Publications by authors named "Yoshiyuki Matsui"

114 Publications

Prognostic implication of staging of seminal vesicle invasion in patients with prostatic adenocarcinoma after prostatectomy.

Int J Urol 2021 Jul 21. Epub 2021 Jul 21.

Department of, Pathology, National Cancer Center Hospital, Tokyo, Japan.

Objectives: To evaluate whether the extent of seminal vesicle invasion of prostatic adenocarcinoma can stratify the risk of biochemical recurrence after radical prostatectomy.

Methods: We carried out radical prostatectomy for 1309 patients with prostatic adenocarcinoma between 2006 and 2019; 135 (10.3%) patients had seminal vesicle invasion. After excluding patients with neo-/adjuvant therapy, we reviewed 105 patients. We analyzed the correlation of the extent of seminal vesicle invasion and biochemical recurrence-free survival after prostatectomy and adjusted by various clinicopathological factors in multivariate analyses. Seminal vesicle invasion was stratified into three groups; the proximal part from the base was defined as level 1, followed by level 2 and the distal part as level 3.

Results: Among the 105 patients, 30 (29%), 54 (51%) and 21 patients (20%) had seminal vesicle invasion at levels 1, 2 and 3, respectively. Median times to biochemical recurrence were 110, 67 and 12 months in patients with levels 1, 2 and 3, respectively (P = 0.002). The extent of seminal vesicle invasion was the independent risk factor for biochemical recurrence in univariate (level 3 vs 1, P = 0.001; level 3 vs 2, P = 0.015) and multivariate analyses (level 3 vs 1, P = 0.025; level 3 vs 2, P = 0.030).

Conclusions: The extent of seminal vesicle invasion might be a significant predictor of biochemical recurrence in prostate cancer patients undergoing radical prostatectomy.
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http://dx.doi.org/10.1111/iju.14643DOI Listing
July 2021

Impact of histological variants on outcomes in patients with urothelial carcinoma treated with pembrolizumab: a propensity score matching analysis.

BJU Int 2021 Jun 10. Epub 2021 Jun 10.

Department of Urology, University of Toyama, Toyama, Japan.

Objectives: To assess the impact of histological variants on survival and response to treatment with pembrolizumab in patients with chemo-resistant urothelial carcinoma (UC).

Patients And Methods: The medical records of 755 patients with advanced UC who received pembrolizumab were reviewed retrospectively. Patients were classified into pure UC (PUC) and each variant. Best overall response (BOR) and overall survival (OS) were compared between the groups using a propensity score matching (PSM).

Results: Overall, 147 (19.5%) patients harboured any histological variant UC (VUC). After PSM, there were no significant differences in the objective response rate (ORR, 24.5% vs 17.3%, P = 0.098) or disease control rate (DCR, 36.7% vs 30.2%, P = 0.195) when comparing patients with any VUC and PUC. Furthermore, any VUC, as compared with PUC, was associated with a similar risk of death (hazard ratio [HR] 0.90, 95% confidence interval [CI] 0.68-1.20; P = 0.482). Squamous VUC, which was the most frequent variant in the cohort, had a comparable ORR, DCR and OS as compared with PUC or non-squamous VUC. The patients with sarcomatoid VUC (n = 19) had significantly better ORR (36.8%, P = 0.031), DCR (52.6%, P = 0.032), and OS (HR 0.37, 95% CI 0.15-0.90; P = 0.023) compared to patients with PUC.

Conclusions: The presence of variant histology did not seem to affect BOR or OS after pembrolizumab administration in patients with chemo-resistant UC. The patients with sarcomatoid VUC achieved favourable responses and survival rates compared to PUC.
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http://dx.doi.org/10.1111/bju.15510DOI Listing
June 2021

Treatment results of radiotherapy to both the prostate and metastatic sites in patients with bone metastatic prostate cancer.

J Radiat Res 2021 May;62(3):511-516

Department of Radiation Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.

Although systemic therapy is the standard treatment for metastatic prostate cancer, a randomized controlled trial showed radiotherapy to the prostate improved overall survival of metastatic prostate cancer patients with the low metastatic burden. Additionally, a randomized phase II trial showed that metastasis-directed therapy for oligo-recurrent prostate cancer improved androgen-deprivation therapy (ADT)-free survival. Therefore, administering radiotherapy to both prostate and metastatic regions might result in better outcomes. Thus, we report the treatment results of radiotherapy to both prostate and metastatic regions. Our institutional database was searched for patients who received radiotherapy to the prostate and metastatic regions. We summarized patient characteristics and treatment efficacy and performed statistical analysis to find possible prognostic factors. A total of 35 patients were included in this study. The median age was 66 years, and the median initial prostate-specific antigen (PSA) level was 32 ng/ml. The Gleason score was 7 in 10 patients, 8 in 13 patients, and 9 in 12 patients. The median radiotherapy dose was 72 Gy to the prostate and 50 Gy to the metastatic bone region. The 8-year overall survival, cause-specific survival, progression-free survival, and freedom from biochemical failure rate were 81, 85, 53, and 57%. Among the 35 patients, 12 were disease-free even after ADT was discontinued. In selected patients with metastatic prostate cancer, ADT and radiotherapy to the prostate and metastatic sites were effective. Patients with good response to ADT may benefit from radiotherapy to both prostate and metastatic regions.
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http://dx.doi.org/10.1093/jrr/rraa056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127693PMC
May 2021

Non-maintenance intravesical Bacillus Calmette-Guérin induction therapy with eight doses in patients with high- or highest-risk non-muscle invasive bladder cancer: a retrospective non-randomized comparative study.

BMC Cancer 2021 Mar 11;21(1):266. Epub 2021 Mar 11.

Department of Urology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.

Background: To explore possible solutions to overcome chronic Bacillus Calmette-Guérin (BCG) shortage affecting seriously the management of non-muscle invasive bladder cancer (NMIBC) in Europe and throughout the world, we investigated whether non-maintenance eight-dose induction BCG (iBCG) was comparable to six-dose iBCG plus maintenance BCG (mBCG).

Methods: This observational study evaluated 2669 patients with high- or highest-risk NMIBC who treated with iBCG with or without mBCG during 2000-2019. The patients were classified into five groups according to treatment pattern: 874 (33%) received non-maintenance six-dose iBCG (Group A), 405 (15%) received six-dose iBCG plus mBCG (Group B), 1189 (44%) received non-maintenance seven-/eight-dose iBCG (Group C), 60 (2.2%) received seven-/eight-dose iBCG plus mBCG, and 141 (5.3%) received only ≤5-dose iBCG. Recurrence-free survival (RFS), progression-free survival, and cancer-specific survival were estimated and compared using Kaplan-Meier analysis and the log-rank test, respectively. Propensity score-based one-to-one matching was performed using a multivariable logistic regression model based on covariates to obtain balanced groups. To eliminate possible immortal bias, 6-, 12-, 18-, and 24-month conditional landmark analyses of RFS were performed.

Results: RFS comparison confirmed that mBCG yielded significant benefit following six-dose iBCG (Group B) in recurrence risk reduction compared to iBCG alone (groups A and C) before (P < 0.001 and P = 0.0016, respectively) and after propensity score matching (P = 0.001 and P = 0.0074, respectively). Propensity score-matched sequential landmark analyses revealed no significant differences between groups B and C at 12, 18, and 24 months, whereas landmark analyses at 6 and 12 months showed a benefit of mBCG following six-dose iBCG compared to non-maintenance six-dose iBCG (P = 0.0055 and P = 0.032, respectively). There were no significant differences in the risks of progression and cancer-specific death in all comparisons of the matched cohorts.

Conclusions: Although non-maintenance eight-dose iBCG was inferior to six-dose iBCG plus mBCG, the former might be an alternative remedy in the BCG shortage era. To overcome this challenge, further investigation is warranted to confirm the real clinical value of non-maintenance eight-dose iBCG.
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http://dx.doi.org/10.1186/s12885-021-07966-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948348PMC
March 2021

The use of hyperbaric oxygen to treat actinic rectal fistula after SpaceOAR use and radiotherapy for prostate cancer: a case report.

BMC Urol 2020 Dec 14;20(1):196. Epub 2020 Dec 14.

Department of Radiation Therapy, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo, Japan.

Background: In definitive radiation therapy for prostate cancer, the SpaceOAR® System, a hydrogel spacer, is widely used to decrease the irradiated dose and toxicity of rectum. On the other hand, periprostatic abscesses formation and rectal perforation are known as rare adverse effects of SpaceOAR. Nevertheless, there is a lack of reports clarifying the association between aggravation of abscesses and radiation therapy, and hyperbaric oxygen therapy (HBOT) is effective for a peri-SpaceOAR abscess and rectal perforation.

Case Presentation: We report a case of a 78-year-old high-risk prostate cancer patient. After SpaceOAR insertion into the correct space, he started to receive external beam radiation therapy (EBRT). He developed a fever, perineal pain and frequent urination after the completion of EBRT, and the magnetic resonance imaging (MRI) revealed a peri-SpaceOAR abscess. Scheduled brachytherapy was postponed, administration of antibiotics and opioid via intravenous drip was commenced, and transperineal drainage was performed. After the alleviation of the abscess, additional EBRT instead of brachytherapy was performed with MRI-guided radiation therapy (MRgRT). On the last day of the MRgRT, perineal pain reoccurred, and MRI and colonoscopy detected the rectal perforation. He received an intravenous antibiotics drip and HBOT, and fully recovered from the rectal perforation.

Conclusions: Our report indicates that EBRT can lead to a severe rectum complication by causing inflammation for patients with a peri-SpaceOAR abscess. Furthermore, HBOT was effective for the peri-SpaceOAR abscess and rectal perforation associated with EBRT.
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http://dx.doi.org/10.1186/s12894-020-00767-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737272PMC
December 2020

Risk stratification for the prognosis of patients with chemoresistant urothelial cancer treated with pembrolizumab.

Cancer Sci 2021 Feb 21;112(2):760-773. Epub 2020 Dec 21.

Department of Urology, University of Tsukuba, Tsukuba, Japan.

The use of immune checkpoint inhibitors to treat urothelial carcinoma (UC) is increasing rapidly without clear guidance for validated risk stratification. This multicenter retrospective study collected clinicopathological information on 463 patients, and 11 predefined variables were analyzed to develop a multivariate model predicting overall survival (OS). The model was validated using an independent dataset of 292 patients. Patient characteristics and outcomes were well balanced between the discovery and validation cohorts, which had median OS times of 10.2 and 12.5 mo, respectively. The final validated multivariate model was defined by risk scores based on the hazard ratios (HRs) of independent prognostic factors including performance status, site of metastasis, hemoglobin levels, and the neutrophil-to-lymphocyte ratio. The median OS times (95% confidence intervals [CIs]) for the low-, intermediate-, and high-risk groups (discovery cohort) were not yet reached (NYR) (NYR-19.1), 6.8 mo (5.8-8.9), and 2.3 mo (1.2-2.6), respectively. The HRs (95% CI) for OS in the low- and intermediate-risk groups vs the high-risk group were 0.07 (0.04-0.11) and 0.23 (0.15-0.37), respectively. The objective response rates for in the low-, intermediate-, and high-risk groups were 48.3%, 28.8%, and 10.5%, respectively. These differential outcomes were well reproduced in the validation cohort and in patients who received pembrolizumab after perioperative or first-line chemotherapy (N = 584). In conclusion, the present study developed and validated a simple prognostic model predicting the oncological outcomes of pembrolizumab-treated patients with chemoresistant UC. The model provides useful information for external validation, patient counseling, and clinical trial design.
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http://dx.doi.org/10.1111/cas.14762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893997PMC
February 2021

Current Multimodality Treatments Against Brain Metastases from Renal Cell Carcinoma.

Authors:
Yoshiyuki Matsui

Cancers (Basel) 2020 Oct 6;12(10). Epub 2020 Oct 6.

The Department of Urology, National Cancer Center Hospital, Tokyo 104-0045, Japan.

In patients with renal cell carcinoma, brain metastasis is generally one of the poor prognostic factors. However, the recent introduction of molecular target therapy and immune checkpoint inhibitor has remarkably advanced the systemic treatment of metastatic renal cell carcinoma and prolonged the patients' survival. The pivotal clinical trials of those agents usually excluded patients with brain metastasis. The incidence of brain metastasis has been increasing in the actual clinical setting because of longer control of extra-cranial disease. Brain metastasis subgroup data from the prospective and retrospective series have been gradually accumulated about the risk classification of brain metastasis and the efficacy and safety of those new agents for brain metastasis. While the local treatment against brain metastasis includes neurosurgery, stereotactic radiosurgery, and conventional whole brain radiation therapy, the technology of stereotactic radiosurgery has been especially advanced, and the combination with systemic therapy such as molecular target therapy and immune checkpoint inhibitor is considered promising. This review summarizes recent progression of multimodality treatment of brain metastasis of renal cell carcinoma from literature data and explores the future direction of the treatment.
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http://dx.doi.org/10.3390/cancers12102875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600559PMC
October 2020

Clinical outcomes of definitive whole pelvic radiotherapy for clinical lymph node metastatic prostate cancer.

Cancer Med 2020 09 4;9(18):6629-6637. Epub 2020 Aug 4.

Department of Radiation Oncology, National Cancer Center Hospital, Tokyo, Japan.

Background: In this study, we aim to present the clinical outcomes of radiotherapy (RT) in clinical pelvic lymph node-positive prostate cancer (cN1) patients. We also analyze the prognostic factors with focus on RT dose escalation to metastatic lymph nodes (LN).

Methods: We retrospectively analyzed the data from cN1 patients who were treated with definitive RT and androgen deprivation therapy (ADT) between June 2004 and February 2016. All patients received localized irradiation to the prostate region and whole pelvis irradiation. Some patients received intensity-modulated radiation therapy with RT dose escalation to metastatic LN. Univariate analyses using log-rank test were performed to find prognostic factors between patient subgroups.

Results: Fifty-one consecutive patients were identified. The median follow-up period for all patients was 88 (range 20-157) months. Primary Gleason pattern and LN RT dose were statistically significant prognostic factors for relapse-free survival (RFS) and distant metastasis-free survival (DMFS). Especially, RT dose escalation (60 Gy or more) to metastatic LN significantly improved RFS and DMFS compared with standard dose RT (4-year RFS 90.6% vs 82.1%, 7-year RFS 90.6% vs 58.0%, P = .015; 4-year DMFS 90.6% vs 82.1%, 7-year DMFS 90.6% vs 62.8%, P = .023). The following factors were all statistically significant for biochemical relapse-free survival (BRFS): T stage, LN RT dose, local RT dose, and ADT duration period. Any significantly different toxicity was not seen for each LN or local RT dose except for the incident rate of grade 2 or more acute urinary retention, which was significantly higher in the higher LN RT dose (60 Gy or more) group by the Chi-square test.

Conclusions: RT dose escalation to metastatic LN in cN1 patients improves BRFS, RFS, and DMFS at 4 and 7 years, without increasing severe adverse events.
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http://dx.doi.org/10.1002/cam4.2985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7520291PMC
September 2020

Three-dimensional simulation analysis of microdissection testicular sperm extraction for patients with non-obstructive azoospermia.

Andrology 2020 09 18;8(5):1214-1221. Epub 2020 May 18.

Department of Urology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Background: Microdissection testicular sperm extraction (microTESE) is considered the gold standard method of sperm retrieval from patients with non-obstructive azoospermia (NOA). For careful and thorough examination of seminiferous tubules during microTESE, maximizing surface area of the testicles which we are able to search is essential.

Objectives: To develop a systematic procedure for microTESE to maximize surface area and to achieve high sperm retrieval rate (SRR) in microTESE.

Materials And Methods: We simulated microTESE using three-dimensional (3D) simulation model and analyzed mathematically the sum of the surface area in various methods. The best method obtained from this simulation model was applied to 102 patients with NOA from 2014 to 2018. These new clinical results were compared with those of 56 patients who underwent a previous method of microTESE from 2011 to 2014.

Results: The mathematical 3D simulation model of microTESE indicated that a longitudinal incision on the tunica albuginea and following transverse slicing incisions of testicular parenchyma maximized the surface area coverage. Forty-six (45%) out of 102 patients who underwent microTESE with the new method had successful retrieval of testicular spermatozoa compared with 16 (29%) of 56 patients with the previous method of microTESE (P = .04).

Discussion: Transverse resections of parenchyma in our method run parallel to the courses of intratesticular arteries and do not interfere with the blood supply. The small amount of extracted seminiferous tubules was equivalent to that of the previous method, and no patients exhibited post-operative symptoms of androgen deficiency in our study. As for post-operative pain, our new method was comparable with the previous method. Although our study needs a longer follow-up, there will be limited effects on testicular functions.

Conclusion: Longitudinal incision on the tunica albuginea and following transverse slicing incisions in the testicular parenchyma maximized the surface area and improved the SRR of microTESE.
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http://dx.doi.org/10.1111/andr.12812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7522677PMC
September 2020

Barriers for sperm cryopreservation in advanced germ cell tumor patients: a 20-year experience.

Int J Clin Oncol 2020 May 1;25(5):906-911. Epub 2020 Jan 1.

Department of Urology, Kyoto University Hospital, 54 Shogoin Kawaharacho, Sakyo-ku, Kyoto, 6068507, Japan.

Background: This study aimed to investigate barriers to sperm cryopreservation for patients with advanced germ cell tumors.

Methods: We reviewed data collected from patients who underwent chemotherapy for advanced germ cell tumors in our institutions from 1996 to 2016. We divided sperm cryopreservation procedures into three steps: offering information about sperm cryopreservation, patients' decision making and sperm collection, and investigating the barriers in each step.

Results: Of the 91 patients, 43 (47%) successfully completed sperm cryopreservation. Thirty (33%) patients were not offered information about sperm cryopreservation from the doctors. Nine patients (9.9%) were offered but declined preservation. Nine patients (9.9%) were not able to provide sperm because of azoospermia (5) and anejaculation (4). Among 43 patients who successfully provided sperm, 10 (23%) had their cryopreserved sperm used for 21 cycles of in vitro fertilization. Ten pregnancies and 7 fatherhoods were achieved. Thirteen patients (30%) had their cryopreserved sperm discarded without use, whereas 20 (47%) continued preserving their sperm for a median 12.5 years.

Conclusions: Not only offering proper information about sperm cryopreservation, but also shared decision making prior to chemotherapy, and considering fertility preservation before orchiectomy are imperative. The rate of use of preserved sperm was relatively high, but decision making for sperm disposal should also be supported.
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http://dx.doi.org/10.1007/s10147-019-01607-7DOI Listing
May 2020

Durable response after cessation of anti-programmed death 1 therapy in four melanoma patients.

J Dermatol 2019 Dec 3;46(12):e461-e462. Epub 2019 Oct 3.

Department of Dermatology, Sapporo Medical University School of Medicine, Sapporo, Japan.

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http://dx.doi.org/10.1111/1346-8138.15095DOI Listing
December 2019

Add-on effects of tadalafil in tamsulosin-treated patients with small benign prostatic enlargement: A randomized, placebo-controlled, double-blind, crossover study.

Neurourol Urodyn 2020 01 2;39(1):237-242. Epub 2019 Oct 2.

Department of Urology, Kyoto University Hospital, Kyoto, Japan.

Aim: To assess the add-on effects of tadalafil in patients with a relatively small benign prostatic enlargement (BPE) treated with tamsulosin.

Methods: From September 2014 to July 2018, we prospectively studied patients (aged 50 years or more) attending our hospital who had received tamsulosin for small BPE (20-40 mL) for 4 weeks at least and still had residual lower urinary tract symptoms (LUTS) with total International Prostate Symptom Scores (IPSS) of at least 8 and IPSS-quality of life scores at least 3. We randomized eligible patients into two groups: one of which received tadalafil 5 mg once daily for 6 weeks, followed by placebo for 6 weeks, and the other of which received placebo followed by tadalafil in the same manner. The patients were reviewed at our outpatient clinic after 2, 6, 8, and 12 weeks.

Results: There were 13 patients in the tadalafil-placebo and 13 in the placebo-tadalafil group. Their median ages (range) were 70 (65-85) and 73 (50-80) years, prostatic volumes (median) 30.0 (22.0-39.7) and 32.0 (20.1-39.5) mL, and total IPSS (median) 17 (10-27) and 16 (10-24), respectively. The primary endpoints, namely mean changes of total IPSS from baseline, were 1.85 on placebo and -3.42 on tadalafil; this difference is statistically significant (difference: -1.57; 95% confidence interval: -3.00, -0.69; P = .032). We encountered no adverse effects.

Conclusions: Add-on of tadalafil for symptomatic patients with small BPE treated with tamsulosin appears to be effective and safe.
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http://dx.doi.org/10.1002/nau.24175DOI Listing
January 2020

Efficacy of Immediate Postoperative Instillation of Chemotherapy for Primary Non-Muscle-Invasive Bladder Cancer in Real-World Clinical Practice.

Clin Genitourin Cancer 2019 10 30;17(5):e1003-e1010. Epub 2019 May 30.

Department of Urology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Background: Non-muscle-invasive bladder cancer (NMIBC) can be treated using transurethral resection (TUR), but high incidence of intravesical recurrence remains a clinical challenge. Single immediate postoperative instillation of chemotherapy (IPIOC) is controversial for NMIBC patients with intermediate recurrence risk. The aim of the present study was to report the efficacy and toxicity of IPIOC, particularly in intermediate-risk NMIBC patients, in the real-world setting.

Patients And Methods: We retrospectively analyzed 363 consecutive patients with primary NMIBC who underwent radical TUR at Kyoto University Hospital between 2007 and 2016.

Results: In low-risk patients, recurrence-free survival (RFS) was significantly better for IPIOC than non-IPIOC (2-year RFS: 89.3% vs. 59.4%; P = .001). In intermediate-risk patients, IPIOC was associated with significantly longer RFS compared with non-IPIOC (2-year RFS: 85.5% vs. 58.2%; P = .011). IPIOC and bacillus Calmette-Guérin (BCG) were independent predictors for post-TUR recurrence (non-IPIOC vs. IPIOC: hazard ratio [HR], 2.33; 95% confidence interval [CI], 1.14-4.88; P = .02; non-BCG vs. BCG: HR, 2.22; P = .045, 95% CI, 1.02-5.30). In the high-risk group, only BCG was an independent prognostic factor of recurrence in a multivariate Cox proportional hazards model (HR, 2.55; P = .006, 95% CI, 1.32-4.87). There were no significant differences between the BCG-only group and the IPIOC with BCG group in Grade 3 or more local (16 patients [21%] vs. 21 patients [24%]; P = .61) or systemic (3 patients [4%] vs. 6 patients [7%]; P = .40) toxicity rates.

Conclusion: Our study showed the efficacy of IPIOC for the prevention of intravesical recurrence in primary intermediate-risk NMIBC patients regardless of BCG therapy.
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http://dx.doi.org/10.1016/j.clgc.2019.05.028DOI Listing
October 2019

TP53 codon 72 polymorphism is associated with FGFR3 and RAS mutation in non-muscle-invasive bladder cancer.

PLoS One 2019 1;14(8):e0220173. Epub 2019 Aug 1.

Department of Urology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.

Objective: TP53, a well-known tumor-suppressor gene in bladder carcinogenesis, has a functional single-nucleotide polymorphism on codon 72. The aim of this study was to elucidate the association between TP53 codon 72 polymorphism and somatic mutations in bladder cancer.

Material And Methods: Germline TP53 codon 72 polymorphism and somatic mutations of 50 cancer-associated genes were analyzed in 103 bladder cancer patients (59 non-muscle-invasive and 44 muscle-invasive), using Taqman genotyping assay and target sequencing, respectively. The expression of FGF-FGFR signaling pathway genes was analyzed by RNA sequencing of frozen tissue.

Results: The allele frequency of TP53 codon 72 in our cohort was 37, 42, and 21% for Arg/Arg, Arg/Pro, and Pro/Pro, respectively. Interestingly, the prevalence of FGFR3 mutation was higher in patients with the Arg allele, whereas that of the RAS mutation was higher in patients without the Arg allele. The same association was seen in non-muscle-invasive bladder cancer (NMIBC) patients and no differences were observed in muscle-invasive bladder cancer patients. In NMIBC, FGFR1 expression was higher in patients without the Arg allele and FGFR3 expression was higher in patients with the Arg allele.

Conclusion: The germline TP53 codon 72 polymorphism was associated with mutations of FGFR3 or RAS and expression of FGFR1 and FGFR3 in NMIBC. These findings provide new insight into the molecular mechanisms underlying the influence of the genetic background on carcinogenesis in bladder cancer.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0220173PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6675066PMC
March 2020

Inhibition of GLI2 with antisense-oligonucleotides: A potential therapy for the treatment of bladder cancer.

J Cell Physiol 2019 11 22;234(11):20634-20647. Epub 2019 Apr 22.

Department of Urologic Sciences, Vancouver Prostate Centre, University of British Columbia, Vancouver, Canada.

The sonic hedgehog (SHH) signaling pathway plays an integral role in the maintenance and progression of bladder cancer (BCa) and SHH inhibition may be an efficacious strategy for BCa treatment. We assessed an in-house human BCa tissue microarray and found that the SHH transcription factors, GLI1 and GLI2, were increased in disease progression. A panel of BCa cell lines show that two invasive lines, UM-UC-3 and 253J-BV, both express these transcription factors but UM-UC-3 produces more SHH ligand and is less responsive in viability to pathway stimulation by recombinant human SHH or smoothened agonist, and less responsive to inhibitors including the smoothened inhibitors cyclopamine and SANT-1. In contrast, 253J-BV was highly responsive to these manipulations. We utilized a GLI1 and GLI2 antisense oligonucleotide (ASO) to bypass pathway mechanics and target the transcription factors directly. UM-UC-3 decreased in viability due to both ASOs but 253J-BV was only affected by GLI2 ASO. We utilized the murine intravesical orthotopic human BCa (mio-hBC) model for the establishment of noninvasive BCa and treated tumors with GLI2 ASO. Tumor size, growth rate, and GLI2 messenger RNA and protein expression were decreased. These results suggest that GLI2 ASO may be a promising new targeted therapy for BCa.
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http://dx.doi.org/10.1002/jcp.28669DOI Listing
November 2019

Giant multilocular prostatic cystadenoma.

World J Surg Oncol 2019 Feb 26;17(1):42. Epub 2019 Feb 26.

Department of Colorectal Surgery, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 1040045, Japan.

Background: The giant multilocular prostatic cystadenoma is a very rare benign tumor of the prostate gland. It is composed of predominantly cystic enlarged prostatic glands in a fibrous stroma and spreads extensively into the pelvis. Because of the large size at the time of diagnosis, it is not always possible to determine the exact point of origin for these multilocular cystic neoplasms. Thus, diagnosis before histological examination of a surgical specimen is often difficult. Here, we present a case involving one of the largest giant multilocular prostatic cystadenomas reported in the literature and discuss preoperative diagnoses and appropriate surgical approaches for this rare retroperitoneal tumor.

Case Presentation: A 50-year-old man presented with a 2-year history of abdominal distension and lower urinary symptoms. Enhanced CT showed a large retroperitoneal mass with multiple septations in the pelvis and lower abdomen, measuring 30 cm in size, surrounding the rectum and displacing the bladder, prostate, and seminal vesicle to the right anterior side. MRI showed multiple cysts with a simple fluid appearance on T2-weighted images and enhanced solid components on gadolinium-enhanced fat-saturated T1-weighted images, suggesting the retroperitoneal mass as leiomyoma with cystic degeneration or perivascular epithelioid cell tumor. Biopsy of the mass showed a spindle cell tumor with focal smooth muscle differentiation. Differential diagnosis comprising leiomyoma, low-grade leiomyosarcoma, and perivascular epithelioid cell tumor was made. Complete resection of the tumor with low anterior resection of the rectum was performed. The tumor was solid with multilocular cavities containing blackish-brown fluid and measured 33 × 23 × 10 cm. Histologically, the tumor was composed of variously sized dilated glandular structures lined by prostatic epithelia surrounded by fibromuscular stroma. The prostatic nature of the lesions was confirmed by immunohistochemical staining of the epithelium for prostate-specific antigen. Thus, pathological diagnosis was a giant multilocular prostatic cystadenoma.

Conclusions: We present our experiences with one of the largest giant multilocular prostatic cystadenomas. When a retroperitoneal huge lesion with locular cavities fills the pelvis in a male patient, the possibility of giant multilocular prostatic cystadenoma should be considered before planning for retroperitoneal tumor treatment.
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http://dx.doi.org/10.1186/s12957-019-1579-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391754PMC
February 2019

Docetaxel therapy for classic Kaposi's sarcoma.

Asia Pac J Clin Oncol 2019 06 21;15(3):181-182. Epub 2019 Feb 21.

Department of Dermatology, Sapporo Medical University School of Medicine, Sapporo, Japan.

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http://dx.doi.org/10.1111/ajco.13139DOI Listing
June 2019

Efficacy of combined radiotherapy and anti-programmed death 1 therapy in acral and mucosal melanoma.

J Dermatol 2019 Apr 13;46(4):328-333. Epub 2019 Feb 13.

Department of Dermatology, Sapporo Medical University School of Medicine, Sapporo, Japan.

Some studies showed that clinical response to immune check point inhibitors is lower in acral and mucosal melanoma than in cutaneous melanoma. Although the synergistic effect of radiotherapy (RT) and ipilimumab has been reported in patients with brain metastasis, the efficacy of combined RT and anti-programmed death 1 (PD-1) therapy for acral and mucosal melanoma is unclear. The present study aimed to evaluate the efficacy of combined RT and anti-PD-1 therapy for acral and mucosal melanoma. We retrospectively analyzed patients with acral or mucosal melanoma who were treated with anti-PD-1 and RT at Sapporo Medical University Hospital. In 10 patients (acral, 3; mucosal, 7), the response rate (RR) and the disease control rate (DCR) were 40% and 60%, respectively. As regards mucosal melanoma, four of the seven patients had achieved complete response + partial response, and three had progressive disease (RR = 57.1%). Meanwhile, two of the three patients with acral melanoma had stable disease and one had progressive disease (RR and DCR were 0% and 66.6%, respectively). Except for the patients treated with palliative RT for bone metastasis in the present study, the RR was 50% (4/8 patients), and the DCR was 75% (6/8 patients). Vitiligo developed after RT in five (50%) patients at a median duration of 2 months after RT. The clinical response and the high occurrence of vitiligo suggest that the combination of RT and anti-PD-1 therapy could be effective in some patients with mucosal melanoma.
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http://dx.doi.org/10.1111/1346-8138.14805DOI Listing
April 2019

Sperm cryopreservation: Clinical and fertility outcomes in male oncological patients with germ cell tumors or hematological disorders.

Reprod Med Biol 2018 Oct 30;17(4):500-503. Epub 2018 Sep 30.

Ichioka Urological Clinic Symphonia-Oike 1F, Higashinotoin-Nijo sagaru Kyoto Japan.

Purpose: There is insufficient understanding of the effects of malignant diseases themselves and chemotherapy on semen quality and final fertility outcomes. Here, the authors focused on the patients with malignant diseases who cryopreserved sperm pre- or post-chemotherapy for future fertility, and revealed how clinical settings can affect semen quality and final outcomes.

Methods: The authors reviewed the records of 257 patients with malignant diseases who cryopreserved sperm. Among 257 cases, 113 men with germ cell tumors (GCTs) and 111 men with hematological disorders (HDs) were included in this study. Twenty-five patients who achieved successful outcomes using cryopreserved sperm were also analyzed.

Results: In the men with GCTs and HDs, respectively, differences were observed in age (28 vs 27 years), sperm concentration (32.6 vs 46.1 million/mL,  < 0.05), motility (42.2% vs 41.0%), and the rate of cryopreservation before chemotherapy (90% vs 59%,  < 0.0001). For successful pregnancies and deliveries, age at cryopreservation (30.0 vs 35.3 years,  < 0.05) and disease type (12/16 vs 3/9,  < 0.05) were significant factors.

Conclusions: Compared to patients with GCTs, those with HDs have a lower pregnancy and delivery rate, even though semen quality is higher. Disease type and age at cryopreservation are significant factors for successful outcomes.
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http://dx.doi.org/10.1002/rmb2.12246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6194308PMC
October 2018

Nodule Size After Chemotherapy and Primary-Tumor Teratoma Components Predict Malignancy of Residual Pulmonary Nodules in Metastatic Nonseminomatous Germ Cell Tumor.

Ann Surg Oncol 2018 Nov 6;25(12):3668-3675. Epub 2018 Sep 6.

Urology Division, National Cancer Center Hospital, Tokyo, Japan.

Background: The treatment goal for visceral metastatic nonseminomatous germ cell tumor (NSGCT) is to remove any residual teratoma or viable NSGCT after chemotherapy. However, this provides no therapeutic benefit to patients whose metastases necrotize on their own. This study therefore analyzed NSGCTs with pulmonary metastases to determine preoperative factors that predict necrosis and could help identify patients who might be treated with monitoring rather than surgery.

Methods: The study retrospectively analyzed 41 patients (135 metastatic pulmonary nodules) treated from 1997 to 2016 for NSGCT who showed tumor marker normalization after chemotherapy. Relationships between clinicopathologic characteristics and necrosis in resected pulmonary specimens were analyzed.

Results: Receiver operating characteristic analysis of the pulmonary nodules showed 9 mm to be the optimal cutoff length for predicting necrosis. The logistic regression model showed that absence of teratoma components in the primary tumor and all pulmonary nodules shorter than 10 mm after chemotherapy both were independent predictors of pathologic necrosis in pulmonary specimens. No patients experienced late recurrence (i.e., > 2 years afterward).

Conclusions: The presence of teratoma components in primary tumors and nodular size after chemotherapy predict the pathology of residual pulmonary nodules. Patients whose residual nodules all are shorter than 10 mm and who have no primary-tumor teratoma components might be candidates for careful monitoring before pulmonary resection.
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http://dx.doi.org/10.1245/s10434-018-6742-9DOI Listing
November 2018

Tolerability and Efficacy of Neoadjuvant Chemotherapy with a Tri-Weekly Interval Methotrexate, Doxorubicin, Vinblastine, and Cisplatin Regimen for Patients with Locally Advanced Bladder Cancer.

Case Rep Oncol 2018 May-Aug;11(2):450-460. Epub 2018 Jul 5.

Department of Pharmacy, National Cancer Center Hospital, Tokyo, Japan.

Objective: Compared with standard treatment, a modified tri-weekly MVAC (methotrexate, doxorubicin, vinblastine, and cisplatin) treatment regimen with a high cisplatin dose intensity shows good efficacy and lower toxicity. Thus, we retrospectively investigated the tolerability and efficacy of a modified tri-weekly MVAC neoadjuvant regimen.

Methods: We analyzed 25 patients with locally advanced bladder cancer medicated by a modified tri-weekly MVAC neoadjuvant regimen that omits treatment on days 15 and 22. The efficacy and tolerability were assessed retrospectively.

Results: The numbers of patients in clinical stages 2, 3, and 4 were 13 (52.0%), 1 (4.0%), and 11 (44.0%), respectively. Surgery could be performed on all patients. Five patients (20.0%) had no cancer remaining in their surgical specimens. Remaining non-muscle-invasive cancer without metastasis was observed in 7 patients (28.0%), and the total downstaging rate was 44.0%. The 5-year overall and relapse-free survival rates were 79.0 and 75.0%, respectively. The overall relative dose intensity was 0.90. Serious hematologic toxicities rated grade 3 or greater were leukopenia in 6 patients (24.0%) and anemia in 1 patient (4.0%).

Conclusions: Sufficient efficacy and tolerability of a modified tri-weekly MVAC neoadjuvant regimen were suggested. Thus, tri-weekly modified MVAC may be an option for neoadjuvant chemotherapy of advanced bladder cancer.
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http://dx.doi.org/10.1159/000490458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6071437PMC
July 2018

[Clinical Utility of Upper Urinary Tract Reconstruction by Ileal-Ureter Substitution].

Hinyokika Kiyo 2018 Mar;64(3):87-94

The Department of Urology, Kyoto University Graduate School of Medicine.

We retrospectively reviewed the indications and outcomes of ileal-ureter substitution cases for complex ureteral reconstruction. We analyzed the patient clinical characteristics, outcomes, and complications of eight patients who had ileal ureter substitution surgery at Kyoto University Hospital between 2009 and 2016. The median patient age was 55.5 years (36-79), and the median follow up period was 25.5 months (7-85). Seven patients had unilateral ureteral obstruction (right:left=4:3), and one had bilateral ureteral obstruction. The etiologies of the ureteral defects were ureteral stricture due to non-urologic malignant tumorinvasion (n=2), benign ureteral stricture (n=2), anastomotic stricture after cystectomy (n=2), and iatrogenic ureteral injury (n=2). The mean length of operation time was 384.7 minutes (median 323 minutes, 242-397), and the mean hospital stay was 32.9 days (median 31 days, 19-41). Simple anastomosis of an untailored ileal segment to ureter and bladder was performed in 5 cases, bilateral ureteral anastomosis to a single ileal segment in one case, and in the remaining two cases, the ileal ureter was anastomosed to ileal conduit or neobladder. A nipple valve was used as the antireflux mechanism, in 2 cases but not in the remaining 6 cases. The outcome was favourable in all cases with no stricture and no requirement for further intervention. There was no significant deterioration of renal function in any patient, and no metabolic abnormality was detected. The ileal-ureter substitution appears to be a reasonable option, allowing nephron sparing in complex ureteral reconstruction cases.
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http://dx.doi.org/10.14989/ActaUrolJap_64_3_87DOI Listing
March 2018

Outcomes of active surveillance of clinical stage I non-seminomatous germ cell tumors: sub-analysis of the multi-institutional nationwide case series of the Japanese Urological Association.

Jpn J Clin Oncol 2018 Jun;48(6):565-569

Urology Division, National Cancer Center Hospital, Tokyo, Japan.

Objective: To evaluate the survival rate and risk factors of distant metastasis in stage I non-seminomatous germ cell tumor (NSGCT) cases without adjuvant treatments.

Methods: A national testicular cancer survey of cases newly diagnosed in 2005 and 2008 was conducted by the Japanese Urological Association in 2011. In 159 stage I NSGCT cases, 132 were followed by active surveillance after high orchiectomy. Their recurrence-free survival rate (RFS) was compared with 27 cases that received adjuvant treatments, and clinical and pathological parameters were explored to identify significant risk factors of recurrence.

Results: Within a median follow-up period of 30.3 months (range: 0.3-65.6 months), 16 (12.1%) of the 132 surveillance cases relapsed at 2.8-51.2 months after high orchiectomy (median: 8.35 months). The 2-year RFS rate was 90%. Eleven (68.8%) cases relapsed within 1 year, and five (31.3%) cases relapsed in 3 years or more. Half (50%) of the recurrences were detected by imaging studies alone, 37.5% by imaging combined with tumor markers, and 12.5% by tumor marker elevation alone. The only significant risk factor of recurrence was the existence of embryonal carcinoma elements in the primary testicular tumor (P = 0.0068). There was no significant difference in RFS between cases with active surveillance and adjuvant treatments.

Conclusions: The present report is the first large scale study of clinical stage I NSGCTs in Japan. Active surveillance appears to be an effective treatment option for patients with clinical stage I NSGCTs.
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http://dx.doi.org/10.1093/jjco/hyy051DOI Listing
June 2018

Monopolar vs. bipolar transurethral resection for non-muscle invasive bladder carcinoma: A post-hoc analysis from a randomized controlled trial.

Urol Oncol 2018 Jul 13;36(7):338.e1-338.e11. Epub 2018 Apr 13.

Department of Urology, Harasanshin Hospital, Fukuoka, Japan.

Purpose: Traditionally, transurethral resection of bladder tumors (TURB) is performed using monopolar technique. Bipolar resection has been postulated to reduce complications. In this study we compare safety and efficacy between monopolar TURB (mTURB) and bipolar TURB (bTURB) for patients with primary non-muscle invasive bladder cancer (NMIBC).

Materials And Methods: Data were obtained from an international multicenter randomized clinical trial that compared the use of white light cystoscopy with narrow band imaging-assisted TURB using the Olympus system between 2010 and 2014. Main outcomes of interest were operative time, perioperative, and postoperative complications, and 12-month recurrence-free survival.

Results: In total, 716 patients were treated for primary NMIBC with mTURB (310 patients) or bTURB (406 patients). The use of white light cystoscopy or narrow band imaging was equally distributed between the 2 resection techniques. Multilevel logistic and linear regression corrected for possible confounders showed no significant difference between mTURB and bTURB for postoperative complications (OR = 1.76, P = 0.180), postoperative bleeding (OR = 1.27, P = 0.722), and the combination of intra + postoperative bleeding (OR = 1.992, P = 0.108). Additionally, no significant difference was found between mTURB and bTURB concerning operative time (1.05min. longer for bTURB, P = 0.536), intraoperative bleeding requiring intervention (OR:1.38, P=0.809), incidence of obturator reflex (OR = 0.93, P = 0.854), and bladder perforation (OR = 3.05, P = 0.195). In total, 185 patients (25.8%) developed a recurrence (mTURB = 88, bTURB = 97). Recurrence-free survival at 12 months in the mTURB and bTURB group was 70% and 74% (P = 0.410), respectively.

Conclusion: Based on these results, bTURB is as safe and effective as mTURB in treatment of primary NMIBC. bTURB seems to have no evident advantages over mTURB with respect to operation time, perioperative and postoperative complication rates, and recurrence rates at 12 months.
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http://dx.doi.org/10.1016/j.urolonc.2018.03.015DOI Listing
July 2018

A comparison of nephrotoxicity between patients with a solitary-functioning kidney and those with bilateral-functioning kidneys in cisplatin-based chemotherapy for advanced urothelial carcinoma: a Japanese retrospective multi-institutional study.

BMC Cancer 2018 03 14;18(1):290. Epub 2018 Mar 14.

Department of Urology, Faculty of Medicine, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki, 305‑8575, Japan.

Background: To compare the prevalence of nephrotoxicity between patients with a solitary-functioning kidney versus those with bilateral-functioning kidneys during the administration of cisplatin-based chemotherapy for advanced urothelial carcinoma.

Methods: We retrospectively analyzed 244 advanced urothelial carcinoma patients treated with cisplatin-based chemotherapy between 2004 and 2010 at 17 institutes in Japan. The 24 h creatinine clearance, Cockcroft-Gault formula, and estimated glomerular filtration rate equation (eGFR), were compared before all chemotherapies. The urinary tract function status was determined based on the data of nephroureterectomy, hydronephrosis, and relief of upper urinary tract obstruction. A total of 244 patients were divided into four groups according to their urinary tract functioning status and eGFR results, including bilateral-functioning kidneys with pretreatment eGFR ≥60 mL/min/1.73 m group (n = 83, 34.0%); a solitary-functioning kidney with pretreatment eGFR ≥60 mL/min/1.73 m group (n = 36, 14.8%); bilateral-functioning kidneys with pretreatment eGFR < 60 mL/min/1.73 m group (n = 45, 18.4%); and a solitary-functioning kidney with pretreatment eGFR < 60 mL/min/1.73 m group (n = 80, 32.8%).

Results: The prevalence of nephrotoxicity with impaired eGFR of > 10% and 30% from baseline in the post-third-course of chemotherapy was significantly higher in patients with bilateral-functioning kidneys than in those with a solitary-functioning kidney, among patients with pretreatment eGFR < 60 mL/min/1.73 m (p = 0.023 and p = 0.026). During all courses of chemotherapy, the prevalence of nephrotoxicity with impaired eGFR of > 20% from baseline were significantly higher in patients with bilateral-functioning kidneys than those with a solitary-functioning kidney among patients with pretreatment eGFR < 60 mL/min/1.73 m (p = 0.034), whereas no significant difference was observed among patients with pretreatment eGFR ≥60 mL/min/1.73 m.

Conclusions: The results suggest that cisplatin-based chemotherapy may have more nephrotoxicity in patients with bilateral-functioning kidneys than in those with a solitary-functioning kidney.
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http://dx.doi.org/10.1186/s12885-018-4186-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5853031PMC
March 2018

Development of RNA-FISH Assay for Detection of Oncogenic FGFR3-TACC3 Fusion Genes in FFPE Samples.

PLoS One 2016 8;11(12):e0165109. Epub 2016 Dec 8.

Department of Urology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.

Introduction And Objectives: Oncogenic FGFR3-TACC3 fusions and FGFR3 mutations are target candidates for small molecule inhibitors in bladder cancer (BC). Because FGFR3 and TACC3 genes are located very closely on chromosome 4p16.3, detection of the fusion by DNA-FISH (fluorescent in situ hybridization) is not a feasible option. In this study, we developed a novel RNA-FISH assay using branched DNA probe to detect FGFR3-TACC3 fusions in formaldehyde-fixed paraffin-embedded (FFPE) human BC samples.

Materials And Methods: The RNA-FISH assay was developed and validated using a mouse xenograft model with human BC cell lines. Next, we assessed the consistency of the RNA-FISH assay using 104 human BC samples. In this study, primary BC tissues were stored as frozen and FFPE tissues. FGFR3-TACC3 fusions were independently detected in FFPE sections by the RNA-FISH assay and in frozen tissues by RT-PCR. We also analyzed the presence of FGFR3 mutations by targeted sequencing of genomic DNA extracted from deparaffinized FFPE sections.

Results: FGFR3-TACC3 fusion transcripts were identified by RNA-FISH and RT-PCR in mouse xenograft FFPE tissues using the human BC cell lines RT112 and RT4. These cell lines have been reported to be fusion-positive. Signals for FGFR3-TACC3 fusions by RNA-FISH were positive in 2/60 (3%) of non-muscle-invasive BC (NMIBC) and 2/44 (5%) muscle-invasive BC (MIBC) patients. The results of RT-PCR of all 104 patients were identical to those of RNA-FISH. FGFR3 mutations were detected in 27/60 (45%) NMIBC and 8/44 (18%) MIBC patients. Except for one NMIBC patient, FGFR3 mutation and FGFR3-TACC3 fusion were mutually exclusive.

Conclusions: We developed an RNA-FISH assay for detection of the FGFR3-TACC3 fusion in FFPE samples of human BC tissues. Screening for not only FGFR3 mutations, but also for FGFR3-TACC3 fusion transcripts has the potential to identify additional patients that can be treated with FGFR inhibitors.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0165109PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5145148PMC
July 2017

[Deceased Donor Kidney Transplantation from a Liver Transplantation Recipient].

Hinyokika Kiyo 2016 Oct;62(10):529-534

The Department of Urology, Kyoto University Hospital.

We report a 40-year-old man with end-stage renal disease due to IgA nephropathy who underwent deceased donor kidney transplantation. The donor was diagnosed to be brain-dead due to cerebral hemorrhage after her second liver transplantation for non-viral liver cirrhosis. Intraoperative 1-hour biopsy of the graft kidney revealed moderate global glomerular sclerosis (22%) and interstitial fibrosis (40%) consistent with underlying nephrosclerosis or calcineurin inhibitor nephrotoxicity. Although hemodialysis was needed until the graft began functioning several days after the kidney transplantation, the postoperative clinical course thereafter was uneventful and the graft functioned well with stable serum creatinine levels around 2.4 mg/dl at 6 monthspos toperatively.
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http://dx.doi.org/10.14989/ActaUrolJap_62_10_529DOI Listing
October 2016

A multiplex urinary immunoassay for bladder cancer detection: analysis of a Japanese cohort.

J Transl Med 2016 10 7;14(1):287. Epub 2016 Oct 7.

Clinical and Translational Research Program, University of Hawaii Cancer Center, 701 Ilalo St, Rm 327, Honolulu, HI, 96813, USA.

Background: Bladder cancer (BCa) is among the most commonly diagnosed malignancies worldwide, and due the high rate of post-operative disease recurrence, it is one of the most prevalent in many countries. The development of non-invasive molecular assays that can accurately detect and monitor BCa would be a major advance, benefiting both patients and healthcare systems. We have previously identified a urinary protein biomarker panel that is being developed for application in at-risk patient cohorts. Here, we investigated the potential utility of the multiplex assay in a Japanese cohort.

Methods: The Japanese study cohort collected from urology clinics at two institutions was comprised of a total of 288 subjects. The protein biomarker panel (IL8, MMP9, MMP10, ANG, APOE, SDC1, A1AT, PAI1, CA9, VEGFA) was monitored in voided urine samples collected prior to cystoscopy using a custom multiplex ELISA assay. The diagnostic performance of the biomarker panel was assessed using receiver operator curves, predictive modeling and descriptive statistics.

Results: Urinary biomarker concentrations were significantly elevated in cases versus controls, and in cases with high-grade and muscle-invasive tumors. The AUC for the 10-biomarker assay was 0.892 (95 % confidence interval 0.850-0.934), with an overall diagnostic sensitivity specificity of 0.85 and 0.81, respectively. A predictive model trained on the larger institutional cohort correctly identified 99 % of the cases from the second institution.

Conclusions: Urinary levels of a 10-biomarker panel enabled discrimination of patients with BCa. The multiplex urinary diagnostic assay has the potential to be developed for the non-invasive detection of BCa in at-risk Japanese patients.
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http://dx.doi.org/10.1186/s12967-016-1043-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5055716PMC
October 2016

Impact of acute kidney injury defined by CTCAE v4.0 during first course of cisplatin-based chemotherapy on treatment outcomes in advanced urothelial cancer patients.

Clin Exp Nephrol 2017 Aug 26;21(4):732-740. Epub 2016 Aug 26.

Department of Urology, Faculty of Medicine, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki, 305-8575, Japan.

Background: The Kidney Disease: Improving Global Outcomes group (KDIGO) defined acute kidney injury (AKI) as an elevation of serum creatinine (sCR) exceeding 0.3 mg/dl within 48 h. The widely used adverse events criteria for chemotherapy, Common Toxicity Criteria for Adverse Events Version 4.0 (CTCAE v4.0), also defined AKI as sCR exceeding 0.3 mg/dl, but with no provision of a time course. Here, we attempted to clarify the impact of AKI (CTCAE v4.0) during cisplatin-based chemotherapy on clinical outcome of patients with advanced urothelial cancer (UC).

Methods: This multicenter retrospective study included 230 UC patients who received cisplatin-based chemotherapy.

Results: During the first chemotherapy course, AKI (CTCAE v4.0) episodes were observed in 61 patients (26.5 %), whereas only four patients (1.5 %) experienced AKI (KDIGO) episodes. Both the pretreatment estimated glomerular filtration rate (eGFR) and creatinine clearance by Cockcroft-Gault formula were not efficient predictors for the development of AKI (CTCAE v4.0). AKI (CTCAE v4.0) impacted renal function: at the start of second-course chemotherapy, the average eGFR of the patients with AKI (CTCAE v4.0) was 54.1 ml/min/1.73 m, significantly lower than that of patients without AKI (CTCAE v4.0) (63.4 ml/min/1.73 m). As a result, only 57.4 % of patients with AKI (CTCAE v4.0) received the planned treatment at the second course. The survival of the patients who developed AKI (CTCAE v4.0) was significantly worse than that of the patients who did not. The 3-year OSs were 10.3 and 21.4 %, respectively (P = 0.02).

Conclusion: The present study demonstrated that AKI (CTCAE v4.0) during chemotherapy had a negative impact on both the intensity of subsequent chemotherapy and oncological outcomes.
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http://dx.doi.org/10.1007/s10157-016-1327-zDOI Listing
August 2017

Factors predicting efficacy and adverse effects of enzalutamide in Japanese patients with castration-resistant prostate cancer: results of retrospective multi-institutional study.

Int J Clin Oncol 2016 Dec 28;21(6):1155-1161. Epub 2016 Jun 28.

Department of Urology, Kyoto University Graduate School of Medicine, 54 Shogoinkawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.

Background: We aimed to evaluate the factors predicting efficacy and adverse effects of enzalutamide in patients with castration-resistant prostate cancer.

Methods: We retrospectively evaluated data on 345 patients who had received enzalutamide for castration-resistant prostate cancer in 20 hospitals (Kyoto University Hospital and other satellite hospitals). Cox proportional hazards regression analysis was performed to identify factors predicting prostate-specific antigen (PSA) progression after enzalutamide treatment and logistic regression analysis for those associated with development of adverse effects.

Results: PSA titers decreased by >50 % in 197 patients (57 %). The median PSA progression free survival was 163 days. Gleason score >8 (HR 2.078, 95 % CI 1.37-3.153, P = 0.00058), performance status ≥1 (HR 2.292, 95 % CI 1.463-3.592, P = 0.000296), presence of bone metastasis (HR 1.774, 95 % CI 1.019-3.090, P = 0.0429), visceral metastasis (HR 2.127, 95 % CI 1.215-3.722, P = 0.00823), previous steroid treatment (HR 1.780, 95 % CI 1.207-2.626, P = 0.00361) and docetaxel treatment (HR 1.602, 95 % CI 1.051-2.442, P = 0.0284) significantly predicted the efficacy of enzalutamide. Adverse effects, including fatigue or appetite loss, occurred in 169 patients (49 %), 48 (18 %) of whom stopped enzalutamide. Age >75 years (HR 1.980, 95 % CI 1.270-3.09, P = 0.00246) and lower enzalutamide dose (HR 0.437, 95 % CI 0.255-1.270, P = 0.00249) were significantly associated with development of adverse effects.

Conclusions: Enzalutamide treatment is effective in patients with castration-resistant prostate cancer with low Gleason scores, good performance status, without bone or visceral metastasis and no prior steroid or docetaxel treatment. Lower doses of enzalutamide decrease the incidence of adverse effects, especially in older patients.
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http://dx.doi.org/10.1007/s10147-016-1004-yDOI Listing
December 2016
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