New risk stratification for adjuvant nivolumab for high-risk muscle-invasive urothelial carcinoma.

Objectives: We aim to evaluate the risk of recurrence after neoadjuvant chemotherapy followed by radical cystectomy, particularly in ypT2 disease in patients with urothelial carcinoma, because it is not clear if all eligible patients with high-risk muscle-invasive urothelial carcinoma should be treated with adjuvant nivolumab. Materials and Methods: We analysed the radiological and clinicopathological features, including cT and ypT stages, of 197 patients who had undergone two to four cycles of cisplatin-based neoadjuvant chemotherapy and radical cystectomy without adjuvant chemotherapy. We stratified the risk of postoperative recurrence by these factors. Results: The median observation period was 29.6 (interquartile range, 11.4-71.7) months, and disease recurrence was observed in 58 patients. Multivariate analysis revealed that ypT stage (P = 0.019) and lymphovascular invasion (P = 0.015) were independent risk factors for postoperative recurrence. The ypT2 group (n = 38) had significantly better recurrence-free survival than the ypT3 group (n = 41) (median recurrence-free survival: not reached vs. 13.4 months, respectively, P = 0.005). In ypT2 disease, the cT2 and ypT2 group (n = 15), which was diagnosed as cT2 preoperatively and then diagnosed as ypT2 postoperatively, had significantly better recurrence-free survival than the cT3/4 and ypT2 group (n = 23) (median recurrence-free survival: not reached vs. 63.1 months, respectively, P = 0.034). There was no significant difference in recurrence-free survival between the ypT ≤ 1 (n = 106) and the cT2 and ypT2 groups (median recurrence-free survival: not reached in both, P = 0.962). Conclusion: Patients with cT2 and ypT2 stage have a relatively low risk of recurrence and thus have a lower need for adjuvant nivolumab, particularly those with ypT2.

Complete response to pembrolizumab in a patient with recurrent and metastatic urothelial bladder carcinoma reflecting coexisting sarcomatoid subtype and glandular differentiation: a case report.

In advanced urothelial carcinoma (UC), approximately 20% of patients respond to pembrolizumab, an anti-programmed cell death-1 (PD-1) antibody. Herein, we reported a single case of UC showing coexistence of sarcomatoid subtype and glandular differentiation. Notably, only glandular differentiation was recurrent, probably progressive, and metastatic, which showed complete response to pembrolizumab. An 80-year-old woman presented with hematuria and dysuria, and an intra-vesical tumor was detected on ultrasound. Transurethral resections (TUR) were performed three times. In the first TUR, a sub-pedunculated tumor and a flat lesion were closely but independently located. Pathologically, the sub-pedunculated tumor was an invasive UC, sarcomatoid subtype. Meanwhile, the flat lesion was invasive UC with glandular differentiation. Despite the second and the additional TUR, the tumor was growing and a lymph node metastasis was detected. The third TUR specimen showed UC with glandular differentiation, and a positive PD-L1 expression as well as high density CD8-positive lymphocytic cells infiltration were observed. Pembrolizumab was administered for four courses after terminating the chemotherapy. The CT scan revealed shrinkage of both primary tumor and metastases. Cystectomy and lymph nodes dissection were performed, and no residual carcinoma was detected. The therapeutic effect was regarded as pathological complete response. Pembrolizumab could be effective for special subtype or divergent differentiation of UC, particularly in an event of an 'immune hot' tumor. Supplementary Information: The online version contains supplementary material available at 10.1007/s13691-022-00568-5.

Efficacy of abiraterone acetate for high-risk hormone-naïve metastatic prostate cancer: A comparison with combined androgen blockade therapy with bicalutamide and androgen deprivation therapy alone.

BACKGROUND: The treatment landscape for men with metastatic hormone-naïve prostate cancer (mHNPC) has dramatically changed with the approval of next-generation anti-androgen drugs. We compared the treatment efficacy of abiraterone with that of combined androgen blockade (CAB) therapy and androgen deprivation therapy (ADT) alone in men with high-risk mHNPC. METHODS: In total, 146 Japanese men with high-risk mHNPC were retrospectively analyzed. As initial hormonal therapy, 30, 83, and 33 men were treated with ADT plus abiraterone (ABI group), ADT plus bicalutamide (CAB group), and ADT alone (ADT group), respectively. Treatment efficacy was compared using time to castration resistance (TTCR) and prostate-specific antigen (PSA) response among the groups. Propensity score matching analysis was also performed to adjust for baseline differences. RESULTS: The median (95% confidence interval [CI]) TTCR in the ABI, CAB, and ADT groups were not reached, 10.7 (7.6-13.8) months and 11.0 (7.9-12.4) months, respectively, and it was significantly longer in the ABI group than in the other groups (p = 0.0012, p = 0.0008). In propensity score matching analysis, the median TTCR was also significantly longer in the ABI group than in the other groups (hazard ratio [HR], 0.47; 95% CI, 0.22-0.98; p = 0.010; HR, 0.32; 95% CI, 0.12-0.85; p = 0.004). The number of men who achieved PSA levels ≤0.2 ng/mL after propensity score matching were significantly higher in the ABI group than in the other groups. CONCLUSIONS: Our results provide important evidence regarding the superiority of abiraterone over CAB therapy and ADT alone for initial treatment for men with newly diagnosed mHNPC.

Case Study: A Japanese patient with metastatic renal cell carcinoma who achieved long-term treatment-free survival with pembrolizumab and axitinib in the KEYNOTE-426 phase III trial of pembrolizumab and axitinib versus sunitinib.

Introduction: Our patient treated with pembrolizumab and axitinib is one of the longest survivors in Japan on KEYNOTE 426, despite adverse events, including delayed-onset hepatitis. We herein present a detailed clinical course and short discussion on the case. Case presentation: This was a 49-year-old male with clear cell renal cell carcinoma and lung metastases. After cytoreductive nephrectomy, treatment with pembrolizumab plus axitinib was initiated and the patient demonstrated a radiographic partial response as best response. The main adverse event was pembrolizumab-induced delayed-onset hepatitis, which was successfully treated with prednisolone. Pembrolizumab was re-initiated and completed. Conclusion: The survival benefit in the present case may be due to the initial potent anti-cancer effects of axitinib and durable immune effects of pembrolizumab, leading to long-term treatment-free survival.

Impact of Cytoreductive Nephrectomy Following Nivolumab Plus Ipilimumab Therapy for Patients With Advanced Renal Cell Carcinoma.

BACKGROUND/AIM: CheckMate 214 study revealed that nivolumab plus ipilimumab combination therapy showed a strong and durable effect compared to sunitinib for patients with advanced renal cell carcinoma (aRCC). Most of the patients underwent previous nephrectomy before systemic treatment. We retrospectively investigated the clinical outcomes of Japanese patients treated with cytoreductive nephrectomy following nivolumab plus ipilimumab for aRCC. PATIENTS AND METHODS: Seventy-nine patients were treated with systemic therapy for aRCC between October 2018 and August 2021 at the Saitama Medical University International Medical Center. Ten of 61 patients treated with nivolumab plus ipilimumab underwent cytoreductive nephrectomy after the combined immunotherapy. RESULTS: The median overall survival and progression-free survival were 24.3 and 15.9 months, respectively. The objective response rate was 50.8%; 9.8% of patients had a complete response, and the median time to objective response was 3.2 (range=1.3-19.7) months. The estimated percentage of patients who sustained an objective response at 30 months was 73.0%. Twenty-three patients (74%) in the complete or partial response (CR/PR) group, 11 patients (52%) in the stable disease (SD) group, and two patients (22%) in the progressive disease (PD) group had immune-related adverse events of grade 3 or higher, respectively. For all 10 patients, cytoreductive nephrectomy following nivolumab plus ipilimumab treatment were completed safely. Three patients achieved a pathological complete response without viable cancer cells. Only two patients had residual lesions on images after deferred cytoreductive nephrectomy; the remaining patients achieved radiological CR. CONCLUSION: Cytoreductive nephrectomy after nivolumab plus ipilimumab treatment could be useful in a limited number of cases, possibly resulting in curative nephrectomy due to the durable therapeutic effect of immunotherapy.

Safety of adjuvant gemcitabine plus cisplatin chemotherapy in a patient with bilateral ureteral cancer undergoing hemodialysis.

An 80 year old Japanese man with bilateral ureteral cancer underwent laparoscopic bilateral nephroureterectomy and lymph-node dissection. The pathological stage of the left and right ureteral tumors was pT3pN0M0. He received two courses of adjuvant gemcitabine and cisplatin chemotherapy while undergoing hemodialysis. The standard dose of gemcitabine and 50% of the standard dose of cisplatin were administered on the same day. Hemodialysis was started 6 h after gemcitabine administration and 1 h after cisplatin administration. The side effects were evaluated according to the Common Terminology Criteria for Adverse Events v4.0. In the first course, Grade 4 side effects including leukopenia, neutropenia, and thrombocytopenia were observed. He was treated with granulocyte colony-stimulating factor and platelet transfusion. Because the second course was administered without reducing the doses, granulocyte colony-stimulating factor was administered prophylactically, and Grade 4 side effects were reduced to Grade 3. Gemcitabine plus cisplatin chemotherapy can be administered safely in a patient with advanced ureteral cancer undergoing hemodialysis by adequately managing adverse events.

Laparoendoscopic single-site simple nephrectomy and reduced port procedure for inflammatory nonfunctioning kidney.

INTRODUCTION: To describe laparoendoscopic single-site simple nephrectomy and reduced port simple nephrectomy for inflammatory nonfunctioning kidney. CASE PRESENTATION: Case 1: a 58-year-old female with fever was referred to our hospital. Computed tomography demonstrated a markedly atrophic right kidney and mild hydronephrosis. Case 2: a 64-year-old male with a history of several intra-abdominal surgeries visited our hospital with a complaint of left back pain and fever. Computed tomography demonstrated left marked hydronephrosis, thinning of renal parenchyma, and duplicated inferior vena cava. After antibiotic treatment, transperitoneal reduced port simple nephrectomy and retroperitoneal laparoendoscopic single-site simple nephrectomy were performed in Case 1 and 2, respectively, because the function of the affected kidney was almost lost on renography. Although adhesion was slightly noted around the renal hilum in Case 1, neither conversion to laparotomy nor placement of additional ports was needed. CONCLUSION: Laparoendoscopic single-site simple nephrectomy and reduced port simple nephrectomy for inflammatory nonfunctioning kidney may be options for experienced laparoscopic surgeons.

Development of novel ACN (albumin, C-reactive protein and neutrophil-to-lymphocyte ratio) prognostication model for patients with metastatic renal cell carcinoma receiving first-line molecular-targeted therapy.

PURPOSE: The objective of this study was to develop a novel prognostication model in patients with treatment-naïve metastatic renal cell carcinoma (mRCC). METHODS: This study included 325 consecutive mRCC patients receiving first-line molecular-targeted therapy at 4 institutions. Potential parameters associated with overall survival (OS) in these patients were investigated to develop a novel stratification model. RESULTS: Median OS of the 325 patients was 38 months. A multivariable analysis of several factors identified independent predictors associated with unfavorable OS as follows: no previous nephrectomy, Karnofsky performance status <80%, albumin (Alb) ≤3.5 g/dl, C-reactive protein (CRP) >0.5 mg/dl and neutrophil-to-lymphocyte ratio (NLR) >3. Of these 5 independent OS predictors, 3 numeric factors were used to develop the ACN (Alb, CRP, and NLR) model by dividing patients into 3 groups according to the positive numbers of these 3 numeric risk factors. Median OS durations were 63, 37, and 11 months in the favorable (n = 105, 32.3%, without risk factors), intermediate (n = 88, 27.1%, with a single risk factor), and poor (n = 132, 40.6%, with multiple risk factors) risk groups, respectively. The ACN model as a prognostication tool was shown to be superior to the Memorial Sloan Kettering Cancer Center (MSKCC) and the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) models by both the concordance index and decision curve analysis. CONCLUSIONS: The ACN model could stratify the prognostic risk of mRCC patients receiving first-line targeted therapy more accurately than the MSKCC and IMDC models.

Dorsal Vein Complex Preserving Technique During Robot-Assisted Radical Prostatectomy.

Background: Recently, two techniques of robot-assisted radical prostatectomy (RARP), which preserve dorsal vein complex (DVC), endopelvic fascia, and full neurovascular bundle (NVB), through anterior approach were reported. The techniques in a relatively large workspace seem less technically demanding than Retzius-sparing RARP. In this case report, we present a further modified technique of transperitoneal-anterior-antegrade approach with a division of the endopelvic fascia to reduce the technical demands. Case Presentation: In a routine evaluation, a 65-year-old man was shown to have a prostate-specific antigen level of 5.07 ng/mL. Prostatic biopsy revealed a Gleason score of 6 (3 + 3) adenocarcinoma in 2 of the 12 specimens, and the clinical stage was diagnosed as cT2aN0M0. RARP was performed including transperitoneal full NVB sparing, antegrade preservation of DVC, and division of endopelvic fascia to increase the prostate mobility and reduce technical demands. The patient completely gained continence on the day after removal of the catheter, and potency was recovered 30 days after surgery. Conclusion: Our DVC preservation technique in the transperitoneal-anterior-antegrade approach with a division of the endopelvic fascia during RARP may be safe, reduce technical demands, and facilitate early recovery of continence and sexual function after surgery.

Reduced port laparoscopic radical nephrectomy using an umbilical zigzag skin incision for renal cell carcinoma.

Reduced port laparoscopic radical nephrectomy (RPLRN) is an equivalent approach to conventional laparoscopic radical nephrectomy (LRN). In LRN, one wound generally needs to be extended for specimen extraction; therefore, some ingenuity is needed to achieve a good cosmetic outcome. We herein describe our initial experience of RPLRN using an umbilical zigzag skin incision for renal cell carcinoma (RCC). A 64-year-old female [body mass index (BMI): 20.0 kg/m2] was diagnosed with right RCC, which was 35 mm in diameter (clinical T1aN0M0). Case 2: a 68-year-old male (BMI: 23.2 kg/m2) was diagnosed with right RCC, which was 58 mm in diameter (clinical T1bN0M1), and perinephric fat was relatively thick. The procedure was safely completed in both cases. Total operative times, pneumoperitoneal times, and estimated blood loss in Case 1 and 2 were 90 and 145 min, 49 and 90 min, and 5 and 80 ml, respectively, and the times required to construct umbilical ports and close umbilical wounds were 8 and 9 min and 33 and 46 min, respectively. In Case 1, the specimen was easily extracted without the extension of the umbilical skin incision, whereas it was extended by an additional 2 cm in Case 2. The umbilical wound was inconspicuous in both cases. RPLRN using an umbilical zigzag skin incision for RCC was safely performed without complications, and clashing between instruments was minimized. The high level of cosmesis is advantageous and an umbilical zigzag skin incision may contribute to more widespread use of RPLRN for RCC; however, further studies on long-term oncological outcomes are needed.

Prognostic significance of p16 expression in high-grade prostate adenocarcinoma.

Management of advanced hormone-naïve prostate cancer (HNPC) is a critical public health issue. Useful prognostic markers are thus needed to select patients who will benefit from recently introduced upfront therapies. p16 expression is an adverse prognostic marker in prostate cancer. The present study aimed to determine whether p16 expression would serve as an adverse prognostic marker in advanced HNPC. A total of 79 patients diagnosed by needle biopsy with adenocarcinoma Gleason score ≥8 between 2010 and 2013 at Aichi Medical University were included in this study. The median patient age was 73 (range 52-87) years. The median follow-up was 62 months (range 2-98). Fourteen patients had p16-positive samples. Fifteen patients died from prostate cancer, 10 of whom were in the p16-positive group. p16 positivity was associated with clinical T stage (P < 0.001), presence of IDC-P (P < 0.001), distant metastasis (P < 0.001) and lymph node metastasis (P < 0.001). These results indicate that p16 expression is associated with adverse prognostic factor of prostate cancer and suggest that p16 expression may provide useful information for treatment planning and identifying suitable candidates for upfront chemotherapy or androgen receptor axis-targeted therapy.

Discontinuation of first-line molecular-targeted therapy and prognosis in patients with metastatic renal cell carcinoma: Impact of disease progression vs. adverse events.

OBJECTIVES: We evaluated the impact of discontinuation of first-line (1L) molecular-targeted therapy on prognostic outcomes among patients with metastatic renal cell carcinoma (mRCC). METHODS: Study patients with mRCC were treated with 1L molecular-targeted agents at 4 separate institutions. Prognostic outcomes in this patient cohort were analyzed retrospectively based on whether discontinuation of 1L therapy was related to adverse events (AEs) or progression of disease (PD). RESULTS: Of the 201 patients enrolled, 117 patients (58%) and 84 patients (42%) discontinued 1L targeted therapy due to PD and AEs, respectively. Second-line therapy was subsequently provided to 101 (86%) and 66 (79%) of the patients who discontinued 1L therapy secondary to PD or AEs, respectively. Patients who discontinued 1L therapy due to AEs were significantly older than those with PD. The progression-free survival and overall survival from the initiation of 1L targeted therapy were significantly longer in patients who discontinued 1L therapy due to AE than in those who discontinued 1L therapy due to PD. The OS from the initiation of second-line targeted therapy was significantly longer in patients who discontinued 1L therapy due to AE than those with PD. Furthermore, AE as a reason for discontinuation of 1L targeted therapy as opposed to PD was independently associated with longer progression-free survival and OS as determined by multivariate analysis. CONCLUSIONS: Our findings suggest that mRCC patients who discontinue 1L therapy due to AEs have a more favorable prognosis than those who discontinue therapy due to PD.

Prognostic Stratification of the IMDC Intermediate Risk Group After Treatment With First-line Molecular-targeted Therapy for Metastatic Renal Cell Carcinoma.

BACKGROUND/AIM: The therapeutic outcomes of patients with metastatic renal cell carcinoma (mRCC) have dramatically improved with the introduction of molecular-targeted agents. The observational multicenter study was conducted to develop a novel stratification system for the intermediate risk group of the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model. PATIENTS AND METHODS: The present study included 252 Japanese patients with mRCC who received first-line molecular-targeted therapy at four institutions. RESULTS: The 252 patients were classified into the favorable, intermediate, and poor risk groups by the IMDC model. For the intermediate risk group, multivariate analysis of the six factors included in the IMDC model revealed that a low performance status, anemia, and a high platelet count were independent predictors of poor overall survival (OS). The intermediate risk group was subsequently divided into the following two groups (int -group 1 and 2) by the three independent OS predictors. Significant differences in the OS were noted among the IMDC favorable risk group, int-group 1, int-group 2, and poor risk group. CONCLUSION: The novel stratification presented in this study could be a useful tool for further prognostication of patients with mRCC classified into the intermediate risk group according to the IMDC model after first-line molecular-targeted therapy.

A case of castration-resistant prostate cancer with liver metastases achieved a complete response by docetaxel chemotherapy.

Castration-resistant prostate cancer (CRPC) patients with liver metastases have an extremely poor prognosis. Herein, we report a rare patient who achieved a complete response by docetaxel chemotherapy for this aggressive disease. A 67-year-old Japanese male diagnosed with local prostate cancer [initial prostate specific antigen (PSA) of 10.3 ng/mL, a highest Gleason score of eight] received radical prostatectomy (RP) followed by salvage radiotherapy for PSA recurrence without distant metastases. After four years, androgen deprivation therapy was commenced for both local recurrence and elevated PSA. After a further four years, despite good control of PSA (1.2 ng/mL), other clinical findings including radiographic images revealed CRPC with multiple liver metastases. Ten cycles of docetaxel chemotherapy achieved a complete response for more than five years. In conclusion, even if a patient has CRPC with liver metastases, early diagnostic imaging irrespective of the PSA level may provide a better response to early docetaxel chemotherapy.

Efficacy of Nivolumab Plus Ipilimumab in a Patient With Renal Cell Carcinoma Concomitant With Cardiac Metastasis: A Case Report.

BACKGROUND/AIM: Patients with metastatic renal cell carcinoma (RCC) with cardiac metastasis have had poor outcomes in the era of molecular targeted therapy. There are few reported outcomes for patients with cardiac metastasis of RCC treated with immune checkpoint inhibitors (ICIs). CASE REPORT: A 32-year-old female presented with metastatic RCC (unclassified type) with contralateral renal and cardiac metastases, as well as renal hilar lymph node metastases (cT4N2M1). An 18F-fluorodeoxyglucose (FDG) positron-emission tomography (PET) computed tomographic (CT) scan was useful in diagnosing cardiac metastasis. Nivolumab plus ipilimumab achieved prominent shrinkage of almost all tumors except for one cardiac tumor. FDG-PET/CT scan also revealed the marked attenuation of FDG uptake in each tumor. In addition, a needle biopsy of the remaining primary renal tumor was pathologically observed to have no viable cancer cells. CONCLUSION: This successful case suggests that ICIs might provide a better outcome even for patients with cardiac metastasis of RCC, and that FDG-PET/CT scan might be useful for therapeutic assessment, as well as diagnosis.

Clinical pharmacokinetics of flomoxef in prostate tissue and dosing considerations for prostatitis based on site-specific pharmacodynamic target attainment.

Flomoxef is used to treat bacterial prostatitis; however, its prostatic pharmacokinetics have not been fully clarified. Flomoxef (500 or 1000 mg) was administered to patients with benign prostatic hypertrophy (n = 54). After a 0.5-h infusion, venous blood samples were drawn at time points of 0.5-5 h, and prostate tissue samples were collected at time points of 0.5-1.5 h during transurethral resection of the prostate. The drug concentrations in plasma and prostate tissue were analyzed pharmacokinetically and used for a stochastic simulation to predict the probability of attaining pharmacodynamic target in prostate tissue. Showing dose linearity in the prostatic pharmacokinetics, flomoxef rapidly penetrated into prostate tissue, with a prostate/plasma ratio of 0.48-0.50 (maximum drug concentration) and 0.42-0.55 (area under the drug concentration-time curve). Against the tested populations of Escherichia coli, Klebsiella and Proteus species isolates, 0.5-h infusion of 1000 mg three times daily achieved a ≥90% expected probability of attaining the bactericidal target (70% of the time above the minimum inhibitory concentration [MIC]) in prostate tissue. The site-specific pharmacodynamic-based breakpoint (the highest MIC at which the target-attainment probability in prostate tissue was >90%) values were 0.25 mg/L (MIC for 90th percentile of E. coli and Klebsiella species) for 500 mg four times daily and 0.5 mg/L (MIC90 of Proteus species) for 1000 mg four times daily. These results help to fully characterize the prostatic pharmacokinetics of flomoxef, while also helping to rationalize and optimize the dosing regimens for prostatitis based on site-specific pharmacodynamic target attainment.

Increased infiltration of CCR4-positive regulatory T cells in prostate cancer tissue is associated with a poor prognosis.

BACKGROUND: Regulatory T cells (Tregs) play important roles in the suppression of immune responses, including antitumor immune responses. C-C chemokine receptor 4 (CCR4) is highly expressed on effector Tregs, and anti-CCR4 antibody is attracting attention as a novel immunotherapeutic agent for solid tumors. This study aimed to evaluate the expression of CCR4-positive Tregs (CCR4+Tregs) in prostate cancer and estimate the clinical potential of CCR4-targeting therapy for prostate cancer. METHODS: A total of 15 radical prostatectomy (RP) specimens and 60 biopsy specimens from individuals diagnosed with prostate cancer were analyzed to evaluate the infiltration of CCR4+Tregs in prostate cancer. The relationships between the number of CCR4+Tregs and clinical parameters were investigated in RP and biopsy specimens. Moreover, the total number of Tregs, CCR4+Tregs, and T cells and the ratio of CCR4+Tregs to Tregs and T cells in biopsy specimens were compared between patients with poor prognosis who progressed to castration-resistant prostate cancer (CRPC) within 12 months (n = 13) and those with good prognosis who were stable with hormone-sensitive prostate cancer over 12 months (n = 47). Furthermore, biopsy specimens were divided into two groups: low and high CCR4+Treg expression groups and the prognosis was compared between them. RESULTS: There was a higher expression of CCR4+Tregs in RP specimens with a higher (≥8) Gleason score than in those with a lower (<8) Gleason score (P = .041). In biopsy specimens, 65.9% Tregs were positive for CCR4. The number of CCR4+Tregs positively correlated with clinical stage (P < .001) and Gleason score (P = .006). The total number of Tregs and CCR4+Tregs significantly increased in the poor prognosis group compared with that in the good prognosis group (P = .024 and .01, respectively). Furthermore, patients with lower CCR4+Treg expression levels showed a significantly longer time to progression to CRPC (not reached vs 27.3 months; P < .001) and median survival time (not reached vs 69.0 months; P = .014) than those with higher expression levels. CONCLUSIONS: CCR4+Tregs are highly infiltrated in the prostate tissue of patients with poor prognosis with potential to progress to CRPC. Furthermore, the degree of infiltration of CCR4+Tregs is related to the prognosis of prostate cancer.

Prostate-specific antigen response patterns during cabazitaxel therapy in patients with metastatic castration-resistant prostate cancer.

BACKGROUND: The objective of this study was to categorize prostate-specific antigen (PSA) response during cabazitaxel therapy in patients with metastatic castration-resistant prostate cancer (mCRPC) into different patterns and to investigate the prognostic impact of the PSA response patterns. METHODS: We reviewed data from patients with mCRPC who had been treated with cabazitaxel therapy at four institutions belonging to Tokai Urologic Oncology Research Seminar. Patients eligible for this study had received at least three cycles of cabazitaxel treatment at three- or four-week intervals. The PSA response patterns were categorized as primary resistance (PR), response (RE), stabilization (ST), and fluctuating (FL). The overall survival (OS) was compared among the patterns. RESULTS: Data from a total of 50 patients were analyzed in this study. The number of patients exhibiting PR, RE, ST and FL patterns were 18 (36%), 14 (28%), 12 (24%) and 6 (12%), respectively. The median (95% CI) OS of patients with PR and RE patterns was 10.7 (5.6-15.9) and 14.9 (6.8-23.0) months, respectively, and was not reached for patients with ST and FL patterns. The OS of patients with the FL pattern was significantly better than that of patients with PR (P = 0.012) and RE (P = 0.010) patterns. CONCLUSION: There were some patients whose PSA were fluctuating during cabazitaxel therapy in patients with mCRPC. Because the prognosis of such patients was relatively good, the judgment to discontinue the cabazitaxel therapy after PSA rise followed by decrease should be made prudently.

Optimal Timing of Cabazitaxel Introduction for Japanese Patients With Metastatic Castration-resistant Prostate Cancer.

BACKGROUND/AIM: Limited information is available to help physicians decide when to introduce cabazitaxel for metastatic castration-resistant prostate cancer (mCRPC) patients. The objective of this study was to assess the optimal timing of cabazitaxel introduction. PATIENTS AND METHODS: The clinical outcomes of 66 mCRPC patients receiving cabazitaxel following failure of docetaxel were retrospectively analyzed. RESULTS: Among the parameters possibly affecting the timing of cabazitaxel introduction, only an increased prostate-specific antigen (PSA) value from the diagnosis of CRPC had a significant impact on overall survival (OS) after the introduction of cabazitaxel. Furthermore, there was a significant correlation between the increased PSA value from the diagnosis of CRPC and the baseline PSA value at cabazitaxel introduction. Multivariate analysis showed that only the baseline PSA value at cabazitaxel introduction is an independent predictor of OS. CONCLUSION: A comparatively low PSA value could be an alternative index suggesting the optimal timing for cabazitaxel introduction.

Targeting lactate dehydrogenase­A promotes docetaxel­induced cytotoxicity predominantly in castration­resistant prostate cancer cells.

Docetaxel (DOC) is one of the most effective chemotherapeutic agents against castration­resistant prostate cancer (CRPC). Despite an impressive initial clinical response, the majority of patients eventually develop resistance to DOC. In tumor metabolism, where tumors preferentially utilize anaerobic metabolism, lactate dehydrogenase (LDH) serves an important role. LDH controls the conversion of pyruvate to lactate, with LDH­A, one of the predominant isoforms of LDH, controlling this metabolic process. In the present study, the role of LDH­A in drug resistance of human prostate cancer (PC) was examined by analyzing 4 PC cell lines, including castration­providing strains PC3, DU145, LNCaP and LN­CSS (which is a hormone refractory cell line established from LNCaP). Sodium oxamate (SO) was used as a specific LDH­A inhibitor. Changes in the expression level of LDH­A were analyzed by western blotting. Cell growth and survival were evaluated with a WST­1 assay. Cell cycle progression and apoptotic inducibility were evaluated by flow cytometry using propidium iodide and Annexin V staining. LDH expression was strongly associated with DOC sensitivity in PC cells. SO inhibited growth of PC cells, which was considered to be caused by the inhibition of LDH­A expression. Synergistic cytotoxicity was observed by combining DOC and SO in LN­CSS cells, but not in LNCaP cells. This combination treatment induced additive cytotoxic effects in PC­3 and DU145 cells, caused cell cycle arrest in G2­M phase and increased the number of cells in the sub­G1 phase of cell cycle in LN­CSS cells. SO promoted DOC induced apoptosis in LN­CSS cells, which was partially caused by the inhibition of DOC­induced increase in LDH­A expression. The results strongly indicated that LDH­A serves an important role in DOC resistance in advanced PC cells and inhibition of LDH­A expression promotes susceptibility to DOC, particularly in CRPC cells. The present study may provide valuable information for developing targeted therapies for CRPC in the future.