Twenty-six million Americans are estimated to have chronic kidney disease (CKD) with increased risk for cardiovascular disease and end stage renal disease. CKD is frequently undiagnosed and patients ...are unaware, hampering intervention. A tool for accurate and timely identification of CKD from electronic medical records (EMR) could improve healthcare quality and identify patients for research. As members of eMERGE (electronic medical records and genomics) Network, we developed an automated phenotyping algorithm that can be deployed to identify rapidly diabetic and/or hypertensive CKD cases and controls in health systems with EMRs It uses diagnostic codes, laboratory results, medication and blood pressure records, and textual information culled from notes. Validation statistics demonstrated positive predictive values of 96% and negative predictive values of 93.3. Similar results were obtained on implementation by two independent eMERGE member institutions. The algorithm dramatically outperformed identification by ICD-9-CM codes with 63% positive and 54% negative predictive values, respectively.
Abstract
INTRODUCTION:
Germline BRCA mutations are an independent prognostic factor for PrCa prognosis and treatment outcomes. BRCA tumours are associated with chromosomal instability due to ...underlying DNA repair deficiency; however, recurrent patterns of genomic aberrations in this context have not been explored.
METHODS:
We collected PrCa formalin-fixed paraffin-embedded samples from diagnostic biopsies and/or prostatectomies from 5 BRCA1 and 24 BRCA2 germline mutation carriers, which were matched with at least 1 sporadic PrCa (ie PrCa with no germline mutation) by stage and treatment. All samples were reviewed by an expert pathologist, and the tumour relevant areas were selected for further analyses. Recurrent chromosomal abnormalities in PrCa were also analyzed using previously described fluorescence in situ hybridization (FISH) “break-apart” and/or “fusion” assays, including a novel FISH “combined break-fusion” assay for TMPRSS2-ERG designed with probes flanking 3´and 5´of ERG and 5´of TMPRSS2. Genomic abnormalities were confirmed by a second method (qPCR or IHC) whenever possible.
RESULTS:
No differences in Gleason score between mutation carriers and non-carriers were seen (p = 0.134). Neuroendocrine phenotype was not identified in any sample. The “break-apart” assay identified interstitial deletion of genomic sequences between TMPRSS2 and ERG in all BRCA mutated tumours in at least one focus (100%), compared with 45% of non-carriers (P<0.001). The novel “break-fusion” assay allowed us to identify TMPRSS2 as the fusion partner in all cases, excluding other potential partners previously described. ETV1 rearrangements were identified in 3.5% of carriers and in 4% of non-carriers (P = 0.662).
CONCLUSIONS:
The presence of TMPRRSS2-ERG fusion gene in all BRCA mutated tumours in our series identifies a non-random androgen-driven event on the background of high chromosomal instability. Our findings suggests that BRCA mutated PrCa is androgen-dependent which may have important implications for the management of these patients.
Citation Format: Elena Castro, Floortje Van de Poll, Elena Piñeiro, Paz Nombela, Elizabeth Bancroft, Koveela Govindasami, Michelle Guy, G Kovacs, Steve Ellis, Antonis Antoniu, Douglas Easton, Zsofia Kote-Jarai, Fatima Al-Sharour, David Olmos, Rosalind Eeles. High-Frequency of TMPRSS2-ERG fusion gene identifies a non-random androgen-driven event of chromosomal instability in BRCA mutated prostate cancer. abstract. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4249. doi:10.1158/1538-7445.AM2015-4249
Population-based genome wide association studies have identified a locus at 9p22.2 associated with ovarian cancer risk, which also modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. ...We conducted fine-scale mapping at 9p22.2 to identify potential causal variants in BRCA1 and BRCA2 mutation carriers. Genotype data were available for 15,252 (2,462 ovarian cancer cases) BRCA1 and 8,211 (631 ovarian cancer cases) BRCA2 mutation carriers. Following genotype imputation, ovarian cancer associations were assessed for 4,873 and 5,020 SNPs in BRCA1 and BRCA 2 mutation carriers respectively, within a retrospective cohort analytical framework. In BRCA1 mutation carriers one set of eight correlated candidate causal variants for ovarian cancer risk modification was identified (top SNP rs10124837, HR: 0.73, 95%CI: 0.68 to 0.79, p-value 2× 10-16). These variants were located up to 20 kb upstream of BNC2. In BRCA2 mutation carriers one region, up to 45 kb upstream of BNC2, and containing 100 correlated SNPs was identified as candidate causal (top SNP rs62543585, HR: 0.69, 95%CI: 0.59 to 0.80, p-value 1.0 × 10-6). The candidate causal in BRCA1 mutation carriers did not include the strongest associated variant at this locus in the general population. In sum, we identified a set of candidate causal variants in a region that encompasses the BNC2 transcription start site. The ovarian cancer association at 9p22.2 may be mediated by different variants in BRCA1 mutation carriers and in the general population. Thus, potentially different mechanisms may underlie ovarian cancer risk for mutation carriers and the general population.
Mastectomy is the treatment of reference for local relapse after breast cancer (BC). The aim of this study was to document the feasibility and the results of associating lumpectomy with partial ...breast irradiation by interstitial brachytherapy (IB) as local treatment for an isolated ipsilateral BC local recurrence (LR).
Between 1975 and 1996 at Marseille and Nice Cancer Institutes, 4026 patients received lumpectomy and radiotherapy (RT) (50–80 Gy) for a localized breast cancer of which 473 presented a LR. Among these patients, 69 (14.6%) received a second lumpectomy followed by IB, which delivered 30 Gy (Nice,
n = 24) or 45–50 Gy (Marseille,
n = 45) with 3 to 8
192Ir wires in 1 or 2 planes on the 85% isodose.
Median age at LR was 58.2 years, median follow-up since primary BC was 10 years, and median follow-up after the second conservative treatment was 50.2 months (range, 2–139 months). Immediate tolerance was good in all cases. Grade 2 to 3 long-term complications (LTC) according to IB dose were 0%, 28%, and 32%, respectively, for 30 Gy, 45 to 46 Gy, and 50 Gy (
p = 0.01). Grade 2 to 3 LTC according to total dose were 4% and 30%, respectively, for total doses (initial RT plus IB) ≤ 100 Gy or >100 Gy (
p = 0.008). Logistic regression showed that the only factor associated with Grade 2 to 3 complications was higher IB doses (
p = 0.01). We noted 11 second LRs (LR2), 10 distant metastases (DM), and 5 specific deaths. LR2 occurred either in the tumor bed (50.8%) or close to the tumor bed (34.3%) or in another quadrant (14.9%). Kaplan-Meier 5-year freedom from (FF) LR2 (FFLR2), FFDM, and DFS were 77.4%, 86.7%, and 68.9%, respectively. Overall 5-year survival (OS) was 91.8%. Univariate analysis showed the following factors associated with a higher FFLR2: (1) number of wires used for IB (3–4 vs. 5–8 wires,
p = 0.006), (2) IB doses (30–45 Gy vs. 46–60 Gy,
p = 0.05), (3) number of planes (1 vs. 2,
p = 0.05), (4) interval between primary breast cancer and LR (< 36 months vs. ≥36 months,
p = 0.06). Multivariate analysis showed two factors associated with better local control: (1) number of wires (5–8 wires,
p = 0.013) and (2) interval between primary breast cancer and LR ≥36 months (
p = 0.039). The multivariate analysis showed two factors associated with better FFDM: (1) absence of initial axilla involvement (
p = 0.019) and (2) relapse in a different location (
p = 0.04). These two factors were also associated with a higher OS.
Our experience showed that second conservative treatments for local relapse were feasible and gave results comparable to standard mastectomy. We recommend delivering IB doses of at least 46 Gy in 2 planes when initial radiotherapy delivered 50 Gy. The study gives enough information to encourage a Phase III trial that compares radical mastectomy to conservative procedures for localized breast cancer recurrences.
Electronic medical records (EMR) contain a longitudinal collection of laboratory data that contains valuable phenotypic information on disease progression of a large collection of patients. These ...data can be potentially used in medical research or patient care; finding disease progression subtypes is a particularly important application. There are, however, two significant difficulties in utilizing this data for statistical analysis: (a) a large proportion of data is missing and (b) patients are in very different stages of disease progression and there are no well-defined start points of the time series. We present a Bayesian machine learning model that overcomes these difficulties. The method can use highly incomplete time-series measurement of varying lengths, it aligns together similar trajectories in different phases and is capable of finding consistent disease progression subtypes. We demonstrate the method on finding chronic kidney disease progression subtypes.
By year 1911 radioactivity had been discovered for over a decade, but its origin remained a mystery. Rutherford's discovery of the nucleus and the subsequent discovery of the neutron by Chadwick ...started the field of subatomic physics - a quest for understanding the fundamental constituents of matter.This book reviews the important achievements in subatomic physics in the past century. The chapters are divided into two parts: nuclear physics and particle physics. Written by renowned authors who have made major developments in the field, this book provides the academics and researchers an essential overview of the present state of knowledge in nuclear and particle physics.Sample Chapter(s)The Early Years and Beyond (530 KB)Contents:Nuclear Physics:Particle Physics, From Rutherford to the LHC (S Weinberg)The Early Years and Beyond (E M Henley and A García)100 Years of Nuclear Mass Measurements and Models (G T Garvey)Symmetries and Dynamical Symmetries in Nuclei (I Talmi)Nuclear Fission (R Vogt and J Randrup)Parity- and Time-Reversal Tests in Nuclear Physics (D Hertzog and M J Ramsey-Musolf)High Energy Nuclear Physics: From Bear Mountain to the LHC (L McLerran)Chiral Symmetry in Subatomic Physics (U-G Meiβner)Exotic Nuclei Far From the Stability Line (K Hagino, I Tanihata and H Sagawa)Particle Physics:A Short History of Colliders (L Evans)4π-Detectors (C Tully)Large Underground Detectors for Proton Decay and Neutrino Physics (K Scholberg)Jets and QCD (S D Ellis and D E Soper)Diffractive Phenomena in High Energy Processes (L Frankfurt and M Strikman)Weak Interactions: From Current-Current to Standard Model and Beyond (R N Mohapatra)Neutrino Physics (L Wolfenstein)Introduction to Renormalization in Field Theory (L-F Li)Lattice Gauge Theory and the Origin of Mass (A S Kronfeld)String Theory and M-Theory (J H Schwarz)Readership: Students, researchers and academics interested in nuclear and particle physics.
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Background: Biochemical relapse after local treatment for prostate cancer (PCa) indicates recurrent disease and is associated with shorter cause-specific survival (CSS). Germline ...BRCA mutations are associated with worse PrCa outcomes. In this study, we analyzed biochemical-progression free survival (bPFS) after conventional treatments for localized PCa in a cohort of BRCA patients from the UK. Currently, BRCA1/2 carriers are treated with the same protocols used for non-carriers. Methods: In this retrospective case-control study, each BRCA carrier (10 BRCA1 and 34 BRCA2) treated with radical prostatectomy (RP) or external beam radiotherapy (RT) was matched with 3 non-carriers (NC) by: age at diagnosis (±5 yrs), TNM stage, Gleason score, presenting PSA, local treatment (RT or RP), androgen-deprivation therapy (ADT) and year of treatment (±5yrs). All NC were screened for BRCA1 and BRCA2 mutations. Biochemical failure was reviewed according to ASTRO and NCCN criteria. The Kaplan-Meier method and a multivariate Cox regression model adjusted by matching factors were employed. Results: 176 patients (pts) were included. Median follow-up was 97 months (ms). Median age at diagnosis was 58.5 yrs (43-75). 80 pts received RT (16 BRCA2, 4 BRCA1, 60 NC) and 85% also received ADT≥6 ms. 96pts underwent RP (18 BRCA2, 6 BRCA1 and 72 NC). Following RT treatment, 5yrs-CSS was 96% in NC and 47% in BRCA carriers (p=2x10
-5
), whilst no difference was seen after RP (5yrs-CSS was 98.5% in NC vs 93.3% in BRCA). Five-years bFPFS after RT was 74% in NC and 24% in BRCA (p=0.002). No difference was observed in 5yrs-bPFS between BRCA carriers and NC treated with RP (52% vs 66% , p=0.346). The adjusted MVA (including tumour stage, local treatment, ADT and BRCA status) confirmed the independent prognostic value of BRCA status for bPFS and CSS. Among BRCA carriers, the independent risk was greater when the analysis was limited to BRCA2 pts . Conclusions: Our results suggest that BRCA carriers have worse local disease control than NC when conventionally treated with RT. No differences in bPFS were observed in pts treated with RP after >8 yrs median follow-up. These results may have implications for tailoring clinical management in these patients.
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