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Background: Acute pancreatitis (AP) is a serious, mechanistically not entirely resolved side effect of L-asparaginase-containing treatment for acute lymphoblastic leukemia (ALL). To find new candidate variations for AP, we conducted a genome-wide association study (GWAS). Methods: In all, 1,004,623 single-nucleotide variants (SNVs) were analyzed in 51 pediatric ALL patients with AP (cases) and 1388 patients without AP (controls). Replication used independent patients. Results: The top-ranked SNV (rs4148513) was located within the ABCC4 gene (odds ratio (OR) 84.1; p = 1.04 × 10−14). Independent replication of our 20 top SNVs was not supportive of initial results, partly because rare variants were neither present in cases nor present in controls. However, results of combined analysis (GWAS and replication cohorts) remained significant (e.g., rs4148513; OR = 47.2; p = 7.31 × 10−9). Subsequently, we sequenced the entire ABCC4 gene and its close relative, the cystic fibrosis associated CFTR gene, a strong AP candidate gene, in 48 cases and 47 controls. Six AP-associated variants in ABCC4 and one variant in CFTR were detected. Replication confirmed the six ABCC4 variants but not the CFTR variant. Conclusions: Genetic variation within the ABCC4 gene was associated with AP during the treatment of ALL. No association of AP with CFTR was observed. Larger international studies are necessary to more conclusively assess the risk of rare clinical phenotypes.

We have studied human umbilical vein (HUVEC) and bovine aortic endothelial cells (BAEC) for the presence of elements of the kinin-kallikrein system. Kinin generation was measured in homogenates of endothelial cells using a radioimmunoassay with a human bradykinin antibody; it was measured after homogenization and was constant over a time interval of 120 min. Addition of exogenous kallikrein (50 mU) led to a five fold increase in kinin concentrations after 5 min in the homogenates, which declined within 2 h. Pretreatment of BAEC with dextran sulfate (0.1 mg/ml) resulted in a 80% reduction in kinin generation. Staining of endothelial cells using an antiserum against glandular kallikrein showed kallikrein immunoreactivity in all cells. Glandular kallikrein activity was measured in homogenates by a colorimetric method. Activities of 3.5 ± 0.4 mU/106 cells in HUVEC and 7.5 ± 0.8 mU/106 cells in BAEC were detected. These data indicate the presence of all key elements of the kinin-kallikrein system in the vascular endothelium. Thus, our results support the existence of a local kallikrein-kinin system in the vascular wall which may contribute to the regulation of local inflammatory processes and the regulation of vascular tone.

Comparably little is known about breast cancer (BC) risks in women from families tested negative for BRCA1/2 mutations despite an indicative family history, as opposed to BRCA1/2 mutation carriers. We determined the age-dependent risks of first and contralateral breast cancer (FBC, CBC) both in noncarriers and carriers of BRCA1/2 mutations, who participated in an intensified breast imaging surveillance program. The study was conducted between January 1, 2005, and September 30, 2017, at 12 university centers of the German Consortium for Hereditary Breast and Ovarian Cancer. Two cohorts were prospectively followed up for incident FBC (n = 4,380; 16,398 person-years [PY], median baseline age: 39 years) and CBC (n = 2,993; 10,090 PY, median baseline age: 42 years). Cumulative FBC risk at age 60 was 61.8% (95% CI 52.8-70.9%) for BRCA1 mutation carriers, 43.2% (95% CI 32.1-56.3%) for BRCA2 mutation carriers and 15.7% (95% CI 11.9-20.4%) for noncarriers. FBC risks were significantly higher than in the general population, with incidence rate ratios of 23.9 (95% CI 18.9-29.8) for BRCA1 mutation carriers, 13.5 (95% CI 9.2-19.1) for BRCA2 mutation carriers and 4.9 (95% CI 3.8-6.3) for BRCA1/2 noncarriers. Cumulative CBC risk 10 years after FBC was 25.1% (95% CI 19.6-31.9%) for BRCA1 mutation carriers, 6.6% (95% CI 3.4-12.5%) for BRCA2 mutation carriers and 3.6% (95% CI 2.2-5.7%) for noncarriers. CBC risk in noncarriers was similar to women with unilateral BC from the general population. Further studies are needed to confirm whether less intensified surveillance is justified in women from BRCA1/2 negative families with elevated risk.

Background: Biological therapies for severe asthma have been demonstrated to effectively reduce exacerbations, by approximately 50-60% in RCTs. From clinical experience, some patients may experience complete resolution of exacerbations. However, the proportion of complete responders in a real-life setting has not been reported. Methods: The Danish Severe Asthma Register (DSAR) is a nationwide register of all Danish patients commenced on biological therapy. We identified all patients who had received at least one year of treatment with either omalizumab, mepolizumab, benralizumab, or reslizumab, and assessed the proportion of patients without exacerbations during the first year of treatment. Results: There were 97 patients followed for at least one year treated with omalizumab (n=16), mepolizumab (n=69), benralizumab (n=8), or reslizumab (n=4). These patients experienced a median number of exacerbations of 3 (1-5) in the previous 12 months before start of biological treatment. After one year, 61 (63%) patients had had no exacerbations on biological therapy. The proportion of patients without exacerbations was 67%, 65%, 67%, and 25% for omalizumab, mepolizumab, benralizumab, and reslizumab, respectively. Conclusion: More than half of patients treated with biologics for severe asthma had no exacerbations during the first year of treatment. The potential for down-titration of treatment should be explored in this group.

Percutaneous radiofrequency ablation is a safe and effective minimally invasive treatment option in selected patients with T1a tumors of the kidney with a low complication rate. We describe two cases that developed the rare but severe complication of thermal injury-induced strictures of the upper urinary tract and its consecutive management.

Neurodegeneration with brain iron accumulation (NBIA) is a group of neurodegenerative disorders characterized by iron accumulation in the basal ganglia. Recently, mutations in CoA synthase (COASY) have been identified as a cause of a novel NBIA subtype (COASY Protein-Associated Neurodegeneration, CoPAN) in two patients with dystonic paraparesis, parkinsonian features, cognitive impairment, behavior abnormalities, and axonal neuropathy. COASY encodes an enzyme required for Coenzyme A (CoA) biosynthesis. Using whole exome sequencing (WES) we identified compound heterozygous COASY mutations in two siblings with intellectual disability, ataxic gait, progressive spasticity, and obsessive-compulsive behavior. The "eye-of-the tiger-sign," a characteristic hypointense spot within the hyperintense globi pallidi on MRI found in the most common subtype of NBIA (Pantothenate Kinase-Associated Neurodegeneration, PKAN), was not present. Instead, bilateral hyperintensity and swelling of caudate nucleus, putamen, and thalamus were found. In addition, our patients showed a small corpus callosum and frontotemporal and parietal white matter changes, expanding the brain phenotype of patients with CoPAN. Metabolic investigations showed increased free carnitine and decreased acylcarnitines in the patientś dried blood samples. Carnitine palmitoyl transferase 1 (CPT1) deficiency was excluded by further enzymatic and metabolic investigations. As CoA and its derivate Acetyl-CoA play an essential role in fatty acid metabolism, we assume that abnormal acylcarnitine profiles are a result of the COASY mutations. This report not only illustrates that WES is a powerful tool to elucidate the etiology of rare genetic diseases, but also identifies unique neuroimaging and metabolic findings that may be key features for an early diagnosis of CoPAN.

SummaryBackground Hairdressing is one of the professions with the highest risk of occupational skin and respiratory diseases. The incidence of these diseases in hairdressing apprentices has been studied only sparsely. Objective To determine the incidence of skin and respiratory diseases in hairdressing apprentices, and to explore whether hairdressing apprentices leave the trade during training because of these diseases. Methods A 3-year follow-up questionnaire study was conducted among 248 hairdressing apprentices and a control group comprising 816 young adults from the general population. Results The incidence rate ratios (IRRs) for contact urticaria (IRR 4.7, 95%CI: 2.6–8.6), hand eczema (IRR 1.7, 95%CI: 1.1–2.6) and rhinitis symptoms (IRR 1.6, 95%CI: 1.2–2.2) were significantly increased in the hairdressing apprentices, whereas wheezing was similar between groups. During the follow-up period, 21.8% of the hairdressing apprentices had left the trade, and 70.3% of these had left because of health complaints. The most frequently reported reasons for leaving were musculoskeletal pain (47.4%) and skin diseases (47.4%), followed by respiratory symptoms (23.7%). Conclusions Hairdressing apprentices are at increased risk for contact urticaria, hand eczema and rhinitis symptoms compared with the general population, and a substantial proportion leave the trade because of these diseases, causing a ‘healthy worker survivor effect.’

Asymptomatic microscopic hematuria (AMH) is incidentally found during routine health screenings. In the clinical evaluation of persistent AMH imaging modalities, CT urography, MR urography, and retrograde pyelography are of diagnostic importance. In case of pathologic findings (e.g., contrast-filling defects), endoscopic evaluation is mostly performed. To our knowledge, we report the first case of a patient with persistent AMH caused by biopsy-proven renal papillary hyperplasia.

Background Occupational allergy may serve as a model of allergy development in adults. Objective We aimed at describing respiratory allergy and IgE sensitization across different exposure strata defined by time, technology, and exposure control. Methods In a retrospective (1970-2017) cohort of industrial enzyme production employees, monitored by an occupational medical center, 5024 individuals were surveyed. Five exposure groups and risk levels for sensitization and allergic disease were analyzed on the basis of demographic characteristics, hiring decade, and smoking status. Results Of all persons entering the company 47 years from 1970, 149 developed occupational allergy (incidence rate, 2.72/1000 person-years). In a multivariate cause-specific Cox proportional hazards model, the hazard of allergy was significantly related to decade of recruitment. Compared with the 1970s, the hazard ratio (HR) uniformly decreased from 0.85 (95% CI, 0.57-1.27) in the 1980s to 0.16 (95% CI, 0.05-0.52) in the 2010s. Compared with expected highest exposed group, the HRs were 0.48 (95% CI, 0.31-76) and 0.13 (95% CI, 0.06-0.30) in less exposed production areas and 0.92 (95% CI, 0.48-1.73) and 0.23 (95% CI, 0.10-0.53) in different laboratory areas. The HR of smoking was 2.03 (95% CI, 1.41-2.93). The pattern of sensitizations also showed clear associations to recruitment decade, exposure, and smoking. Among individuals sensitized but not yet allergic, a high IgE level was the only risk factor (HR, 3.03; 95% CI, 1.82-5.04) for subsequent allergy development. Conclusions The impact of exposure is dose-related and linked to the sensitization step, which may subsequently lead to allergy development. For primary prevention of enzyme allergy, exposure control is mandatory and achievable despite increasing production volumes.

The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification., Ohio State University Comprehensive Cancer Center Barretos Cancer Hospital. Grant Number: FINEP ‐ CT‐INFRA (02/2010) Breast Cancer Foundation of New Zealand Canadian Institutes of Health Research. Grant Number: PSR‐SIIRI‐701 Cancer Research UK. Grant Numbers: C8197/A16565, C5047/A8384, C1281/A12014, C12292/A11174, C1287/A10710, C1287/A10118, C1287/A16563, C5047/A10692, C5047/A15007 Department of Defence, USA. Grant Number: W81XWH‐10‐1‐0341 Helsinki University Hospital Research fund Scientific Foundation Asociación Española Contra el Cáncer Leiden University Medical Centre. Grant Number: Grant 30.925 Generalitat de Catalunya. Grant Numbers: PERIS_MedPerCan, URDCat, 2017SGR1282, 2017SGR496 Royal Society of New Zealand Cancer Council Victoria Netherlands Organization for Scientific Research (NWO). Grant Number: Grant 017.008.022 Breast Cancer Research Foundation Cancer Foundation of Western Australia EU H2020. Grant Number: 634935 Fundación Mutua Madrileña Seventh Framework Programme. Grant Numbers: 634935, 223175, 633784 Cancer Council South Australia Government of Galicia. Grant Number: Consolidation and structuring program: IN607B Cancer Council Tasmania Italian Association of Cancer Research. Grant Number: 15547 Queensland Cancer Fund AstraZeneca National Institute of Health (USA). Grant Numbers: 1U19 CA148065‐01, CA128978, CA192393, 1U19 CA148537, P50 CA1162091, CA116167, 1U19 CA148112 Newcastle University Dutch Cancer Society KWF. Grant Numbers: KWF/Pink Ribbon‐11704, UL2012‐5649 National Institute for Health Research. Grant Number: Manchester Biomedical Research centre (IS‐BRC‐1215 National Council of Technological and Scientific Development (CNPq) Instituto de Salud Carlos III. Grant Numbers: FIS PI15/00355, FIS PI13/01711, CIBERONC, FIS PI16/01218, PI16/00563 French National Institute of Cancer National Breast Cancer Foundation National Health and Medical Research Council. Grant Numbers: ID1061778, ID1104808 Carlos III National Health Centro de Investigación Biomédica en Red de Enferemdades Raras. Grant Number: ACCI 2016: ER17P1AC7112/2018 Cancer Council NSW Deutsche Krebshilfe. Grant Numbers: (#110837, #70111850 Fondazione Pisa. Grant Number: Grant “Clinical characterization of BRCA 1/2 Mis

DNA methylation changes in peripheral blood DNA have been shown to be associated with solid tumors. We sought to identify methylation alterations in whole blood DNA that are associated with breast cancer (BC). Epigenome-wide DNA methylation profiling on blood DNA from BC cases and healthy controls was performed by applying Infinium HumanMethylation450K BeadChips. Promising CpG sites were selected and validated in three independent larger sample cohorts via MassARRAY EpiTyper assays. CpG sites located in three genes (cg06418238 in RPTOR, cg00736299 in MGRN1 and cg27466532 in RAPSN), which showed significant hypomethylation in BC patients compared to healthy controls in the discovery cohort (p < 1.00 x 10-6) were selected and successfully validated in three independent cohorts (validation I, n =211; validation II, n=378; validation III, n=520). The observed methylation differences are likely not cell-type specific, as the differences were only seen in whole blood, but not in specific sub cell-types of leucocytes. Moreover, we observed in quartile analysis that women in the lower methylation quartiles of these three loci had higher ORs than women in the higher quartiles. The combined AUC of three loci was 0.79 (95%CI 0.73-0.85) in validation cohort I, and was 0.60 (95%CI 0.54-0.66) and 0.62 (95%CI 0.57-0.67) in validation cohort II and III, respectively. Our study suggests that hypomethylation of CpG sites in RPTOR, MGRN1 and RAPSN in blood is associated with BC and might serve as blood-based marker supplements for BC if these could be verified in prospective studies.

Background Little is known about the occurrence of respiratory symptoms among hairdressing apprentices during their training. Therefore, in this study, we examined whether hairdressing apprentices are at increased risk of rhinitis and asthma symptoms when compared with other young adults from the general population. Methods A questionnaire was completed by 504 hairdressing apprentices and 1400 control participants from the general population with a similar age, gender, and geographic distribution. Results The 1-year prevalence of rhinitis symptoms was higher in hairdressing apprentices than in controls (58.1% vs 46.6%; odds ratio, 1.59; 95% confidence interval, 1.30-1.98), and the prevalence was higher among hairdressing apprentices in the last years of training compared with apprentices in the first year of training (62.4% vs 41.8%, p = 0.003). Current smoking was more common in hairdressing apprentices (28.4% vs 17.2%, p < 0.001). Asthma symptoms were equally common in the 2 groups; however, hairdressing apprentices had a later age of onset of wheezing than did the controls (18 years vs 14 years, p < 0.00001) and a decreased risk of wheezing (odds ratio, 0.72; 95% confidence interval, 0.54 to 0.95) after adjusting for smoking, education level, and degree of rurality. Bleaching products were the most frequently reported cause of rhinitis and asthma symptoms in hairdressing apprentices. Conclusions Hairdressing apprentices seem to have an increased risk of occupational rhinitis, and bleaching products are the main cause of respiratory symptoms. In addition, our findings suggest that a healthy worker effect exists in relation to asthma among hairdressing apprentices.

Objectives Currently, patients with persistent moderate-to-severe house dust mite (HDM) allergic rhinitis despite use of symptom-relieving medication can be offered subcutaneously administered allergy immunotherapy (SQ SCIT; Alutard SQ) as standard care of treatment in Denmark. Recently, a HDM sublingually administered allergy immunotherapy tablet (SQ SLIT-tablet; ACARIZAX) has been developed for at-home treatment. The purpose of this analysis is to compare the costs related to treatment and administration of SQ SLIT-tablet and SQ SCIT. Methods Assuming equal efficacy between ther SQ SLIT-tablet and SQ SCIT, the cost-minimization analysis was the most appropriate for the comparison. According to guidelines and Summary of Product Characteristics, the treatment duration of SQ SLIT-tablet is 3 years and 3-5 years for SQ SCIT. The courses of treatment vary among patients and, therefore, the costs of treatment have been calculated for an average patient with HDM respiratory allergic disease (RAD) receiving either SQ SLIT-tablet or SQ SCIT. All costs associated with allergy immunotherapy were collected, i.e., cost of medication, administration and treatment setting, and discounted according to Danish guidelines. Comprehensive univariate sensitivity analyses were carried out. Results The treatment costs for an average patient with HDM RAD are €3094 for SQ SLIT-tablet and €3799 for SQ SCIT; however, when adding indirect costs to the calculations the total costs of the treatments are €3697 and €6717 for SQ SLIT-tablet and SQ SCIT, respectively. Therefore, if 2500 patients with HDM RAD were treated with SQ SLIT-tablet instead of SQ SCIT, it would elicit a saving to the healthcare system of ∼€1.8 million. The conclusion was robust to any changes in the sensitivity analysis. Conclusion With regards to the cost of treating Danish patients with HDM RAD, it is clearly cost-saving to treat patients with SQ SLIT-tablet compared to SQ SCIT.

Summary Minimal residual disease (MRD) at the end of induction therapy is important for risk stratification of acute lymphoblastic leukaemia (ALL), but bone marrow (BM) aspiration is often postponed or must be repeated to fulfil qualitative and quantitative criteria for morphological assessment of haematological remission and/or MRD analysis. The impact of BM aspiration delay on measured MRD levels and resulting risk stratification is currently unknown. We analysed paired MRD data of 289 paediatric ALL patients requiring a repeat BM aspiration. MRD levels differed in 108 patients (37%) with a decrease in the majority (85/108). This would have resulted in different risk group allocation in 64 of 289 patients (23%) when applying the ALL-Berlin-Frankfurt-Munster 2000 criteria. MRD change was associated with the duration of delay; 40% of patients with delay ≥7 days had a shift to lower MRD levels compared to only 18% after a shorter delay. Patients MRD-positive at the original but MRD-negative at the repeat BM aspiration (n = 50) had a worse 5-year event-free survival than those already negative at first aspiration (n = 115) (86 ± 5% vs. 94 ± 2%; P = 0·024). We conclude that BM aspirations should be pursued as scheduled in the protocol because delayed MRD sampling at end of induction may result in false-low MRD load and distort MRD-based risk assessment.

Background The aim of this study was to assess whether minimal residual disease (MRD) at the end of induction front-line treatment can serve as a surrogate endpoint for event-free survival (EFS) in childhood B-lineage acute lymphoblastic leukemia. Methods The analysis was based on individual data of 4830 patients from two large phase III trials that asked a randomized question on the effect of different corticosteroids (dexamethasone vs prednisone) during induction chemotherapy on EFS. The association between MRD classified in three ordered categories [negative = 0, low positive = (>0 and Results MRD at the end of induction was a poor surrogate for treatment effect on EFS at the trial level, with Rtrial2 = 0.09 (95% confidence interval [CI] = 0.00 to 0.29), whereas at the individual level it was strongly associated with EFS, with an odds ratio of 3.90 (95% CI = 3.35 to 4.44) of failure for patients with higher compared with lower MRD levels. Additional sensitivity and relevant subgroup analyses confirmed these findings at both trial- and patient-level association. Conclusions Although MRD is a robust biomarker highly predictive of outcome for individual patients, clinicians and regulatory bodies should be cautious in using early MRD response in the context of complex multiagent acute lymphoblastic leukemia therapy as an early surrogate endpoint to predict the effect of a randomized treatment intervention on long-term EFS.

Purpose Delayed intensification (DI) is an integral part of treatment of childhood acute lymphoblastic leukemia (ALL), but it is associated with relevant toxicity. Therefore, standard-risk patients of trial AIEOP-BFM ALL 2000 (Combination Chemotherapy Based on Risk of Relapse in Treating Young Patients With ALL) were investigated with the specific aim to reduce treatment intensity. Patients and Methods Between July 2000 and July 2006, 1,164 patients (1 to 17 years of age) with standard-risk ALL (defined as the absence of high-risk cytogenetics and undetectable minimal residual disease on days 33 and 78) were randomly assigned to either experimental reduced-intensity DI (protocol III; P-III) or standard DI (protocol II; P-II). Cumulative drug doses of P-III were reduced by 30% for dexamethasone and 50% for vincristine, doxorubicin, and cyclophosphamide, which shortened the treatment duration from 49 to 29 days. The study aimed at noninferiority of reduced-intensity P-III; analyses were performed according to treatment given. Results For P-III and P-II, respectively, the 8-year rate of disease-free survival (± SE) was 89.2 ± 1.3% and 92.3 ± 1.2% ( P = .04); cumulative incidence of relapse, 8.7 ± 1.2% and 6.4 ± 1.1% ( P = .09); and overall survival, 96.1 ± 0.8% and 98.0 ± 0.6% ( P = .06). Patients with ETV6-RUNX1–positive ALL and patients 1 to 6 years of age performed equally well in both arms. The incidence of death during remission was comparable, which indicates equivalent toxicity. The 8-year cumulative incidence rate of secondary malignancies was 1.3 ± 0.5% and 0.6 ± 0.4% for P-III and P-II, respectively ( P = .37). Conclusion Although the criteria used for the standard-risk definition in this trial identified patients with exceptionally good prognosis, reduction of chemotherapy was not successful mainly because of an increased rate of relapse. The data suggest that treatment reduction is feasible in specific subgroups, which underlines the biologic heterogeneity of this cohort selected according to treatment response.

Background There is no international consensus up to which age women with a diagnosis of triple-negative breast cancer (TNBC) and no family history of breast or ovarian cancer should be offered genetic testing for germline BRCA1 and BRCA2 (gBRCA) mutations. Here, we explored the association of age at TNBC diagnosis with the prevalence of pathogenic gBRCA mutations in this patient group. Methods The study comprised 802 women (median age 40 years, range 19–76) with oestrogen receptor, progesterone receptor, and human epidermal growth factor receptor type 2 negative breast cancers, who had no relatives with breast or ovarian cancer. All women were tested for pathogenic gBRCA mutations. Logistic regression analysis was used to explore the association between age at TNBC diagnosis and the presence of a pathogenic gBRCA mutation. Results A total of 127 women with TNBC (15.8%) were gBRCA mutation carriers (BRCA1: n = 118, 14.7%; BRCA2: n = 9, 1.1%). The mutation prevalence was 32.9% in the age group 20–29 years compared to 6.9% in the age group 60–69 years. Logistic regression analysis revealed a significant increase of mutation frequency with decreasing age at diagnosis (odds ratio 1.87 per 10 year decrease, 95%CI 1.50–2.32, p 10% for women diagnosed below approximately 50 years. Conclusions Based on the general understanding that a heterozygous mutation probability of 10% or greater justifies gBRCA mutation screening, women with TNBC diagnosed before the age of 50 years and no familial history of breast and ovarian cancer should be tested for gBRCA mutations. In Germany, this would concern approximately 880 women with newly diagnosed TNBC per year, of whom approximately 150 are expected to be identified as carriers of a pathogenic gBRCA mutation.

Background: Medulloblastoma is associated with rare hereditary cancer predisposition syndromes; however, consensus medulloblastoma predisposition genes have not been defined and screening guidelines for genetic counselling and testing for paediatric patients are not available. We aimed to assess and define these genes to provide evidence for future screening guidelines. Methods: In this international, multicentre study, we analysed patients with medulloblastoma from retrospective cohorts (International Cancer Genome Consortium [ICGC] PedBrain, Medulloblastoma Advanced Genomics International Consortium [MAGIC], and the CEFALO series) and from prospective cohorts from four clinical studies (SJMB03, SJMB12, SJYC07, and I-HIT-MED). Whole-genome sequences and exome sequences from blood and tumour samples were analysed for rare damaging germline mutations in cancer predisposition genes. DNA methylation profiling was done to determine consensus molecular subgroups: WNT (MBWNT), SHH (MBSHH), group 3 (MBGroup3), and group 4 (MBGroup4). Medulloblastoma predisposition genes were predicted on the basis of rare variant burden tests against controls without a cancer diagnosis from the Exome Aggregation Consortium (ExAC). Previously defined somatic mutational signatures were used to further classify medulloblastoma genomes into two groups, a clock-like group (signatures 1 and 5) and a homologous recombination repair deficiency-like group (signatures 3 and 8), and chromothripsis was investigated using previously established criteria. Progression-free survival and overall survival were modelled for patients with a genetic predisposition to medulloblastoma. Findings: We included a total of 1022 patients with medulloblastoma from the retrospective cohorts (n=673) and the four prospective studies (n=349), from whom blood samples (n=1022) and tumour samples (n=800) were analysed for germline mutations in 110 cancer predisposition genes. In our rare variant burden analysis, we compared these against 53 105 sequenced controls from ExAC and identified APC, BRCA2, PALB2, PTCH1, SUFU, and TP53 as consensus medulloblastoma predisposition genes according to our rare variant burden analysis and estimated that germline mutations accounted for 6% of medulloblastoma diagnoses in the retrospective cohort. The prevalence of genetic predispositions differed between molecular subgroups in the retrospective cohort and was highest for patients in the MBSHH subgroup (20% in the retrospective cohort). These estimates were replicated in the prospective clinical cohort (germline mutations accounted for 5% of medulloblastoma diagnoses, with the highest prevalence [14%] in the MBSHH subgroup). Patients with germline APC mutations developed MBWNT and accounted for most (five [71%] of seven) cases of MBWNT that had no somatic CTNNB1 exon 3 mutations. Patients with germline mutations in SUFU and PTCH1 mostly developed infant MBSHH. Germline TP53 mutations presented only in childhood patients in the MBSHH subgroup and explained more than half (eight [57%] of 14) of all chromothripsis events in this subgroup. Germline mutations in PALB2 and BRCA2 were observed across the MBSHH, MBGroup3, and MBGroup4 molecular subgroups and were associated with mutational signatures typical of homologous recombination repair deficiency. In patients with a genetic predisposition to medulloblastoma, 5-year progression-free survival was 52% (95% CI 40–69) and 5-year overall survival was 65% (95% CI 52–81); these survival estimates differed significantly across patients with germline mutations in different medulloblastoma predisposition genes. Interpretation: Genetic counselling and testing should be used as a standard-of-care procedure in patients with MBWNT and MBSHH because these patients have the highest prevalence of damaging germline mutations in known cancer predisposition genes. We propose criteria for routine genetic screening for patients with medulloblastoma based on clinical and molecular tumour characteristics. Funding: German Cancer Aid; German Federal Ministry of Education and Research; German Childhood Cancer Foundation (Deutsche Kinderkrebsstiftung); European Research Council; National Institutes of Health; Canadian Institutes for Health Research; German Cancer Research Center; St Jude Comprehensive Cancer Center; American Lebanese Syrian Associated Charities; Swiss National Science Foundation; European Molecular Biology Organization; Cancer Research UK; Hertie Foundation; Alexander and Margaret Stewart Trust; V Foundation for Cancer Research; Sontag Foundation; Musicians Against Childhood Cancer; BC Cancer Foundation; Swedish Council for Health, Working Life and Welfare; Swedish Research Council; Swedish Cancer Society; the Swedish Radiation Protection Authority; Danish Strategic Research Council; Swiss Federal Office of Public Health; Swiss Research Foundation on Mobile Communication; Masaryk University; Ministry of Health of the Czech Republic; Research Council of Norway; Genome Canada; Genome BC; Terry Fox Research Institute; Ontario Institute for Cancer Research; Pediatric Oncology Group of Ontario; The Family of Kathleen Lorette and the Clark H Smith Brain Tumour Centre; Montreal Children's Hospital Foundation; The Hospital for Sick Children: Sonia and Arthur Labatt Brain Tumour Research Centre, Chief of Research Fund, Cancer Genetics Program, Garron Family Cancer Centre, MDT's Garron Family Endowment; BC Childhood Cancer Parents Association; Cure Search Foundation; Pediatric Brain Tumor Foundation; Brainchild; and the Government of Ontario.

Purpose Somatic deletions that affect the lymphoid transcription factor–coding gene IKZF1 have previously been reported as independently associated with a poor prognosis in pediatric B-cell precursor (BCP) acute lymphoblastic leukemia (ALL). We have now refined the prognostic strength of IKZF1 deletions by analyzing the effect of co-occurring deletions. Patients and Methods The analysis involved 991 patients with BCP ALL treated in the Associazione Italiana Ematologia ed Oncologia Pediatrica–Berlin-Frankfurt-Muenster (AIEOP-BFM) ALL 2000 trial with complete information for copy number alterations of IKZF1, PAX5, ETV6, RB1, BTG1, EBF1, CDKN2A, CDKN2B, Xp22.33/Yp11.31 (PAR1 region; CRLF2, CSF2RA, and IL3RA), and ERG; replication of findings involved 417 patients from the same trial. Results IKZF1 deletions that co-occurred with deletions in CDKN2A, CDKN2B, PAX5, or PAR1 in the absence of ERG deletion conferred the worst outcome and, consequently, were grouped as IKZF1plus. The IKZF1plus group comprised 6% of patients with BCP ALL, with a 5-year event-free survival of 53 ± 6% compared with 79 ± 5% in patients with IKZF1 deletion who did not fulfill the IKZF1plus definition and 87 ± 1% in patients who lacked an IKZF1 deletion ( P ≤ .001). Respective 5-year cumulative relapse incidence rates were 44 ± 6%, 11 ± 4%, and 10 ± 1% ( P ≤ .001). Results were confirmed in the replication cohort, and multivariable analyses demonstrated independence of IKZF1plus. The IKZF1plus prognostic effect differed dramatically in analyses stratified by minimal residual disease (MRD) levels after induction treatment: 5-year event-free survival for MRD standard-risk IKZF1plus patients was 94 ± 5% versus 40 ± 10% in MRD intermediate- and 30 ± 14% in high-risk IKZF1plus patients ( P ≤ .001). Corresponding 5-year cumulative incidence of relapse rates were 6 ± 6%, 60 ± 10%, and 60 ± 17% ( P ≤ .001). Conclusion IKZF1plus describes a new MRD-dependent very-poor prognostic profile in BCP ALL. Because current AIEOP-BFM treatment is largely ineffective for MRD-positive IKZF1plus patients, new experimental treatment approaches will be evaluated in our upcoming trial AIEOP-BFM ALL 2017.

Мочепузырный болевой синдром/интерстициальный цистит (МБС/ИЦ) является хроническим заболеванием, которое характеризуется постоянными позывами к мочеиспусканию и болью. Целью работы было сравнить клиническую эффективность существующих на рынке препаратов для внутрипузырной терапии МБС/ИЦ и оценить их фармакоэкономический эффект. Был проведен поиск в сервисах Pubmed/Medline статей по внутрипузырной терапии МБС/ИЦ. Всего найдено 345 публикаций, из которых 326 были исключены. Проведена статистическая оценка размера эффекта (РЭ) по степени уменьшения симптомов и по количеству пациентов, ответивших на терапию. Окончательный список, состоящий из 19 статей по внутрипузырной терапии МБС/ИЦ, состоял из 5 проспективных контролируемых исследований (КИ), остальные считались неконтролируемыми. Общее количество пациентов, которые вошли в исследование, составляло 801, 228 из которых были в КИ. Среди КИ, самая большая ВЭ как по уменьшению симптоматики, так и по ответу на терапию, наблюдалась для высокомолекулярной гиалуроновой кислоты (ВМ-ГК), с похожими данными в двух неконтролируемых исследованиях. Количество внутрипузырных введений препарата для получения эффекта у пациента составляло 2,67 для полисульфата пентозана и 1,31 для ВМ-ГК, что превосходило все остальные препараты. ВМ-ГК была значительно более выгодной в отношении эффективности затрат, по сравнению с остальными схемами инстилляций. Данный мета-анализ сочетает в себе медицинские и фармакоэкономические аспекты и демонстрирует преимущество высокомолекулярной гиалуроновой кислоты перед другими препаратами для внутрипузырного введения. Прямого сравнения между различными препаратами не было проведено вследствие особенностей дизайна взятых для анализа исследований.

The aim of this study was to evaluate the impact of hours worked by a urologist before performing ureteroscopy on its safety and efficacy.Patients treated at a single institution from January 2010 to December 2013 were analyzed. The study assessed patient, stone and surgical parameters, stone-free rates and intraoperative complications performed in three work duration categories: less than 6 h, 6-12 h and more than 12 h of urologist's work. Statistical analyses included the chi-squared test, Kruskal-Wallis test, and univariate and multivariate logistic regression analyses.In total, 469 ureteroscopies were analyzed. Intraoperative complications differed non-significantly in the corresponding time categories: ureteral perforations (6 h 4.4%, 6-12 h 3.2%,12 h 7%, p = 0.46) and avulsions (all 0%). Rates for complete stone removal were 82% within the first 12 h vs 70.2% after 12 h (p = 0.03). Corresponding partial stone-free rates were 4.1% vs 3.5% (p = 0.83) and rates of unsuccessful ureteroscopy were 13.8% vs 26.3% (p = 0.01). In multivariate regression analysis, patients treated after 12 h of urologist's work had a 2.4 times higher risk of an unsuccessful ureteroscopy [odds ratio (OR) = 2.4, 95% confidence interval (CI) 1.2-4.7, p = 0.001] and lower chances of complete stone removal (OR = 0.46, 95% CI 0.24-0.89, p = 0.02). The odds of ureteral perforations were similar (p = 0.28).Work duration before ureteroscopy did not affect its safety. Stone-free rates decreased with increasing working time. Working time exceeding 12 h was identified as an independent risk factor for impaired stone-free rates.

CIMBA Consortium et al., PMID: 25849179, [Importance]: Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists. [Objective]: To identify mutation-specific cancer risks for carriers of BRCA1/2. [Design, Setting, and Participants]: Observational study ofwomen whowere ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19 581 carriers of BRCA1 mutations and 11 900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents.We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position.We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk. [Exposures]: Mutations of BRCA1 or BRCA2. [Main Outcomes and Measures]: Breast and ovarian cancer risks. [Results]: Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR = 1.46; 95%CI, 1.22-1.74; P = 2 × 10-6), c.4328 to c.4945 (BCCR2; RHR = 1.34; 95%CI, 1.01-1.78; P = .04), and c. 5261 to c.5563 (BCCR2', RHR = 1.38; 95%CI, 1.22-1.55; P = 6 × 10-9).We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR = 0.62 (95%CI, 0.56-0.70; P = 9 × 10-17). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR = 1.71; 95%CI, 1.06-2.78; P = .03), c.772 to c.1806 (BCCR1'; RHR = 1.63; 95%CI, 1.10-2.40; P = .01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95%CI, 1.69-3.16; P = .00002).We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHR = 0.51; 95%CI, 0.44-0.60; P = 6 × 10-17). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR = 0.57; 95%CI, 0.41-0.80; P = .001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both BRCA1 and BRCA2 mutation carriers. [Conclusions and Relevance]: Breast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations., Dr Antoniou and the CIMBA data management are funded by Cancer Research UK. Dr Easton is a Principal Research Fellow of Cancer Research UK. Dr Rebbeck is supported by R01-CA083855, R01-CA102776, and P50-CA083638 from the National Institutes of Health (NIH). Dr Rebbeck, Dr Nathanson, Ms Friebel, and Dr Domchek are supported by the Basser Research Center at the University of Pennsylvania. Dr Nathanson is supported by the Breast Cancer Research Foundation. Drs Domchek and Nathanson are supported by the Rooney Family Foundation. Dr Poppe is supported by R01-CA112520 from NIH. Cancer Research UK provided financial support for this work. Dr Antoniou is a Senior Cancer Research UK Cancer Research Fellow. Dr Phillips is a National Breast Cancer Foundation (Australia) Practitioner Fellow.

Background: Aberrations in DNA methylation patterns are well-described in human malignancies. However, the existence of the ‘CpG island methylator phenotype’ (CIMP) in human breast cancer is still controversial. Materials & methods: Illumina's HumanMethylation 450K BeadChip was used to analyze genome-wide DNA methylation patterns. Chromosomal abnormalities were determined by array-based CGH. Results: Invasive lobular breast carcinomas exhibit the highest number of differentially methylated CpG sites and a strong inverse correlation of aberrant DNA hypermethylation and copy number alterations. Nine differentially methylated regions within seven genes discriminating the investigated subgroups were identified and validated in an independent validation cohort and correlated to a better relapse-free survival. Conclusion: These results depict a clear difference between genetically and epigenetically unstable breast carcinomas indicating different ways of tumor progression and/or initiation, which strongly supports the association of CIMP with the lobular subtype and provide new options for detection and therapy.

Whole exome sequencing (WES) is well established in research and is now being introduced into clinically indicated diagnostics (so-called clinical exomes). We evaluated the diagnostic yield and clinical implications of WES in 72 patients from 60 families with undiagnosed neurodevelopmental disorders (NDD), neurometabolic disorders, and dystonias. Pathogenic or likely pathogenic variants leading to a molecular diagnosis could be identified in 21 of the 60 families (overall 35%, in 36% of patients with NDD, in 43% of patients with neurometabolic disorders, in 25% of patients with dystonias). In one family two coexisting autosomal recessive diseases caused by homozygous pathogenic variants in two different genes were diagnosed. In another family, a homozygous frameshift variant in STRADA was found to cause a severe NDD with early onset epilepsy, brain anomalies, hypotonia, heart defect, nephrocalcinosis, macrocephaly and distinctive facies so far designated as PMSE (polyhydramnios, megalencephaly, symptomatic epilepsy) syndrome. In 7 of the 21 families with a molecular diagnosis the pathogenic variants were only identified by clinical follow-up, manual reevaluation of the literature, a change of filter setting, and/or reconsideration of inheritance pattern. Most importantly, clinical implications included management changes in 8 cases and impact on family planning in 20 families with a molecular diagnosis. This study shows that reevaluation and follow-up can improve the diagnostic rate and that WES results have important implications on medical management and family planning. Furthermore, we could confirm STRADA as a gene associated with syndromic ID but find it questionable if the current designation as PMSE depicts the most important clinical features.

Introduction and Objectives: Bladder cancer is characterized by gender-dependent disparities. To further address this issue, we analysed a prospective, multicentre cystectomy registry. Methods: An online database was developed that included patient demographics, intra/perioperative data, surgical data and in-house complications. Results: Four hundred fifty-eight patients (112 [24.5%] women and 346 [75.5%] men) were analysed. Men and women were comparable regarding age (mean 68 years), body mass index (mean 26.5) and the mean Charlson score (4.8). Women had more advanced tumour-stages (pT3/pT4; women: 57.1%; men: 48.1%). The rate of incontinent urinary diversion was higher in women (83.1%) than in men (60.2%) and in a multivariate analysis, the strongest predictors were M+ status (OR 11.2), female gender (OR 6.9) and age (OR 6.5). Women had a higher intraoperative blood transfusion rate. The overall rate of in-house complications was similar in both genders (men: 32.0%, women: 32.6%). Severe (Clavien-Dindo grade >2) medical (women: 6.3%; men: 5.2%) and surgical (women: 21.5%; men: 14.4%) in-house complications, however, were more frequent in women. Conclusions: This multicentre registry demonstrates several gender-related differences in patients undergoing radical cystectomy. The higher transfusion rate, the rare use of orthotopic bladder substitutes and the higher in-house complication rate underline the higher complexity of this procedure in women.

This study prospectively investigated the immunohistochemical expression of interleukin-2 receptor (IL-2R) and interleukin-6 (IL-6) in patients with prostate cancer and benign prostatic hyperplasia (BPH), and a possible association of these conditions with asymptomatic inflammatory prostatitis National Institutes of Health (NIH) category IV.The study included 139 consecutive patients who underwent transurethral resection of the prostate and transvesical enucleation of the prostate (n = 82) or radical prostatectomy (n = 57). To characterize inflammatory changes the criteria proposed by Irani et al. [J Urol 1997;157:1301-3] were used. IL-2R and IL-6 expression was studied by a standard immunohistochemical method. Results were correlated with tumour, node, metastasis stage, Gleason scores, total prostate-specific antigen, International Prostate Symptom Score and body mass index.IL-2R and IL-6 expression was significantly higher in neoplastic prostate cancer tissue than in normal tissue of prostate cancer patients (p0.001 and p0.04, respectively). Prostate cancer patients with prostatitis showed significantly higher IL-2R expression than those without inflammation (p0.03). In patients with BPH, expression of IL-2R as well as IL-6 was higher in patients with prostatitis than in those without (p0.01 and p0.02, respectively).IL-2R and IL-6 expression was significantly higher in prostate cancer tissue than in normal tissue. Patients with asymptomatic inflammatory prostatitis NIH category IV showed significantly greater activity.

Breast cancer (BC) is the leading cause of cancer-related mortality in women worldwide. Changes in DNA methylation in peripheral blood could be associated with malignancy at early stage. However, the BC-associated DNA methylation signatures in peripheral blood were largely unknown. Here, we performed a genome-wide methylation screening and identified a BC-associated differentially methylated CpG site cg27091787 in the hyaluronoglucosaminidase 2 gene (HYAL2) (discovery round with 72 BC case and 24 controls: p = 2.61 × 10(-9) adjusted for cell-type proportions). The substantially decreased methylation of cg27091787 in BC cases was confirmed in two validation rounds (first validation round with 338 BC case and 507 controls: p < 0.0001; second validation round with 189 BC case and 189 controls: p < 0.0001). In addition to cg27091787, the decreased methylation of a 650-bp CpG island shore of HYAL2 was also associated with increased risk of BC. Moreover, the expression and methylation of HYAL2 were inversely correlated with a p-value of 0.006. To note, the BC-associated decreased HYAL2 methylation was replicated in the T-cell fraction (p = 0.034). The cg27091787 methylation level enabled a powerful discrimination of early-stage BC cases (stages 0 and I) from healthy controls [area under curve (AUC) = 0.89], and was robust for the detection of BC in younger women as well (age < 50, AUC = 0.87). Our study reveals a strong association between decreased HYAL2 methylation in peripheral blood and BC, and provides a promising blood-based marker for the detection of early BC.

Objectives: To evaluate the impact of retrograde pyelography (RPG) in patients treated with ureteroscopy (URS) for ureteral calculi. Methods: Retrospective analysis of patients treated with and without RPG prior to URS at a single institution from 2010 to 2013. Assessment of stone-free rates and intraoperative complications. Results: Out of 469 URS, 211 (45%) were done with and 258 (55%) without RPG. Complete stone removal was achieved in 86.8% without RPG compared to 73% with RPG (p = 0.0001). Partial stone removal rates were similar in both groups (p = 0.77). Stone removal was not achieved in 9.3 vs. 22.7% (p = 0.0001), with concordant findings in the distal (7.4 vs. 16.9%, p = 0.007) and the proximal ureter (14.5 vs. 38.6%, p = 0.002). Patients with RPG had a threefold higher chance of an unsuccessful URS (OR 3.05, 1.71-5.43, p < 0.0001) and were less likely of having a complete stone removal (OR 0.37, 0.22-0.61, p < 0.0001). Ureteral avulsions (0%) and ureteral perforation rates were similar (4.7 vs. 3.8%, p = 0.65). Conclusions: Patients treated with an RPG prior to URS had significantly inferior stone-free rates. RPG was identified as an independent risk factor for inferior results. RPG neither facilitates nor diminishes complication rates during URS.

There is increasing evidence for an inherited genetic basis of susceptibility to acute lymphoblastic leukaemia (ALL) in children. In particular, genome-wide association studies (GWAS) have identified nine genomic regions with common polymorphisms associated with ALL risk. However, these loci cumulatively only explain a minority of the genetic risk of childhood ALL, and differences in the etiology amongst molelcular subtypes of ALL remain poorly understood. In this study, we performed one of the largest ALL susceptibility GWAS, totalling 5,321 cases and 16,666 controls of European descent, to comprehensively map ALL risk loci. With this large sample size, we also sought to identify risk genes for two major subtypes of ALL, namely those with ETV6-RUNX1 fusion and hyperdiploid ALL. This meta-analysis included four previously published GWAS datasets with European cases from the UK ALL cohorts and the German Berlin-Frankfurt-Münster ALL trials, and the US cases enrolled on ALL trials in Children's Oncology Group and at St. Jude Children's Research Hospital (Nat Genet2009, Blood 2012, Nat Genet 2013, Blood 2013, Nat Commun 2018). The replication series included 2,237 ALL cases of non-European ancestry from the COG and St. Jude GWAS cohorts. For each GWAS dataset, the genotypes of ~10 million SNPs in each study were imputed. After filtering out SNPs on the basis of minor allele frequency and imputation quality, we assessed associations between ALL status and SNP genotype in each study using logistic regression. Risk estimates were combined through an inverse variance weighted fixed-effects meta-analysis. The meta-analysis identified 16 risk loci above genome-wide significance (P < 5 x 10-8), of which ten confirmed previously published associations. Of the six new candidate risk loci, four were validated in the replication series (P < 0.05): for all B-ALL at 9q21.3 (nearest gene TLE1), for hyperdiploid ALL at 5q31.1 (C5orf56) and 6p21.31 (BAK1), and for ETV6-RUNX1 positive ALL at 17q21.32 (IGF2BP1). As well as providing further evidence for the 21q22.3 (ERG) association for all B-ALL, we also identified novel risk variants with the hyperdiploid subtype-specific association. To gain insight into the biological basis of association signals, we examined the epigenetic landscape of risk regions in B-cells. Of particular note, hyperdiploid ALL-specific risk variant at 6p21 is located within an intron 1kb downstream of the BAK1 transcription start site and possess histone marks characteristic of active promoter activity and open chromatin accessibility. The top SNP at this locus falls within a transcription factor binding cluster, and the C-risk allele is associated with reduced BAK1 expression (P Analysis of disruption of transcription factor binding sites at ALL risk loci genome wide identified over-representation of PBX1 (P=0.007), TCF3 (P=0.007), ETS1 (P=0.009), RUNX1 (P=0.012) and ERG (P=0.030), BRD4 (P=0.007), and NR3C1 (P=0.009). Many of these transcription factors are also somatically mutated in ALL, pointing to multiple mechanisms by which they can contribute to leukemogenesis. Using the Linkage Disequilibrium Adjusted Kinships method, we estimated that ALL risk loci identified so far accounted for 31% of the total variance in genetic risk of this cancer. Polygenic risk score analysis indicates that an individual in the top 1% of genetic risk would have a 4.7-fold increased risk of ALL when compared to an individual with median genetic risk. In summary, our study provides further evidence for inherited susceptibility to ALL and support for subtype specificity at risk loci. Our findings also highlight a model of ALL pathogenesis relying on transcriptional deregulation, particularly of genes involved in B cell differentiation. Disclosures Raetz: Pfizer: Research Funding. Mullighan:Pfizer: Honoraria, Other: speaker, sponsored travel, Research Funding; AbbVie: Research Funding; Loxo Oncology: Research Funding; Amgen: Honoraria, Other: speaker, sponsored travel; Illumina: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: sponsored travel. Hunger:Amgen: Consultancy, Equity Ownership; Bristol Myers Squibb: Consultancy; Jazz: Honoraria; Novartis: Consultancy. Schrappe:Together with study group from SHIRE, JazzPharma, Servier, SigmaTau, Amgen, and Novartis.: Research Funding; SHIRE, Servier, and JazzPharma: Honoraria. Relling:Servier Pharmaceuticals: Research Funding. Loh:Medisix Therapeutics, Inc.: Membership on an entity's Board of Directors or advisory committees.

Background: TH2-biased immune responses are important in allergy pathogenesis. Mechanisms of allergen-specific immunotherapy (SIT) might include the induction of regulatory T cells (Tregs) and immunoglobulin (Ig) G4 blocking antibodies, a reduction in the number of effector cells, and skewing of the cytokine profile towards a TH1-polarized immune response. We investigated the effects of SIT on T cells, on immunomodulation of human leukocyte antigen (HLA)-G, which has been associated with allergy, on regulatory cytokine expression, and on serum allergen-specific antibody subclasses (IgE and IgG4). Methods: Eleven birch and/or grass pollen-allergic patients and 10 healthy nonatopic controls were studied before and during SIT. Tregs, chemokine receptors, soluble HLA-G (sHLA-G), Ig-like transcript (ILT) 2, specific IgE, and IgG4 were studied. Peripheral blood mononuclear cells (PBMCs) were stimulated with pollen extract in vitro and immune factors were evaluated. Results: During SIT, the main changes in the peripheral blood were an increase in CXCR3+CD4+CD25+CD127low/- Tregs and a decrease in CCR4+CD4+CD25+CD127low/- Tregs, an increase in allergen-specific IgG4, and a decrease in sHLA-G during the first half of the treatment period. In the PBMC in vitro experiments, the following changes were observed upon allergen-stimulation: an increase in CD4+CD25+CD127low/- Tregs and ILT2+CD4+CD25+CD127low/- Tregs, an increase in IL-10 and IL-2 levels, and an increase in sHLA-G that was most pronounced at the start of SIT. Conclusions: The changes in CXCR3+CD4+CD25+CD127low/- Treg, IgG4, and sHLA-G levels in the peripheral blood and in ILT2+ Treg, IL-10, IL-2, and sHLA-G levels upon in vitro allergen stimulation suggest an upregulation in immunomodulatory factors and, to some degree, a shift towards TH1 during SIT.

Background: Our recent genome-wide association study identified a novel breast cancer susceptibility locus at 9q31.2 (rs865686). Methods: To further investigate the rs865686–breast cancer association, we conducted a replication study within the Breast Cancer Association Consortium, which comprises 37 case–control studies (48,394 cases, 50,836 controls). Results: This replication study provides additional strong evidence of an inverse association between rs865686 and breast cancer risk [study-adjusted per G-allele OR, 0.90; 95% confidence interval (CI), 0.88; 0.91, P = 2.01 × 10−29] among women of European ancestry. There were ethnic differences in the estimated minor (G)-allele frequency among controls [0.09, 0.30, and 0.38 among, respectively, Asians, Eastern Europeans, and other Europeans; P for heterogeneity (Phet) = 1.3 × 10−143], but no evidence of ethnic differences in per allele OR (Phet = 0.43). rs865686 was associated with estrogen receptor–positive (ER+) disease (per G-allele OR, 0.89; 95% CI, 0.86–0.91; P = 3.13 × 10−22) but less strongly, if at all, with ER-negative (ER−) disease (OR, 0.98; 95% CI, 0.94–1.02; P = 0.26; Phet = 1.16 × 10−6), with no evidence of independent heterogeneity by progesterone receptor or HER2 status. The strength of the breast cancer association decreased with increasing age at diagnosis, with case-only analysis showing a trend in the number of copies of the G allele with increasing age at diagnosis (P for linear trend = 0.0095), but only among women with ER+ tumors. Conclusions: This study is the first to show that rs865686 is a susceptibility marker for ER+ breast cancer. Impact: The findings further support the view that genetic susceptibility varies according to tumor subtype. Cancer Epidemiol Biomarkers Prev; 21(10); 1783–. ©2012 AACR.

Journal article A recent two-stage genome-wide association study (GWAS) identified five novel breast cancer susceptibility loci on chromosomes 9, 10, and 11. To provide more reliable estimates of the relative risk associated with these loci and investigate possible heterogeneity by subtype of breast cancer, we genotyped the variants rs2380205, rs1011970, rs704010, rs614367, and rs10995190 in 39 studies from the Breast Cancer Association Consortium (BCAC), involving 49,608 cases and 48,772 controls of predominantly European ancestry. Four of the variants showed clear evidence of association (P â ¤ 3 Ã 10(-9) ) and weak evidence was observed for rs2380205 (P = 0.06). The strongest evidence was obtained for rs614367, located on 11q13 (per-allele odds ratio 1.21, P = 4 Ã 10(-39) ). The association for rs614367 was specific to estrogen receptor (ER)-positive disease and strongest for ER plus progesterone receptor (PR)-positive breast cancer, whereas the associations for the other three loci did not differ by tumor subtype. EC Seventh Framework Programme - grant number HEALTH-F2-2009-223175 peer-reviewed

Recently, de novo heterozygous variants in DDX3X have been reported in about 1.5% of 2659 females with previously unexplained intellectual disability (ID). We report on the identification of DDX3X variants in two unrelated girls with clinical features of Toriello-Carey Syndrome (T-CS). In patient 1, the recurrent variant c.1703C>T; p.(P568L) was identified when reconsidering X-linked de novo heterozygous variants in exome sequencing data. In patient 2, the DDX3X variant c.1600C>G; p.(R534G) was also detected by exome sequencing. Based on these data, de novo heterozygous DDX3X variants should be considered not only in females with unexplained ID, but also in individuals with a clinical diagnosis of T-CS.

Breast cancer (BC) is the leading cancer in women worldwide. Changes in DNA methylation in peripheral blood could be associated with malignant diseases. Making use of screening results by llumina 27K Methylation Assay, we validated demethylation of five CpG sites of S100P gene in blood cell DNA of BC patients by three independent retrospective studies with subjects from different centers (Validation I: 235 familial BC case and 206 controls, odds ratio per -1% methylation1.03, and P6.00 × 10-8 for all five CpG sites; Validation II: 189 sporadic BC case and 189 controls, odds ratio per -1% methylation1.03, P8.0 × 10-5 for four CpG sites; Validation III: 156 sporadic BC case and 151 controls, odds ratio per -1% methylation1.03, P6.0 × 10-4 for four CpG sites). In addition, the blood-based S100P methylation pattern was similar among BC patients with differential clinical characteristics regardless of stage, receptor status and menopause status. The observed BC-associated decreased S100P methylation in blood mainly originates from the leucocytes subpopulations but not B cells. The methylation levels of most S100P CpG sites were inversely correlated with the expression of S100P in leucocytes (P1.2 × 10-4) and in tissue (P1.1 × 10-4). This study reveals significant association between blood-based decreased S100P methylation and BC, and provides another proof for the application of altered DNA methylation signatures from blood cells as potential markers for the detection of BC, especially for the early stage.

Purpose To prospectively assess anxiety and depression in patients undergoing diagnostic cystoscopy. Methods Patients presenting for outpatient diagnostic cystoscopy were recruited from four European urological departments. Anxiety and depression were assessed with the 'Hospital Anxiety and Depression Scale' (HADS) before cystoscopy and after 1 week. Statistical analyses, including the Chi-square test, univariate, and multivariate logistic regression analyses, were carried out with SPSS v. 21 (IBM Corp., Armonk, NY). Results Prior to cystoscopy, 30.2 % of patients were anxious and 24.8 % depressive (n = 442). In the post-examination period, anxiety declined to 24.5 %, while depression was unchanged (24.4 %). Pre-cystoscopy anxiety was significantly more common in women (41.8 vs. 24.5 %, p < 0.0001), patients aged < 65 years (34.9 vs. 25.9 %, p = 0.04), and in those being examined with rigid cystoscopes (35.7 vs. 23.9 %, p = 0.007). In multivariate regression analyses, female gender (OR 2.6, p < 0.0001)

The 'Individualized Therapy for Relapsed Malignancies in Childhood' (INFORM) precision medicine study is a nationwide German program for children with high-risk relapsed/refractory malignancies, which aims to identify therapeutic targets on an individualised basis. In a pilot phase, reported here, we developed the logistical and analytical pipelines necessary for rapid and comprehensive molecular profiling in a clinical setting. Fifty-seven patients from 20 centers were prospectively recruited. Malignancies investigated included sarcomas (n = 25), brain tumours (n = 23), and others (n = 9). Whole-exome, low-coverage whole-genome, and RNA sequencing were complemented with methylation and expression microarray analyses. Alterations were assessed for potential targetability according to a customised prioritisation algorithm and subsequently discussed in an interdisciplinary molecular tumour board. Next-generation sequencing data were generated for 52 patients, with the full analysis possible in 46 of 52. Turnaround time from sample receipt until first report averaged 28 d. Twenty-six patients (50%) harbored a potentially druggable alteration with a prioritisation score of 'intermediate' or higher (level 4 of 7). Common targets included receptor tyrosine kinases, phosphoinositide 3-kinase-mammalian target of rapamycin pathway, mitogen-activated protein kinase pathway, and cell cycle control. Ten patients received a targeted therapy based on these findings, with responses observed in some previously treatment-refractory tumours. Comparative primary relapse analysis revealed substantial tumour evolution as well as one case of unsuspected secondary malignancy, highlighting the importance of re-biopsy at relapse. This study demonstrates the feasibility of comprehensive, real-time molecular profiling for high-risk paediatric cancer patients. This extended proof-of-concept, with examples of treatment consequences, expands upon previous personalised oncology endeavors, and presents a model with considerable interest and practical relevance in the burgeoning era of personalised medicine.

Induction therapy for childhood acute lymphoblastic leukemia (ALL) traditionally includes prednisone; yet, dexamethasone may have higher antileukemic potency, leading to fewer relapses and improved survival. After a 7-day prednisone prephase, 3720 patients enrolled on trial Associazione Italiana di Ematologia e Oncologia Pediatrica and Berlin-Frankfurt-Munster (AIEOP-BFM) ALL 2000 were randomly selected to receive either dexamethasone (10 mg/m(2) per day) or prednisone (60 mg/m(2) per day) for 3 weeks plus tapering in induction. The 5-year cumulative incidence of relapse (± standard error) was 10.8 ± 0.7% in the dexamethasone and 15.6 ± 0.8% in the prednisone group (P < .0001), showing the largest effect on extramedullary relapses. The benefit of dexamethasone was partially counterbalanced by a significantly higher induction-related death rate (2.5% vs 0.9%, P = .00013), resulting in 5-year event-free survival rates of 83.9 ± 0.9% for dexamethasone and 80.8 ± 0.9% for prednisone (P = .024). No difference was seen in 5-year overall survival (OS) in the total cohort (dexamethasone, 90.3 ± 0.7%; prednisone, 90.5 ± 0.7%). Retrospective analyses of predefined subgroups revealed a significant survival benefit from dexamethasone only for patients with T-cell ALL and good response to the prednisone prephase (prednisone good-response [PGR]) (dexamethasone, 91.4 ± 2.4%; prednisone, 82.6 ± 3.2%; P = .036). In patients with precursor B-cell ALL and PGR, survival after relapse was found to be significantly worse if patients were previously assigned to the dexamethasone arm. We conclude that, for patients with PGR in the large subgroup of precursor B-cell ALL, dexamethasone especially reduced the incidence of better salvageable relapses, resulting in inferior survival after relapse. This explains the lack of benefit from dexamethasone in overall survival that we observed in the total cohort except in the subset of T-cell ALL patients with PGR. This trial was registered at www.clinicaltrials.gov (BFM: NCT00430118, AIEOP: NCT00613457).

IKZF1 gene deletions have been associated with a poor outcome in pediatric precursor B-cell acute lymphoblastic leukemia. To assess the prognostic relevance of IKZF1 deletions for patients treated on Berlin-Frankfurt-Münster Study Group trial ALL-BFM 2000, we screened 694 diagnostic acute lymphoblastic leukemia samples by Multiplex Ligation-dependent Probe Amplification. Patients whose leukemic cells bore IKZF1 deletions had a lower 5-year event-free survival (0.69±0.05 vs. 0.85±0.01; P0.0001) compared to those without, mainly due to a higher cumulative incidence of relapses (0.21±0.04 vs. 0.10±0.01; P=0.001). Although IKZF1 deletions were significantly associated with the P2RY8-CRLF2 rearrangement, their prognostic value was found to be independent from this association. Thus, IKZF1 deletion is an independent predictor of treatment outcome and a strong candidate marker for integration in future treatment stratification strategies on ALL-BFM protocols. Clinicaltrials.gov identifier: NCT00430118.

The aim of this study was to assess the psychological distress of men with prostate cancer (PC) throughout the whole process from initial diagnosis to therapy and to evaluate patients' tolerance regarding treatment delay.This prospective study, performed between July 2007 and March 2010, evaluated the psychological distress of 28 men who underwent prostate biopsy (PB), who were confronted with a cancer diagnosis and were about to undergo radical prostatectomy (RP). Three evaluation points were defined: E1, immediately before PB; E2, after definitive diagnosis and when RP was scheduled; and E3, on the day of admission for RP.Emotional distress was highest before PB, declining significantly until RP (p = 0.02). Symptoms of depression and anxiety were low at all evaluation points, with anxiety rising significantly after cancer diagnosis (p = 0.008). Concerns about postoperative erectile dysfunction and incontinence were registered at all evaluation points. Concerns about the effect on their partnership due to PC were low. The patient's tolerable waiting time for RP differed significantly from daily practice.Anxiety and depression as well as concerns about a negative effect on their partnership were shown to play a minor role in patients during the interval between PB and RP, while distress and concerns about erectile dysfunction and urinary incontinence were more prevalent. Support from the patient's medical and social environment and a sound partnership may have a protective effect on emotional status. Waiting time for surgery exceeded the patients' tolerated time-frames and may further contribute to the psychological distress of PC.

In this study, we analyzed a "variant of uncertain significance" (VUS) located in exon 23 of the BRCA2 gene exhibited by six members of five distinct families with hereditary breast cancer (BC). The variant was identified by DNA sequencing, and cDNA analysis revealed its co-expression with wild-type mRNA. We analyzed co-occurrence with other pathological mutations in BRCA1/2, performed a case-control study, looked for evolutionary data and used in-silico analyses to predict its potential clinical significance. Sequencing revealed an in frame deletion of 126 nucleotides in exon 23, leading to a deletion of 42 amino acids (c.9203_9328del126, p.Pro2992_Thr3033del). All of the VUS-carriers suffered from either BC or ovarian/pancreatic cancer. No other definite pathologic mutation of BRCA genes was found in the five families. The identified deletion could not be observed in a control cohort of 2,652 healthy individuals, but in 5 out of 916 (0.5%) tested BC families without a bona fide pathogenic BRCA1/2 mutation (P = 0.0011). According to these results, the in frame deletion c.9203_9328del126 is a rare mutation strongly associated with familial BC. In summary, our investigations indicate that this BRCA2 deletion is pathogenic.

The 19p13.1 breast cancer susceptibility locus is a modifier of breast cancer risk in BRCA1 mutation carriers and is also associated with the risk of ovarian cancer. Here, we investigated 19p13.1 variation and risk of breast cancer subtypes, defined by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) status, using 48,869 breast cancer cases and 49,787 controls from the Breast Cancer Association Consortium (BCAC). Variants from 19p13.1 were not associated with breast cancer overall or with ER-positive breast cancer but were significantly associated with ER-negative breast cancer risk [rs8170 OR, 1.10; 95% confidence interval (CI), 1.05–1.15; P = 3.49 × 10−5] and triple-negative (ER-, PR-, and HER2-negative) breast cancer (rs8170: OR, 1.22; 95% CI, 1.13–1.31; P = 2.22 × 10−7). However, rs8170 was no longer associated with ER-negative breast cancer risk when triple-negative cases were excluded (OR, 0.98; 95% CI, 0.89–1.07; P = 0.62). In addition, a combined analysis of triple-negative cases from BCAC and the Triple Negative Breast Cancer Consortium (TNBCC; N = 3,566) identified a genome-wide significant association between rs8170 and triple-negative breast cancer risk (OR, 1.25; 95% CI, 1.18–1.33; P = 3.31 × 10−13]. Thus, 19p13.1 is the first triple-negative–specific breast cancer risk locus and the first locus specific to a histologic subtype defined by ER, PR, and HER2 to be identified. These findings provide convincing evidence that genetic susceptibility to breast cancer varies by tumor subtype and that triple-negative tumors and other subtypes likely arise through distinct etiologic pathways. Cancer Res; 72(7); 1795–803. ©2012 AACR.