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BACKGROUND: The aim of this study is to examine chronic kidney disease (CKD) as a risk factor for bladder recurrence and cancer-specific and total mortality in a cohort of patients with upper urinary tract (UUT) urothelial carcinoma (UC) treated by means of nephroureterectomy. STUDY DESIGN: Cohort study. SETTINGS & PARTICIPANTS: 150 patients with primary UC of the ureter or renal pelvis treated by means of nephroureterectomy at a single center. PREDICTOR: Presence and severity of CKD according to preoperative markers of kidney damage, estimated glomerular filtration rate calculated using the Modification of Diet in Renal Disease Study equation, and other covariates. OUTCOMES & MEASUREMENTS: Subsequent bladder recurrences, cancer-specific survival, and overall survival. RESULTS: Of 150 patients, 37 (25%) had no CKD, 71 patients (47%) had CKD stages 1 to 4, and 42 patients (28%) had CKD stage 5. 41 (27%) and 31 patients (21%) reported exposure to herbal medicine or tobacco use, respectively. During a mean follow-up of 4 years, 53 patients (35%) developed bladder recurrence and 27 (18%) died, of whom 14 (9.3%) died of cancer. Overall 5-year bladder recurrence-free and cancer-specific survival rates were 62% and 89%, respectively (n = 150). Risks of bladder recurrence were 2.43 (95% confidence interval, 1.00 to 5.93) and 3.95 (95% confidence interval, 1.59 to 9.80), greater in patients with CKD stages 1 to 4 and CKD stage 5 compared with patients without CKD, respectively. Ureteral involvement of the primary tumor (hazard ratio, 1.97; 95% confidence interval, 1.12 to 3.48) also was associated significantly with an increased rate of bladder recurrence. The risk of death from all causes or UC was not significantly greater in patients with CKD stages 1 to 4 or CKD stage 5 compared with those without CKD. Higher tumor stage (pT2 to 4) was associated significantly with overall death (hazard ratio, 5.15; 95% confidence interval, 1.84 to 14.48). LIMITATIONS: A retrospective study in an area of high incidence of both UUT-UC and CKD. CONCLUSIONS: Advancing CKD stage of patients and positive ureteral involvement of the primary tumor (especially in the lower ureter) are associated with greater risk of subsequent bladder recurrence in patients with UUT-UC treated by means of radical surgery. Copyright © 2007 by Elsevier Inc. [ABSTRACT FROM AUTHOR]

Background/Objectives: Patients with non-metastatic castration-resistant prostate cancer (nmCRPC) and high-risk features frequently have progression to life-threatening metastasis without second-generation antiandrogens. This study investigated nmCRPC patients for the survival and prognostic factors from a cohort before the approved use of second-generation antiandrogens. Methods: From March 2016 to January 2021, 326 patients treated with second-generation antiandrogens for metastatic castration-resistant prostate cancer (mCRPC) or metastatic castration-sensitive prostate cancer were retrieved. Forty-four patients experiencing nmCRPC with no use of second-generation antiandrogens were reviewed. The prognostic factors, at initial diagnosis or at nmCRPC, associated with metastasis-free survival (MFS) and overall survival (OS) were analyzed. Results: The median follow-up time after nmCRPC was 46 months. The median PSA level at nmCRPC was 2.7 ng/mL. Thirty-eight of forty-four patients with nmCRPC had a PSA doubling time (PSADT) of 10 months or shorter, and the median PSADT was 4 months. The median OS from nmCRPC was 53 months, and the median interval for nmCRPC patients progressing to mCRPC was 20 months. Upon univariate analysis, PSADT < 10 months ( p = 0.049) and the very-high-risk group at the initial diagnosis ( p = 0.043) were associated with significantly shorter post-nmCRPC MFS. The very-high-risk group ( p = 0.031) was associated with significantly worse post-nmCRPC OS. In terms of survivals from the initial diagnosis of prostate cancer, Gleason grade ≥ 8 was the only independent factor with MFS and OS. Conclusions: Without second-generation antiandrogens, nmCRPC patients with PSADT <10 months and in the initial very-high-risk group developed subsequent mCRPC in a significantly faster fashion. Patients of the very-high-risk group had shorter survival rates after nmCRPC.

Aim: The aim of the third Asia-Pacific Advanced Prostate Cancer Consensus Conference (APAC APCCC 2023) was to discuss the application in the Asia-Pacific (APAC) region of consensus statements from the 4th Advanced Prostate Cancer Consensus Conference (APCCC 2022)., Methods: The one-day meeting in July 2023 brought together 27 experts from 14 APAC countries. The meeting covered five topics: (1) Intermediate- and high-risk and locally advanced prostate cancer; (2) Management of newly diagnosed metastatic hormone-sensitive prostate cancer; (3) Management of non-metastatic castration-resistant prostate cancer; (4) Homologous recombination repair mutation testing; (5) Management of metastatic castration-resistant prostate cancer. Pre- and post-symposium polling gathered APAC-specific responses to APCCC consensus questions and insights on current practices and challenges in the APAC region., Results: APAC APCCC highlights APAC-specific considerations in an evolving landscape of diagnostic technologies and treatment innovations for advanced prostate cancer. While new technologies are available in the region, cost and reimbursement continue to influence practice significantly. Individual patient considerations, including the impact of chemophobia on Asian patients, also influence decision-making., Conclusion: The use of next-generation imaging, genetic testing, and new treatment combinations is increasing the complexity and duration of prostate cancer management. Familiarity with new diagnostic and treatment options is growing in the APAC region. Insights highlight the continued importance of a multidisciplinary approach that includes nuclear medicine, genetic counseling, and quality-of-life expertise. The APAC APCCC meeting provides an important opportunity to share practice and identify APAC-specific issues and considerations in areas of low evidence where clinical experience is growing., (© 2024 The Authors. Asia‐Pacific Journal of Clinical Oncology published by John Wiley & Sons Australia, Ltd.)

Purpose: Active surveillance (AS) is one of the management options for patients with low-risk and select intermediate-risk prostate cancer (PC). However, factors predicting disease reclassification and conversion to active treatment from a large population of pure Asian cohorts regarding AS are less evaluated. This study investigated the intermediate-term outcomes of patients with localized PC undergoing AS., Materials and Methods: This cohort study enrolled consecutive men with localized non-high-risk PC diagnosed in Taiwan between June 2012 and Jan 2023. The study endpoints were disease reclassification (either pathological or radiographic progression) and conversion to active treatment. The factors predicting endpoints were evaluated using the Cox proportional hazards model., Results: A total of 405 patients (median age: 67.2 years) were consecutively enrolled and followed up with a median of 64.6 months. Based on the National Comprehensive Cancer Network (NCCN) risk grouping, 70 (17.3%), 164 (40.5%), 140 (34.6%), and 31 (7.7%) patients were classified as very low-risk, low-risk, favorable-intermediate risk, and unfavorable intermediate-risk PC, respectively. The 5-year reclassification rates were 24.8%, 27.0%, 18.6%, and 25.3%, respectively. The 5-year conversion rates were 20.4%, 28.8%, 43.6%, and 37.8%, respectively. A prostate-specific antigen density (PSAD) of ≥0.15 ng/mL² predicted reclassification (hazard ratio [HR] 1.84, 95% confidence interval [CI] 1.17-2.88) and conversion (HR 1.56, 95% CI 1.05-2.31). A maximal percentage of cancer in positive cores (MPCPC) of ≥15% predicted conversion (15% to <50%: HR 1.41, 95% CI 0.91-2.18; ≥50%: HR 1.97, 95% CI 1.1453-3.40) compared with that of <15%. A Gleason grade group (GGG) of 3 tumor also predicted conversion (HR 2.69, 95% CI 1.06-6.79; GGG 3 vs 1). One patient developed metastasis, but none died of PC during the study period (2,141 person-years)., Conclusions: AS is a viable option for Taiwanese men with non-high-risk PC, in terms of reclassification and conversion. High PSAD predicted reclassification, whereas high PSAD, MPCPC, and GGG predicted conversion., Competing Interests: The authors have nothing to disclose., (Copyright © 2024 Korean Society for Sexual Medicine and Andrology.)

Purpose: Biomarkers predicting clinically significant prostate cancer (sPC) before biopsy are currently lacking. This study aimed to develop a non-invasive urine test to predict sPC in at-risk men using urinary metabolomic profiles., Materials and Methods: Urine samples from 934 at-risk subjects and 268 treatment-naïve PC patients were subjected to liquid chromatography/mass spectrophotometry (LC-MS)-based metabolomics profiling using both C18 and hydrophilic interaction liquid chromatography (HILIC) column analyses. Four models were constructed (training cohort [n=647]) and validated (validation cohort [n=344]) for different purposes. Model I differentiates PC from benign cases. Models II, III, and a Gleason score model (model GS) predict sPC that is defined as National Comprehensive Cancer Network (NCCN)-categorized favorable-intermediate risk group or higher (Model II), unfavorable-intermediate risk group or higher (Model III), and GS ≥7 PC (model GS), respectively. The metabolomic panels and predicting models were constructed using logistic regression and Akaike information criterion., Results: The best metabolomic panels from the HILIC column include 25, 27, 28 and 26 metabolites in Models I, II, III, and GS, respectively, with area under the curve (AUC) values ranging between 0.82 and 0.91 in the training cohort and between 0.77 and 0.86 in the validation cohort. The combination of the metabolomic panels and five baseline clinical factors that include serum prostate-specific antigen, age, family history of PC, previously negative biopsy, and abnormal digital rectal examination results significantly increased AUCs (range 0.88-0.91). At 90% sensitivity (validation cohort), 33%, 34%, 41%, and 36% of unnecessary biopsies were avoided in Models I, II, III, and GS, respectively. The above results were successfully validated using LC-MS with the C18 column., Conclusions: Urinary metabolomic profiles with baseline clinical factors may accurately predict sPC in men with elevated risk before biopsy., Competing Interests: The authors have nothing to disclose., (Copyright © 2024 Korean Society for Sexual Medicine and Andrology.)

Purpose: Our previous study revealed that elevated C-C motif chemokine ligand 2 (CCL2) secretion by irradiated cancer cells recruited C-C motif chemokine receptor 2 (CCR2)-positive myeloid cells and polarized M2-type tumor-associated macrophages (TAMs), promoting lung metastasis in an established mouse model. This study investigated the impact of CCL2 and TAMs on adaptive immunity., Methods: We assessed the influence of CCL2 and TAMs on adaptive immunity through two ectopic allograft mouse models constructed with MB49 bladder cancer cells and Lewis lung carcinoma cells. Both models exhibited delayed primary tumor growth following radiation therapy (RT), but RT promoted the development of pulmonary metastases in C57BL/6 mice. Additionally, we employed a direct coculture system to investigate the interaction between macrophages and target cells in the context of adaptive immunity., Results: C-C motif chemokine receptor 4 (CCR4)-positive regulatory T cells (Tregs) were recruited to the postirradiated tumor microenvironment (TME). Utilizing a CCR4 antagonist to inhibit CCL2-CCR4 activation reversed the infiltration of CCR4 + Tregs and reduced the incidence of pulmonary metastases. In addition, a positive feedback loop between M2-type TAMs and Tregs was observed. The combined blockade of the CCL2-CCR4 and CCL2-CCR2 signaling pathways further decreased the risk of RT-promoted lung metastasis., Conclusion: The recruitment of CCR4 + Tregs to the postirradiated TME increases the metastatic potential of tumor cells through increased interactions with M2-type TAMs. A significant reduction in post-RT lung metastases in ectopic mouse models was achieved by disrupting the recruitment of both CCR4 + Tregs and CCR2 + myeloid cells, which are TAM precursors., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Docetaxel-based chemotherapy has generally been considered as one of the effective treatments for castration-resistant prostate cancer (PCa). However, clinical treatment with docetaxel often encounters a number of undesirable effects, including drug resistance. Tubulin isoforms have been previously examined for their resistance to docetaxel in many cancers, but their real mechanisms remained unclear. In this study, a series of docetaxel-resistant PC/DX cell sublines were established by chronically exposing PC3 to progressively increased concentrations of docetaxel. Western blotting results showed significantly higher expression of acetyl-tubulin, α-tubulin, β-tubulin, γ-tubulin, and βIII-tubulin in PC/DX25 than in parental PC3 cells. PC/DX25 with greater resistance to docetaxel had higher levels of acetyl-tubulin and mitotic centromere-associated kinesin (MCAK) than PC3 cells. This study found that docetaxel induced the expression of acetyl-tubulin and MCAK in PC3 cells at a dose- and time-dependent manner. Both mRNA and protein levels of histone deacetylase 6 (HDAC6) were significantly decreased in PC/DX25 compared with PC3 cells. PC3 increased the resistance to docetaxel by HDAC6 knockdown and Tubastatin A (HDAC6 inhibitor). Conversely, PC/DX25 reversed the sensitivity to docetaxel by MCAK knockdown. Notably, flow cytometry analysis revealed that MCAK knockdown induced significantly sub G1 fraction in PC/DX cells. Overexpression of polo-like kinase-1 increased the cell survival rate and resistance to docetaxel in PC3 cells. Moreover, epidermal growth factor receptor (EGFR) activation induced the upregulation of acetyl-tubulin in docetaxel-resistant PCa cells. These findings demonstrated that the EGFR-mediated upregulated expression of acetyl-tubulin played an important role in docetaxel-resistant PCa., (© 2023 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia, Ltd on behalf of Kaohsiung Medical University.)

Purpose: Currently, there are no accurate markers for predicting potentially lethal prostate cancer (PC) before biopsy. This study aimed to develop urine tests to predict clinically significant PC (sPC) in men at risk., Methods: Urine samples from 928 men, namely, 660 PC patients and 268 benign subjects, were analyzed by gas chromatography/quadrupole time-of-flight mass spectrophotometry (GC/Q-TOF MS) metabolomic profiling to construct four predictive models. Model I discriminated between PC and benign cases. Models II, III, and GS, respectively, predicted sPC in those classified as having favorable intermediate risk or higher, unfavorable intermediate risk or higher (according to the National Comprehensive Cancer Network risk groupings), and a Gleason sum (GS) of ≥ 7. Multivariable logistic regression was used to evaluate the area under the receiver operating characteristic curves (AUC)., Results: In Models I, II, III, and GS, the best AUCs (0.94, 0.85, 0.82, and 0.80, respectively; training cohort, N = 603) involved 26, 24, 26, and 22 metabolites, respectively. The addition of five clinical risk factors (serum prostate-specific antigen, patient age, previous negative biopsy, digital rectal examination, and family history) significantly improved the AUCs of the models (0.95, 0.92, 0.92, and 0.87, respectively). At 90% sensitivity, 48%, 47%, 50%, and 36% of unnecessary biopsies could be avoided. These models were successfully validated against an independent validation cohort (N = 325). Decision curve analysis showed a significant clinical net benefit with each combined model at low threshold probabilities. Models II and III were more robust and clinically relevant than Model GS., Conclusion: This urine test, which combines urine metabolic markers and clinical factors, may be used to predict sPC and thereby inform the necessity of biopsy in men with an elevated PC risk., (© 2023. BioMed Central Ltd., part of Springer Nature.)

The role of prostate cryoablation was still uncertain for patients with high-risk prostate cancer (PC). This study was designed to investigate 10-year disease-free survival and establish a nomogram in localized high-risk PC patients. Between October 2008 and December 2020, 191 patients with high-risk PC who received primary total prostate cryoablation (PTPC) were enrolled. The primary endpoint was biochemical recurrence (BCR), defined using Phoenix criteria. The performance of pre-operative and peri-operative nomograms was determined using the Harrell concordance index (C-index). Among the cohort, the median age and PSA levels at diagnosis were 71 years and 12.3 ng/mL, respectively. Gleason sum 8-10, stage ≥ T3a, and PSA > 20 ng/mL were noted in 27.2%, 74.4%, and 26.2% of patients, respectively. During the median follow-up duration of 120.4 months, BCR-free rates at 1, 3, 5, and 10 years were 92.6%, 76.6%, 66.7%, and 50.8%, respectively. The metastasis-free, cancer-specific, and overall survival rates were 89.5%, 97.4%, and 90.5% at 10 years, respectively. The variables in the pre-operative nomogram for BCR contained PSA at diagnosis, clinical stage, and Gleason score (C-index: 0.73, 95% CI, 0.67-0.79). The variables in the peri-operative nomogram for BCR included PSA at diagnosis, Gleason score, number of cryoprobes used, and PSA nadir (C-index: 0.83, 95% CI, 0.78-0.88). In conclusion, total prostate cryoablation appears to be an effective treatment option for selected men with high-risk PC. A pre-operative nomogram can help select patients suitable for cryoablation. A peri-operative nomogram signifies the importance of the ample use of cryoprobes and helps identify patients who may need early salvage treatment.

Purpose: To investigate the survival outcomes of metastatic castration-resistant prostate cancer (mCRPC) patients receiving first-line novel androgen receptor axis-targeted therapies (ARATs) and prognostic factors for patient survival., Methods: This retrospective study obtained data from 202 patients who started abiraterone acetate or enzalutamide as first-line therapy for mCRPC between 2016 and 2021 from a single academic center. The primary endpoint was overall survival (OS) defined as the interval from the start of ARAT to death, loss to follow-up, or the end of the study period. The secondary endpoints were PSA decline, PSA nadir, and time to nadir (TTN) after ARATs. Kaplan-Meier survival analyses were applied for depicting OS. Cox proportional hazards model with inversed probability of treatment weighing-adjustment was used to validate the effect of patient, disease, and treatment response factors on OS., Results: Among 202 patients, 164 patients were treated with first-line ARATs alone and 38 patients received second-line chemotherapy. The median OS was not reached in patients with first-line ARATs alone and was 38.8 months in those with subsequent chemotherapy after failure from ARATs. OS was not different between the use of abiraterone and enzalutamide, though enzalutamide showed a higher rate of PSA decline ≧ 90% (56% versus 40%, p = 0.021) and longer TTN (5.5 versus 4.7 months, p = 0.019). Multivariable analysis showed that PSA nadir > 2 ng/mL [hazard ratio (HR) 7.04, p < 0.001] and TTN<7 months (HR 2.18, p = 0.012) were independently associated with shorter OS. Patients with both of these poor prognostic factors had worse OS compared to those who had 0-1 factors (HR 9.21, p < 0.001)., Conclusions: Patients with mCRPC who received first-line ARATs had better survival if they had a PSA nadir[Formula: see text]2 ng/mL or a TTN[Formula: see text]7 months. Further study is needed to determine if an early switch in therapy for those in whom neither is achieved may impact OS., (© 2023. The Author(s).)

Background: Although trimodality therapy resecting tumours followed by chemoradiotherapy is emerged for muscle-invasive bladder cancer (MIBC), chemotherapy produces toxicities. Histone deacetylase inhibitors have been identified as an effective strategy to enhance cancer radiotherapy (RT)., Methods: We examined the role of HDAC6 and specific inhibition of HDAC6 on BC radiosensitivity by performing transcriptomic analysis and mechanism study., Results: HDAC6 knockdown or HDAC6 inhibitor (HDAC6i) tubacin exerted a radiosensitizing effect, including decreased clonogenic survival, increased H3K9ac and α-tubulin acetylation, and accumulated γH2AX, which are similar to the effect of panobinostat, a pan-HDACi, on irradiated BC cells. Transcriptomics of shHDAC6-transduced T24 under irradiation showed that shHDAC6 counteracted RT-induced mRNA expression of CXCL1, SERPINE1, SDC1 and SDC2, which are linked to cell migration, angiogenesis and metastasis. Moreover, tubacin significantly suppressed RT-induced CXCL1 and radiation-enhanced invasion/migration, whereas panobinostat elevated RT-induced CXCL1 expression and invasion/migration abilities. This phenotype was significantly abrogated by anti-CXCL1 antibody, indicating the key regulator of CXCL1 contributing to BC malignancy. Immunohistochemical evaluation of tumours from urothelial carcinoma patients supported the correlation between high CXCL1 expression and reduced survival., Conclusion: Unlike pan-HDACi, the selective HDAC6i can enhance BC radiosensitization and effectively inhibit RT-induced oncogenic CXCL1-Snail-signalling, thus further advancing its therapeutic potential with RT., (© 2023. The Author(s).)

Purpose: The high incidence of upper urinary tract urothelial carcinoma (UTUC) in Taiwan is largely due to exposure to aristolochic acid (AA), a principal component of Aristolochia-based herbal medicines. Here we systematically review the molecular epidemiology, clinical presentation and biomarkers associated with AA-induced UTUC., Methods: This is a narrative review. Medline, Embase, and Web of Science were searched from inception to December 31, 2021. Studies evaluating the association, detection, and clinical characteristics of AA and UTUC were included., Results: A nationwide database revealed 39% of the Taiwanese population had been exposed to AA-containing herbs between 1997 and 2003. Epidemiological reports revealed AA posed a significantly higher hazard for renal failure and UTUC in herbalists and the general population who ingested AA-containing herbs. The presence of aristolactam-DNA adducts and a distinctive signature mutation, A:T to T:A transversions, located predominantly on the non-transcribed DNA strand, with a strong preference for deoxyadenosine in a consensus sequence (CAG), was observed in many UTUC patients. Clinically, AA-related UTUC patients were characterized by a younger age, female gender, impaired renal function and recurrence of contralateral UTUC. To date, there are no preventive measures, except prophylactic nephrectomy, for subjects at risk of AA nephropathy or AA-related UTUC., Conclusion: AA exposure via Aristolochia-based herbal medicines is a problem throughout Taiwan, resulting in a high incidence of UTUC. Aristolactam-DNA adducts and a distinctive signature mutation, A:T to T:A transversions, can be used as biomarkers to identify AA-related UTUC. AA-related UTUC is associated with a high recurrence rate of contralateral UTUC., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Aristolochic acid (AA) is a carcinogen in upper urinary tract urothelial carcinoma (UTUC). This study investigated the latency period between AA exposure and UTUC development., Materials and Methods: This population-based cohort study was designed using record linkage of the National Health Insurance Research Database (NHIRD), Taiwan Cancer Registry Dataset, and cause-of-death data in Taiwan. Those aged 40-79 years were enrolled in this study. Patients who died or had renal insufficiency or UTUC before 2005 were excluded. The doses of AA exposure and rates of comorbidities between 2000 and 2005 were obtained. The Cox proportion hazard model was used to estimate the risk of UTUC between 2005 and 2016. In addition, the Cox model with time-varying coefficient of AA was used to measure the latency period of UTUC., Results: Of the 752,232 participants enrolled from the NHIRD, 520,871 (68.29%), 210,447 (27.59%), and 31,415 (4.12%) were exposed to cumulative AA doses of 0-1 mg, 1-150 mg, and >150 mg, respectively. A total of 1,147 (0.15%) patients were diagnosed with UTUC between 2005 and 2016. The latency periods of UTUC in middle-aged (40-59 years old) men with cumulative AA doses of 1-150 mg and middle-aged women with cumulative AA doses of 1-150 mg and >150 mg were 8, 9, and 7 years, respectively. Among the aged (60-79 years) individuals, no time-varying effect was observed, and the latency period could not be measured., Conclusion: A decreased risk of UTUC was observed after the ban on AA in Taiwan, especially in middle-aged women with moderate to high doses of AA exposure and men with moderate doses of AA exposure. The latency period of UTUC varies with age, the dose of AA exposure, and sex., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Jhuang, Chiu, Hsieh, Chen, Pu and Lee.)

Epigenetic effects of environmental pollutants may be related to carcinogenesis. This study aimed to explore the association between the global DNA methylation marker: 5-methyl-2-deoxycytidine (5mdC) and renal cell carcinoma (RCC), and further investigated whether plasma folate and vitamin B 12 levels and 5mdC modified the association between blood cadmium concentrations and RCC. We recruited 174 RCC patients and 673 non-RCC controls. Blood cadmium concentrations, plasma folate and vitamin B 12 levels were measured. The amount of 5mdC in the DNA sample was expressed as percentages of the total cytosine content. An increase of 5mdC (%) and plasma folate and vitamin B 12 levels were associated with decreasing odds ratio (OR) of RCC. Although plasma folate levels were not directly associated with 5mdC (%), a combined effect was observed with the odds of low plasma folate levels and low 5mdC (%) were greater among RCC patients compared to controls (OR (95% confidence interval, CI) = 11.86 (5.27-26.65)). Additionally, we observed that the odds of low plasma folate and high blood cadmium levels were greater among RCC patients than in controls (OR (95% CI): 8.15 (1.39-7.13)). This study provides suggestive evidence that plasma folate levels may modify the associations between 5mdC (%) or blood cadmium concentrations and RCC.

Novel hormonal agents (NHAs) have significantly improved outcomes in men with advanced prostate cancer. However, it remains unclear whether NHAs are associated with subsequent cognitive impairment. Thus, we sought to perform a network meta-analysis to compare the risk of cognitive impairment across NHA types. Databases (PubMed, Embase, Scopus, and Web of Science), trial registries (Clinicaltrial.gov), the European Medicines Agency, and the US Food and Drug Administration drug safety reports were searched from inception through July 30, 2021. Eligible studies were clinical trials evaluating the risk of cognitive impairment between NHAs and placebo/standard care. Two independent investigators extracted the data and performed quality assessments using the Cochrane Risk of Bias Tool and ROBINS-I. We estimated the risk ratios by the frequentist approach and calculated the ranking probabilities of all treatments with the surface under the cumulative ranking probabilities. The primary outcome and secondary outcome were odds ratio (OR) and incidence rate ratio of cognitive impairment, respectively. We identified 15 trials with 14,723 participants comparing HNAs with placebo/standard care. Treatments associated with cognitive impairment, from the most to the least, were enzalutamide (OR, 3.66; 95% confidence interval [CI], 2.84-4.73), apalutamide (OR, 1.76; 95% CI, 1.08-2.87), abiraterone acetate (OR, 1.64; 95% CI, 1.01-2.45), and darolutamide (OR, 1.11 95% CI, 0.51-2.39). After adjustment of treatment time duration, enzalutamide still had the highest risk of cognitive impairment with an incidence rate ratio of 2.17 (95% CI, 1.65-2.78). These findings suggest that NHAs, especially enzalutamide, may increase the risk of cognitive impairment compared with placebo/standard care., (© 2022 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Purpose: Radiation therapy (RT) is mainly used for bladder preservation in patients with muscle-invasive bladder cancer. The response of urothelial tumors to RT remains unsatisfactory. We investigated the interaction of RT and tumor-associated macrophages (TAMs) in the context of bladder cancer radioresistance., Methods and Materials: We evaluated the therapeutic effects of RT and TAM distribution by establishing an ectopic allograft mouse model. A Transwell coculture system was used to simulate the interaction between TAMs and MB49 bladder cancer cells in the tumor microenvironment. Cytokines and chemokines were analyzed in irradiated MB49 cells. Colony formation and Boyden chamber assays were used to assess the cytotoxic effects and the effects of TAMs on MB49 cell invasion, respectively., Results: Local RT delayed primary tumor growth but promoted pulmonary metastases in C57BL/6 mice. Increased secretion of C-C motif chemokine ligand (CCL2) by irradiated MB49 cells, especially in the presence of M1-type TAMs, contributed to the infiltration of bone marrow-derived C-C motif chemokine receptor 2 (CCR2)-positive myeloid cells and the polarization of M1-type TAMs toward the M2 type to promote MB49 cell invasion. Blockade of CCL2-CCR2 activation by a CCR2 antagonist reversed the phenotypic TAM transformation and suppressed pulmonary metastases., Conclusions: Bladder cancer cells responded to RT by producing CCL2, which recruited TAM precursors from bone marrow and polarized M1-type TAMs toward the M2 type. This phenotypic TAM transformation promoted the pulmonary metastasis of bladder cancer cells after RT. Disrupting the CCL2-CCR2 signaling axis in combination with RT holds promise for improving RT efficacy in bladder cancer., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Programmed cell death protein 1 (PD-1) checkpoint blockade therapy requires the CD28 co-stimulatory receptor for CD8 + T cell expansion and cytotoxicity. However, CD28 expression is frequently lost in exhausted T cells and during immune senescence, limiting the clinical benefits of PD-1 immunotherapy in individuals with cancer. Here, using a cereblon knockin mouse model that regains in vivo T cell response to lenalidomide, an immunomodulatory imide drug, we show that lenalidomide reinstates the anti-tumor activity of CD28-deficient CD8 + T cells after PD-1 blockade. Lenalidomide redirects the CRL4 Crbn ubiquitin ligase to degrade Ikzf1 and Ikzf3 in T cells and unleashes paracrine interleukin-2 (IL-2) and intracellular Notch signaling, which collectively bypass the CD28 requirement for activation of intratumoral CD8 + T cells and inhibition of tumor growth by PD-1 blockade. Our results suggest that PD-1 immunotherapy can benefit from a lenalidomide combination when treating solid tumors infiltrated with abundant CD28 - T cells., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of prostate cancer was published in 2020. It was therefore decided, by both the ESMO and the Singapore Society of Oncology (SSO), to convene a special, virtual guidelines meeting in November 2021 to adapt the ESMO 2020 guidelines to take into account the differences associated with the treatment of prostate cancer in Asia. These guidelines represent the consensus opinions reached by experts in the treatment of patients with prostate cancer representing the oncological societies of China (CSCO), India (ISMPO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence and was independent of the current treatment practices and drug access restrictions in the different Asian countries. The latter were discussed when appropriate. The aim is to provide guidance for the optimisation and harmonisation of the management of patients with prostate cancer across the different regions of Asia., Competing Interests: Disclosure RK declares institutional payments from Pfizer, MSD, BMS, Eisai, Amgen, Astellas, J&J, Novartis and Merck and support for meeting attendance or travel from Pfizer, MSD, BMS, Eisai, Amgen, Astellas, J&J, Novartis and Merck. EC declares an institutional grant from Janssen, consulting fees from Astellas, AstraZeneca, Bayer, MSD and Pfizer, fees and honoraria for lectures, presentations from Astellas, AstraZeneca, Bayer, Janssen, MSD and Pfizer and support for attending meetings or travel from AstraZeneca and Janssen. AW declares personal fees from MS, MSD, Pfizer, Eisai and IPSEN and participation on a data safety monitoring or advisory board for BMS, MSD, Pfizer, Eisai and IPSEN. KF declares institutional honoraria for participation in advisory boards and talks for: Amgen, Astellas, Astrazeneca, Bayer, Clovis, Janssen, MSD, Novartis/AAA, Pfizer and Sanofi, and personal honoraria for participation to advisory boards for CureVac and Orion. MLKC declares payments or honoraria from ImmunoScape, IQVIA, Telix, Atsellas, AstraZeneca, Bayer, Illumina, Janssen, MSD, Pfizer and Varian, participation on a data safety monitoring or advisory board for AstraZeneca, Astellas, Bayer Pharma, Illumina, Janssen Pharma, MSD Oncology and Varian, a grant from Ferring, stock option in Digital Life Line, a role with the F1000—Head and Neck Cancer Section, Singapore Society of Oncology and Head Neck Caner International Group and other financial interests in Medlever and Varian. HM declares personal fees from CIPLA, Novartis, AstraZeneca, Roche, Eli Lilly, Merck, Pfizer, MSD, CADILA, Bard India and Somex Research. YM declares payments or honoraria from BMS, MSD and Takeda, participation on an advisory board for Chugai Pharmaceutical and Takeda and local PI, institutional, financial interest from MSD. JLL declares institutional grants or contracts from Pfizer, Novartis BMS, Janssen, MSD, Roche/Genetech, AstraZeneca/MedImmune, Seagen Astellas, Bayer, Schering Pharma, Lilly and Merck and participation on a data safety monitoring or advisory board from Pfizer Korea, Astella Korea, BMS, Merck, MSD, AstraZeneca, stocks or stock options from Myovant Sciences, Amgen, Johnson and Johnson and Merck. YSP declares honoraria and consulting fees from MSD, Roche, Merck, Ipsen, BMS/ONO, Novartis, Pfizer, Astellas, Janssen and GSK and support for attending meetings and/or travel from Ipsen, BMS/ONO, Novartis, Pfizer, Astellas and Janssen. MS declares research grants from Johnson and Johnson, payments or honoraria from Johnson and Johnson, AstraZeneca, Amgen and CIPLA, support for meeting attendance from Astellas, fees for participation in data monitoring or advisory boards from Johnson and Johnson, Amgen and AstraZeneca and receipt of equipment/materials for a compassionate programme for drugs/drug samples from Johnson and Johnson, AstraZeneca and Astellas. HJL declares participation on a data safety monitoring or advisory board for Astellas Korea. HK declares payments or honoraria from Astellas, AstraZeneca, Janssen, Sanofi and Takeda and payment for expert testimony and participation in an advisory board for Janssen. KP declares institutional research funding from Dr Reddy’s Laboratories Inc., Fresenius Kabi India Pvt. Ltd., Alkem Laboratories, Natco Pharma Ltd., BDR Pharmaceuticals Intl. Pvt. Ltd and Roche Holding AG and a role with ICON and the FHNO. GC declares institutional grants from Merck, consulting fees from BMS, Roche, Pfizer, MSD, AstraZeneca, Daichii Sankyo, Lilly, Novartis Ellipsis and Seagen, payment or honoraria from Pfizer and Lilly and support for attending meetings from Roche and Pfizer. EP declares grants and contracts form the National Cancer Centre research fund and Singapore Health Duke-NUS Oncology Academic Clinical Programme Sarcoma Research Fund award and Vice Presidency of the SSO. SPC declares consulting fees from BMS, AstraZeneca, Roche and Eisai and payment or honoraria from BMS, AstraZeneca, Roche, MSD, Eisai and Servier. SP declares fees for consultancy/advisory roles from AbbVie, Amgen, AstraZeneca, Bayer, Beigene, Biocartis, Boehringer Ingelheim, BMS, Clovis, Daiichi Sankyo, Debiopharm, ecancer, Eli Lilly, Elsevier, Foundation Medicine, Illumina, Imedex, Incyte, Janssen, Medscape, MSD, Merck Serono, Merrimack, Novartis, Pharma Mar, Phosplatin Therapeutics, PER, Pfizer, PRIME, Regeneron, Roche/Genentech, RTP, Sanofi, Seattle Genetics and Takeda, speaker roles for AstraZeneca, Boehringer Ingelheim, BMS, ecancer, Eli Lilly, Illumina, Imedex, Medscape, MSD, Novartis, PER, Pfizer, Prime, Roche/Genentech, RTP, Sanofi, Takeda and the receipt of grants/research support: (Sub) investigator in trials (institutional financial support for trials) sponsored by Amgen, AstraZeneca, Biodesix, Boehringer Ingelheim, BMS, Clovis, GSK, Illumina, Lilly, MSD, Merck Serono, Mirati, Novartis, Pfizer, Phosplatin Therapeutics and Roche/Genentech. TY declares institutional grants or contracts from Taiho Pharmaceuticals, Sumitomo Dainippon, Ono Pharmaceuticals, Chugai Pharmaceuticals, Amgen K.K., Parexel International, MSD K.K., Daiichi Sankyo and Sanofi. All other authors have declared no conflicts of interest., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

To compare clinical outcomes between the use of robotic-assisted laparoscopic radical prostatectomy (RP) and radiotherapy (RT) with long-term androgen deprivation therapy (ADT) in locally advanced prostate cancer (PC), 315 patients with locally advanced PC (clinical T-stage 3/4) were considered for analysis retrospectively. Propensity score-matching at a 1:1 ratio was performed. The median follow-up period was 59.2 months (IQR 39.8-87.4). There were 117 (37.1%) patients in the RP group and 198 (62.9%) patients in the RT group. RT patients were older and had higher PSA at diagnosis, higher Gleason score grade group and more advanced T-stage (all p < 0.001). After propensity score-matching, there were 68 patients in each group. Among locally advanced PC patients, treatment with RP had a higher risk of biochemical recurrence compared to the RT group. In multivariate Cox regression analysis, treatment with RT plus ADT significantly decreased the risk of biochemical failure (HR 0.162, p < 0.001), but there was no significant difference in local recurrence, distant metastasis and overall survival (p = 0.470, p = 0.268 and p = 0.509, respectively). This information supported a clinical benefit in BCR control for patients undergoing RT plus long-term ADT compared to RP., (© 2022. The Author(s).)

Objective: Prostate-specific antigen levels after transurethral enucleation of the prostate may serve as indicators of residual cancer foci. The objective of this study was to investigate the association between the post-transurethral enucleation of the prostate nadir prostate-specific antigen level and prostate cancer., Materials and Methods: We retrospectively reviewed the data of 428 men who underwent transurethral enucleation of the prostate between March 2015 and April 2021. Based on the following exclusion criteria, we excluded 106 men from our analysis: men with metastatic prostate cancer, incomplete transurethral enucleation of the prostate, and missing prostate-specific antigen or prostate size data. Three hundred and twenty-two patients were finally enrolled in our study. These patients were classified into four groups according to the surgical pathology: benign, transition zone (cancer only in the adenoma or transition zone), peripheral zone, and transition and peripheral zones. The optimal cutoff post-transurethral enucleation of the prostate nadir prostate-specific antigen level that predicted residual prostate cancer was determined using receiver operating characteristic curve analysis., Results: In total, 71 (22.0%) men exhibited prostate cancer (median follow-up, 38.0 months). The benign and combined cancer groups showed similar adenoma removal rates (103.0% and 106.7%, respectively). The median nadir prostate-specific antigen levels after transurethral enucleation of the prostate were 0.76, 0.63, 1.79, and 1.70 ng/ml in the benign, transition zone, peripheral zone, and transition and peripheral zone groups, respectively (p < 0.001), with no difference between the benign and transition zone groups (p = 0.458); this suggested that complete transurethral enucleation of the prostate removed all cancer nests in the adenoma in the transition zone group. Receiver operating characteristic curve analysis showed that nadir prostate-specific antigen ≧1.7 ng/ml predicted residual cancer (area under the curve: 0.787) or cancer with a Gleason score of ≧7 (area under the curve: 0.816) in the remaining prostate. Limitations include the retrospective design and the perioperative peripheral zone biopsy rate., Conclusions: The post-transurethral enucleation of the prostate nadir prostate-specific antigen ≧1.7 ng/ml after complete transurethral enucleation of the prostate can predict significant residual cancer. Prostate cancer patients with low post-transurethral enucleation of the prostate prostate-specific antigen levels can be conservatively managed., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Cheng, Hong, Lu, Chang, Hung, Feng, Liu, Chow, Chang, Chen and Pu.)

Although prostate cancer (PC) is the most common cancer among men in the Western world, there are no good biomarkers that can reliably differentiate between potentially aggressive and indolent PC. This leads to overtreatment, even for patients who can be managed conservatively. Previous studies have suggested that nuclear lamin proteins-especially lamin B1 (LMNB1)-play important roles in PC progression. However, the results of these studies are inconsistent. Here, we transfected the LMNB1 gene into the telomerase reverse transcriptase-immortalized benign prostatic epithelial cell line, EP156T to generate a LMNB1-overexpressing EP156T (LMN-EP156T) cell line with increased cellular proliferation. However, LMN-EP156T cells could neither form colonies in soft agar, nor establish subcutaneous growth or metastasis in the xenograft NOD/SCID mouse model. In addition, immunohistochemical staining of LMNB1 in PC specimens from 143 patients showed a statistically significant trend of stronger LMNB1 staining with higher Gleason scores. A univariate analysis of the clinicopathological parameters of 85 patients with PC who underwent radical prostatectomy revealed that pathological stage, resection margin, and extracapsular extension were significant predictors for biochemical recurrence (BCR). However, LMNB1 staining showed only a non-significant trend of association with BCR (high vs. low staining: hazard ratio (HR), 1.83; 95% confidence interval (CI), 0.98-3.41; P = 0.059). In multivariate analysis, only pathological stage was a significant independent predictor of BCR (pT3 vs. pT2: HR, 2.29; 95% CI, 1.18-4.43; P = 0.014). In summary, LMNB1 may play a role in the early steps of PC progression, and additional molecular alterations may be needed to confer full malignancy potential to initiated cells., Competing Interests: None., (AJCR Copyright © 2022.)

Introduction: Enzalutamide significantly improved clinical outcomes compared with placebo in patients with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) with disease progression despite androgen deprivation therapy (ADT) in the PREVAIL study. However, few patients from Asia were enrolled. Our study (NCT02294461) aimed to evaluate the safety and efficacy of enzalutamide in this disease setting in patients in mainland China, Korea, Taiwan, and Hong Kong., Methods: In this double-blind, phase III study, patients with asymptomatic/mildly symptomatic metastatic prostate cancer and disease progression despite ADT were randomized to enzalutamide (160 mg/day) or placebo. The primary endpoint was time to prostate-specific antigen (PSA) progression. Secondary endpoints included overall survival, radiographic progression-free survival, time to first skeletal-related event (SRE), time to initiation of cytotoxic chemotherapy, PSA response ≥ 50%, best overall soft-tissue response, and safety. Pre-planned interim analysis was scheduled following approximately 175 PSA-progression events (67% of targeted total of 261 events). An additional 5-year landmark analysis of overall survival, time to antineoplastic therapy, and safety was performed., Results: The double-blind study period was stopped after interim analysis owing to the benefit of enzalutamide over placebo. Overall, 388 patients were randomized (enzalutamide, n = 198; placebo, n = 190). Baseline characteristics were balanced between treatment groups. Enzalutamide significantly reduced risk of PSA progression vs placebo (hazard ratio 0.38; 95% CI 0.27-0.52; P < 0.0001). Median time to PSA progression was 8.31 months with enzalutamide and 2.86 months with placebo. Secondary endpoints, including 5-year overall survival, were significantly improved with enzalutamide, except time to first SRE. Adverse-event incidence was similar between enzalutamide and placebo. Fatigue was the most common drug-related adverse event in both treatment groups., Conclusion: Enzalutamide significantly reduced risk of PSA progression, improved secondary efficacy endpoints, and was well tolerated in chemotherapy-naïve Asian patients with mCRPC with disease progression despite ADT., Trial Registration: www., Clinicaltrials: gov NCT02294461., (© 2022. The Author(s).)

Background/purpose: Several strategies have been reported for improving the integrity of transurethral resection of bladder tumor (TURBT). However, no standard has been established. Stratified TURBT (SR) is one of protocols for TURBT, wherein exophytic tumors are first resected and retrieved, and tumor bases are then resected. In this study, we aimed to evaluate the outcomes of SR in patients with nonmuscle invasive bladder cancer (NMIBC)., Methods: From January 2012 to December 2017, patients newly diagnosed as having NMIBC with a follow-up period of more than 2 years were enrolled and categorized into SR and conventional TURBT (CR) groups. Propensity score matching at a 2:1 ratio was performed. Outcomes were the detrusor muscle sampling rate, recurrence-free survival (RFS), and progression-free survival (PFS)., Results: In total, 205 patients were included in our study. The detrusor muscle sampling rate was higher in the SR group (P = 0.043). After propensity score matching, 162 patients were selected for outcome analysis, with 108 and 54 patients undergoing SR and CR, respectively. Compared with the CR group, the SR group showed a lower recurrence rate (P = 0.015) and better RFS in univariate (P = 0.010) and multivariate (P = 0.006) Cox proportional hazards regression. Progression rate and PFS were not significantly different between the two groups., Conclusion: SR results in a higher detrusor muscle sampling rate and better disease outcomes. Our findings suggest that SR is a promising strategy for TURBT in patients with NMIBC., Competing Interests: Declarations of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2021 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of renal cell carcinoma was published in 2019 with an update planned for 2021. It was therefore decided by both the ESMO and the Singapore Society of Oncology (SSO) to convene a special, virtual guidelines meeting in May 2021 to adapt the ESMO 2019 guidelines to take into account the ethnic differences associated with the treatment of renal cell carcinomas in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with renal cell carcinoma representing the oncological societies of China (CSCO), India (ISMPO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence and was independent of the current treatment practices and drug access restrictions in the different Asian countries. The latter were discussed when appropriate., Competing Interests: Disclosure RK declares institutional payments from Pfizer, Merck Sharp & Dohme (MSD), Bristol Myers Squibb (BMS), Eisai, Amgen, Astellas, Johnson & Johnson (J&J), Novartis and Merck, support for meeting attendance or travel from Pfizer, MSD, BMS, Eisai, Amgen, Astellas, J&J, Novartis and Merck. CP declares consulting fees from AstraZeneca, BMS, Eisai, EUSA Pharma, Ipsen, Merck, MSD, Novartis and Pfizer, payment or honoraria from Angelini Pharma, AstraZeneca, BMS, Eisai, EUSA Pharma, General Electric, Ipsen, Janssen, Merck, MSD, Novartis and Pfizer, support for attending meetings and/or travel from Roche. AW declares personal fees from MS, MSD, Pfizer, EISAI and IPSEN, participation on a data safety monitoring or advisory board for BMS, MSD, Pfizer, EISAI, IPSEN. TP declares research funding from Merck Serono, MSD, Roche, BMS, AstraZeneca, Astellas, Novartis, J&J, Seattle Genetics, Pfizer, Exelixis and Eisai, honoraria from Merck Serono, MSD, Roche, BMS, AstraZeneca, Astellas, Novartis, J&J, Seattle Genetics, Pfizer, Exelixis and Eisai. QSN declares support for attending meetings and/or travel from BMS, Boehringer Ingelheim, MSD and Astellas, participation on a data safety monitoring or advisory board for MSD and Boehringer Ingelheim. MSc declares honoraria from BMS, MSD, Merck, Roche, Pfizer, EUSA, EISAI, EXELIXIS and Ipsen, consulting fees from BMS, MSD, Merck, Roche, Pfizer, EUSA, EISAI, EXELIXIS and Ipsen, support for attending meetings and/or travel from BMS, Roche, Pfizer and Ipsen, participation on a data or safety monitoring board for BMS, MSD, Merck, Roche, Pfizer, EUSA, EISAI, EXELIXIS and Ipsen. YM declares payments or honoraria from BMS, MSD and Takeda, participation on an advisory board for Chugai Pharmaceutical and Takeda, local PI, institutional, financial interest from MSD. JL declares grants or contracts from Pfizer, Ipsen, BMS, MSD, Merck, Roche, AstraZeneca, Seattle Genetics, participation on a data safety monitoring or advisory board from Pfizer Korea, Astella Korea, BMS, Merck, MSD, AstraZeneca, stocks or stock options from Myovant Sciences, Amgen, J&J and Merck. FC declares payment for educational events from Eisai and Pfizer, receipt of equipment for a patient sampling programme from Pfizer. Y-SP declares honoraria and consulting fees from MSD, Roche, Merck, Ipsen, BMS/ONO, Novartis, Pfizer, Astellas, Janssen and GlaxoSmithKline (GSK), support for attending meetings and/or travel from Ipsen, BMS/ONO, Novartis, Pfizer, Astellas and Janssen. MSa declares research grants from Roche and MSD, payments or honoraria from MSD, Novartis, Roche, Pfizer, Eisai, Novartis, AstraZeneca, Amgen and Ipsen, receipt of equipment/materials for a compassionate programme for drugs/drug samples from Pfizer, AstraZeneca, Novartis, Ipsen, Eisai and MSD. HL declares payment or honoraria from MSD, Amgen, Astellas and IPSEN, participation on a data safety monitoring or advisory board for MSD and Astellas. HK declares payment or honoraria from BMS, MSD, Merck Biopharma, Takeda and Pfizer. GSB (deceased). GC declares institutional grants from Merck, consulting fees from BMS, Pfizer, MSD, AstraZeneca, Daichii Sankyo, Lilly, Novartis and Seattle Genetics, payment or honoraria from AstraZeneca, Roche and Daichii Sankyo. SC declares consulting fees from BMS, AstraZeneca, MSD, Roche and Servier, payment or honoraria from BMS, AstraZeneca, Roche, Ipsen, MSD Eisai and Bayer, consulting fees from BMS, AstraZeneca, MSD, Roche and Servier and stock or stock options in BMS and Agenus Oncology. SP declares fees for consultancy/advisory roles from AbbVie, Amgen, AstraZeneca, Bayer, Beigene, Biocartis, Boehringer Ingelheim, BMS, Clovis, Daiichi Sankyo, Debiopharm, ecancer, Eli Lilly, Elsevier, Foundation Medicine, Illumina, Imedex, Incyte, Janssen, Medscape, MSD, Merck Serono, Merrimack, Novartis, Pharma Mar, Phosplatin Therapeutics, PER, Pfizer, PRIME, Regeneron, Roche/Genentech, RTP, Sanofi, Seattle Genetics, Takeda, speaker roles for AstraZeneca, Boehringer Ingelheim, BMS, ecancer, Eli Lilly, Illumina, Imedex, Medscape, MSD, Novartis, PER, Pfizer, Prime, Roche/Genentech, RTP, Sanofi, Takeda and the receipt of grants/research support: (Sub) investigator in trials (institutional financial support for trials) sponsored by Amgen, AstraZeneca, Biodesix, Boehringer Ingelheim, BMS, Clovis, GSK, Illumina, Lilly, MSD, Merck Serono, Mirati, Novartis, and Pfizer, Phosplatin Therapeutics, Roche/Genentech. TY declares institutional grants or contracts from Taiho Pharmaceuticals, Sumitomo Dainippon, Ono Pharmaceuticals, Chugai Pharmaceuticals, Amgen, Parexel International, MSD, Daiichi Sankyo, and Sanofi. All other authors have declared no conflicts of interest. See also ICMJE forms., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Prostate-specific antigen (PSA) is considered neither sensitive nor specific for prostate cancer (PCa). We aimed to compare total PSA (tPSA), percentage of free PSA (%fPSA), the PSA density (PSAD), Prostate Health Index (PHI), and the PHI density (PHID) to see which one could best predict clinically significant prostate cancer (csPCa): a potentially lethal disease., Methods: A total of 412 men with PSA of 2-20 ng/mL were prospectively included. Serum biomarkers for PCa was collected before transrectal ultrasound guided prostate biopsy. PHI was calculated by the formula: (p2PSA/fPSA) x √tPSA. PHID was calculated as PHI divided by prostate volume measured by transrectal ultrasound., Results: Of the 412 men, 134 (32.5%) and 94(22.8%) were diagnosed with PCa and csPCa, respectively. We used the area under the receiver operating characteristic curve (AUC) and decision curve analyses (DCA) to compare the performance of PSA related parameters, PHI and PHID in diagnosing csPCa. AUC for tPSA, %fPSA, %p2PSA, PSAD, PHI and PHID were 0.56、0.63、0.76、0.74、0.77 and 0.82 respectively for csPCa detection. In the univariate analysis, the prostate volume, tPSA, %fPSA, %p2PSA, PHI, PSAD, and PHID were all significantly associated with csPCa, and PHID was the most important predictor (OR 1.41, 95% CI 1.15-1.72). Besides, The AUC of PHID was significantly larger than PHI in csPCa diagnosis ( p =0.004). At 90% sensitivity, PHID had the highest specificity (54.1%) for csPCa and could reduce the most unnecessary biopsies (43.7%) and miss the fewest csPCa (8.5%) when PHID ≥ 0.67. In addition to AUC, DCA re-confirmed the clinical benefit of PHID over all PSA-related parameters and PHI in csPCa diagnosis. The PHID cut-off value was positively correlated with the csPCa ratio in the PHID risk table, which is useful for evaluating csPCa risk in a clinical setting., Conclusion: The PHID is an excellent predictor of csPCa. The PHID risk table may be used in standard clinical practice to pre-select men at the highest risk of harboring csPCa., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Chiu, Cheng, Pu, Lu, Hong, Chung, Chiang and Huang.)

Background: Several lymph node-related prognosticators were reported in bladder cancer patients with lymph node involvement and receiving radical cystectomy. However, extranodal extension (ENE) remained a debate to predict outcomes., Methods: A retrospective analysis of 1303 bladder cancer patients receiving radical cystectomy and bilateral pelvic lymph node dissection were identified in the National Taiwan Cancer Registry database from 2011 to 2017. Based on the 304 patients with lymph node involvement, the presence of ENE and major clinical information were recorded and calculated. The overall survival (OS) and cancer-specific survival (CSS) were estimated with Kaplan-Meier analysis and compared using the log-rank test. Hazard ratios (HR) and the associated 95% confidence intervals were calculated in the univariate and stepwise multivariable models., Results: In the multivariable analysis, ENE significantly reduced OS (HR = 1.74, 95% CI 1.09-2.78) and CSS (HR = 1.69, 95% CI 1.01-2.83) more than non-ENE. In contrast, adjuvant chemotherapy was significantly associated with better OS and CSS upon the identification of pathological nodal disease., Conclusions: Reduced OS and CSS outcomes were observed in the pathological nodal bladder cancer patients with ENE compared with those without ENE. After the identification of pathological nodal disease, adjuvant chemotherapy was associated with better survival outcomes.

Increasing evidence has revealed the contributions of long noncoding RNAs (lncRNAs) in the modulation of drug resistance in gastric cancer. In the present study, we explored the role of a novel lncRNA, RP11-874J12.4, in regulating chemoresistance in gastric cancer and determined the underlying molecular mechanisms. We observed that compared with normal controls, human gastric cancer tissues and cell lines, including MKN-45 and AGS cells, expressed higher RP11-874J12.4 levels. RP11-874J12.4 knockdown sensitized MKN-45 and AGS cells to docetaxel and cisplatin in terms of cell viability and apoptosis rate. In addition, RP11-874J12.4 was found to be a competing endogenous RNA that sponged microRNA (miR)-3972, which showed significantly reduced expression in human gastric cancer tissues and cell lines. Furthermore, signal sequence receptor subunit 2 (SSR2) was identified as a downstream target of miR-3972, and the miR-3972/SSR2 axis was found to regulate chemoresistance in MKN-45 and AGS cells. SSR2 downregulation further sensitized gastric cancer cells with RP11-874J12.4 knockdown to chemotherapeutic drugs via enhanced apoptosis, which was evidenced by significantly upregulated expressions of cleaved caspase-3, cleaved caspase-9, and Bax and downregulated expression of Bcl-2. Furthermore, RP11-874J12.4 knockdown markedly inhibited the growth of xenograft MKN-45 cells in nude mice, which was associated with an increased expression of miR-3972 and decreased expression of SSR2 in tumors. Therefore, the RP11-874J12.4/miR-3972/SSR2 axis plays important roles in the regulation of chemoresistance in MKN-45 and AGS cells and may serve as a target for the diagnosis and treatment of human gastric cancer., Competing Interests: None., (AJTR Copyright © 2021.)

Background: The addition of androgen-deprivation therapy (ADT) or pelvic radiation to prostate bed salvage radiotherapy (SRT) has been debated for prostate cancer patients with biochemical recurrence (BCR) after radical prostatectomy. This study aimed to assess the outcomes and propose prediction models for exclusive prostate bed SRT., Methods: This is a prospective observational cohort study with patients who underwent SRT with a pre-SRT PSA < 1.5 ng/mL after radical prostatectomy. Patients were treated with 70-Gy SRT to the prostate bed exclusively. Kaplan-Meier survival analyses and Cox regression analyses were applied for depicting and predicting BCR-free survival, ADT-free survival, and metastasis-free survival (MFS). Regression-based coefficients were used to develop nomograms., Results: A total of 105 patients were included and 91 patients were eligible. The median follow-up period was 39 months. The 5-year BCR-free survival, ADT-free survival, and MFS were 37%, 50%, and 66%, respectively. Multivariable analysis showed that a pre-SRT PSA < 0.45 ng/mL was the only independent factor associated with longer BCR-free survival ( p = 0.034), while a PSA-DT > 8 months had better ADT-free survival ( p = 0.008). Patients with a PSA-DT > 8 months showed a 100% MFS and a 43% 5-year absolute benefit in MFS than a PSA-DT ≤ 8 months. All patients with a pre-SRT PSA < 0.45 ng/mL and PSA-DT > 8 months were free from subsequent ADT and any metastasis., Conclusions: In patients with a PSA < 0.45 ng/mL and PSA-DT > 8 months for post-prostatectomy BCR, prostate bed SRT provided excellent outcomes without the need for concomitant ADT or pelvic radiotherapy.

We investigated the association between tumor location on multiparametric magnetic resonance imaging (mpMRI) and outcomes of prostate cancer patients after primary total prostate cryoablation (PTPC). Between March 2010 and December 2012, consecutive 192 prostate cancer patients receiving PTPC were enrolled. Tumor locations were determined and classified as anterior apex (AA), anterior midgland (AM), anterior base (AB), posterior apex (PA), posterior midgland (PM) and posterior base (PB) using mpMRI. Midline location, central location, seminal vesicle invasion, extraprostatic extension, multiple tumors, and tumor volume were also identified. Prostate local recurrence and biochemical failure were considered as primary and secondary endpoints, respectively. Tumors on mpMRI were identified in 148 (77.1%) patients. Tumor locations were most frequently noted in PM (89, 46.4%), followed by AM (55, 28.6%), PB (53, 27.6%), PA (46, 24%), AA (35, 18.2%) and AB (31, 16.1%). Midline and central tumors were observed in 34 (17.7%) and 14 (7.3%) patients, respectively. During a median follow-up duration of 81 months (range, 2-114 months), 71 (37.0%) and 29 (40.8%) patients experienced biochemical failure and local recurrence, respectively. Multivariable analyses revealed only AA tumors increased the risk of local recurrences (HR = 2.98, 95% CI. 1.36-6.49). None of location-related parameters was associated with biochemical failure. Tumor location on mpMRI has a significant association with local tumor recurrence in patients receiving PTPC. Physicians should be cautious when conducting cryoablation for prostate tumors in AA location., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Aristolochic acids (AA) and arsenic are chemical carcinogens associated with urothelial carcinogenesis. Here we investigate the combined effects of AA and arsenic toward the risk of developing upper tract urothelial carcinoma (UTUC)., Methods: Hospital-based ( n = 89) and population-based (2,921 cases and 11,684 controls) Taiwanese UTUC cohorts were used to investigate the association between exposure to AA and/or arsenic and the risk of developing UTUC. In the hospital cohort, AA exposure was evaluated by measuring aristolactam-DNA adducts in the renal cortex and by identifying A>T TP53 mutations in tumors. In the population cohort, AA exposure was determined from prescription health insurance records. Arsenic levels were graded from 0 to 3 based on concentrations in well water and the presence of arseniasis-related diseases., Results: In the hospital cohort, 43, 26, and 20 patients resided in grade 0, 1+2, and 3 arseniasis-endemic areas, respectively. Aristolactam-DNA adducts were present in >90% of these patients, indicating widespread AA exposure. A>T mutations in TP53 were detected in 28%, 44%, and 22% of patients residing in grade 0, 1+2, and 3 arseniasis-endemic areas, respectively. Population studies revealed that individuals who consumed more AA-containing herbs had a higher risk of developing UTUC in both arseniasis-endemic and nonendemic areas. Logistic regression showed an additive effect of AA and arsenic exposure on the risk of developing UTUC., Conclusions: Exposure to both AA and arsenic acts additively to increase the UTUC risk in Taiwan., Impact: This is the first study to investigate the combined effect of AA and arsenic exposure on UTUC., (©2020 American Association for Cancer Research.)

Aims: To investigate the molecular function and mechanisms of JHDM1D antisense 1 (JHDM1D-AS1) during gastric cancer (GC) progression., Materials and Methods: The qPCR assay was used to detect the JHDM1D-AS1 and miR-450a-2-3p expression levels in GC tissues and cell lines. Bioinformatics analysis was used for exploring the lncRNA-microRNA-mRNA interaction network. We performed dual-luciferase reporter assay and qPCR assay in order to validate the direct interactions. We explored the JHDM1D-AS1 and miR-450a-2-3p on GC progression by using JHDM1D-AS1 siRNA and miR-450a-2-3p inhibitor; in vitro CCK-8 assay, colony formation assay, and invasion assay were conducted. Further, in vivo animal experiments were performed, and the expression levels of miR-450a-2-3p and PRAF2 in the tumor tissues were detected using qPCR and western blot analysis., Key Findings: The expression levels of JHDM1D-AS1 and miR-450a-2-3p in GC tissues and cell lines were higher and lower as compared to those in the corresponding normal controls, respectively. Moreover, high levels of JHDM1D-AS1 were closely related with metastasis and the GC TNM stage. Functionally, JHDM1D-AS1 depletion caused an obvious reduction in cell proliferation and invasion both in vitro and in vivo, while the addition of miR-450a-2-3p inhibitor could nullify these effects. Mechanically, JHDM1D-AS1 promoted GC progression via the sponging of miR-450a-2-3p in order to increase PRAF2 expression., Significance: The present results showed that the increased expression of JHDM1D-AS1 was closely associated with tumor progression of GC. JHDM1D-AS1/miR-450a-2-3p/PRAF2 axis may be a promising target for GC treatment., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Amyloid-β (Aβ) peptides and hyperphosphorylated tau protein are the most important pathological markers of Alzheimer's disease (AD). Neuroinflammation and oxidative stress are also involved in the development and pathological mechanism of AD. Hypoxia inducible factor-1α (HIF-1α) is a transcriptional factor responsible for cellular and tissue adaption to low oxygen tension. Emerging evidence has revealed HIF-1α as a potential medicinal target for neurodegenerative diseases. On the one hand, HIF-1α increases AβPP processing and Aβ generation by promoting β/γ-secretases and suppressing α-secretases, inactivates microglia and reduces their activity, contributes to microglia death and neuroinflammation, which promotes AD pathogenesis. On the other hand, HIF-1α could resist the toxic effect of Aβ, inhibits tau hyperphosphorylation and promotes microglial activation. In summary, this review focuses on the potential complex roles and the future perspectives of HIF-1α in AD, in order to provide references for seeking new drug targets and treatment methods for AD.

High total urinary arsenic concentrations and low estimated glomerular filtration rate (eGFR) increase the risk of renal cell carcinoma (RCC). This study aimed to determine whether other metals or metalloids can affect RCC. A total of 401 patients with RCC and 774 age- and sex-matched controls were recruited between November 2006 and December 2012 in Taiwan. Surgical resection or image-guided biopsy of renal tumors was performed to pathologically verify RCC. High-performance liquid chromatography linked to a hydride generator and atomic absorption spectrometer were used to measure the urinary arsenic species concentrations. Inductively coupled plasma mass spectrometry was used to determine plasma selenium and red blood cell cadmium and lead concentration. Plasma selenium levels were inversely related to RCC, whereas red blood cell cadmium levels were directly related to RCC. The odds ratio (OR) and 95% confidence interval (CI) were 0.14 (95% CI, 0.10-0.20) and 1.33 (95% CI, 1.03-1.72), respectively. A low plasma selenium level tended to interact with high total urinary arsenic levels or with high red blood cell cadmium concentration to increase the OR of RCC. In particular, low eGFR multiplicatively interacted with high red blood cell cadmium concentration to increase the OR of RCC (P interaction =0.003). This study was the first to find a significant multiplicative interaction between eGFR and the red blood cell cadmium levels on the increased OR of RCC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier B.V.)

Colorectal cancer (CRC) is one of the most commonly diagnosed cancers worldwide. ABL1 (c-Abl) is a non-receptor tyrosine kinase, whose role, and molecular mechanism in CRC remain largely unclear. The aim of this study was to elucidate the role of ABL1 to obtain information on colon cancer gene mutation. We analyzed the tissue samples obtained from patients with CRC, CRC cell lines, and the immunodeficient mice. The proliferation, cell cycle, and apoptosis of CRC cells were examined. IPA software was used to analyze the molecules involved in CRC after ABL1 RNA interference. We found ABL1 was highly expressed in CRC tissues and cells. This high expression was associated with the TNM stage of CRC patients. In exon 8 of the ABL1 gene, we identified a novel mutation of C1222C deletion, which was related to the CRC stage. Depletion of ABL1 resulted in the inhibition of proliferation and escalation of apoptosis in two CRC cell lines, SW480, and HCT-116. Our in vivo study also demonstrated that depletion of ABL1 reduced CRC tumor progression. The results of the ingenuity pathway analysis indicated that the expression of 732 genes was upregulated and that of 691 genes was downregulated in mice transplanted with ABL1-downregulated CRC cells, among which we confirmed that depletion of ABL1 inhibited TGF-β1 via IRS1/PI3K/AKT pathway in CRC progression. These findings demonstrated that ABL1 plays an important role and that it can be a potential molecular target for CRC therapy., (Copyright © 2020 Liu, Cao, Zhu, Ma, Murtaza, Li, Wang and Pu.)

Background: Hyperglycemia is associated with series of process leading to oncogenesis. Evidence has shown that diabetes mellitus (DM) seems to be associated with poor prognosis in patients with bladder cancer. However, evidence on the effect of glycemic control on the outcomes of bladder cancer is still limited. In the current study, we aimed to investigate the effect of DM and glycemic control on the prognosis of bladder cancer., Methods: We conducted a retrospective chart review of a prospective database from January 2012 to December 2017. Patients with newly diagnosed non-muscle invasive bladder cancer (NMIBC) were included. They were classified into the DM and non-DM groups. Prognosis including recurrence rate, progression rate, recurrence-free survival (RFS), and progression-free survival was compared between the two groups. Subgroup analysis of the DM subgroup, in which patients were classified by HbA1C level, was conducted to investigate the effect of glycemic control., Results: A total of 287 patients were included in our study, with 61 patients in the DM group and 226 patients in the non-DM group. No statistically significant difference was found in the prognosis between the DM and non-DM groups. Subgroup analysis revealed higher recurrence rate (P = 0.037) and worse RFS (log-rank P = 0.019) in patients with HbA1C ≥ 7., Conclusions: DM is not a risk factor for recurrence and progression in patients with NMIBC. However, poor glycemic control is associated with poor prognosis in patients with both DM and NMIBC. Further prospective studies are needed to confirm current results.

Our study showed that total urinary arsenic concentrations were positively correlated with renal cell carcinoma (RCC). Chronic inflammation is a key player in the development of RCC. This study explored the association between nucleotide-binding domain-like receptor protein 3 (NLRP3) genotypes and the development of RCC. We also investigated whether any of the NLRP3 genotypes modified the risk between arsenic and RCC. We recruited 350 RCC patients and 700 age-sex matched controls. RCC was confirmed by pathological assessment following surgical resection or image-guided biopsy of a renal tumor. Fifteen sites of NLRP3 gene polymorphisms were identified using the Agena Bioscience MassARRAY platform. The concentrations of the urinary arsenic species were determined by HPLC-HG-AAS. There was a significant dose-dependent association between arsenic and RCC. In addition, six of thirteen NLRP3 alleles, including rs12239046 C, rs10925025 G, rs1539019 C, rs10925026 A, rs10157379 T, and rs12143966 A, had increased odds ratios (ORs) for RCC than other NLRP3 alleles. Among these sites, we found the novel haplotype of five tag-SNPs (C-A-A-A-A) was significantly related to RCC, the OR and 95% confidence interval was 1.44 (1.08-1.92). Furthermore, participants with high total urinary arsenic levels and the NLRP3 rs1539019 C allele had significantly multiplicative and additive interactions for the risk of RCC (p interaction  = 0.012). This study is the first to identify the modified effects of NLRP3 risk alleles involved in the association between arsenic and RCC risk in a population with low arsenic exposure.

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., (© 2019 The Authors BJU International Published by John Wiley & Sons Ltd on behalf of BJU International.)

Gastric cancer (GC) is one of the most common malignancies of the digestive system worldwide. Multiple long noncoding RNAs (lncRNAs) participate in the regulation of GC development and metastasis. In this study, we aimed to elucidate the expression and function of lncRNA IGFL2-AS1 in GC. We found that IGFL2-AS1 was highly expressed in GC tissues and cell lines. Knockdown of IGFL2-AS1 suppressed GC cell proliferation, migration, and invasion in vitro. Furthermore, we identified that IGFL2-AS1 exerted its function as a molecular sponge of miR-802. MiR-802 was demonstrated to be a tumor suppressor, and overexpression of miR-802 suppressed GC cell growth, migration, and invasion. Mechanistically, we revealed that the cAMP-regulated phosphoprotein 19 (ARPP19) was a direct target of miR-802 and could reverse the inhibitory function of miR-802. Moreover, our results confirmed that knockdown of IGFL2-AS1 inhibited GC tumor development in an in vivo GC tumor xenograft model. In summary, our data suggest that the IGFL2-AS1/miR-802/ARPP19 axis plays a critical role in the progression and metastasis of GC. Therapies targeting the IGFL2-AS1/miR-802/ARPP19 axis can potentially improve GC treatment., (© 2020 Wiley Periodicals, Inc.)

To evaluate the predictive accuracy of the %p2PSA and prostate health index (PHI) in predicting aggressive pathological outcomes in patients with prostate cancer (PCa) undergoing radical prostatectomy (RP), we enrolled 91 patients with organ-confined PCa who were treated with robot-assisted RP. p2PSA levels and the PHI were investigated for their ability to predict pathological results. The %p2PSA and PHI were both significantly higher in patients with ≥pT3 disease, high-risk disease, positive surgical margin, or seminal vesical invasion (SVI). In univariable analysis, p2PSA derivatives were significant predictors of the presence of ≥pT3 disease, high-risk disease, positive surgical margin, and SVI. To predict adverse pathological outcomes at a sensitivity of 90%, p2PSA derivatives had higher specificity than standard PSA derivatives. In multivariable analysis, additional increases in the area under the receiver operating characteristic curve (AUC) were observed with the %p2PSA and PHI for ≥pT3 disease, high-risk disease, and positive surgical margin (8.2% and 2.7%, 6.2% and 4.1%, and 8.6% and 5.4%, respectively). A PHI ≥61.26 enhanced the predictive accuracy of the model for SVI by increasing the AUC from 0.624 to 0.819 (p = 0.009). The preoperative %p2PSA and PHI accurately predict adverse pathological results and are useful for decision-making.

Objectives: To investigate the treatment pattern of non-muscle invasive bladder cancer patients among urologists in Japan, Korea and Taiwan, with emphasis on compliance with important treatment guidelines., Methods: A Web-based questionnaire survey was conceived by representative members of each country's urological oncology society and was open from June 2016 to February 2017 to each society's members. Descriptive statistics and multinomial logistic regression analysis were used., Results: A total of 2334 urologists were invited and 701 responded to the survey with a response rate of 30.0%. Instruments used during transurethral resection of bladder cancer varied significantly between countries and depended on their availability. The re-transurethral resection rate for pT1 or high-grade disease >50% of the time was significantly higher in Japan than in the other two countries, but the collective rate was just 49%. The frequency of intravesical therapy in intermediate- to high-risk disease was generally consistent across countries. However, the choice of agent between chemotherapy and bacillus Calmette-Guérin was significantly different between countries. Maintenance bacillus Calmette-Guérin was used <10% of the time by 45% of respondents, the most important reasons being fear of side-effects, followed by a lack of efficacy and shortage of drug supply., Conclusions: There are significant differences between Japan, Korea and Taiwan in the management of intermediate- to high-risk non-muscle invasive bladder cancer. The results of this survey can serve as the basis for joint efforts to develop common clinical guidelines., (© 2019 The Japanese Urological Association.)

The aim of this study was to investigate prognostic molecular targets for selecting patients with muscle-invasive bladder cancer undergoing bladder-preserving therapy. Pretreatment biopsy samples from patients with muscle-invasive bladder cancer receiving trimodality bladder-preserving therapy were analyzed for expression levels of p53, p16, human epidermal growth factor receptor-2 (Her-2), epidermal growth factor receptor (EGFR), nuclear factor-kappa B (NFκB; p65), E-cadherin, matrix metalloproteinase-9 (MMP9), meiotic recombination 11 homolog (MRE11), programmed death-1 ligand (PD-L1), and mismatch repair proteins (MLH1, PMS2, MSH2, and MSH6) by immunohistochemical (IHC) staining. The correlations between these molecular markers with local progression-free survival (LPFS), distant metastasis-free survival (DMFS), and overall survival (OS) were explored. Biopsy samples from 41 out of 60 patients were evaluated using IHC. Univariate analysis revealed that the high expression of NFκB is associated with significantly worse LPFS, DMFS, and OS, and low expression of p16 is associated with significantly lower LPFS. Upon further multivariate analysis including sex, age, stage, and selected unfavorable factors in the model, NFκB and p16 independently remained significant. The investigational in vitro study demonstrated that irradiation induces up-regulation of NFκB signaling. Irradiated bladder cancer cells showed increased invasion capability and clonogenic survival; inhibition of NFκB signaling by an NFκB inhibitor, SC75741, or RNA interference reversed the observed increases. NFκB expression (p65) is associated with prognostic significance for both LPFS and DMFS in patients treated with bladder-preserving therapy, with consistent impact on cell viability of bladder cancer cells. NFκB may be a putative molecular target to help with outcome stratification.

Background: The incidence of prostate cancer (PC) in Asian countries is increasing for reasons that are not clear. Data describing how PC is diagnosed and treated are fragmented across Asia, with marked intercountry and intracountry differences in outcome and knowledge gaps in clinical diagnostic and treatment practices. To address these knowledge gaps, we have established a PC disease registry with the aim of providing a comprehensive picture of PC diagnosis, prognosis, treatment and outcome, population characteristics, and comorbidities in real-world clinical practice in Asia., Methods: This is a multinational, multicenter, longitudinal, and observational registry of PC patients presenting to participating tertiary-care hospitals in eight Asian countries (www.clinicaltrials.gov NCT02546908. Registry Identifier: NOPRODPCR4001). Approximately 3500-4000 eligible patients with existing or newly diagnosed high-risk localized PC (cohort 1), nonmetastatic biochemically recurrent PC (cohort 2), or metastatic PC (cohort 3) will be consecutively enrolled and followed-up for 5 years. An enrollment cap of 600 patients each will be applied to cohorts 1 and 2. Disease status is collected at enrollment, and outcome variables captured at 3-monthly intervals include diagnostic/staging, treatments including reason for change, laboratory results, comorbidities, and concomitant medications. Treatments and survival outcomes will be captured real time until study end. Patient-reported quality-of-life will be measured every 6 months, and medical resource utilization summarized at study end. Data analysis will include exploratory analyses of potential associations between multiple risk factors and socioeconomic variables with disease progression and evaluation of various treatments for PC including novel therapies on clinical outcome and health-related quality-of-life outcomes., Results: 3636 men with PC were enrolled until July 2018; 416 in cohort 1, 399 in cohort 2 and 2821 in cohort 3., Discussion: A total of 3636 patients were enrolled until July 2018. The prospective disease registry will provide comprehensive and wide-ranging real-world information on how PC is diagnosed and treated in Asia. Such information can be used to inform policy development for best practice and direct clinical study design evaluating new treatments.

Purpose: To analyze the trifecta outcome (functional, anatomical, and surgical aspects) of surgical reconstruction for ureteral lesions and investigate the factors affecting the success rate of such reconstruction., Methods: We retrospectively reviewed the data of patients who underwent ureteral reconstruction at our institute between March 2007 and November 2016. Patient profiles, surgical methods, complications, ureteral stenting, laboratory data, and image studies were collected. The trifecta outcome was defined as preserved renal function, no progression of hydronephrosis, and no long-term stenting. The primary endpoint was the percentage of patients who achieved the trifecta outcome. The secondary endpoint was risk factors for trifecta outcome failure., Results: We retrospectively reviewed 178 adult patients who had undergone ureteral reconstruction. The median follow-up period was 37.4 months. In total, 70 (39.3%) patients had iatrogenic ureteral injuries and 108 (60.7%) patients had non-iatrogenic ureteral lesions. Overall, 70% of the patients achieved the trifecta outcome after ureteral reconstruction. A multivariate analysis revealed that risk factors for trifecta failure were malignant diseases [odds ratio (OR) 2.93, p = 0.005], a history of pelvic radiation (OR 3.08, p = 0.032), preoperative estimated glomerular filtration rate < 60 (OR 2.52, p = 0.039), and a type of reconstruction ureteroureterostomy (OR 2.99, p = 0.014)., Conclusions: Trifecta outcome could be used to evaluate the ureteral reconstruction in iatrogenic injury and non-iatrogenic ureteral lesions. This study revealed several risk factors that affected the trifecta outcome.

In this study, we investigated post-orchiopexy testicular growth of undescended testes (UDTs) at different primary locations and determined the risk factors for testicular atrophy (TA). We conducted a retrospective chart review of boys who had undergone orchiopexy for UDTs during January 2001-December 2013. Patient profile, age at operation, primary UDT location, and testicular volume were noted. TA was defined as ≥50% loss of volume after orchiopexy. The primary endpoints were testicular growth and TA after orchiopexy. The secondary endpoint was risk factors for TA. In total, 182 boys had undergone regular ultrasonography; the median follow-up period was 34 months. Among 230 UDTs, 18 (7.8%) atrophic testicles were identified within a median interval of 13 months after orchiopexy. TA rates were 3.3% (1/30), 6.9% (12/173), and 18.5% (5/27) in primary suprascrotal, canalicular, and above-inguinal UDTs, respectively. The survival probability of UDT was 91%, 92% and 100% when orchiopexy was performed in age ≤1 year, 1 < age ≤2 years, and 100% in age >2 years, respectively. Multivariate analysis revealed that inguinal and above-inguinal UDTs (hazard ratio [HR] 11.76, 95% confidence interval [CI] 1.55-89.33, p = 0.017) and genetic or endocrine disorders (HR 3.19, 95% CI 1.19-8.56, p = 0.021) were the risk factors for TA, but not age at operation, premature birth, and laterality. Thus, TA incidence was higher when patients had high primary testicular locations. Early orchiopexy before two years of age may be associated with higher TA risk, while most testicles have promising growth after orchiopexy.

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., (© 2018 The Authors BJU International © 2018 BJU International Published by John Wiley & Sons Ltd.)

Background/purpose: Prostate specific antigen (PSA) with low specificity that causes unnecessary prostate biopsies increases clinical morbidities, psychological stress, and medical expenses. We aimed to test the accuracy and cutoff value of Prostate Health Index (PHI) in men for prostate cancer detection., Methods: We prospectively enrolled 213 men who underwent prostate biopsy with PSA≦10 ng/ml or abnormal findings on digital rectal examination. Total PSA (tPSA), free PSA (fPSA) and p2PSA levels were measured by serum samples before prostate biopsy. PHI was calculated as (p2PSA/fPSA) × √tPSA. Multivariable logistic regression analyses were used to predict the risk of cancer and detect clinically significant prostate cancer., Results: 33 (27.0%) patients were confirmed with the diagnoses of prostate cancer by prostate biopsy. The levels of p2PSA, %p2PSA, and PHI showed statistically significant differences between prostate cancer patients and non-cancer patients. %p2PSA and PHI had the highest area under the receiver operating characteristic curve (AUC) of 0.723 and 0.772 (both p < 0.001), respectively, predicting cancer detection at biopsy than other predictors (tPSA, fPSA, %fPSA, and PSA density (AUC: 0.544, 0.538, 0.593, and 0.664, respectively). In multivariable logistic regression, %p2PSA had a statistical significant odds ratio 8.51 (p = 0.003) and PHI had an odds ratio with marginal significance 4.18 (p = 0.06)., Conclusion: %p2PSA and PHI increased the diagnostic accuracy with significantly greater sensitivity and specificity than tPSA. We determined an optimal cut-off value of PHI among Taiwanese population. These findings support the usefulness in the decisional process of prostate biopsy., (Copyright © 2018. Published by Elsevier B.V.)