Recent evidence suggests that the prognostic impact of gene mutations in patients with chronic lymphocytic leukemia (CLL) may differ depending on the immunoglobulin heavy variable (IGHV) gene somatic hypermutation (SHM) status. In this study, we assessed the impact of nine recurrently mutated genes (BIRC3, EGR2, MYD88, NFKBIE, NOTCH1, POT1, SF3B1, TP53, and XPO1) in pre-treatment samples from 4580 patients with CLL, using time-to-first-treatment (TTFT) as the primary end-point in relation to IGHV gene SHM status. Mutations were detected in 1588 (34.7%) patients at frequencies ranging from 2.3–9.8% with mutations in NOTCH1 being the most frequent. In both univariate and multivariate analyses, mutations in all genes except MYD88 were associated with a significantly shorter TTFT. In multivariate analysis of Binet stage A patients, performed separately for IGHV-mutated (M-CLL) and unmutated CLL (U-CLL), a different spectrum of gene alterations independently predicted short TTFT within the two subgroups. While SF3B1 and XPO1 mutations were independent prognostic variables in both U-CLL and M-CLL, TP53, BIRC3 and EGR2 aberrations were significant predictors only in U-CLL, and NOTCH1 and NFKBIE only in M-CLL. Our findings underscore the need for a compartmentalized approach to identify high-risk patients, particularly among M-CLL patients, with potential implications for stratified management.

Background Emergency Department imaging volume has increased significantly in North America and Asia. Purpose To assess Emergency Department imaging trends in a European center. Material and Methods The institutional radiological information system was queried for all computed tomography (CT), ultrasound (US), and magnetic resonance (MR) studies performed for the Emergency Department during 2002–2017. Descriptive statistics and linear regression analyses were used to assess overall study rates and temporal trends in overall and after-hours imaging after adjusting for patient visitations. Results CT use increased significantly from 38/1000 visits to 108/1000 at the end of the observation by 5.5 new exams per 1000 visits/year ( P < 0.0001). US use increased gradually at a rate of 1.2/1000 per year during 2002–2008 with an accelerated annual increase of 6.4/1000 in 2009–2011 ( P < 0.0001) raising US rates from 7/1000 to 28/1000 visits per year with stable rates from 2012 onwards. After on-site MR became available in 2004, its use increased from 0.3/1000 to 7/1000 at a rate of 1.9/1000 visits per year in 2005–2009 ( P < 0.0001) and remained stable from 2010. While there was a significant increase in after-hours imaging, growth remained proportional to the overall trend in the use of CT, MR, and night-time CT with the exception of a slight decrease in after-hour US in favor of standard working hours ( P < 0.0001). Conclusion All modalities increased significantly in volume adjusted usage. US and MR rates have been stable since 2012 and 2010, respectively, after periods of increase while CT use continues to increase. Demand for after-hours imaging was mostly proportional to the overall trend.

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Germline mutations increase risk of breast cancer and other malignancies. BRCA2 has been shown to play a role in telomere protection and maintenance. Telomere length (TL) has been studied as a modifying factor for various diseases, including breast cancer. Previous research on TL in mutation carriers has produced contradicting results. We measured blood TL, using a high-throughput monochrome multiplex qPCR method, in a well-defined Icelandic cohort of female mutation carriers ( = 169), sporadic breast cancer patients ( = 561), and healthy controls ( = 537). Breast cancer cases had significantly shorter TL than unaffected women ( < 0.0001), both mutation carriers ( = 0.0097) and noncarriers ( = 0.00006). Using exclusively samples acquired before breast cancer diagnosis, we found that shorter telomeres were significantly associated with increased breast cancer risk in mutation carriers [HR, 3.60; 95% confidence interval (CI), 1.17-11.28;, 0.025] but not in non-carriers (HR,1.40; 95% CI, 0.89-2.22; , 0.15). We found no association between TL and breast cancer-specific survival. Blood TL is predictive of breast cancer risk in mutation carriers. Breast cancer cases have significantly shorter TL than unaffected women, regardless of status, indicating that samples taken after breast cancer diagnosis should not be included in evaluations of TL and breast cancer risk. Our study is built on a well-defined cohort, highly accurate methods, and long follow-up and can therefore help to clarify some previously published, contradictory results. Our findings also suggest that BRCA2 has an important role in telomere maintenance, even in normal blood cells..

Our previous studies showed an association between monoallelic BRCA2 germline mutations and dysfunctional telomeres in epithelial mammary cell lines and increased risk of breast cancer diagnosis for women with BRCA2 999del5 germline mutation and short telomeres in blood cells. In the current study, we analyzed telomere dysfunction in lymphoid cell lines from five BRCA2 999del5 mutation carriers and three Fanconi Anemia D1 patients by fluorescence in situ hybridization (FISH). Metaphase chromosomes were harvested from ten lymphoid cell lines of different BRCA2 genotype origin and analyzed for telomere loss (TL), multitelomeric signals (MTS), interstitial telomere signals (ITS) and extra chromosomal telomere signals (ECTS). TL, ITS and ECTS were separately found to be significantly increased gradually between the BRCA2+/+, BRCA2+/- and BRCA2-/- lymphoid cell lines. MTS were found to be significantly increased between the BRCA2+/+ and the BRCA2+/- heterozygous (p < 0.0001) and the BRCA2-/- lymphoid cell lines (p < 0.0001) but not between the BRCA2 mutated genotypes. Dysfunctional telomeres were found to be significantly increased in a stepwise manner between the BRCA2 genotypes indicating an effect of BRCA2 haploinsufficiency on telomere maintenance.