Prognostic value of pre-treatment risk stratification and post-treatment neutrophil/lymphocyte ratio change for pembrolizumab in patients with advanced urothelial carcinoma.

BACKGROUND: Pembrolizumab is effective in a limited number of patients with advanced urothelial carcinoma (UC). Therefore, we evaluated the prognostic value of clinical biomarkers following pembrolizumab treatment in patients with advanced UC. METHODS: We retrospectively reviewed the medical records of 121 patients with platinum-refractory advanced UC who received pembrolizumab. Inflammation-based prognostic scores before and 6 weeks after the treatment were recorded. The categorical variables influencing overall survival (OS) and objective response rate (ORR) were analyzed. RESULTS: Multivariate analyses showed that pretreatment Eastern Cooperative Oncology Group (ECOG) performance score (PS), presence of only lymph node metastasis (only LN mets), C-reactive protein (CRP), and neutrophil/lymphocyte ratio (NLR) were independent prognostic factors for OS (P = 0.0077; RR = 2.42, P = 0.0049; RR = 0.36, P = 0.0047; RR = 2.53, and P = 0.0079; RR = 2.33, respectively). The pretreatment risk stratification using ECOG PS, only LN mets, CRP, and NLR was used for estimating the OS (P < 0.0001) and ORR (P < 0.0001). Furthermore, changes in NLR in response to pembrolizumab were significantly associated with the OS (P = 0.0002) and ORR (P = 0.0023). This change was also significantly correlated with OS even in the high-risk group stratified by this pretreatment risk stratification (P = 0.0069). CONCLUSIONS: This pretreatment risk stratification may be used for estimating the OS and ORR of patients with advanced UC treated with pembrolizumab. If changes in NLR in response to pembrolizumab treatment improve, pembrolizumab should be continued.

Prognostic value of risk stratification using blood parameters for nivolumab in Japanese patients with metastatic renal-cell carcinoma.

BACKGROUND: Nivolumab is a standard treatment for previously treated advanced renal-cell carcinoma. However, nivolumab is effective in only a limited number of patients; therefore, we evaluated the prognostic value of several biomarkers, including inflammation-based prognostic scores and changes in these scores following nivolumab treatment in Japanese patients with metastatic renal-cell carcinoma. METHODS: We retrospectively reviewed the medical records of 65 patients with previously treated metastatic renal-cell carcinoma and who received nivolumab. Inflammation-based prognostic scores, including neutrophil/lymphocyte ratio, platelet/lymphocyte ratio, lymphocyte/monocyte ratio, and Glasgow prognostic score before and 6 weeks after the treatment were recorded. Categorical variables influencing disease-specific survival were compared using Cox proportional-hazards regression models. RESULTS: Univariate analysis showed that Memorial Sloan-Kettering Cancer Center risk score (P = 0.0052), lactate dehydrogenase (P = 0.0266), lymphocyte/monocyte ratio (P = 0.0113), and platelet/lymphocyte ratio (P = 0.0017) had a significant effect on disease-specific survival. Multivariate analyses showed that platelet/lymphocyte ratio and lactate dehydrogenase were found to be independent prognostic factors for disease-specific survival (P = 0.0008, risk ratio (RR) = 7.95, 95% confidence interval, 2.16-51.64 and P = 0.0123, RR = 3.92, 95% confidence interval, 1.37-10.80, respectively). The combination of platelet/lymphocyte ratio and lactate dehydrogenase was the most significant prognostic biomarker in metastatic renal-cell carcinoma (P < 0.0001). Changes in lymphocyte/monocyte ratio and platelet/lymphocyte ratio in response to nivolumab were significant prognostic factors for disease-specific survival (P < 0.0001 and P = 0.0477, respectively). CONCLUSIONS: The combination of platelet/lymphocyte ratio and lactate dehydrogenase may be a potential biomarker for estimating disease-specific survival in Japanese patients with metastatic renal-cell carcinoma treated by nivolumab.

Identification of curable high-risk prostate cancer using radical prostatectomy alone: who are the good candidates for undergoing radical prostatectomy among patients with high-risk prostate cancer?

BACKGROUND: Currently, there is no consensus regarding which patients with high-risk prostate cancer (PCa) would benefit the most by radical prostatectomy (RP). We aimed to identify patients with high-risk PCa who are treatable by RP alone. METHODS: We retrospectively reviewed data on 315 patients with D'Amico high-risk PCa who were treated using RP without neoadjuvant or adjuvant therapy at the institutions of the Yamaguchi Uro-Oncology Group between 2009 and 2013. The primary endpoint was biochemical progression-free survival (bPFS) after RP. Risk factors for biochemical progression were extracted using the Cox proportional hazard model. We stratified the patients with high-risk PCa into 3 subgroups based on bPFS after RP using the risk factors. RESULTS: At a median follow-up of 49.9 months, biochemical progression was observed in 20.5% of the patients. The 2- and 5-year bPFS after RP were 89.4 and 70.0%, respectively. On multivariate analysis, Gleason score (GS) at biopsy (≥ 8, HR 1.92, p < 0.05) and % positive core (≥ 30%, HR 2.85, p < 0.005) were independent predictors of biochemical progression. Patients were stratified into favorable- (0 risk factor; 117 patients), intermediate- (1 risk factor; 127 patients), and poor- (2 risk factors; 57 patients) risk groups, based on the number of predictive factors. On the Cox proportional hazard model, this risk classification model could significantly predict biochemical progression after RP (favorable-risk, HR 1.0; intermediate-risk, HR 2.26; high-risk, HR 5.03; p < 0.0001). CONCLUSION: The risk of biochemical progression of high-risk PCa after RP could be stratified by GS at biopsy (≥ 8) and % positive core (≥ 30%).

Use of preoperative performance status and hemoglobin concentration to predict overall survival for patients aged ≥ 75 years after radical cystectomy for treatment of bladder cancer.

BACKGROUND: The standard of care for treatment of localized muscle-invasive bladder cancer (MIBC) is radical cystectomy (RC). The patient's condition may affect management of MIBC, especially for elderly patients with more comorbid conditions and lower performance status. We retrospectively evaluated the association between clinicopathological data and outcomes for patients with bladder cancer (BCa) treated by RC. We particularly focused on elderly patients (age ≥75 years) with BCa. METHODS: We enrolled 254 patients with BCa who underwent RC and urinary diversion with or without pelvic lymph node dissection. We assessed perioperative complications and clinicopathological data affecting overall survival (OS) after RC. RESULTS: The incidence of complications was 34.3 %, and that of severe complications (Grade 3-5) was 16.5 %. The elderly group experienced more severe complications (P = 0.042). Median follow-up was 43.0 months (range 1.0-155.6). Five-year OS after RC was 62.7 %. OS after RC was no different for patients aged ≥75 and <75 years (P = 0.983). Multivariate analysis revealed that Eastern Cooperative Oncology Group performance status (ECOG PS) and hemoglobin (Hb) concentration were associated with all-cause mortality. Hb concentration of <12.6 g/dl was an independent predictor of a poor prognosis among elderly patients after RC for BCa. ECOG PS >1 tended to affect OS after RC in this group. CONCLUSION: ECOG PS and preoperative Hb concentration were useful for prediction of clinical outcome after RC for elderly patients. This information may aid decision-making in the treatment of elderly patients with MIBC.

Impact of variant histology on disease aggressiveness and outcome after nephroureterectomy in Japanese patients with upper tract urothelial carcinoma.

BACKGROUND: Patients with urinary bladder urothelial carcinoma (UC) with variant histology have features of more advanced disease and a likelihood of poorer survival than those with pure UC. We investigated the impact of variant histology on disease aggressiveness and clinical outcome after radical nephroureterectomy (RNU) in Japanese patients with upper tract UC (UTUC). Information on variant histology might guide appropriate patient selection for adjuvant therapy after RNU. METHODS: We enrolled 502 UTUC patients treated with RNU in this retrospective cohort study, and analyzed associations of variant histology with clinicopathological variables and disease-specific survival. RESULTS: The median follow-up was 41.4 months. A total of 60 (12.0 %) UTUC patients had variant histology. UTUC with variant histology was significantly associated with advanced pathological T stage (pT ≥ 3), higher tumor grade (G3), and more lymphovascular invasion (P < 0.0001). Variant histology in all patients was significantly associated with worse disease-specific survival after RNU on univariate analysis (P = 0.0004), but this effect did not remain significant on multivariate analysis. However, variant histology was a significantly independent predictor for disease-specific survival in patients with pT ≥ 3 tumors (P = 0.0095). CONCLUSIONS: UTUC with variant histology might be a phenotype of high-grade, locally aggressive advanced tumors rather than of systemic disease. Variant histology may be useful for selection of patients with pT ≥ 3 UTUC for adjuvant therapy. Prospective studies in a larger number of patients with a centralized pathological review are needed to confirm our results.

Risk group stratification based on preoperative factors to predict survival after nephroureterectomy in patients with upper urinary tract urothelial carcinoma.

BACKGROUND: After radical nephroureterectomy (RNU), substantial numbers of patients with upper urinary tract urothelial carcinoma (UUT-UC) are ineligible for adjuvant chemotherapy owing to diminished renal function. Accurate preoperative prediction of survival is considered important because neoadjuvant chemotherapy may be as effective for high-risk UUT-UC as for muscle-invasive bladder cancer. We performed risk group stratification to predict survival based on specific preoperative factors. METHODS: We enrolled 536 UUT-UC patients treated with RNU in this retrospective cohort study and assessed preoperative clinical and laboratory variables influencing disease-specific survival. RESULTS: The median follow-up was 40.9 months. Using univariate analysis, tumor location; number of tumors; hydronephrosis; clinical T stage; clinical N category; voided urine cytology; neoadjuvant chemotherapy; hemoglobin; white blood cell (WBC) counts; and C-reactive protein had a significant influence on disease-specific survival (P < 0.05). Multivariate analysis revealed that clinical T stage, voided urine cytology, and WBC were independent predictors (P = 0.041, P = 0.020, and P = 0.017, respectively). We divided patients into three risk groups based on the number of the three independent predictors: 0, low risk; 1, intermediate risk; 2 and 3, high risk. Significant differences in disease-specific survival were found among these risk groups (P ≤ 0.0047). CONCLUSIONS: Our results suggest that risk group stratification based on preoperative clinical T stage, voided urine cytology, and WBC counts may be useful for selection of UUT-UC patients for neoadjuvant chemotherapy. Prospective studies with larger numbers of patients and a longer follow-up period are needed to confirm our results.

Can docetaxel therapy improve overall survival from primary therapy compared with androgen-deprivation therapy alone in Japanese patients with castration-resistant prostate cancer? A multi-institutional cooperative study.

BACKGROUND: To verify the actual clinical benefit of docetaxel (DOC) therapy and to explore the prognostic factors that may predict overall survival in Japanese patients with castration-resistant prostate cancer (CRPC). METHODS: Baseline characteristics-matched CRPC patients who received conventional androgen-deprivation therapy (ADT) or ADT plus DOC were compared retrospectively. The primary endpoint was overall survival (OS) from primary therapy. Secondary endpoints were response of tumor(s), prostate-specific antigen (PSA) levels, and toxicity. RESULTS: Median OS was significantly longer in the DOC group (n = 117) than the control group (n = 118) (94.0 vs. 70.0 months, P = 0.0077) and the corresponding hazard ratio (HR) for death in DOC group was 0.566 [95% confidence interval (95%CI) 0.370-0.867; P = 0.0088]. Effective DOC groups [medium dose (50-69 mg/m(2)) and high dose (≥70 mg/m(2))] had significantly longer median OS than control even when survival times were calculated from the start of castration-resistant events (151 vs. 36 months; P = 0.0173) and the corresponding HR for death in the DOC group was 0.515 (95%CI 0.293-0.903; P = 0.0205). In multivariate analysis, statistically significant prognostic indicators were Gleason score, time to CRPC events, and receipt of DOC therapy. Response rate of both measurable lesion and PSA was not significantly different between each DOC dose group. Grade 3 or 4 adverse events associated with low- [30-49 mg/m(2)], medium-, and high-dose DOC were 21.9, 35.7, and 90.7%, respectively. No death due to DOC therapy was reported. CONCLUSION: Treatment with DOC improves OS from primary therapy compared with conventional ADT alone in Japanese patients with CRPC.

Risk group stratification to predict recurrence after transurethral resection in Japanese patients with stage Ta and T1 bladder tumours: validation study on the European Association of Urology guidelines.

OBJECTIVE: • To validate the European Association of Urology (EAU) guidelines on risk group stratification to predict recurrence in Japanese patients with stage Ta and T1 bladder tumours. PATIENTS AND METHODS: • A cohort of 592 Japanese patients who were treated with transurethral resection (TUR) and histopathologically diagnosed with Ta and T1 urothelial carcinoma of the bladder were enrolled in this retrospective study. • The primary endpoint of the present study was recurrence-free survival, and the median follow-up duration was 37 months in recurrence-free survivors. RESULTS: • Multivariate Cox proportional hazards regression analysis showed that the Eastern Cooperative Oncology Group performance status (ECOG PS), prior recurrence rate, number of tumours and T category were independent predictors of time to recurrence (P < 0.05). According to the EAU guidelines for predicting recurrence, the vast majority of Japanese patients were classified into intermediate risk. • The intermediate-risk patients were further divided into intermediate-low-risk and intermediate-high-risk subgroups based on the European Organization for Research and Treatment of Cancer risk table, and a significant difference in the recurrence-free survival rates was found between these subgroups (P < 0.001). • It was also found that patients with high risk combined with intermediate-high risk had significantly poorer recurrence-free survival rates than those with low risk combined with intermediate-low risk (P < 0.001). CONCLUSIONS: • This is the first report on the ECOG PS as a potentially useful predictor for bladder tumour recurrence. • The risk group stratification of the EAU guidelines for recurrence might not be applicable to Japanese patients with Ta and T1 bladder tumours, but the subgroup classification of intermediate risk could be appropriate.

Association between erythropoietin requirements and antihypertensive agents.

BACKGROUND: Angiotensin-converting enzyme inhibitors (ACI) and angiotensin II receptor blockers (ARB) have been reported to increase recombinant human erythropoietin (rHuEPO) requirements. We performed a cross-sectional study to investigate an association of antihypertensive agents including these two with the rHuEPO dose in chronic hemodialysis patients. METHODS: We studied 625 patients undergoing hemodialysis therapy in 11 dialysis units. The association between the rHuEPO dose and antihypertensive agents was statistically analyzed. RESULTS: The mean hemoglobin (Hb) level and rHuEPO dose corrected by body weight were 10.5 g/dl and 95.2 U/kg/week, respectively. When the patients were subdivided into four groups according to the number of prescribed antihypertensive agents (G-0, G-1, G-2, and G-3; patients prescribed with no medication, 1, 2, and >3 drugs, respectively), a significantly low dose of rHuEPO was observed in G-0 compared to the other groups. Unpaired t test showed a higher dose of rHuEPO in the presence of ARB, alpha-blockers, or calcium channel blockers (CCB). The rHuEPO dose was higher in the elderly, in females, and in patients with diabetes or hypertension. In multiple regression analysis, age, sex, rHuEPO dose, serum albumin level, and duration of dialysis therapy but not antihypertensive drugs were independent factors for the Hb level. In contrast, the rHuEPO dose was significantly associated with a low level of Hb, age, females, and CCB use. However, since CCB use was strongly associated not only with rHuEPO dose but also with systolic blood pressure and the use of alpha-blockers and ARB, these findings might be caused by erythropoietin (EPO)-induced hypertension. CONCLUSION: There was an association between the number of antihypertensive agents and rHuEPO dose in chronic hemodialysis patients. However, no significant relation was indicated between ARB/ACI use and EPO requirements.

Angiotensin-II combined intra-arterial chemotherapy for locally advanced bladder cancer: a case series study at a single institution.

Patients with locally advanced bladder cancer are at significant risk for metastases. We aimed to evaluate the usefulness of intra-arterial chemotherapy (IAC) combined with angiotensin-II (AT-II) in such patients. The possibility of bladder preservation is also discussed. Patients were enrolled if they had muscle-invasive bladder cancer (stage T2 to T4NxM0). Cisplatin, pirarubicin, and AT-II were infused through the tumor-feeding arteries. Cause-specific survival was the end point. We enrolled 37 patients who were treated with neoadjuvant IAC and 5 patients with adjuvant IAC. There were 7 patients (16.7%) with pathological complete remission. Overall 5-year and 10-year survival rates of the patients were 61.3% and 47.7%, respectively. The 5-year cause-specific survival rate was 100% for the clinical T2 group and 63% for the T3-4 group, and the 8-year survival rate was 33% and 63%, respectively. There was no statistically significant difference between these two groups (P=0.445). Multivariable analysis using tumor number, pattern of growth, and tumor size seemed to independently correlate with cause-specific survival, but there were no significant differences. Our results suggest that intra-arterial chemotherapy combined with AT-II is a useful treatment for patients with locally advanced bladder cancer, since this modality achieves a favorable response rate without severe toxicity or mortality.

[A case of emphysematous pyelonephritis successfully treated by percutaneous drainage guided by CT and review of previous cases reported in Japan].

A 40-year-old woman with diabetes mellitus was admitted to our hospital for a high fever and left back pain. She was initially diagnosed with acute pyelonephritis by laboratory data and started with intravenous antibiotics. However, her general condition worsened. Computed tomography (CT) showed a gas shadow within the left renal parenchyma and we made a diagnosis of emphysematous pyelonephritis. Percutaneous drainage guided by CT was performed immediately. She recovered and was discharged. Cultures of the pus grew Escherichia coli. We review previous cases of emphysematous pyelonephritis reported in Japan, and discuss the etiology, treatment and prognosis of such cases.

[Clinical evaluation of the effect of tamsulosin hydrochloride and cernitin pollen extract on urinary disturbance associated with benign prostatic hyperplasia in a multicentered study].

We evaluated the clinical efficacy and safety of tamsulosin hydrochloride and cernitin pollen extract in 243 patients with urinary disturbance associated with benign prostatic hyperplasia. They were assigned randomly to 3 groups, oral tamsulosin hydrochloride, cernitin pollen extract and their combination were administered for 12 weeks. The international prostate symptom score, post-voided residual urine and uroflowmetrogram were obtained before and after treatment. The international prostate symptom score improved in each group and then the maximum flow rate and average flow rate also increased significantly in the tamsulosin hydrochloride-administered groups. In conclusion, the administration of only tamsulosin hydrochloride and the combination of tamsulosin hydrochloride and cernitin pollen extract seemed more effective then the administration of only cernitin pollen extract in the treatment of urinary disturbance associated with benign prostatic hyperplasia.

Expression of thymidine phosphorylase in human superficial bladder cancer.

BACKGROUND: The purpose of the present paper was to investigate the expression level of thymidine phosphorylase (TPase) in superficial bladder cancer tissues obtained by transurethral resection, and determine whether its expression correlates with tumor recurrence. METHODS: From March 1998 to December 2001, 99 patients with superficial bladder cancer were diagnosed and treated at eight affiliated hospitals. Tissue specimens obtained by transurethral resection of superficial bladder cancer (TURBT) were applied to immunohistochemical study using anti-TPase antibody as well as pathological diagnosis. The data were subjected to statistical analysis. RESULTS: Using MoAb 654-1 as the primary antibody, TPase was clearly stained in human bladder cancer tissues. The maximum TPase level measured by enzyme-linked immunosorbent assay (ELISA) method in normal bladder tissues was 18.7 U/mg protein. The TPase activity was 2.8-fold higher in tumors than in normal bladder samples (P = 0.037). The TPase positivity rates determined by immunohistochemical and ELISA methods were distinctly correlated (P = 0.046). For the recurrence-free rates in pT1 tumors treated by TURBT alone (n = 46), there were no statistically significant differences between Tpase-positive or -negative cases. CONCLUSIONS: The TPase expression determined by ELISA and immunohistochemistry is significantly up-regulated in superficial bladder tumors compared with normal bladder samples. However, TPase expression by immunohistochemistry is not a predictive index of recurrence-free rate for superficial bladder cancer treated with TURBT alone.

Novel prophylactic effect of doxifluridine in superficial bladder cancer.

OBJECTIVES: The prophylactic effect of 5'-deoxy-5-fluorouridine (5'-DFUR) has not been fully studied in superficial bladder cancer. The aims of this work were to investigate the prophylactic effects of 5'-DFUR in terms of tumor recurrence after transurethral resection of bladder tumor (TURBT) and to study whether thymidine phosphorylase (TdRPase) immunostaining predicts tumor recurrence. MATERIAL AND METHODS: A total of 112 patients with pTa or pT1 bladder cancer were eligible for the analysis and were allocated to either an adjuvant group (TURBT+5'-DFUR; n = 47; initial 23 months) or a control group (TURBT alone; n = 65, final 23 months). Tumor specimens were studied immunohistochemically using anti-TdRPase antibody. RESULTS: Tumor recurrence was observed in 54 of the patients (48%) after a median follow-up period of 26.8 months. No significant clinico-pathologic bias was observed between the two groups. Although patients in the adjuvant group had a significantly higher recurrence-free survival rate than those in the control group when considering 78 patients with pathological T1 tumors (p = 0.0272) and 65 patients who did not recur within 12 months (p = 0.001), overall there was no significant difference between the two groups. Multivariate analysis revealed that 5'-DFUR administration was the strongest predictor of late tumor recurrence, which was defined as development of recurrence 12 months after TURBT (hazard ratio 5.744; 95% CI 1.495-30.45; p = 0.0094). Immunostaining did not predict prophylactic effects of 5'-DFUR. Mild, reversible toxicity was found in 9/58 (15.5%) of the cases evaluated. CONCLUSIONS: Oral administration of 5'-DFUR after TURBT did not prevent tumor recurrence in the overall cohort, although this novel drug may have a prophylactic effect in patients belonging to several subgroups.