Salvage Androgen Deprivation Therapy as Potential Treatment for Recurrence after Robot-Assisted Radical Prostatectomy.

BACKGROUND: The efficacy of intermittent androgen deprivation therapy (ADT) for biochemical recurrence (BCR) after robot-assisted radical prostatectomy (RARP) is unknown, and its usefulness in Japanese practice needs to be investigated. METHODS: We conducted a retrospective analysis of 85 patients who underwent RARP and were selected for intermittent ADT for postoperative recurrence at Kanazawa University Hospital between 2009 and 2019. Intermittent ADT was administered for 2 years. If prostate-specific antigen levels increased post-treatment, intermittent ADT was reinitiated. The median follow-up period was 47 months. RESULTS: The 73 patients had completed the initial course of ADT, and 12 were under initial ADT. The 5-year castration-resistant prostate-cancer-free survival rates, cancer-specific survival, and overall survival were 92.7%, 98.3%, and 94.7%, respectively. A subgroup analysis of 69 patients who completed intermittent ADT was conducted to evaluate the BCR rate following initial ADT. The 5-year BCR-free survival rate was 53.2%. Multivariate analysis identified testosterone ≤ 0.03 ng/mL during ADT as the sole predictor of BCR after ADT. CONCLUSIONS: Salvage intermittent ADT may be an effective treatment option for BCR after RARP. In addition, it would be useful to confirm strong testosterone suppression as a criterion for transition to intermittent therapy.

Comprehensive analysis of perioperative hypotension in photodynamic diagnosis-assisted transurethral resection of bladder tumor with 5-aminolevulinic acid.

OBJECTIVE: Intraoperative hypotension remains a serious adverse event of photodynamic diagnosis-assisted transurethral resection of bladder tumor with oral administration of 5-aminolevulinic acid. We conducted a re-analysis of perioperative hypotension in photodynamic diagnosis-assisted transurethral resection of the bladder tumor with oral 5-aminolevulinic acid to ascertain its safety. METHODS: A total of 407 cases who underwent transurethral resection of bladder tumors in our institution were reviewed (274 cases for the PDD group with photodynamic diagnosis and 133 for the white light (WL) group without). A classification of hypotension severity was devised to identify risk factors for clinically troublesome hypotension. The distribution of hypotension severity in each of the PDD and WL groups was compared. Additionally, the patient background and perioperative data by hypotension severity were compared only in the PDD group. RESULTS: More patients with moderate and severe hypotension were noted in the PDD group. The renal function was lower with increasing hypotension severity in the PDD group. More patients on general anesthesia were included in the mild and moderate hypotension group, whereas more patients on spinal anesthesia were included in the severe hypotension group. Furthermore, the frequency of side effects other than hypotension tended to increase with hypotension severity. CONCLUSIONS: Renal function impairment and the other adverse effects of 5-aminolevulinic acid may be risk factors for severe hypotension. Mild or moderate hypotension may be caused by general anesthesia and severe hypotension may be caused by spinal anesthesia. To elucidate specific risk factors, further case-control studies are warranted.

A seed link connector protruding into the bladder formed a bladder stone.

Introduction: Low-dose-rate brachytherapy is performed for localized prostate cancer. We report the first case of a bladder stone encompassing the seed migrated into the bladder in a patient treated with low-dose-rate brachytherapy. Case presentation: A man was diagnosed with prostate cancer and underwent low-dose-rate brachytherapy. After 2 months, dysuria occurred, and ultrasonography revealed a needle-shaped high-intensity protruding from the prostate into the bladder. Cystoscopy examination found a seed link connector. With the possibility of natural dissolution of the seed link, careful observation was chosen. However, 16 months later, hematuria occurred, and an X-ray revealed a bladder stone encompassing the seed. Compared with the X-ray right after seeding, the seed located near the right bladder neck had fallen. The seed was removed by transurethral bladder lithotripsy. Conclusion: Seeds should be carefully located within the prostate, otherwise a bladder stone may be formed encompassing the seed.

Does the quality of endoscopic equipment influence the recurrence rate after photodynamic diagnosis-assisted transurethral resection of bladder tumor?

BACKGROUND: Photodynamic diagnosis-assisted transurethral resection of bladder tumor (PDD-TURBT) for nonmuscle-invasive bladder cancer is superior to conventional white-light TURBT for cancer detection. However, when performing PDD-TURBT, cystoscopy findings vary depending on the quality of the endoscopic equipment. In this study, we compared the effects of different types of endoscopic equipment on postoperative outcomes. METHODS: Patients who underwent their first PDD-TURBT at our clinic were selected. Patients on whom PDD-TURBT was performed using endoscopic equipment A were sorted into Group A, and patients on whom PDD-TURBT was performed using equipment S were sorted into Group S. The characteristics, recurrence-free survival (RFS), and recurrence frequency of these patients were retrospectively investigated and compared. The prognostic factors for RFS were also analyzed. RESULTS: A total of 49 patients were included in Group A and 46 in Group S. In Group S, a higher detection rate (8.2% vs. 30.4 %, p < 0.01) of carcinoma in situ (CIS) was noted. RFS tended to be better in Group S (HR 0.63, p = 0.15). The frequency of recurrence also tended to be lower in Group S (4.92 vs. 3.66 per 10,000 person-days, p = 0.08). Furthermore, CIS (HR 0.30, p = 0.04) and Bacillus Calmette-Guerin therapy (HR: 0.26, p = 0.01) were significant favorable prognostic factors for RFS. CONCLUSION: The quality of the endoscopic equipment may influence postoperative recurrence after PDD-TURBT. Higher-quality endoscopic instruments have superior CIS detection capabilities, which can lead to improvements in postoperative outcomes with the appropriate selection of postoperative adjuvant therapy.

Procalcitonin in advanced urological cancer-bacterial versus non-bacterial infections: prospective cohort study.

OBJECTIVES: Patients with advanced cancer may develop bacterial infections (BI) as their general condition worsens, but general blood tests often find it difficult to distinguish them from non-bacterial infections (NBI). The present prospective study was undertaken to investigate the effectiveness of serum procalcitonin levels in distinguishing between BI and NBI in patients with advanced urological cancer. METHODS: This study prospectively evaluated patients diagnosed with locally advanced or metastatic or recurrent urological cancer in our department from September 2013 to December 2019. Body temperature was measured in the axilla and the measurement results were recorded. Febrile episodes of ≥38.0°C were analysed, and written patient consent was obtained at the onset of the fever. RESULTS: Of 75 patients enrolled in the present study, 90 febrile episodes were analysed. A total of 34 of 90 febrile episodes were regarded as BI, and the remaining 56 febrile episodes as NBI. The median procalcitonin value was significantly higher in the BI group (p=0.0015), while no significant difference was found between the two groups for white blood cell count and C reactive protein. Additionally, a white blood cell count of less than 1.0×10ˆ9/L resulted in BI in all cases. The procalcitonin receiver operating characteristic area under the curve was 0.710 (95% CI 0.586 to 0.83), excluding cases with white blood cell counts of <1.0 × 103/µL. CONCLUSIONS: Procalcitonin is a rapid and affordable marker for differentiation between BI and NBI in patients with advanced urological cancer.

Bone Turnover Markers, n-Terminal Propeptide of Type I Procollagen and Tartrate-Resistant Acid Phosphatase Type 5b, for Predicting Castration Resistance in Prostate Cancer.

Bone is a common site of prostate cancer metastasis. Bone turnover markers n-terminal propeptide of type I procollagen (P1NP) and tartrate-resistant acid phosphatase type 5b (TRACP-5b) are highly sensitive to bone remodeling activity. However, their prognostic significance as markers of prostate cancer is unknown. This study retrospectively examined the usefulness of P1NP and TRACP-5b as prognostic biomarkers. Castration-resistant prostate cancer recurrence-free survival (CFS) was estimated using the Kaplan-Meier method. A predictive model for CFS was constructed using multivariate analysis. This study enrolled 255 patients diagnosed with prostate cancer at Kanazawa University Hospital. The median follow-up was 115.1 months. Patients with both high serum P1NP and TRACP-5b levels, defined as having a poor bone turnover category (BTC), had significantly shorter CFS. Multivariate analysis identified Gleason score, metastasis, and BTC poor as predictors for castration resistance in prostate cancer. Using these three factors, a prognostic model was established, categorizing patients into low-risk (no or one factor) and high-risk (two or three factors) groups. In the low-risk group, the median CFS was not reached, contrasting with 19.1 months in the high-risk group (hazard ratio, 32.23, p < 0.001). Combining P1NP and TRACP-5b may better predict castration resistance.

Enzalutamide versus Abiraterone Plus Prednisolone for Nonmetastatic Castration-Resistant Prostate Cancer: A Sub-Analysis from the ENABLE Study for PCa.

Enzalutamide (ENZ) and abiraterone plus prednisolone (ABI) can improve the survival of patients with castration-resistant prostate cancer (CRPC). However, the agent that is more effective against nonmetastatic CRPC remains unclear. To evaluate the agent that can be used as the first-line treatment for CRPC, an investigator-initiated, multicenter, randomized controlled trial (ENABLE Study for PCa) including both metastatic and nonmetastatic CRPC was conducted in Japan. The prostate-specific antigen (PSA) response rate, overall survival, some essential survival endpoints, and safety of patients with nonmetastatic CRPC were also analyzed. In this subanalysis, 15 and 26 patients in the ENZ and ABI arms, respectively, presented with nonmetastatic CRPC. There was no significant difference in terms of the PSA response rate between the ENZ and ABI arms (80% and 64%, respectively; p = 0.3048). The overall survival did not significantly differ between the two arms (HR: 0.68; 95% CI: 0.22-2.14, p = 0.5260). No significant differences were observed in terms of radiographic progression-free survival and cancer-specific survival between the ENZ and ABI arms (HR: 0.81; 95% CI: 0.35-1.84; p = 0.6056 and HR: 0.72; 95% CI: 0.19-2.73; p = 0.6443, respectively). Only four and six patients in the ENZ and ABI arms, respectively, had ≥grade 3 adverse events. ABI and ENZ had similar efficacy and safety profiles in patients with nonmetastatic CRPC.

Does radical cystectomy have a better prognosis than bladder conservative treatment in the real world?

PURPOSE: To compare the prognosis and quality of life between radical cystectomy and bladder conservative treatment for muscle invasive bladder cancer in the real world. MATERIALS AND METHODS: Patients treated for muscle invasive bladder cancer without metastases were retrospectively evaluated for overall survival, progression-free survival, and rehospitalization. RESULTS: Of the 141 patients, 62 underwent bladder conservative treatment and 79 underwent radical cystectomy. Patients who underwent radical cystectomy had significantly better progression-free survival (HR: 1.83, 95% CI: 1.12-3.00; p < 0.01) and overall survival (HR: 1.82, 95% CI: 0.99-3.34; p = 0.03) than those who underwent conservative treatment. However, there was no significant difference in prognosis between patients who refused to undergo radical cystectomy and those who underwent. In addition, rehospitalization rates for complications and additional treatment were significantly higher in patients who received conservative treatment (69.3% vs. 34.2%; p < 0.01), and the length of hospital stay was also prolonged compared to patients who received radical cystectomy (26 vs. 9 days; p = 0.03). CONCLUSIONS: Overall, conservative treatment had a significantly poorer prognosis than radical cystectomy, but there was no significant difference in prognosis when comparing patients who refused radical cystectomy and received conservative treatment with those who received radical cystectomy. However, hospitalization rates and length of stay were significantly worse for patients who chose conservative treatment, which may lead to a decline in quality of life.

Atezolizumab plus chemotherapy versus placebo plus chemotherapy in untreated locally advanced or metastatic urothelial carcinoma (IMvigor130): final overall survival analysis results from a randomised, controlled, phase 3 study.

BACKGROUND: IMvigor130 demonstrated statistically significant investigator-assessed progression-free survival benefit with first-line atezolizumab plus platinum-based chemotherapy (group A) versus placebo plus platinum-based chemotherapy (group C) in patients with locally advanced or metastatic urothelial carcinoma. Overall survival was not improved in interim analyses. Here we report the final overall analysis for group A versus group C. METHODS: In this global, partially blinded, randomised, controlled, phase 3 study, patients (aged ≥18 years) with previously untreated locally advanced or metastatic urothelial cancer and who had an Eastern Cooperative Oncology Group performance status of 0-2 were enrolled at 221 hospitals and oncology centres in 35 countries. Patients were randomly assigned (1:1:1), with a permuted block method (block size of six) and an interactive voice and web response system, stratified by PD-L1 status, Bajorin risk factor score, and investigator's choice of platinum-based chemotherapy, to receive atezolizumab plus platinum-based chemotherapy (group A), atezolizumab monotherapy (group B), or placebo plus platinum-based chemotherapy (group C). Sponsors, investigators, and patients were masked to assignment to atezolizumab or placebo (ie, group A and group C) and atezolizumab monotherapy (group B) was open label. For groups A and C, all patients received gemcitabine (1000 mg/m2 intravenously; day 1 and day 8 of each 21-day cycle), plus investigator's choice of carboplatin (area under curve 4·5 mg/mL per min or 5 mg/mL per min; intravenously) or cisplatin (70 mg/m2 intravenously), plus either atezolizumab (1200 mg intravenously) or placebo on day 1 of each cycle. Co-primary endpoints of the study were investigator-assessed progression-free survival and overall survival for group A versus group C in the intention-to-treat (ITT) population (ie, all randomised patients), and overall survival for group B versus group C, tested hierarchically. Final overall survival and updated safety outcomes (safety population; all patients who received any amount of any study treatment component) for group A versus group C are reported here. The final prespecified boundary for significance of the overall survival analysis was one-sided p=0·021. The trial is registered with ClinicalTrials.gov, NCT02807636, and is active but no longer recruiting. FINDINGS: Between July 15, 2016, and July 20, 2018, 1213 patients were enrolled and randomly assigned to treatment, of whom 851 were assigned to group A (n=451) and group C (n=400). 338 (75%) patients in group A and 298 (75%) in group C were male, 113 (25%) in group A and 102 (25%) in group C were female, and 346 (77%) in group A and 304 (76%) in group C were White. At data cutoff (Aug 31, 2022), after a median follow up of 13·4 months (IQR 6·2-30·8), median overall survival was 16·1 months (95% CI 14·2-18·8; 336 deaths) in group A versus 13·4 months (12·0-15·3; 310 deaths) in group C (stratified hazard ratio 0·85 [95% CI 0·73-1·00]; one-sided p=0·023). The most common grade 3-4 treatment-related adverse events were anaemia (168 [37%] of 454 patients who received atezolizumab plus chemotherapy vs 133 [34%] of 389 who received placebo plus chemotherapy), neutropenia (167 [37%] vs 115 [30%]), decreased neutrophil count (98 [22%] vs 95 [24%]), thrombocytopenia (95 [21%] vs 70 [18%]), and decreased platelet count (92 [20%] vs 92 [24%]). Serious adverse events occurred in 243 (54%) patients who received atezolizumab plus chemotherapy and 196 (50%) patients who received placebo plus chemotherapy. Treatment-related deaths occurred in nine (2%; acute kidney injury, dyspnoea, hepatic failure, hepatitis, neutropenia, pneumonitis, respiratory failure, sepsis, and thrombocytopenia [n=1 each]) patients who received atezolizumab plus chemotherapy and four (1%; unexplained death, diarrhoea, febrile neutropenia, and toxic hepatitis [n=1 each]) who received placebo plus chemotherapy. INTERPRETATION: Progression-free survival benefit with first-line combination of atezolizumab plus platinum-based chemotherapy did not translate into a significant improvement in overall survival in the ITT population of IMvigor130. Further research is needed to understand which patients might benefit from first-line combination treatment. No new safety signals were observed. FUNDING: F Hoffmann-La Roche.

Atezolizumab monotherapy versus chemotherapy in untreated locally advanced or metastatic urothelial carcinoma (IMvigor130): final overall survival analysis from a randomised, controlled, phase 3 study.

BACKGROUND: The primary analysis of IMvigor130 showed a significant progression-free survival benefit with first-line atezolizumab plus platinum-based chemotherapy (group A) versus placebo plus platinum-based chemotherapy (group C) in patients with locally advanced or metastatic urothelial cancer. However, this finding did not translate into significant overall survival benefit for group A versus group C at the final analysis, precluding formal statistical testing of outcomes with atezolizumab monotherapy (group B) versus group C. Here we report the final overall survival results for group B versus group C; this report is descriptive and should be considered exploratory due to the study's statistical design. METHODS: In this global, partially blinded, randomised, controlled, phase 3 study, patients (aged ≥18 years) who had locally advanced or metastatic urothelial cancer previously untreated in the metastatic setting and Eastern Cooperative Oncology Group performance status of 0-2 were enrolled at 221 hospitals and oncology centres in 35 countries. Patients were randomly assigned (1:1:1), using a permuted block method (block size of six) and an interactive voice and web response system, stratified by PD-L1 status, Bajorin score, and investigator's choice of platinum-based chemotherapy, to receive either atezolizumab plus platinum-based chemotherapy (group A), atezolizumab alone (group B), or placebo plus platinum-based chemotherapy (group C). Sponsors, investigators, and patients were masked to assignment to atezolizumab or placebo in group A and group C; atezolizumab monotherapy in group B was open label. For groups B and C, atezolizumab (1200 mg) or placebo was administered intravenously every 3 weeks. Chemotherapy involved 21-day cycles of gemcitabine (1000 mg/m2 body surface area on day 1 and day 8 of each cycle) plus the investigator's choice of carboplatin (area under the curve 4·5 mg/mL per min or 5 mg/mL per min) or cisplatin (70 mg/m2 body surface area), administered intravenously. Co-primary endpoints were progression-free survival and overall survival in group A versus group C, and overall survival in group B versus group C, tested hierarchically, in the intention-to-treat (ITT) population, and then the populations with high PD-L1 tumour expression (immune cell [IC] expression score of IC2/3) if the results from group A versus group C were significant. Here, we report the co-primary endpoint of overall survival for group B versus group C in the ITT and IC2/3 populations. The ITT population for this analysis comprised concurrently enrolled patients in groups B and C who were randomly assigned to treatment. For the safety analysis, all patients enrolled in group B and group C who received any study treatment were included. The trial is registered with ClinicalTrials.gov, NCT02807636, and is active but no longer recruiting. FINDINGS: Between July 15, 2016, and July 20, 2018, 1213 patients were enrolled and randomly assigned to treatment, of whom 362 patients were assigned to group B and 400 to group C, of whom 360 and 359, respectively, were enrolled concurrently (ITT population). 543 (76%) of 719 patients were male, 176 (24%) were female, and 534 (74%) were White. As of data cutoff (Aug 31, 2022), after a median follow-up of 13·4 months (IQR 6·2-30·8), median overall survival was 15·2 months (95% CI 13·1-17·7; 271 deaths) in group B and 13·3 months (11·9-15·6; 275 deaths) in group C (stratified hazard ratio 0·98 [95% CI 0·82-1·16]). The most common grade 3-4 treatment-related adverse events were anaemia (two [1%] in patients who received atezolizumab monotherapy vs 133 [34%] in those who received placebo plus chemotherapy), neutropenia (one [<1%] vs 115 [30%]), decreased neutrophil count (0 vs 95 [24%]), and decreased platelet count (one [<1%] vs 92 [24%]). Serious adverse events occurred in 163 (46%) patients versus 196 (50%). Treatment-related deaths occurred in three (1%; n=1 each, pneumonia, interstitial lung disease, large intestinal obstruction) patients who received atezolizumab monotherapy and four (1%; n=1 each, diarrhoea, febrile neutropenia, unexplained death, toxic hepatitis) who received placebo plus chemotherapy. INTERPRETATION: The final analysis from IMvigor130 did not show a significant improvement in overall survival with first-line atezolizumab monotherapy compared with platinum-based chemotherapy in the intention-to-treat population. The safety profile of atezolizumab monotherapy remained acceptable after extended follow-up, with no new safety signals. FUNDING: F Hoffmann-La Roche.

Overall Survival by Response to First-line Induction Treatment with Atezolizumab plus Platinum-based Chemotherapy or Placebo plus Platinum-based Chemotherapy for Metastatic Urothelial Carcinoma.

Standard-of-care first-line treatment for metastatic urothelial carcinoma (mUC) is platinum-based chemotherapy (CTx). Maintenance immunotherapy is a treatment option for patients without progressive disease (PD) after induction CTx. IMvigor130 was a randomised, phase 3 study evaluating atezolizumab plus platinum-based CTx (arm A), atezolizumab monotherapy (arm B), or placebo plus platinum-based CTx (arm C) as first-line treatment for mUC. The primary progression-free survival (PFS) analysis showed a statistically significant PFS benefit favouring arm A versus arm C, which did not translate into overall survival (OS) benefit at the final OS analysis. We report exploratory analyses based on response to combination induction treatment (arm A vs arm C) using final OS data. Post-induction OS was analysed for patients without PD during induction (4-6 CTx cycles) who received at least one dose of single-agent atezolizumab/placebo maintenance treatment. Post-progression OS was analysed for patients with PD during induction CTx. Addition of atezolizumab to CTx did not impact OS outcomes, regardless of response to induction CTx, with hazard ratios of 0.84 (95% confidence interval [CI] 0.63-1.10) for patients without PD and 0.75 (95% CI 0.54-1.05) for those with PD during induction CTx. Treatment effects appeared to be greatest for patients treated with cisplatin and for those with PD-L1-high tumours. Patient summary: The IMvigor130 trial showed that addition of atezolizumab to chemotherapy (CTx) did not improve survival over CTx alone in patients with bladder cancer. Overall, patients whose cancer did not progress during initial treatment tended to live longer than patients whose cancer did progress, but addition of atezolizumab to CTx did not help either group live longer in comparison to CTx alone. However, the results suggest that patients who received a certain CTx drug (cisplatin) or who had high levels of a marker called PD-L1 in their tumour may get the most improvement from addition of atezolizumab to CTx.The IMvigor130 trial is registered on ClinicalTrials.gov as NCT02807636.

Role of Positive Biopsy Core Ratio in Prostate Cancer Patients.

BACKGROUND/AIM: The percentage of positive cores (PPC) is increasingly recognized as a prognostic factor in prostate cancer. However, the usefulness of PPC for patients undergoing androgen deprivation therapy (ADT) and high-risk group has not been adequately studied. PATIENTS AND METHODS: A retrospective analysis was conducted of 255 patients who underwent prostate biopsy (all-case group). We examined the efficacy of PPC as a prognostic biomarker. RESULTS: Eighty-nine patients were treated with ADT alone (ADT group), and 107 patients were classified as high-risk (high-risk group). The median duration of follow-up was 112.4 months, 85.3 months, and 110.0 months for the all-case, ADT, and high-risk groups, respectively. Patients with PPC >60% had significantly shorter prostate cancer-specific survival (CSS) and castration-resistant prostate cancer-free survival (CFS) in the all-case and ADT groups. In the high-risk group, patients with PPC >60% had shorter CFS but no difference in CSS. Multivariate analysis showed that significant independent predictors of prostate CSS were the presence of metastasis at diagnosis and PPC >60% in the all-case and ADT groups. CONCLUSION: PPC may be a prognostic factor in ADT treated and high-risk prostate patients.

Efficacy of keishibukuryogan for hot flashes in prostate cancer patients receiving androgen deprivation therapy: a sub-analysis focusing on hormonal and cytokine levels.

Background: The current study attempted to elucidate the mechanisms of keishibukuryogan (TJ-25) efficacy by focusing on hormonal and cytokine levels. This is a sub-analysis of serum hormonal and cytokine levels extracted from the single-arm prospective study. Methods: Twenty-five participants were administrated TJ-25 at a dose of 2.5 g three times daily for 12 weeks, and competed for a diary of their hot flashes conditions. Various hormonal and cytokine values, including interleukin (IL)-8 and tumor necrosis factor-α (TNF-α), were measured at the baseline and 12-week visits. The correlation of hot flashes with hormonal and cytokine levels at baseline was investigated. As part of the responder analyses, all participants were divided into two groups based on the median baseline values of all hormones and cytokines at baseline, and the change amounts in strength and frequency of hot flashes from baseline to 12-week visits in both groups were compared. Furthermore, a correlation in change amounts (Δ values) by TJ-25 administration between hot flashes and each parameter was also conducted. Results: Hot flashes intensity was inversely related to estradiol levels (r=-0.433, P=0.019), and frequency was inversely related to progesterone levels (r=-0.415, P=0.025). In the responder analyses, the effectiveness of TJ-25 for hot flash strength increased in the patients with higher levels of TNF-α at baseline (P=0.0372). TJ-25 was more efficient in frequency in the patients with higher levels of IL-8 (P=0.0312). TJ-25 efficacy, on the other hand, was not significantly associated with changes in any hormonal or cytokine levels between the baseline and 12-week visits. However, ΔIL-8 and ΔTNF-α were not significantly correlated with Δstrength and Δfrequency of hot flashes by TJ-25 administration. Conclusions: Hot flashes were inversely correlated with estradiol and progesterone levels. TJ-25 was more effective in patients with higher TNF-α and IL-8 levels, with no significant change in serum levels caused by the treatment. The suggestive mechanism for the effects of keishibukuryogan is that this drug doesn't suppress the production of IL-8 and TNF-α, but may inhibit some actions of these cytokines.

Editorial for the Special Issue on High-Risk Localized and Locally Advanced Prostate Cancer.

The recent development of imaging modalities, such as diffusion-weighted whole-body imaging with background suppression (DWIBS) and positron emission tomography of prostate-specific membrane antigen (PSMA-PET) with a radioactive diagnostic agent, has enabled the detection of minute metastases in patients diagnosed with high-risk localized and locally advanced prostate cancer by conventional modalities [...].

Combination of Sarcopenia and Hypoalbuminemia Is a Poor Prognostic Factor in Surgically Treated Nonmetastatic Renal Cell Carcinoma.

PURPOSE: The purpose of this study is to observe how preoperative sarcopenia and hypoalbuminemia affect the oncological outcome of nonmetastatic renal cell carcinoma (RCC) after partial or radical nephrectomy. METHODS: This study retrospectively analyzes 288 Japanese patients with nonmetastatic RCC who underwent radical treatment at Kanazawa University Hospital between October 2007 and December 2018. Relationships between sarcopenia as indicated by the psoas muscle mass index and hypoalbuminemia (albumin ≤ 3.5 g/dL) with overall survival (OS) and metastasis-free survival (MFS) were determined. RESULTS: The study found that 110 (38.2%) of the 288 patients were sarcopenic and 29 (10.1%) had hypoalbuminemia. The combination of sarcopenia and hypoalbuminemia was associated with a shorter OS and MFS (p for trend = 0.0007 and <0.0001, respectively), according to Kaplan-Meier curves. The concurrent presence of sarcopenia and hypoalbuminemia were found to be significant and independent predictors of poor MFS (hazard ratio (HR), 2.96; 95% confidence interval (95% CI), 1.05-8.39; p = 0.041) and poor OS (HR, 6.87; 95% CI, 1.75-26.94; p = 0.006), respectively. CONCLUSIONS: In Japanese patients with surgically treated nonmetastatic RCC, combined preoperative sarcopenia and hypoalbuminemia was a significant predictor of poor survival.

Efficacy and Safety of First-Line Cytokines versus Sunitinib and Second-Line Axitinib for Patients with Metastatic Renal Cell Carcinoma (ESCAPE Study): A Phase III, Randomized, Sequential Open-Label Study.

BACKGROUND: The sequence of first-line cytokine and second-line molecular targeted therapies may be suitable for some patients with metastatic renal cell carcinoma (mRCC) because of the expectation of complete remission and durable response achieved with cytokine therapy. METHODS: This was a phase III randomized controlled trial investigating the outcomes of low-dose interleukin-2 (IL-2) plus interferon alfa (IFNα) versus sunitinib as the first line and axitinib as the second line in patients with low- and intermediate-risk mRCC. RESULTS: Thirty-five patients were randomly assigned. The total progression-free survival (PFS) to the end of the second line was 29.0 months (95% CI, 11.7-46.3) in the IL-2 + IFNα group and 16.3 months (95% CI, 6.3-26.4) in the sunitinib group. The PFS hazard ratio for the IL-2 + IFNα group relative to the sunitinib group was 0.401 (95% CI, 0.121-1.328; p = 0.135). The hazard ratio for overall survival (OS) was 1.675 (95% CI, 0.418-6.705; p = 0.466), which was better in the sunitinib group than in the IL-2 + IFNα group but not statistically significant. The types of adverse events (AEs) differed significantly, although there was no significant difference in the incidence of AEs. CONCLUSIONS: There was a trend toward better total PFS for IL-2 + IFNα, but it was not significant. There was also no advantage of IL-2 + IFNα in terms of OS. The study was underpowered to draw any definitive conclusions. The results showed no clear advantage of IL-2 + IFNα over sunitinib in the first-line setting; however, it may be an option in some relatively low-risk mRCC cases due to the difference in the AE profile. This trial was registered with the University Hospital Medical Information Network (UMIN), center identifier UMIN 000012522.

Novel α-Trifluoromethyl Chalcone Exerts Antitumor Effects Against Prostate Cancer Cells.

BACKGROUND/AIM: Despite treating advanced prostate cancer (PCa) with androgen deprivation therapy, it eventually progresses to castration-resistant PCa. Subsequently, taxanes are administered, but when PCa becomes resistant to taxanes, another treatment is needed, which has not yet been established. We previously synthesized a novel α-trifluoromethyl chalcone, YS71, and reported its antitumor effects against PCa cells. In this study, we confirmed its efficacy against androgen-sensitive, androgen-independent, and taxane-resistant PCa cells. MATERIALS AND METHODS: The PCa cell lines used were LNCaP, PC-3, DU145, PC-3-TxR (paclitaxel-resistant), PC-3-TxR/CxR (paclitaxel- and cabazitaxel-resistant), DU145-TxR, and DU145-TxR/CxR. The antiproliferative effects of YS71 were evaluated using proliferation assay. The reverse transcriptase transcription-polymerase chain reaction and western blot were performed to determine the expression level of androgen receptor (AR), whereas luciferase assay was performed to determine the AR activity. Furthermore, TUNEL assay and western blot were performed to investigate the mechanism of the antiproliferative effect. RESULTS: YS71 exerted a dose-dependent antitumor effect, inhibited AR activity, and induced apoptosis in all PCa cells in a dose-dependent manner. Western blot showed that YS71 increased the levels of apoptosis-related proteins, cleaved caspase-3, and cleaved PARP, and decreased the levels of the antiapoptotic proteins, Bcl-xL and Bcl-2. In addition, microarray analysis revealed that YS71 decreased several cancer-related genes. CONCLUSION: YS71 exhibits antitumor activity by inducing apoptosis in PCa cells, including taxane-resistant cells. It could be a potential future therapeutic option for hormone- and chemotherapy-resistant PCa.

The CCL2-CCR2 Axis Contributes to Migration of Cabazitaxel-resistant Prostate Cancer Cells.

BACKGROUND/AIM: Developing resistance to cabazitaxel is a major challenge in patients with docetaxel- and castration-resistant prostate cancer (CRPC) since it is frequently administered as a last resort. We have previously reported that CCL2 induces resistance to the antiproliferative effect of cabazitaxel in DU145-TxR/CxR prostate cancer cell lines. However, how CCL2 induces resistance to the antimigration effect of cabazitaxel remains unclear. MATERIALS AND METHODS: We established a cabazitaxel-resistant cell line, DU145-TxR/CxR, from a previously established paclitaxel-resistant cell line, DU145-TxR, which was confirmed to show docetaxel resistance. We performed migration assay and analyzed the expression of epithelial-mesenchymal transition markers using DU145-TxR/CxR with or without CCL2 silencing with small interfering RNA (siRNA) transfection. RESULTS: Cabazitaxel inhibited the migration of DU145 cells through the inactivation of STAT3. A CCR2 (a specific receptor of CCL2) antagonist suppressed the migration of DU145-TxR and DU145-TxR/CxR cells under cabazitaxel treatment. Western blotting revealed that the CCR2 antagonist inhibited STAT3 phosphorylation in DU145-TxR and DU145-TxR/CxR cells under cabazitaxel treatment. CCL2 silencing with siRNA in DU145-TxR and DU145-TxR/CxR cells decreased migration through STAT3 and p38 inactivation. Furthermore, CCL2 activated AKT, and CCR2 antagonist inhibited AKT phosphorylation in DU145-TxR and DU145-TxR/CxR cells with recovery of sensitivity to cabazitaxel under cabazitaxel treatment. CONCLUSION: The CCL2-CCR2 axis is a key contributor to resistance to the antimigration effect of cabazitaxel in prostate cancer cells. CCL2-CCR2 axis inhibition may be a potential therapeutic target against chemoresistant CRPC in combination with cabazitaxel.

Comparison of postoperative urinary continence and incontinence types between conventional and Retzius-sparing robot-assisted radical prostatectomy.

AIMS: This study aimed to investigate the postoperative urinary continence rate and incontinence types compared over time between conventional robot-assisted radical prostatectomy (C-RARP) and Retzius-sparing RARP (RS-RARP). METHODS: All 61 cases were selected from the C-RARP and RS-RARP by propensity score matching, and the pad scale, 24-h pad weight test, and International consultation on incontinence questionnaire-short form (ICIQ-SF) were followed-up over time up to 12 months. RESULTS: The probability of urinary continence per pad scale evaluation differed according to how it was defined: the continence rate 12 months after C-RARP and RS-RARP were 94% and 95% for 1 pad/day, 85% and 92% for 1 security pad/day, 61% and 85% for no pad use, respectively, which were all significantly better with RS-RARP. The results of the 24-h pad weight test were significantly better with RS-RARP at both 3 and 12 months, with median C-RARP versus RS-RARP values of 5 versus 1 g and 2 versus 0 g, respectively. In terms of types of urinary incontinence, the rates of postoperative stress urinary incontinence (SUI) increased in both procedures but to a lesser extent in RS-RARP. Other types of urinary incontinence, such as urge incontinence and terminal dribbling, did not differ significantly before and after surgery and between the two procedures. CONCLUSIONS: Postoperative urinary continence was better with RS-RARP than with C-RARP per all follow-up parameters until 12 months postoperatively. Postoperative SUI was significantly lower with RS-RARP than with C-RARP, which was considered the main reason for better postoperative urinary continence with RS-RARP.

Sarcopenia Is Associated With Aggressive Clinicopathological Outcomes and Is a Poor Prognostic Indicator for Non-metastatic Renal Cell Carcinoma.

BACKGROUND/AIM: We aimed to describe the impact of preoperative sarcopenia on the oncological outcome of non-metastatic renal cell carcinoma (RCC) after surgical treatment. PATIENTS AND METHODS: Data on 299 Japanese patients with non-metastatic RCC who underwent radical treatment at Kanazawa University Hospital between October 2007 and December 2018 were extracted. Clinicopathological features and survival prognosis of patients stratified by the presence or absence of sarcopenia as indicated by the psoas muscle mass index (PMI) were retrospectively analyzed. PMI <516.8 and <235.1 mm2/m2 at the L3 level for male and female were defined as the cutoff values for sarcopenia, respectively. RESULTS: Of 299 patients, 113 (37.8%) were classified as sarcopenic. The sarcopenia group showed a larger tumor size, worse pathological tumor stage and histological grade, and more frequent lymphovascular invasion than the non-sarcopenia group. According to Kaplan-Meier curves, sarcopenia was associated with a shorter overall survival (OS) and metastasis-free survival (p=0.0174 and 0.0306, respectively). Multivariate analysis identified sarcopenia as a significant and independent prognostic factor for poor OS (hazard ratio, 2.58; 95% confidence interval=1.09-6.08; p=0.030). CONCLUSION: Sarcopenia is a significant factor indicating worse pathological outcomes and poor survival prognosis in surgically treated non-metastatic RCC.