8 research outputs found
Finishing the euchromatic sequence of the human genome
The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead
Neoadjuvant Androgen Deprivation Therapy Leads to Immediate Impairment of Vitality/Hormonal and Sexual Quality of Life: Results of a Multicenter Prospective Study
Long-term follow-up after radiotherapy for prostate cancer with and without rectal hydrogel spacer: A pooled prospective evaluation of quality of life
Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/162689/2/bju15097_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162689/1/bju15097.pd
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Stereotactic body radiation therapy (SBRT) versus conventionally fractionated external beam radiation therapy in unfavorable intermediate-risk prostate cancer: An inverse propensity matched analysis
e17054
Background: Conventionally fractionated radiotherapy (CFRT) or moderately hypofractionated radiotherapy (MFRT) ± short-course androgen deprivation therapy (ADT) is commonly employed for unfavorable intermediate-risk (UIR) prostate cancer. Stereotactic body radiation therapy (SBRT) has not been widely adopted, but may have radiobiologic advantages over more conventionally fractionated treatments. We hypothesized that radiotherapy dose-escalation with SBRT (35-40Gy in ≤5 fractions) is associated with improved overall survival (OS) relative to biologically equivalent doses of CFRT (72-86.4Gy in 1.8-2.0Gy/fraction) or MFRT (≥60Gy in 2.4-3.2Gy/fraction) ± ADT. Methods: The National Cancer Database (NCDB) was used to identify 28,028 men with UIR prostate cancer who received CFRT with (n = 12,872) or without ADT (n = 12,984), MFRT with (n = 251) or without ADT (n = 281), and SBRT with (n = 212) or without ADT (n = 1,428). SBRT+ADT patients were excluded due to low patient numbers. Inverse probability of treatment weighting was used to balance measured confounders. Unweighted- and weighted- multivariable analysis (MVA) using Cox regression was used to compare OS hazard ratios. Results: Relative to CFRT without ADT, CFRT+ADT (Hazard Ratio (HR): 0.92, [95% Confidence Interval: 0.87-0.97], P = .002) and SBRT without ADT (HR: 0.74 [0.61-0.89], P = .002) were both associated with improved OS on MVA. Relative to CFRT+ADT, SBRT without ADT correlated with improved OS on MVA (HR: 0.81 [0.67-0.99], P = .04). Weight-adjusted MVA demonstrated that SBRT (HR: 0.80 [0.65-0.98], P = .036) and ADT (HR: 0.91 [0.86-0.97], P = .002) correlated with improved OS. SBRT was not associated with improved OS relative to MFRT. Conclusions: Using inverse propensity treatment weighting, we adjusted for age, comorbidity score, and tumor factors, and observed a significant overall survival benefit in favor of administering dose-escalated SBRT over CFRT+ADT. To our knowledge, this is the first study to show that SBRT is associated with improved OS relative to CFRT for men with UIR prostate cancer. Together, this suggests that SBRT offers a cheaper and shorter course of therapy that mitigates COVID-19 exposure, which also is associated with improved OS relative to CFRT for UIR prostate cancer and may obviate the need for ADT in this population. While we await results from several ongoing clinical trials, we believe this study lends support to the use of SBRT in men with UIR prostate cancer
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Association of survival and local radiotherapy to the bladder versus chemotherapy alone for patients with metastatic urothelial carcinoma (mUC)
413
Background: Limited data exists on the role of local therapy for metastatic urothelial carcinoma of the bladder (mUC). Large database analysis have inherent limitations but can shed light on survival outcomes in a real-world population and in scenarios not easily studied in a randomized fashion. We hypothesized that in the NCDB, radiotherapy (RT) to the bladder plus chemotherapy (CT) would be associated with improved overall survival (OS) vs CT alone. Methods: We queried the NCDB for newly diagnosed mUC cases (cT1-4 N0-3 M1) from 2004-2015 treated with CT alone vs CT plus RT to ≥ 45 Gy to the bladder. Cystectomy patients were excluded. To account for lead time bias, we excluded patients with < 2 months of follow-up. Variables for multivariable analysis (MVA) and matching included: age, sex, Charlson-Deyo comorbidity index (CCI), cT/N stage, facility type/location, insurance, year of diagnosis, and number of CT agents. Overall survival (OS) was estimated using the Kaplan-Meier method. Multivariable Cox proportional hazards analyses was performed. Propensity score matching (all variables) and exact matching (CCI score, age +/- 5 years, cT stage) was performed. Results: 4,459 patients with newly diagnosed mUC received either CT+ RT (n = 337) or CT alone (n = 4,122). Median follow-up was 10.7 months (range 2-144). Median RT dose was 57.6 Gy (IQR, 50.0– 63.0 Gy). Median OS for CT+RT was 13.8 (95% CI, 12.1-15.5) vs. 8.4 months (95% CI, 7.5-9.4) for CT (P < 0.0001). In MVA, RT was associated with improved OS (HR, 0.70; 95% CI, 0.62-0.79; P < 0.0001). Increasing age, comorbidity score, and cT-stage were associated with worse OS (P < 0.001). In subgroup analysis of patients without other comorbidities (CCI of 0), median OS for CT+RT was 14.4 (95% CI, 12.1-16.7) vs 11.1 months (95% CI, 10.7-11.5) for CT (P = 0.001). For patients with cT2-3N0 disease, median OS for CT+RT was 14.0 months (95% CI, 6.8-21.3) vs 10.9 months (95% CI, 10.1-11.7) for CT (P = 0.001). On propensity matched analysis (337 CT+RT and 337 CT patients), CT+RT was associated with improved OS (median 13.8 vs 8.5 months; P < 0.0001; MVA HR 0.59, 95% CI 0.50-0.69, P < 0.0001). On exact matched analysis (205 CT+RT and 205 CT patients), CT+RT was associated with improved OS (median 13.5 vs 9.9 months; P = 0.002; MVA HR 0.67, 95% CI 0.57-0.79, P = 0.002). Landmark analysis for patients living ≥6 months (median OS 16.3 vs 13.6 months, P = 0.004) and ≥12 months (median OS 22.2 vs 19.1 months, P = 0.029) demonstrated improved OS for CT+RT. Conclusions: In this large contemporary series, mUC patients treated with local RT plus CT had improved OS compared to CT alone. The magnitude of the effect persisted with matching and landmark analysis to try to mitigate the effect of selection bias, though we could not control for extent of metastatic disease. These findings are hypothesis-generating; a prospective trial evaluating the impact of bladder RT in mUC is warranted
Immunotherapy with pembrolizumab in surgically resectable head and neck squamous cell carcinoma.
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Integrated clinicopathologic and molecular risk stratification for disease recurrence in muscle-invasive bladder cancer
490 Background: Integrating molecular subtypes, gene transcripts associated with disease recurrence (DR), and clinicopathologic features may help risk stratify muscle-invasive bladder cancer (MIBC) patients & guide therapy selection. We hypothesized that combined transcriptomic & clinical data would improve risk stratification for DR (local or distant) after cystectomy +/- adjuvant chemotherapy. Methods: We identified 401 MIBC patients (pT2-4 N0-N3 M0) in The Cancer Genome Atlas with detailed demographic, clinical, pathologic, and treatment-related data. We split the data into training (60%) & testing (40%) sets. We produced RNA gene expression scores for molecular subtype using 48 established, relevant genes (PMID 28988769). In the training set, we performed feature selection by conducting random forest modeling of an additional 108 genes associated with DR. We kept genes of highest importance based on the evaluation of increasing mean-squared error & node purity. We excluded highly correlated genes & used the false discovery rate method for multiple hypotheses testing. We performed univariable analyses on genes of highest importance, molecular subtype, & clinicopathologic variables. Using adjusted multivariable analyses (MVA), we built two models: with & without transcriptomic data. Using the testing set, we compared the final models' performance to predict DR, using receiver operating characteristics & area under the curve (AUC). Results: Median follow-up was 18 months (range 1-168). 104 patients recurred with a 5-yr cumulative incidence of 34.6%[28.6-40.5%]. Using the training set, we identified 6 genes significantly associated with DR (VEGFA, TRMT1, FGFR2B, ERBB2, MMP14, PDGFC). The final MVA showed that the new 6-gene signature (HR 1.61, 95% CI 1.27-2.05, p < 0.001); immune molecular subtype [increased expression of PD-L1, PD-1, IDO1, CXCL11, L1CAM, SAA1] (HR 0.52, 95% CI 0.29-0.94, p = 0.03); smoking status (HR 1.17 per 10 pack-years, 95% CI 1.05-1.29, p = 0.005); and local failure risk factors [≥pT3 with negative margins & ≥10 nodes removed (HR 1.63, 95% CI 1.15-2.32, p = 0.006); ≥pT3 and positive margins OR < 10 nodes removed (HR 3.26, 95%CI 2.43 to 4.09, p = 0.007)], were all significantly associated with DR. This combined model outperformed a stand-alone clinicopathologic model (AUC 0.75 vs. 0.66) in the testing set. The combined model stratified patients based on DR risk into 3 groups with 5-yr cumulative incidences of 19.8%[7.7-31.9%] (low-risk); 34.5%[26.1-42.8%] (intermediate); and 49.8%[37.7-61.9%] (high), Gray’s Test p < 0.0001. Conclusions: To our knowledge, this study is the first to integrate clinicopathologic & transcriptomic information (including molecular subtype) to better stratify MIBC patients by risk of recurrence. This stratification may help guide decision-making for adjuvant treatment. Further validation is warranted