Managing advanced prostate cancer in the Asia Pacific region: "Real-world" application of Advanced Prostate Cancer Consensus Conference 2019 statements.

AIM: The second Asia-Pacific Advanced Prostate Cancer Consensus Conference (APAC APCCC 2020) gathered insights into the real-world application in the Asia-Pacific (APAC) region of consensus statements from the 3rd Advanced Prostate Cancer Consensus Conference (APCCC 2019). METHODS: The 4-h our virtual meeting in October 2020 brought together 26 experts from 14 APAC countries to discuss APCCC 2019 recommendations. Presentations were prerecorded and viewed prior to the meeting. A postmeeting survey gathered views on current practice. RESULTS: The meeting and survey highlighted several developments since APAC APCCC 2018. Increased access and use in the region of PSMA PET/CT imaging is providing additional diagnostic and staging information for advanced prostate cancer and influencing local and systemic therapy choices. Awareness of oligometastatic disease, although not clearly defined, is increasing. Novel androgen receptor pathway antagonists are expanding treatment options. Cost and access to contemporary treatments and technologies continue to be a significant factor influencing therapeutic decisions in the region. With treatment options increasing, multidisciplinary treatment planning, shared decision making, and informed choice remain critical. A discussion on the COVID-19 pandemic highlighted challenges for diagnosis, treatment, and clinical trials and new service delivery models that will continue beyond the pandemic. CONCLUSION: APAC-specific prostate cancer research and data are important to ensure that treatment guidelines and recommendations reflect local populations and resources. Facilitated approaches to collaboration across the region such as that achieved through APAC APCCC meetings continue to be a valuable mechanism to ensure the relevance of consensus guidelines within the region.

Impact of warm ischaemia time on postoperative renal function after partial nephrectomy for clinical T1 renal cell carcinoma: a propensity score-matched study.

OBJECTIVES: To analyse the effect of prolonged warm ischaemia time (WIT) on long-term renal function after partial nephrectomy (PN), as controversy still exists as to whether prolonged WIT adversely affects the incidence of chronic kidney disease (CKD) after PN. PATIENTS AND METHODS: We reviewed data from 1816 patients who underwent PN for a clinical T1 renal tumour. The propensity scores for prolonged WIT were calculated with the shorter WIT group (<30 min) matched to the longer WIT group (≥30 min) in a 2:1 ratio. Multivariate analysis was used to determine independent predictors for occurrence of postoperative CKD [defined as an estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m2 ] and major renal function deterioration (MRFD; defined as an eGFR decrease of ≥25% postoperatively). RESULTS: After propensity score matching, there was no significant difference in CKD-free survival between the two WIT groups (P = 0.787). Furthermore, longer WIT did not show any significant associations with postoperative CKD-free survival [hazard ratio (HR) 1.002, 95% confidence interval (CI) 0.989-1.015; P = 0.765) and MRFD-free survival (HR 1.014, 95% CI 1.000-1.028; P = 0.055). From further subgroup analyses using more specific WIT thresholds (≤20, 21-30, 31-40, 41-50, ≥50 min) and status of preoperative CKD, no significant differences were noted in CKD and MRFD-free survival amongst the subgroups (all P > 0.05). CONCLUSIONS: Prolonged WIT was not associated with increased incidence of CKD or MRFD after PN.

NVP-BEZ235, a dual PI3K/mTOR inhibitor synergistically potentiates the antitumor effects of cisplatin in bladder cancer cells.

The PI3K/Akt/mTOR pathway is a prototypic survival pathway and constitutively activated in many malignant conditions. Moreover, activation of the PI3K/Akt/mTOR pathway confers resistance to various cancer therapies and is often associated with a poor prognosis. In this study, we explored the antitumor effect of NVP-BEZ235, a dual PI3K/mTOR inhibitor in cisplatin-resistant human bladder cancer cells and its synergistic interaction with cisplatin. A human bladder cancer cell line with cisplatin resistance was exposed to escalating doses of NVP-BEZ235 alone or in combination with cisplatin and antitumor effects was determined by the CCK-8 assay. Based on a dose-response study, synergistic interaction between NVP-BEZ235 and cisplatin was evaluated by combination index (CI), three-dimensional model and clonogenic assay. The combination of NVP-BEZ235 and cisplatin caused significant synergistic antitumor effect in cisplatin-resistant bladder cancer cells over a wide dose range and reduced the IC50 of NVP-BEZ235 and cisplatin by 5.6- and 3.6-fold, respectively. Three-dimensional synergy analysis resulted in a synergy volume of 388.25 µM/ml2% indicating a strong synergistic effect of combination therapy. The combination therapy caused cell cycle arrest and caspase-dependent apoptosis. Although NVP-BEZ235 suppressed PI3K/mTOR signaling without any paradoxical induction of Akt activity, it caused MEK/ERK pathway activation. The present study demonstrated that the PI3K/mTOR dual inhibitor NVP-BEZ235 can synergistically potentiate the antitumor effects of cisplatin in cisplatin-resistant bladder cancer cells though the suppression of cell cycle progression and the survival pathway as well as induction of caspase-dependent apoptosis.

Trends in renal function after radical nephrectomy: a multicentre analysis.

OBJECTIVE: To evaluate serial changes in renal function by investigating various clinical factors after radical nephrectomy (RN). PATIENTS AND METHODS: The study population consisted of 2068 consecutive patients who were treated at multiple institutions by RN for renal cortical tumour without metastasis between 1999 and 2011. We measured the serial change in estimated glomerular filtration rate (eGFR) and clinical factors during a 60-month follow-up period. The changes in eGFR over time were analysed according to baseline eGFR (eGFR ≥60 and 15-59 mL/min/1.73m(2) ) using a linear mixed model. The independent prognostic value of various clinical factors on the increase in eGFR was ascertained by multivariate mixed regression model. RESULTS: Overall, there was a subsequent restoration of renal function over the 60 months. The slope for the relationship between the eGFR and the time since RN was 0.082 (95% confidence interval [CI] 0.039-0.104; P < 0.001) and 0.053 (95% CI 0.006-0.100; P = 0.038) in each baseline group, indicating that each month after RN was associated with an increase in eGFR of 0.082 and 0.053 mL/min/1.73m(2) , respectively. When we analysed renal function based on various factors, postoperative eGFR of patients with diabetes mellitus, old age (≥70 years) or a preoperative eGFR of <30 mL/min/1.73 m(2) , was decreased or maintained at a certain level without any improvement in renal function. Preoperative predictors of an increase in eGFR after RN were young age, no DM, no hypertension, a preoperative eGFR of ≥30 mL/min/1.73m(2) and time after surgery (≥36 months). CONCLUSIONS: Renal function recovered continuously during the 60-month follow-up period after RN. However, the trends in functional recovery change were different according to various clinical factors and such information should be discussed with patients when being counselled about their treatment for renal cell carcinoma (RCC).

Does obesity affect the accuracy of prostate-specific antigen (PSA) for predicting prostate cancer among men undergoing prostate biopsy.

UNLABELLED: What's known on the subject? and what does the study add?: As most urologist known, obesity significantly lowers serum PSA levels. So there is some concern about delayed diagnosis of prostate cancer in obese men. In the present study, we found that the accuracy level of PSA for detecting prostate cancer was not significantly different between different obesity levels. A well-designed study adjusting for several factors, e.g. diet, exercise, medication and comorbidity, which may possibly compensate for the associated effects on PSA levels, is needed for confirmation of the present findings. OBJECTIVE: To investigate prostate-specific antigen (PSA) accuracy in detecting prostate cancer according to body mass index (BMI) in Asian men with a PSA level of <30 ng/mL using contemporary multicore (≥ 12) prostate biopsy. PATIENTS AND METHODS: We reviewed the records of 3471 patients, whose initial PSA levels were <30 ng/mL, who underwent multicore (≥ 12) transrectal ultrasound-guided prostate biopsy between January 2004 and May 2011. BMI was categorised as performed previously for the Asian population: <23, 23-24.9, 25-29.9, and ≥ 30 kg/m(2) . PSA accuracy for detecting prostate cancer in each BMI group was assessed based on the receiver operating characteristics-derived area under the curve. RESULTS: The mean age and median PSA level were inversely associated with BMI; the median PSA level in each BMI category was 7.84, 7.75, 7.33 and 5.79 ng/mL, respectively (P < 0.001). In all, prostate cancer was detected from biopsy in 1102 (31.7%) patients. The PSA accuracy for predicting prostate cancer in all patients was estimated to be 0.607, and PSA accuracies in each BMI category were 0.638, 0.572, 0.613 and 0.544, respectively; there was no significant difference among the groups in terms of PSA accuracy. CONCLUSIONS: The accuracy of PSA in predicting prostate cancer did not change regardless of BMI category in Asian men. However, as patients with higher BMIs had lower PSA levels than those with lower BMIs, it can therefore be suggested that the PSA threshold should be lower in obese men to discriminate between prostate cancer and benign conditions in the real clinical situation.

Application of simplified Fuhrman grading system in clear-cell renal cell carcinoma.

OBJECTIVE: To investigate the efficacy of simplified (two- or three-tiered) Fuhrman grading systems as prognostic indicators in clear-cell renal cell carcinoma (RCC). PATIENTS AND METHODS: By reviewing records, various clinicopathological factors were assessed in 431 patients who received surgical management for clear-cell RCC. A conventional four-tiered Fuhrman grading system was compared with a modified two-tiered grading system (Fuhrman grades I and II were combined as one class, and grades III and IV as another) and also with a three-tiered grading system (only grades I and II were combined). Efficacies of grading systems were assessed via univariate analyses and multivariate models for prediction of cancer-specific survival. RESULTS: In univariate analysis, the four-tiered and three-tiered grading systems showed similar accuracies (76.5 vs 76.2%, P =0.614) for predicting cancer-specific survival, which were greater than that of the two-tiered system (72.5%; both P < 0.05). Of the three grading systems, only the three-tiered system was an independent predictor of cancer-specific survival in multivariate analysis (P = 0.046). When receiver operating characteristic-derived areas under the curve (AUCs) of multivariate models for predicting cancer-specific survivals were assessed, AUCs for models including the three-tiered Fuhrman grading system and the conventional four-tiered Fuhrman grading system were the same (95.3%), followed by that of a model incorporating the two-tiered grading system (95.1%). CONCLUSION: A modified, three-tiered Fuhrman grading system can be considered an appropriate option in the application of a nuclear grading system to the prognostication of clear-cell RCC in both univariate analysis and multivariate model setting.

Application of the Epstein criteria for prediction of clinically insignificant prostate cancer in Korean men.

OBJECTIVE: To investigate the rate of pathologically confirmed unfavourable prostate cancers among Korean men who fulfilled the contemporary Epstein criteria for clinically insignificant prostate cancer. PATIENTS AND METHODS: This was a retrospective study of 131 Korean men who underwent radical prostatectomy (RP) for clinically insignificant prostate cancer as defined by contemporary Epstein criteria. We assessed the percentage of unfavourable prostate cancer (pathological Gleason sum > or = 7 and/or extraprostatic extension [EPE]) among these men and tried to identify useful predictors for such unfavourable tumour profiles using uni- and multivariate analyses. RESULTS: Among 131 men with clinically insignificant prostate cancer, 40 (30.5%) had pathological Gleason > or = 7 tumours after RP. Of these 40 men, four (3.1%) also had EPE on examination of RP specimen. All those who did not have Gleason score upgrading after RP had organ-confined disease from examination of RP specimen. Overall, 40 (30.5%) of the 131 men who fulfilled the contemporary Epstein criteria for clinically insignificant prostate cancer before RP had pathologically unfavourable disease. Among our patients, no significant preoperative predictor of pathologically unfavourable disease was identified using uni- and multivariate analyses. CONCLUSION: Our results showed that a significant proportion of contemporary Korean patients who meet all the conditions of the contemporary Epstein criteria for prediction of clinically insignificant prostate cancer might actually harbour prostate cancer with unfavourable pathological features. Such findings should be considered when treatment options are contemplated based upon the Epstein criteria among Asian patients.

Effects of ovariectomy and oestrogen replacement on the function and expression of Rho-kinase in rat bladder smooth muscle.

OBJECTIVE: To investigate the effects of ovariectomy and oestrogen replacement on the function and expression of Rho-kinase in rat bladder smooth muscle, as the actual effects of oestrogen deprivation on bladder smooth muscle are unclear. MATERIALS AND METHODS: Female Sprague-Dawley rats were placed into one of three groups: sham-operated, bilateral ovariectomy-only, and bilateral ovariectomy plus oestrogen replacement groups. In the last group, oestrogen was replaced by weekly injection of beta-estradiol 17-cypionate (250 microg/kg subcutaneously for 6 weeks) beginning at 1 week after ovariectomy, whereas the other groups received vehicle-only injections for 6 weeks. After treatment, the bladder was removed for muscle strip studies to evaluate the effects of Y-27632, a specific inhibitor of Rho-kinase, on baseline tension and carbachol-induced tonic contractions. Also, the protein expression of RhoA and Rho-kinase isoenzymes was assessed by Western blot analysis. RESULTS: Of the three groups, incubation with 10 microm Y-27632 resulted in the largest decrease in baseline tension of strips from the bilateral ovariectomy-only group, but this was not statistically significant (P > 0.05). For carbachol-induced tonic contractions, strips from the bilateral ovariectomy-only group were attenuated the most among the three groups after adding Y-27632 (P < 0.05). However, there were no significant differences in the levels of RhoA and the two Rho-kinase isoenzymes in bladder tissues from the three groups. CONCLUSION: Our data show that oestrogen might inhibit the function of Rho-kinase in bladder smooth muscle, while having no significant effect on its expression. This finding might help to explain the greater incidence of urinary tract symptoms suggestive of overactive bladder after the menopause in women.

Effect of glycine on recovery of bladder smooth muscle contractility after acute urinary retention in rats.

OBJECTIVE: To investigate the effects of glycine on the recovery of bladder smooth muscle contractility after acute urinary retention. MATERIALS AND METHODS: Bladder overdistension was induced in Sprague-Dawley rats by an infusion of saline (twice the threshold volume), maintained for 2 h. From 15 min before emptying of the bladder until 2 h after, saline or glycine solution was infused i.v. At 30 min, 2 h and 1 week after bladder emptying, samples of bladder tissue were taken for muscle strip study, malondialdehyde (MDA) assay, ATP assay, Western blotting for apoptosis-related molecules (Bcl-2, Bax, Caspase-3), and histological analysis including terminal deoxynucleotidyl transferase-mediated nick-end labelling staining. The results were compared among normal control, saline-treated and glycine-treated rats. RESULTS: In the glycine-treated group, muscle strip contractile responses induced by electrical-field stimulation and carbachol were both significantly greater at 1 week after bladder emptying than in the saline-treated group. The results of the ATP assay appeared to correspond with those of the muscle strip study. The saline-treated group had significantly higher MDA levels at 30 min after bladder emptying than the glycine-treated group. At 2 h after bladder emptying, there was significantly more apoptosis and greater leukocyte infiltration in the saline-treated group than in the glycine-treated group. While pro-apoptotic Bax and caspase-3 were down-regulated, Bcl-2 was up-regulated in the glycine-treated group. CONCLUSION: Glycine infusions might improve the contractile responses of bladder smooth muscle after acute urinary retention by reducing oxidative damage and apoptosis.