Long-term Outcomes Following Active Surveillance of Low-grade Prostate Cancer: A Population-based Study Using a Landmark Approach.

PURPOSE: Active surveillance is widely used to manage low-risk prostate cancer, but population-level long-term outcomes are limited. Our objective was to determine long-term population-level oncological outcomes in active surveillance patients. A secondary objective examined the active surveillance discontinuation rate. MATERIALS AND METHODS: In this retrospective, population-based study using linked administrative databases from Ontario, Canada, we identified low-grade prostate cancer patients managed with active surveillance or initial treatment between 2002-2014. The 10- and 15-year metastasis-free survival, overall survival, and cancer-specific survival were compared between active surveillance and initial treatment. A landmark of 24 months was selected for the primary analysis. Long-term outcomes were examined using multivariable proportional hazards models and a propensity-based approach. RESULTS: The cohort consisted of 21,282 low-grade prostate cancer patients with a median follow-up of 9.8 years. At 10-year follow-up the survival rate of remaining on active surveillance was 39%, metastasis-free survival was 94.2%, overall survival 88.7%, and cancer-specific survival 98.1%. In adjusted models active surveillance was associated with higher risk of metastasis (HR 1.34, 95%CI 1.15-1.57), overall mortality (HR 1.12, 95%CI 1.01-1.24), and prostate cancer-specific mortality (HR 1.66, 95%CI 1.15-2.39) compared to initial treatment. Survival analysis using 7,525 propensity-matched pairs was consistent with the primary analysis for metastasis-free survival, overall survival and cancer-specific survival. CONCLUSIONS: In this large population-based study of long-term outcomes in men with low-grade prostate cancer, active surveillance is associated with excellent long-term metastasis-free survival and overall survival. However, long-term cancer-specific survival was slightly inferior (1% worse at 10 years with active surveillance), and this must be balanced against known harms of overtreatment.

Multimodal Biomarkers That Predict the Presence of Gleason Pattern 4: Potential Impact for Active Surveillance.

PURPOSE: Latent grade group ≥2 prostate cancer can impact the performance of active surveillance protocols. To date, molecular biomarkers for active surveillance have relied solely on RNA or protein. We trained and independently validated multimodal (mRNA abundance, DNA methylation, and/or DNA copy number) biomarkers that more accurately separate grade group 1 from grade group ≥2 cancers. MATERIALS AND METHODS: Low- and intermediate-risk prostate cancer patients were assigned to training (n=333) and validation (n=202) cohorts. We profiled the abundance of 342 mRNAs, 100 DNA copy number alteration loci, and 14 hypermethylation sites at 2 locations per tumor. Using the training cohort with cross-validation, we evaluated methods for training classifiers of pathological grade group ≥2 in centrally reviewed radical prostatectomies. We trained 2 distinct classifiers, PRONTO-e and PRONTO-m, and validated them in an independent radical prostatectomy cohort. RESULTS: PRONTO-e comprises 353 mRNA and copy number alteration features. PRONTO-m includes 94 clinical, mRNAs, copy number alterations, and methylation features at 14 and 12 loci, respectively. In independent validation, PRONTO-e and PRONTO-m predicted grade group ≥2 with respective true-positive rates of 0.81 and 0.76, and false-positive rates of 0.43 and 0.26. Both classifiers were resistant to sampling error and identified more upgrading cases than a well-validated presurgical risk calculator, CAPRA (Cancer of the Prostate Risk Assessment; P < .001). CONCLUSIONS: Two grade group classifiers with superior accuracy were developed by incorporating RNA and DNA features and validated in an independent cohort. Upon further validation in biopsy samples, classifiers with these performance characteristics could refine selection of men for active surveillance, extending their treatment-free survival and intervals between surveillance.

An online Sexual Health and Rehabilitation eClinic (TrueNTH SHAReClinic) for prostate cancer patients: a feasibility study.

PURPOSE: The primary objective was to determine the feasibility of implementing the TrueNTH SHAReClinic as a pan-Canadian sexual health and rehabilitation intervention for patients treated for localized prostate cancer. METHODS: The feasibility study was designed to evaluate the accessibility and acceptability of the intervention. Participants from five institutions across Canada were enrolled to attend one pre-treatment and five follow-up online clinic visits over 1 year following their prostate cancer (PC) treatment. RESULTS: Sixty-five patients were enrolled in the intervention. Website analytics revealed that 71% completed the intervention in its entirety, including the educational modules, with an additional 10% completing more than half of the intervention. Five thousand eighty-three views of the educational modules were made along with 654 views of the health library items. Over 1500 messages were exchanged between participants and their sexual health coaches. At 12 months, the intervention received an overall average participant rating of 4.1 out of 5 on a single item satisfaction measure. CONCLUSION: Results support the TrueNTH SHAReClinic as highly acceptable to participants as defined by intervention adherence and engagement. The TrueNTH SHAReClinic demonstrated promise for being a feasible and potentially resource-efficient approach to effectively improving the sexual well-being of patients after PC treatment.

Factors Associated with Discontinuation of Active Surveillance among Men with Low-Risk Prostate Cancer: A Population-Based Study.

PURPOSE: The purpose of this study was to describe the uptake, discontinuation and variation of active surveillance (AS) by provider and patient level characteristics. MATERIALS AND METHODS: This observational, population-based study used linked administrative databases and pathology reports to identify all men diagnosed with Gleason score ≤6 prostate cancer (PC) between January 1, 2008 and December 31, 2014 in Ontario, Canada. The Cochran-Armitage test was used for AS trend over time. Treatment-free survival was estimated using cumulative incidence function. Factors associated with discontinuation of AS were evaluated using Cox proportional hazard models. RESULTS: Active surveillance was the initial management strategy for 8,541 cases (51%). Use of AS significantly increased from 38% in 2008 to 69% in 2014 (p=0.001). Men on AS were significantly older (64 years, SD 8.0) than those on initial treatment (62 years, SD 7.7; p=0.001). After a median followup of 48 months, 4,337 (51%) patients had discontinued AS. Treatment-free survival for AS patients at 1, 3, and 5 years were 85%, 58% and 52%, respectively. Median time to definitive treatment after initial AS was 16 months (IQR 11-25 months). Factors associated with AS discontinuation were younger age at diagnosis, year of diagnosis, higher comorbidities, treatment at academic center, treatment by physician and institution in the highest volume tertile, and adverse cancer-specific characteristics (higher prostate specific antigen [PSA], higher number of positive cores and higher percentage of core involvement at diagnosis). CONCLUSIONS: Although the uptake of AS significantly increased over time, there has been a relatively high rate of discontinuation over 5 years. Factors associated with transition to definitive treatment were younger age, care provided by higher volume physicians and institutions, higher PSA and greater PC volume at diagnosis. These results may help guide policy making, developing quality indicators, and developing targeted continued education for physician and patients embarking on AS to establish realistic expectations.

Real-World Practice Patterns and Predictors of Continuous versus Intermittent Androgen Deprivation Therapy Use for Prostate Cancer in Older Men.

PURPOSE: Phase-III randomized control trial evidence suggests intermittent androgen deprivation therapy (IADT) is not significantly inferior to continuous androgen deprivation therapy (ADT) for patients with prostate cancer (PC). However, clinical practice and guidelines differ in their recommendations. We evaluate real-world utilization and practice patterns of IADT. MATERIALS AND METHODS: Ontario men ≥65 years of age with PC who initiated ADT for ≥3 months were identified (1997-2017). Lapses in ADT ≥6 months (initial gap) and ≥3 months (subsequent gaps) were used to classify IADT. Neoadjuvant/adjuvant therapy was excluded. Disease stage adjustment was completed for patients with likely metastatic disease based on de novo presentation with ADT. Patient and physician predictors of IADT were analyzed using multivariable logistic regression. RESULTS: We identified 8,544 patients with 1,715 having previously received local therapy. Among all patients, 16.4% received IADT. This ranged from 11.4%-24.8% across health-planning regions and increased to 26.6% in those with previous local therapy. Mean followup was 8.3 years. Patients with prior local therapy (OR 1.85, 95% CI 1.59-2.17, p <0.001) and those in the highest income quintile (OR 1.32, 95% CI 1.08-1.60, p=0.005) had increased odds of receiving IADT. Radiation oncologists were more likely to use IADT than urologists (OR 1.99, 95% CI 1.59-2.50, p <0.001), as were physicians with more experience (≥10 years in practice: OR 1.44, 95% CI 1.11-1.88, p=0.007). In specialty-stratified analyses, case volume was significantly associated with IADT for radiation oncologists (highest quartile: OR 1.73, 95% CI 1.14-2.62, p=0.009). CONCLUSIONS: IADT remains underutilized for patients with PC who ≥65 years of age with only 1 in 4 to 1 in 6 eligible patients receiving this form of care. Clinical, sociodemographic and physician characteristics play an important role in treatment selection.

Risk perception and psychological morbidity in men at elevated risk for prostate cancer.

OBJECTIVE: As prostate-specific antigen (psa) makes prostate cancer (pca) screening more accessible, more men are being identified with conditions that indicate high risk for developing pca, such as elevated psa and high-grade intraepithelial neoplasia (hgpin). In the present study, we assessed psychological well-being and risk perception in individuals with those high-risk conditions. METHODS: A questionnaire consisting of a psychological symptom survey, a trait risk-aversion survey, and a cancer-specific risk perception survey was administered to 168 patients with early-stage localized pca and 69 patients at high risk for pca (n = 16 hgpin, n = 53 psa > 4 ng/mL). Analysis of variance was used to examine differences in psychological well-being and appraisal of risk between the groups. RESULTS: Compared with the pca group, the high-risk group perceived their risk of dying from something other than pca to be significantly lower (p = 0.007). However, pca patients reported significantly more clinically important psychological symptoms. CONCLUSIONS: The identification of prostate conditions that predict progression to cancer might not result in the psychological symptoms commonly experienced by pca patients, but does appear to be related to a distorted perception of the disease's mortal risk. Patients with pca experience reduced psychological well-being, but better understand the risks of pca recurrence and death. Education on the risks and outcomes of pca can help at-risk men to view health assessments with reduced worry.

Opioid Use After Nephrectomy for Kidney Cancer in Ontario: A Population-Based Study.

OBJECTIVE: To compare the odds of early and prolonged post-operative opioid use in patients undergoing minimally invasive surgery (MIS) vs open surgery for nephrectomy. METHODS: For opioid-naïve patients in Ontario who underwent nephrectomy for kidney cancer (1994-2017, n = 7900), post-discharge opioid use was determined by prescriptions in the Ontario Drug Benefit database (age ≥65 years) and the Narcotics Monitoring System (all patients from 2012). Early opioid use was defined as ≥1 prescription 1-90 days after surgery. Two separate definitions of prolonged opioid use were examined: (1) prescription(s) for ≥60 days during post-operative days 90-365; (2) ≥1 prescriptions between both of: 1-90 days AND 91-180 days after surgery. Predictors of opioid use were assessed using multivariable generalized estimating equation logistic regression, accounting for surgeon clustering. RESULTS: Overall, 67.4% of patients received early opioid prescriptions; however, prolonged use was low, ranging from 1.6 to 4.4% of patients depending on the definition. In multivariable analysis, open nephrectomy was associated with higher odds of early opioid use compared to MIS nephrectomy (Odds Ratio [OR] 1.36, 95% Confidence Interval [CI] 1.19-1.55). Surgery type was not significantly associated with prolonged opioid use for either definition (OR 1.22, CI 0.79-1.89 and OR 1.06, CI 0.83-1.35). CONCLUSIONS: In this population-level study of patients undergoing nephrectomy for kidney cancer, patients who received open surgery were at increased odds of receiving early post-operative opioids compared to MIS. Prolonged opioid use was low overall and was not significantly with associated with type of surgery.

Salvage radical prostatectomy following primary high intensity focused ultrasound for treatment of prostate cancer.

PURPOSE: High intensity focused ultrasound for the treatment of primary prostate cancer is increasing in a subset of men seeking definitive treatment with reduced morbidity. We review outcomes in men undergoing salvage radical prostatectomy after failed whole gland high intensity focused ultrasound. MATERIALS AND METHODS: Prospective data were collected for men presenting with an increasing prostate specific antigen and biopsy proven prostate cancer after high intensity focused ultrasound from 2007 to 2010 who underwent salvage open radical prostatectomy with a 22-month median followup, including prostate specific antigen, prostate volume, pathology results, continence and erectile function. RESULTS: Data for 15 men were available, including median age 64 years (IQR 55-69), Gleason score before high intensity focused ultrasound of 6 (8), Gleason score 7 (7), median cores positive 39% (IQR 17%-63%) and median prostate specific antigen 7 ng/ml (IQR 5-8). Whole gland high intensity focused ultrasound achieved median nadir prostate specific antigen 1.1 ng/ml (IQR 0.5-3.1). Biopsy after high intensity focused ultrasound demonstrated Gleason score 6 (in 3 patients), 7 (9) and 8/9 (3), and 42% (IQR 25%-50%) cores positive and a median time from high intensity focused ultrasound to radical prostatectomy of 22 months (IQR 7-26). Perioperative morbidity was limited to 1 transfusion in a patient with a rectal injury. Pathologically extensive periprostatic fibrosis was found with persistent prostate cancer, as pT3 disease (in 9 of 14), Gleason scores 6 (2), 7 (9) and 8 of 9 (4), with focally positive margins in 3 of 11 (pT3a). Postoperative prostate specific antigen was unrecordable in 14 of 15 patients with further treatment in 2. Postoperative continence (more than 12 months of followup) yielded no pad use in 6 of 10 men with universally poor erectile function. CONCLUSIONS: Radical prostatectomy as salvage is feasible for men in whom high intensity focused ultrasound failed, but with a higher morbidity than for primary surgery. Pathology results are alarming given the number of cases with extraprostatic extension yet early followup data suggest acceptable oncologic control. These results should be factored in when counseling men who wish to undergo primary high intensity focused ultrasound.

Recurrent ectopic pregnancy on tubal remnant treated by laparoscopic resection: loop and stitch.

Ectopic pregnancies occur in about 1-2 % of all pregnancies, with a high rate of maternal mortality due to bleeding caused by the rupture of the ectopic pregnancy. Ipsilateral ectopic pregnancy on a tubal remnant after salpingectomy is rare and it is associated with a higher mortality rate when compared to other ectopic pregnancies. Diagnosis and treatment of these pregnancies can be difficult, requiring a multidisciplinary management to plan the best treatment for the patient. The objective of this video is to show the laparoscopic removal of a tubal pregnancy on the stump of a previous salpingectomy with the application of three laparoscopic rings/endoloops ® to isolate the tubal portion from the uterus.

Step-by-step surgical procedures for a correct identification of the sentinel lymph node in endometrial cancer.

BACKGROUND: In patients with endometrial cancer, the common method for assessing the status of lymph nodes (LN) is lymphadenectomy. The sentinel lymph node (SLN) biopsy is a revolutionary concept and it will play an increasingly important role in surgical practice. The surgical technique of the sentinel lymph node is less destructive than lymphadenectomy, and it requires less anatomical knowledge. METHODS: Step by step technique of cervical injection, the preparation of the anatomical spaces and the identification of the main structures to detect and remove the SLN safely in patients affected by endometrial cancer stage IA. RESULTS: We identify the three different lymphatic pathways drainage from the uterine cervix and show how anatomical retroperitoneal knowledge is essential for the safe dissection of anatomical spaces. In literature it is reported that in about 9% of cases the SLN is located at the lumbo-aortic level, so it is clear how important it is to know the anatomy to follow the highlighted lymph pathway to identify first lymph node absorber of the drainage. CONCLUSION: Anatomical knowledge and the correct preparation of the anatomical spaces make the identification of the sentinel lymph node safe and feasible.

Long-term use of 5-alpha-reductase inhibitors is safe and effective in men on active surveillance for prostate cancer.

BACKGROUND: Although 5-alpha-reductase inhibitors (5ARIs) have been shown to benefit men with prostate cancer (PCa) on active surveillance (AS), their long-term safety remains controversial. Our objective is to describe the long-term association of 5ARI use with PCa progression in men on AS. MATERIALS/SUBJECTS AND METHODS: The cohort of men with low-risk PCa was derived from a prospectively maintained AS database at the Princess Margaret (1995-2016). Pathologic, grade, and volume progression were the primary end points. Kaplan-Meier time-to-event analysis was performed and Cox proportional hazards regression was used to determine predictors of progression where 5ARI exposure was analyzed as a time-dependent variable. Patients who came off AS prior to any progression events were censored at that time. RESULTS: The cohort included 288 men with median follow-up of 82 months (interquartile range: 37-120 months). Among non-5ARI users (n = 203); 114 men (56.2%) experienced pathologic progression compared with 24 men (28.2%) in the 5ARI group (n = 85), (p < 0.001). Grade and volume progression were higher in the non-5ARI group compared with the 5ARI group (n = 82; 40.4% vs. n = 19; 22.4% respectively, p = 0.003 for grade progression; n = 87; 43.1% and n = 15; 17.7%, respectively for volume progression p < 0.001). Lack of 5ARI use was independently positively associated with pathologic progression (HR: 2.65; CI: 1.65-4.24), grade progression (HR: 2.75; CI: 1.49-5.06), and volume progression (HR: 3.15; CI: 1.78-5.56). The frequency of progression to high-grade (Grade Group 4-5) tumors was not significantly different between the groups. CONCLUSIONS: Use of 5ARIs diminished both grade and volume progression without an increased risk of developing Grade Groups 4-5 disease.

Complex surgery and perioperative systemic therapy for genitourinary cancer of the retroperitoneum.

Objective: The purpose of the present guideline is to recommend surgical or systemic treatment for metastatic testicular cancer; T3b or T4, or node-positive, and metastatic renal cell cancer (rcc); and T3, T4, or node-positive upper tract urothelial (utuc) cancer. Methods: Draft recommendations were formulated based on evidence obtained through a systematic review of randomized controlled trials, comparative retrospective studies, and guideline endorsement. The draft recommendations underwent an internal review by clinical and methodology experts, and an external review by clinical practitioners. Results: The primary literature search yielded eight guidelines, five systematic reviews, and twenty-seven primary studies that met the eligibility criteria. Conclusions: Cytoreductive nephrectomy should no longer be considered the standard of care in patients with T3b or T4, or node-positive, and metastatic rcc. Eligible patients should be treated with systemic therapy and have their primary tumour removed only after review at a multidisciplinary case conference (mcc). Adjuvant sunitinib after surgery is not recommended. Patients with venous tumour thrombus should be considered for surgical intervention. Patients with T3, T4, or node-positive utuc should have their tumour removed without delay. Decisions concerning lymph node dissection should be done at a mcc and be based on stage, expertise, and imaging. Adjuvant systemic treatment is recommended for resected high-risk utuc. Patients with metastasis-positive testicular cancer with residual tumour after systemic treatment should be treated at specialized centres. For all complex retroperitoneal surgeries, the evidence shows that higher-volume centres are associated with lower rates of procedure-related mortality, and patients should be referred to higher-volume centres for surgical resection.

The Drosophila saxophone gene: a serine-threonine kinase receptor of the TGF-beta superfamily.

The Drosophila decapentaplegic (dpp) gene encodes a transforming growth factor-beta (TGF-beta)-like protein that plays a key role in several aspects of development. Transduction of the DPP signal was investigated by cloning of serine-threonine kinase transmembrane receptors from Drosophila because this type of receptor is specific for the TGF-beta-like ligands. Here evidence is provided demonstrating that the Drosophila saxophone (sax) gene, a previously identified female sterile locus, encodes a TGF-beta-like type I receptor. Embryos from sax mothers and dpp embryos exhibit similar mutant phenotypes during early gastrulation, and these two loci exhibit genetic interactions, which suggest that they are utilized in the same pathway. These data suggest that sax encodes a receptor for dpp.

Impact of a novel prioritization framework on clinician-led oncology drug submissions.

Background: In Canada, requests for public reimbursement of cancer drugs are predominately initiated by pharmaceutical manufacturers. Clinician-led submissions provide a mechanism to initiate the drug funding process when industry does not submit a request for funding consideration. Although such requests are resource-intensive to produce, Cancer Care Ontario (cco) has the capacity to facilitate clinician-led submissions. In 2014, cco began developing a cancer drug prioritization framework that allocates resources to systematically address a growing number of clinician-identified funding gaps with clinician-led submissions. Methods: Cancer site-specific drug advisory committees established by cco consist of health care practitioners whose roles include identifying and prioritizing funding gaps. The committees submit their identified gaps to a cross-cancer-site prioritization exercise in which the requests are ranked based on a set of guiding principles derived from health technology assessment. The requests are then sequentially allocated the resources needed to meet submission requirements. Whether the funding gap is of provincial or pan-Canadian relevance determines where the submission is filed for assessment. Results: Since its inception, the cco framework has identified 17 funding gaps in 9 cancer sites. In 4 prioritizations, the framework supported 6 submissions. As of June 2018, the framework had contributed to the eventual funding of more than 9 new drug-indication pairs, with more awaiting funding consideration. Conclusions: The cco prioritization framework has enabled clinicians to effectively and systematically identify, prioritize, and fill funding gaps not addressed by industry. Ultimately, the framework helps to ensure that patients can access evidence-informed and cost-effective therapies. The framework will continue to evolve as it encounters new challenges, including funding requests for rare indications.

The Prostate Cancer Rehabilitation Clinic: a biopsychosocial clinic for sexual dysfunction after radical prostatectomy.

Purpose: The most prevalent intervention for localized prostate cancer (pca) is radical prostatectomy (rp), which has a 10-year relative survival rate of more than 90%. The improved survival rate has led to a focus on reducing the burden of treatment-related morbidity and improving the patient and partner survivorship experience. Post-rp sexual dysfunction (sdf) has received significant attention, given its substantial effect on patient and partner health-related quality of life. Accordingly, there is a need for sdf treatment to be a fundamental component of pca survivorship programming. Methods: Most research about the treatment of post-rp sdf involves biomedical interventions for erectile dysfunction (ed). Although findings support the effectiveness of pro-erectile agents and devices, most patients discontinue use of such aids within 1 year after their rp. Because side effects of pro-erectile treatment have proved to be inadequate in explaining the gap between efficacy and ongoing use, current research focuses on a biopsychosocial perspective of ed. Unfortunately, there is a dearth of literature describing the components of a biopsychosocial program designed for the post-rp population and their partners. Results: In this paper, we detail the development of the Prostate Cancer Rehabilitation Clinic (pcrc), which emphasizes multidisciplinary intervention teams, active participation by the partner, and a broad-spectrum medical, psychological, and interpersonal approach. Conclusions: The goal of the pcrc is to help patients and their partners achieve optimal sexual health and couple intimacy after rp, and to help design cost-effective and beneficial rehabilitation programs.

Impact of Abiraterone Acetate and Enzalutamide on Symptom Burden of Patients with Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer.

AIMS: Treatments and disease burden of metastatic castration-resistant prostate cancer (mCRPC) considerably affect a patient's quality of life. However, patient-reported symptom burden data are still largely insufficient. This study sought to compare the self-reported symptom burden of men with chemotherapy-naive (CN) mCRPC treated with abiraterone acetate (AA) or enzalutamide (EZ) in routine clinical practice. MATERIALS AND METHODS: Between 2011 and 2015, 189 CN-mCRPC patients who had received AA (n = 76) or EZ (n = 113) at the Princess Margaret Cancer Centre were included. The Edmonton Symptom Assessment System (ESAS) score, baseline demographic information, comorbidities, Eastern Cooperative Oncology Group performance status, laboratory data and narcotic analgesic use were recorded for each patient. The minimal clinically important difference was assessed using ±1 point change from baseline for each ESAS symptom. Mixed model for repeated measures (MMRM) was used to estimate and compare the longitudinal ESAS score changes from baseline in AA and EZ groups adjusted for age, baseline ESAS scores, treatment group, treatment duration and time. RESULTS: The median (interquartile range) treatment duration with AA and EZ was 10 (6-16) and 12 (7-18) months, respectively (P = 0.19). Fatigue was rated the most distressing symptom at baseline and following treatment in both groups. There were no statistically significant differences in the proportion of patients with clinically meaningful symptom improvement or worsening after AA or EZ administration in any of the ESAS-based physical and psychological symptoms over time. In MMRM analyses, there were no significant differences in adjusted mean scores from baseline to 3, 6, 9 and 12 months for any of the ESAS items between AA and EZ groups. CONCLUSION: Physical and psychological symptoms assessed by ESAS were comparable in CN-mCRPC men treated with AA or EZ in the real-world clinical setting. Further studies are warranted to confirm these findings.

Bone Health and Bone-targeted Therapies for Prostate Cancer: a Programme in Evidence-based Care - Cancer Care Ontario Clinical Practice Guideline.

AIMS: To make recommendations with respect to bone health and bone-targeted therapies in men with prostate cancer. MATERIALS AND METHODS: A systematic review was carried out by searching MEDLINE, EMBASE and the Cochrane Library from inception to January 2016. Systematic reviews and randomised-controlled trials were considered for inclusion if they involved therapies directed at improving bone health or outcomes such as skeletal-related events, pain and quality of life in patients with prostate cancer either with or without metastases to bone. Therapies included medications, supplements or lifestyle modifications alone or in combination and were compared with placebo, no treatment or other agents. Disease-targeted agents such as androgen receptor-targeted and chemotherapeutic agents were excluded. Recommendations were reviewed by internal and external review groups. RESULTS: In men with prostate cancer receiving androgen deprivation therapy, baseline bone mineral density testing is encouraged. Denosumab should be considered for reducing the risk of fracture in men on androgen deprivation therapy with an increased fracture risk. Bisphosphonates were effective in improving bone mineral density, but the effect on fracture was inconclusive. No medication is recommended to prevent the development of first bone metastasis. Denosumab and zoledronic acid are recommended for preventing or delaying skeletal-related events in men with metastatic castration-resistant prostate cancer. Radium-223 is recommended for reducing symptomatic skeletal events and prolonging survival in men with symptomatic metastatic castration-resistant prostate cancer. CONCLUSIONS: The recommendations represent a current standard of care that is feasible to implement, with outcomes valued by clinicians and patients.

Multiparametric Magnetic Resonance Imaging in the Diagnosis of Prostate Cancer: A Systematic Review.

A systematic review was conducted to investigate the use of multiparametric magnetic resonance imaging (MPMRI) followed by targeted biopsy in the diagnosis of clinically significant prostate cancer (CSPC) and to compare it with transrectal ultrasound-guided (TRUS-guided) systematic biopsy in patients with an elevated risk of prostate cancer who are either biopsy-naive or who have a previous negative TRUS-guided biopsy. MEDLINE, PubMed and EMBASE (1997 to April 2014), the Cochrane Library and six relevant conferences were searched to find eligible studies. Search terms indicative of 'prostate cancer' and 'magnetic resonance imaging' with their alternatives were used. Twelve systematic reviews, 52 full texts and 28 abstracts met the preplanned study selection criteria; data from 15 articles were extracted. In patients with an elevated risk of prostate cancer who were biopsy-naive, MPMRI followed by targeted biopsy could detect 2-13% of CSPC patients whom TRUS-guided systematic biopsy missed; TRUS-guided systematic biopsy could detect 0-7% of CSPC patients whom MPMRI followed by targeted biopsy missed. In patients with an elevated risk of prostate cancer who had a previous negative TRUS-guided biopsy, MPMRI followed by targeted biopsy detected more CSPC patients than repeated TRUS-guided systematic biopsy in all four studies, with a total of 516 patients, but only one study reached a statistically significant difference. In patients with an elevated risk of prostate cancer who are biopsy-naive, there is insufficient evidence for MPMRI followed by targeted biopsy to be considered the standard of care. In patients who had a prior negative TRUS-guided systematic biopsy and show a growing risk of having CSPC, MPMRI followed by targeted biopsy may be helpful to detect more CSPC cases as opposed to a repeat TRUS-guided systematic biopsy.

The tolkin gene is a tolloid/BMP-1 homologue that is essential for Drosophila development.

The Drosophila decapentaplegic (dpp) gene, a member of the transforming growth factor beta superfamily of growth factors, is critical for specification of the embryonic dorsal-ventral axis, for proper formation of the midgut, and for formation of Drosophila adult structures. The Drosophila tolloid gene has been shown to genetically interact with dpp. The genetic interactions between tolloid and dpp suggests a model in which the tolloid protein participates in a complex containing the DPP ligand, its protease serving to activate DPP, either directly or indirectly. We report here the identification and cloning of another Drosophila member of the tolloid/bone morphogenic protein (BMP) 1 family, tolkin, which is located 700 bp 5' to tolloid. Its overall structure is like tolloid, with an N-terminal metalloprotease domain, five complement subcomponents C1r/C1s, Uegf, and Bmp1 (CUB) repeats and two epidermal growth factor (EGF) repeats. Its expression pattern overlaps that of tolloid and dpp in early embryos and diverges in later stages. In larval tissues, both tolloid and tolkin are expressed uniformly in the imaginal disks. In the brain, both tolloid and tolkin are expressed in the outer proliferation center, whereas tolkin has another stripe of expression near the outer proliferation center. Analysis of lethal mutations in tolkin indicate it is vital during larval and pupal stages. Analysis of its mutant phenotypes and expression patterns suggests that its functions may be mostly independent of tolloid and dpp.