Intraoperative Fluorescence Imaging for Detection of Sentinel Lymph Nodes and Lymphatic Vessels during Open Prostatectomy using Indocyanine Green.

PURPOSE: We investigated the feasibility and validity of intraoperative fluorescence imaging using indocyanine green for the detection of sentinel lymph nodes and lymphatic vessels during open prostatectomy. MATERIALS AND METHODS: Indocyanine green was injected into the prostate under transrectal ultrasound guidance just before surgery. Intraoperative fluorescence imaging was performed using a near-infrared camera system in 66 consecutive patients with clinically localized prostate cancer after a 10-patient pilot test to optimize indocyanine green dosing, observation timing and injection method. Lymphatic vessels were visualized and followed to identify the sentinel lymph nodes. Confirmatory pelvic lymph node dissection including all fluorescent nodes and open radical prostatectomy were performed in all patients. RESULTS: Lymphatic vessels were successfully visualized in 65 patients (98%) and sentinel lymph nodes in 64 patients (97%). Sentinel lymph nodes were located in the obturator fossa, internal and external iliac regions, and rarely in the common iliac and presacral regions. A median of 4 sentinel lymph nodes per patient was detected. Three lymphatic pathways, the paravesical, internal and lateral routes, were identified. Pathological examination revealed metastases to 9 sentinel lymph nodes in 6 patients (9%). All pathologically positive lymph nodes were detected as sentinel lymph nodes using this imaging. No adverse reactions due to the use of indocyanine green were observed. CONCLUSIONS: Intraoperative fluorescence imaging using indocyanine green during open prostatectomy enables the detection of lymphatic vessels and sentinel lymph nodes with high sensitivity. This novel method is technically feasible, safe and easy to apply with minimal additional operative time.

Improved survival in patients with metastatic renal cell carcinoma undergoing cytoreductive nephrectomy in the era of targeted therapy.

BACKGROUND: We aimed to review our clinical experience of cytoreductive nephrectomy for patients with metastatic renal cell carcinoma (mRCC) and to identify factors associated with postoperative prognosis in these patients. METHODS: This study included a total of 164 Japanese patients with mRCC who underwent cytoreductive nephrectomy and subsequently received immunotherapy and/or molecular-targeted therapy between 2000 and 2010. RESULTS: Baseline characteristics of the 164 patients were as follows: median age was 66 years; metastatic sites included the lung in 133 (81.1 %), bone in 44 (26.8 %), and other in 37 (22.6 %); and 34 (20.7 %), 106 (64.7 %), and 24 (14.6 %) patients were classified into favorable, intermediate-risk, and poor-risk groups, respectively, according to the Memorial Sloan-Kettering Cancer Center (MSKCC) risk model. As postoperative systemic therapy, 80 patients (48.8 %) were treated with immunotherapy alone; the remaining 84 (51.2 %) received molecular-targeted agents irrespective of previous treatment with immunotherapy. Median overall survival of these 164 patients was 25.8 months. Univariate analysis identified the MSKCC risk classification, preoperative C-reactive protein (CRP) level, metastatic site, nodal involvement, presence of sarcomatoid features, histological subtype, and introduction of molecular-targeted agents as significant predictors of overall survival, among which only the preoperative CRP level and introduction of molecular-targeted agents appeared to be independently associated with overall survival. CONCLUSIONS: Treatment with molecular-targeted agents following cytoreductive nephrectomy may contribute to improve the survival of patients with mRCC compared with immunotherapy alone, and it may be important to employ an aggressive systemic treatment for patients with an increased preoperative value of CRP.

Acquired resistance to sunitinib in human renal cell carcinoma cells is mediated by constitutive activation of signal transduction pathways associated with tumour cell proliferation.

UNLABELLED: WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Although there have been a few studies investigating the molecular mechanism mediating the acquisition of resistance to molecular-targeted agents, including sunitinib, by renal cell carcinoma (RCC) cells, this mechanism remains largely unclear. The maintenance of protein kinase activation during sunitinib treatment may be involved in the acquisition of a phenotype resistant to sunitinib in RCC, and additional treatment with agents targeting activated protein kinases could be a promising approach for overcoming resistance to sunitinib in RCC. OBJECTIVE: To characterise the mechanism involved in the acquired resistance to sunitinib, a potential inhibitor of multiple receptor tyrosine kinases (RTKs), in renal cell carcinoma (RCC). MATERIALS AND METHODS: A parental human RCC cell line, ACHN (ACHN/P), was continuously exposed to increasing doses of sunitinib, and a cell line resistant to sunitinib (ACHN/R), showing an ≈5-fold higher IC50 (concentration that reduces the effect by 50%) than that of ACHN/P, was developed. RESULTS: ACHN/R appeared to acquire significant cross resistance to sorafenib; however, there were no significant differences in sensitivities to the Mammalian target of rapamycin inhibitors, temsirolimus and everolimus, between ACHN/P and ACHN/R. After sunitinib treatment, the expression levels of phosphorylated Akt and p44/42 mitogen-activated protein kinase in ACHN/P, but not those in ACHN/R, were significantly inhibited. RTK assay showed that treatment of ACHN/P with sunitinib resulted in the marked downregulation of several phosphorylated RTKs compared with that of ACHN/R. Additional treatment with a specific inhibitor of Akt significantly increased the sensitivity of ACHN/R to sunitinib, but not that of ACHN/P. There were no significant differences between in vivo growth patterns of ACHN/P and ACHN/R in mice before and after the administration of sunitinib; however, the proportion of cells positive for TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling) staining in ACHN/P tumour was significantly greater than that in ACHN/R tumour in mice treated with sunitinib. CONCLUSION: The maintenance of protein kinase activation during sunitinib treatment may be involved in the acquisition of resistant phenotype to sunitinib in RCC cells.

Third-line sunitinib following sequential use of cytokine therapy and sorafenib in Japanese patients with metastatic renal cell carcinoma.

BACKGROUND: The aim of this study was to evaluate the use of sunitinib as third-line therapy for metastatic renal cell carcinoma (mRCC). METHODS: This study included a total of 35 consecutive Japanese patients with mRCC who were treated with third-line sunitinib after sequential use of cytokine therapy (interferon-α and/or interleukin-2) and sorafenib between September 2008 and December 2010. The clinical outcomes of third-line sunitinib in these patients were retrospectively reviewed. RESULTS: Of the 35 patients, 3 (8.6%), 28 (80.0%) and 4 (11.4%) were judged to have a partial response, stable disease and progressive disease, respectively, as the best response to sunitinib. The median progression-free survival (PFS) and overall survival (OS) of these patients following the introduction of sunitinib were 10.9 and 14.2 months, respectively. Of several factors examined, response to sorafenib and performance status appeared to be independently associated with PFS and OS, respectively, on multivariate analyses. The common grade 3-4 adverse events related to third-line sunitinib were thrombocytopenia (51.4%), neutropenia (42.9%) and hypertension (14.3%). CONCLUSION: Despite the low response rate, third-line sunitinib is well tolerated and could provide comparatively favorable prognostic outcomes in Japanese patients with mRCC after first-line cytokine therapy and second-line sorafenib; therefore, treatment with sunitinib could be one on the therapeutic options for patients with mRCC even after the failure of sequentially performed systemic therapies, such as cytokine therapy and sorafenib.

Orthotopic sigmoid vs. ileal neobladders in Japanese patients: a comparative assessment of complications, functional outcomes, and quality of life.

OBJECTIVES: To compare the clinical outcomes of sigmoid and ileal neobladders (NBs) created following radical cystectomy. MATERIALS AND METHODS: This study included 90 and 144 Japanese patients undergoing radical cystectomy and orthotopic NB reconstruction with a sigmoid and ileal segment, respectively. Postoperative clinical outcomes between the sigmoid and ileal NB groups (SNBG and INBG) were compared. RESULTS: In this series, 110 early and 51 late complications occurred in 71 and 41 patients, respectively; however, there was no significant difference in the incidence of complications between SNBG and INBG. At 1 year postoperatively, there were no significant differences in the proportion of spontaneous voiders and the continence status between these 2 groups; however, despite the lack of significant differences in the maximal flow rate and voided volume, the post-void residual in SNBG was significantly smaller than that in INBG. Voiding functional outcomes at 5 years postoperatively were also obtained from 28 and 49 in SNBG and INBG, respectively. Although there were no significant changes in the functional outcomes in SNBG, the proportion of spontaneous voiders and post-void residual in INBG at 5 years postoperatively were significantly poorer than those at 1 year postoperatively. Furthermore, the postoperative health-related quality of life assessed by a Short-Form 36 survey did not show any significant differences in all 8 scores between these 2 groups. CONCLUSIONS: Both types of NB reconstruction resulted in comparatively satisfactory outcomes; however, the voiding function, particularly that on long-term follow-up, in SNBG appeared to be more favorable than that in INBG.

Oncological outcome of docetaxel-based chemotherapy for Japanese men with metastatic castration-resistant prostate cancer.

OBJECTIVES: To retrospectively review the oncologic outcomes of docetaxel-based chemotherapy in Japanese men with metastatic castration-resistant prostate cancer (mCRPC). MATERIALS AND METHODS: This study included 257 consecutive Japanese patients with mCRPC who were treated with docetaxel-based chemotherapy between April 2007 and March 2010. The prognostic significance of several clinicopathologic factors in these patients was analyzed. RESULTS: In these 257 patients, the median age and serum value of prostate-specific antigen (PSA) prior to docetaxel-based chemotherapy were 72 years and 43.0 ng/ml, respectively. Of these patients, 64 (24.9%) and 193 (75.1%) received docetaxel as a weekly (30 mg/m(2)) and 3-weekly (70-75 mg/m(2)) regimen, respectively, and estramustine (EM) was administered in combination with docetaxel in 137 (53.3%). PSA decline was observed in 205 patients (79.8%), including 143 (55.6%) achieving PSA decline ≥ 50%. The median progression-free survival and overall survival (OS) were 4.3 and 25.4 months, respectively. Of several factors examined, univariate analysis identified performance status (PS), PSA value, significant clinical pain, bone metastasis, prior treatment with EM, treatment cycle, and PSA response as significant predictors of OS, of which only PS, significant clinical pain, prior treatment with EM, treatment cycle, and PSA response appeared to be independently related to OS on multivariate analysis. Furthermore, there were significant differences in OS according to positive numbers of these 5 independent risk factors. CONCLUSIONS: Oncologic outcomes in Japanese mCRPC patients receiving docetaxel-based chemotherapy is generally favorable, and the risk stratification presented in this study may contribute to precisely predicting the prognosis of such patients.

Prognostic Factors Influencing Postoperative Development of Chronic Kidney Disease in Patients with Small Renal Tumors who Underwent Partial Nephrectomy.

BACKGROUND: The objective of this study was to determine factors associated with the postoperative development of chronic kidney disease (CKD) following partial nephrectomy. PATIENTS AND METHODS: This study included 109 patients with normal renal function treated with partial nephrectomy for small renal tumors. Of these, 73 and 36 patients underwent open partial nephrectomy (OPN) and laparoscopic partial nephrectomy (LPN), respectively. RESULTS: Among several parameters, there was a significant difference only in the ischemia time between the OPN and LPN groups. During the median observation period of 53.4 months, CKD, defined as estimated glomerular filtration rate (eGFR) less than 60 ml/min/1.73 m(2), developed in 29 (39.7%) and 14 (38.9%) patients in the OPN and LPN groups, respectively. Univariate analysis identified age at surgery, diabetes and preoperative eGFR as significant predictors of the postoperative development of CKD; however, only age at surgery and preoperative eGFR appeared to be independently related to CKD-free survival. In fact, there was a significant difference in the CKD-free survival between patients without any independent risk factor and those with at least one of these independent risk factors. CONCLUSIONS: Careful management following partial nephrectomy is necessary for elderly patients and/or those with impaired renal function, even mild, before surgery.

Significance of ureteroscopic biopsy grade in patients with upper tract urothelial carcinoma.

BACKGROUND: The objective of this study was to assess the significance of the ureteroscopic biopsy grade for patients with upper tract urothelial carcinoma (UTUC). PATIENTS AND METHODS: This study included 40 patients who were diagnosed with a single focus of UTUC by ureteroscopic biopsy and subsequently underwent nephroureterectomy. The significance of the biopsy grade as a predictive factor for pathological outcomes of nephroureterectomy was retrospectively analyzed. RESULTS: Of these 40 patients, 19 (47.5%) and 21 (52.5%) were diagnosed with low and high grade UTUC, respectively. The ureteroscopic biopsy grade matched the pathological grade of surgically resected specimens in 35 of the 40 cases (87.5%), and there was a significant correlation between the biopsy and pathological grades (p < 0.001). Furthermore, the biopsy grade was also shown to be closely associated with the pathological stage (p < 0.001); that is, only 1 of the 19 patients (5.3%) with biopsy low grade UTUC were pathologically diagnosed as having muscle invasive disease, while 17 of the 21 patients (81.0%) with biopsy high grade UTUC appeared to show tumor invasion into muscle or deeper. CONCLUSIONS: The grade of UTUC on ureteroscopic biopsy could provide accurate diagnostic information on the final pathology of nephroureterectomy specimens.

Significance of docetaxel-based chemotherapy as treatment for metastatic castration-resistant prostate cancer in Japanese men over 75 years old.

OBJECTIVES: The objective of this study was to evaluate the significance of docetaxel-based chemotherapy in elderly Japanese men with metastatic castration-resistant prostate cancer (CRPC). MATERIALS AND METHODS: This study included a total of 159 consecutive patients aged≥75 years with mCRPC who were treated with docetaxel-based chemotherapy. The efficacy and tolerability of this therapy were retrospectively analyzed. RESULTS: In these 159 patients, the median age and prostate-specific antigen (PSA) level before docetaxel-based chemotherapy were 78 years and 44.0 ng/ml, respectively. Of these patients, 42 (26.4%) and 117 (73.6%) received docetaxel as a weekly (30 mg/m2) and 3-weekly (70 mg/m2) regimen, respectively, and estramustine was administered combining with docetaxel in 77 (48.4%). Following docetaxel-based chemotherapy, PSA declined in 118 patients (74.3%), including 87 (54.6%) achieving a PSA decline≥50%, and the median progression-free survival and overall survival (OS) were 2.9 and 23.2 months, respectively. Of several factors examined, univariate analysis identified performance status (PS), significant clinical pain, bone metastasis, schedule of treatment, treatment cycle, and PSA response as significant predictors of OS, of which only PS, treatment cycle, and PSA response appeared to be independently associated with OS on multivariate analysis. The major grade 3-4 toxicities were myelosuppression, including neutropenia, anemia, and thrombocytopenia in 78 (49.1%), 22 (13.8%), and 14 (8.8%), respectively. CONCLUSIONS: These findings suggest that docetaxel-based chemotherapy is clinically feasible in Japanese men aged≥75 years with mCRPC considering the cancer control as well as safety associated with this therapy.

Expression profile of E-cadherin and N-cadherin in non-muscle-invasive bladder cancer as a novel predictor of intravesical recurrence following transurethral resection.

The objective of this study was to investigate the impact of the expression profile of E-cadherin and N-cadherin in newly diagnosed non-muscle-invasive bladder cancer (NMIBC) on the probability of intravesical recurrence in patients undergoing transurethral resection (TUR). This study included 115 consecutive patients diagnosed as having NMIBC following TUR. Expression levels of E-cadherin and N-cadherin in TUR specimens from these patients were measured by immunohistochemical staining. In this series, intravesical recurrence occurred in 35 of 115 patients (30.4%). Immunohistochemical study showed that positive expression of E-cadherin and N-cadherin were noted in 62 (53.9%) and 48 (41.7%) specimens, respectively. Intravesical recurrence was detected in only 7 of 62 patients (11.3%) with positive E-cadherin expression, while 33 of 48 patients (68.8%) with positive N-cadherin expression developed intravesical recurrence. When patients were divided into 4 groups according to the positivities of E-cadherin and N-cadherin expression, intravesical recurrence was detected in 27 of 30 patients (90.0%) with negative E-cadherin as well as positive N-cadherin expression, and the intravesical recurrence-free survival of this group was significantly poorer than those of the remaining 3 groups. Furthermore, negative E-cadherin as well as positive N-cadherin expression was identified as the most powerful independent predictor for intravesical recurrence following TUR on multivariate analysis. These findings suggest that the loss of E-cadherin and gain of N-cadherin expression in on NMIBC appeared to be significantly associated with postoperative recurrence; therefore, the switch from E-cadherin to N-cadherin expression might be involved in the mechanism underlying intravesical recurrence of on NMIBC.

Significant impact of age at diagnosis on the prognosis of Japanese patients with pT1 renal cell carcinoma following surgical resection.

OBJECTIVE: • To retrospectively review oncological outcomes following surgical resection in Japanese patients with pT1 renal cell carcinoma (RCC). PATIENTS AND METHODS: • The present study included a total of 832 consecutive Japanese patients who underwent either radical or partial nephrectomy and were subsequently diagnosed as having localized pT1 RCC. • The significance of several clinicopathological factors in their postoperative outcomes was analysed. RESULTS: • The median (range) age of the 832 patients was 66 (31-90) years. Radical and partial nephrectomies were performed for 710 patients (85.3%) and 122 patients (14.7%), respectively. Distribution of pathological stage was pT1a in 582 patients (70.0%) and pT1b in 250 patients (30.0%). • During the observation period (median 44 months, range 3-114 months), postoperative disease recurrence developed in 38 patients (4.6%) and death occurred in 34 (4.1%). The 5-year recurrence-free and overall survival rates were 93.6% and 94.1%, respectively. • Of several factors examined, only age at diagnosis was identified as an independent predictor of both postoperative disease recurrence and overall survival in these patients. Furthermore, there were significant differences in the recurrence-free and overall survivals among patient groups stratified by age at diagnosis. CONCLUSION: • These findings suggest that age at diagnosis is a significant predictor of disease recurrence as well as overall survival in patients with pT1 RCC following surgical resection; therefore, intensive follow-up of older patients is necessary even for those with pT1 RCC.

Inhibition of tumor growth and sensitization to chemotherapy by RNA interference targeting interleukin-6 in the androgen-independent human prostate cancer PC3 model.

The objective of the present study was to investigate the inhibitory effects of interleukin-6 (IL-6) secretion by androgen-independent human prostate cancer PC3 cells on their growth and chemosensitivity. In this study, we established PC3 in which the expression vector containing short hairpin RNA (shRNA) targeting IL-6 was introduced (PC3/sh-IL6). Changes in the growth and sensitivity to docetaxel in PC3/sh-IL6 were compared with those in PC3 transfected with control vector alone (PC3/Co). Concentration of IL-6 in the culture supernatant from PC3/sh-IL6 was approximately 20% of that from PC3/Co. Both in vitro and in vivo, the growth of PC3/sh-IL-6 was significantly inferior to that of PC3/Co, accompanying downregulation of Bcl-2, Bcl-xL, phosphorylated Akt, p44/42 mitogen-activated protein kinase, and signal transducers and activation of transcription 3 in PC3/sh-IL-6 compared with that in PC3/Co. Despite the higher sensitivity of PC3/sh-IL6 to docetaxel than that of PC3/Co, the secretion of IL-6 by both cell lines was increased after treatment with docetaxel due to the formation of positive autocrine loops between these cell lines and NFκB signaling pathways. Furthermore, combined treatment with the proteasome inhibitor bortezomib, which completely inhibited the docetaxel-induced IL-6 secretion via the inactivation of NFκB signaling, resulted in the marked sensitization of these cell lines to docetaxel both in vitro and in vivo. These findings suggest that suppressed IL-6 secretion using shRNA, either alone or in combination with docetaxel and bortezomib, could be a useful therapeutic strategy against androgen-independent prostate cancer.

Age at diagnosis as a powerful predictor for disease recurrence after radical nephrectomy in Japanese patients with pT1 renal cell carcinoma.

OBJECTIVES: To review clinical outcomes and to identify clinicopathological variables as predictors of disease recurrence in a cohort of Japanese patients undergoing radical nephrectomy for renal cell carcinoma (RCC). METHODS: The present study included a total of 710 consecutive Japanese patients who underwent radical nephrectomy and were diagnosed as having localized pT1 RCC. The significance of several clinicopathological factors in predicting postoperative disease recurrence was assessed by univariable and multivariable analyses. RESULTS: Median age was 66 years (range 32-90 years). Open and laparoscopic radical nephrectomies were carried out for 436 (61.4%) and 274 (38.6%) patients, respectively. Tumor size was 4 cm or less in 461 (64.9%) patients and greater than 4 cm and 249 (35.1%) patients. During the observation period (median 36 months; range 3-111 months), postoperative disease recurrence developed in 37 patients (5.2%), of whom 10 (1.4%) died of disease progression. The 1-, 3- and 5-year recurrence-free survival rates were 98.3%, 95.0% and 92.7%, respectively. Age at diagnosis and tumor size were found to be significantly associated with recurrence-free survival at both univariable and multivariable analysis. Furthermore, there were significant differences in the recurrence-free survival with respect to both independent predictors. CONCLUSIONS: Age at diagnosis in addition to tumor size appears to be independently related to disease recurrence in Japanese patients with pT1 RCC. Thus, an intensive follow up for older patients seems to be advisable.

Assessment of long-term quality of life in patients with orthotopic neobladder followed for more than 5 years.

INTRODUCTION: We analyzed the general health QOL (GH-GOL), urinary QOL, and sexual QOL in patients with orthotopic neobladder who were followed for more than 5 years. MATERIALS AND METHODS: Eighty-six (male 78, female 8) patients who underwent orthotopic neobladder and followed for more than 5 years were enrolled in this study. QOL regarding general health and urinary function were surveyed by SF-36 and ICSmaleSF, respectively. Sexual function was assessed by International Index of Erectile Function (IIEF-5). Satisfaction with urinary and sexual function was evaluated by visual analogue scale (VAS). RESULTS: On overall analysis by SF-36, 2 categories (role-physical functioning and role-emotional functioning) showed significantly lower scores, although bodily pain showed a better than average score for Japanese people of the same age. While patients who required clean intermittent catheterizaion (CIC) or had daytime incontinence presented worse scores in several categories on SF-36, the presence of enuresis did not affect SF-36 score. ICSmaleSF survey showed that voiding symptoms significantly impaired QOL in patients who required CIC and incontinence symptoms significantly impaired QOL in patients who had daytime incontinence and enuresis. With regard to sexual function, most patients (88%) had lost sexual function. On VAS, satisfaction with urinary function was 5.63, and sexual function was only 0.98. CONCLUSIONS: Although GH-QOL was generally well maintained, the presence of CIC or daytime incontinence impaired GH-QOL. Most were not satisfied with their level of sexual function 5 years after orthotopic neobladder construction.

The antiandrogen bicalutamide activates the androgen receptor (AR) with a mutation in codon 741 through the mitogen activated protein kinase (MARK) pathway in human prostate cancer PC3 cells.

The objective of this study was to assess the effect of antiandrogen on the activation of mutated androgen receptor (AR) and its signaling pathway in prostate cancer. We transfected the AR gene with a point mutation at codon 741 (tryptophan to leucine; W741L) into human androgen-independent prostate cancer PC3 cells lacking the expression of AR, and established PC3 cells overexpressing mutant type AR (PC3/W741L). Changes in the phenotype in these cells were compared to those in PC3 cells transfected with wild- type AR (PC3/Wild) and control vector alone (PC3/Co). There was no significant differences in the growth among PC3/Co, PC3/Wild and PC3/W741L cells. A transactivation assay using these cells showed that bicalutamide activated W741L mutant type AR, but not wild-type AR, while hydroxyflutamide failed to activate either type of ARs. Treatment with specific inhibitors of the MAPK or STST3 pathway (UO126 or AG490, respectively), in contrast to treatment with the Akt pathway inhibitor LY294002, significantly inhibited the dihydrotestosterone-induced activation of both wild-type and mutant ARs; however, activation of W741L mutant AR by bicalutamide was significantly inhibited by treatment with UO126, in contrast to treatment with AG490 or LY294002. Furthermore, treatment of PC3/W741L with bicalutamide, in contrast to treatment with hydroxyflutamide, resulted in significant upregulation of phosphorylated p44/42 MAPK. These findings suggest that the MAPK pathway might be involved in the activation of the AR with a point mutation at codon 741 induced by treatment with the antiandrogen bicalutamide.

Influence of nerve-sparing procedure on early recovery of urinary continence after laparoscopic radical prostatectomy.

PURPOSE: This study considered the influence of the nerve-sparing procedure on early recovery of urinary continence after laparoscopic radical prostatectomy according to preoperative erectile function. PATIENTS AND METHODS: There were 135 patients eligible for assessment of the status of urinary continence after surgery. The patients were divided into two groups according to the International Index of Erectile Function (IIEF)-5 score: Group 1, >or=14 (56 patients); group 2, <14 (79 patients). The correlation between urinary continence and patient age at surgery, body mass index, preoperative prostate-specific antigen level, preoperative IIEF-5 score, and an attempted nerve-sparing procedure was investigated. RESULTS: Overall continence rates were 13%, 41%, 63%, and 79% at 1, 3, 6, and 12 months, respectively. The rate in group 2 was significantly lower than that in group 1 6 months after surgery (P = 0.0286), and the rate in patients without attempted nerve sparing was significantly lower than that in those with an attempted nerve-sparing procedure at 3 months (P = 0.0084). The rate in group 2 of patients without attempted nerve sparing was significantly lower than that in those with an attempted nerve-sparing procedure at both 3 months (P = 0.0046) and 6 months postoperatively (P = 0.0356). CONCLUSIONS: Preoperative erectile function and the nerve-sparing procedure were predictors of early recovery of urinary continence after laparoscopic radical prostatectomy. If each case fulfills the oncologic criteria for nerve sparing, we should attempt nerve sparing to facilitate the early recovery of urinary continence despite the degree of preoperative erectile function.

Prediction of response to combined immunotherapy with interferon-alpha and low-dose interleukin-2 in metastatic renal cell carcinoma: expression patterns of potential molecular markers in radical nephrectomy specimens.

OBJECTIVES: To evaluate the expression levels of multiple molecular markers in radical nephrectomy specimens from patients with metastatic renal cell carcinoma (RCC) who received combined immunotherapy with interferon-alpha (IFN-alpha) and low-dose interleukin-2 (IL-2) and to identify factors predicting susceptibility to this therapy. METHODS: This study included 40 patients with metastatic clear cell RCC undergoing combined immunotherapy with IFN-alpha and low-dose IL-2 following radical nephrectomy. Expression levels of 10 markers, including Aurora-A, Bcl-2, clusterin, heat shock protein 27, heat shock protein 90, Ki-67, matrix metalloproteinase-2, matrix metalloproteinase-9, p53 and vascular endothelial growth factor, in RCC specimens were measured using immunohistochemical staining. RESULTS: In this series, one, 10, 15 and 16 patients were diagnosed as showing complete response, partial response, stable disease and progressive disease, respectively. Expression levels of Bcl-2 and Ki-67 had significant impacts on the response to this therapy. Furthermore, cancer-specific survival was significantly associated with the expression levels of Ki-67 and Bcl-2 in addition to performance status, presence of metastases at diagnosis, metastatic organ and C-reactive protein on univariate analysis. Only the presence of metastases at diagnosis and Ki-67 expression level appeared to be independent predictors of cancer-specific survival on multivariate analysis. CONCLUSIONS: It would be useful to consider the expression levels of potential molecular markers, particularly Ki-67, in addition to clinical parameters, such as the presence of metastases at diagnosis, to select metastatic RCC patients likely to benefit from combined immunotherapy.

Expression of potential molecular markers in renal cell carcinoma: impact on clinicopathological outcomes in patients undergoing radical nephrectomy.

OBJECTIVES: To evaluate the expression levels of several potential molecular markers in renal cell carcinoma (RCC), to clarify the significance of these markers as prognostic predictors in patients undergoing radical nephrectomy (RN). PATIENTS AND METHODS: The study included 153 patients with clinically organ-confined RCC undergoing RN. Expression levels of 12 proteins, including Aurora-A, Bcl-2, Bcl-xL, clusterin, heat-shock protein 27 (HSP27), HSP70, HSP90, Ki-67, matrix metalloproteinase (MMP)-2 and -9, p53 and vascular endothelial growth factor, in RN specimens obtained from these 153 patients were measured by immunohistochemical staining. RESULTS: Of the 12 markers, clusterin, HSP27, Ki-67, MMP-2 and -9 expression were significantly associated with several conventional prognostic factors. Univariate analysis also identified these five markers as significant predictors of disease recurrence, while mode of presentation, pathological stage, grade and microvascular invasion were also significant. Of these significant factors, Ki-67 expression, pathological stage and microvascular invasion appeared to be independently related to disease recurrence. Furthermore, there were significant differences in recurrence-free survival according to positive numbers of these three independent factors, i.e. disease recurred in four of 56 patients who were negative for risk factors (7%), 17 of 71 positive for one risk factor (24%), and 20 of 26 positive for two or three risk factors (77%). CONCLUSIONS: Combined evaluation of Ki-67 expression, pathological stage and microvascular invasion would be particularly useful for further refinement of the system for predicting the outcome after RN for patients with RCC.

Analysis of factors predicting intravesical recurrence of superficial transitional cell carcinoma of the bladder without concomitant carcinoma in situ.

BACKGROUND: The objective of this study was to investigate risk factors for intravesical recurrence in patients with superficial bladder cancer without concomitant carcinoma in situ (CIS). METHODS: In this series, we analyzed data from patients with newly diagnosed superficial Ta or T1 transitional cell carcinoma (TCC) of the bladder without concomitant CIS who underwent complete transurethral resection (TUR) without any adjuvant intravesical instillation therapies. Multivariate analysis was used to determine significant risk factors affecting intravesical recurrence after TUR. Differences in clinicopathological features between primary and recurrent tumors were also characterized. RESULTS: Among 341 patients undergoing TUR of Ta or T1 bladder cancer, 187 diagnosed as having concomitant CIS and/or treated with adjuvant intravesical therapy were excluded, and the remaining 154 were evaluated. Intravesical recurrence was detected in 64 of the 154 patients, showing a 5-year recurrence-free survival rate of 58.3%. Among several factors examined, only tumor size was significantly associated with intravesical recurrence. Multivariate analysis identified tumor size as an independent predictor for intravesical recurrence irrespective of other parameters including age, gender, multiplicity, growth pattern, grade and stage. Recurrent tumors were significantly smaller and of a lower grade and lower stage than primary tumors, despite the absence of differences in growth pattern and the multiplicity between them. CONCLUSIONS: These findings suggest that primary tumor size could be used as a potential risk factor for predicting intravesical recurrence following TUR of superficial TCC of the bladder without concomitant CIS, and that the pathological characteristics of recurrent tumors are more favorable than those of primary tumors.

The limited significance of a longer duration of neoadjuvant hormonal therapy prior to radical prostatectomy for high-risk prostate cancer in Japanese men.

INTRODUCTION: The objective of this study was to evaluate the therapeutic significance of a longer duration of neoadjuvant hormonal therapy (NHT) followed by radical prostatectomy (RP) in Japanese men with high-risk prostate cancer. MATERIALS AND METHODS: This study included a total of 42 patients with high-risk prostate cancer who were treated with NHT for >or=8 months prior to RP. In this series high-risk prostate cancer was defined as clinical stage T2c or T3, pretreatment serum prostate-specific antigen (PSA) >20 ng/ml and/or a biopsy Gleason score of 8-10. Biochemical recurrence was defined as a serum PSA level of >or=0.2 ng/ml. The data of these patients were retrospectively reviewed to clarify the relationships between treatment outcomes and various clinicopathological parameters. RESULTS: The clinical stage was T2c in 13 patients and T3 in 29, the median value of pretreatment serum PSA was 43.3 ng/ml (range 9.7-322.2), and the biopsy Gleason score was 6 in 3 patients, 7 in 16 and >or=8 in 23. Following NHT (median 12 months, range 8-27), the median value of serum PSA decreased to 0.05 ng/ml (<0.01-18.3 ng/ml), and 15 patients (35.7%) were pathologically downstaged. During the median follow-up of 38 months (range 8-58), 11 patients (26.2%) developed biochemical recurrence, and the multivariate analysis identified pretreatment serum PSA, biopsy Gleason score and percentage of positive biopsy core as independent predictors of biochemical recurrence. The 3-year biochemical recurrence-free survival rate of the 42 patients was 68.3%, which was not significantly different from that of 34 patients who underwent RP for high-risk prostate cancer without NHT during the same period. CONCLUSION: A longer duration of NHT followed by RP for patients with high-risk prostate cancer resulted in a comparatively favorable outcome. However, despite the nonrandomized retrospective analysis, the present findings suggest no significant impact of long-term NHT on biochemical recurrence. Longer follow-up is needed to determine whether this therapeutic strategy is beneficial for high-risk prostate cancer patients.