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.

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.

[Does alpha1-blocker provide additional improvement of quality-of-life in patients with overactive bladder?--a multi-center prospective randomized trial between anti-cholinergic (propiverine chloride) with and without alpha1-blocker (urapidil)].

AIM: Storage/filling symptoms caused by overactive bladder (OAB) are bothersome to patients. The aim of this study is to clarify if alpha1-blocker provides additional benefit in combination with anticholinergic treatment in patients with OAB. METHODS: In total, 100 patients (men/women: 43/57, mean age: 71.3 years) who had frequency (more than eight times a day) and urgency (more than three times a week) were prospectively randomized, and allocated to two groups (monotherapy group [n = 52]: propiverine alone or combination group [n = 48]: propiverine plus urapidil). The primary end point was to compare the improvement of storage symptoms (numbers of frequency, urgency, disappearance of urge incontinence) as well as patients' quality of life (QOL) assessed by King's Health Questionnaires (KHQ) at baseline, 2 weeks, and 6 weeks after the start of treatment in both groups. The second end point was to evaluate the safety of these agents. RESULTS: Statistically significant improvements in terms of urgency and frequency were observed in both groups at two-weeks after the start of treatment as compared with baseline (p < 0.01 and < 0.05, respectively), while no inter-group difference was observed between the two groups. Significant improvement of QOL was observed after six weeks treatment in overall mean score, general health perception, incontinence impact, sleep/energy domains in both groups as compared with baseline. No significant difference was observed in terms of toxic events between the two groups. CONCLUSIONS: Although both groups showed identical improvement of storage symptoms and tolerability, no additional benefit of alpha1-blocker was observed.

[Idiopathic adrenal hematoma: a case report].

We report a rare case of idiopathic adrenal hematoma. Including our case, 13 such cases have been described in Japan. A 63-year-old [correction of 65] woman was admitted to our hospital for further examination of a right adrenal mass on ultrasonography. Laboratory tests including hormonal assay were within the normal ranges. Computed tomography showed a tumor with calcification measuring 3.0 x 2.0 cm in the right adrenal gland. Magnetic resonance imaging (MRI) revealed a mass with heterogeneous low to iso signal intensity on T1-weighted images and high signal intensity on T2-weighted images. A peripheral rim of the mass was slightly enhanced on dynamic MRI. The patient underwent laparoscopic adrenalectomy. Histopathological examination revealed an old hematoma without neoplastic cells or vascular lesions and these findings were evidence of idiopathic adrenal hematoma.

Isotopic analysis of calcium in blood plasma and bone from mouse samples by multiple collector-ICP-mass spectrometry.

The biological processing of Ca produces significant stable isotope fractionation. The level of isotopic fractionation can provide key information about the variation in dietary consumption or Ca metabolism. To investigate this, we measured the 43Ca/42Ca and 44Ca/42Ca ratios for bone and blood plasma samples collected from mice of various ages using multiple collector-ICP-mass spectrometry (MC-ICP-MS). The 44Ca/42Ca ratio in bones was significantly (0.44-0.84 per thousand) lower than the corresponding ratios in the diet, suggesting that Ca was isotopically fractionated during Ca metabolism for bone formation. The resulting 44Ca/42Ca ratios for blood plasma showed almost identical, or slightly higher, values (0.03-0.2 per thousand) than found in a corresponding diet. This indicates that a significant amount of Ca in the blood plasma was from dietary sources. Unlike that discovered for Fe, there were no significant differences in the measured 44Ca/42Ca ratios between female and male specimens (for either bone or blood plasma samples). Similarity, the 44Ca/42Ca ratios suggests that there were no significant differences in Ca dietary consumption or Ca metabolism between female and male specimens. In contrast, the 44Ca/42Ca ratios of blood plasma from mother mice during the lactation period were significantly higher than those for all other adult specimens. This suggests that Ca supplied to infants through lactation was isotopically lighter, and the preferential supply of isotopically lighter Ca resulted in isotopically heavier Ca in blood plasma of mother mice during the lactation period. The data obtained here clearly demonstrate that the Ca isotopic ratio has a potential to become a new tool for evaluating changes in dietary consumption, or Ca metabolism of animals.

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.

Expression of mRNA for growth factors and extracellular matrix proteins after injury to cultured peritoneal cells: does the healing process contribute to peritoneal ultrastructural alteration?

The purpose of this study was to investigate the possibility that healing processes following repeated injury by nonphysiological dialysate play a significant role in the pathogenesis of peritoneal ultrastructural alteration, mediated by the production of growth factors and extracellular matrix proteins (ECM). To test a possible mechanism for peritoneal membrane alteration, we investigated whether chemically injured peritoneal mesothelial cells and fibroblasts upregulate their production of growth factors and ECM as a consequence of the healing process. Using 1 N NaOH, circular wounds of uniform surface area were made in monolayers of subconfluent rat peritoneal mesothelial cells (RPMC) and peritoneal fibroblasts (RPFB). At 0, 24, and 72 h after wounding, changes in mRNA expression of transforming growth factor-beta 1 (TGF-Beta1), b-FGF, HGF, VEGF, and FN were semiquantified by reverse transcription-polymerase chain reaction. Nonwounded monolayers of RPMC and RPFB were used as controls with mRNA expression being determined at the same times. For RPMC, TGF-Beta1, HGF, b-FGF, and FN mRNA gradually increased up to 72 h postwounding to 1.5-fold, 1.6-fold, 1.3-fold, and 2.1-fold of the control levels, respectively. A significant increase was only observed for TGF-Beta1, while VEGF showed the least change with time. For RPFB, HGF, b-FGF, VEGF, and FN mRNA expression were slightly suppressed compared to control levels up to 72 h postwounding. TGF-Beta1, however, increased markedly above control expression levels by the end of the wound healing process. The production of profibrotic growth factors by mesothelial cells in response to injury may represent a mechanism whereby fibroblast activation, resulting in fibroblast hyperplasia and excessive extracellular matrix accumulation, culminates in alteration of the peritoneal membrane ultrastructure.

Does surgical repair of pelvic prolapse improve patients' quality of life?

OBJECTIVES: The aims of this study were to evaluate the efficacy of surgical repair in patients with pelvic prolapse, and to assess the postoperative quality of life (QOL). METHODS: A total of 70 patients (mean age: 66.7 years) underwent transvaginal two-corner bladder neck suspension in combination with transvaginal hysterectomy (63 cases), and anterior with (49) or without (21) posterior colporrhaphy. The status of recurrence and complications were followed in all patients at a mean follow-up period of 32.0 months. Postoperative patients' quality of life (QOL) consisting of four items (sensation of vaginal bulging, urinary incontinence, difficulty to urinate, and health-related QOL) was assessed in 52 cases whose were followed at least two years (mean: 41.6 months, range: 24.3-69.1). RESULTS: Sixty-eight patients (97%) were recurrence-free. Nine of the 39 (23%) patients with difficulty to urinate before surgery had persistent symptoms postoperatively. Multivariate analysis revealed that cystometric abnormalities, voiding symptoms at seventh days after surgery, and weak detrusor contraction were independent prognostic factors for persistent voiding symptoms. As for the QOL, all items had significant improvement at 13 months after surgery as compared to baseline condition. A longitudinal study showed improvement of these symptoms sustained at least up to four years. CONCLUSIONS: This study suggests that surgical repair can achieve results with long-term durability as well as improving the QOL. In addition, assessment of the detrusor function may be needed for patients who complain difficulty to urinate in avoiding persistent such symptoms.

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.