Characterization and prediction of OATP1B activity in prostate cancer patients on abiraterone acetate using endogenous biomarker coproporphyrin I.

Organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 are important hepatic transporters. We previously identified OATP1B3 being critically implicated in the disposition of abiraterone. We aimed to further investigate the effects of abiraterone on the activities of OATP1B1 and OATP1B3 utilizing a validated endogenous biomarker coproporphyrin I (CP-I). We utilized OATP1B-transfected cells to characterize the inhibitory potential of abiraterone against OATP1B-mediated uptake of CP-I. Inhibition constant (Ki) was incorporated into our physiologically based pharmacokinetic (PBPK) modeling to simulate the systemic exposures of CP-I among cancer populations receiving either our model-informed 500 mg or clinically approved 1000 mg abiraterone acetate (AA) dosage. Simulated data were compared with clinical CP-I concentrations determined among our 9 metastatic prostate cancer patients receiving 500 mg AA treatment. Abiraterone inhibited OATP1B3- but not OATP1B1-mediated uptake of CP-I in vitro, with an estimated Ki of 3.93 µM. Baseline CP-I concentrations were simulated to be 0.81 {plus minus} 0.26 ng/mL, and determined to be 0.72 {plus minus} 0.16 ng/mL among metastatic prostate cancer patients, both of which were higher than those observed for healthy subjects. PBPK simulations revealed an absence of OATP1B3-mediated interaction between abiraterone and CP-I. Our clinical observations confirmed that CP-I concentrations remained comparable to baseline levels up to 12 weeks post 500 mg AA treatment. Using CP-I as an endogenous biomarker, we identified the inhibition of abiraterone on OATP1B3 but not OATP1B1 in vitro, which was predicted and observed to be clinically insignificant. We concluded that the interaction risk between AA and substrates of OATP1Bs is low. Significance Statement We utilized the endogenous biomarker coproporphyrin I (CP-I) and identified abiraterone as a moderate inhibitor of organic anion transporting polypeptide (OATP) 1B3 in vitro. Subsequent physiologically based pharmacokinetic (PBPK) simulations and clinical observations suggested an absence of OATP1B-mediated interaction between abiraterone and CP-I among prostate cancer patients. This multi-pronged study concluded that the interaction risk between abiraterone acetate and substrates of OATP1Bs is low, demonstrating the application of PBPK-CP-I modelling in predicting OATP1B-mediated interaction implicating abiraterone.

Cardiovascular disease risk assessment and multidisciplinary care in prostate cancer treatment with ADT: recommendations from the APMA PCCV expert network.

PURPOSE: Androgen deprivation therapy (ADT) is the mainstay approach for prostate cancer (PCa) management. However, the most commonly used ADT modality, gonadotropin-releasing hormone (GnRH) agonists, has been associated with an increased risk of cardiovascular disease (CVD). METHODS: The PCa Cardiovascular (PCCV) Expert Network, consisting of multinational urologists, cardiologists and oncologists with expertise in managing PCa, convened to discuss challenges to routine cardiovascular risk assessment in PCa management, as well as how to mitigate such risks in the current treatment landscape. RESULTS: The experts identified several barriers, including lack of awareness, time constraints, challenges in implementing risk assessment tools and difficulties in establishing multidisciplinary teams that include cardiologists. The experts subsequently provided practical recommendations to improve cardio-oncology care for patients with PCa receiving ADT, such as simplifying cardiovascular risk assessment, individualising treatment based on CVD risk categories, establishing multidisciplinary teams and referral networks and fostering active patient engagement. A streamlined cardiovascular risk-stratification tool and a referral/management guide were developed for seamless integration into urologists' practices and presented herein. The PCCV Expert Network agreed that currently available evidence indicates that GnRH antagonists are associated with a lower risk of CVD than that of GnRH agonists and that GnRH antagonists are preferred for patients with PCa and a high CVD risk. CONCLUSION: In summary, this article provides insights and guidance to improve management for patients with PCa undergoing ADT.

Glutathione-S-Transferase Theta 2 (GSTT2) Modulates the Response to Bacillus Calmette-Guérin Immunotherapy in Bladder Cancer Patients.

Glutathione-S-transferases (GST) enzymes detoxify xenobiotics and are implicated in response to anticancer therapy. This study evaluated the association of GST theta 1 (GSTT1), GSTT2, and GSTT2B with Mycobacterium bovis Bacillus Calmette-Guérin (BCG) response in non-muscle-invasive bladder cancer treatment. In vitro assessments of GSTT2 knockout (KO) effects were performed using cell lines and dendritic cells (DCs) from GSTT2KO mice. Deletion of GSTT2B, GSTT1, and single-nucleotide polymorphisms in the promoter region of GSTT2 was analysed in patients (n = 205) and healthy controls (n = 150). Silencing GSTT2 expression in MGH cells (GSTT2BFL/FL) resulted in increased BCG survival (p < 0.05) and decreased cellular reactive oxygen species. In our population, there are 24.2% with GSTT2BDel/Del and 24.5% with GSTT2BFL/FL. With ≤ 8 instillations of BCG therapy (n = 51), 12.5% of GSTT2BDel/Del and 53.8% of GSTT2BFL/FL patients had a recurrence (p = 0.041). With ≥9 instillations (n = 153), the disease recurred in 45.5% of GSTT2BDel/Del and 50% of GSTT2BFL/FL. GSTT2FL/FL patients had an increased likelihood of recurrence post-BCG therapy (HR 5.5 [1.87-16.69] p < 0.002). DCs from GSTT2KO mice produced three-fold more IL6 than wild-type DCs, indicating a robust inflammatory response. To summarise, GSTT2BDel/Del patients respond better to less BCG therapy and could be candidates for a reduced surveillance regimen.

Psychological Health of Surgeons in a Time of COVID-19: A Global Survey.

OBJECTIVE: To assess the degree of psychological impact among surgical providers during the COVID-19 pandemic. SUMMARY OF BACKGROUND DATA: The COVID-19 pandemic has extensively impacted global healthcare systems. We hypothesized that the degree of psychological impact would be higher for surgical providers deployed for COVID-19 work, certain surgical specialties, and for those who knew of someone diagnosed with, or who died, of COVID-19. METHODS: We conducted a global web-based survey to investigate the psychological impact of COVID-19. The primary outcomes were the depression anxiety stress scale-21 and Impact of Event Scale-Revised scores. RESULTS: A total of 4283 participants from 101 countries responded. 32.8%, 30.8%, 25.9%, and 24.0% screened positive for depression, anxiety, stress, and PTSD respectively. Respondents who knew someone who died of COVID-19 were more likely to screen positive for depression, anxiety, stress, and PTSD (OR 1.3, 1.6, 1.4, 1.7 respectively, all P < 0.05). Respondents who knew of someone diagnosed with COVID-19 were more likely to screen positive for depression, stress, and PTSD (OR 1.2, 1.2, and 1.3 respectively, all P < 0.05). Surgical specialties that operated in the head and neck region had higher psychological distress among its surgeons. Deployment for COVID- 19-related work was not associated with increased psychological distress. CONCLUSIONS: The COVID-19 pandemic may have a mental health legacy outlasting its course. The long-term impact of this ongoing traumatic event underscores the importance of longitudinal mental health care for healthcare personnel, with particular attention to those who know of someone diagnosed with, or who died of COVID-19.

Prostate Health Index Density Outperforms Prostate-specific Antigen Density in the Diagnosis of Clinically Significant Prostate Cancer in Equivocal Magnetic Resonance Imaging of the Prostate: A Multicenter Evaluation.

PURPOSE: We compare Prostate Health Index, Prostate Health Index density, and PSA density in predicting clinically significant prostate cancer in MRI-guided prostate biopsy. MATERIALS AND METHODS: This is a multicenter evaluation of prospectively maintained prostate biopsy databases at 10 urology centers. Men with Prostate Health Index and MRI-guided targeted and systematic prostate biopsy performed and without prior prostate cancer diagnosis were included. The additional value of PSA density, Prostate Health Index, and Prostate Health Index density to MRI PI-RADS (Prostate Imaging Reporting & Data System) score was evaluated with multivariable analyses, area under the curve, and decision curve analyses. The proportion of unnecessary biopsies that can be avoided are estimated for clinically significant prostate cancer (International Society of Urological Pathology group ≥2 prostate cancer). RESULTS: A total of 1,215 men were analyzed. Prostate cancer and clinically significant prostate cancer were diagnosed in 51% (617/1,215) and 35% (422/1,215) of men, respectively. Clinically significant prostate cancer was diagnosed in 4.4% (3/68), 15% (72/470), 39% (176/446), and 74% (171/231) of highest PI-RADS score of 2, 3, 4, and 5 lesions, respectively. In multivariable analyses, independent predictors for clinically significant prostate cancer detection included Prostate Health Index (OR 1.04), prostate volume (OR 0.97), and PI-RADS score 4 (OR 2.81) and 5 (OR 8.34). Area under the curve for clinically significant prostate cancer of PI-RADS + Prostate Health Index density (0.85) was superior to PI-RADS + PSA density (0.81), Prostate Health Index density (0.81), Prostate Health Index (0.78), PI-RADS (0.76), PSA density (0.72), and PSA (0.60) in the whole cohort, and the superiority of Prostate Health Index density was also observed in PI-RADS 3 lesions. Decision curve analysis showed Prostate Health Index density achieving the best net clinical benefit in PI-RADS 3 or 4 cases. Among PI-RADS 3 lesions, using cutoffs of PSA density 0.15, Prostate Health Index 38.0, and Prostate Health Index density 0.83 could reduce 58%, 67%, and 72% of unnecessary biopsies, respectively. CONCLUSIONS: Prostate Health Index density outperformed Prostate Health Index or PSA density in clinically significant prostate cancer detection in men with multiparametric MRI performed, and further reduced unnecessary biopsies in PI-RADS 3 lesions.

Molecular profiling reveals a tumor-promoting phenotype of monocytes and macrophages in human cancer progression.

Monocytes and macrophages are major components of the tumor microenvironment, but their contributions to human cancer are poorly understood. We used molecular profiling combined with functional assays to investigate the role of these cells in human renal cell carcinoma (RCC). Blood monocytes from RCC patients displayed a tumor-promoting transcriptional profile that supported functions like angiogenesis and invasion. Induction of this protumor phenotype required an interleukin-1 receptor (IL-1R)-dependent mechanism. Indeed, targeting of IL-1-IL-1R axis in a human RCC xenograft model abrogated the protumor phenotype of tumor-associated macrophages (TAMs) and reduced tumor growth in vivo. Supporting this, meta-analysis of gene expression from human RCC tumors showed IL1B expression to correlate with myelomonocytic markers, protumor genes, and tumor staging. Analyzing RCC patient tumors confirmed the protumor phenotype of TAMs. These data provide direct evidence for a tumor-promoting role of monocytes and macrophages in human cancer and indicate IL-1-IL-1R as a possible therapeutic target.

The impact of body mass index on oncological and surgical outcomes of patients undergoing nephrectomy: a systematic review and meta-analysis.

OBJECTIVE: To perform a systematic review and meta-analysis to evaluate the impact of body mass index (BMI) on oncological (primary) and surgical (secondary) outcomes of patients who underwent nephrectomy, as obesity or high BMI is a known risk factor for renal cell carcinoma (RCC) and predictor of poorer outcomes. METHODS: Studies were identified from four electronic databases from database inception to 2 June 2021, according to the Preferred Reporting Items for Systematic Review and Meta-analysis statement. The review protocol was registered in the International Prospective Register of Systematic Reviews with the identification number: CRD42021275124. RESULTS: A total of 18 studies containing 13 865 patients were identified for the final meta-analysis. Regarding oncological outcomes, higher BMI predicted higher overall survival (BMI >25 vs BMI <25 kg/m2 : hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.58-0.85), cancer-specific survival (BMI >25 vs BMI <25 kg/m2 : HR 0.60, 95% CI 0.50-0.73; BMI 25-30 vs BMI <25 kg/m2 : HR 0.46, 95% CI 0.23-0.95; BMI >30 vs BMI <25 kg/m2 : HR 0.50, 95% CI 0.36-0.69), and recurrence-free survival rates (BMI >25 vs BMI <25 kg/m2 : HR 0.72, 95% CI 0.63-0.82; BMI 25-30 vs BMI <25 kg/m2 : HR 0.59, 95% CI 0.42-0.82). Those with a lower BMI fared better in surgical outcomes, such as operation time and warm ischaemic time, although the absolute difference was minimal and unlikely to be clinically significant. There was no difference between groups for length of hospital stay, intraoperative or postoperative complications, blood transfusion requirements, and conversion to open surgery. CONCLUSION: Our study suggests that a higher BMI is associated with improved long-term oncological survival and similar perioperative outcomes as a lower BMI. More research into the underlying biological and physiological mechanisms will enable better understanding of the effect of BMI, beyond mere association, on post-nephrectomy outcomes.

5-alpha reductase inhibitors and MRI prostates: actively reducing prostate sizes and ambiguity.

BACKGROUND: Magnetic resonance imaging (MRI) scans are increasingly first-line investigations for suspected prostate cancer, and essential in the decision for biopsy. 5-alpha reductase inhibitor (5-ARI) use has been shown to reduce prostate size and prostate cancer risk. However, insufficient data exists on how 5-ARI use affects MRI findings and yield of biopsy. This study explores the differences in imaging and prostate cancer diagnoses between patients receiving and not receiving 5-ARI therapy. METHODS: From 2015 to 2020, we collected retrospective data of consecutive patients undergoing prostate biopsy at one centre. We included patients who were biopsy-naïve, had prior negative biopsies, or on active surveillance for low-grade prostate cancer. Clinical and pathological data was collected, including 5-ARI use, Prostate Imaging Reporting and Data System (PIRADS) classification and biopsy results. RESULTS: 351 men underwent saturation biopsy with or without targeted biopsies. 54 (15.3%) had a history of 5-ARI use. On mpMRI, there was no significant difference between the 5ARI and non-5-ARI groups in PIRADS distribution, number of lesions, and lesion location. Significantly fewer cancers were detected in the 5-ARI group (46.3% vs. 68.0%; p < 0.01). There were no significant differences in PIRADS distribution in 5-ARI patients with positive and negative biopsy. CONCLUSION: Our study found significant differences in biochemical, imaging and biopsy characteristics between 5-ARI and non-5-ARI groups. While both groups had similar PIRADS distribution, 5-ARI patients had a lower rate of positive biopsies across all PIRADS categories, which may suggest that the use of 5ARI may confound MRI findings. Further studies on how 5-ARI therapy affects the imaging characteristics of prostate cancer should be performed.

Prostate cancer.

The management of prostate cancer continues to evolve rapidly, with substantial advances being made in understanding the genomic landscape and biology underpinning both primary and metastatic prostate cancer. Similarly, the emergence of more sensitive imaging methods has improved diagnostic and staging accuracy and refined surveillance strategies. These advances have introduced personalised therapeutics to clinical practice, with treatments targeting genomic alterations in DNA repair pathways now clinically validated. An important shift in the therapeutic framework for metastatic disease has taken place, with metastatic-directed therapies being evaluated for oligometastatic disease, aggressive management of the primary lesion shown to benefit patients with low-volume metastatic disease, and with several novel androgen pathway inhibitors significantly improving survival when used as a first-line therapy for metastatic disease. Research into the molecular characterisation of localised, recurrent, and progressive disease will undoubtedly have an impact on clinical management. Similarly, emerging research into novel therapeutics, such as targeted radioisotopes and immunotherapy, holds much promise for improving the lives of patients with prostate cancer.

Utility of serum biomarkers for predicting cancer in patients with previous negative prostate biopsy.

PURPOSE: To review the role of serum biomarkers: prostate-specific antigen (PSA), PSA density (PSAD), free:total PSA ratio, prostate health index (PHI) and PHI density (PHID), along with magnetic resonance imaging (MRI) for identification of clinically significant prostate cancer (PCa), comparing their utility in patients with persistently raised PSA levels after a prior negative prostate biopsy (PNB). METHODS: In this single-centre prospective observational study conducted from September 2015 to October 2020, patients underwent a saturation biopsy via the transperineal route. If a Prostate Imaging Reporting and Data System version 2 (PIRADS) 3 and above lesion was seen on MRI, targeted biopsies were also obtained. Information on clinical history, lesion characteristics, PIRADS classification and follow-up was collected. The sensitivity, specificity and area under curve (AUC) for each of the biomarkers were calculated. RESULTS: 351 men underwent saturation biopsy with or without targeted biopsies. 103 patients had a PNB. Among this PNB cohort, 43 (41.7%) men had a benign outcome, while 60 (58.3%) men had histopathologically diagnosed PCa, of which 41 (39%) were clinically significant. All patients underwent multiparametric MRI scans prior to biopsy. Within this cohort, PHI and PHID had the best abilities to predict for clinically significant PCa with an AUC of 0.73 and 0.70 respectively, compared to 0.65 for PSAD, 0.34 for free:total PSA and 0.56 for PSA. CONCLUSION: A significant proportion of patients are diagnosed with PCa after a PNB. This study shows that PHI and PHI densities may be suitable adjuncts predicting for clinically significant PCa in patients with PNB.

Tumor-targeting albumin nanoparticles as an efficacious drug delivery system and potential diagnostic tool in non-muscle-invasive bladder cancer therapy.

Current intravesical chemotherapy for non-muscle invasive bladder cancer (NMIBC) has limited efficacy due to loss of the instilled agent from urine voiding and the agent's lack of specificity for the tumors. We developed a nanocarrier (txCD47-HNP, ∼100 nm) based on human serum albumin conjugated with a peptide that targets the cluster of differentiation 47 receptor overexpressed on bladder cancer (BC) cells. The IC50 of gemcitabine elaidate (GEM) loaded in the txCD47-HNP was almost an order of magnitude lower than that of free GEM. In a mouse orthotopic BC model, GEM loaded in txCD47-HNP effectively reduced the tumor burden. Tumor cells in BC patients' urine can also be targeted by fluorescence-labeled txCD47-HNP resulting in >83 % of the cells exhibiting fluorescence. Thus, txCD47-HNP can potentially be a theranostic agent in NMIBC management by serving as a targeted drug delivery vehicle as well as an alternative to urine cytology.

Predictive biomarkers of response to bacillus Calmette-Guérin immunotherapy and bacillus Calmette-Guérin failure for non-muscle invasive bladder cancer.

Within the heterogeneous population of patients with bacillus Calmette-Guérin failure, there are clear differences in prognosis and therapy with regard to the timeline when bacillus Calmette-Guérin failure occurred. There are a variety of classifications which include bacillus Calmette-Guérin refractory disease, relapsing, unresponsive, and intolerant. Further profiling of these patients may help to shed light on other forms of therapy that are less radical. We hereby summarize the different biomarkers that predicts for response to bacillus Calmette-Guérin immunotherapy and bacillus Calmette-Guérin failure for non-muscle invasive bladder cancer.

Tryptophan-kynurenine ratio as a biomarker of bladder cancer.

OBJECTIVES: To investigate plasma and urinary kynurenine (KYN)-tryptophan (TRP) ratios in bladder cancer, expression of indoleamine 2,3-dioxygenase 1 (IDO1) in relation to tryptophan 2,3-dioxygenase (TDO2) in bladder tumour, and the correlation of KYN-TRP ratio with bladder tumour burden. METHODS: Metabotyping of the TRP-KYN metabolic axis was performed via a clinical case-control study. Expression of IDO1 and TDO2 was measured in human biopsied tissues. Correlational experiments between KYN-TRP ratio and bladder tumour were performed using a murine orthotopic prostate-specific antigen (PSA)-secreting MB49 bladder cancer model. RESULTS: We established for the first time that plasma TRP level was significantly decreased, while both plasma and urinary KYN-TRP ratios were significantly higher in bladder cancer patients, and expression level of IDO1 but not TDO2 was increased in human bladder tumour. We reported the positive correlation between IDO1 expression, KYN-TRP ratio, normalized PSA to creatinine, and bladder tumour burden in the murine model. CONCLUSION: Kynurenine-tryptophan ratio is a promising surveillance biomarker for bladder cancer, but would require further validation before clinical translation.

Cost-effectiveness of MRI targeted biopsy strategies for diagnosing prostate cancer in Singapore.

BACKGROUND: To evaluate the cost-effectiveness of six diagnostic strategies involving magnetic resonance imaging (MRI) targeted biopsy for diagnosing prostate cancer in initial and repeat biopsy settings from the Singapore healthcare system perspective. METHODS: A combined decision tree and Markov model was developed. The starting model population was men with mean age of 65 years referred for a first prostate biopsy due to clinical suspicion of prostate cancer. The six diagnostic strategies were selected for their relevance to local clinical practice. They comprised MRI targeted biopsy following a positive pre-biopsy multiparametric MRI (mpMRI) [Prostate Imaging - Reporting and Data System (PI-RADS) score ≥ 3], systematic biopsy, or saturation biopsy employed in different testing combinations and sequences. Deterministic base case analyses with sensitivity analyses were performed using costs from the healthcare system perspective and quality-adjusted life years (QALY) gained as the outcome measure to yield incremental cost-effectiveness ratios (ICERs). RESULTS: Deterministic base case analyses showed that Strategy 1 (MRI targeted biopsy alone), Strategy 2 (MRI targeted biopsy ➔ systematic biopsy), and Strategy 4 (MRI targeted biopsy ➔ systematic biopsy ➔ saturation biopsy) were cost-effective options at a willingness-to-pay (WTP) threshold of US$20,000, with ICERs ranging from US$18,975 to US$19,458. Strategies involving MRI targeted biopsy in the repeat biopsy setting were dominated. Sensitivity analyses found the ICERs were affected mostly by changes to the annual discounting rate and prevalence of prostate cancer in men referred for first biopsy, ranging between US$15,755 to US$23,022. Probabilistic sensitivity analyses confirmed Strategy 1 to be the least costly, and Strategies 2 and 4 being the preferred strategies when WTP thresholds were US$20,000 and US$30,000, respectively. LIMITATIONS AND CONCLUSIONS: This study found MRI targeted biopsy to be cost-effective in diagnosing prostate cancer in the biopsy-naïve setting in Singapore.

Slow-, Tight-Binding Inhibition of CYP17A1 by Abiraterone Redefines Its Kinetic Selectivity and Dosing Regimen.

Substantial evidence underscores the clinical efficacy of inhibiting CYP17A1-mediated androgen biosynthesis by abiraterone for treatment of prostate oncology. Previous structural analysis and in vitro assays revealed inconsistencies surrounding the nature and potency of CYP17A1 inhibition by abiraterone. Here, we establish that abiraterone is a slow-, tight-binding inhibitor of CYP17A1, with initial weak binding preceding the subsequent slow isomerization to a high-affinity CYP17A1-abiraterone complex. The in vitro inhibition constant of the final high-affinity CYP17A1-abiraterone complex ( ( K i * = 0.39 nM )yielded a binding free energy of -12.8 kcal/mol that was quantitatively consistent with the in silico prediction of -14.5 kcal/mol. Prolonged suppression of dehydroepiandrosterone (DHEA) concentrations observed in VCaP cells after abiraterone washout corroborated its protracted CYP17A1 engagement. Molecular dynamics simulations illuminated potential structural determinants underlying the rapid reversible binding characterizing the two-step induced-fit model. Given the extended residence time (42 hours) of abiraterone within the CYP17A1 active site, in silico simulations demonstrated sustained target engagement even when most abiraterone has been eliminated systemically. Subsequent pharmacokinetic-pharmacodynamic (PK-PD) modeling linking time-dependent CYP17A1 occupancy to in vitro steroidogenic dynamics predicted comparable suppression of downstream DHEA-sulfate at both 1000- and 500-mg doses of abiraterone acetate. This enabled mechanistic rationalization of a clinically reported PK-PD disconnect, in which equipotent reduction of downstream plasma DHEA-sulfate levels was achieved despite a lower systemic exposure of abiraterone. Our novel findings provide the impetus for re-evaluating the current dosing paradigm of abiraterone with the aim of preserving PD efficacy while mitigating its dose-dependent adverse effects and financial burden. SIGNIFICANCE STATEMENT: With the advent of novel molecularly targeted anticancer modalities, it is becoming increasingly evident that optimal dose selection must necessarily be predicated on mechanistic characterization of the relationships between target exposure, drug-target interactions, and pharmacodynamic endpoints. Nevertheless, efficacy has always been perceived as being exclusively synonymous with affinity-based measurements of drug-target binding. This work demonstrates how elucidating the slow-, tight-binding inhibition of CYP17A1 by abiraterone via in vitro and in silico analyses was pivotal in establishing the role of kinetic selectivity in mediating time-dependent CYP17A1 engagement and eventually downstream efficacy outcomes.

United in Fight against prOstate cancer (UFO) registry: first results from a large, multi-centre, prospective, longitudinal cohort study of advanced prostate cancer in Asia.

OBJECTIVES: To document the management of advanced prostate cancer including diagnosis, prognosis, treatment, and care, in real-world practice in Asia using the United in Fight against prOstate cancer (UFO) registry. PATIENTS AND METHODS: We established a multi-national, longitudinal, observational registry of patients with prostate cancer presenting to participating tertiary care hospitals in eight Asian countries. A total of 3636 eligible patients with existing or newly diagnosed high-risk localised prostate cancer (HRL), non-metastatic biochemically recurrent prostate cancer (M0), or metastatic prostate cancer (M1), were consecutively enrolled and are being followed-up for 5 years. Patient history, demographic and disease characteristics, treatment and treatment decisions, were collected at first prostate cancer diagnosis and at enrolment. Patient-reported quality of life was prospectively assessed using the European Quality of Life-five Dimensions, five Levels (EQ-5D-5L) and Functional Assessment of Cancer Therapy for Prostate Cancer questionnaires. In the present study, we report the first interim analysis of 2063 patients enrolled from study start (15 September 2015) until 18 May 2017. RESULTS: Of the 2063 enrolled patients, 357 (17%), 378 (19%), and 1328 (64%) had HRL, M0 or M1 prostate cancer, respectively. The mean age at first diagnosis was similar in each group, 56% of all patients had extracapsular extension of their tumour, 28% had regional lymph node metastasis, and 53% had distant metastases. At enrolment, 62% of patients had at least one co-morbidity (mainly cardiovascular disease or diabetes), 91.8% of M1 patients had an Eastern Cooperative Oncology Group performance score of <2 and the mean EQ-5D-5L visual analogue score was 74.6-79.6 across cohorts. Treatment of M1 patients was primarily with combined androgen blockade (58%) or androgen-deprivation therapy (either orchidectomy or luteinising hormone-releasing hormone analogues) (32%). Decisions to start therapy were mainly driven by treatment guidelines and disease progression. Decision to discontinue therapy was most often due to disease progression (hormonal drug therapy) or completion of therapy (chemotherapy). CONCLUSION: In the UFO registry of advanced prostate cancer in Asia, regional differences exist in prostate cancer treatment patterns that will be explored more deeply during the follow-up period; prospective follow-up is ongoing. The UFO registry will provide valuable descriptive data on current disease characteristics and treatment landscape amongst patients with prostate cancer in Asia.

Gmcsf and Ifnα gene therapy improves the response to BCG immunotherapy in a murine model of bladder cancer.

Aim: To develop a strategy to improve response to bacillus Calmette-Gueri (BCG) using cytokine gene therapy (Gmcsf + Ifnα). Materials & methods: MB49-PSA tumor-bearing C57BL/6N mice were assigned into four groups: control; Gmcsf + Ifnα therapy; BCG therapy or combined therapy (Gmcsf + Ifnα and BCG). In schedule 1, cytokine gene therapy was delivered before BCG therapy (eight instillations). In schedule 2, cytokine gene and BCG therapy were instilled alternatively (eight instillations). Tumors were analyzed by immunohistochemistry and mRNA analysis and urinary immune cells by flow cytometry. Results: Combined therapy in schedule 2 reduced tumor growth, increased immune cell recruitment and was associated with reduced inflammation when compared with BCG therapy. Conclusion: Alternating cytokine gene delivery with BCG therapy modulates the tumor environment increasing receptivity to BCG.

Management of patients with advanced prostate cancer in the Asia Pacific region: 'real-world' consideration of results from the Advanced Prostate Cancer Consensus Conference (APCCC) 2017.

OBJECTIVE: The Asia Pacific Advanced Prostate Cancer Consensus Conference (APAC APCCC 2018) brought together 20 experts from 15 APAC countries to discuss the real-world application of consensus statements from the second APCCC held in St Gallen in 2017 (APCCC 2017). FINDINGS: Differences in genetics, environment, lifestyle, diet and culture are all likely to influence the management of advanced prostate cancer in the APAC region when compared with the rest of the world. When considering the strong APCCC 2017 recommendation for the use of upfront docetaxel in metastatic castration-naïve prostate cancer, the panel noted possible increased toxicity in Asian men receiving docetaxel, which would affect this recommendation in the APAC region. Although androgen receptor-targeting agents appear to be well tolerated in Asian men with metastatic castration-resistant prostate cancer, access to these drugs is very limited for financial reasons across the region. The meeting highlighted that cost and access to contemporary treatments and technologies are key factors influencing therapeutic decision-making in the APAC region. Whilst lower cost/older treatments and technologies may be an option, issues of culture and patient or physician preference mean, these may not always be acceptable. Although generic products can reduce cost in some countries, costs may still be prohibitive for lower-income patients or communities. The panellists noted the opportunity for a coordinated approach across the APAC region to address issues of access and cost. Developments in technologies and treatments are presenting new opportunities for the diagnosis and treatment of advanced prostate cancer. Differences in genetics and epidemiology affect the side-effect profiles of some drugs and influence prescribing. CONCLUSIONS: As the field continues to evolve, collaboration across the APAC region will be important to facilitate relevant research and collection and appraisal of data relevant to APAC populations. In the meantime, the APAC APCCC 2018 meeting highlighted the critical importance of a multidisciplinary team-based approach to treatment planning and care, delivery of best-practice care by clinicians with appropriate expertise, and the importance of patient information and support for informed patient choice.

The Role of Vitamin D Receptor Polymorphisms in Predicting the Response to Therapy for Nonmuscle Invasive Bladder Carcinoma.

PURPOSE: Clinical and pathological predictors of bladder carcinoma recurrence and progression are relatively well defined. However, there is a paucity of genetic data specifically on the association of single nucleotide polymorphisms in specific genes for predicting recurrence and progression following immunotherapy. The VDR gene was found to regulate the immunomodulatory effects of vitamin D and it enhances the innate immunity system. We evaluated 3 VDR single nucleotide polymorphisms and their predictive role on the response to immunotherapy. MATERIALS AND METHODS: Patients with bladder cancer at intermediate-high risk who underwent post-transurethral resection intravesical bacillus Calmette-Guérin in Singapore and Hong Kong from 1995 to 2014 were recruited for analysis. We evaluated 3 VDR single nucleotide polymorphisms using polymerase chain reaction. Kaplan-Meier survival curves and relationships with outcomes were analyzed by multivariable Cox regression. RESULTS: A total of 338 predominantly Chinese patients were included in study. Individuals carrying the VDR genotype Bsm A/G were significantly associated with lower time to recurrence after bacillus Calmette-Guérin therapy (p <0.001). On multivariable analysis the HR of recurrence in patients with the Bsm A allele was 3.95 times that in patients without the allele (p = 0.037). Patients with the VDR GATC subhaplotype were 3.05 times more likely than patients with other subhaplotypes to experience recurrences (p = 0.003). Study limitations include the small sample size and the lack of information on previous bacillus Calmette-Guérin vaccine exposure and on vitamin D levels. CONCLUSIONS: Our findings in this study suggest that various VDR single nucleotide polymorphisms are associated with recurrences after bacillus Calmette-Guérin immunotherapy. Further functional studies should be performed to elucidate the significance of the VDR gene in the management of bladder cancer and the potential therapy implications.