In vitro and in vivo roles of glucocorticoid and vitamin D receptors in the control of neonatal cardiomyocyte proliferative potential.

Cardiomyocyte (CM) proliferative potential varies considerably across species. While lower vertebrates and neonatal mammals retain robust capacities for CM proliferation, adult mammalian CMs lose proliferative potential due to cell-cycle withdrawal and polyploidization, failing to mount a proliferative response to regenerate lost CMs after cardiac injury. The decline of murine CM proliferative potential occurs in the neonatal period when the endocrine system undergoes drastic changes for adaptation to extrauterine life. We recently demonstrated that thyroid hormone (TH) signaling functions as a primary factor driving CM proliferative potential loss in vertebrates. Whether other hormonal pathways govern this process remains largely unexplored. Here we showed that agonists of glucocorticoid receptor (GR) and vitamin D receptor (VDR) suppressed neonatal CM proliferation. We next examined CM nucleation and proliferation in neonatal mutant mice lacking GR or VDR specifically in CMs, but we observed no difference between mutant and control littermates at postnatal day 14. Additionally, we generated compound mutant mice that lack GR or VDR and express dominant-negative TH receptor alpha in their CMs, and similarly observed no increase in CM proliferative potential compared to dominant-negative TH receptor alpha mice alone. Thus, although GR and VDR activation is sufficient to inhibit CM proliferation, they seem to be dispensable for neonatal CM cell-cycle exit and polyploidization in vivo. In addition, given the recent report that VDR activation in zebrafish promotes CM proliferation and tissue regeneration, our results suggest distinct roles of VDR in zebrafish and rodent CM cell-cycle regulation.

Utility of 30-day mortality as a quality metric for palliative radiation treatment: A population-based analysis from Queensland, Australia.

INTRODUCTION: Palliative radiotherapy (PRT) is frequently used to treat symptoms of advanced cancer, however benefits are questionable when life expectancy is limited. The 30-day mortality rate after PRT is a potential quality indicator, and results from a recent meta-analysis suggest a benchmark of 16% as an upper limit. In this population-based study from Queensland, Australia, we examined 30-day mortality rates following PRT and factors associated with decreased life expectancy. METHODS: Retrospective population data from Queensland Oncology Repository was used. Study population data included 22,501 patients diagnosed with an invasive cancer who died from any cause between 2008 and 2017 and had received PRT. Thirty-day mortality rates were determined from the date of last PRT fraction to date of death. Cox proportional hazards models were used to identify factors independently associated with risk of death within 30 days of PRT. RESULTS: Overall 30-day mortality after PRT was 22.2% with decreasing trend in more recent years (P = 0.001). Male (HR = 1.20, 95% CI = 1.13-1.27); receiving 5 or less radiotherapy fractions (HR = 2.97, 95% CI = 2.74-3.22 and HR = 2.17, 95% CI = 2.03-2.32, respectively) and receiving PRT in a private compared to public facility (HR = 1.61, 95% CI = 1.51-1.71) was associated with decreased survival. CONCLUSION: The 30-day mortality rate in Queensland following PRT is higher than expected and there is scope to reduce unnecessarily protracted treatment schedules. We encourage other Australian and New Zealand centres to examine and report their own 30-day mortality rate following PRT and would support collaboration for 30-day mortality to become a national and international quality metric for radiation oncology centres.

Unmet needs in breast cancer survivors are common, and multidisciplinary care is underutilised: the Survivorship Needs Assessment Project.

PURPOSE: The transition from a breast cancer patient to a survivor can be associated with significant physical, psychological, and social challenges. Development of multidisciplinary evidence-based care during the post-treatment period is a key area of cancer research. This study examined survivorship issues, unmet needs and perceptions about care among a cohort of breast cancer survivors. METHODS: Participants were 130 women diagnosed with breast cancer for at least one year, and attending a hospital breast or oncology outpatient clinic. They completed a series of self-report questionnaires assessing demographic and clinical characteristics, unmet needs, severity of survivorship issues, use of multidisciplinary services, clinical benchmarks, survivorship care satisfaction, and suggestions for service improvements. RESULTS: There was an average of 4.9 unmet survivorship needs, with 67% of participants reporting at least one unmet need. Fear of cancer recurrence, stress, coordination of medical care and negative iatrogenic impacts of hormonal treatments were key concerns. The cancer support team typically consisted of medical and nursing staff, and family/friends, and most were satisfied with their survivorship care. There was minimal use of other multidisciplinary clinicians and support groups. Provision of additional dietary and cancer recurrence education, and a written treatment plan were identified as key areas of service improvement. CONCLUSION: Despite high satisfaction ratings, survivorship issues and unmet needs were relatively common, particularly among younger participants. Use of multidisciplinary care was inconsistent and overall underutilised. IMPLICATIONS FOR CANCER SURVIVORS: Ongoing specific evaluation and optimisation of existing models of multidisciplinary survivorship care are essential in meeting the complex needs of breast cancer survivors.

Quality and access - Early experience of implementing a virtual stereotactic chart round across a national network.

INTRODUCTION: Stereotactic radiation therapy is a highly specialised technique which requires careful and structured implementation. As part of a national stereotactic programme implementation, protocols were developed and a national stereotactic chart round was formed, which strongly recommended attendance and presentation of all cases before treatment. Herein, we describe our experiences launching a national chart round and its importance in a stereotactic programme. METHOD: Stereotactic chart rounds were held via videoconference between July 2018 and July 2019. Data collected included attendances, patient-related information including, diagnosis, clinical background, treatment intent, prescribed dose and fractionation and technical approach. Consensus recommendations regarding changes to treatment approaches were also recorded. RESULTS: For the 12 months recorded, there were 1126 attendances, from 144 individual attendees, across 21 locations. In total, 285 cases (237 new cases, and 48 re-presentations) were presented by 27 radiation oncologists (ROs) from 13 different locations. From the cases presented, 65 changes were recommended from 53 patients (22.3%), including 27 (11.4%) changes to contours, 18 (7.6%) changes to dose prescription/fractionation, 9 (3.8%) changes to plan dosimetry, 1 (0.4%) changes to treatment technique and 10 (4.2%) recommendations for which stereotactic radiation therapy was not advised. A significant inverse relationship was found between frequency of recommended changes and the individual RO's stereotactic case load (P < 0.002). CONCLUSION: The implementation of a national stereotactic chart held via videoconference has ensured national protocol compliance across the network of locations. Furthermore, the chart rounds have allowed the entire multidisciplinary team to be provided with mentorship and guidance. Increasing number of cases presented was associated with lower rates of recommended changes highlighting the impact of experience and the need for continued mentorship.

Is prospective MRI mapping of the changes in the volume of the prostate gland in prostate cancer patients undergoing 6 months of neo-adjuvant androgen deprivation therapy a step towards a trial to determine those who may benefit from treatment intensification or extended duration?

INTRODUCTION: Neo-adjuvant androgen deprivation therapy prior to radiotherapy (RT) causes shrinkage of the prostate gland, but the changes in volume have never been mapped over time in detail, nor have the associations between volume reduction and testosterone escape or prostate-specific antigen (PSA) kinetics been determined. METHODS: Fifty consecutive patients with prostate cancer were treated with 6 months of triptorelin prior to definitive RT. The volume of the prostate gland was measured at the outset and every 6-7 weeks thereafter using MRI scans. The volumes were calculated using a planimetric method, and inter-rater reliability was checked. Factors associated with a large initial volume and greater reductions in it were assessed. RESULTS: The median volume at the outset was 45 cc, and the median reductions every 6 weeks thereafter were 23, 18, 9 and 5%. The inter-rater agreement was high (r > 0.9, P < 0.001). There were no baseline clinical factors associated with a high initial prostate volume, but the initial volume was associated with greater volume reduction. Testosterone escape had no effect on the reduction, and changes in volume were not reflected in PSA response kinetics. CONCLUSIONS: Reductions in volume continue throughout a 6-month course of neo-adjuvant therapy but are greatest during the first 6 weeks. Although individualisation of the duration or intensity of the hormone treatment warrants further investigation, the role of prostate gland volume reduction remains uncertain. More detailed studies of tumour volume might be possible if the imaging required was acceptable and accessible to patients.

Evidence for hormonal control of heart regenerative capacity during endothermy acquisition.

Tissue regenerative potential displays striking divergence across phylogeny and ontogeny, but the underlying mechanisms remain enigmatic. Loss of mammalian cardiac regenerative potential correlates with cardiomyocyte cell-cycle arrest and polyploidization as well as the development of postnatal endothermy. We reveal that diploid cardiomyocyte abundance across 41 species conforms to Kleiber's law-the ¾-power law scaling of metabolism with bodyweight-and inversely correlates with standard metabolic rate, body temperature, and serum thyroxine level. Inactivation of thyroid hormone signaling reduces mouse cardiomyocyte polyploidization, delays cell-cycle exit, and retains cardiac regenerative potential in adults. Conversely, exogenous thyroid hormones inhibit zebrafish heart regeneration. Thus, our findings suggest that loss of heart regenerative capacity in adult mammals is triggered by increasing thyroid hormones and may be a trade-off for the acquisition of endothermy.