). A significant increase in IgG antibody titers was correlated highly significantly with an improved overall survival of patients. In multivariate analysis, total IgG proved to be an independent prognostic marker for overall survival (p = 0.002). IgG subclass analysis did not reveal any correlation of IgG1, IgG3 and IgG4 levels with overall survival, while increased immunoglobulin G2 (IgG2) values, although statistically not significant, tended to correlate with prolonged patient survival. MUC1-specific IgM antibodies were shown not to be predictive of overall survival. Altogether, humoral immune responses appear to play a crucial part in the tumor immunity of breast cancer patients. The present data confirms the positive impact of tumor-specific IgG on prolonged overall survival in breast cancer patients. MUC1-antibody testing might be a useful tool to identify high-risk patients who may need adjuvant therapy and potentially might benefit from MUC1-directed immunotherapy.
doi:10.1080/2162402X.2015.1057387
PMCID: PMC4760286  PMID: 26942066
ADCC; B cells; breast cancer; immunoglobulin G; MUC1-specific antibodies; prognosis
25.  Effects of xanthine oxidase inhibitors on cardiovascular disease in patients with gout: a cohort study 
The American journal of medicine  2015;128(6):653.e7-653.e16.
Background
Hyperuricemia and gout are associated with an increased risk of cardiovascular disease (CVD). It is unknown whether treating hyperuricemia with xanthine oxidase inhibitors (XOI) including allopurinol and febuxostat modifies cardiovascular risks.
Methods
We used U.S. insurance claims data to conduct a cohort study among gout patients, comparing XOI initiators to non-users with hyperuricemia defined as serum uric acid level ≥6.8mg/dl. We calculated incidence rates (IR) of a composite fatal and non-fatal cardiovascular outcome that included myocardial infarction, coronary revascularization, stroke, and heart failure. Propensity score (PS)-matched Cox proportional hazards regression compared the risk of composite cardiovascular endpoint in XOI initiators vs. those with untreated hyperuricemia, controlling for baseline confounders. In a subgroup of patients with uric acid levels available, PS-matched Cox regression further adjusted for baseline uric acid levels.
Results
There were 24,108 PS-matched pairs with mean age of 51 years and 88% male. The IR per 1,000 person-years for composite CVD was 24.1 (95%CI 22.6–26.0) in XOI initiators and 21.4 (95%CI 19.8–23.2) in the untreated hyperuricemia group. The PS-matched HR for composite CVD was 1.16 (95%CI 0.99–1.34) in XOI initiators versus those with untreated hyperuricemia. In subgroup analyses, the PS-matched HR for composite CVD adjusted for serum uric acid levels was 1.10 (95%CI 0.74–1.64) among XOI initiators.
Conclusions
Among patients with gout, initiation of XOI was not associated with an increased or decreased cardiovascular risk compared to those with untreated hyperuricemia. Subgroup analyses adjusting for baseline uric acid levels also showed no association between XOI and cardiovascular risk.
doi:10.1016/j.amjmed.2015.01.013
PMCID: PMC4442710  PMID: 25660249
xanthine oxidase inhibitor; allopurinol; febuxostat; gout; cardiovascular disease; myocardial infarction; stroke; heart failure

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