Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial.

BACKGROUND: Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. METHODS: RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. FINDINGS: Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60-69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0-10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612-0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6-75·7) in the short-course ADT group and 78·1% (74·2-81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. INTERPRETATION: Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. FUNDING: Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society.

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial.

BACKGROUND: Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. METHODS: RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. FINDINGS: Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61-69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1-10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688-1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4-82·5) in the no ADT group and 80·4% (76·6-83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. INTERPRETATION: Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population. FUNDING: Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society.

Impact of spironolactone exposure on prostate cancer incidence amongst men with heart failure: A Pharmacoepidemiological study.

AIMS: Aldosterone has been found to influence cancer cell growth, cell cycle regulation and cell migration, including in prostate cancer cells. Spironolactone is an aldosterone antagonist used for managing chronic heart failure (HF) with known antiandrogenic effects. We examined the effect of spironolactone exposure amongst men with HF on the incidence of prostate cancer. METHODS: This retrospective cohort study utilized provincial clinical and administrative databases from the Manitoba Centre for Health Policy. Incident cases of prostate cancer were identified from the provincial cancer registry, and spironolactone exposure was quantified from pharmacare databases. A multivariable proportional hazards model was used to assess the time-dependent impact of spironolactone exposure on prostate cancer incidence. RESULTS: A total of 18 562 men with newly diagnosed HF from 2007 to 2015 with a median age of 72 years (interquartile range: 61-81) and a median follow-up from HF diagnosis to prostate cancer incidence of 2.7 years (interquartile range: 1.1-4.9) were included. A time-dependent multivariable analysis of spironolactone exposure following HF diagnosis found a reduced the risk of prostate cancer hazard ratio 0.55 (95% confidence interval 0.31-0.98, P = .043). CONCLUSION: Spironolactone exposure significantly reduced the incidence of prostate cancer amongst men with HF. These findings support the plausibility of aldosterone as a promoter of prostate cancer growth and development. Prospective clinical trials are warranted to further assess the role of spironolactone or other mineralocorticoid receptor antagonists as a means to prevent prostate cancer development or as an adjunctive measure to prostate cancer treatments.

Complete genome sequence of ornithogalum virus 3.

Ornithogalum thyrsoides, a widely cultivated bulbous ornamental plant endemic to South Africa, has significant commercial value as a pot plant and for the production of cut flowers. However, infection by viruses threatens the success of commercial cultivation, as symptoms negatively affect the appearance of the plant and flowers. To date, four Ornithogalum-infecting viruses have been reported. Complete genome sequence data are available for three of these viruses, but the genome of the potyvirus ornithogalum virus 3 (OV3) has not been fully sequenced. In this study, the complete sequence of OV3 was determined by high-throughput sequencing (HTS) and validated by Sanger sequencing. Based on recognition of protease cleavage patterns and multiple sequence alignments with closely related viruses, the polyprotein of OV3 was predicted to be proteolytically cleaved to produce 10 mature peptides containing domains conserved in members of the genus Potyvirus. Phylogenetic analysis and species demarcation criteria confirm the previous classification of OV3 as a member of a separate species in this genus. This is the first report of a complete genome sequence of OV3.

Factors Associated with Long-Term Prostate Cancer Survival after Palliative Radiotherapy to a Bone Metastasis and Contemporary Palliative Systemic Therapy: A Retrospective, Population-Based Study.

BACKGROUND: Radiation therapy (RT) is an established palliative treatment for bone metastases; however, little is known about post-radiation survival and factors which impact it. The aim of this study was to assess a population-based sample of metastatic prostate cancer patients receiving palliative radiation therapy to bone metastases and contemporary palliative systemic therapy and identify factors that impact long-term survival. MATERIALS/METHODS: This retrospective, population-based, cohort study assessed all prostate cancer patients receiving palliative RT for bone metastases at a Canadian provincial Cancer program during a contemporary time period. Baseline patient, disease, and treatment characteristics were extracted from the provincial medical physics databases and the electronic medical record. Post-RT Survival intervals were defined as the time interval from the first fraction of palliative RT to death from any cause or date of the last known follow-up. The median survival of the cohort was used to dichotomize the cohort into short- and long-term survivors following RT. Univariable and multivariable hazard regression analyses were performed to identify variables associated with post-RT survival. RESULTS: From 1 January 2018 until 31 December 2019, 545 palliative RT courses for bone metastases were delivered to n = 274 metastatic prostate cancer patients with a median age of 76 yrs (Interquartile range (IQR) 39-83) and a median follow-up of 10.6 months (range 0.2 to 47.9). The median survival of the cohort was 10.6 months (IQR 3.5-25 months). The ECOG performance status of the whole cohort was ≤2 in n = 200 (73%) and 3-4 in n = 67 (24.5%). The most commonly treated sites of bone metastasis were the pelvis and lower extremities n = 130 (47.4%), skull and spine n = 114 (41.6%), and chest and upper extremities n = 30 (10.9%). Most patients had CHAARTED high volume disease n = 239 (87.2%). On multivariable hazard regression analysis, an ECOG performance status of 3-4 (p = 0.02), CHAARTED high volume disease burden (p = 0.023), and non-receipt of systemic therapy (p = 0.006) were significantly associated with worse post-RT survival. CONCLUSION: Amongst metastatic prostate cancer patients treated with palliative radiotherapy to bone metastases and modern palliative systemic therapies, ECOG performance status, CHAARTED metastatic disease burden, and type of first-line palliative systemic therapy were significantly associated with post-RT survival durations.

Metformin for Prevention of Anthropometric and Metabolic Complications of Androgen Deprivation Therapy in Prostate Cancer Patients Receiving Radical Radiotherapy: A Phase II Randomized Controlled Trial.

BACKGROUND: Patients with prostate cancer undergoing treatment with radical radiation therapy (RT) plus androgen deprivation therapy (ADT) experience a constellation of deleterious metabolic and anthropometric changes related to hypogonadism that are associated with increased morbidity and mortality. We assessed the effect of metformin versus placebo to blunt the adverse effects of ADT on body weight, waist circumference, and other metabolic parameters. METHODS AND MATERIALS: This phase 2, multicenter, randomized controlled trial (RCT) randomized normoglycemic men with locally advanced prostate cancer receiving radical RT and ADT (18-36 months) in a 1:1 ratio to receive metformin 500 mg by mouth 3 times a day (for 30-36 months) versus identical placebo. RESULTS: From December 2015 to October 2019, 83 men were randomized with median follow-up of 23 months. Baseline mean body mass Index (BMI) of the cohort was 30.2 (range 22.2-52.5). Change in mean weight relative to baseline was lower among men who received metformin compared with placebo at 5 months (-1.80 kg, P = .038), but was not significant with longer follow-up (1 year: +0.16 kg, P = .874). Although participants on ADT had increases in waist circumference in both study arms, metformin did not significantly reduce these changes (1 year: +2.79 cm (placebo) versus +1.46 cm (metformin), P = .336). Low-density lipoprotein (LDL) cholesterol was lower in the metformin arm (-0.32 mmol/L) compared with the placebo arm (-0.03 mmol/L) at 5 months (P = .022), but these differences were not significant with longer follow-up (1 year: -0.17 mmol/L vs -0.19 mmol/L, P = .896). There were no differences in HbA1C, triglyceride, high-density lipoprotein (HDL) cholesterol, and total cholesterol by study arm. CONCLUSIONS: Men receiving radical RT and ADT gained weight and had increases in waist circumference over time that metformin did not significantly mitigate. Although this study did not observe any preventive effect of metformin on the anthropometric and metabolic complications of ADT, metformin continues to be studied in phase 3 RCTs in this patient population to assess its potential antineoplastic effects.

Social-capital-based mental health interventions for refugees: A systematic review.

With over 80 million people forcibly displaced worldwide, providing safe, healthy, and supportive places for refugees has become an imperative for national governments, aid organizations, and host communities. While much has been written about the needs of these displaced people, organizations and practitioners tend to focus on essential material needs, medical care, and food and water provisioning. Yet a growing body of evidence points to the potential role of social capital - the bonding, bridging, and linking social ties that connect us to one another - as a critical resource for these refugees. We have little data about social capital interventions at individual and community levels to assist with mental health for this vulnerable population, and even less methodical evidence about such interventions' impact. This systematic review analyzes nearly 400 articles to find patterns in the literature on how social-capital-based interventions can improve the mental health of refugees. Within the studies of interventions that met our filtering criteria, the reinforcement or creation of social capital, especially bridging and linking types, serves as a crucial resource to help this vulnerable group. Specifically, our review showed that community and multilevel social capital interventions are key to curbing mental health symptoms among refugees. Given this scanty evidence base among a group so vulnerable to mental health problems, this review serves as an explicit invitation for researchers to further examine social capital interventions among refugees.

Do Sustainable Palliative Single Fraction Radiotherapy Practices Proliferate or Perish 2 Years after a Knowledge Translation Campaign?

In early 2017, the Canadian Partnership Against Cancer and CancerCare Manitoba undertook a comprehensive knowledge translation (KT) campaign to improve the utilization of single fraction radiotherapy (SFRT) over multiple fraction radiotherapy (MFRT) for palliative management of bone metastases. The campaign significantly increased short-term SFRT utilization. We assess the time-dependent effects of KT-derived SFRT utilization 12-24 months removed from the KT campaign in a Provincial Cancer Program. This study identified patients receiving palliative radiotherapy for bone metastases in Manitoba in the 2018 calendar year using the provincial radiotherapy database. The proportion of patients treated with SFRT in 2018 was compared to 2017. Logistic regression analyses identified risk factors associated with MFRT receipt. In 2018, 1008 patients received palliative radiotherapy for bone metastasis, of which 63.3% received SFRT, a small overall increase in SFRT use over 2017 (59.1%). However, 41.1% of ROs demonstrated year-over-year decreases in SFRT utilization, indicative of a time-dependent loss of SFRT prescription habits derived from KT. Although SFRT use increased slightly overall in 2018, evidence of compliance fatigue was observed, suggestive of a time-perishing property of RO prescription behaviours derived from KT methodologies. Verification of the study's findings in larger cohorts would be beneficial. These findings highlight the need for additional longitudinal KT reinforcement practices in the years following KT campaigns.

Further evidence of the relationship between case typicality and diagnostic performance: implications for medical education.

We have produced further evidence demonstrating that DDx performance is a function of a test case's typicality. Medical educators might consider exploring how cognitive scientists have used the typicality assumption to investigate and enhance the instruction and assessment of subjects engaged in other classification tasks. Further substantiation of the applicability and utility of the assumptions making up the abstraction and exemplar theories used to explain DDx performance could serve as the basis for effective and efficient curricular reforms in medical education.

A sequential procedure for implementing a computer-based information system.

A sequential procedure is presented for the foodservice manager to follow when considering initial implementation of a computer-based information system (CBIS). A feasibility study is recommended as a first step to analyze the information desired and resources available in order to determine objectives of the proposed CBIS. Alternative CBIS design plans should then be evaluated against critical success factors to determine the direction of initial CBIS efforts. Application software, which provides needed support, then determines the hardware needed. Information about vendors and the suitability of the CBIS to meet needs should be determined next. The following management procedures are suggested: utilization of project management skills, identification of roles for the project team members, and initiation of a phased implementation strategy. Finally, to ensure control of the CBIS project, evaluation and documentation are advised.

Characterization and interconversion of polymorphs of premafloxacin, a new quinolone antibiotic.

The quinolone antibiotic premafloxacin crystallizes in at least five solid modifications, including three anhydrous phases (Forms I-III), a hydrate, and a methanolate. The anhydrous phases were studied by optical microscopy, X-ray powder diffraction, HPLC, hot-stage microscopy, dynamic moisture sorption gravimetry, differential scanning calorimetry, thermal gravimetry, and solution and isothermal calorimetry. Dry samples of Form I converted to Form II and ultimately to Form III through a sequence of melts and recrystallizations. Form III was stable to its melting temperature near 200 degrees C. Humidified samples of Form I converted directly to Form III via a moisture-mediated solid-state phase transformation at temperatures as low as 40 degrees C. The calorimetric and solubility data confirmed that Form III was lower in free energy and enthalpy than Form I at room temperature. Our investigation revealed that Form I was not crystallized directly from solution. Rather, Form I was the product of facile solid-state desolvation of the methanol solvate.

In-plant considerations for off-site emergency response to reactor accidents.

This study develops in-plant decision criteria for immediate off-site emergency-response implementation during severe accidents at nuclear power reactors. Decision criteria are defined based on reactor-accident physical processes, in-plant accident monitoring information, and results of consequence calculations performed to determine the effectiveness of offsite protective measures vs the time of their implementation. A simple plant information management scheme is developed based on generic PWR considerations.

Surface characterizations of spin-coated films of ethylcellulose and hydroxypropyl methylcellulose blends.

Films of pure ethylcellulose (EC) and hydroxypropyl methylcellulose (HPMC) polymers and EC/HPMC blends were prepared from solutions by spin coating where isopropyl alcohol (IPA), water, and IPA/water cosolvent were used as solvents. Surface structures of the films were investigated using optical microscopy, atomic force microscopy (AFM), and Raman mapping and spectroscopy. For the films prepared from EC/HPMC blend solutions using the IPA/water cosolvent, different domain structures such as islands or pits and phase separation between EC and HPMC were observed by optical microscopy and AFM. The nature of the polymer components on the surface of the films was identified by Raman mapping and spectroscopy. Experimental results also indicated that polymer composition, solvent, and temperature during spin coating had significant impacts on surface structures of the films.

Pseudoaneurysm complicating knee arthroscopy.

Pseudoaneurysm formation is a rare complication of knee arthroscopy. Cases reported in the literature have involved the popliteal, superior and inferior medial geniculate, and the inferior lateral geniculate arteries. These cases have all been described as presenting within 2 to 3 weeks of the arthroscopic procedure. Described here are two unique cases, the first a delayed presentation and the second involving the recurrent anterior tibial artery.