Published papers

Purpose: Focal therapy (FT) is a treatment modality for prostate cancer that aims to reduce side effects. However, it remains difficult to select eligible candidates. We herein examined eligibility factors for hemi-ablative FT for prostate cancer. Methods: We identified 412 patients who were diagnosed with unilateral prostate cancer by biopsy and had undergone radical prostatectomy between 2009 and 2018. Among these patients, 111 underwent MRI before biopsy, had 10–20 core biopsies performed, and did not receive other treatments before surgery. Fifty-seven patients with prostate-specific antigen ≥ 15 ng/mL and biopsy Gleason score (GS) ≥ 4 + 3 were excluded. The remaining 54 patients were evaluated. Both lobes of the prostate were scored using Prostate Imaging Reporting and Data System version 2 on MRI. Ineligible patients for FT were defined as those with ≥ 0.5 mL GS6 or GS ≥ 3 + 4 in the biopsy-negative lobe, ≥ pT3, or lymph node involvement. Selected predictors of eligibility for hemi-ablative FT were analyzed. Results: Among our cohort of 54 patients, 29 (53.7%) were eligible for hemi-ablative FT. A multivariate analysis identified a PI-RADS score < 3 in the biopsy-negative lobe (p = 0.016) as an independent predictor of eligibility for FT. Thirteen out of 25 ineligible patients had GS ≥ 3 + 4 tumors in the biopsy-negative lobe, half of whom (6/13) also had a PI-RADS score < 3 in the biopsy-negative lobe. Conclusion: The PI-RADS score in the biopsy-negative lobe may be important in the selection of eligible candidates for FT. The findings of this study will help reduce missed significant prostate cancers and improve FT outcomes.

INTRODUCTION: Even in the era of laparoscopic radical prostatectomy (LRP) and robot-assisted laparoscopic radical prostatectomy (RALP), we sometimes encounter patients with severe urinary incontinence after surgery. The aim of the present study was to identify predictors of urinary continence recovery among patients with urinary incontinence immediately after surgery (UIIAS). MATERIALS AND METHODS: We identified 274 patients with clinically localized prostate cancer who underwent LRP and RALP between 2011 and 2018. UIIAS was defined as a urine loss ratio > 0.15 on the first day of urethral catheter removal. Urinary continence recovery was defined as using ≤ 1 pad/day one year after surgery. In the present study, we evaluated factors affecting urinary function recovery one year after surgery among patients with urinary incontinence immediately after LRP and RALP. RESULTS: UIIAS was observed in 191 out of 274 patients (69.7%). A multivariate analysis identified age (<65 years, p = 0.015) as an independent predictor affecting immediate urinary continence. Among 191 incontinent patients, urinary continence one year after surgery improved in 153 (80.1%). A multivariate analysis identified age (<65 years, p = 0.003) and estimated blood loss (≥ 100 mL, p = 0.044) as independent predictors affecting urinary continence recovery one year after surgery. CONCLUSION: The present results suggest that younger patients and patients with higher intraoperative blood loss recover urinary continence one year after surgery even if they are incontinent immediately after surgery.

Background: The treatment strategy for prostate-specific antigen (PSA) progression in patients who receive salvage radiation therapy (RT) for biochemical recurrence (BCR) after radical prostatectomy (RP) is salvage androgen deprivation therapy (ADT). However, its optimal timing is highly controversial. Methods: The study sample consisted of 77 men who underwent RP, received salvage RT against BCR, and underwent salvage ADT for PSA progression. The endpoint of this study was development to castration-resistant prostate cancer (CRPC), from the start of salvage RT. Results: The median follow-up time was 9.5 years, and 20 patients experienced CRPC. The multivariable analysis identified PSA-doubling time (PSA-DT) ≤ 12 months (hazard ratio, 3.5) and seminal vesicle invasion (SVI) (hazard ratio, 4.4) as independent risk factors. We defined the high-risk and low-risk groups as those with one or two risk factors and no risk factors, respectively. In the high-risk group, a significant difference in time to CRPC was observed between patients who received salvage ADT at PSA ≤ 1.0 ng/mL (n = 8) and at > 1.0 ng/mL (n = 27) (10-year non-CRPC rate: 100.0% vs. 46.3%, respectively). In contrast, in the low-risk group, no significant difference in CRPC-free survival was observed between patients who received salvage ADT at PSA ≤ 1.0 ng/mL (n = 14) and at > 1.0 ng/mL (n = 28) (10-year non-CRPC rate: 86.4% vs. 80.8%, respectively). Conclusion: In high-risk patients (PSA-DT ≤ 12 months and/or SVI), salvage ADT for PSA progression after salvage RT should be started before the PSA levels exceed 1.0 ng/mL.

PURPOSE: In general, the index lesion of prostate cancer has the largest tumor volume, the highest Grade Group (GG), and the highest stage (concordant cases). However, these factors sometimes do not coincide within one lesion (discordant cases). In such discordant cases, the largest tumor may not be of biological significance and the secondary tumor may more greatly impact the prognosis. MATERIALS AND METHODS: We retrospectively reviewed the medical records of patients who underwent radical prostatectomy, and we identified 580 (85.3%) concordant cases and 100 (14.7%) discordant cases. The end point of this study was biochemical recurrence, and median followup was 4.2 years. RESULTS: Among discordant cases in which GGs of the largest tumor and the highest GG tumor differed, the majority (67 patients) had the largest tumor of GG 2, and we set them as the study cohort. On the other hand, we regarded 212 concordant cases with an index tumor of GG 2 as the control cohort. The study cohort comprised 48 (71.6%) patients with a secondary tumor of GG 3 and 19 (28.4%) with a secondary tumor of GG 4/5. Kaplan-Meier curves revealed that the 5-year biochemical recurrence-free survival rates were 76%, and 67%, respectively. The 5-year biochemical recurrence-free survival rate of the control cohort was 91%, which was significantly better than that of the study cohort (p=0.013 and p=0.014, respectively). CONCLUSIONS: Our study suggests that the prognosis of discordant cases is better determined by the secondary cancer lesion with the highest GG instead of the largest lesion.

Introduction: The aim of this retrospective study was to elucidate predictors of survival in metastatic renal cell carcinoma (mRCC) patients in an International Metastatic Renal Cell Carcinoma Database Consortium favorable risk group treated with frontline therapy without immune checkpoint inhibitors. Methods: A total of 238 patients with mRCC were reviewed. Among them, 55 patients in favorable risk group treated with single-agent systemic therapy were retrospectively analyzed. Clinical and pathological data were retrieved and analyzed retrospectively. The prognostic effect of each marker on overall survival (OS) was investigated with univariate and multivariate Cox's proportional hazards regression models. Results: After a median follow-up of 46.2 months after first-line treatment initiation, the median progression-free survival (PFS) was 29.3 months, and the median OS has not been reached. The estimated percentage of patients who were alive at 12 and 24 months were 96.1 and 94.1%, respectively. Multivariate analysis revealed that the long-term duration of first-line treatment (hazard ratio [HR]: 0.972, 95% confidence interval [CI]: 0.944-0.997, p = 0.0299) and the metastases limited to lung (HR: 3.852, 95% CI: 1.080-24.502, p = 0.0361) were independent predictors for longer OS in favorable risk mRCC patients. Conclusion: First-line systemic therapy for favorable risk mRCC patients with a single agent resulted in relatively longer PFS and OS. A longer duration of first-line treatment and lung only metastases are correlated with longer OS.

To evaluate biological characteristics and transitions of upper tract urothelial carcinoma (UTUC) through metachronous bladder tumors after radical nephroureterectomy (RNU), we con-ducted immunohistochemical (IHC) staining of tumor specimens of UTUC tumor origin, non-mus-cle-invasive bladder cancer (NMIBC) and MIBC progressed after intravesical recurrence (IVR), and bladder primary MIBC. Fibroblast growth factor receptor 3 (FGFR3), p53, cytokeratin 5/6 (CK5/6), and CK20 were stained to examine expression rates. After expression assessment with heatmap clustering, the overexpression of four biomarkers from UTUC origin to metachronous MIBC progression was analyzed with clinicopathological variables. We found that high CK20 and low CK5/6 expression were both observed in UTUC tumor origin and subsequent NMIBC after RNU. By in-vestigating molecular expression in the IVR specimen, we observed that low pT stage bladder recurrence occupied the majority of CK20 high CK5/6 low expression, but would change to CK20 low CK5/6 high expression as it progressed to MIBC. UTUC metachronous MIBC has different characteristics compared with bladder primary MIBC, which comprises favorable biological features such as high FGFR3 expression, and follows favorable prognosis compared to those without FGFR3 ex-pression. The present study demonstrated that the biological characteristics of UTUC tumor origin shifts from luminal to basal-like features with progression to MIBC, but FGFR3 expression taken over from UTUC origin may comprise a favorable entity compared to primary MIBC.

Objective: Pheochromocytoma is a rare neuroendocrine tumour that secretes catecholamines and originates in the adrenal gland. Although surgical resection is the only curative therapy for pheochromocytoma, it is associated with a risk of haemodynamic instability (HDI), such as extremely high blood pressure and/or post tumour removal hypotension and shock. We investigated the risk factors for HDI during pheochromocytoma surgery. Design and Patients: Eighty-two patients who underwent laparoscopic adrenalectomy for pheochromocytoma between July 2002 and February 2020 were examined. We excluded 3 patients with bilateral disease and 11 without detailed 24 h urinary data. We defined HDI as systolic blood pressure ≥ 200 or <80 mmHg. We investigated the risk factors for HDI during laparoscopic adrenalectomy for pheochromocytoma. Results: There were 29 males and 39 females with a median age of 50.5 years. Tumours were localised on the right adrenal gland in 28 patients and on the left in 40. The median tumour diameter was 37.5 mm and the median pneumoperitoneum time was 93.5 min. Twenty-five out of sixty-eight patients (37%) developed HDI. A multivariate analysis identified diabetes mellitus (DM; odds ratio: 3.834; 95% confidence interval: 1.062–13.83; p =.04) as an independent predictor of HDI. In terms of hormonal data, median 24 h urinary epinephrine levels (p =.04) and metanephrine levels (p =.01) were significantly higher in the HDI group. DM was also considered as a risk factor for prolonged HDI (p =.02). Conclusion: Surgeons and anaesthesiologists need to be aware of the risk of HDI and its prolongation during laparoscopic adrenalectomy for pheochromocytoma for DM patients.

© 2020 Elsevier Inc. Introduction: The aim of this study was to validate contemporary grading systems, in particular, the Gleason grade group (GGG) 5. Patients and Methods: We retrospectively reviewed the clinicopathologic data of 176 patients who underwent radical prostatectomy and whose pathologic results were GGG 4 or 5. The endpoints were biochemical recurrence (BCR) and castration-resistant prostate cancer (CRPC). Results: The GGG 4 group was composed of 69 patients. The GGG 5 group consisted of 78 patients with GS 4+5 and 29 patients with GS 5+4 or higher. The 5-year BCR-free survival rates for men with GGG 4, GS 4+5, and GS 5+4 or higher were 59%, 54%, and 20%, respectively, and the 5-year CRPC-free survival rates were 98%, 100%, and 88%, respectively. Both the BCR- and CRPC-free survival rates were significantly higher in GS 4+5 than in GS 5+4 or higher (P < .001 and P = .002, respectively), but there were no significant differences between GGG 4 and GS 4+5 (P = .702 and P = .803, respectively). The multivariate analysis demonstrated that GS 5+4 or higher (hazard ratio, 3.4; P = .002) and lymphovascular invasion (hazard ratio, 3.4; P < .001) greatly affected BCR. Conclusion: Our follow-up study revealed that men with GS 4+5 and those with GGG 4 had a similar prognosis. However, there was a significant discrepancy in prognosis between GS 4+5 and GS 5+4 or higher. This suggested that GGG 4 and 5 in the contemporary prostate cancer grading system should be reviewed. Furthermore, lymphovascular invasion may be useful to subgroup these pathologically high-risk patients.

Background: Routine use of neoadjuvant hormonal therapy (NHT) before radical prostatectomy (RP) is not recommended, but it is sometimes performed to reduce the prostate size and tumor volume or to prevent tumor progression during the wait times for surgery in clinical practice. On the other hand, the impact of NHT on the pattern of biochemical recurrence (BCR) is unknown. Methods: We retrospectively examined 1749 consecutive patients who underwent RP between 1996 and 2017. Among the patients who met the inclusion criteria, BCR developed in 240 of non-NHT patients and in 120 of NHT patients during the mean follow-up period of 6.9 years. We examined the impact of NHT on the PSA-doubling time (DT) following BCR at different times after RP. Results: The median PSA-DTs in non-NHT patients who experienced BCR in the first year after surgery, between 1 and 2 years, between 2 and 3 years, between 3 and 4 years, between 4 and 5 years, and at > 5 years were 5.5, 8.8, 11.3, 17.7, 18.2, and 18.4 months, respectively. On the other hand, those in NHT patients were 1.4, 4.1, 9.1, 13.4, 27.2, and 19.3 months, respectively. The differences of PSA-DTs in the first year after surgery (p < 0.001) and between 1 and 2 years (p = 0.005) were significant between non-NHT and NHT patients. Conclusion: Patients who received NHT had a higher risk of a rapid PSA increase when they experienced BCR, especially within 2 years after RP. In order to not miss the optimal timing of salvage treatment for BCR, intensive PSA follow-up is necessary.

Objective: The aim of this study was to evaluate the clinical significance of the on-treatment C-reactive protein (CRP) status during systemic treatment as the predictive marker for the response of subsequent nivolumab monotherapy in patients with refractory metastatic renal cell carcinoma (mRCC). Patients and methods: A total of 73 mRCC patients treated with nivolumab were retrospectively reviewed. We evaluated the serum CRP levels before and after molecular-targeted treatments. Patients whose CRP did not exceed baseline value were defined as the CRP-control group and the others were defined as the CRP-progression group. The clinical impact of CRP-control on the efficacy of nivolumab was assessed. Results: Twenty-four patients (33%) were categorized into the CRP-control group. The CRP-control group patients (median PFS not reached) had significantly longer PFS than the CRP-progression group (median PFS 11.9 months, 95% confidence interval, CI 4.1–19.8, p = 0.038). The CRP-control group had a tendency of longer OS from nivolumab initiation than the CRP-progression group (p = 0.071). By multivariate analysis, the on-treatment CRP-control was the independent predictive factor for PFS (hazard ratio HR 0.37, 95% CI 0.14–0.99, p = 0.047). Conclusion: The on-treatment CRP-control could be the predictive factor for the efficacy of nivolumab in refractory mRCC patients.

© 2018 The Authors. Published by FEBS Press and John Wiley & Sons Ltd. Bacillus Calmette–Guérin (BCG) is widely used in the clinic to effectively treat superficial urinary bladder cancer. However, a significant proportion of patients who fail to respond to BCG risk cystectomy or death. Though more than 3 million cancer treatments with BCG occur annually, surprisingly little is known about the initial signaling cascades activated by BCG. Here, we report that BCG induces a rapid intracellular Ca 2+ (calcium ion) signal in bladder cancer cells that is essential for activating the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and for synthesizing and secreting proinflammatory cytokines, including interleukin 8 (IL-8). A similar Ca 2+ response was observed when cells were exposed to the supernatant of BCG. Studying cellular molecular mechanisms involved in the BCG signaling event, we found pivotal roles for phospholipase C and the Toll-like receptor 4. Further assessment revealed that this signaling pathway induces synthesis of IL-8, whereas exocytosis appeared to be controlled by global Ca 2+ signaling. These results shed new light on the molecular mechanisms underlying BCG treatment of bladder cancer, which can help in improving therapeutic efficacy and reducing adverse side effects.

© 2018 The Author(s). Background: Cancers are heterogeneous and contain various types of irregular structures that can go undetected when examining them with standard two-dimensional microscopes. Studies of intricate networks of vasculature systems, e.g., the tumour lymphatic microvessels, benefit largely from three-dimensional imaging data analysis. Methods: The new DIPCO (Diagnosing Immunolabeled Paraffin-Embedded Cleared Organs) imaging platform uses three-dimensional light-sheet microscopy and whole-mount immunolabelling of cleared samples to study proteins and micro-anatomies deep inside of tumours. Results: Here, we uncovered the whole three-dimensional lymphatic microvasculature of formalin-fixed paraffin-embedded (FFPE) tumours from a cohort of 30 patients with bladder cancer. Our results revealed more heterogeneous spatial deviations in more advanced bladder tumours. We also showed that three-dimensional imaging could determine tumour stage and identify vascular or lymphatic system invasion with higher accuracy than standard two-dimensional histological diagnostic methods. There was no association between sample storage times and outcomes, demonstrating that the DIPCO pipeline could be successfully applied on old FFPE samples. Conclusions: Studying tumour samples with three-dimensional imaging could help us understand the pathological nature of cancers and provide essential information that might improve the accuracy of cancer staging.

© 2018 The Author(s). Background: Cisplatin is the most commonly used chemotherapeutic agent in the treatment of patients with metastatic and/or recurrent urothelial cancer. However, the effectiveness of these treatments is severely limited due to the development of cisplatin resistance. Cancer stem cells have been documented as one of the key hypotheses involved in chemoresistance. CD44v8-10 has been identified as one of the new cancer stem cells markers and was recently shown to enhance the antioxidant system by interaction with xCT, a subunit of the cystine transporter modulating intracellular glutathione synthesis. The aim of the present study was to investigate the clinical role of CD44v8-10 and the molecular mechanism underlying the acquisition of cisplatin resistance through CD44v8-10 in urothelial cancer. Methods: We analyzed the clinical significance of the immunohistochemical CD44v9 expression, which detects the immunogen of human CD44v8-10, in 77 urothelial cancer patients treated with cisplatin-based systemic chemotherapy for recurrence and/or metastasis. We then evaluated the biological role of CD44v8-10 in the acquisition of cisplatin resistance using the urothelial cancer cell lines, T24 and T24PR, which were generated to acquire resistance to cisplatin. Results: The 5-year cancer-specific survival rate was significantly lower in the CD44v9-positive group than in the CD44v9-negative group (P = 0.008). Multivariate analyses revealed that CD44v9 positivity was an independent risk factor of cancer-specific survival (P = 0.024, hazard ratio = 5.16) in urothelial cancer patients who had recurrence and/or metastasis and received cisplatin-based chemotherapy. The expression of CD44v8-10 and xCT was stronger in T24PR cells than in T24 cells. The amount of intracellular glutathione was significantly higher in T24PR cells than in T24 cells (p < 0.001), and intracellular reactive oxygen species production by cisplatin was lower in T24PR cells than in T24 cells. Furthermore, the knockdown of CD44v8-10 by siRNA led to the recovery of cisplatin sensitivity in T24PR cells. Conclusions: CD44v9 in tumor specimens has potential as a novel indicator for identifying a cisplatin-chemoresistant population among urothelial cancer patients. CD44v8-10 contributes to reactive oxygen species defenses, which are involved in chemoresistance, by promoting the function of xCT, which adjusts the synthesis of glutathione.

Cancers acquire resistance to systemic treatment with platinum-based chemotherapy (eg, cisplatin [CDDP]) as a result of a dynamic intratumoral heterogeneity (ITH) and clonal repopulation. However, little is known about the influence of chemotherapy on ITH at the single-cell level. Here, mapping the transcriptome of cancers treated with CDDP by scRNA-seq, we uncovered a novel gene, COX7B, associated with platinum-resistance, and surrogate marker, CD63. Knockdown of COX7B in cancer cells decreased the sensitivity of CDDP whereas overexpression recovered the sensitivity of CDDP. Low COX7B levels correlated with higher mortality rates in patients with various types of cancer and were significantly associated with poor response to chemotherapy in urinary bladder cancer. Tumor samples from patients, who underwent CDDP therapy, showed decreased COX7B protein levels after the treatment. Analyzing scRNA-seq data from platinum-naïve cancer cells demonstrated a low-COX7B subclone that could be sorted out from bulk cancer cells by assaying CD63. This low-COX7B subclone behaved as cells with acquired platinum-resistance when challenged to CDDP. Our results offer a new transcriptome landscape of platinum-resistance that provides valuable insights into chemosensitivity and drug resistance in cancers, and we identify a novel platinum resistance gene, COX7B, and a surrogate marker, CD63.

We performed a retrospective study comparing clinical outcomes between patients with initially diagnosed muscle-invasive bladder cancer (MIBC) without a history of non-MIBC (NMIBC) and those with MIBC that progressed from NMIBC. A history of NMIBC was independently associated with cancer death in cT2-T4a MIBC patients treated with radical cystectomy and without lymph node involvement. MIBC that progresses from NMIBC may not respond to neoadjuvant chemotherapy. Purpose: To investigate whether a history of non–muscle-invasive bladder cancer (NMIBC) plays a prognostic role in patients with muscle-invasive bladder cancer (MIBC) treated with radical cystectomy in the era when neoadjuvant chemotherapy was established as standard therapy for MIBC. Patients and Methods: A total of 282 patients who were diagnosed with cT2-T4aN0M0 bladder cancer treated with open radical cystectomy at our institutions were included. Initially diagnosed MIBC without a history of NMIBC was defined as primary MIBC group (n = 231), and MIBC that progressed from NMIBC was defined as progressive MIBC (n = 51). Results: The rate of cT3/4a tumors was significantly higher in the primary MIBC group than in the progressive MIBC group (P = .004). Five-year recurrence-free survival and cancer-specific survival (CSS) rates for the primary MIBC group versus progressive MIBC group were 68.2% versus 55.9% (P = .039) and 76.1% versus 61.6% (P = .005), respectively. Progressive MIBC (hazard ratio, 2.170; P = .008) was independently associated with cancer death. In the primary MIBC group, the 5-year CSS rate in patients treated with neoadjuvant chemotherapy was 85.4%, which was significantly higher than that in patients without (71.5%, P = .023). In the progressive MIBC group, no significant differences were observed in CSS between patients treated with and without neoadjuvant chemotherapy. Conclusion: MIBC that progressed from NMIBC had a significantly worse clinical outcome than MIBC without a history of NMIBC and may not respond as well to neoadjuvant chemotherapy. These results are informative, even for NMIBC patients treated with conservative intravesical therapy.

© The Author(s) 2018. Published by Oxford University Press. All rights reserved. Objectives: Progression-free survival of first-line targeted therapy greatly influences the survival of patients with metastatic renal cell carcinoma. We evaluated whether post-treatment inflammatory markers and lactate dehydrogenase levels had impacts on progression-free survival prediction in addition to those of conventional predictors. Methods: Two hundred and fifteen patients whose tumors were clear cell type and in whom first-line targeted therapies could be continued for >1 month were evaluated. Pretreatment clinical factors, pathological factors and laboratory data 1 month after targeted therapy initiation—including inflammatory markers (neutrophil count, neutrophil-to-lymphocyte ratio and C-reactive protein) and lactate dehydrogenase—were reviewed. To identify progression-free survival predictors, multivariate analyses were done. Results: The 1-year progression-free survival rate was 47%. Female gender, Karnofsky performance status <80%, time from diagnosis to systemic treatment <12 months, pretreatment C-reactive protein >3.0 mg/dl and post-treatment neutrophil-to-lymphocyte ratio >3.0 were independent predictors for progression-free survival. In contrast, neither C-reactive protein increase nor neutrophil-to-lymphocyte ratio increase after targeted therapy initiation were independent predictors. Pretreatment lactate dehydrogenase, post-treatment lactate dehydrogenase and lactate dehydrogenase decline were not independent predictors. When all patients were stratified by these independent factors into three groups (0 risk vs. 1 or 2 risks vs. 3 or more risks), there were significant differences in progression-free survival rates between the groups (P < 0.0001). Furthermore, there were also significant differences in overall survival rates between the groups (P < 0.0001). Conclusions: Integration of post-treatment neutrophil-to-lymphocyte ratio value with pretreatment factors may lead to the establishment of effective predictive model for disease progression in patients with metastatic clear cell renal cell carcinoma who received first-line targeted therapies.

© 2019 Elsevier Inc. Objective: To investigate the influence of the zonal origin of prostate cancer and extraprostatic extension on biochemical recurrence (BCR). Patients and methods: We included 638 consecutive patients undergoing radical prostatectomy between 2005 and 2015 who did not receive neoadjuvant/adjuvant therapy. The largest lesion was defined as the index tumor. We categorized each patient into the transition zone (TZ) or peripheral zone (PZ) group based on the lesion where the index tumor existed. Differences in the BCR defined as increasing prostate-specific antigen rate between groups were examined by Kaplan-Meier analysis and the Cox proportional hazards model. Results: There were 293 (46%) patients with TZ cancer and 345 (54%) with PZ cancer. TZ cancer was significantly associated with a higher prostate-specific antigen (P = 0.012), lower biopsy positive core rate (P = 0.020), lower pathological Gleason score (P = 0.017), lower pathological stage (P = 0.002), and lower rate of seminal vesicle invasion (P = 0.002). During a median follow-up period of 59 months, 79 patients (12%) developed BCR. In the entire cohort, the PZ origin (hazard ratio: 1.68, P = 0.033) and extraprostatic extension were independent risk factors for BCR. The 3-, 5-, and 7-year BCR-free survival rates of patients with pT3a TZ cancer were 89%, 88%, and 86%, respectively, which were significantly better than those of patients with pT3a PZ cancer (80%, 74%, and 62%, P = 0.012), but were similar to those of the pT2 cancer cohort (92%, 91%, and 90%, P = 0.376). Conclusion: TZ cancer had more favorable pathological characteristics and oncological outcome than PZ cancer especially in pT3a cases.

© 2019, The Author(s). Purpose: To investigate whether volumetric imaging of tumor vasculature can be used to phenotypically characterize advanced upper tract urothelial carcinoma, and if this technique can distinguish aggressive invasive tumors from non-aggressive superficial ones. Methods: In a pilot study, two TaG1 and two T3G3 formalin-fixed paraffin-embedded (FFPE) tumor samples were examined using the DIPCO pipeline (Tanaka et al. in Nature Biomed Eng 1(10):796–806. https://doi.org/10.1038/s41551-017-0139-0, 2017). Briefly, punch biopsies of FFPE tumors were deparaffinized, cleared, immunolabeled with the vessel marker CD34 and imaged with a light-sheet microscope. Thereafter, the three-dimensional (3D) vasculature of the tumors was analyzed and characterized using a specialized image processing software. Results: We found that T3G3 tumors had increased CD34 density kurtosis and skewness compared to TaG1 tumors. This suggests that analysis of the 3D vasculature can distinguish between high-grade invasive and low-grade superficial tumors. Conclusions: Volumetric imaging of tumor samples may represent novel methodology that can complement conventional histopathology. Volumetric imaging enabled us to differentiate between invasive and non-invasive upper tract urothelial carcinoma. The method is of particular interest in diagnostic work-up of patients with upper tract urothelial carcinoma as previous findings indicate that volumetric imaging of vascular patterns could be used to differentiate superficial and invasive urothelial carcinoma, irrespective of if the tumor sample was deep or superficial. However, further and more extensive studies are required before this method can be applied clinically.

© 2019, Japan Society of Clinical Oncology. Background: The later-line treatment of metastatic renal cell carcinoma (mRCC) has been drastically changing by the development of immune-oncology drugs and molecular targeted treatment in recent years. Although the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model is useful for second-line setting, this model has the problem that over 50% patients are classified as intermediate risk group. The aim of this study is to evaluate whether the serum C-reactive protein (CRP) levels prior to second-line treatment could divide intermediate risk group patients. Methods: We retrospectively reviewed 82 consequent intermediate-risk mRCC patients who received second-line molecular targeted therapy. We classified patients who had serum CRP higher than 0.5 mg/dl in elevated CRP group because the median baseline serum CRP level before second-line treatment was 0.51 mg/dl. We assessed the prognostic impact of serum CRP levels prior to second-line treatment initiation to predict overall survival (OS). Results: Thirty-three out of 82 (40%) patients demonstrated elevated baseline CRP levels. The median OS of elevated and non-elevated CRP group was 11.5 (95% CI 5.4–17.5) and 29.4 (95% CI 25.5–33.5) months, respectively (p = 0.001). The serum CRP elevation could predict prognosis in intermediate risk patients treated with second-line treatment (HR 2.5, 95% CI 1.4–4.2, p = 0.001). Conclusions: The serum CRP levels after first-line treatment termination could divide intermediate risk group mRCC patients into two prognostic subgroups in second-line targeted treatment setting.

© The Author(s) 2019. Published by Oxford University Press. All rights reserved. Background: International Metastatic Renal Cell Carcinoma Database Consortium model predicts the outcomes of metastatic renal cell carcinoma stratified into favorable, intermediate, and poor risk groups (FG, IG, and PG, respectively), with approximately 50% of patients being classified as IG. We aimed to generate better risk model based on the sub-classification of IG. Methods: We analyzed records of 213 consecutive patients receiving molecular targeted therapy. Age, gender, histology, type of initial molecular targeted therapy, serum laboratory data, previous nephrectomy and immunotherapy, and metastatic sites were used for IG sub-stratification. Modified and original models were compared using a concordance correlation coefficient analysis. Results: Median follow-up was 17.8 months. Serum albumin, serum C-reactive protein, and bone metastases were independent predictors of overall survival (OS) in IG. IG was sub-classified into low-, middle-, and high-risk IG according to the number of predictors. The following modified model was developed: modified FG (FG & low-risk IG), modified IG (middle-risk IG), and modified PG (PG & high-risk IG). Concordance indices for original and modified models were 0.68 and 0.73, respectively (P < 0.001). OS was significantly longer in modified PG treated with mammalian target of rapamycin inhibitors as second-line therapy than with tyrosine kinase inhibitors, whereas this was not observed in the original model. Conclusions: We successfully developed modified IMDC model using a two-step process: the original IMDC plus an IG sub-stratification, and demonstrated that it predicts outcomes more accurately than original model.