Across taxa, the seasonal transition between non‐breeding and breeding states is controlled by localised thyroid hormone signalling in the deep brain via reciprocal switching of deiodinase enzyme ...expression from type 3 (DIO3) to type 2 (DIO2). This reciprocal switch is considered to be mediated by increasing thyroid‐stimulating hormone β (TSHβ) release from the pars tuberalis, which occurs in response to a change in photoperiod. Although well characterised in a handful of model organisms in controlled laboratory settings, this pathway remains largely unexplored in free‐living animals under natural environmental conditions. In this comparative gene expression study, we investigated hypothalamic thyroid hormone signalling in two seasonally breeding subspecies of white‐crowned sparrow (Zonotrichia leucophrys), across the entirety of their annual cycles. The migratory Gambel's (Z. l. gambelii) and resident Nuttall's (Z. l. nuttalii) subspecies differ with respect to timing of reproduction, as well as life history stage and migratory strategies. Although DIO3 mRNA expression was elevated and DIO2 mRNA expression was reduced in the wintering period in both subspecies, DIO2 peaked in both subspecies prior to the onset of reproduction. However, there was differential timing between subspecies in peak DIO2 expression. Intriguingly, seasonal modulation of TSHβ mRNA was only observed in migrants, where expression was elevated at the start of breeding, consistent with observations from other highly photoperiodic species. There was no correlation between TSHβ, DIO2 and gonadotropin‐releasing hormone‐I mRNA or reproductive metrics in residents. Based on these observed differences, we discuss potential implications for our understanding of how changes in medial basal hypothalamic gene expression mediates initiation of seasonal reproduction.
Seasonal changes in neuroendocrine genes associated with regulation of reproductive physiology were examined in migrant and resident subspecies of songbird. Evidence for reciprocal switching of hypothalamic deiodinase expression favoring inhibition of local thyroid signaling in winter to favoring conversion of T4 to T3 prior to breeding was found. A seasonal increase in TSHβ expression temporally associated with development of reproductive physiology was found in migrants but not residents despite evidence of reciprocal switching of deiodinase expression in both subspecies.
Residency experiences and teaching in oncology among urology residents are variable across Canada. We sought to identify how radiation and medical oncology concepts, as they pertain to genitourinary ...malignancies, are taught to urology residents.
A total of 190 trainees enrolled in Canadian urology residency training programs were invited to participate in the study from January 2016 to June 2016. Participants completed an online questionnaire addressing the training they received.
The overall response rate was 32%. Twenty-three percent of respondents were in their fellowship year; 17%, 20%, 10%, 17%, and 12% were first-, second-, third-, fourth-, and fifth-year residents, respectively, with a median of four (range 1-9) respondents from each training program. Ninety-five percent of respondents had academic half-day (AHD) as part of their training that included radiotherapy (61%) and chemotherapy (51%) teaching. Most respondents indicated their main exposure to chemotherapy and radiation came from informal teaching in urology clinics. Twenty-nine percent and 41%, of participants had mandatory rotations in radiation and medical oncology, respectively. Only 6% of respondents used their voluntary elective time in these disciplines and most voluntary electives were of 1-2-week duration. Despite this, 90% of respondents preferred some mandatory radiation and medical oncology training.
Most of the limited exposure that urology residents have to medical and radiation oncology is through AHD or informal urology clinics, despite a desire among current urology trainees to have clinical exposure in these areas. Moving forward, urology residency programs should consider integrating medical and radiation oncology rotations into the residency program curriculum.
The purpose of this article was to generate an algorithm to calculate radiobiological endpoints and composite indices and use them to compare volumetric modulated arc therapy (VMAT) and 3-dimensional ...conformal radiation therapy (3D-CRT) techniques in patients with locally advanced non-small cell lung cancer.
The study included 25 patients with locally advanced non-small cell lung cancer treated with 3D-CRT at our center between January 1, 2010, and December 31, 2014. The planner generated VMAT plans using clones of the original computed tomography scans and regions of interest volumes, which did not include the original 3D plans. Both 3D-CRT and VMAT plans were generated using the same dose-volume constraint worksheet. The dose-volume histogram parameters for planning target volume and relevant organs at risk (OAR) were reviewed. The calculation engine was written in the R programming language; the user interface was developed with the "shiny" R Web library. Dose-volume histogram data were imported into the calculation engine and tumor control probability (TCP), normal tissue complication probability (NTCP), composite cardiopulmonary toxicity index (CPTI), morbidity index: MI = ∑
(w
∗ NTCP
), uncomplicated TCP (UTCP=TCP∗∏k=1#ofOARs1-NTCP
100, and therapeutic gain (TG): ie, TG = TCP ∗ (100 - MI) were calculated.
TCP was better with 3D-CRT (12.62% vs 11.71%, P < .001), whereas VMAT demonstrated superior NTCP esophagus (4.45% vs 7.39%, P = .02). NTCP spinal cord (0.001% vs 0.009%, P = .001), and NTCP heart/perfusion defect (44.57% vs 56.42%, P = .016). There was no difference in NTCP lung (6.27% vs 7.62%, P = .221) and NTCP heart/pericarditis (0.001% vs 0.15%, P = .129) between 2 techniques. VMAT showed substantial improvement in morbidity index (11.06% vs. 14.31%, P = 0.01), CPTI (47.59% vs 59.41%, P = .03), TG (P = .035), and trend toward superiority in UTCP (5.89 vs 4.75, P=.057).
The study highlights the utility of the radiobiological algorithm and summary indices in comparative plan evaluation and demonstrates benefits of VMAT over 3D-CRT.
Planning and delivery for permanent breast seed implant (PBSI) are performed with the ipsilateral arm raised; however, changes in implant geometry can be expected because of healing and anatomical ...motion as the patient resumes her daily activities. The purpose of this study is to quantify the effect of ipsilateral arm position on postplan dosimetry.
Twelve patients treated at the Tom Baker Cancer Centre were included in this study. Patients underwent two postimplant CT scans on the day of implant (Day 0) and two scans approximately 8 weeks later (Day 60). One scan at each time was taken with the ipsilateral arm raised, recreating the planning scan position, and the other with both arms down in a relaxed position beside the body, recreating a more realistic postimplant arm position. Postplans were completed on all four scans using deformable image registration (MIM Maestro).
On the Day 0 scan, the V200 for the evaluation planning target volume was significantly increased in the arm-down position compared with the arm-up position. Lung, rib, and chest wall dose were significantly reduced at both time points. Left anterior descending coronary artery, heart, and skin dose showed no significant differences at either time point.
Although some dosimetric indices show significant differences between the arm-up and arm-down positions, the magnitude of these differences is small and the values remain indicative of implant quality. Despite the delivery of the majority of dose with the arm down, it is reasonable to use CT scans taken in the arm-up position for postplanning.
Adjuvant radiotherapy (aRT) can improve biochemical progression-free survival in patients with high-risk features (HRF) after radical prostatectomy (RP). Guidelines from Alberta and the Genitourinary ...Radiation Oncologists of Canada (GUROC) recommend that patients with HRF be referred to radiation oncologists (RO) based on the findings from three randomized, controlled trials (RCT). Our study examines the impact of these recommendations both pre- (2005) and post- (2012) publication of RCT and GUROC guideline establishment.
Patients undergoing RP during 2005 and 2012 were identified from the provincial cancer registry. Charts were retrospectively reviewed and variables of interest were linked to the registry data. RO referral patterns for each year were determined and variables influencing referral (extracapsular extension, positive margin, seminal vesicle invasion, and post-RP prostate-specific antigen PSA) were compared.
Median time to referral was 26.4 months in 2005 compared to 3.7 months 2012 (p<0.001). Among patients referred post-RP, a higher proportion was referred within six months in 2012 (21%) as compared to 2005 (13%) (p=0.003). Among eligible patients in 2012, 30% were referred for discussion of aRT compared to 24% in 2005 (p=0.003). There was a marked drop in patients referred for salvage radiation therapy beyond six months and a rise in the number of patients who are never referred.
Despite an increase in referral rates to RO post-RP from 2005-2012, more than 50% of those patients with HRF did not receive a referral. Initiatives aimed at improving multidisciplinary care and guideline adherence should be undertaken.
Nearly 50% of cancer patients undergo radiotherapy. Late radiotherapy toxicity affects quality-of-life in long-term cancer survivors and risk of side-effects in a minority limits doses prescribed to ...the majority of patients. Development of a test predicting risk of toxicity could benefit many cancer patients. We aimed to meta-analyze individual level data from four genome-wide association studies from prostate cancer radiotherapy cohorts including 1564 men to identify genetic markers of toxicity. Prospectively assessed two-year toxicity endpoints (urinary frequency, decreased urine stream, rectal bleeding, overall toxicity) and single nucleotide polymorphism (SNP) associations were tested using multivariable regression, adjusting for clinical and patient-related risk factors. A fixed-effects meta-analysis identified two SNPs: rs17599026 on 5q31.2 with urinary frequency (odds ratio OR 3.12, 95% confidence interval CI 2.08–4.69, p-value 4.16×10−8) and rs7720298 on 5p15.2 with decreased urine stream (OR 2.71, 95% CI 1.90–3.86, p-value=3.21×10−8). These SNPs lie within genes that are expressed in tissues adversely affected by pelvic radiotherapy including bladder, kidney, rectum and small intestine. The results show that heterogeneous radiotherapy cohorts can be combined to identify new moderate-penetrance genetic variants associated with radiotherapy toxicity. The work provides a basis for larger collaborative efforts to identify enough variants for a future test involving polygenic risk profiling.
•SNPs rs17599026 and rs7720298 increase risk of urinary toxicity following radiotherapy in prostate cancer patients.•Data from heterogeneous radiotherapy cohorts can be meta-analyzed to identify genetic variants associated with toxicity.•A SNP-based predictive assay could improve the therapeutic index of radiotherapy and aid in individualization of cancer treatment.
Risk of radiotherapy side-effects in a minority limits doses given to the majority. A test is needed to predict risks so treatments are personalized. Recent whole-genome studies in a few hundred patients found none or one genetic variant increasing side-effect risk. Larger studies are needed, but difficult because treatments differ between centers. Our study of >1500 prostate cancer patients from four centers found two variants. The research shows combining heterogeneous radiotherapy datasets works and larger collaborative efforts identifying enough variants for a future test are worthwhile. As nearly 50% of cancer patients have radiotherapy, our work could benefit many people.
We aimed to determine the impact of clinical practice guidelines (CPG) on rates of radiation oncologist (RO) referral, androgen-deprivation therapy (ADT), radiation therapy (RT), and radical ...prostatectomy (RP) in patients with high-risk prostate cancer (HR-PCa).
All men >18 years, diagnosed with PCa in 2005 and 2012 were identified from the Alberta Cancer Registry. Patient age, aggregated clinical risk group (ACRG) score, Gleason score (GS), pre-treatment prostate-specific antigen (PSA), RO referral, and treatment received were extracted from electronic medical records. Logistic regression modelling was used to examine associations between RO referral rates and relevant factors.
HR-PCa was diagnosed in 261 of 1792 patients in 2005 and 435 of 2148 in 2012. Median age and ACRG scores were similar in both years (p>0.05). The rate of patients with PSA >20 were 67% and 57% in 2005 and 2012, respectively (p=0.004). GS ≤6 was found in 13% vs. 5% of patients, GS 7 in 27% vs. 24%, and GS ≥8 in 59% vs. 71% in 2005 and 2012, respectively (p<0.001). In 2005, RO referral rate was 68% compared to 56% in 2012 (p=0.001), use of RT + ADT was 53% compared to 32% (p<0.001), and RP rate was 9% vs. 17% (p=0.002). On regression analysis, older age, 2012 year of diagnosis and higher PSA were associated with decreased RO referral rates (odds ratios OR 0.49, 95% confidence interval CI 0.39-0.61; OR 0.51, 95% CI 0.34-0.76; and OR 0.64, 95% CI 0.39-0.61), respectively p<0.001).
Since CPG creation in 2005, RO referral rates and ADT + RT use declined and RP rates increased, which demonstrates a need to improve adherence to CPG in the HR-PCa population.
Introduction: Adjuvant radiotherapy (aRT) can improve biochemical progression-free survival in patients with high-risk features (HRF) after radical prostatectomy (RP). Guidelines from Alberta andthe ...Genitourinary Radiation Oncologists of Canada (GUROC) recommend that patients with HRF be referred to radiation oncologists (RO) based on the findings from three randomized, controlled trials(RCT). Our study examines the impact of these recommendations both pre- (2005) and post- (2012) publication of RCT and GUROC guideline establishment.Methods: Patients undergoing RP during 2005 and 2012 were identified from the provincial cancer registry. Charts were retrospectively reviewed and variables of interest were linked to the registry data. RO referral patterns for each year were determined and variables influencing referral (extracapsular extension, positive margin, seminal vesicle invasion, and post-RP prostate-specific antigen PSA) were compared.Results: Median time to referral was 26.4 months in 2005 compared to 3.7 months 2012 (p<0.001). Among patients referred post-RP, a higher proportion was referred within six months in 2012 (21%)as compared to 2005 (13%) (p=0.003). Among eligible patients in 2012, 30% were referred for discussion of aRT compared to 24% in 2005 (p=0.003). There was a marked drop in patients referredfor salvage radiation therapy beyond six months and a rise in the number of patients who are never referred.Conclusions: Despite an increase in referral rates to RO post-RP from 2005–2012, more than 50% of those patients with HRF did not receive a referral. Initiatives aimed at improving multidisciplinary care and guideline adherence should be undertaken.
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