Comparative effectiveness of multiple androgen receptor signaling inhibitor medicines with androgen deprivation therapy for metastatic hormone-sensitive prostate cancer: a study in the real world.

Background: The current treatment strategy for metastatic Hormone-Sensitive Prostate Cancer (mHSPC) is the combination of Androgen Receptor Signaling Inhibitors (ARSIs) medicines with androgen deprivation therapy (ADT). However, there is a lack of real-world data comparing the efficacy of different ARSI pharmaceuticals. Therefore, the objective of this study was to compare the effectiveness and safety of bicalutamide, abiraterone, enzalutamide, and apalutamide in combination with ADT for patients with mHSPC. Methods: We retrospectively analyzed 82 patients diagnosed with mHSPC, including 18 patients treated with abiraterone acetate with prednisone, 21 patients with enzalutamide, 20 patients with apalutamide, and 23 patients with bicalutamide. We evaluated PSA progression-free survival (PSA-PFS), imaging progression-free survival (r PFS), castration resistance progression-free survival (CRPC-PFS), and overall survival (OS) using Kaplan-Meier survival analyses. Additionally, we explored relevant factors affecting prognosis through univariate and multivariate Cox risk-proportionality models. PSA response rates at 3, 6, and 12 months, nadir PSA levels (nPSA), and time to nadir (TTN) in different medication subgroups after treatment were documented, and we used one-way ANOVA to determine the effect of these measures on patient prognosis. Results: In comparison with bicalutamide, both enzalutamide and apalutamide have shown significant advantages in delaying disease progression among mHSPC patients. Specifically, enzalutamide has been found to significantly prolong PSA-PFS (HR 2.244; 95% CI 1.366-3.685, p=0.001), rPFS (HR 2.539; 95% CI 1.181-5.461; p= 0.007), CRPC-PFS (HR 2.131; 95% CI 1.295-3.506; p= 0.003), and OS (HR 2.06; 95% CI 1.183-3.585; P=0.005). Similarly, apalutamide has significantly extended PSA-PFS (HR 5.071; 95% CI 1.711-15.032; P= 0.003) and CRPC-PFS (HR 6.724; 95% CI 1.976-22.878; P=0.002) among patients. On the other hand, the use of abiraterone in combination with ADT did not demonstrate a significant advantage in delaying diseases progression when compared with the other three agents in mHSPC patients. There were no significant differences in overall adverse event rates among the four pharmaceuticals in terms of safety. Additionally, the observation of PSA kinetics revealed that enzalutamide, apalutamide, and abiraterone acetate had a significant advantage in achieving deep PSA response (PSA ≤ 0.2 ng/ml) compared with bicalutamide (p=0.007 at 12 months). Enzalutamide and apalutamide exhibited preeminence efficacy, with no substantial difference observed between the two medications. Conclusions: Abiraterone, enzalutamide, and apalutamide were found to significantly reduce and stabilize PSA levels in mHSPC patients more quickly and thoroughly than bicalutamide. Furthermore, enzalutamide and apalutamide were found to significantly prolong survival and delay disease progression in mHSPC patients compared with bicalutamide. It should be noted that abiraterone did not demonstrate a significant advantage in delaying disease compared with enzalutamide and apalutamide. After conducting drug toxicity analyses, it was determined that there were no significant differences among the four drugs.

Transperitoneal vs retroperitoneal laparoscopic radical nephrectomy: a double-arm, parallel-group randomized clinical trial.

OBJECTIVE: To compare the outcomes of patients undergoing Retroperitoneal laparoscopic Radical nephrectomy (RLRN) and Transperitoneal laparoscopic Radical nephrectomy (TLRN). METHODS: A total of 120 patients with localized renal cell carcinoma were randomized into either RLRN or TLRN group. Mainly by comparing the patient perioperative related data, surgical specimen integrity, pathological results and tumor results. RESULTS: Each group comprised 60 patients. The two group were equivalent in terms of perioperative and pathological outcomes. The mean integrity score was significantly lower in the RLRN group than TLRN group. With a median follow-up of 36.4 months after the operation, Kaplan-Meier survival analysis showed no significant difference between RLRN and TLRN in overall survival (89.8% vs. 88.5%; P = 0.898), recurrence-free survival (77.9% vs. 87.7%; P = 0.180), and cancer-specific survival (91.4% vs. 98.3%; P = 0.153). In clinical T2 subgroup, the recurrence rate and recurrence-free survival in the RLRN group was significantly worse than that in the TLRN group (43.2% vs. 76.7%, P = 0.046). Univariate and multivariate COX regression analysis showed that RLRN (HR: 3.35; 95%CI: 1.12-10.03; P = 0.030), male (HR: 4.01; 95%CI: 1.07-14.99; P = 0.039) and tumor size (HR: 1.23; 95%CI: 1.01-1.51; P = 0.042) were independent risk factor for recurrence-free survival. CONCLUSIONS: Our study showed that although RLRN versus TLRN had roughly similar efficacy, TLRN outperformed RLRN in terms of surgical specimen integrity. TLRN was also significantly better than RLRN in controlling tumor recurrence for clinical T2 and above cases. TRIAL REGISTRATION: Chinese Clinical Trial Registry ( https://www.chictr.org.cn/showproj.html?proj=24400 ), identifier: ChiCTR1800014431, date: 13/01/2018.

Atorvastatin Enhances Inhibitory Effects of Irradiation on Tumor Growth by Reducing MSH2 Expression Both in Prostate Cancer Cells and Xenograft Tumor Models.

BACKGROUND: Prostate cancer (PCa) is the fourth most common tumor in males. OBJECTIVE: This study aimed to investigate effects of atorvastatin (AS) on PCa cells proliferation and clarify the associated mechanisms. METHODS: PCa cell lines were cultured and treated with irradiation (IR) (4 Gy), AS (6 µg/ml), transfected with Bcl-2 siRNA, and then divided into different groups. Xenograft tumor mouse model was established. Bcl-2 and MSH2 gene transcription and protein expression were evaluated using RT-PCR assay and western blot assay. Plate clone formation assay was employed to examine colony formation. MTT assay was used to detect cell viabilities. Flow cytometry analysis was utilized to verify apoptosis. Co-immunoprecipitation and immuno-fluorescence assay were used to identify interaction between Bcl-2 and MSH2. RESULTS: IR significantly reduced colony formation, enhanced Bcl-2 and reduced MSH2 gene transcription in PCa cells compared to un-treated cells (p<0.05). AS significantly strengthened radio-therapeutic effects of IR on colony formation, decreased cell apoptosis and increased Bcl-2 gene transcription/protein expression in PCa cells compared to single IR treatment cells (p<0.05). AS combining IR down-regulated MSH2 gene transcription/protein expression in PCa cells compared to single IR treatment cells (p<0.05). Bcl-2 interacted with MSH2 both in PCa cells and tumor tissues administrating with AS. AS enhanced reductive effects of IR on tumor size of Xenograft tumor mice. CONCLUSION: Atorvastatin administration enhanced inhibitory effects of IR either on PCa cells or tumor size of Xenograft tumor mice. The inhibitory effects of atorvastatin were mediated by reducing MSH2 expression and triggering interaction between Bcl-2 and MSH2, both in vitro and in vivo levels.

miR-541-3p enhances the radiosensitivity of prostate cancer cells by inhibiting HSP27 expression and downregulating ß-catenin.

Heat shock protein 27 (HSP27), a regulator of cell survival, can enhance the resistance of cancer cells to radiotherapy. As microRNA-541-3p (miR-541-3p) was recently predicted to be a putative upstream modulator of HSP27, the present study was designed to investigate the function and mechanism underlying how miR-541-3p modulates the radiosensitivity of prostate cancer (PCa) cells by regulating HSP27. Through quantitative PCR, miR-541-3p was determined to be poorly expressed in PCa tissues relative to normal controls, whereas its expression was enhanced after radiotherapy. Consistently, miR-541-3p expression levels in PCa cells were elevated after radiation. Cell viability and proliferation and apoptosis under radiation were subsequently evaluated in response to loss-of-function of miR-541-3p. It was found that inhibition of miR-541-3p facilitated the viability and proliferation of PCa cells and promoted their apoptosis post radiation, hence reducing the radiosensitivity of LNCaP cells. Dual-luciferase reporter assay identified that miR-541-3p negatively regulated the HSP27 mRNA expression by targeting its 3'-UTR. Meanwhile, miR-541-3p overexpression inhibited the ß-catenin expression by targeting HSP27. Furthermore, HSP27 or ß-catenin overexpression was noted to significantly reverse the miR-541-3p-mediated changes in the biological functions of PCa cells post radiation, suggesting that HSP27-dependent activation of ß-catenin might be the mechanism responsible for the promotive effect of miR-541-3p on radiosensitivity. Collectively, this study suggests that miR-541-3p specifically inhibits the HSP27 expression and downregulates ß-catenin, thereby enhancing the radiosensitivity of PCa cells. Our findings highlight the underlying mechanism of the miR-541-3p/HSP27/Wnt/ß-catenin axis regarding radiotherapy for PCa.

Atorvastatin Enhances Effects of Radiotherapy on Prostate Cancer Cells and Xenograft Tumor Mice Through Triggering Interaction Between Bcl-2 and MSH2.

BACKGROUND Prostate cancer (PCa) is considered to be the 4th most common cancer in males in the world. This study aimed to explore effects of atorvastatin on colony formation of PCa cells and radio-resistance of xenograft tumor models. MATERIAL AND METHODS PCa cell lines, including PC3, DU145, and Lncap, were treated with irradiation (4 Gy) and/or atorvastatin (6 µg/mL). Cells were divided into tumor cell group, irradiation treatment group (IR group) and irradiation+atorvastatin treatment group (IR-AS group). Xenograft tumor mouse model was established. Plate clone formation assay (multi-target/single-hit model) was conducted to evaluate colony formation. Flow cytometry analysis was employed to detect apoptosis. Interaction between Bcl-2 and MSH2 was evaluated with immuno-fluorescence assay. RESULTS According to the plate colony formation assay and multi-target/single-hit model, IR-treatment significantly suppressed colony formation in PCa cells (including PC3, DU145, and Lncap cells) compared to no-IR treated cells (P<0.05). Atorvastatin remarkably enhanced inhibitive effects of irradiation on colony formation of PCa cells (P<0.05), however, the IR+AS group demonstrated no effects on apoptosis, comparing to IR group (P>0.05). Atorvastatin administration (IR+AS group) significantly reduced tumor size of IR-treated PCa cells-induced xenograft tumor mice (P<0.05). Bcl-2 interacted with MSH2 both in tumor tissues of xenograft tumor mice. CONCLUSIONS Atorvastatin administration inhibited colony formation in PCa cells and enhanced effects of radiotherapy on tumor growth of xenograft tumor mice, which might be associated with interaction between Bcl-2 and MSH2 molecule.

Synergistic effect of bladder cancer-specific oncolytic adenovirus in combination with chemotherapy.

Gene therapy with adenoviral early region gene (E1A) may enhance the susceptibility of neoplastic cells to chemotherapy-induced cell death. Our previous study developed a urothelium-specific oncolytic serotype 5 adenovirus (Ad5) with the uroplakin II (UPII) promoter controlling E1A expression. The present study investigated whether this urothelium-specific recombinant adenovirus (Ad5-UPII-E1A) enhanced mitomycin (MMC) and hydroxycamptothecin (HCPT) sensitization and drug-induced apoptosis in bladder cancer cells. The results of the MTT assay revealed that combination therapy, using Ad5-UPII-E1A and MMC or HCPT, synergistically inhibited the viability of bladder cancer cells in a dose- and time-dependent manner when compared with either agent alone. When cells were treated with Ad5-UPII-E1A alone they arrested in the G1 phase, but cell cycle analysis by flow cytometry revealed S phase arrest when treated with combined therapy. Treatment with MMC or HCPT enhanced Ad5-UPII-E1A-induced apoptosis in 5,637 cells, observed by transmission electron microscopy. Western blot analysis revealed that MMC and HCPT enhanced the E1A expression of the Ad5-UPII-E1A vectorin a dose-dependent manner. The present study demonstrated that Ad5-UPII-E1A combined with MMC or HCPT resulted in synergistic cytotoxicity in a process which involved the promotion of apoptosis in bladder cancer cell lines. MMC and HCPT also promoted the oncolytic effect of Ad5-UPII-E1A. Thus, treatment using Ad5-UPII-E1A combined with MMC or HCPT may be an attractive strategy for the sensitization of bladder cancer to chemotherapy.

Effect of combined treatment of radiation and tissue-specific recombinant oncolytic adenovirus on bladder cancer cells.

PURPOSE: Gene therapy combined with radiation has shown promising potential for the treatment of tumors. This paper aimed to clarify the synergistic effect of radiotherapy combined with the bladder cancer tissue-specific oncolytic adenovirus (Ad-PSCAE-UPII-E1A) on bladder cancer cells and to study the underlying synergy mechanisms of the combined treatment. MATERIALS AND METHODS: The Adenovirus carrying E1A under control of UPII promoter and prostate stem cell antigen enhancer (PSCAE) were successfully constructed. The viability of bladder cancer cells BIU-87 and EJ was determined by MTT assay. The apoptotic assay was demonstrated by flow cytometry and TEM. Virus titer was determined by TCID50 assay, and proteins Mre11, Chk2-Thr68, and E1A were analyzed by Western blot method. RESULTS: Oncolytic adenovirus combined with radiotherapy improved antitumor efficacy compared with the single treatment at a time and was X-ray dosage-dependent. When the adenovirus infection was scheduled at 24 h after irradiation, cancer cells had the lowest viability. Adenovirus and irradiation induced cell death through the caspase-3 related apoptotic pathway, and bladder cancer cells were arrested at the G1 (BIU-87) or S phase (EJ). Autophagic vacuoles were observed in bladder cancer cells treated with radiation and adenovirus. After irradiation, more virus particles were observed in the BIU-87 and EJ cells. However, by a TCID50 assay, there was no difference in virus titter between irradiated bladder cancer cells and unirradiated cells. The proteins Mre11, Chk2-Thr68 which involved in the DNA break repair pathway were decreased while γ-H2AX-Ser139 increased; at the same time, the E1A gene and the hexon proteins of oncolytic adenovirus were increased after irradiation. CONCLUSIONS: Our results proved synergistic antitumor effect of adenovirus Ad-PSCAE-UPII-E1A and radiation, which might be a potential therapeutic strategy for bladder cancer.

[Updated roles of SIRT1 in prostate diseases].

Silent information regulator 1(SIRT1),an NAD+dependent class-III histone deacetylase,is implicated in diverse cellular processes. SIRT1 has been reported as a key regulator of metabolism,oxidative stress,and cell survival,proliferation,apoptosis and autophagy. It also plays an important role in a variety of physiological processes and health conditions,including aging,inflammation,metabolic disease,tumor,cardiovascular disease,and neurodegeneration. In recent years,the incidence of prostate diseases is increasing,but the therapeutic options are relatively limited. The importance of SIRT1 in prostate diseases has become increasingly apparent,and more rational application of sirtuin inhibitors or activators is shedding new light on the management of prostate diseases.This review focuses on the role of SIRT1 in prostate diseases and introduces some novel strategies for their diagnosis and treatment.

Photoselective green-light laser vaporisation vs. TURP for BPH: meta-analysis.

This study sought to evaluate the efficacy and safety of photoselective vaporisation (PVP) vs. transurethral resection of the prostate (TURP) for patients with benign prostatic hyperplasia (BPH). Eligible studies were identified from electronic databases (Cochrane Library, PubMed and EMBASE). The database search, quality assessment and data extraction were performed independently by two reviewers. Efficacy (primary outcomes: maximum urinary flow rate (Q(max)), international prostate symptom score (IPSS), postvoid residual urine (PVR) and quality of life (QoL); secondary outcomes: operative time, hospital time and catheter removal time) and safety (complications, such as transfusion and capsular perforation) were explored by using Review Manager 5.0. Six randomized controlled trials (RCTs) and five case-controlled studies of 1398 patients met the inclusion criteria. A meta-analysis of the extractable data showed that there were no differences in IPSS, Q(max), QoL or PVR between PVP and TURP (mean difference (MD): prostate sizes <70 ml, Q(max) at 24 months, MD=0.01, P=0.97; IPSS at 12 months, MD=0.18, P=0.64; QoL at 12 months, MD=-0.00, P=0.96; PVR at 12 months, MD=0.52, P=0.43; prostate sizes >70 ml, Q(max) at 6 months, MD=-3.46, P=0.33; IPSS at 6 months, MD=3.11, P=0.36; PVR at 6 months, MD=25.50, P=0.39). PVP was associated with a shorter hospital time and catheter removal time than TURP, whereas PVP resulted in a longer operative time than TURP. For prostate sizes <70 ml, there were fewer transfusions, capsular perforations, incidences of TUR syndrome and clot retentions following PVP compared with TURP. These results indicate that PVP is as effective and safe as TURP for BPH at the mid-term patient follow-up, in particular for prostate sizes <70 ml. Due to the different energy settings available for green-light laser sources and the higher efficiency and performance of higher-quality lasers, large-sample, long-term RCTs are required to verify whether different energy settings affect outcomes.

Biodistribution and safety assessment of bladder cancer specific recombinant oncolytic adenovirus in subcutaneous xenografts tumor model in nude mice.

BACKGROUND: The previous works about safety evaluation for constructed bladder tissue specific adenovirus are poorly documented. Thus, we investigated the biodistribution and body toxicity of bladder specific oncolytic adenovirus Ad-PSCAE-UPII-E1A (APU-E1A) and Ad-PSCAE-UPII-E1A-AR (APU-E1A-AR), providing meaningful information prior to embarking on human clinical trials. MATERIALS AND METHOD: Conditionally replicate recombinant adenovirus (CRADs) APU-E1A, APU-EIA-AR were constructed with bladder tissue specific UroplakinII(UPII) promoter to induce the expression of Ad5E1A gene and E1A-AR fusing gene, and PSCAE was inserted at upstream of promoter to enhance the function of promoter. Based on the cytopathic and anti-tumor effect of bladder cancer, these CRADs were intratumorally injected into subcutaneous xenografts tumor in nude mice. We then determined the toxicity through general health and behavioral assessment, hepatic and hematological toxicity evaluation, macroscopic and microscopic postmortem analyses. The spread of the transgene E1A of adenovirus was detected with RT-PCR and Western blot. Virus replication and distribution were examined with APU-LUC administration and Luciferase Assay. RESULTS: General assessment and body weight of the animals did not reveal any alteration in general behavior. The hematological alterations of groups which were injected with 5x10(8) pfu or higher dose (5x10(9) pfu) of APU-E1A and APU-E1A-AR showed no difference in comparison with PBS group, and only slight increased transaminases in contrast to PBS group at 5x10(9) pfu of APU-E1A and APU-E1A-AR were observed. E1A transgene did not disseminate to organs outside of xenograft tumor. Virus replication was not detected in other organs beside tumor according to Luciferase Assay. CONCLUSIONS: Our study showed that recombinant adenovirus APU-E1A-AR and APU-E1A appear safe with 5x10(7) pfu and 5x10(8) pfu intratumorally injection in mice, without any discernable effects on general health and behavior.