Improve Prostate Cancer Survival Research Articles

Intratumoral vitamin D signaling and lethal prostate cancer.

High circulating vitamin D levels and supplementation may lower prostate cancer mortality. To probe for direct effects of vitamin D signaling in the primary tumor, we assessed how activation of intratumoral vitamin D signaling in prostate cancer is associated with lethal prostate cancer during long-term follow-up. Among 404 participants with primary prostate cancer in the Health Professionals Follow-up Study and the Physicians' Health Study, we defined a gene score of expected activated intratumoral vitamin D signaling consisting of transcriptionally upregulated (CYP27A1, CYP2R1, RXRA, RXRB, and VDR) and downregulated genes (CYP24A1 and DHCR7). We contrasted vitamin D signaling in tumors that progressed to lethal disease (metastases/prostate cancer-specific death, n = 119) over up to three decades of follow-up with indolent tumors that remained nonmetastatic for >8 years post-diagnosis (n = 285). The gene score was downregulated in tumor tissue compared with tumor-adjacent histologically normal tissue of the same men. Higher vitamin D gene scores were inversely associated with lethal prostate cancer (odds ratio for highest versus lowest quartile: 0.46, 95% confidence interval: 0.21-0.99) in a dose-response fashion and after adjusting for clinical and pathologic factors. This association appeared strongest among men with high predicted plasma 25-hydroxyvitamin D3 and men with body mass index ≥25 kg/m2. Findings were replicated with broader gene sets. These data support the hypothesis that active intratumoral vitamin D signaling is associated with better prostate cancer outcomes and provide further rationale for testing how vitamin D-related interventions after diagnosis could improve prostate cancer survival through effects on the tumor.

Complex Epidemiology of Prostate Cancer in Asian Countries

The incidence of prostate cancer (PCa) has increased worldwide in recent years along with the recommendation for prostate-specific antigen testing, and mortality has been declining owing to advances in fragmented and simplified access to treatment care. However, GLOBOCAN (Global Cancer Observatory) data show that this result is not true for all countries. It has been reported that the degree of PCa progression at diagnosis and survival rates differ among racial groups. Based on various comparisons between Caucasians and Asians, it was inferred that survival rates were higher in Asians despite the higher degree of progression at diagnosis, suggesting a better prognosis for life compared with Caucasians. The survey among Asian countries did not reveal any obvious differences among Asian subregions; rather, it inferred that the impact of the level of development among the countries was significant. The development of healthcare systems and medical care could improve PCa survival in developing countries.

The Journal of Urology® Home Study Course 2023 Volume 209/210.

The Journal of Urology® Home Study Course 2023 Volume 209/210.

Abstract 2362: Long non-coding RNA NORAD interaction with miR-346 impacts DNA damage response and anti-tumor immunity in prostate cancer

Abstract NORAD (NOn-Coding RNA Activated by DNA Damage) is a highly-abundant, evolutionarily-conserved lncRNA. It maintains mitosis, DNA damage repair (DDR), and chromosomal integrity through PUM1/2 sequestration (PUM1/2 activity increases turnover of DDR factors), and through formation of a TOPO2-containing complex critical for genome integrity. We show that NORAD activity is regulated by microRNA-346 (miR-346), which disrupts NORAD:PUM2, interaction, leading to PUM2 destabilization and derepression of PUM1/2 DDR targets in prostate cancer (PCa) cells. RNA-seq reveals widespread miR-346 dysregulation of DNA damage, DNA replication and cell cycle transcripts. A novel method for high resolution, amplification-free genome-wide mapping of double strand DNA breaks (DSBs) (INDUCE-seq) reveals miR-346 induces DSBs specifically at transcription start sites characterized by phospho-PolII/CTCF/ZFX binding - a phenomenon not previously described for any microRNA. Mechanistically, DSBs result from miR-346 activation of transcription, R-loop formation and replicative catastrophe. This results in rapid dose-dependent induction of DNA damage, leading to checkpoint activation and cytosolic DNA accumulation, rescuable by NORAD. This cytosolic DNA activates cytokine-inducing cGAS-STING/RIG-1 innate immune pathways. Indeed, RNA-seq analysis reveals the top NORAD-enriched pathway as interferon signaling, while cytokine arrays reveal secretion of pro-Treg, MDSC and TAM factors by NORAD-overexpressing cells. NORAD inversely correlates with tumor immune response in gene expression data sets, and expression-based immune infiltration scoring predicts increased M2 macrophages, and reduced NK, CD8+ve, Th1 and cytotoxic T cells in NORAD-high vs NORAD-low PCa, indicating an ‘immune-cold' microenvironment. Excitingly, NORAD silencing results in several thousand-fold increase in mature miR-346 without affecting pri-miR levels, supporting NORAD's ability to drive target-directed microRNA decay (TDMD) of miR-346 as a critical novel genome protection mechanism. However, miR-346-induced DNA damage is in part NORAD-independent, since miR-346 induces DSBs within 1h, and in contrast to most miRs is predominantly chromatin-bound (NORAD is cytoplasmic). Critically, miR-346 sensitizes PCa cells to DNA-damaging chemotherapy and PARP inhibition. MiR-346 expression is associated with improved PCa survival, and reduced in high vs low Gleason grade PCa. Notably, NORAD strongly correlates with DDR signatures in early-stage, but not advanced metastatic PCa. Despite its DDR-promoting activity, and in contrast to miR-346, it is associated with worse survival across multiple patient cohorts. In conclusion, these data demonstrate that the NORAD:miR-346 interaction determines DNA damage response and innate immune pathway activity to regulate tumor immune response in PCa. Citation Format: Claire Fletcher, Lin Deng, Folake Orafidiya, Wei Yuan, Ines Figueiredo, Bora Gurel, Damien Leach, Fadi Issa, Antje Neeb, Denisa Bogdan, Felix Dobbs, Yiannis Philippou, Emma A. Murphy, Shuang G. Zhao, Joanna Hester, Richard J. Bryant, Simon H. Reed, Karen E. Knudsen, Ian G. Mills, Johann de Bono, Charlotte L. Bevan. Long non-coding RNA NORAD interaction with miR-346 impacts DNA damage response and anti-tumor immunity in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2362.

A new bioinformatics approach identifies overexpression of GRB2 as a poor prognostic biomarker for prostate cancer

A subset of prostate cancer displays a poor clinical outcome. Therefore, identifying this poor prognostic subset within clinically aggressive groups (defined as a Gleason score (GS) ≧8) and developing effective treatments are essential if we are to improve prostate cancer survival. Here, we performed a bioinformatics analysis of a TCGA dataset (GS ≧8) to identify pathways upregulated in a prostate cancer cohort with short survival. When conducting bioinformatics analyses, the definition of factors such as “overexpression” and “shorter survival” is vital, as poor definition may lead to mis-estimations. To eliminate this possibility, we defined an expression cutoff value using an algorithm calculated by a Cox regression model, and the hazard ratio for each gene was set so as to identify genes whose expression levels were associated with shorter survival. Next, genes associated with shorter survival were entered into pathway analysis to identify pathways that were altered in a shorter survival cohort. We identified pathways involving upregulation of GRB2. Overexpression of GRB2 was linked to shorter survival in the TCGA dataset, a finding validated by histological examination of biopsy samples taken from the patients for diagnostic purposes. Thus, GRB2 is a novel biomarker that predicts shorter survival of patients with aggressive prostate cancer (GS ≧8).

Salvage Therapies After 18F-Fluciclovine Detected Prostate Cancer Recurrences.

F-Fluciclovine is the most recent prostate cancer (PCa)-directed PET radiotracer approved by the US Food and Drug Administration for detection of recurrent PCa. We report the treatments and outcomes of patients at our institution with PCa recurrences detected on F-fluciclovine PET/CT. We identified men with recurrent PCa detected on F-fluciclovine PET/CT performed between 2017 and 2018 who were previously treated definitively and analyzed their patterns of care and cancer-specific outcomes. We identified 28 men with recurrent PCa detected on F-fluciclovine PET/CT. Twenty-three were initially treated with surgery and 13 also received postoperative radiation therapy (RT). Five patients were initially treated with definitive radiation. After surgery, the median time to F-fluciclovine PET/CT was 67 months (median prostate-specific antigen [PSA] of 1.63 ng/mL). After RT, the median time to F-fluciclovine PET/CT was 95 months with median PSA of 13.31 ng/mL. Six men recurred locally, 9 recurred in the pelvic nodes, 9 had distant nodal recurrences, and 4 had osseous metastases. Of the patients initially treated with surgery, 4 received salvage radiation and 3 received androgen deprivation therapy (ADT). Of the patients initially treated with surgery and postoperative RT, 3 received salvage pelvic nodal dissection, 4 received salvage radiation, and 2 received ADT. Of the patients initially treated with radiation, 4 received salvage ADT. All had PSA decline after salvage therapy. F-fluciclovine PET/CT can localize PCa recurrences, and subsequent salvage therapies appear effective with decreasing PSA. Longer follow-up will reveal if these diagnostic tests and subsequent therapies will improve PCa survival.

The prostate cancer precision screening program: a preliminary report after recruitment of 2 159 men

Objective: The Chinese Anti-Cancer Association Genitourinary Cancer Committee Prostate Cancer Working Group released Consensus of prostate cancer (PCa) screening in 2017. This program aims to evaluate the methods and significance of prostate cancer precision screening in high risk population. Methods: A total of 2 159 eligible males enrolled from 13 community centers and 3 screening centers received PSA test from April 2017 to August 2018. Prostate-specific antigen (PSA) determination in serum with a cut-off of ≥4.0 ng/ml was the main screening test and indication for biopsy. The interviewer-administered questionnaire covered demographic characteristics and environmental exposure factors. The associations between these factors and prostate cancer risk were determined by multivariable unconditional logistic regression models. Results: Altogether, 271 cases (12.6%) had a confirmed PSA increase ≥ 4.0 μg/L (median 9.1, range 4.0-25.0). Subsequently, 57 subjects (21.0%) out of the 271 PSA-suspicious men underwent prostate biopsy, and 34 (59.6%) were confirmed as prostate cancer. Until now, the overall prostate cancer incidence in the first screening round was1.57%. There were no statistical differences in the distributions of PSA-suspicious and prostate cancer incidence between community centers and screening centers (P=0.578 and 0.735). Age (OR: 2.63; 95%CI: 1.84-3.75, P<0.001) and chronic prostatitis history (OR: 2.02; 95%CI: 1.55-2.63, P<0.001) were significantly associated with PSA level. After adjustment for these factors, older age (OR: 4.04; 95%CI: 1.71-9.59, P=0.002) and statins use (OR: 3.09; 95%CI: 1.25-7.69, P=0.015) were associated with an elevated risk of PCa. Conclusions: It is of substantial significance to screen prostate cancer in high risk population. Both community centers and screening centers methods are effective. Although largely underestimated, the incidence of PCa in the targeted Chinese population is higher than expected. Older men have a high risk of harboring PCa. Our study suggests a decreased risk of PCa in men with statins use. Prostate Cancer Precision Screening is promising to improve prostate cancer survival in China.

Perplexity of penile rehabilitation following radical prostatectomy.

Radical prostatectomy has significantly improved prostate cancer survival rates but continues to have a negative impact on the patient's erectile function (EF). In attempts to improve erectile dysfunction (ED), clinicians have incorporated different treatment modalities to restore EF. Penile rehabilitation consists of understanding the mechanisms that affect post-prostatectomy EF and utilizing pharmacologic agents, devices, and interventions to promote the male sexual function. This article aims to summarize the available scientific research involving penile rehabilitation. Even though the current literature lacks to prove its irrefutable effectiveness, penile rehabilitation has a positive impact at the molecular and cellular levels, and it is widely adopted in clinic practices.

Abstract 4226: Association between NSAID, statins, and bisphosphonates and prostate cancer survival during androgen deprivation therapy

Abstract We study the association between non-steroidal anti-inflammatory drugs (NSAIDs), Statins, and Bisphosphonates (BPs), and prostate cancer (PCa) survival during androgen deprivation therapy (ADT). STAMPEDE trial has demonstrated better PCa-specific survival in men using combination of celecoxib (CEL) and zoledronic acid (ZA) during ADT compared to ADT alone. The mechanism is unclear. ZA inhibits mevalonate pathway (MevP) previously linked with cancer growth. We evaluated PCa survival among men on ADT and simultaneously using BPs including ZA or statins, another drug group inhibiting MevP, and NSAIDs including CEL. We hypothesized that combined use of a MevP inhibitor and NSAID would be associated with improved PCa survival. Our study cohort includes 4,428 men from the Finnish Randomized Study of PCa Screening (FinRSPC) initiating ADT in 1995-2015. Cox proportional hazards model with adjustment for age, FinRSPC study arm, tumor clinical characteristics and co-morbidities (obtained from national registries) was used to calculate HRs and 95% CI for PCa death. Medication use was analyzed as time-dependent variable. Compared to non-users, the risk of PCa death was increased in users of NSAIDs or acetaminophen, and lowered in statin users. Use of BPs or coxibs alone were not associated with the risk. Coxibs and statins together were associated with lowered risk to a similar degree as statins alone. No statistically significant risk differences were observed for other combinations. Statin users with high-risk prostate cancer undergoing ADT have lowered risk of PCa death. NSAID users have increased risk of PCa death, which becomes statistically insignificant when used with statins. Statin and BP use together shows no statistically significant evidence of negating the effects of statin. No clear additive benefit was observed for statins and coxibs together over statins alone. Our findings do not support additive benefits of MevP inhibitor and NSAIDs. Statistical significance codes: *** : p = 0.001, ** : p = 0.01, * : p = 0.1DrugHR95 % CISignificanceStatin0.780.680.90***Acetylsalisylic acid0.900.761.07Coxib1.070.941.22NSAID1.171.041.31**Acetaminophen1.661.511.82***Bisphosphonate0.790.381.64Bisphosphonate and NSAID0.890.551.42Statin and NSAID1.070.901.27Statin and Bisphosphonate1.140.861.50Coxib and Bisphosphonate0.850.421.74Coxib and Statin0.800.621.02*EAU tumor Risk Group2.662.353.00*** Citation Format: Paavo V. Raittinen, Kirsi Talala, Kimmo Taari, Teuvo L. Tammela, Pauliina Ilmonen, Anssi Auvinen, Teemu J. Murtola. Association between NSAID, statins, and bisphosphonates and prostate cancer survival during androgen deprivation therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4226.

New Opportunities for Targeting the Androgen Receptor in Prostate Cancer.

Recent genomic analyses of metastatic prostate cancer have provided important insight into adaptive changes in androgen receptor (AR) signaling that underpin resistance to androgen deprivation therapies. Novel strategies are required to circumvent these AR-mediated resistance mechanisms and thereby improve prostate cancer survival. In this review, we present a summary of AR structure and function and discuss mechanisms of AR-mediated therapy resistance that represent important areas of focus for the development of new therapies.

Local Treatment of Metastatic Prostate Cancer: What is the Evidence So Far?

Background Advances in technological, laboratorial, and imaging studies and new treatments available in the last decades significantly improved prostate cancer survival rates. However, this did not occur in metastatic prostate cancer (mPCa) at diagnosis which, in young and fit patients, will become invariably resistant to the established treatments. Progression will lead to an impairment in patients' quality of life and disease-related death. Methods The authors intend to perform a literature review of the advantages of primary treatment of mPCa. Articles were retrieved and filtered for relevance from PubMed, SciELO, and ScienceDirect until March 2017. Results Primary treatment is currently indicated only in cases of nonmetastatic PCa. Nonetheless, there might be some benefits in doing local treatment in mPCa in order to control local disease, prevent new metastasis, and improve the efficacy of chemotherapy and hormonotherapy with similar complications rate when compared to locally confined cancer. Independent factors that have a negative influence are age above 70 years, cT4 stage or high-grade disease, PSA ≥ 20 ng/ml, and pelvic lymphadenopathies. The presence of 3 or more of these factors conditions CSS and OS is the same between patients who performed local treatment and those who did not. Metastasis degree and location number can also influence outcome. Meanwhile, patients with visceral metastases have worse results. Conclusions There is growing evidence supporting local treatment in cases of metastatic prostate cancer at diagnosis in the context of a multimodal approach. However, it should be kept in mind that most of the existing studies are retrospective and it would be important to make consistent prospective studies with well-defined patient selection criteria in order to sustain the existing data and understand the main indications to select patients and perform primary treatment in mPCa.

Do Aspirin and Other NSAIDs Confer a Survival Benefit in Men Diagnosed with Prostate Cancer? A Pooled Analysis of NIH-AARP and PLCO Cohorts.

Prostate cancer is one of the leading causes of cancer-related death in U.S. men. There is an unmet need to identify modifiable risk factors for prostate cancer survival. Experimental studies have suggested that nonsteroidal anti-inflammatory drugs (NSAIDs) may improve prostate cancer survival through antithrombotic and anti-inflammation mechanisms. Results from previous observational studies have been equivocal, and few have assessed whether an etiologically relevant time window of exposure exists. We sampled incident prostate cancer cases from two large U.S. prospective cohorts, NIH-AARP Diet and Health Study and PLCO Cancer Screening Trial, to investigate whether pre- and postdiagnostic aspirin and non-aspirin NSAID use were associated with prostate cancer-specific and all-cause mortality. Cox proportional hazards regression models estimated hazard ratios (HRs) and 95% confidence intervals (CIs). Study-specific results were meta-analyzed using fixed-effects models. Pre- and postdiagnostic aspirin or non-aspirin NSAID use were not statistically significantly associated with prostate cancer-specific mortality. However, occasional (less than daily) and daily aspirin users five years or more before prostate cancer diagnosis had 18% (HR = 0.82; 95% CI = 0.75-0.90) and 15% (HR = 0.85; 95% CI = 0.77-0.94) reduced all-cause mortality versus nonusers. Similarly, postdiagnostic occasional and daily aspirin use were associated with 17% (HR = 0.83; 95% CI=0.72-0.95) and 25% (HR = 0.75; 95% CI = 0.66-0.86) reduced all-cause mortality, independent of prediagnostic aspirin use. This study suggests that aspirin or non-aspirin NSAIDs are not associated with prostate cancer survival. However, aspirin use both before and after prostate cancer diagnosis was associated with longer overall survival, highlighting the importance of comorbidity prevention among prostate cancer survivors. Cancer Prev Res; 10(7); 410-20. ©2017 AACR.

Abstract B26: Pre- and post-diagnostic use of nonsteroidal anti-inflammatory drugs and prostate cancer mortality among men diagnosed with prostate cancer in the NIH-AARP and PLCO cohorts

Abstract Background: Prostate cancer is the second leading cause of cancer death in American men, but few modifiable risk factors have been established for prostate cancer progression and survival. Experimental studies have suggested that nonsteroidal anti-inflammatory drugs (NSAIDs) may improve prostate cancer survival through anti-thrombotic and anti-inflammation mechanisms. However, previous observational studies have shown mixed results. No study has examined over-the-counter non-aspirin NSAIDs in relation to prostate cancer survival. Few studies have assessed aspirin use before prostate cancer diagnosis in relation to prostate cancer survival, and whether any etiologically relevant time window of exposure exists remains unclear. Methods: We assessed two cohorts of prostate cancer cases from two large prospective studies in the United States NIH-AARP Diet and Health Study and Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial to investigate associations of aspirin and other nonselective non-aspirin NSAID use before and after prostate cancer diagnosis with prostate cancer-specific and all-cause mortality. Cox proportional hazards models with age as the time metric were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results across the two studies were meta-analyzed in a fixed effects model if consistent associations were observed. Results: We did not find statistically significant associations of pre- or post-diagnostic NSAID use with prostate cancer-specific mortality. However, aspirin users versus nonusers five years or more before prostate cancer diagnosis had a 14% (95%CI=0.74 to 1.00) and a 16% (95%CI=0.78 to 0.89) reduced prostate cancer-specific and all-cause mortality when combining the two studies. Post-diagnostic occasional (less than once per day) and daily aspirin use were associated with 17% (95%CI=0.72 to 0.95) and 25% (95%CI=0.66 to 0.86) reductions in all-cause mortality independent of pre-diagnostic use, comparing with no use. Conclusions: This analysis suggests a modest delayed survival benefit of aspirin use before prostate cancer diagnosis and highlights the importance of comorbidity prevention among prostate cancer survivors. Citation Format: Cindy Ke Zhou, Sarah E. Daugherty, Amanda Black, Linda M. Liao, Neal D. Freedman, Christian C. Abnet, Ruth Pfeiffer, Michael B. Cook. Pre- and post-diagnostic use of nonsteroidal anti-inflammatory drugs and prostate cancer mortality among men diagnosed with prostate cancer in the NIH-AARP and PLCO cohorts. [abstract]. In: Proceedings of the AACR Special Conference: Improving Cancer Risk Prediction for Prevention and Early Detection; Nov 16-19, 2016; Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(5 Suppl):Abstract nr B26.

Abstract 3416: Association between pre-diagnostic circulating 25-hydroxyvitamin D and cancer survival

Abstract Background: Vitamin D has many anti-cancer properties such as reducing angiogenesis, inflammation, and cell proliferation, and enhancing apoptosis and cellular differentiation. Epidemiological studies are inconsistent across cancer sites, showing inverse, positive, and null associations with 25-hydroxyvitamin D [25(OH)D] blood concentrations (i.e., the accepted biomarker of vitamin D status). We previously reported that higher 25(OH)D status was related to improved prostate cancer survival, yet few other studies have examined pre-diagnostic vitamin D concentrations and survival after a cancer diagnosis. Methods: Based on measured prospective circulating 25(OH)D from several case-control sets nested within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study of Finnish men, we examined serum 25(OH)D (DiaSorin LIAISON 25(OH)D TOTAL assay) in relation to overall and site-specific cancer survival among 3,740 men and 1,946 cancer deaths occurring through December, 2013. Multivariate-adjusted proportional hazard regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association between 25(OH)D and survival from malignant melanoma, non-Hodgkin lymphoma, and cancers of the colorectum, lung, prostate, kidney, stomach, oropharynx, larynx, bladder, esophagus, liver, and pancreas. Results: Baseline serum 25(OH)D concentrations were significantly higher among men who were alive at the end of follow-up compared with men who died from their cancer (medians 35.0 vs. 32.1 nmol/L, respectively; p = 0.003). Higher baseline 25(OH)D was associated with lower overall cancer death (HR = 0.75, 95% CI 0.65-0.87 for highest vs. lowest quintile, p-trend 0.0001). Excluding the prostate cancer cases did not materially alter this association (HR = 0.79, 95% CI 0.67-0.82 for highest vs. lowest quintile, p-trend 0.006). Organ site-specific survival showed higher 25(OH)D to be associated with lower risk of death from the following cancers: prostate (Q5 vs. Q1 HR = 0.74, 95% CI 0.53-1.03), renal (Q5 vs. Q1 HR = 0.58, 95% CI 0.32-1.04), stomach (Q5 vs. Q1 HR = 0.49, 95% CI 0.30-0.82), oropharynx/larynx (Q5 vs. Q1 HR = 0.55, 95% CI 0.28-1.06), and melanoma (T3 vs. T1 HR = 0.41, 95% CI 0.18-0.94), and higher risk of death from esophageal cancer (higher vs. below median HR = 1.80, 95% CI 1.04-3.12). Conclusion: Higher pre-diagnostic serum 25(OH)D concentrations were associated with improved overall cancer survival, as well as improved survival for prostate, renal, stomach, oropharyngeal and laryngeal cancers and malignant melanoma, but poorer esophageal cancer survival. The apparent paradox of higher vitamin D status being associated with improved survival, but not necessarily reduced incidence, of these particular cancers deserves further study in other prospective populations. Citation Format: Stephanie J. Weinstein, Alison Mondul, Demetrius Albanes. Association between pre-diagnostic circulating 25-hydroxyvitamin D and cancer survival. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3416.

Urologic cancer in China

Cancer remains to be the second most common cause of death, and its incidence and mortality rates are increasing in China. According to the 2015 National Central Cancer Registry (NCCR) of China, the incidence of bladder cancer and prostate cancer ranked sixth and seventh, respectively, in male cancers. The majority of prostate cancer patients were diagnosed at an advanced stage. Early diagnosis of prostate cancer is the key to improve prostate cancer survival in China. Radical prostatectomy or radical radiotherapy is the main treatment for localized prostate cancer, and a comprehensive therapy based on androgen deprivation therapy is the treatment for advanced disease. The most common histologic types of bladder cancer in China were urothelial carcinoma, followed by adenocarcinoma and squamous carcinoma. The majority of patients were diagnosed using white-light cystoscopy with biopsy. Fluorescence and narrow-band imaging cystoscopy had additional detection rates and are becoming more popular. Following Chinese guidelines, most non-muscle invasive bladder cancer patients were treated with diagnostic transurethral resection and more than half of the muscle invasive bladder cancer patients were treated with radical cystectomy. Due to the increased detection rate of kidney tumors by ultrasound in physical examination, the number of incidentally diagnosed renal cell carcinoma has increased. Localized kidney cancers are more and more often treated by nephron-sparing surgery. Radical nephrectomy is still the main treatment option for patients with locally advanced renal cell carcinoma. Both laparoscopic and robotic-assisted laparoscopic surgeries have been used in big medical centers. Both testicular cancer and penile cancer have lower incidence levels than that in Europe. As we have an enormous population base, the absolute patient number is big. The diagnosis and treatment follows the Chinese guidelines. In China, both medical professionals and public should concern more on the early diagnosis, as there is not enough cancer prevention information available. Urologists should also take a more active role in educating the population.

Statin use and risk of disease recurrence and death after radical prostatectomy.

Statins have been linked with improved prostate cancer survival and lower risk of recurrence in men treated with radiation therapy. However, the association is unclear for surgically-treated men. We studied the risk of prostate cancer recurrence and death by statin usage after radical prostatectomy in a cohort of prostate cancer patients treated with radical prostatectomy. A cohort of 1,314 men who underwent curative-intent radical prostatectomy at the Tampere University Hospital, Tampere, Finland during 1995-2009 were linked to national prescription database to obtain detailed information on statin purchases. The risk of PSA recurrence and death (overall and prostate cancer-specific) by statin use before and after the surgery were evaluated using Cox regression with model adjustment for tumor characteristics, total cholesterol and simultaneous use of antidiabetic and antihypertensive drugs. Tissue expression of putative prognostic markers were measured from a subgroup of 323 men. During the median follow-up of 8.6 years after surgery 484 men recurred, while 244 men died (32 due to prostate cancer). In general statin use before or after prostatectomy was not associated with risk of disease recurrence or death. Tissue expression of Ki-67 and ERG modified the association between statin use and risk of disease recurrence; the risk estimates were lower in men with Ki-67 expression above the median (P for interaction 0.001 and 0.004 for statin use before and after prostatectomy, respectively) and no ERG expression in the tumor tissue (P for interaction 0.006 and 0.011). Statin use generally did not affect prostate cancer prognosis after prostatectomy. The effect on disease recurrence may depend on tumor properties, such as proliferation activity. Thus possible future prospective studies should recognize and enroll subgroups of prostate cancer patients most likely to benefit from statins.

Epidemiology of prostate cancer in China: an overview and clinical implication

Prostate cancer is a currently common disease in Chinese male. The incidence is increasing rapidly in urban area and the mortality is high in rural area. According to characteristics of disease stage, advancement in early diagnosis of prostate cancer is the key to improve prostate cancer survival in China. Because of the remarkable disparity in economic and health care across mainland China, a selective prostate cancer screen approach may be a better alternative to spread. Therefore, indepth researches in optimization of prostate specific antigen screen and validation biomarkers of aggressive prostate cancer should be advocated. Furthermore, physicians should take a more active role in population education.

Nobiletin suppresses cell viability through AKT pathways in PC-3 and DU-145 prostate cancer cells.

BackgroundNobiletin is a non-toxic dietary flavonoid that possesses anti-cancer properties. Nobiletin has been reported to reduce the risk of prostate cancer, but the mechanism is not well understood. In this study, we investigated the effects of nobiletin in prostate cancer cell lines PC-3 and DU-145.MethodsNobiletin was isolated from a polymethoxy flavonoid mixture using HPLC, cell viability was analyzed with MTS-based assays. Protein expression was examined by ELISA and western blotting. Gene expression was examined by luciferase assay. And the pathways were examined by manipulating genetic components with plasmid transfection.ResultsData showed that nobiletin decreased cell viability in both prostate cell lines, with a greater reduction in viability in PC-3 cells. HIF-1α expression and AKT phosphorylation were decreased in both cell lines. The VEGF expression was inhibited in PC-3 but not DU-145 cells. cMyc expression was decreased in DU-145 cells. Nobiletin down-regulated NF-κB (p50) expression in nuclei of DU145 cells but not whole cells. It also suppressed NF-κB expression in both whole cells and nuclei of PC-3 cells. Increasing HIF-1α levels reversed nobiletin’s inhibitory effects on VEGF expression, and up-regulating AKT levels reversed its inhibitory effects on HIF-1α expression. We speculate that AKT influences cell viability probably by its effect on NF-κB in both prostate cells. The effect of nobiletin on VEGF expression in PC-3 cell lines was through the AKT/HIF-1α pathway.ConclusionTaken together, our results show that nobiletin suppresses cell viability through AKT pathways, with a more profound effect against the more metastatic PC-3 line. Due to this enhanced action against a more malignant cell type, nobiletin may be used to improve prostate cancer survival rates.

Sociodemographic disparities in treatment receipt for prostate cancer: A population-based study.

e16514 Background: Prostate cancer (PC) treatment remains controversial. Little is known about how this controversy plays out in routine clinical practice. Most studies of treatment patterns are from the US, specialist centres, and/or involve selected patients. In a national, population-based analysis, using linked cancer registration and hospital in-patient data, we investigated associations between socio-demographic and clinical factors and PC treatment in Ireland. Methods: PC cases (ICD10 C61) diagnosed 2002-2008, and with a hospital in-patient episode within one year of diagnosis (n=9658) were included. Comorbidity (assessed by Charlson and Elixhauser indices) was determined from diagnoses on hospital episodes. Multinomial logistic regression was used to investigate associations between age, marital status, smoking status, area of residence, deprivation category, comorbidity, diagnosis period, stage and Gleason score, and receipt of different treatment modalities. Results: Age was a significant determinant of treatment receipt, after adjusting for socio-demographic and clinical factors. Compared to younger men, men aged ≥70 were significantly less likely to undergo radical prostatectomy (RP), and significantly more likely to be treated by TURPS, androgen deprivation therapy (ADT) or radiotherapy with ADT. Within the 40-69 age-group, likelihood of RP decreased with increasing age. After adjusting for age and other factors, presence of comorbidities, overall, had a moderate impact on treatment receipt. Some conditions had a stronger effect (e.g. congestive heart failure). There were strong variations in treatment by area of residence, which persisted after adjustment for age, comorbidity and other factors. Conclusions: These results suggest socio-demographic factors, including patient age and area of residence, strongly influence PC treatment. Strategies to reduce these disparities have potential to improve PC survival and mortality in the population.

Statin use is associated with improved prostate cancer survival: is it time for a clinical trial?

Evaluation of: Gutt R, Tonlaar N, Kunnavakkam R, Karrison T, Weichselbaum RR, Liauw SL. Statin use and risk of prostate cancer recurrence in men treated with radiation therapy. J. Clin. Oncol. 28, 2653–2659 (2010).Recent studies have reported an inverse association between statin use and risk of advanced prostate cancer. Thus, it is possible that statin exposure delays progression of prostate tumors to an advanced stage. The study by Gutt and colleagues gives two important contributions to this field of research. With a cohort of 691 men undergoing curative-intent radiation therapy for prostate cancer between 1996 and 2008, and with a median follow-up of 50 months, they demonstrate that statin use is associated with improved relapse-free survival. The result supports the idea that statins could delay prostate cancer progression. In addition, they demonstrate that low low-density lipoprotein levels are associated with improved relapse-free survival, supporting the idea that the prostate cancer progression-preventing effects of statins could be, at least in part, mediated by their systemic low-density lipoprotein-lowering effect. The study adds to the growing body of evidence on statins’ benefits against prostate cancer. The results have important implications when designing possible future clinical studies on this topic.