Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk

The significance of anemia in squamous cell head and neck cancer treated with surgery and postoperative radiotherapy

The objective of this study was to investigate the prognostic significance of the hemoglobin (Hb) levels at different timepoints in locally advanced squamous cell carcinoma of the head and neck (SCCHN). Included were 111 patients. The hemoglobin levels were assessed before surgery (PreS-Hb), between surgery and radiotherapy (HbAAC), before postoperative radiotherapy (PreRT-Hb) and at the end of radiotherapy (EndRT-Hb). HbAAC takes into account the duration of anemia during the interval between surgery and radiotherapy. Higher HbAAC corresponds with lower Hb levels. Five year locoregional control (LRC) among patients with HbAAC ≥ median was 72% and significantly worse as compared to the 88% in case of HbAAC < median (p = 0.0097). Multivariate analysis for LRC showed that the HbAAC was a prognostic factor. Overall survival (OS) after 3 years was 77% in case of HbAAC < median and 34% in case of HbAAC ≥ median (p < 0.0002). Multivariate analysis for OS showed that the PreS-Hb and HbAAC were prognostic factors. Hb level between surgery and radiotherapy is an important prognostic factor for both LRC and OS among patients with SCCHN treated with surgery and postoperative radiotherapy

Dosimetric impact of contouring and image registration variability on dynamic 125I prostate brachytherapy

Purpose: The quality of permanent prostate brachytherapy can be increased by addition of imaging modalities in the intraoperative procedure. This addition involves image registration, which inherently has inter- and intraobserver variabilities. We sought to quantify the inter- and intraobserver variabilities in geometry and dosimetry for contouring and image registration and analyze the results for our dynamic 125I brachytherapy procedure. Methods and Materials: Five observers contoured 11 transrectal ultrasound (TRUS) data sets three times and 11 CT data sets one time. The observers registered 11 TRUS and MRI data sets to cone beam CT (CBCT) using fiducial gold markers. Geometrical and dosimetrical inter- and intraobserver variabilities were assessed. For the contouring study, structures were subdivided into three parts along the craniocaudal axis. Results: We analyzed 165 observations. Interobserver geometrical variability for prostate was 1.1 mm, resulting in a dosimetric variability of 1.6% for V100 and 9.3% for D90. The geometric intraobserver variability was 0.6 mm with a V100 of 0.7% and D90 of 1.1%. TRUS–CBCT registration showed an interobserver variability in V100 of 2.0% and D90 of 3.1%. Intraobserver variabilities were 0.9% and 1.6%, respectively. For MRI–CBCT registration, V100 and D90 were 1.3% and 2.1%. Intraobserver variabilities were 0.7% and 1.1% for the same. Conclusions: Prostate dosimetry is affected by interobserver contouring and registration variability. The observed variability is smaller than underdosages that are adapted during our dynamic brachytherapy procedure

Cone-beam CT-based adaptive planning improves permanent prostate brachytherapy dosimetry : An analysis of 1266 patients

PURPOSE: To evaluate adaptive planning for permanent prostate brachytherapy and to identify the prostate regions that needed adaptation. METHODS AND MATERIALS: After the implantation of stranded seeds, using real-time intraoperative planning, a transrectal ultrasound (TRUS)-scan was obtained and contoured. The positions of seeds were determined on a C-arm cone-beam computed tomography (CBCT)-scan. The CBCT-scan was registered to the TRUS-scan using fiducial gold markers. If dose coverage on the combined image-dataset was inadequate, an intraoperative adaptation was performed by placing remedial seeds. CBCT-based intraoperative dosimetry was analyzed for the prostate (D90, V100, and V150) and the urethra (D30). The effects of the adaptive dosimetry procedure for Day 30 were separately assessed. RESULTS: We analyzed 1266 patients. In 17.4% of the procedures, an adaptation was performed. Without the dose contribution of the adaptation Day 30 V100 would be < 95% for half of this group. On Day 0, the increase due to the adaptation was 11.8 ± 7.2% (1SD) for D90 and 9.0 ± 6.4% for V100. On Day 30, we observed an increase in D90 of 12.3 ± 6.0% and in V100 of 4.2 ± 4.3%. For the total group, a D90 of 119.6 ± 9.1% and V100 of 97.7 ± 2.5% was achieved. Most remedial seeds were placed anteriorly near the base of the prostate. CONCLUSION: CBCT-based adaptive planning enables identification of implants needing adaptation and improves prostate dose coverage. Adaptations were predominantly performed near the anterior base of the prostate