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Objective To investigate the diagnostic performance and safety of a three-dimensional 14-core biopsy (3D14PBx) method, which is a combination of the transrectal six-core and transperineal eight-core biopsy methods. Patients and Methods Between December 2005 and August 2010, 1103 men underwent 3D14PBx at our institutions and were analysed prospectively. Biopsy criteria included a PSA level of 2.5–20 ng/mL or abnormal digital rectal examination (DRE) findings, or both. The primary endpoint of the study was diagnostic performance and the secondary endpoint was safety. We applied recursive partitioning to the entire study cohort to delineate the unique contribution of each sampling site to overall and clinically significant cancer detection. Results Prostate cancer was detected in 503 of the 1103 patients (45.6%). Age, family history of prostate cancer, DRE, PSA, percentage of free PSA and prostate volume were associated with the positive biopsy results significantly and independently. Of the 503 cancers detected, 39 (7.8%) were clinically locally advanced (≥cT3a), 348 (69%) had a biopsy Gleason score (GS) of ≥7, and 463 (92%) met the definition of biopsy-based significant cancer. Recursive partitioning analysis showed that each sampling site contributed uniquely to both the overall and the biopsy-based significant cancer detection rate of the 3D14PBx method. The overall cancer-positive rate of each sampling site ranged from 14.5% in the transrectal far lateral base to 22.8% in the transrectal far lateral apex. As of August 2010, 210 patients (42%) had undergone radical prostatectomy, of whom 55 (26%) were found to have pathologically non-organ-confined disease, 174 (83%) had prostatectomy GS ≥7 and 185 (88%) met the definition of prostatectomy-based significant cancer. Conclusions This is the first prospective analysis of the diagnostic performance of an extended biopsy method, which is a simplified version of the somewhat redundant super-extended three-dimensional 26-core biopsy. As expected, each sampling site uniquely contributed not only to overall cancer detection, but also to significant cancer detection. 3D14PBx is a feasible systematic biopsy method in men with PSA

Study Type – Prognosis (inception cohort) Level of Evidence 2 What's known on the subject? and What does the study add? The criteria used for selecting patients with prostate cancer for active surveillance (AS) are still not satisfactory due to the difficulty in predicting the significance of the prostate cancer. Urologists could predict insignificant prostate cancer by incorporating cumulative cancer length and biopsy Gleason score, derived from extended biopsy. The present study has added new criteria for predicting insignificant prostate cancer, which would lead to a better selection of candidates for AS. OBJECTIVE • To develop extended biopsy based criteria for predicting insignificant cancer (IC) using extended biopsy findings. PATIENTS AND METHODS • From 2000 to 2009, 1575 patients with prostate cancer were primarily treated by radical prostatectomy in two referral hospitals. • Of these, the study cohort comprised 499 patients with extended biopsy confirmed, clinically organ-confined (cT1–2N0M0) prostate cancer with PSA levels of

Study Type – Prognosis (cohort) Level of Evidence 2a What's known on the subject? and What does the study add? C-reactive protein (CRP) level has been shown to be a significant prognostic factor for various malignancies, including urothelial carcinoma treated surgically. Apart from CRP level, several prognostic factors have been identified for advanced urothelial carcinoma patients receiving a second-line chemotherapy. CRP could also be a significant prognostic factor for advanced urothelial carcinoma patients receiving a second-line chemotherapy. CRP kinetics, the dynamic change of CRP concentration, has a strong impact on survival. Adding to the baseline CRP status at the start of treatment, the normalization of CRP during treatment is significantly associated with prognosis. The period with normalized CRP level was strongly correlated with survival period. Therefore, CRP could be a potential biomarker for advanced urothelial carcinoma patients. OBJECTIVE • To assess the impact of C-reactive protein (CRP) kinetics, the effect of dynamic changes of CRP concentration on the survival of patients with locally advanced or metastatic urothelial carcinoma (UC) treated by single chemotherapeutic regimen including cisplatin was examined. PATIENTS AND METHODS • Eighty patients with advanced UC, who failed treatment of advanced UC with the first-line chemotherapy or who received perioperative treatment of neoadjuvant or adjuvant settings, were treated with gemcitabine, etoposide and cisplatin (GEP) as second-line chemotherapy. • Patients were divided into three groups according to CRP kinetics based on baseline and nadir CRP concentrations. Patients whose baseline CRP levels were

Study Type – Diagnostic (exploratory cohort) Level of Evidence 3a What's known on the subject? and What does the study add? Initial transrectal 12-core biopsy has a small but definite risk of missing anterior significant prostate cancers irrespective of age, PSA, prostate volume and DRE findings. Our study yields valuable information for diagnosis and treatment decision of prostate cancer based on transrectal 12-core biopsy. OBJECTIVE • To characterize prostate cancers missed by initial transrectal 12-core biopsy. PATIENTS AND METHODS • Between 2002 and 2008, 715 men with prostate-specific antigen levels in the range 2.5–20 ng/mL or abnormal digital rectal examination underwent three-dimensional 26-core prostate biopsy (i.e. a combination of transrectal 12-core biopsy and transperineal 14-core biopsy) on initial examination. • Of the 257 patients diagnosed with cancer, 120 patients subsequently underwent radical prostatectomy. • Cancers were grouped into TR12-negative cancers (i.e. not detected through transrectal 12-core biopsy but detected through transperineal 14-core biopsy) and TR12-positive (i.e. detected through transrectal 12-core biopsy) cancers. • Clinicopathological characteristics of the TR12-negative and TR12-positive cancers were evaluated. RESULTS • TR12-negative cancers comprised 21% of the three-dimensional 26-core biopsy-detected cancers. • The frequency of cancers with a biopsy Gleason score ≤6 and that of cancers with a biopsy primary Gleason grade ≤3 was higher in TR12-negative cancers, at 58% and 83%, respectively, than in TR12-positive cancers, at 25% (P < 0.001) and 53% (P < 0.001), respectively. • The median number of positive cores in TR12-negative cancers was two out of 26. • TR12-negative cancers were more frequently located anteriorly than posteriorly. • The incidence of the TR12-negative cancers was not associated significantly with any clinical variable. CONCLUSION • Many of the cancers missed by initial transrectal 12-core biopsy are probably low-grade and low-volume diseases, although initial transrectal 12-core biopsy has a small but definite risk of missing anterior significant cancers.

Study Type--Therapy (case series). Level of Evidence 4. What's known on the subject? and What does the study add? A randomized prospective phase III clinical trial for systemic treatment-naive metastatic renal cell cancer (RCC) patients demonstrated the superiority of sunitinib over interferon with an acceptable safety profile. However, a commonly asked question is whether patients with RCC in clinical trials are representative of those with this disease being seen in ordinary clinical practice. To our knowledge, this is the first report of sunitinib for the Japanese patients with metastatic RCC in ordinary clinical practice. The estimated median PFS and OS in this study were 9.3 and 32.2 months, respectively. The application of the MSKCC model distinctly separated OS curves (P Objectives • To report the treatment efficacy and safety profile of sunitinib for patients with metastatic renal cell carcinoma (RCC) in ordinary clinical practice. • In addition, to investigate the prognostic clinicopathological factors in these patients. Patients and methods • The present study consisted of native Japanese patients with metastatic RCC, comprising 29 pretreated and 34 systemic treatment-naive patients. • Univariate and multivariate analyses were performed by the log-rank test and the Cox proportional hazards model, respectively. Results • Estimated median progression-free survival and overall survival (OS) were 9.3 months (95% confidence interval, CI, 5.0-13.7) and 32.2 months (95% CI, 24.4-40.0), respectively. • Among the patients pretreated before sunitinib, two patients were treated with initialized systemic therapy with sorafenib and the remaining 27 were initialized with interferon-α. • The OS from the initial systemic therapy of the patients in pretreated groups was 79.6 months (95% CI, 14.6-144.5). • The application of the Memorial Sloan-Kettering Cancer Center model distinctly separated the OS curves (P Conclusions • Sunitinib has a favourable efficacy/safety profile for Japanese metastatic RCC patients in clinical practice. • The estimated median OS was >2 years with acceptable tolerability. • The median OS from the initial systemic therapy of the pretreated patients was >6 years. • Memorial Sloan-Kettering Cancer Center prognostic factors still appear to be valid for predicting survival in metastatic RCC in the era of molecular targeted therapy.

OBJECTIVE To compare the effects of leuprolide acetate and goserelin acetate for suppressing serum testosterone levels in Japanese patients with prostate cancer, as several recent studies suggested that serum testosterone is not always suppressed below the upper limit of the castration range in patients using luteinizing hormone-releasing hormone (LH-RH) agonists, especially leuprolide acetate. PATIENTS AND METHODS In all, 232 patients with prostate cancer, whose serum testosterone levels were measured before and during treatment using a 1- or 3-monthly formulation of leuprolide or goserelin, were enrolled in a retrospective study. The mean age of the patients was 69.8 years and the mean testosterone level before the LHRH treatment was 4.54 ng/mL. The patients had their testosterone levels assessed a mean (range) of 5.4 (1–35) times during the LHRH treatment. A castrate serum testosterone level was defined as ≤0.5 ng/mL. RESULTS The mean maximum testosterone level during 1-monthly leuprolide (40 patients), 3-monthly leuprolide (68), 1-monthly goserelin (50), or 3-monthly goserelin (74) treatment was 0.22, 0.20, 0.19 and 0.20 ng/mL, respectively (not significant). Four patients, including two treated with 1-monthly leuprolide, one with 3-monthly leuprolide and one with 3-monthly goserelin, had serum testosterone above the castrate level, with a maximum of 0.5–0.65 ng/mL. Three of these patients had elevated testosterone only once or twice during the follow-up, and the remaining patient had serum testosterone fluctuating at 0.4–0.6 ng/mL throughout the follow-up. CONCLUSIONS One- and 3-monthly formulations of leuprolide and goserelin have equivalent and sufficient effects to suppress serum testosterone levels in men with prostate cancer. There were testosterone levels just outside the castrate range in a few patients during treatment.

To investigate the diagnostic performance and safety of a three-dimensional 14-core biopsy (3D14PBx) method, which is a combination of the transrectal six-core and transperineal eight-core biopsy methods.Between December 2005 and August 2010, 1103 men underwent 3D14PBx at our institutions and were analysed prospectively. Biopsy criteria included a PSA level of 2.5-20 ng/mL or abnormal digital rectal examination (DRE) findings, or both. The primary endpoint of the study was diagnostic performance and the secondary endpoint was safety. We applied recursive partitioning to the entire study cohort to delineate the unique contribution of each sampling site to overall and clinically significant cancer detection.Prostate cancer was detected in 503 of the 1103 patients (45.6%). Age, family history of prostate cancer, DRE, PSA, percentage of free PSA and prostate volume were associated with the positive biopsy results significantly and independently. Of the 503 cancers detected, 39 (7.8%) were clinically locally advanced (≥cT3a), 348 (69%) had a biopsy Gleason score (GS) of ≥7, and 463 (92%) met the definition of biopsy-based significant cancer. Recursive partitioning analysis showed that each sampling site contributed uniquely to both the overall and the biopsy-based significant cancer detection rate of the 3D14PBx method. The overall cancer-positive rate of each sampling site ranged from 14.5% in the transrectal far lateral base to 22.8% in the transrectal far lateral apex. As of August 2010, 210 patients (42%) had undergone radical prostatectomy, of whom 55 (26%) were found to have pathologically non-organ-confined disease, 174 (83%) had prostatectomy GS ≥7 and 185 (88%) met the definition of prostatectomy-based significant cancer.This is the first prospective analysis of the diagnostic performance of an extended biopsy method, which is a simplified version of the somewhat redundant super-extended three-dimensional 26-core biopsy. As expected, each sampling site uniquely contributed not only to overall cancer detection, but also to significant cancer detection. 3D14PBx is a feasible systematic biopsy method in men with PSA20 ng/mL.

Objective To assess the level of a bone-formation marker, the amino-terminal propeptide of type I procollagen (PINP), for its utility in indicating bone metastasis in patients with prostate cancer. Patients and methods Several bone formation markers, i.e. PINP, the carboxy-terminal propeptide of type I procollagen (PICP), bone-specific alkaline phosphatase (BALP), and bone Gla protein (BGP), a bone resorption marker (pyridinoline cross-linked carboxy-terminal telopeptide, ICTP), and prostate specific antigen (PSA) were measured in 40 patients without and 25 patients with bone metastasis. No patient had undergone previous treatment, except for six who developed bone metastasis while undergoing hormone therapy. Results All markers except BGP were significantly higher in patients with bone metastasis than in those without. The levels of PINP correlated best with the extent of disease, although the levels of PSA, BALP and ICTP also correlated well. While PINP had the largest area under the receiver-operator characteristic curve, PSA, BALP and ICTP also produced useful curves. Conclusion The bone formation marker PINP seems to be useful for discriminating patients with and without bone metastasis. PINP may help in the early and accurate diagnosis of bone metastasis in such patients.

What's known on the subject? and What does the study add? The criteria used for selecting patients with prostate cancer for active surveillance (AS) are still not satisfactory due to the difficulty in predicting the significance of the prostate cancer. Urologists could predict insignificant prostate cancer by incorporating cumulative cancer length and biopsy Gleason score, derived from extended biopsy. The present study has added new criteria for predicting insignificant prostate cancer, which would lead to a better selection of candidates for AS.• To develop extended biopsy based criteria for predicting insignificant cancer (IC) using extended biopsy findings.• From 2000 to 2009, 1575 patients with prostate cancer were primarily treated by radical prostatectomy in two referral hospitals. • Of these, the study cohort comprised 499 patients with extended biopsy confirmed, clinically organ-confined (cT1-2N0M0) prostate cancer with PSA levels of20 ng/mL. • Cancer information obtained through extended biopsy included cumulative cancer length (CCL) divided by the number of biopsy cores (CCL/core).• Pathological examination revealed 39 ICs (7.8%). All these ICs fell in a category of prostate cancer with clinical stage ≤ T2a and 2005 International Society of Urological Pathology Consensus Conference (ISUP) modified biopsy Gleason score ≤ 7. • Accordingly, we analysed predictors of IC in a subset cohort of 370 patients in this category. A multivariate logistic regression analysis revealed that 2005 ISUP modified biopsy Gleason score and CCL/core were independently significant predictors of IC. • We determined a threshold value of CCL/core of 0.20 mm for predicting IC using receiver operating characteristic analysis. • Based on these findings, we developed simple extended biopsy based criteria for predicting IC as follows: (i) PSA level of20 ng/mL; (ii) Clinical stage ≤ T2a; (iii) 2005 ISUP modified biopsy Gleason score ≤ 6; (iv) CCL/core of0.20 mm. • The specificity of the criteria was 91%, which was significantly higher than the value from a subset of criteria without item iv (P0.001).• We have developed extended biopsy based criteria for predicting IC incorporating the 2005 ISUP modified biopsy Gleason score and CCL/core.

To assess the impact of C-reactive protein (CRP) kinetics, the effect of dynamic changes of CRP concentration on the survival of patients with locally advanced or metastatic urothelial carcinoma (UC) treated by single chemotherapeutic regimen including cisplatin was examined.Eighty patients with advanced UC, who failed treatment of advanced UC with the first-line chemotherapy or who received perioperative treatment of neoadjuvant or adjuvant settings, were treated with gemcitabine, etoposide and cisplatin (GEP) as second-line chemotherapy. Patients were divided into three groups according to CRP kinetics based on baseline and nadir CRP concentrations. Patients whose baseline CRP levels were5 mg/L, patients whose baseline CRP levels were ≥5 mg/L and normalized (5 mg/L), and patients whose baseline CRP levels were ≥5 mg/L and never normalized were assigned to non-elevated, normalized and non-normalized CRP groups, respectively. The prognostic impact of CRP kinetics and the correlation between normalized CRP period and overall survival period were determined.In 46 (57%) of the 80 patients, CRP levels were elevated at the diagnosis of advanced UC. During treatment, after a median follow-up period of 12 months CRP levels were normalized in 24 (71%) of 34 patients, whereas CRP levels remained elevated in the remaining 10 patients. Overall survival rates were significantly different between the non-elevated, normalized, and non-normalized CRP groups (P0.001), with 1-year survival rates of 72, 51 and 14%, respectively. On multivariate analysis including Eastern Cooperative Oncology Group performance status, visceral metastasis, number of metastatic sites, previous definitive surgery, anaemia, baseline and nadir CRP levels (mg/L), and CRP kinetics status, CRP kinetics was an independent and significant factor for overall survival. The normalized CRP period was significantly correlated with the overall survival period in 52 patients who died.CRP kinetics is significantly associated with the prognosis and survival period of patients with advanced UC treated by chemotherapy. Although larger confirmatory studies are warranted to validate our results, CRP can potentially be a useful biomarker for patients with advanced UC.

• To characterize prostate cancers missed by initial transrectal 12-core biopsy.• Between 2002 and 2008, 715 men with prostate-specific antigen levels in the range 2.5-20 ng/mL or abnormal digital rectal examination underwent three-dimensional 26-core prostate biopsy (i.e. a combination of transrectal 12-core biopsy and transperineal 14-core biopsy) on initial examination. • Of the 257 patients diagnosed with cancer, 120 patients subsequently underwent radical prostatectomy. • Cancers were grouped into TR12-negative cancers (i.e. not detected through transrectal 12-core biopsy but detected through transperineal 14-core biopsy) and TR12-positive (i.e. detected through transrectal 12-core biopsy) cancers. • Clinicopathological characteristics of the TR12-negative and TR12-positive cancers were evaluated.• TR12-negative cancers comprised 21% of the three-dimensional 26-core biopsy-detected cancers. • The frequency of cancers with a biopsy Gleason score ≤ 6 and that of cancers with a biopsy primary Gleason grade ≤ 3 was higher in TR12-negative cancers, at 58% and 83%, respectively, than in TR12-positive cancers, at 25% (P0.001) and 53% (P0.001), respectively. • The median number of positive cores in TR12-negative cancers was two out of 26. • TR12-negative cancers were more frequently located anteriorly than posteriorly. • The incidence of the TR12-negative cancers was not associated significantly with any clinical variable.• Many of the cancers missed by initial transrectal 12-core biopsy are probably low-grade and low-volume diseases, although initial transrectal 12-core biopsy has a small but definite risk of missing anterior significant cancers.

Study Type--Therapy (case series). Level of Evidence 4. What's known on the subject? and What does the study add? A randomized prospective phase III clinical trial for systemic treatment-naïve metastatic renal cell cancer (RCC) patients demonstrated the superiority of sunitinib over interferon with an acceptable safety profile. However, a commonly asked question is whether patients with RCC in clinical trials are representative of those with this disease being seen in ordinary clinical practice. To our knowledge, this is the first report of sunitinib for the Japanese patients with metastatic RCC in ordinary clinical practice. The estimated median PFS and OS in this study were 9.3 and 32.2 months, respectively. The application of the MSKCC model distinctly separated OS curves (P0.001), suggesting that MSKCC prognostic factors might be still valid to predict survival in metastatic RCC in the era of molecular targeted therapy.• To report the treatment efficacy and safety profile of sunitinib for patients with metastatic renal cell carcinoma (RCC) in ordinary clinical practice. • In addition, to investigate the prognostic clinicopathological factors in these patients.• The present study consisted of native Japanese patients with metastatic RCC, comprising 29 pretreated and 34 systemic treatment-naïve patients. • Univariate and multivariate analyses were performed by the log-rank test and the Cox proportional hazards model, respectively.• Estimated median progression-free survival and overall survival (OS) were 9.3 months (95% confidence interval, CI, 5.0-13.7) and 32.2 months (95% CI, 24.4-40.0), respectively. • Among the patients pretreated before sunitinib, two patients were treated with initialized systemic therapy with sorafenib and the remaining 27 were initialized with interferon-α. • The OS from the initial systemic therapy of the patients in pretreated groups was 79.6 months (95% CI, 14.6-144.5). • The application of the Memorial Sloan-Kettering Cancer Center model distinctly separated the OS curves (P0.001). • The most common grade 3 adverse events were fatigue (53%), thrombocytopaenia (48%), hand-foot syndrome (16%), anaemia (20%), hypertension (10%) and leucopaenia (9%), although these events were manageable and reversible.• Sunitinib has a favourable efficacy/safety profile for Japanese metastatic RCC patients in clinical practice. • The estimated median OS was2 years with acceptable tolerability. • The median OS from the initial systemic therapy of the pretreated patients was6 years. • Memorial Sloan-Kettering Cancer Center prognostic factors still appear to be valid for predicting survival in metastatic RCC in the era of molecular targeted therapy.

OBJECTIVE To investigate the rate of objective response and the skeletal-related event (SRE)-free survival after combined therapy with radiotherapy (RT) and zoledronate in patients with bone metastases from renal cell carcinoma (RCC). PATIENTS AND METHODS In all, 23 patients with RCC metastatic to bone were included in this retrospective study, of whom 13 had RT to bone metastases with no bisphosphonate therapy between 2000 and 2006, while the remaining 10 had combined therapy with RT and zoledronate (RT + Z) in 2006 and 2007. Significant calcifications of osteolytic metastases and/or shrinkage of bone lesions, as measured by computed tomography, were defined as a partial response. SREs were defined as any of pathological fracture, spinal cord compression, bone surgery, or additional RT to the bone. RESULTS In the RT + Z group, six patients had a partial response, showing evidence of calcification of their osteolytic bone metastases, while in the RT group, only one patient did (P = 0.019). One patient in the RT + Z group had an SRE, while 10 in the RT group had SREs (P = 0.003). The median SRE-free survival time was not reached in the RT + Z group, but in the RT group it was 18.7 months (P = 0.046). CONCLUSION Combined therapy as RT + Z achieved a higher objective response rate (six of 10) and prolonged SRE-free survival than RT alone in patients with bone metastases from RCC.