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V1 User226776 声望 2 5天前 上传
Internal and external generalizability of temporal dose–response relationships for xerostomia following IMRT for head and neck cancer
Abstract Background and purpose To study internal and external generalizability of temporal dose–response relationships for xerostomia after intensity-modulated radiotherapy (IMRT) for head and neck cancer, and to investigate potential amendments of the QUANTEC guidelines. Material and methods Objective xerostomia was assessed in 121 patients (nCohort1 = 55; nCohort2 = 66) treated to 70 Gy@2 Gy in 2006–2015. Univariate and multivariate analyses (UVA, MVA with 1000 bootstrap populations) were conducted in Cohort1, and generalizability of the best-performing MVA model was investigated in Cohort2 (performance: AUC, p-values, and Hosmer–Lemeshow p-values (pHL)). Ultimately and for clinical guidance, minimum mean dose thresholds to the contralateral and the ipsilateral parotid glands (Dmeancontra, Dmeanipsi) were estimated from the generated dose–response curves. Results The observed xerostomia rate was 38%/47% (3 months) and 19%/23% (11–12 months) in Cohort1/Cohort2. Risk of xerostomia at 3 months increased for higher Dmeancontra and Dmeanipsi (Cohort1: 0.17·Dmeancontra + 0.11·Dmeanipsi-8.13; AUC = 0.90 ± 0.05; p = 0.0002 ± 0.002; pHL = 0.22 ± 0.23; Cohort2: AUC = 0.81; p < 0.0001; pHL = 0.27). The identified minimum Dmeancontra thresholds were lower than in the QUANTEC guidelines (Cohort1/Cohort2: Dmeancontra = 12/19 Gy; Dmeancontra, Dmeanipsi = 16, 25/20, 26 Gy). Conclusions Increased Dmeancontra and Dmeanipsi explain short-term xerostomia following IMRT. Our results also suggest decreasing Dmeancontra to below 20 Gy, while keeping Dmeanipsi to around 25 Gy. Long-term xerostomia was less frequent, and no dose–response relationship was established for this follow-up time.
V1 User226776 声望 2 3周前 上传
Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome
Background & Aims Multigene panels are commercially available tools for hereditary cancer risk assessment that allow for next-generation sequencing of numerous genes in parallel. However, it is not clear if these panels offer advantages over traditional genetic testing. We investigated the number of cancer predisposition gene mutations identified by parallel sequencing in individuals with suspected Lynch syndrome. Methods We performed germline analysis with a 25-gene, next-generation sequencing panel using DNA from 1260 individuals who underwent clinical genetic testing for Lynch syndrome from 2012 through 2013. All patients had a history of Lynch syndrome–associated cancer and/or polyps. We classified all identified germline alterations for pathogenicity and calculated the frequencies of pathogenic mutations and variants of uncertain clinical significance (VUS). We also analyzed data on patients’ personal and family history of cancer, including fulfillment of clinical guidelines for genetic testing. Results Of the 1260 patients, 1112 met National Comprehensive Cancer Network (NCCN) criteria for Lynch syndrome testing (88%; 95% confidence interval [CI], 86%–90%). Multigene panel testing identified 114 probands with Lynch syndrome mutations (9.0%; 95% CI, 7.6%−10.8%) and 71 with mutations in other cancer predisposition genes (5.6%; 95% CI, 4.4%−7.1%). Fifteen individuals had mutations in BRCA1 or BRCA2; 93% of these met the NCCN criteria for Lynch syndrome testing and 33% met NCCN criteria for BRCA1 and BRCA2 analysis (P = .0017). An additional 9 individuals carried mutations in other genes linked to high lifetime risks of cancer (5 had mutations in APC, 3 had bi-allelic mutations in MUTYH, and 1 had a mutation in STK11); all of these patients met NCCN criteria for Lynch syndrome testing. A total of 479 individuals had 1 or more VUS (38%; 95% CI, 35%–41%). Conclusions In individuals with suspected Lynch syndrome, multigene panel testing identified high-penetrance mutations in cancer predisposition genes, many of which were unexpected based on patients’ histories. Parallel sequencing also detected a high number of potentially uninformative germline findings, including VUS.
V1 User226776 声望 2 1个月前 上传
Phosphorylation of the endothelial nitric oxide synthase at Ser-1177 is required for VEGF-induced endothelial cell migration
Abstract Vascular endothelial growth factor (VEGF) stimulates endothelial cell (EC) migration. The protein kinase Akt activates the endothelial NO synthase (eNOS) by phosphorylation of Ser-1177. Therefore, we investigated the contribution of Akt-mediated eNOS phosphorylation to VEGF-induced EC migration. Inhibition of NO synthase or overexpression of a dominant negative Akt abrogated VEGF-induced cell migration. In contrast, overexpression of constitutively active Akt was sufficient to induce cell migration. Moreover, transfection of an Akt site phospho-mimetic eNOS (S1177D) potently stimulated EC migration, whereas a non-phosphorylatable mutant (S1177A) inhibited VEGF-induced EC migration. Our data indicate that eNOS activation via phosphorylation of Ser-1177 by Akt is necessary and sufficient for VEGF-mediated EC migration.
V1 User226776 声望 2 1个月前 上传
Bladder Cancer Mortality after Spinal Cord Injury over 4 Decades
Purpose We estimate bladder cancer mortality in people with spinal cord injury compared to the general population. Materials and Methods Data and statistics were retrieved from the National Spinal Cord Injury Statistical Center and the National Center for Health Statistics. The mortality experience of the 45,486 patients with traumatic spinal cord injury treated at a Spinal Cord Injury Model System or Shriners Hospital was compared to the general population using a standardized mortality ratio. The standardized mortality ratio data were further stratified by age, gender, race, time since injury and injury severity. Results Our study included 566,532 person-years of followup between 1960 and 2009, identified 10,575 deaths and categorized 99 deaths from bladder cancer. The expected number of deaths from bladder cancer would have been 14.8 if patients with spinal cord injury had the same bladder cancer mortality as the general population. Thus, the standardized mortality ratio is 6.7 (95% CI 5.4–8.1). Increased mortality risk from bladder cancer was observed for various ages, races and genders, as well as for those injured for 10 or more years and with motor complete injuries. Bladder cancer mortality was not significantly increased for ventilator users, those with motor incomplete injuries or those injured less than 10 years. Conclusions Individuals with a spinal cord injury can potentially live healthier and longer by reducing the incidence and mortality of bladder cancer. Study findings highlight the need to identify at risk groups and contributing factors for bladder cancer death, leading to the development of prevention, screening and management strategies.

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