Publications by authors named "Tomonori Habuchi"

356 Publications

Characteristics of α2,3-sialyl N-glycosylated PSA as a biomarker for clinically significant prostate cancer in men with elevated PSA level.

Prostate 2021 Sep 21. Epub 2021 Sep 21.

Department of Urology, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori, Japan.

Background: The presence of glycosylated isoforms of prostate-specific antigen (PSA) in prostate cancer (PC) cells is a potential marker of their aggressiveness. We characterized the origin of α2,3-sialylated prostate-specific antigen (S23PSA) by tissue-based sialylation-related gene expression and studied the performance of S23PSA density (S23PSAD) alone and in combination with multiparametric magnetic resonance imaging (MRI) for the detection of clinically significant prostate cancer in men with elevated PSA.

Methods: Tissue-based quantification of S23PSA and sialyltransferase and sialidase gene expression was evaluated in 71 radical prostatectomy specimens. The diagnostic performance of S23PSAD was studied in 1099 men retrospectively enrolled in a multicenter systematic biopsy (SBx) cohort. We correlated the S23PSAD with Prostate Imaging Reporting and Data System (PI-RADS) scores in 98 men prospectively enrolled in a single-center MRI-targeted biopsy (MRI-TBx) cohort. The primary outcome was the PC-diagnostic performance of the S23PSAD, the secondary outcome was the avoidable biopsy rate of S23PSAD combined with DRE and total PSA (tPSA), and with or without PI-RADS.

Results: S23PSA was significantly higher in Gleason pattern 4 and 5 compared with benign prostate tissue. In the retrospective cohort, the performance of S23PSAD for detecting PC was superior to tPSA or PSA density (PSAD) (AUC: 0.7758 vs. 0.6360 and 0.7509, respectively). In the prospective cohort, S23PSAD was superior to tPSA, PSAD, and PI-RADS (AUC: 0.7725 vs. 0.5901, 0.7439 and 0.7305, respectively), and S23PSAD + PI-RADS + DRE + tPSA was superior to DRE + tPSA+PI-RADS with avoidance rate of MRI-TBx (13% vs. 1%) at 30% risk threshold.

Conclusions: The diagnostic performance of S23PSAD was superior to conventional strategies but comparable to mpMRI.
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http://dx.doi.org/10.1002/pros.24239DOI Listing
September 2021

External validation of the REMARCC model for the selection of cytoreductive nephrectomy in patients with primary metastatic renal cell carcinoma: A multicenter retrospective study.

Urol Oncol 2021 Sep 17. Epub 2021 Sep 17.

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

Objectives: This study aims to evaluate the utility of the scoring system of the Registry for Metastatic Renal Cell Carcinoma (REMARCC) model on the overall survival (OS) of patients undergoing cytoreductive nephrectomy (CN).

Methods: A total of 278 patients with primary metastatic renal cell carcinoma (mRCC) treated with first-line tyrosine kinase inhibitors (TKIs) between January 2008 and November 2019 were identified. The c-index and net benefit between the REMARCC score were compared with the International mRCC Database Consortium (IMDC) score in patients with CN (CN group, n = 146). The effect of the REMARCC score on OS was compared between the CN group and patients without CN (non-CN group, n = 132) using Cox regression analysis under the propensity score-based inverse probability of treatment weighting (IPTW) method to adjust for group imbalances.

Results: Of the 146 patients with CN, the c-index of the REMARCC model (0.60) was higher than the IMDC model (0.54). The decision curve analysis showed the advantage of REMARCC model predicting OS compared with the IMDC model. OS was significantly longer in the REMARCC low-score (0-2) than that in the high-score (3-6) among the patients with CN. IPTW-adjusted Cox regression analyses showed that OS was significantly longer in the CN group than that in the non-CN group among the patients with REMARCC low-score but was not significantly different between the groups among the patients with REMARCC high-score.

Conclusions: The REMARCC score may be active for selecting the CN candidate in patients treated with TKIs.
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http://dx.doi.org/10.1016/j.urolonc.2021.08.015DOI Listing
September 2021

Clinical impact of detecting low-frequency variants in cell-free DNA on treatment of castration-resistant prostate cancer.

Clin Cancer Res 2021 Sep 15. Epub 2021 Sep 15.

Department of Urology, Hirosaki University Graduate School of Medicine.

Purpose: Although cell-free DNA (cfDNA) testing is expected to drive cancer precision medicine, little is known about the significance of detecting low-frequency variants in circulating cell-free tumor DNA (ctDNA) in castration-resistant prostate cancer (CRPC). We aimed to identify genomic profile including low-frequency variants in ctDNA from CRPC patients and investigate the clinical utility of detecting variants with variant allele frequency (VAF) below 1%.

Experimental Design: This prospective, multicenter cohort study enrolled CRPC patients eligible for treatment with abiraterone or enzalutamide. We performed targeted sequencing of pre-treatment cfDNA and paired leukocyte DNA with molecular barcodes, and ctDNA variants with a VAF {greater than or equal to} 0.1% were detected using an in-house pipeline. We investigated progression-free survival (PFS) and overall survival (OS) after different ctDNA fraction cutoffs were applied.

Results: One hundred patients were analyzed (median follow-up 10.7 months). We detected deleterious , , and variants even in samples with ctDNA fraction below 2%. When the ctDNA fraction cutoff value of 0.4% was applied, significant differences in PFS and OS were found between patients with and without defects in or [hazard ratio (HR), 2.52; 95% confidence interval (CI), 1.24-5.11; = 0.0091] and (HR, 3.74; 95% CI, 1.60-8.71; = 0.0014). However, these differences were no longer observed when the ctDNA fraction cutoff value of 2% was applied, and approximately 50% of the samples were classified as ctDNA unquantifiable.

Conclusions: Detecting low-frequency ctDNA variants with a VAF < 1% is important to identify clinically informative genomic alterations in CRPC.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-2328DOI Listing
September 2021

Effect of HLA genotype on intravesical recurrence after bacillus Calmette-Guérin therapy for non-muscle-invasive bladder cancer.

Cancer Immunol Immunother 2021 Aug 11. Epub 2021 Aug 11.

Department of Urology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

The intravesical administration of bacillus Calmette-Guérin (BCG) is widely used to control the intravesical recurrence of non-muscle-invasive bladder cancer (NMIBC). This study aimed to reveal the effects of zygosity on human leukocyte antigen (HLA) genes and individual HLA genotypes on intravesical recurrence after intravesical BCG therapy for NMIBC. This study included Japanese patients who had received intravesical BCG for NMIBC. HLA genotyping of HLA-A, B, C, and DRB1 was performed. The effect of HLA zygosity and HLA genotype on intravesical recurrence was evaluated. Among 195 patients, those homozygous for the HLA-B supertype were more likely than those heterozygous for the HLA-B supertype to experience intravesical recurrence by univariate analysis (hazard ratio [HR], 95% confidence interval [CI]; 1.87, 1.14-3.05, P = 0.012) and multivariate analysis (HR, 95% CI; 2.26, 1.02-5.01, P = 0.045). Patients with B07 or B44 had a decreased risk of intravesical recurrence by univariate analysis (HR, 95% CI; 0.43, 0.24-0.78, P = 0.0056) and multivariate analysis (HR, 95% CI; 0.36, 0.16-0.82, P = 0.016). This study suggests the importance of the diversity and specificity of HLA-B loci in the antitumor effect of BCG immunotherapy for NMIBC. These findings may contribute to the delineation of risk strata for BCG therapy and improve the medical management of NMIBC.
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http://dx.doi.org/10.1007/s00262-021-03032-0DOI Listing
August 2021

Cancer Antigen 15-3 Serum Level as a Biomarker for Advanced Micropapillary Urothelial Carcinoma of the Bladder: A Case Report.

Case Rep Oncol 2021 May-Aug;14(2):1019-1024. Epub 2021 Jun 29.

Department of Urology, Akita University School of Medicine, Akita, Japan.

A 73-year-old woman with no history of disease was referred to our hospital with fatigue and joint pain. Screening blood test showed that her cancer antigen 15-3 (CA 15-3) serum level was elevated to 36.6 U/mL, and a contrast-enhanced computed tomography scan revealed a bladder tumor without metastasis. Cystoscopy showed a papillary and a small kissing tumor, and the histopathological analysis of the bladder tumor obtained by transurethral resection (TUR) showed invasive urothelial carcinoma (UC) with micropapillary variant (pT1). At 4 weeks after TUR, the CA 15-3 serum level was markedly increased to 180.6 U/mL, and radiographic examinations revealed multiple regional and nonregional lymph node metastases. The patient received systemic therapy with gemcitabine and cisplatin. After 3 cycles of chemotherapy, the size of all lymph node metastases reduced by 80% in diameter, and the CA 15-3 serum level decreased from 238.2 to 11.4 U/mL. Immunohistological analysis showed that the bladder tumor was positive for mucin 1, of which CA 15-3 is an epitope. In our patient, changes in the CA 15-3 serum levels were in congruence with the clinical course of advanced micropapillary UC (MPUC). Therefore, the CA 15-3 serum level may be a potentially valuable biomarker for MPUC.
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http://dx.doi.org/10.1159/000515781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8299383PMC
June 2021

Outcomes of axitinib versus sunitinib as first-line therapy to patients with metastatic renal cell carcinoma in the immune-oncology era.

Cancer Med 2021 Sep 27;10(17):5839-5846. Epub 2021 Jul 27.

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

Although combination immune checkpoint inhibitor (immuno-oncology [IO]) therapy is the first-line treatment for metastatic renal cell carcinoma (mRCC), it mostly causes resistance and tumor regrowth. Therefore, an optimal second-line therapy is necessary. Such therapy typically comprises vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs). This study was aimed at comparing the efficacy of two TKIs-axitinib and sunitinib-in mRCC patients. From January 2008 to October 2018, we registered 703 mRCC patients from 8 Japanese institutes. Of these, 408 patients received axitinib or sunitinib as the first-line treatment. Thereafter, efficacy and survival rate were compared between the axitinib and sunitinib groups. To reduce the effects of selection bias and potential confounders, propensity score matching analysis was performed. Axitinib and sunitinib were administered in 274 and 134 patients, respectively. More than 25% of the patients received nivolumab sequence therapy. To calculate the propensity scores for each patient, we performed multivariate logistic regression analysis. The objective response rate, progression-free survival (PFS), cause-specific survival, and overall survival (OS) were significantly better in the axitinib group than in the sunitinib group. Furthermore, the OS was better in the nivolumab-treated patients in the axitinib group. Axitinib showed higher efficacy and afforded greater survival benefits than did sunitinib when administered as first-line therapy in mRCC patients. Thus, from among VEGFR-TKIs, axitinib might be a possible option for application in the middle of IO drug-based treatment sequences.
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http://dx.doi.org/10.1002/cam4.4130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419787PMC
September 2021

Comparison of parenchymal volume loss assessed by three-dimensional computed tomography volumetry and renal functional recovery between conventional and robot-assisted laparoscopic partial nephrectomy.

Asian J Endosc Surg 2021 Jul 5. Epub 2021 Jul 5.

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

Objectives: We retrospectively investigated if robot-assisted laparoscopic partial nephrectomy (RAPN) contributes to a decrease in resected parenchymal volume (RPV), an increase in postoperative parenchymal volume (PPV), and an improvement of postoperative renal function when compared with conventional laparoscopic partial nephrectomy (LPN) using a three-dimensional image analysis system.

Methods: Patients who underwent LPN (n = 37) and RAPN (n = 66) from November 2013 to November 2018 were included in this study. All patients had a tumor diameter of 4 cm or less. Patients with an anatomical or functional single kidney were excluded. RPV and PPV were measured using SYNAPSE VINCENT®. The surgical outcomes were compared between the two groups.

Results: Warm ischemic time in the RAPN group was significantly shorter than that in the LPN group (p < 0.001). The ratio of RPV to tumor volume (RPV/TV) in the RAPN group was significantly lower than that in the LPN group (p = 0.016). PPV in the RAPN group was significantly higher than that in the LPN group (p = 0.049). The decreased estimated glomerular filtration rate in the RAPN group was significantly lower than that in the LPN group on days 1, 7, 30, 90, and 180 after surgery.

Conclusions: Postoperative renal function in the RAPN group was significantly better than that in the LPN group in both the short and long term. In addition to a short warm ischemia time, the decreased RPV/TV and increased PPV may have contributed to the improvement of postoperative renal function.
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http://dx.doi.org/10.1111/ases.12966DOI Listing
July 2021

Prognosis of Japanese metastatic renal cell carcinoma patients in the targeted therapy era.

Int J Clin Oncol 2021 Oct 30;26(10):1947-1954. Epub 2021 Jun 30.

Department of Urology, Yamagata University Faculty of Medicine, Iida-Nishi 2-2-2, Yamagata, 990-9585, Japan.

Background: The aims of this study were to investigate prognosis and validate prognostic models [Memorial Sloan-Kettering Cancer Center (MSKCC), International Metastatic Renal Cell Carcinoma Data Consortium (IMDC), and Japanese metastatic renal cancer (JMRC) models] in the targeted therapy era in Japanese patients with metastatic renal cell carcinoma.

Methods: We retrospectively analyzed 692 patients who were diagnosed with mRCC from January 2008 to August 2018 in the Michinoku Japan Urological Cancer Study Group database. Nivolumab as sequential therapy was widely used. Other immune checkpoint inhibitors were excluded from this study.

Results: The median overall survival (95% confident interval) in all, MSKCC favorable, intermediate, and poor risk patients was 41.0 months (33.9-46.8), not reached (63.5 to not estimable), 46.8 months (37.1-52.9), and 10.4 months (8.9-14.4), respectively. The median overall survival (95% confident interval) in IMDC favorable, intermediate, and poor risk patients was not reached (61.6 to not estimable), 47.4 months (41.4-56.5), and 11.5 (9.9-16.3), respectively. The c-index of the MSKCC, IMDC, and JMRC models calculated at mRCC diagnosis was 0.680, 0.689, and 0.700, respectively. No statistical differences were found in the c-index among the models.

Conclusion: While the real-world overall survival in Japanese patients with mRCC in the targeted therapy era improved compared to that previously reported in the cytokine era, there was no clear difference in the survival of poor risk patients between these eras. There were no differences in the superiority among the models.
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http://dx.doi.org/10.1007/s10147-021-01979-9DOI Listing
October 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

Impact of Nerve-Sparing Status on Positive Surgical Margin Location and Biochemical Recurrence in Patients with Prostate Cancer Post Radical Prostatectomy.

Ann Surg Oncol 2021 Sep 9;28(9):5341-5348. Epub 2021 Jun 9.

Department of Urology, Akita University School of Medicine, Akita, Japan.

Purpose: This study was designed to assess the relationship between nerve-sparing (NS) status, positive surgical margin (PSM) location, and biochemical recurrence (BCR) based on a multicenter, radical prostatectomy (RP) database.

Methods: We retrospectively reviewed data from 726 patients who underwent RP without any neoadjuvant or adjuvant treatment between 2010 and 2014. We statistically assessed the impact of NS sides on PSM location and BCR.

Results: PSM rates were 21.9% in the 726 patients studied, 13.2% in patients with ≤pT2, and 46.8% in patients with ≥pT3. Regarding PSM locations, the anterior-apex (AA) was the most common site for PSM (43.3%). After adjusting for confounding factors, bilateral nerve sparing (BNS) had a significantly higher odds ratio of PSM than the absence of NS did (odds ratio [OR] 3.04, 95% confidence interval [CI] 1.85-4.99). In the UNS RP in patients with ≤pT2, non-AA PSM on the non-NS side was significantly higher than that on the NS side (92.9% vs. 45.5%, p = 0.009). In all patients, 5.8% experienced BCR during a median follow-up of 43.5 months. PSM was significantly associated with BCR-free survival in patients with ≤pT2 (p = 0.013), but not in patients with ≥pT3 (p = 0.185). Non-AA PSM at the non-NS side was an independent risk factor for BCR (hazard ratio [HR] 2.56, 95% confidence interval [CI] 1.12-5.85), whereas AA PSMs, including NS/non-NS sides and non-AA PSM at the NS side, were not associated with BCR-free survival.

Conclusions: Avoidance of non-AA PSM on the non-NS side may be rather important for maintaining BCR-free survival after RP.
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http://dx.doi.org/10.1245/s10434-021-10281-xDOI Listing
September 2021

Impact of pretreatment anemia on upfront abiraterone acetate therapy for metastatic hormone-sensitive prostate cancer: a multicenter retrospective study.

BMC Cancer 2021 May 25;21(1):605. Epub 2021 May 25.

Department of Urology, Department of Advanced Blood Purification Therapy, Hirosaki University Graduate School of Medicine, 5 Zaifu-chou, Hirosaki, 036-8562, Japan.

Background: Anemia has been a known prognostic factor in metastatic hormone-sensitive prostate cancer (mHSPC). We therefore examined the effect of anemia on the efficacy of upfront abiraterone acetate (ABI) in patients with mHSPC.

Methods: We retrospectively evaluated 66 mHSPC patients with high tumor burden who received upfront ABI between 2018 and 2020 (upfront ABI group). We divided these patients into two groups: the anemia-ABI group (hemoglobin < 13.0 g/dL, n = 20) and the non-anemia-ABI group (n = 46). The primary objective was to examine the impact of anemia on the progression-free survival (PFS; clinical progression or PC death before development of castration resistant PC) of patients in the upfront ABI group. Secondary objectives included an evaluation of the prognostic significance of upfront ABI and a comparison with a historical cohort (131 mHSPC patients with high tumor burden who received androgen deprivation therapy (ADT/complete androgen blockade [CAB] group) between 2014 and 2019).

Results: We found that the anemia-ABI group had a significantly shorter PFS than the non-anemia-ABI group. A multivariate Cox regression analysis showed that anemia was an independent prognostic factor of PFS in the upfront ABI group (hazard ratio, 4.66; P = 0.014). Patients in the non-anemia-ABI group were determined to have a significantly longer PFS than those in the non-anemia-ADT/CAB group (n = 68) (P < 0.001). However, no significant difference was observed in the PFS between patients in the anemia-ABI and the anemia-ADT/CAB groups (n = 63). Multivariate analyses showed that upfront ABI could significantly prolong the PFS of patients without anemia (hazard ratio, 0.17; P < 0.001), whereas ABI did not prolong the PFS of patients with anemia.

Conclusion: Pretreatment anemia was a prognostic factor among mHSPC patients who received upfront ABI. Although the upfront ABI significantly improved the PFS of mHSPC patients without anemia, its efficacy in patients with anemia might be limited.
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http://dx.doi.org/10.1186/s12885-021-08206-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8152305PMC
May 2021

Flexible fibre optic vs digital ureteroscopy and enhanced vs unenhanced imaging for diagnosis and treatment of upper tract urothelial carcinoma (UTUC): results from the Clinical Research Office of the Endourology Society (CROES)-UTUC registry.

BJU Int 2021 May 24. Epub 2021 May 24.

Department of Urology, Medipol Mega University Hospital, Istanbul Medipol University, Istanbul, Turkey.

Objectives: To compare the oncological outcomes of patients with upper tract urothelial carcinoma (UTUC) undergoing kidney-sparing surgery (KSS) with fibre-optic (FO) vs digital (D) ureteroscopy (URS). To evaluate the oncological impact of image-enhancement technologies such as narrow-band imaging (NBI) and Image1-S in patients with UTUC.

Patients And Methods: The Clinical Research Office of the Endourology Society (CROES)-UTUC registry is an international, multicentre, cohort study prospectively collecting data on patients with UTUC. Patients undergoing flexible FO- or D-URS for diagnostic or diagnostic and treatment purposes were included. Differences between groups in terms of overall survival (OS) and disease-free survival (DFS) were evaluated.

Results: The CROES registry included 2380 patients from 101 centres and 37 countries, of whom 401 patients underwent URS (FO-URS 186 and D-URS 215). FO-URS were performed more frequently for diagnostic purposes, while D-URS was peformed when a combined diagnostic and treatment strategy was planned. Intra- and postoperative complications did not differ between the groups. The 5-year OS and DFS rates were 91.5% and 66.4%, respectively. The mean OS was 42 months for patients receiving FO-URS and 39 months for those undergoing D-URS (P = 0.9); the mean DFS was 28 months in the FO-URS group and 21 months in the D-URS group (P < 0.001). In patients who received URS with treatment purposes, there were no differences in OS (P = 0.9) and DFS (P = 0.7). NBI and Image1-S technologies did not improve OS or DFS over D-URS.

Conclusions: D-URS did not provide any oncological advantage over FO-URS. Similarly, no differences in terms of OS and DFS were found when image-enhancement technologies were compared to D-URS. These findings underline the importance of surgeon skills and experience, and reinforce the need for the centralisation of UTUC care.
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http://dx.doi.org/10.1111/bju.15494DOI Listing
May 2021

Comparison of pembrolizumab with conventional chemotherapy after first-line platinum-based chemotherapy for advanced urothelial carcinoma in real-world practice: A multicenter retrospective study.

Int J Urol 2021 Sep 24;28(9):899-905. Epub 2021 May 24.

Department of, 1Urology and, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.

Objectives: To assess the clinical benefit of pembrolizumab as second-line therapy for advanced urothelial carcinoma.

Methods: We retrospectively compared the effects of pembrolizumab with those of conventional chemotherapy on the prognosis of patients with advanced urothelial carcinoma at six hospitals between January 2004 and August 2020. We compared the oncological outcomes between the patients treated with pembrolizumab and those treated with conventional chemotherapy using Kaplan-Meier curve analysis and multivariate Cox regression analysis with the inverse probability of treatment weighting method.

Results: The numbers of patients in the pembrolizumab and chemotherapy groups were 121 and 67, respectively. Patients in the pembrolizumab group were significantly older (median 72 vs 66 years, P = 0.001), and had poor Eastern Cooperative Oncology Group performance status (median 1 vs 0, P = 0.001). The unadjusted Kaplan-Meier curve analysis showed no significant differences in the median overall survival from the first-line chemotherapy (24.7 months vs 16.3 months, P = 0.159). Inverse probability of treatment weighting-adjusted multivariate Cox proportional hazards analyses showed a significant difference between the pembrolizumab and chemotherapy groups in overall survival (P = 0.003, hazard ratio 0.63).

Conclusions: Despite the non-negligible age difference between the trial and our clinical practice, our study supports the benefit of second-line pembrolizumab over chemotherapy in real-world practice.
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http://dx.doi.org/10.1111/iju.14601DOI Listing
September 2021

Macrophage inhibitory cytokine-1 induced by a high-fat diet promotes prostate cancer progression by stimulating tumor-promoting cytokine production from tumor stromal cells.

Cancer Commun (Lond) 2021 May 27;41(5):389-403. Epub 2021 Mar 27.

Department of Urology, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan.

Background: Recent studies have indicated that a high-fat diet (HFD) and/or HFD-induced obesity may influence prostate cancer (PCa) progression, but the role of HFD in PCa microenvironment is unclear. This study aimed to delineate the molecular mechanisms of PCa progression under HFD milieus and define the stromal microenvironment focusing on macrophage inhibitory cytokine-1 (MIC-1) activation.

Methods: We investigated the effects of HFD on PCa stromal microenvironment and MIC-1 signaling activation using PC-3M-luc-C6 PCa model mice fed with HFD or control diet. Further, we explored the effect of periprostatic adipocytes derived from primary PCa patients on activation and cytokine secretion of prostate stromal fibroblasts. Expression patterns and roles of MIC-1 signaling on human PCa stroma activation and progression were also investigated.

Results: HFD stimulated PCa cell growth and invasion as a result of upregulated MIC-1 signaling and subsequently increased the secretion of interleukin (IL)-8 and IL-6 from prostate stromal fibroblasts in PC-3M-luc-C6 PCa mouse model. In addition, periprostatic adipocytes directly stimulated MIC-1 production from PC-3 cells and IL-8 secretion in prostate stromal fibroblasts through the upregulation of adipose lipolysis and free fatty acid release. The increased serum MIC-1 was significantly correlated with human PCa stroma activation, high serum IL-8, IL-6, and lipase activity, advanced PCa progression, and high body mass index of the patients. Glial-derived neurotrophic factor receptor α-like (GFRAL), a specific receptor of MIC-1, was highly expressed in both cytoplasm and membrane of PCa cells and surrounding stromal fibroblasts, and the expression level was decreased by androgen deprivation therapy and chemotherapy.

Conclusion: HFD-mediated activation of the PCa stromal microenvironment through metabolically upregulated MIC-1 signaling by increased available free fatty acids may be a critical mechanism of HFD and/or obesity-induced PCa progression.
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http://dx.doi.org/10.1002/cac2.12137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8118591PMC
May 2021

Anaphylaxis Induced by Intravenous Tacrolimus Administration During Kidney Transplant Surgery: A Case Report.

Transplant Proc 2021 May 10;53(4):1292-1294. Epub 2021 Mar 10.

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

A 35-year-old male patient with end-stage renal disease due to vesicoureteral reflux preemptively received a renal graft from his father. The patient had a history of allergy to contrast-enhancing media. He received oral tacrolimus (TAC) and mycophenolate mofetil without any problems for 2 days before kidney transplantation. During the induction period of the surgery, his systolic blood pressure (sBP) decreased to 60 mmHg approximately 1 hour after initiating intravenous tacrolimus (TAC-IV) and intravenous piperacillin (PIPC), and the anesthesiologist suspected drug-induced anaphylaxis and stopped administration of the medications. Because TAC had been administered preoperatively without any adverse events, PIPC was suspected as the causative agent of the anaphylaxis. After the patient's hemodynamics returned to baseline, TAC-IV was restarted. However, his sBP rapidly decreased to 40 mmHg and the patient developed wheezing. He was diagnosed with drug-induced anaphylaxis due to castor oil derivatives in the TAC-IV formulation. The patient's sBP was restored with the administration of some vasopressors, and kidney transplantation was then performed without difficulty. Two days after kidney transplantation, oral TAC was administered without anaphylaxis. Clinicians should consider that not only the drug itself but also its additives or metabolites could induce anaphylaxis.
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http://dx.doi.org/10.1016/j.transproceed.2021.02.010DOI Listing
May 2021

Short-term outcomes of risk-adapted upfront docetaxel administration in patients with metastatic hormone-sensitive prostate cancer: a multicenter prospective study in Japan.

Med Oncol 2021 Mar 13;38(4):37. Epub 2021 Mar 13.

Department of Urology, Akita University School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan.

We conducted a risk-adapted upfront docetaxel (DOC) in patients with metastatic hormone-sensitive prostate cancer (mHSPC). Here, we reported an interim analysis of the study. The study enrolled 68 patients with newly diagnosed mHSPC between 2016 and 2018. According to the presence of visceral metastasis, an EOD score ≥ 3, or prostate-specific antigen (PSA) level at 3 months of ≥ 1 ng/mL, patients were divided into low- and high-risk groups. Patients were treated with androgen deprivation therapy (ADT) with or without bicalutamide; those in the high-risk group received upfront treatment involving six cycles of DOC (70 mg/m). Short-term treatment effect, adverse events, and quality of life (QOL) were evaluated. Fifty (73.5%) were classified in the high-risk group, and 46 (67%) received upfront ADT + DOC. In the ADT + DOC group, 43.5% (20/46) patients achieved a PSA level ≤ 0.2 ng/mL. PSA nadir and time to PSA nadir were 0.291 ng/mL and 288 days, respectively. In the ADT + DOC group, 76.1% (35/42) patients had adverse events (AEs) of grade ≥ 3. During a median follow-up of 18.5 months, 36.4% (8/22) patients in the ADT group and 43.5% (20/46) in the ADT + DOC group had CRPC. Two QOL scores including the physical status and appetite loss at 6 months significantly worsened in the ADT + DOC group but was resolved by 12 months. Upfront DOC achieved high PSA responses without long-term QOL deterioration. However, the short-term outcomes were limited. Longer follow-up is needed to determine the survival advantage.
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http://dx.doi.org/10.1007/s12032-021-01480-3DOI Listing
March 2021

The association between missense polymorphisms in SRD5A2 and HSD3B1 and treatment failure with abiraterone for castration-resistant prostate cancer.

Pharmacogenomics J 2021 Aug 1;21(4):440-445. Epub 2021 Mar 1.

Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Missense polymorphism in HSD3B1, encoding 3β-hydroxysteroid dehydrogenase-1, was associated with outcome after abiraterone treatment. Other androgen-metabolizing enzymes may be involved in therapeutic effect in abiraterone. In this study, we investigated the significance of polymorphisms in genes involved in androgen and abiraterone metabolisms in prostate cancer patients treated with abiraterone. A total of 99 Japanese male castration-resistant prostate cancer patients treated with abiraterone between 2014 and 2018 were included. Genomic DNA was obtained from whole blood samples, and genotyping on SRD5A2 (rs523349), CYP17A1 (rs743572), CYP17A1 (rs2486758), and AKR1C3 (rs12529) was performed by PCR-based technique. Among the 99 patients, 32 (32.3%), 49 (49.5%), and 18 patients (18.2%) carried GG, GC, and CC alleles in SRD5A2, respectively. CC allele was associated with lower risk of treatment failure (hazard ratio, 0.43; 95% confidence interval, 0.20-0.87; P = 0.017) on multivariate analyses, compared with GG/GC alleles. In the combination model using HSD3B1 and SRD5A2 polymorphisms, compared with the combination of AA in HSD3B1 and GG/GC in SRD5A2, other combinations were associated with lower risk of treatment failure (hazard ratio, 0.34; 95% confidence interval, 0.17-0.62; P = 0.0003) on multivariate analyses. This study showed that SRD5A2 genetic variation was associated with the risk of treatment failure in abiraterone. Combinational use of genetic variation in HSD3B1 with SRD5A2 genetic variation augmented the ability of prognostic stratification.
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http://dx.doi.org/10.1038/s41397-021-00220-0DOI Listing
August 2021

Therapeutic effects of the combined androgen blockade therapy versus luteinizing hormone-releasing hormone analog monotherapy in patients with hormone naïve metastatic prostate cancer: a multi-institutional comparative analysis.

Transl Androl Urol 2021 Jan;10(1):417-425

Department of Urology, Hirosaki University School of Medicine, Hirosaki, Japan.

Background: The clinical benefit of the combined androgen blockade (CAB) therapy over luteinizing hormone-releasing hormone analog (LH-RHa) monotherapy for hormone naïve metastatic prostate cancer (mHNPC) is unclear. Therefore, we retrospectively compare the effectiveness of CAB with the LH-RHa monotherapy on the prognosis of Japanese patients with mHNPC.

Methods: We retrospectively evaluated the prognosis of 517 patients diagnosed with mHNPC between August 2001 and May 2017. The patients' data were obtained from the Michinoku Urological Cancer Research Group database and Hirosaki University-related hospitals. Patients were divided into the CAB and LH-RHa monotherapy groups based on primary androgen deprivation therapy (ADT). Overall survival (OS), cancer-specific survival (CSS), and castrate-resistant prostate cancer-free survival (CRPC-FS) were compared between the two groups using the Kaplan-Meier curve analysis. Inverse probability of treatment weighting (IPTW)-adjusted Cox hazard proportional analyses was performed to investigate the effect of primary ADT on oncological outcomes.

Results: The median age was 73 years old. The numbers of patients in the CAB and LH-RHa monotherapy groups were 447 and 70, respectively. The Kaplan-Meier curve analysis showed no significant differences in either 5-year OS (56.7% 52.5%, P=0.277), CSS (61.1% 56.4%, P=0.400), and CRPC-FS (33.1% 31.1%, P=0.529) between the groups. IPTW-adjusted multivariate Cox hazard proportional analyses showed no significant differences in OS, CSS, and CRPC-FS between the two groups.

Conclusions: No significant differences in oncological outcomes were observed between the CAB and LH-RHa monotherapy groups in patients with mHNPC.
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http://dx.doi.org/10.21037/tau-20-966DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844496PMC
January 2021

Cavernous Branched Nerve Regeneration Using Non-Tubular Artificial Nerve Sheets Using Freeze-Dried Alginate Gel Combined With Polyglycolic Acid Mesh in a Rat Model.

Sex Med 2021 Feb 12;9(1):100308. Epub 2021 Jan 12.

Department of Urology, Akita University School of Medicine, Akita, Japan. Electronic address:

Introduction: Neuroprotection and neuroregeneration of cavernous nerve plexus by biological/bioengineering solutions may have the potential to maintain erectile function.

Aims: We evaluated the efficacy of a newly developed artificial nerve sheet using freeze-dried alginate (ALG) with polyglycolic acid (PGA) mesh in a rat model.

Methods: Bilateral cavernous nerves of male rats were excised to make an approximately 2 mm gap. A piece of the sponge-like freeze-dried sheet created by covalent cross-linking of ALG gel combined with PGA mesh was placed over the gap to cover each stump without any neural anastomosis. We compared erectile functions in the ALG groups with those in the sham group and the bilateral nerve excision group (n = 12, each).

Main Outcome Measures: Main outcome measure was a rat model with cavernous nerve excision.

Results: All rats in the sham group had erection at 63 or 64 days, and mating behavior was confirmed in 10 rats (83.3%) of the sham group at 56 to 62 days. No erection and mating behavior was observed in the excision group. Ten of the 12 (83.3%) rats in the ALG group had a mating behavior and an erection, and the rates of erection and mating behavior were significantly higher in the ALG group than those in the excision group (P < .01, P < .01, respectively). Using a retrograde FluoroGold, the rate of FluoroGold positive pelvic ganglia proximal to the gap at 61 or 62 days was significantly higher in the ALG group than that in the excision group (P = .014).

Conclusion: The results of our animal study have demonstrated that simply filling the cavernous nerve gap using the non-tubular artificial nerve sheets made of ALG with PGA mesh restored erectile function after cavernous nerve excision. Narita S, Obara T, Ishikawa N, et al. Cavernous Branched Nerve Regeneration Using Non-Tubular Artificial Nerve Sheets Using Freeze-Dried Alginate Gel Combined With Polyglycolic Acid Mesh in a Rat Model. Sex Med 2021;9:100308.
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http://dx.doi.org/10.1016/j.esxm.2020.100308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930873PMC
February 2021

Impact of cytoreductive nephrectomy in patients with primary metastatic renal cell carcinoma receiving systemic tyrosine kinase inhibitor therapy: A multicenter retrospective study.

Int J Urol 2021 04 12;28(4):369-375. Epub 2020 Dec 12.

Department of Urology and Advanced Blood Purification Therapy, Hirosaki University Graduate of Medicine, Hirosaki, Aomori, Japan.

Objectives: To compare overall survival between patients with metastatic renal cell carcinoma treated by cytoreductive nephrectomy and those not treated by cytoreductive nephrectomy.

Methods: We retrospectively evaluated 278 patients with metastatic renal cell carcinoma treated with first-line tyrosine kinase inhibitors between January 2008 and November 2019. Patients were divided into two groups: a cytoreductive nephrectomy group (immediate or deferred cytoreductive nephrectomy) and a group who received systemic tyrosine kinase inhibitor therapies alone without cytoreductive nephrectomy (control group). Overall survival comparisons were made in all patients in the control versus the cytoreductive nephrectomy group, the control versus the immediate cytoreductive nephrectomy group, the control versus the deferred cytoreductive nephrectomy group, and the deferred cytoreductive nephrectomy versus the immediate cytoreductive nephrectomy group. Analyses were weighted using the propensity score-based inverse probability of treatment weighting method to adjust for group imbalances.

Results: The median (range) age of the patients was 65 (59-73) years. Of the 278 patients, 132 and 146 were in the control group and the cytoreductive nephrectomy (immediate, n = 107 and deferred, n = 39) group, respectively. A significant difference was noted between the control and cytoreductive nephrectomy groups in age, clinical stage, International Metastatic Renal Cell Carcinoma Database Consortium risk factors, and the number of metastatic sites. Inverse probability of treatment weighting-adjusted Cox regression analysis showed a significant difference in overall survival between the control and the cytoreductive nephrectomy groups and between the control and the immediate or deferred cytoreductive nephrectomy groups. However, there was no significant difference in overall survival between the immediate and the deferred cytoreductive nephrectomy groups.

Conclusions: Our findings suggest that metastatic renal cell carcinoma patients undergoing cytoreductive nephrectomy are more likely to have longer overall survival than those who receive tyrosine kinase inhibitor therapy only.
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http://dx.doi.org/10.1111/iju.14466DOI Listing
April 2021

Significance of the timing of ureteral ligation on prognosis during radical nephroureterectomy for upper urinary tract urothelial cancer.

Int J Urol 2021 Feb 29;28(2):208-214. Epub 2020 Nov 29.

Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Objectives: To investigate the impact on intravesical recurrence and prognosis according to the ureteral ligation timing during radical nephroureterectomy for upper urinary tract urothelial carcinoma.

Methods: We carried out a retrospective chart review of 664 patients with non-metastatic upper urinary tract urothelial carcinoma who underwent radical nephroureterectomy with ureteral ligation (supplementary analysis of JCOG1110A). We excluded patients with previous and/or synchronous bladder cancer, clinically node-positive disease, no ureteral ligation data, those without ureteral ligation and those with any missing data. We investigated the cumulative incidence of intravesical recurrence and cancer-specific mortality, and overall survival between patients with ureteral ligation before renovascular ligation (early ureteral ligation), or ureteral ligation after renovascular ligation (late ureteral ligation).

Results: Early and late ureteral ligation was carried out in 243 patients (36.6%) and 421 patients (63.4%), respectively. Intravesical recurrence occurred in 218 patients (32.8%) during follow up (median 3.9 years). No significant difference in the intravesical recurrence was found between early and late ureteral ligation groups. Meanwhile, survival in the early ureteral ligation group was significantly worse compared with the late ureteral ligation group. Multivariable analysis showed that early ureteral ligation was an independent prognostic factor for overall survival (hazard ratio 1.88, 95% confidence interval 1.24-2.85, P = 0.003) and cancer-specific mortality (hazard ratio 1.93, 95% confidence interval 1.14-3.25, P = 0.014).

Conclusions: Our findings suggest that the incidence of intravesical recurrence is not affected by the timing of ureteral ligation during radical nephroureterectomy. However, early ureteral ligation might have a negative impact on survival outcomes.
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http://dx.doi.org/10.1111/iju.14435DOI Listing
February 2021

[Seminal Vesicle Cystadenoma with Concurrent Prostate Cancer : A Case Report].

Hinyokika Kiyo 2020 Oct;66(10):351-355

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

This case report documents seminal vesicle cystadenoma with concurrent prostate cancer in a 49-yearold man evaluated at follow-up for a high prostate-specific antigen level (12 ng/ml). Transrectal ultrasound-guided prostate biopsy was performed for adenocarcinoma of the prostate (Gleason score 3+4= 7). Staging computed tomography showed a 6.6×5.5×5.0 cm cystic tumorof the seminal vesicle. A possible diagnosis of primary malignant tumor of the seminal vesicle with concurrent organ-confined prostate cancer was considered. However, seminal vesicle tumor biopsy was not performed because the patient underwent open radical prostatectomy with the resection of the seminal vesicle tumor. Histopathologic examination of the seminal vesicle and the prostate revealed cystadenoma (Gleason score 4+3=7) and adenocarcinoma (stage pT2cN0). Neither recurrence of the cystadenoma nor biochemical recurrence of the prostate cancer was observed 5 years and 6 months after the surgery.
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http://dx.doi.org/10.14989/ActaUrolJap_66_10_351DOI Listing
October 2020

First-line axitinib therapy is less effective in metastatic renal cell carcinoma with spindle histology.

Sci Rep 2020 11 18;10(1):20089. Epub 2020 Nov 18.

Department of Urology, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan.

Axitinib, a vascular endothelial growth factor receptor-tyrosine kinase inhibitor, will be used in combination first-line therapies against metastatic renal cell carcinoma (mRCC), but its effects as a first-line monotherapy are unclear. Thus, we aimed to elucidate pretreatment clinical factors that predict the prognosis of patients with mRCC receiving first-line axitinib therapy. We enrolled 63 patients with mRCC treated with axitinib as first-line therapy between Nov. 2003 and Jul. 2018. Progression-free survival (PFS) and overall survival (OS) were assessed using the Wald χ statistic in Cox proportional hazards regression. Median patient age was 67 (range: 25-85) years. Seven (11.1%) patients were classified as being at favorable risk, 33 (52.4%) at intermediate risk, and 23 (36.5%) at poor risk according to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk classification system. Median follow-up duration after axitinib initiation was 14 (range: 1-72) months. Median PFS and OS were 18 months and 65 months, respectively. Cox regression analyses of clinical predictors revealed that high C-reactive protein (CRP) levels were significantly correlated with shorter PFS [hazard ratio (HR), 1.63; 95% confidence interval (CI) 1.7-4.0)], whereas spindle cells and poor IMDC risk scores were related to worse OS (HR, 2.87 and 2.88, respectively; 95% CI 1.4-11.0 and 1.1-8.5, respectively). Thus, patients with mRCC and spindle histology or poor IMDC risk scores had worse OS, and those with high CRP levels had shorter PFS in first-line axitinib treatment. Other therapies might be more suitable for initial management of such patients.
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http://dx.doi.org/10.1038/s41598-020-77135-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7675987PMC
November 2020

Does the Addition of Abiraterone to Castration Affect the Reduction in Bone Mineral Density?

In Vivo 2020 Nov-Dec;34(6):3291-3299

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

Background/aim: The in vivo effect of abiraterone on bone mineral density (BMD) in addition to androgen deprivation therapy was examined using a murine model.

Materials And Methods: The mice were separated into the following groups: control, abiraterone, castration, and castration+abiraterone. The percentage change in the ratio of bone to tissue volume (BV/TV), number of osteoblasts and osteoclasts, and the serum level of bone markers were compared on day 21.

Results: The BV/TV ratio of the abiraterone, castration, and castration+abiraterone groups was lower than that of the control group. However, the change in the BV/TV ratio in the castration+abiraterone group was not significantly different from that in the castration group. There was no significant difference in the serum TRAP5b level and the number of osteoclasts and osteoblasts between the castration+abiraterone and the castration groups.

Conclusion: The addition of abiraterone to castration did not affect BMD in the murine model.
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http://dx.doi.org/10.21873/invivo.12167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811634PMC
June 2021

Prognostic value of plasminogen activator inhibitor-1 in biomarker exploration using multiplex immunoassay in patients with metastatic renal cell carcinoma treated with axitinib.

Health Sci Rep 2020 Dec 15;3(4):e197. Epub 2020 Oct 15.

Department of Urology Akita University Graduate School of Medicine Akita Japan.

Background And Aims: Vascular endothelial growth factor-directed therapies play a significant role in patients with metastatic renal cell carcinoma (mRCC). Biomarkers for predicting treatment efficacy and resistance are required to develop personalized medicine. We evaluated multiple serum cytokine levels in patients with mRCC treated with axitinib to explore predictive biomarkers.

Methods: From September 2012 to October 2015, serum samples were collected from 44 patients with mRCC before treatment and 4 weeks after axitinib initiation. Bio-Plex Pro Human Cancer Biomarker Panels 1 and 2 were used to measure levels of 34 serum biomarkers related to angiogenesis and cell proliferation.

Results: Patients with partial response or stable disease had significantly decreased serum plasminogen activator inhibitor-1 (PAI-1) level from pre-treatment to 4 weeks after axitinib initiation compared with those with progressive disease ( = .022). The median progression-free survival (PFS) and median overall survival (OS) in patients with increased serum PAI-1 level from pre-treatment to 4 weeks after axitinib initiation were significantly shorter than those with decreased serum PAI-1 level ( = .027 and = .026, respectively). Increased serum PAI-1 level from pre-treatment to 4 weeks after axitinib initiation was an independent prognostic marker for shorter PFS and OS in multivariate analyses ( = .015 and = .032, respectively). The immunohistochemical staining intensity of PAI-1 in tumor specimens was significantly associated with Fuhrman grade and presence of distant metastasis ( = .026 and = .010, respectively).

Conclusions: The initial change in serum PAI-1 level in the early stage of axitinib treatment could be a useful prognostic biomarker in patients with mRCC.
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http://dx.doi.org/10.1002/hsr2.197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7559632PMC
December 2020

Comparison of nivolumab plus ipilimumab with tyrosine kinase inhibitors as first-line therapies for metastatic renal-cell carcinoma: a multicenter retrospective study.

Int J Clin Oncol 2021 Jan 16;26(1):154-162. Epub 2020 Oct 16.

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

Background: This study compared real-world outcomes of metastatic renal-cell carcinoma (mRCC) patients treated with tyrosine kinase inhibitors or nivolumab plus ipilimumab.

Methods: Using the International mRCC Database Consortium (IMDC), we retrospectively evaluated intermediate- and poor-risk mRCC patients who were treated with nivolumab plus ipilimumab (Nivo-Ipi), tyrosine kinase inhibitors (TKIs) as the first-line therapy between August 2015 and January 2020. We compared oncological outcomes between the Nivo-Ipi group and TKIs group using multivariate logistic regression analysis with the inverse probability of treatment weighting (IPTW) method.

Results: In this study 278 patients were included. There were 52 and 226 patients in the Nivo-Ipi and TKIs groups (sunitinib 97, axitinib 118, sorafenib 9, pazopanib 2), respectively. The median age in the Nivo-Ipi and TKIs groups were 69 and 67 years, respectively. There was no significant difference in age, performance status, history of nephrectomy, and the IMDC risk group distribution between the groups. The objective response rate was significantly higher in the Nivo-Ipi group (38%) than in the TKIs group (23%, P = 0.018). The IPTW-adjusted Cox regression analysis showed that a significantly longer progression-free survival (hazard ratio 0.60, P = 0.039) and overall survival (hazard ratio 0.51, P = 0.037) rates in the Nivo-Ipi group than those in the TKIs group.

Conclusions: The oncological outcomes of patients receiving the first-line therapy of nivolumab plus ipilimumab in real-world practice were significantly improved in comparison with first-line TKIs therapy.
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http://dx.doi.org/10.1007/s10147-020-01797-5DOI Listing
January 2021

Prognosis of metastatic castration-resistant prostate cancer in the era of the second-generation androgen receptor-targeted agents: A retrospective multicenter study.

Int J Urol 2021 Jan 8;28(1):125-127. Epub 2020 Oct 8.

Department of Urology, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori, Japan.

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http://dx.doi.org/10.1111/iju.14392DOI Listing
January 2021

Validated prognostic significance of YB-1 genetic variation in metastatic prostate cancer.

Pharmacogenomics J 2021 02 22;21(1):102-105. Epub 2020 Sep 22.

Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan.

Genetic polymorphism in YB-1 was previously shown to be associated with the prognosis of advanced prostate cancer patients treated with primary androgen-deprivation therapy. However, the significance of this polymorphism remains invalidated. In this study, we aimed to validate the prognostic significance of the YB-1 genetic polymorphism in metastatic prostate cancer. This study included 79 Japanese patients who were diagnosed as metastatic prostate cancer between 2000 and 2016. Genomic DNA was obtained from patient whole blood samples, and genotyping on YB-1 (rs12030724) was performed by PCR-based technique. The association of genotype in YB-1 with clinicopathological parameters and oncological outcome, including progression-free survival and overall survival, was examined. Homozygous wild-type (AA), heterozygous variant (AT), and homozygous variant (TT) were identified in 47 (59.5%), 26 (32.9%) and 6 patients (7.6%), respectively. Heterozygous/homozygous variant (AT/TT) in YB-1 was significantly associated with lower progression risk compared with homozygous wild-type (AA) (hazard ratio = 0.52; 95% confidence interval = 0.30-0.88, P = 0.015). Consistent with this finding, heterozygous/homozygous variant (AT/TT) in YB-1 was significantly associated with lower risk of any-cause mortality compared with homozygous wild-type (AA) (hazard ratio = 0.46; 95% confidence interval = 0.21-0.93, P = 0.031). Gene polymorphism in YB-1 rs12030724 was validated to be a promising predictive biomarker of androgen-deprivation therapy in metastatic prostate cancer to identify patients requiring more intensive therapeutics.
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http://dx.doi.org/10.1038/s41397-020-00188-3DOI Listing
February 2021

Robotic-assisted laparoscopic partial nephrectomy for renal cell carcinoma in horseshoe kidney: a hybrid technique with conventional laparoscopic surgery.

Int Cancer Conf J 2020 Oct 4;9(4):199-202. Epub 2020 Jun 4.

Department of Urology, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543 Japan.

Robotic-assisted laparoscopic partial nephrectomies (RAPN) have come up to standard treatment for small renal tumors, with a growing indication to accomplish this procedure. Although a horseshoe kidney is one of the most common congenital renal fusion anomalies, surgical planning for tumors is considered difficult because of its poor mobility and abnormal vascular supply. We showed our experience of RAPN in combination with conventional laparoscopic kidney mobilization and dissection for a patient with renal cell carcinoma in a horseshoe kidney. The patient was an otherwise healthy 66-year-old man with 26 mm right renal mass on the lower pole of the horseshoe kidney. Robotic assistance allows for proper tissue dissection, easy to aware unconfirmed vasculatures, and meticulous fine suturing and would overcome the potential challenges involved in the minimally invasive management of such complex anomalies as shown in the patient.
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http://dx.doi.org/10.1007/s13691-020-00420-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450010PMC
October 2020

Treg expansion with trichostatin A ameliorates kidney ischemia/reperfusion injury in mice by suppressing the expression of costimulatory molecules.

Transpl Immunol 2020 12 4;63:101330. Epub 2020 Sep 4.

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

Innate immune reactions are believed to be associated with ischemia/reperfusion injury (IRI), and IRI might be treatable by expanding regulatory T cells (Tregs), which can suppress the excessive responses of the immune system. Organ IRI is known to be closely involved in the expression of costimulatory molecules. The present study aimed to assess whether Tregs endogenously expanded by the administration of trichostatin A (TsA), a histone deacetylase inhibitor, could reduce renal IRI and to clarify their association with the expression of costimulatory molecules in a murine model. In this study, the wild-type mice used for an IRI model were randomly divided into the following four treatment groups: TsA group, DMSO group (control), DMSO+PC61 group, and TsA + PC61 group. Renal injury in the early phase after IRI was ameliorated in the TsA group (increased Tregs) when compared with the other groups. After renal IRI, both the mRNA and the protein levels of anti-inflammatory cytokines, IL-10 and TGF-β in the kidney and spleen were significantly higher in the TsA group than in the other groups, whereas the IL-6 levels were significantly lower in the TsA group than in the other groups. These results were offset by the administration of PC61, supporting that the renoprotective effect of TsA in this study is Treg dependent. mRNA expression levels of CD80, CD86, and ICAM-1 were lower in the TsA group, consistent with Treg control of injury through costimulatory molecules. Our findings suggest that endogenously expanded Tregs coordinate postischemic immune responses and decrease the expression of costimulatory molecules after renal IRI, and thus, they might ameliorate renal IRI. TsA administration for expanding Tregs is a promising therapeutic strategy for renal IRI.
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http://dx.doi.org/10.1016/j.trim.2020.101330DOI Listing
December 2020
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