Publications by authors named "Hiroyuki Nishiyama"

300 Publications

Bacillus Calmette-Guérin-unresponsive non-muscle invasive bladder cancer outcomes in patients without radical cystectomy.

Int J Clin Oncol 2021 Jul 27. Epub 2021 Jul 27.

Department of Urology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan.

Background: Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) is a newly defined subtype that is unlikely to benefit from BCG rechallenge. Radical cystectomy is currently recommended for BCG-unresponsive NMIBC; however, a certain proportion of these patients can be managed with treatments other than that. Herein, we conducted a multicenter retrospective study to analyze the clinical outcomes of BCG-unresponsive NMIBC patients who did not receive radical cystectomy.

Methods: Of the 141 BCG-unresponsive NMIBC patients, 94 (66.7%) received treatment except radical cystectomy. Survival outcomes were calculated from the date of diagnosis using the Kaplan-Meier method and compared using the log-rank test. Prognostic factors were identified using the multivariate Cox regression model. This group was further classified into three groups according to the number of risk factors, and survival outcomes were compared.

Results: Multivariate analyses identified low estimated glomerular filtration rate (< 45 ml/min/1.73 m) and large tumor size (≥ 30 mm) before BCG induction as independent poor prognostic factors for progression-free survival and overall survival, while the latter was also an independent factor for cancer-specific survival. The presence of variant histology was an independent poor prognostic factor for overall survival. The high-risk non-cystectomy group showed a significantly poor prognosis for progression-free survival (hazard ratio: 7.61, 95% confidence interval: 2.11-27.5), cancer-specific survival (10.4, 0.54-70.02), and overall survival (8.28, 1.82-37.7).

Conclusions: Our findings suggest that patients with renal impairment and large tumors should undergo radical cystectomy if the complications and intentions of the patients allow so.
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http://dx.doi.org/10.1007/s10147-021-01988-8DOI Listing
July 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 Jul 27. 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
July 2021

Efficacy and safety of pembrolizumab for older patients with chemoresistant urothelial carcinoma assessed using propensity score matching.

J Geriatr Oncol 2021 Jul 5. Epub 2021 Jul 5.

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

Background: We used real-world and large-scale data to assess the clinical efficacy and safety of pembrolizumab in older patients with advanced urothelial carcinoma (UC).

Methods: A total of 608 patients who received pembrolizumab for the treatment of chemoresistant UC were retrospectively analyzed. All patients were histologically diagnosed with pure UC. Using propensity score matching (PSM) (ECOG performance status, site of metastasis, hemoglobin level and neutrophil-to-lymphocyte ratio, 1:1 matching), the overall survival (OS) and adverse events (AEs) of patients <75 and ≥75 years old were compared.

Results: The median follow-up (IQR) period was 16.1 (9.9-20.5) months. After PSM, there were 215 patients each in the aged <75 years and aged ≥75-year-old groups. The median OS of all patients was estimated to be 10.4 months (95% confidence interval [CI] = 8.8-12.1). After PSM, the median OS was 7.8 months (95% CI = 5.2-10.4) in the <75-year-old group and 10.4 months (95% CI = 7.3-13.5) in the ≥75-year-old group (P = 0.186). Any-grade AEs were more frequently reported in the ≥75-year-old group in comparison to the age <75-year-old group (55.3% vs. 41.9%, P = 0.007), whereas there was no significant difference between the two groups in the incidence of grade ≥3 AEs (10.2% vs. 12.6%, P = 0.544). The objective response rate, defined as complete remission or a partial response, was 22.8% in the <75-year-old group and 25.1% in the ≥75-year-old group (P = 0.651).

Conclusions: The present study demonstrates that age does not affect the efficacy and safety of pembrolizumab treatment for advanced chemoresistant UC. Pembrolizumab treatment should not be avoided based on chronological age; however, close monitoring for the development of treatment-related AE should be considered for older patients.
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http://dx.doi.org/10.1016/j.jgo.2021.07.002DOI Listing
July 2021

Pre-pembrolizumab neutrophil-to-lymphocyte ratio (NLR) predicts the efficacy of second-line pembrolizumab treatment in urothelial cancer regardless of the pre-chemo NLR.

Cancer Immunol Immunother 2021 Jul 7. Epub 2021 Jul 7.

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

Neutrophil-to-lymphocyte ratio (NLR) was reported to be associated with prognosis of urothelial cancer (UC) patients receiving systemic chemotherapy or immunotherapy. However, it has not been elucidated how preceding first-line chemotherapy affects NLR and subsequent second-line pembrolizumab treatment. This multicenter study analyzed 458 patients with metastatic UC who received first-line chemotherapy and second-line pembrolizumab with regard to pre-chemotherapy and pre-pembrolizumab NLR in association with the efficacy of chemotherapy and pembrolizumab treatment. NLR was increased in 47% while decreased in 53% of patients before and after first-line chemotherapy. High pre-chemotherapy NLR (≥ 3) was significantly associated with unfavorable overall (OS, P = 0.0001) and progression-free (P < 0.0001) survivals after first-line chemotherapy. However, pre-chemotherapy NLR showed only modest influence on radiological response and survival after second-line pembrolizumab treatment, whereas pre-pembrolizumab NLR showed higher association. NLR decrease was associated with partial response or greater objective response by first-line chemotherapy, while NLR increase was associated with higher patient age. In conclusion, immediate pre-chemotherapy and pre-pembrolizumab NLR was significantly associated with efficacy of the following treatment, respectively. However, even patients with high pre-chemotherapy NLR achieved favorable OS if they had their NLR reduced by chemotherapy, whereas those with high pre-chemotherapy NLR yielded unfavorable OS if they had their NLR remained high after chemotherapy, suggesting that chemotherapy may have differential effect on the efficacy of subsequent pembrolizumab treatment in UC patients.
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http://dx.doi.org/10.1007/s00262-021-03000-8DOI Listing
July 2021

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

Int J Clin Oncol 2021 Jun 30. 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
June 2021

Impact of Early Exposure to Simulation Program on Undergraduate Medical Students' Interest in Urology.

J Med Educ Curric Dev 2021 Jan-Dec;8:23821205211020750. Epub 2021 May 31.

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

Background: Urological education is as important as surgical training for undergraduates. However, students in undergraduate medical schools have less exposure to urology as their curriculum focuses more on clinical skills, particularly community-based healthcare for a super-aging society. This study aimed to evaluate whether urology-related hands-on training could increase the interest of undergraduate medical students in urology.

Methods: A 1-day elective program in urological surgery at the University of Tsukuba, particularly in robotic, laparoscopic, and endoscopic surgeries, was offered to 85 fourth-year medical students from 2018 to 2020, prior to their clinical clerkship. The average age of the participants was 22 (range: 21-25) years. We used a scoring system that comprised 1-5 Likert-type items to assess training activity, interest in surgery, and interest in urology before and after the course.

Results: Before attending the program, the average scores of interest in urology were 3.53 in 2018, 3.15 in 2019, and 3.00 in 2020. The scores in surgery increased after the program; however, this was not significantly different from scores prior to the program. However, the average interest scores in urology were significantly increased to 3.91 ± 0.63 ( < .05), 3.88 ± 0.58 ( < .01), and 4.00 ± 0.61 ( < 0.01) in 2018, 2019, and 2020, respectively. Total likely scores of this program in 2018, 2019, and 2020 were 4.59, 4.76, and 4.88, respectively, indicating a motivation to study surgery and urology during clinical clerkship.

Conclusions: Urological hands-on training facilitated interest in urology in medical students prior to their clinical clerkship.
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http://dx.doi.org/10.1177/23821205211020750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8186111PMC
May 2021

Novel metastatic burden-stratified risk model in de novo metastatic hormone-sensitive prostate cancer.

Cancer Sci 2021 Jun 19. Epub 2021 Jun 19.

Department of Urology, Kagoshima University, Kagoshima, Japan.

The metastatic burden is a critical factor for decision-making in the treatment of metastatic hormone-sensitive prostate cancer (HSPC). This study aimed to develop and validate a novel risk model for survival in patients with de novo low- and high-burden metastatic HSPC. The retrospective observational study included men with de novo metastatic prostate cancer who were treated with primary androgen-deprivation therapy at 30 institutions across Japan between 2008 and 2017. We created a risk model for overall survival (OS) in the discovery cohort (n = 1449) stratified by the metastatic burden (low vs high) and validated its predictive ability in a separate cohort (n = 951). Based on multivariate analyses, lower hemoglobin levels, higher Gleason grades, and higher clinical T-stage were associated with poor OS in low-burden disease. Meanwhile, lower hemoglobin levels, higher Gleason grade group, liver metastasis, and higher extent of disease scores in bone were associated with poor OS in patients with high-burden disease. In the discovery and validation cohorts, the risk model using the aforementioned parameters exhibited excellent discriminatory ability for progression-free survival and OS. The predictive ability of this risk model was superior to that of previous risk models. Our novel metastatic burden-stratified risk model exhibited excellent predictive ability for OS, and it is expected to have several clinical uses, such as precise prognostic estimation.
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http://dx.doi.org/10.1111/cas.15038DOI Listing
June 2021

ctDNA guiding adjuvant immunotherapy in urothelial carcinoma.

Nature 2021 Jul 16;595(7867):432-437. Epub 2021 Jun 16.

Roche/Genentech, South San Francisco, CA, USA.

Minimally invasive approaches to detect residual disease after surgery are needed to identify patients with cancer who are at risk for metastatic relapse. Circulating tumour DNA (ctDNA) holds promise as a biomarker for molecular residual disease and relapse. We evaluated outcomes in 581 patients who had undergone surgery and were evaluable for ctDNA from a randomized phase III trial of adjuvant atezolizumab versus observation in operable urothelial cancer. This trial did not reach its efficacy end point in the intention-to-treat population. Here we show that ctDNA testing at the start of therapy (cycle 1 day 1) identified 214 (37%) patients who were positive for ctDNA and who had poor prognosis (observation arm hazard ratio = 6.3 (95% confidence interval: 4.45-8.92); P < 0.0001). Notably, patients who were positive for ctDNA had improved disease-free survival and overall survival in the atezolizumab arm versus the observation arm (disease-free survival hazard ratio = 0.58 (95% confidence interval: 0.43-0.79); P = 0.0024, overall survival hazard ratio = 0.59 (95% confidence interval: 0.41-0.86)). No difference in disease-free survival or overall survival between treatment arms was noted for patients who were negative for ctDNA. The rate of ctDNA clearance at week 6 was higher in the atezolizumab arm (18%) than in the observation arm (4%) (P = 0.0204). Transcriptomic analysis of tumours from patients who were positive for ctDNA revealed higher expression levels of cell-cycle and keratin genes. For patients who were positive for ctDNA and who were treated with atezolizumab, non-relapse was associated with immune response signatures and basal-squamous gene features, whereas relapse was associated with angiogenesis and fibroblast TGFβ signatures. These data suggest that adjuvant atezolizumab may be associated with improved outcomes compared with observation in patients who are positive for ctDNA and who are at a high risk of relapse. These findings, if validated in other settings, would shift approaches to postoperative cancer care.
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http://dx.doi.org/10.1038/s41586-021-03642-9DOI 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

Advanced germ cell tumor patients undergoing post-chemotherapy retroperitoneal lymph node dissection: Impact of residual teratoma on prognosis.

Int J Urol 2021 Jun 3. Epub 2021 Jun 3.

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

Objectives: To evaluate the histologic findings and clinical outcomes of post-chemotherapy retroperitoneal lymph node dissection for advanced germ cell tumor.

Methods: We analyzed the medical records of 66 patients who underwent post-chemotherapy retroperitoneal lymph node dissection between 2005 and 2019 at Tsukuba University Hospital.

Results: The proportions of necrosis, teratoma, and viable germ cell tumor in the specimens were 62.1%, 36.4%, and 1.5%, respectively. The 5-year progression-free and overall survival rates were 82.3% and 91.3%, respectively. The 5-year overall survival rate of patients with residual teratoma was significantly worse than that of patients with necrosis only (74.1% vs 100%). Overall, three patients died: one from cancer and two from teratoma with somatic-type malignancy. Of these, two patients relapsed after incomplete resection of residual teratoma. When limited to patients with completely resected teratoma, the 5-year overall survival rate was 91.7%, which did not differ from that for patients with necrosis only. Multivariate analysis showed that presence of teratoma in the primary site and decrease in retroperitoneal lymph node mass to less than 50% of the initial tumor size were independent factors for residual teratoma. However, the absence of these factors could not reliably predict necrosis only in retroperitoneal lymph node dissection specimens.

Conclusions: In our series, 98% of post-chemotherapy retroperitoneal lymph node dissection pathology was either necrosis or teratoma, with viable germ cell tumor only found in 2% of patients. Residual teratoma was associated with poorer prognosis, especially in cases of incomplete resection.
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http://dx.doi.org/10.1111/iju.14587DOI Listing
June 2021

Intravesical Bacillus Calmette-Guérin Treatment for T1 High-Grade Non-Muscle Invasive Bladder Cancer with Divergent Differentiation or Variant Morphologies.

Cancers (Basel) 2021 May 26;13(11). Epub 2021 May 26.

Department of Urology, Nara Medical University, Kashihara, Nara 634-8522, Japan.

The 2016 World Health Organization classification newly described infiltrating urothelial carcinoma (UC) with divergent differentiation (DD) or variant morphologies (VMs). Data comparing oncological outcomes after bladder-preservation therapy using intravesical Bacillus Calmette-Guérin (BCG) treatment among T1 bladder pure UC (pUC), UC with DD (UC-DD), and UC with VMs (UC-VM) are limited. We evaluated 1490 patients with T1 high-grade bladder UC who received intravesical BCG during 2000-2019. They were classified into three groups: 93.6% with pUC, 4.4% with UC-DD, and 2.0% with UC-VM. Recurrence-free, progression-free, and cancer-specific survival following intravesical BCG were compared among the groups using multivariate Cox regression analysis, also used to estimate inverse probability of treatment weighting-adjusted hazard ratio and 95% confidence interval for the outcomes. Glandular differentiation and micropapillary variant were the most common forms in the UC-DD and UC-VM groups, respectively. Of 1490 patients, 31% and 13% experienced recurrence and progression, respectively, and 5.0% died of bladder cancer. Survival analyses revealed the impact of concomitant VMs was significant for cancer-specific survival, but not recurrence-free and progression-free survival compared with that of pUC. Our analysis clearly demonstrated that concomitant VMs were associated with aggressive behavior in contrast to concomitant DD in patients treated with intravesical BCG.
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http://dx.doi.org/10.3390/cancers13112615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8198171PMC
May 2021

Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): an open-label, single-arm, multicentre, phase 2 study.

Lancet Oncol 2021 07 26;22(7):919-930. Epub 2021 May 26.

Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, Netherlands.

Background: Standard treatment for high-risk non-muscle-invasive bladder cancer is transurethral resection of bladder tumour followed by intravesical BCG immunotherapy. However, despite high initial responses rates, up to 50% of patients have recurrence or become BCG-unresponsive. PD-1 pathway activation is implicated in BCG resistance. In the KEYNOTE-057 study, we evaluated pembrolizumab, a PD-1 inhibitor, in BCG-unresponsive non-muscle-invasive bladder cancer.

Methods: We did this open-label, single-arm, multicentre, phase 2 study in 54 sites (hospitals and cancer centres) in 14 countries. In cohort A of the trial, adults aged 18 years or older with histologically confirmed BCG-unresponsive carcinoma in situ of the bladder, with or without papillary tumours, with an Eastern Cooperative Oncology Group performance status of 0-2, and who were ineligible for or declined radical cystectomy were enrolled. All enrolled patients were assigned to receive pembrolizumab 200 mg intravenously every 3 weeks for up to 24 months or until centrally confirmed disease persistence, recurrence, or progression; unacceptable toxic effects; or withdrawal of consent. The primary endpoint was clinical complete response rate (absence of high-risk non-muscle-invasive bladder cancer or progressive disease), assessed by cystoscopy and urine cytology approximately 3 months after the first dose of study drug. Patient follow-ups were done every 3 months for the first 2 years and every 6 months thereafter for up to 5 years. Efficacy was assessed in all patients who received at least one dose of the study drug and met BCG-unresponsive criteria. Safety was assessed in all patients who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov number, NCT02625961, and is ongoing.

Findings: Between Dec 9, 2015, and April 1, 2018, we screened 334 patients for inclusion. 186 patients did not meet inclusion criteria, and 47 patients were assigned to cohort B (patients with BCG-unresponsive high grade Ta or any grade T1 papillary disease without carcinoma in situ; results will be reported separately). 101 eligible patients were enrolled and assigned to receive pembrolizumab. All 101 patients received at least one dose of the study drug and were included in the safety analysis. Five patients had disease that did not meet the US Food and Drug Administration definition of BCG-unresponsive non-muscle-invasive bladder cancer and were therefore not included in the efficacy analysis (n=96). Median follow-up was 36·4 months (IQR 32·0-40·7). 39 (41%; 95% CI 30·7-51·1) of 96 patients with BCG-unresponsive carcinoma in situ of the bladder with or without papillary tumours had a complete response at 3 months. Grade 3 or 4 treatment-related adverse events occurred in 13 (13%) patients; the most common were arthralgia (in two [2%] patients) and hyponatraemia (in three [3%] patients). Serious treatment-related adverse events occurred in eight (8%) patients. There were no deaths that were considered treatment related.

Interpretation: Pembrolizumab monotherapy was tolerable and showed promising antitumour activity in patients with BCG-unresponsive non-muscle-invasive bladder cancer who declined or were ineligible for radical cystectomy and should be considered a a clinically active non-surgical treatment option in this difficult-to-treat population.

Funding: Merck Sharp & Dohme.
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http://dx.doi.org/10.1016/S1470-2045(21)00147-9DOI Listing
July 2021

Discrepancy between clinical and pathological T stages in upper urinary tract urothelial carcinoma: Analysis of the Hospital-Based Cancer Registry data in Japan.

Int J Urol 2021 May 19. Epub 2021 May 19.

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

Objective: To examine the discrepancy between clinical and pathological T stages in patients with urothelial carcinoma of the upper urinary tract treated with radical surgery, and to compare them with the corresponding discrepancy in urothelial carcinoma of the bladder.

Methods: We used the Hospital-Based Cancer Registry data in Japan to extract urothelial carcinoma of the bladder cases (n = 3747) and urothelial carcinoma of the upper urinary tract cases (n = 6831), including urothelial carcinoma of the renal pelvis (n = 3295) and urothelial carcinoma of the ureter (n = 3536) with cT1-4N0M0 diagnosed in 2012-2015, histologically confirmed, and treated with radical surgery without chemotherapy or radiotherapy. We compared the T-stage discrepancy among different tumor locations.

Results: The proportions of overall T-stage discrepancy in the urothelial carcinoma of the renal pelvis (40.8%) and urothelial carcinoma of the ureter (42.9%) groups tended to be higher compared with that in the urothelial carcinoma of the bladder (38.8%) group. The upstaging rate from clinical non-muscle-invasive cancer (≤cT1) to pathological muscle-invasive cancer (≥pT2) was significantly higher in the urothelial carcinoma of the renal pelvis and urothelial carcinoma of the ureter groups compared with the urothelial carcinoma of the bladder group (P = 0.002, P < 0.0001, respectively). Upstaging from clinical organ-confined disease (≤cT2) to pathological non-organ-confined disease (≥pT3) was significantly more frequent in the urothelial carcinoma of the renal pelvis (27.8%, P < 0.0001) and urothelial carcinoma of the ureter (22.3%, P < 0.0001) groups compared with the urothelial carcinoma of the bladder (17.8%) group.

Conclusion: Discrepancy in T staging is significantly higher in patients with urothelial carcinoma of the upper urinary tract compared with those with urothelial carcinoma of the bladder, especially in those with organ-confined disease. As T-stage discrepancy might lead to missed opportunities to carry out perioperative treatment, more accurate diagnostic techniques are required to identify the appropriate urothelial carcinoma candidates for preoperative treatment.
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http://dx.doi.org/10.1111/iju.14583DOI Listing
May 2021

Novel Pan-Pim Kinase Inhibitors With Imidazopyridazine and Thiazolidinedione Structure Exert Potent Antitumor Activities.

Front Pharmacol 2021 3;12:672536. Epub 2021 May 3.

Yakult Central Institute, Yakult Honsha Co. Ltd., Tokyo, Japan.

Pim kinases are overexpressed in various types of hematological malignancies and solid carcinomas, and promote cell proliferation and survival. Here in this study, we investigated the preclinical profile of novel pan-Pim kinase inhibitors with imidazopyridazine and thiazolidinedione structure. Imidazopyridazine-thiazolidinediones inhibited activities of Pim kinases with IC values of tens to hundreds nanomolar. With YPC-21440 and/or YPC-21817, which exhibited especially high inhibitory activities against Pim kinases, we investigated and activities of imidazopyridazine-thiazolidinediones. analysis of binding mode of YPC-21440 and Pim kinases revealed that it directly bound to ATP-binding pockets of Pim kinases. In the kinase panel tested, YPC-21440 and YPC-21817 were highly specific to Pim kinases. These compounds exerted antiproliferative activities against various cancer cell lines derived from hematological malignancies and solid carcinomas. Furthermore, they suppressed phosphorylation of Pim kinase substrates, arrested cell cycle at the G1 phase, and induced apoptosis in cultured cancer cells. In tumor xenograft models, YPC-21440 methanesulfonate and YPC-21817 methanesulfonate exerted antitumor activities. Furthermore, pharmacodynamic analysis with a xenograft model suggested that YPC-21817 methanesulfonate inhibited Pim kinases in tumors. In conclusion, our data revealed that imidazopyridazine-thiazolidinediones are novel Pim kinases inhibitors, effective on various types of cancer cell lines both and .
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http://dx.doi.org/10.3389/fphar.2021.672536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8126654PMC
May 2021

Perioperative pembrolizumab therapy in muscle-invasive bladder cancer: Phase III KEYNOTE-866 and KEYNOTE-905/EV-303.

Future Oncol 2021 Aug 19;17(24):3137-3150. Epub 2021 May 19.

Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Muscle-invasive bladder cancer (MIBC) is associated with high rates of recurrence and poor prognosis despite aggressive treatment. Neoadjuvant chemotherapy before radical cystectomy (RC) improves outcomes in cisplatin-eligible patients; however, the improvement in overall survival is modest. Standard of care for cisplatin-ineligible patients remains RC; more effective systemic therapies are needed. Recent Phase Ib/II studies suggest pembrolizumab monotherapy and combination therapy are effective neoadjuvant therapies for MIBC. The randomized Phase III KEYNOTE-866 and KEYNOTE-905/EV-303 studies are being conducted to evaluate efficacy and safety of perioperative pembrolizumab or placebo with chemotherapy in cisplatin-eligible patients with MIBC (KEYNOTE-866) and of pembrolizumab monotherapy versus pembrolizumab plus enfortumab vedotin versus RC plus pelvic lymph node dissection alone in cisplatin-ineligible patients with MIBC (KEYNOTE-905/EV-303). NCT03924856 & NCT03924895 (ClinicalTrials.gov).
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http://dx.doi.org/10.2217/fon-2021-0273DOI Listing
August 2021

[Informed Consent of the Contraception for Male Cancer Patients under Treatment of Anti‒Cancer Medicine-Current and Future Status].

Gan To Kagaku Ryoho 2021 May;48(5):644-648

Dept. of Urology, University of Tsukuba.

Fertility preservation for male cancer patients is gradually being recognized and the network for clinical practice has progressed, accompanied with the increasing number of local governments which give a subsidy for their sperm cryopreservation. Sperm cryopreservation is recommended, not only for the risk of azoospermia but also for the possibility of increased risk of malformation due to sperm DNA damage. On the other hand, there is no sufficient evidence for the necessity of contraception, its proper duration, and effects depending on the action sites of the corresponding cancer medicine, making it difficult for clinicians to achieve consensus. Here, we discuss the current and future informational provision of contraception and fertility preservation for male cancer patients.
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May 2021

PLD1 promotes tumor invasion by regulation of MMP-13 expression via NF-κB signaling in bladder cancer.

Cancer Lett 2021 Jul 1;511:15-25. Epub 2021 May 1.

Department of Urology, Faculty of Medicine and Graduate School of Comprehensive Human Science, University of Tsukuba, Ibaraki, Japan.

Invasion of bladder cancer (BC) cells from the mucosa into the muscle layer is canonical for BC progression while phospholipase D isoform 1 (PLD1) is known to mediate development of cancer through phosphatidic acid (PA) production. We therefore used in silico, in vitro and in vivo approaches to detail the effect of PLD1 on BC invasion. In BC patients, higher levels of PLD1 expression were associated with poor prognoses. PLD1 knockdown significantly suppressed cellular invasion by human BC cells and matrix metalloproteinase-13 (MMP-13) was observed to mediate this effect. In our mouse bladder carcinogenesis model, the development of invasive BCs was suppressed by PLD1 knockout and a global transcriptomic analysis in this model indicated MMP-13 as a potential tumor invasion gene with NF-κB (nuclear factor-kB) as its transcriptional regulator. Furthermore, PA administration increased MMP-13 expression in line with NF-κB p65 phosphorylation levels. Collectively, we demonstrate that PLD1 promotes tumor invasion of BC by regulation of MMP-13 expression through the NF-κB signaling pathway and that PLD1 might be a potential therapeutic target to prevent clinical progression in BC patients.
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http://dx.doi.org/10.1016/j.canlet.2021.04.014DOI Listing
July 2021

Pembrolizumab for treating advanced urothelial carcinoma in patients with impaired performance status: Analysis of a Japanese nationwide cohort.

Cancer Med 2021 05 1;10(10):3188-3196. Epub 2021 May 1.

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

Background: The benefits of pembrolizumab in patients with advanced urothelial carcinoma (UC) and impaired performance status (PS) remain unknown. This study assessed the safety and efficacy of pembrolizumab in patients with platinum-refractory UC and Eastern Cooperative Oncology Group PS ≥2 to identify which subgroups may benefit from this drug.

Methods: This retrospective nationwide cohort study collected clinicopathological information for 755 patients from 59 institutions. The overall response rate (ORR) and overall survival (OS) were compared among the patients with PS 0-1, 2, and 3-4. Multivariate analysis was conducted to identify factors predicting OS in patients with PS ≥2.

Results: The numbers of patients with PS 0-1, 2, and 3-4 were 602, 98, and 55, respectively; the ORRs in these groups were 29.5, 15.3, and 9.1%, respectively, and the median OS times were 14.3, 3.1, and 2.4 months, respectively. In multivariate Cox regression analysis, a neutrophil-lymphocyte ratio (NLR) ≥3.5 (hazard ratio [HR] = 1.897) and liver metastasis (HR = 2.072) were associated with OS in the PS ≥2 subgroup. The median OS of patients with PS ≥2 without either risk factor was 6.8 months, compared with 3.1 months for patients with one risk factor and 2.3 months for patients with both risk factors.

Conclusions: PS ≥2 portended worse ORR and OS than PS ≤1 despite a comparable safety profile. Among the patients with impaired PS, patients with NLR <3.5 and no liver metastasis may most greatly benefit from pembrolizumab therapy.
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http://dx.doi.org/10.1002/cam4.3863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8124127PMC
May 2021

Bowel obstruction caused by a colonic mass 2 years after living-donor kidney transplantation.

ANZ J Surg 2021 Apr 13. Epub 2021 Apr 13.

Department of Gastrointestinal and Hepatobiliary-Pancreatic Surgery, The University of Tsukuba, Ibaraki, Japan.

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http://dx.doi.org/10.1111/ans.16852DOI Listing
April 2021

Health-Related Quality of Life in Testicular Cancer Survivors in Japan: A Multi-Institutional, Cross-Sectional Study Using the EORTC QLQ-TC26.

Urology 2021 Mar 27. Epub 2021 Mar 27.

Department of Urology, Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Urology, Miyagi Cancer Center, Natori, Japan.

Objective: To evaluate the health-related quality of life (QOL) of testicular cancer (TC) survivors using the Japanese version of the EORTC QLQ-TC26 questionnaire in a multi-institutional, cross-sectional study.

Methods: This study recruited TC survivors who were followed after treatment for TC at eight high-volume institutions between January, 2018 and March, 2019. The participants completed the EORTC QLQ-TC26 questionnaire and mailed the completed questionnaires to a central institution. The QOL scores were assessed according to therapeutic modality (watchful waiting, WW; chemotherapy, CT; and CT followed by retroperitoneal lymph node dissection, CT+RPLND) and follow-up period and compared using analysis of variance and Student's t-test.

Results: A total of 567 TC survivors responded to the questionnaire. The median age at response was 43 years (IQR 35-51 years), and the median follow-up was 5.2 years (IQR 2.2-10.0 years). As for treatment side effects and physical limitations, the scores of the CT+RPLND group were significantly higher than those of the WW group, especially within one year after treatment. In addition, TC survivors in the CT+RPLND group reported high impairment related to job and education problems and future perspective less than 5 years after treatment. Even TC survivors in the WW group were anxious about job and education issues within one year after treatment.

Conclusion: TC survivors were anxious about not only cancer recurrence, but also their jobs and education. TC patients should be given appropriate information on QOL after treatment for TC to attenuate post-treatment anxiety and improve their health-related QOL.
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http://dx.doi.org/10.1016/j.urology.2021.02.039DOI Listing
March 2021

Adjuvant atezolizumab versus observation in muscle-invasive urothelial carcinoma (IMvigor010): a multicentre, open-label, randomised, phase 3 trial.

Lancet Oncol 2021 04 12;22(4):525-537. Epub 2021 Mar 12.

Barts Cancer Institute, Queen Mary University of London, St Bartholomew's Hospital, London, UK.

Background: Despite standard curative-intent treatment with neoadjuvant cisplatin-based chemotherapy, followed by radical surgery in eligible patients, muscle-invasive urothelial carcinoma has a high recurrence rate and no level 1 evidence for adjuvant therapy. We aimed to evaluate atezolizumab as adjuvant therapy in patients with high-risk muscle-invasive urothelial carcinoma.

Method: In the IMvigor010 study, a multicentre, open-label, randomised, phase 3 trial done in 192 hospitals, academic centres, and community oncology practices across 24 countries or regions, patients aged 18 years and older with histologically confirmed muscle-invasive urothelial carcinoma and an Eastern Cooperative Oncology Group performance status of 0, 1, or 2 were enrolled within 14 weeks after radical cystectomy or nephroureterectomy with lymph node dissection. Patients had ypT2-4a or ypN+ tumours following neoadjuvant chemotherapy or pT3-4a or pN+ tumours if no neoadjuvant chemotherapy was received. Patients not treated with neoadjuvant chemotherapy must have been ineligible for or declined cisplatin-based adjuvant chemotherapy. No post-surgical radiotherapy or previous adjuvant chemotherapy was allowed. Patients were randomly assigned (1:1) using a permuted block (block size of four) method and interactive voice-web response system to receive 1200 mg atezolizumab given intravenously every 3 weeks for 16 cycles or up to 1 year, whichever occurred first, or to observation. Randomisation was stratified by previous neoadjuvant chemotherapy use, number of lymph nodes resected, pathological nodal status, tumour stage, and PD-L1 expression on tumour-infiltrating immune cells. The primary endpoint was disease-free survival in the intention-to-treat population. Safety was assessed in patients who either received at least one dose of atezolizumab or had at least one post-baseline safety assessment. This trial is registered with ClinicalTrials.gov, NCT02450331, and is ongoing but not recruiting patients.

Findings: Between Oct 5, 2015, and July 30, 2018, we enrolled 809 patients, of whom 406 were assigned to the atezolizumab group and 403 were assigned to the observation group. Median follow-up was 21·9 months (IQR 13·2-29·8). Median disease-free survival was 19·4 months (95% CI 15·9-24·8) with atezolizumab and 16·6 months (11·2-24·8) with observation (stratified hazard ratio 0·89 [95% CI 0·74-1·08]; p=0·24). The most common grade 3 or 4 adverse events were urinary tract infection (31 [8%] of 390 patients in the atezolizumab group vs 20 [5%] of 397 patients in the observation group), pyelonephritis (12 [3%]) vs 14 [4%]), and anaemia (eight [2%] vs seven [2%]). Serious adverse events occurred in 122 (31%) patients who received atezolizumab and 71 (18%) who underwent observation. 63 (16%) patients who received atezolizumab had a treatment-related grade 3 or 4 adverse event. One treatment-related death, due to acute respiratory distress syndrome, occurred in the atezolizumab group.

Interpretation: To our knowledge, IMvigor010 is the largest, first-completed phase 3 adjuvant study to evaluate the role of a checkpoint inhibitor in muscle-invasive urothelial carcinoma. The trial did not meet its primary endpoint of improved disease-free survival in the atezolizumab group over observation. Atezolizumab was generally tolerable, with no new safety signals; however, higher frequencies of adverse events leading to discontinuation were reported than in metastatic urothelial carcinoma studies. These data do not support the use of adjuvant checkpoint inhibitor therapy in the setting evaluated in IMvigor010 at this time.

Funding: F Hoffmann-La Roche/Genentech.
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http://dx.doi.org/10.1016/S1470-2045(21)00004-8DOI Listing
April 2021

Retroperitoneal lymph node dissection for testicular cancer in a patient with a double inferior vena cava.

IJU Case Rep 2021 Mar 31;4(2):86-88. Epub 2021 Jan 31.

Department of Urology University of Tsukuba Hospital Tsukuba Ibaraki Japan.

Introduction: A double inferior vena cava is a rare anomaly with an incidence ranging from 0.3% to 3.0%. In patients with a double inferior vena cava, it is important to understand the precise anatomy and possible irregular lymph node flow when performing surgery for malignancies.

Case Presentation: A 60-year-old man with a non-seminoma was referred to our hospital after left high orchiectomy. Computed tomography revealed a double inferior vena cava and swollen masses in the para-aortic region. After four cycles of chemotherapy with etoposide and cisplatin, retroperitoneal lymph node dissection was safely performed with a modified template extended to the right side of the paracaval region by referring to three-dimensional images created by SYNAPSE VINCENT® software.

Conclusion: Preoperative three-dimensional images were useful to understand this patient's unusual and complicated anatomical positions.
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http://dx.doi.org/10.1002/iju5.12247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7924090PMC
March 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

Bladder preservation therapy in combination with atezolizumab and radiation therapy for invasive bladder cancer (BPT-ART) - A study protocol for an open-label, phase II, multicenter study.

Contemp Clin Trials Commun 2021 Mar 21;21:100724. Epub 2021 Jan 21.

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

Radical cystectomy (RC) is recommended for muscle-invasive bladder cancer (MIBC) or highest-risk non-muscle-invasive bladder cancer (NMIBC). Trimodal therapy (TMT) is the most favorable strategy among bladder preservation therapies (BPT) for patients who are ineligible for or refuse RC. However, referrals for TMT, especially following chemotherapy, are limited by the patient's condition. Therefore, new BPT approaches are needed. Atezolizumab inhibits programmed death-ligand 1, is well-tolerated in patient populations heavily dominated by renal insufficiency, and is expected to have synergistic anti-tumor effects in combination with radiation therapy (RT). Therefore, we have conducted this open-label phase II multicenter study to evaluate the efficacy and safety of RT in combination with atezolizumab for T2-3 MIBC and highest-risk T1 NMIBC patients. This study was initiated in January 2019, and we aimed to enroll a total of 45 patients. The study is registered in the Japan Registry of Clinical Trials (Identifier: RCT2031180060).
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http://dx.doi.org/10.1016/j.conctc.2021.100724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878176PMC
March 2021

The liposome of trehalose dimycolate extracted from M. bovis BCG induces antitumor immunity via the activation of dendritic cells and CD8 T cells.

Cancer Immunol Immunother 2021 Feb 11. Epub 2021 Feb 11.

Osaka City University, Osaka, Japan.

Intravesical Bovis bacillus Calmette-Guérin (BCG) therapy is the most effective immunotherapy for bladder cancer, but it sometime causes serious side effects because of its inclusion of live bacteria. It is necessary to develop a more active but less toxic immunotherapeutic agent. Trehalose 6,6'-dimycolate (TDM), the most abundant hydrophobic glycolipid of the BCG cell wall, has been reported to show various immunostimulatory activities such as granulomagenesis and adjuvant activity. Here, we developed cationic liposomes incorporating TDM purified from Mycobacterium bovis BCG Connaught, and we investigated the antitumor effect of the cationic liposome TDM (Lip-TDM). Lip-TDM exerted an antitumor effect in bladder cancer, colon cancer, and melanoma-bearing mouse models that was comparable or even superior to that of BCG, with no body weight loss or granuloma formation. The antitumor effect of Lip-TDM disappeared in two types of mice: those with depletion of CD8 T cells, and those with knockout of macrophage-inducible C-type lectin (Mincle) which recognize TDM. Lip-TDM treatment enhanced the maturation and migration of dendritic cells in the tumor microenvironment in a Mincle-dependent manner. Our results elucidate mechanisms that underlie Lip-TDM treatment and suggest that Lip-TDM has potential as a safe and effective treatment for various cancers.
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http://dx.doi.org/10.1007/s00262-021-02870-2DOI Listing
February 2021

[Promotion of Equal Access to Medical Services for Children, Adolescent and Young Adult(CAYA)Cancer Patients with Reproductive Problems-A Nationwide Expansion of the Regional Oncofertility Network in Japan].

Gan To Kagaku Ryoho 2020 Dec;47(12):1691-1696

Dept. of Obstetrics and Gynecology, Gifu University Graduate School of Medicine.

Objectives: Fertility preservation is important for Children, Adolescent and Young Adult(CAYA)cancer patients. Although a regional oncofertility network was established in Japan in 2012, regional inequality persists. This study was aimed at expanding the oncofertility network throughout Japan.

Methods: Oncologists, reproductive medicine specialists, and administrative officials from 24 regions, currently without a regional oncofertility network, conferred to discuss problems and strategies for network expansion.

Results: Regional oncofertility networks had already been established in 4 of 24 regions. Consultation and support and a collaboration system between facilities and individual doctors were found in 13 and 14 regions, respectively. Regarding which organization should lead the network operation, the regions(number)chose the prefecture (10), prefectural cancer centers(10), and OB/GYN department of hospitals specializing in cancer treatment(9). Obstacles to establishing a regional oncofertility network were the lack of manpower(21), budget(19), know-how(16), and specialists( 12).

Discussion: CAYA cancer patients need equal access to oncofertility networks, and a public support system is essential for preserving the fertility of cancer patients. We should organize a oncofertility network in association with prefectural administration. Medical staff training and supply of materials using the Oncofertility Consortium Japan system are required to promote the oncofertility network throughout Japan.
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December 2020

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

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
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