Publications by authors named "Toshinari Yamasaki"

98 Publications

Prognostic value of programmed death-ligand 1 status in Japanese patients with renal cell carcinoma.

Int J Clin Oncol 2021 Jul 21. Epub 2021 Jul 21.

Department of Surgical Pathology, Aichi Medical University Hospital, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan.

Background: Programmed death-ligand 1 (PD-L1) positivity is associated with poor prognosis in renal cell carcinoma (RCC). Because the prognostic impact and effect of confounding factors are less known, we investigated the prognostic significance of PD-L1 expression in Japanese patients with recurrent/metastatic RCC who started systemic therapy in 2010-2015.

Methods: This multicenter, retrospective study recruited patients from 29 Japanese study sites who had prior systemic therapy for RCC (November 2018 to April 2019) and stored formalin-fixed paraffin-embedded primary lesion samples. The primary outcome was overall survival (OS) by PD-L1 expression. Secondary outcomes included OS in subgroups and duration of first- and second-line therapies by PD-L1 expression. OS distributions were estimated using Kaplan-Meier methodology.

Results: PD-L1 expression (on immune cells [IC] ≥ 1%) was observed in 315/770 (40.9%) patients. PD-L1 positivity was more prevalent in patients with poor risk per both Memorial Sloan Kettering Cancer Center [MSKCC] and International Metastatic RCC Database Consortium, and high-risk pathological features (higher clinical stage, nuclear grade and sarcomatoid features). Median OS for PD-L1-positive patients was 30.9 months (95% CI 25.5-35.7) versus 37.5 months (95% CI 34.0-42.6) for PD-L1-negative patients (HR 1.04 [90% CI 0.89-1.22, p = 0.65]; stratified by MSKCC risk and liver metastases). Propensity score weight (PSW)-adjusted OS was similar between PD-L1-positive and -negative patients (median 34.4 versus 31.5 months; estimated PSW-adjusted HR 0.986).

Conclusions: This study suggests PD-L1 status was not an independent prognostic factor in recurrent/metastatic RCC during the study period because PD-L1 positivity was associated with poor prognostic factors, especially MSKCC risk status.
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http://dx.doi.org/10.1007/s10147-021-01993-xDOI Listing
July 2021

Detection of von Hippel-Lindau gene mutation in circulating cell-free DNA for clear cell renal cell carcinoma.

Cancer Sci 2021 May 19. Epub 2021 May 19.

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

The therapeutic landscape of metastatic clear cell renal cell carcinoma (ccRCC) has rapidly expanded, and there is an urgent need to develop noninvasive biomarkers that can select an optimal therapy or evaluate the response in real time. To evaluate the clinical utility of circulating tumor DNA (ctDNA) analysis in ccRCC, we established a highly sensitive assay to detect mutations in von Hippel-Lindau gene (VHL) using a combination of digital PCR and multiplex PCR-based targeted sequencing. The unique assay could detect VHL mutations with a variant allele frequency (VAF) <1.0%. Further, we profiled the mutation status of VHL in 76 cell-free DNA (cfDNA) and 50 tumor tissues from 56 patients with ccRCC using the assay. Thirteen VHL mutations were identified in cfDNA from 12 (21.4%) patients with a median VAF of 0.78% (range, 0.13%-4.20%). Of the 28 patients with VHL mutations in matched tumor tissues, eight (28.6%) also had VHL mutation in cfDNA with a median VAF of 0.47% (range, 0.13%-2.88%). In serial ctDNA analysis from one patient, we confirmed that the VAF of VHL mutation changed consistent with tumor size by radiographic imaging during systemic treatment. In conclusion, VHL mutation in cfDNA was detected only in a small number of patients even using the highly sensitive assay; nevertheless, we showed the potential of ctDNA analysis as a novel biomarker in ccRCC.
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http://dx.doi.org/10.1111/cas.14972DOI Listing
May 2021

Long-term clinical outcomes of external beam radiation therapy for oligometastatic prostate cancer: A combination of prostate-targeted treatment and metastasis-directed therapy.

Int J Urol 2021 Jul 2;28(7):749-755. Epub 2021 Apr 2.

Department of Radiation Oncology and Image-applied Therapy, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Objective: To assess the efficacy of combination of prostate-targeted treatment and metastasis-directed therapy for oligometastatic prostate cancer.

Methods: We retrospectively evaluated the clinical outcomes of synchronously diagnosed oligometastatic prostate cancer patients treated with external beam radiation therapy for the prostate and all metastatic lesions (≤3 lesions) at Kyoto University Hospital between January 2004 and April 2019. The prescribed dose was basically ≥70 Gy for the prostate with or without whole pelvic irradiation, and ≥45 Gy for the metastatic lesions. Clinical outcomes were compared with a contemporary cohort of 55 synchronous oligometastatic prostate cancer patients treated with the standard of care.

Results: In total, 16 consecutive patients with synchronous oligometastatic prostate cancer were analyzed. The median follow-up period was 7.4 years. The 8-year overall survival, prostate cancer-specific survival, biochemical failure-free, clinical failure-free and castration-resistant prostate cancer-free rates were 64.8%, 71.3%, 38.5%, 47.3% and 67.3%, respectively. No grade 3 or higher radiation-induced late toxicities occurred. Patients with prostate-targeted treatment plus metastasis-directed therapy had a significantly higher castration-resistant prostate cancer-free rate than those without prostate-targeted treatment plus metastasis-directed therapy (P = 0.00741).

Conclusions: Prostate-targeted treatment plus metastasis-directed therapy through external beam radiation therapy can result in favorable long-term disease-free and survival outcomes with acceptable morbidities among synchronous oligometastatic prostate cancer patients. Therefore, this approach may represent a promising treatment strategy for this population. Further investigation is required.
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http://dx.doi.org/10.1111/iju.14567DOI Listing
July 2021

Effect of optimal neoadjuvant chemotherapy on oncological outcomes of locally advanced bladder cancer with laparoscopic radical cystectomy: A matched-pair analysis in a multicenter cohort.

Int J Urol 2021 06 7;28(6):656-664. Epub 2021 Mar 7.

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

Objectives: To assess the effect of optimal neoadjuvant chemotherapy of at least three cycles of cisplatin-based regimen on oncological outcomes of clinical stage T3 or higher bladder cancer treated with laparoscopic radical cystectomy.

Methods: Laparoscopic radical cystectomies carried out at 10 institutions were included in this retrospective study. The outcomes of patients who received optimal neoadjuvant chemotherapy and those who did not receive neoadjuvant chemotherapy were compared using propensity score matching in clinical stage T3-4 or T2 cohorts, separately.

Results: Of the 455 patients screened, matched pairs of 54 patients in the clinical T3-4 cohort and 68 patients in the clinical T2 cohort were finally analyzed. In the cT3-4 cohort, the 5-year overall survival (78% vs 41%; P = 0.014), cancer-specific survival (81% vs 44%; P = 0.008) and recurrence-free survival (71% vs 53%; P = 0.049) were significantly higher in the optimal neoadjuvant chemotherapy group than in the no neoadjuvant chemotherapy group; no significant survival difference was shown between the two groups in the cT2 cohort. In the cT3-4 cohort, the incidence of local recurrence (4% vs 26%; P = 0.025) and abdominal or intrapelvic recurrence, including peritoneal carcinomatosis (7% vs 30%; P = 0.038), was significantly lower in the optimal neoadjuvant chemotherapy group.

Conclusions: Administration of optimal neoadjuvant chemotherapy has a significant survival benefit. It decreases the incidence of local and atypical recurrence patterns in patients with clinical stage T3 or higher locally advanced bladder cancer undergoing laparoscopic radical cystectomy.
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http://dx.doi.org/10.1111/iju.14533DOI Listing
June 2021

AUTHOR REPLY.

Urology 2021 Feb;148:158

Department of Urology, Kobe City Medical Centre General Hospital, Kobe, Japan.

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http://dx.doi.org/10.1016/j.urology.2020.08.097DOI Listing
February 2021

Effect of Continued Perioperative Anticoagulant Therapy on Bleeding Outcomes Following Robot-assisted Radical Prostatectomy.

Urology 2021 Feb 25;148:151-158. Epub 2020 Nov 25.

Department of Urology, Kobe City Medical Centre General Hospital, Kobe, Japan.

Objective: To assess the impact of continued perioperative anticoagulant drug administration on bleeding and complications in patients undergoing robot-assisted radical prostatectomy.

Methods: Between January 2014 and January 2020, 620 patients with prostate cancer underwent robot-assisted radical prostatectomies and were retrospectively reviewed. Fourteen patients who discontinued antithrombotic therapy were excluded. Among the 606 included patients, 31 continued anticoagulant therapy during the perioperative phase (anticoagulant group). The anticoagulant group outcomes were compared with those of patients who continued clopidogrel and prasugrel (thienopyridine group = 13), aspirin monotherapy (aspirin group = 61), and no chronic antithrombotic agent (control group = 501). The primary outcome was the incidence of bleeding complications requiring transfusion, additional intervention, or readmission. Secondary outcomes were the incidence of thrombotic complications, estimated blood loss, and overall complication rates.

Results: Among the 31 patients in the anticoagulant group, 20 (65%) used directed oral anticoagulants, 11 (35%) used warfarin, and 5 used combined aspirin. Only 1 (3%) patient in the anticoagulant group required postoperative transfusion, and none required additional interventions or readmission. No significant differences were detected between the anticoagulant and other groups (anticoagulant vs thienopyridine, aspirin, and control groups) regarding bleeding complications (3% vs 8%, P = .51; 0%, P = .34; 0.4%, P = .17, respectively), thrombotic complications (3% vs 0%, P = .70; 2%, P = .56; 0.2%, P = .11, respectively), estimated blood loss (200 vs 100 mL, P = .63; 175 mL, P = .64; 165 mL, P = .74, respectively), or other high-grade complications (6% vs 0%, P = .49; 2%, P = .26; 3%, P = .24, respectively).

Conclusion: Perioperative continuation of anticoagulant use is feasible for patients undergoing robot-assisted radical prostatectomy.
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http://dx.doi.org/10.1016/j.urology.2020.08.095DOI Listing
February 2021

Masked acute rejection of the graft kidney under the recovery of native kidneys in a patient who underwent simultaneous liver and kidney transplantation.

IJU Case Rep 2020 Nov 18;3(6):237-240. Epub 2020 Aug 18.

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

Introduction: Simultaneous liver and kidney transplantation is a life-saving procedure for patients with liver failure and irreversible renal dysfunction. However, some studies have reported the recovery of native renal function after simultaneous liver and kidney transplantation.

Case Presentation: A 33-year-old woman initially underwent living-donor liver transplantation for liver failure. When graft liver failure developed, she also sustained acute renal failure and required continuous hemodiafiltration for 6 weeks. Simultaneous liver and kidney transplantation from a brain-dead donor recovered her liver and renal function. A 1-year protocol graft kidney biopsy revealed acute cellular rejection despite stable serum creatinine levels. Renal scintigraphy showed functional native kidneys masking acute rejection of the graft kidney. The rejection was improved by pulse steroid therapy.

Conclusion: Acute rejection of the graft kidney may silently progress due to recovery of the native kidney function after simultaneous liver and kidney transplantation. Renal scintigraphy and graft kidney biopsy should be considered even if blood tests indicate stable total renal function.
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http://dx.doi.org/10.1002/iju5.12197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609179PMC
November 2020

Increased risk of disease progression in younger men: Analysis of factors predicting biochemical failure and castration-resistant prostate cancer after high-dose intensity-modulated radiation therapy for nonmetastatic prostate cancer.

Urol Oncol 2021 02 27;39(2):131.e9-131.e15. Epub 2020 Oct 27.

Department of Radiation Oncology and Image-applied Therapy, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507 Japan. Electronic address:

Background: The aim of this study was to investigate the clinical significance of the effect of age on disease control in men who received high-dose intensity-modulated radiation therapy (IMRT) for nonmetastatic prostate cancer (NMPCa).

Methods: NMPCa patients with favorable intermediate to very high-risk features (National Comprehensive Cancer Network risk classification) treated with IMRT at our institution between September 2000 and May 2011 were analyzed retrospectively. Treatment consisted of high-dose IMRT (74-78 Gy/37-39 fractions) combined with 6 months of neoadjuvant hormonal therapy. Multivariable analysis using Fine and Gray's regression model was performed to evaluate whether age at initiation of IMRT was associated with biochemical failure (BF) and castration-resistant prostate cancer (CRPC) progression.

Results: A total of 367 patients were analyzed. The median follow-up period was 8.8 years after IMRT. The 5- and 10-year BF rates were 22.1 and 31.7%, and those of CRPC rates were 4.5 and 12.6%, respectively. Multivariable analysis revealed that a younger age (cut-off: 70 years old) at the initiation of IMRT was significantly correlated with both a higher BF rate (hazard ratio: 1.691, P= 0.0064) and higher CRPC rate (hazard ratio: 2.579, P = 0.0079).

Conclusions: Younger men with NMPCa had increased risks of BF and CRPC after high-dose IMRT, and may benefit from more intensive treatments. Our findings should be further tested in prospective studies.
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http://dx.doi.org/10.1016/j.urolonc.2020.09.026DOI Listing
February 2021

Functional and genomic characterization of patient-derived xenograft model to study the adaptation to mTORC1 inhibitor in clear cell renal cell carcinoma.

Cancer Med 2021 01 27;10(1):119-134. Epub 2020 Oct 27.

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

Resistance to the mechanistic target of rapamycin (mTOR) inhibitors, which are a standard treatment for advanced clear cell renal cell carcinoma (ccRCC), eventually develops in most cases. In this study, we established a patient-derived xenograft (PDX) model which acquired resistance to the mTOR inhibitor temsirolimus, and explored the underlying mechanisms of resistance acquisition. Temsirolimus was administered to PDX model mice, and one cohort of PDX models acquired resistance after repeated passages. PDX tumors were genetically analyzed by whole-exome sequencing and detected several genetic alterations specific to resistant tumors. Among them, mutations in ANKRD12 and DNMT1 were already identified in the early passage of a resistant PDX model, and we focused on a DNMT1 mutation as a potential candidate for developing the resistant phenotype. While DNMT1 expression in temsirolimus-resistant tumors was comparable with the control tumors, DNMT enzyme activity was decreased in resistant tumors compared with controls. Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9-mediated heterozygous knockdown of DNMT1 in the temsirolimus-sensitive ccRCC (786-O) cell line was shown to result in a temsirolimus-resistant phenotype in vitro and in vivo. Integrated gene profiles using methylation and microarray analyses of PDX tumors suggested a global shift for the hypomethylation status including promotor regions, and showed the upregulation of several molecules that regulate the mTOR pathway in temsirolimus-resistant tumors. Present study showed the feasibility of PDX model to explore the mechanisms of mTOR resistance acquisition and suggested that genetic alterations, including that of DNMT1, which alter the methylation status in cancer cells, are one of the potential mechanisms of developing resistance to temsirolimus.
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http://dx.doi.org/10.1002/cam4.3578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826464PMC
January 2021

[A Case of Primary Ewing Sarcoma of the Kidney Treated with Multidisciplinary Approach].

Hinyokika Kiyo 2020 Sep;66(9):297-302

The Department of Urology, Kansai Electric Power Hospital.

A woman in her 40s visited our hospital for further examination and treatment of a left renal tumor. Imaging studies showed that the patient had a large left renal tumor, 10.5 cm in diameter, which contained foci of necrosis. Open left radical nephrectomy was performed. In pathological examination, hematoxylin-eosin staining showed uniform small round cells with alveolar growth. Immunohistochemistry findings showed that CD99 and NKX2. 2 were positive, and synaptophysin was focally positive. Fluorescence in situ hybridization confirmed (11 ; 22) (q24 ; q12) chromosomal translocation which led to diagnosis of primary Ewing sarcoma of the kidney. Two months after the surgery, new tumors were found inside and outside of the left psoas muscles and in the left paracolic gutter. Six courses of chemotherapy were administered with VDC (vincristine/doxorubicin/cyclophosphamide) and IE (ifosfamide/etoposide). After completing the combined chemotherapy, the recurrent tumors disappeared completely on imaging. To prevent further recurrence, external radiation was administered to the left retroperitoneal region. About 16 months after the surgery, numerous new tumors appeared in the left retroperitoneal, left pleura, and erector spinae muscles. Chemotherapy was resumed following radiotherapy, and then trabectedin was administered. However, she eventually died of progressive disease at 26 months after the surgery.
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http://dx.doi.org/10.14989/ActaUrolJap_66_9_297DOI Listing
September 2020

Solitary recurrence of prostate cancer surrounded by seminal vesicle/vas deferens-like epithelium.

IJU Case Rep 2020 Sep 30;3(5):171-173. Epub 2020 Jul 30.

Department of Nephro-urologic Surgery Mie University Hospital Tsu Japan.

Introduction: Clinical recurrence of prostate cancer after curative treatment with a limited number of metastases is often termed as oligorecurrence. We report a case of solitary recurrence of prostate cancer surrounded by epithelium of the seminal vesicle or vas deferens.

Case Presentation: A 54-year-old man diagnosed with localized prostate cancer underwent radiation therapy. Six years later, imaging studies detected a solitary recurrence. We performed metastasectomy, and histopathological examination revealed the metastatic lesion surrounded by the epithelium of the seminal vesicle or vas deferens. Surgical resection achieved a complete biochemical response.

Conclusion: We presented with a case of prostate cancer metastasis surrounded by the epithelium of the seminal vesicle or vas deferens.
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http://dx.doi.org/10.1002/iju5.12168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469812PMC
September 2020

Tc-mercaptoacetyltriglycine Cortical Renography Predicts Outcomes in Adult Living Donor Renal Transplant Recipients.

Transplant Proc 2020 Dec 27;52(10):3090-3096. Epub 2020 Jun 27.

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

Background: The clinical utility of Tc-mercaptoacetyltriglycine cortical renography for the prediction of graft function in kidney transplant recipients has been unknown.

Methods: We retrospectively reviewed post-transplant cortical renograms in 40 kidney transplant recipients. We analyzed the correlation between T (elimination half-life) and graft function (measured-to-expected glomerular filtration rate [GFR]) 1 week, and 1, 3, and 6 months post operation compared with whole-kidney renograms.

Results: Delayed drainage (T > 11 minutes) was observed in 22 recipients (55%). T and postoperative GFR ratio were inversely correlated (1 week: R = 0.317, P = .0002; 1 month: R = 0.206, P = .003; 3 months: R = 0.117, P = .031; 6 months: R = 0.161, P = .010). Recipients with delayed drainage had a significantly lower GFR ratio than those with normal drainage 1 week (median, 0.93 vs 1.32; P = .001), 1 month (median, 1.65 vs 2.23; P = .0010), 3 months (median, 1.55 vs 2.17; P = .041), and 6 months (median, 1.67 vs 2.34; P = .018) post operation, respectively. Whole-kidney renograms failed to discriminate recipients with lower GFR ratio at 1, 3, and 6 months.

Conclusions: T in post-transplant cortical renography was inversely correlated with early graft function and may predict early post-transplant graft function.
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http://dx.doi.org/10.1016/j.transproceed.2020.02.169DOI Listing
December 2020

Long-term clinical outcomes of salvage pelvic radiation therapy for oligo-recurrent pelvic lymph nodes after definitive external-beam radiation therapy for non-metastatic prostate cancer.

J Radiat Res 2020 Jul;61(4):622-628

Department of Radiation Oncology and Image-applied Therapy, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507 Japan.

Although salvage external-beam radiation therapy (EBRT) is an attractive treatment option for pelvic lymph nodal recurrence (PeNR) in patients with prostate cancer (PCa), limited data are available regarding its long-term efficacy. This study examined the long-term clinical outcomes of patients who underwent salvage pelvic radiation therapy (sPRT) for oligo-recurrent pelvic lymph nodes after definitive EBRT for non-metastatic PCa. Patients who developed PeNR after definitive EBRT and were subsequently treated with sPRT at our institution between November 2007 and December 2015 were retrospectively analyzed. The prescribed dose was 45-50.4 Gy (1.8-2 Gy per fraction) to the upper pelvis, with up to 54-66 Gy (1.8-2 Gy per fraction) for recurrent nodes. Long-term hormonal therapy was used as neoadjuvant and/or adjuvant therapy. The study population consisted of 12 consecutive patients with PeNR after definitive EBRT (median age: 73 years). The median follow-up period was 58.9 months. The 5-year overall survival, PCa-specific survival, biochemical failure-free, clinical failure-free, and castration-resistant PCa-free rates were 82.5, 100.0, 62.3, 81.8, and 81.8%, respectively. No grade 2 or higher sPRT-related late toxicities occurred. In conclusion, more than half of the study patients treated with sPRT had a long-term disease-free status with acceptable morbidities. Moreover, most of the patients maintained hormonal sensitivity. Therefore, this approach may be a promising treatment method for oligo-recurrent pelvic lymph nodes.
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http://dx.doi.org/10.1093/jrr/rraa044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7336814PMC
July 2020

Successful surgical management of recurrent urachal adenocarcinoma: A case report.

Urol Case Rep 2020 Sep 13;32:101196. Epub 2020 Apr 13.

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

Urachal carcinoma is a rare neoplasm for which there is a lack of a standard effective chemotherapeutic treatment. There is also no standard treatment available for recurrent metastatic urachal carcinoma and the prognosis is generally poor. We report a case of urachal carcinoma where the patient achieved long-term disease-free survival after repeated surgeries for recurrent lung metastases.
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http://dx.doi.org/10.1016/j.eucr.2020.101196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7171456PMC
September 2020

[Kidney Auto-Transplantation for Intraoperative Right Renal Artery Injury in a Single Kidney Patient : A Case Report].

Hinyokika Kiyo 2019 Nov;65(11):455-458

The Department of Urology, Kyoto University Hospital.

A man in his 70's who had undergone left radical nephrectomy for kidney cancer had the right renal artery ablated unexpectedly during pancreatoduodenectomy for a huge duodenal tumor. For this intraoperative emergency, an autologous kidney transplantation was performed with the right kidney being removed, perfused, and transplanted into the right iliac fossa. Warm ischemic time was over 2 hours. The patient developed postoperative hemorrhagic infarction of a renal artery branch, which was successfully treated with intravascular intervention. The patient was weaned off hemodialysis and was discharged in 16 weeks postoperatively.
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http://dx.doi.org/10.14989/ActaUrolJap_65_11_455DOI Listing
November 2019

[Post-Operative Urethral Stricture after Holmium Laser Enucleation of the Prostate].

Hinyokika Kiyo 2019 Nov;65(11):445-449

The Department of Urology, Kyoto University Hospital.

Holmium laser enucleation of the prostate (HoLEP) is a safe and effective surgical procedure for patients suffering from comparatively larger benign prostatic hyperplasia. However, the rate of postoperative urethral stricture (POUS) is relatively high, which can render further invasive intervention. Here we assessed the POUS rate, riskfactors and outcomes in 206 patients with benign prostatic hyperplasia who underwent HoLEP at our hospital between January 2006 and December 2015. POUS was observed in 24 patients (11.7%). The rate of intraoperative urethral stricture was significantly higher in the patients with POUS (8 out of 24 patients, 33.3%) than in those without POUS (12 out of 186 patients, 6.6%). The odds ratio was 7.08, 95% and combination index (CI) was 2.53-19.9, p<0.001). The relative riskfor POUS based on intraoperative urethral stricture was 4.65 (95% CI : 2.28-9.48). The most common POUS site was external urethral orifice (12 out of 24 cases). The POUS onset was significantly earlier in patients with external urethral orifice than the other sites (p=0.0389). The site of postoperative stricture concurred with that of intraoperative stricture at a high rate (7 out of 8 patients). Significant differences were observed between patients with and without POUS within one month in international prostate symptom score, quality of life score and in Qmax after the operation, while they were improved by simple interventions such as bougie. In conclusion, we should consider the possibility of POUS when the patient had an intraoperative stricture in HoLEP.
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http://dx.doi.org/10.14989/ActaUrolJap_65_11_445DOI Listing
November 2019

Low incidence of late recurrence in patients with intermediate-risk prostate cancer treated by intensity-modulated radiation therapy plus short-term androgen deprivation therapy.

Int J Clin Oncol 2020 Apr 9;25(4):713-719. Epub 2019 Dec 9.

Department of Radiation Oncology and Image-Applied Therapy, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.

Objectives: This study evaluated the long-term outcomes of intensity-modulated radiation therapy (IMRT) combined with short-term neoadjuvant androgen deprivation therapy (ADT) in patients with intermediate-risk (IR) prostate cancer (PCa).

Materials And Methods: Patients with IR PCa treated with IMRT at our institution between September 2000 and November 2010 were analyzed retrospectively. The treatment consisted of IMRT (70-78 Gy in 35-39 fractions) combined with 6 months of neoadjuvant ADT. Salvage ADT was initiated when the prostate-specific antigen level was > 4.0 ng/mL RESULTS: In total, 106 consecutive patients with IR PCa (median age: 70 years old) were analyzed. The median follow-up period was 8.0 years. The overall survival, PCa-specific survival, biochemical failure, and clinical failure rates were 99.0%, 100.0%, 6.8%, and 1.9% at 5 years and 89.1%, 100.0%, 11.3%, and 2.9% at 10 years, respectively. Late recurrence (> 5 years) was observed in three cases (2.8%). The cumulative incidence rates of genitourinary (GU) and gastrointestinal (GI) toxicities (grade 2/3) were 10.5% and 5.8% at 5 years, and 14.7% and 5.8% at 10 years, respectively. No patient developed grade 4/5 GU toxicities or grade 3-5 GI toxicities.

Conclusion: IMRT at a dose up to 78 Gy combined with short-term neoadjuvant ADT resulted in excellent long-term disease-free outcomes with acceptable morbidities among patients with IR PCa. In addition, the incidence of late recurrence was very low. Further investigation is warranted to confirm our findings.
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http://dx.doi.org/10.1007/s10147-019-01596-7DOI Listing
April 2020

Detectability of prostate cancer in different parts of the gland with 3-Tesla multiparametric magnetic resonance imaging: correlation with whole-mount histopathology.

Int J Clin Oncol 2020 Apr 2;25(4):732-740. Epub 2019 Dec 2.

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

Background: We investigated whether the detectability of prostate cancer with 3-Tesla (3T) multiparametric magnetic resonance imaging (mpMRI) differs by tumor location.

Methods: We identified 136 patients with prostate cancer who underwent 3-T mpMRI before prostatectomy at a single academic center. Two uroradiologists scored all MRIs with Prostate Imaging-Reporting and Data System version 2 (PI-RADS v2). A genitourinary pathologist mapped tumor foci from serial whole-mount radical prostatectomy sections. We assessed concordance of images with cancer sites. Tumor foci with Gleason score ≥  3 + 4 or volume ≥ 0.5 mL were considered significant.

Results: A total of 122 foci in 106 cases were identified with mpMRI. Twenty-four were PI-RADS 3, 52 were 4, and 46 were 5. A total of 274 tumor foci were identified with whole-mount pathology. The sensitivity stratified by location to detect significant cancer with a PI-RADS cutoff value of 3 was 56.0% overall, 50.0% in the peripheral zone (PZ), 71.2% in the transitional zone (TZ), 62.4% anterior, 49.5% posterior, 42.0% apical, 63.6% in the midgland, and 43.8% in the gland base. In multivariate analysis, tumor location was not a significant predictor of identification by mpMRI. Tumor volume, Gleason score, and index tumor status were significantly associated with identification by mpMRI.

Conclusions: mpMRI detected the majority of high-grade and large cancers, but had low sensitivity in the PZ, posterior, and apex and base of the gland. The high prevalence of low-volume, low-Gleason score index tumors, as well as satellite tumors in those areas, accounted for the difference.
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http://dx.doi.org/10.1007/s10147-019-01587-8DOI Listing
April 2020

LacdiNAc-Glycosylated Prostate-specific Antigen Density is a Potential Biomarker of Prostate Cancer.

Clin Genitourin Cancer 2020 02 17;18(1):e28-e36. Epub 2019 Oct 17.

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

Background: Serum LacdiNAc-glycosylated prostate-specific antigen (LDN-PSA) and LDN-PSA density together with PSA and PSA density (PSAD) were measured as a diagnostic tool for prostate cancer (PCa).

Patients And Methods: We included 150 patients with PCa without hormonal therapy and 41 patients without PCa obtained from the Kyoto University Hospital between 2012 and 2017. LDN-PSA levels were measured through a WFA-anti-PSA antibody sandwich immunoassay using a highly sensitive surface plasmon field-enhanced fluorescence spectroscopy (SPFS) system. Diagnostic performance of serum LDN-PSA and LDN-PSAD was evaluated by measuring the area under the receiver-operating characteristic curve (AUC).

Results: The AUCs of LDN-PSA, LDN-PSAD, and PSAD levels (0.780, 0.848, and 0.835, respectively) detected in patients with PCa were significantly higher (P = .0001, P < .0001, and P < .0001, respectively) than that of PSA (0.590). Moreover, among 143 patients with PCa who received radical prostatectomy (RP), the AUCs of LDN-PSA, LDN-PSAD, and PSAD levels (0.750, 0.812, and 0.769, respectively) detected in patients with a pathologic Gleason grade group ≥ 2 were significantly higher (P = .0170, P = .0028, and P = .0003, respectively) than that of PSA (0.578). In the group comprising 35 patients who received RP with a Gleason grade group 1-graded biopsy, the LDN-PSA, LDN-PSAD, and PSAD levels were significantly different (P = .0097, P = .0024, and P = .0312, respectively). However, PSA alone could not discriminate cases with adverse features (P = .454).

Conclusions: LDN-PSAD is a potential marker for detecting PCa and selecting candidates for RP.
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http://dx.doi.org/10.1016/j.clgc.2019.10.011DOI Listing
February 2020

[Clinical Effect of Nivolumab on Advanced Renal Cell Carcinoma with Peritoneal Metastasis].

Hinyokika Kiyo 2019 Oct;65(10):413-419

The Department of Urology, Kyoto University Hospital.

Peritoneal dissemination or metastasis is a relatively rare presentation of renal cell carcinoma. We report four cases of advanced renal cell carcinoma with peritoneal metastases treated with nivolumab. Three cases showed an objective response in the metastatic lesions including peritoneal sites. After nivolumab administration, the computed tomography scan showed a transient enlargement of peritoneal lesions in two cases, which could be considered as pseudoprogression. Temporal changes of neutrophil-tolymphocyte ratio, C-reactive protein, and eosinophil ratio during the clinical course reflected the treatment effect of nivolumab in these patients, indicating that these could be potential biomarkers of the response. To our knowledge, this is the first case series showing therapeutic activity of nivolumab against peritoneal metastases in patients with renal cell carcinoma.
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http://dx.doi.org/10.14989/ActaUrolJap_65_10_413DOI Listing
October 2019

Systematic chemical screening identifies disulfiram as a repurposed drug that enhances sensitivity to cisplatin in bladder cancer: a summary of preclinical studies.

Br J Cancer 2019 12 1;121(12):1027-1038. Epub 2019 Nov 1.

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

Background: Since the standard gemcitabine and cisplatin (GC) chemotherapy for advanced bladder cancer yields limited therapeutic effect due to chemoresistance, it is a clinical challenge to enhance sensitivity to GC.

Methods: We performed high-throughput screening by using a library of known chemicals and repositionable drugs. A total of 2098 compounds were administered alone or with GC to human bladder cancer cells, and chemicals that enhanced GC effects were screened.

Results: Disulfiram (DSF), an anti-alcoholism drug, was identified as a candidate showing synergistic effects with cisplatin but not with gemcitabine in multiple cell lines. Co-administration of DSF with GC affected cellular localisation of a cisplatin efflux transporter ATP7A, increased DNA-platinum adducts and promoted apoptosis. Micellar DSF nanoparticles (DSF-NP) that stabilised DSF in vivo, enhanced the inhibitory effect of cisplatin in patient-derived and cell-based xenograft models without severe adverse effects. A drug susceptibility evaluation system by using cancer tissue-originated spheroid culture showed promise in identifying cases who would benefit from DSF with cisplatin.

Conclusions: The present study highlighted the advantage of drug repurposing to enhance the efficacy of anticancer chemotherapy. Repurposing of DSF to a chemotherapy sensitiser may provide additional efficacy with less expense by using an available drug with a well-characterised safety profile.
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http://dx.doi.org/10.1038/s41416-019-0609-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6964684PMC
December 2019

Feasibility of laparoscopic adrenalectomy for metastatic adrenal tumors in selected patients: a retrospective multicenter study of Japanese populations.

Int J Clin Oncol 2020 Jan 30;25(1):126-134. Epub 2019 Aug 30.

Department of Urology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-Cho, Sakyo-Ku, Kyoto, 606-8507, Japan.

Background: Because of the small numbers of cases in single centers, the indications for and survival benefits of adrenalectomy for adrenal metastasis remain unclear. We evaluated the outcomes of laparoscopic adrenalectomy for patients with adrenal metastasis.

Methods: We retrospectively analyzed the records of 67 patients who underwent laparoscopic adrenalectomy for metastatic disease from 2003 to 2017 at 11 hospitals. Associations of clinical, surgical, and pathologic features with overall survival (OS) and positive surgical margins were evaluated using univariate and multivariate Cox regression analyses and univariate logistic regression analysis.

Results: Lung cancer (30%) and renal cell carcinoma (30%) were the most common primary tumor types. Intraoperative complications were observed in seven patients (10%) and postoperative complications in seven (10%). The surgical margin was positive in 10 patients (15%). The median OS was 3.8 years. Univariate analysis showed that the tumor size, episodes of extra-adrenal metastasis before adrenalectomy, extra-adrenal metastasis at the time of adrenalectomy, and positive surgical margins were significantly associated with shorter OS (p = 0.022, p = 0.005, p < 0.001, and p = 0.022, respectively). Multivariate analysis showed that extra-adrenal metastasis at the time of adrenalectomy and positive surgical margins remained statistically significant (p = 0.022 and p = 0.049, respectively). In the univariate analysis, the tumor size was significantly associated with positive surgical margins (p = 0.039).

Conclusions: Laparoscopic adrenalectomy for adrenal metastasis can be safely performed in selected patients, and patients with isolated adrenal metastasis and negative surgical margins seem to have more favorable outcomes.
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http://dx.doi.org/10.1007/s10147-019-01533-8DOI Listing
January 2020

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

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

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

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

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

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

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

Efficacy and Safety of Carboplatin Plus Paclitaxel as the First-, Second-, and Third-line Chemotherapy in Men With Castration-resistant Prostate Cancer.

Clin Genitourin Cancer 2019 10 12;17(5):e923-e929. Epub 2019 Jun 12.

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

Introduction: Carboplatin and paclitaxel (CP) had shown moderate efficacy in treating castration-resistant prostate cancer (CRPC) before standard first-line docetaxel chemotherapy became available. Currently, for patients with homology-directed repair gene defects as well as for unselected patients, platinum chemotherapy is administered after all standard treatments have been ineffective. Here, we retrospectively studied the efficacy and safety of CP administered as the first-, second-, and third-line chemotherapy in patients with CRPC.

Patients And Methods: A retrospective chart review was performed for 58 patients with CRPC who received CP between 2001 and 2018 in a single institution. Twenty-seven patients received CP as the first-line chemotherapy, 21 as the second-line after docetaxel, and 10 as the third-line after docetaxel and cabazitaxel. Prostate-specific antigen (PSA) responses (> 50% decline of PSA from baseline), progression-free survival, overall survival, and adverse events were examined.

Results: PSA responses at any time were 55.6%, 19.0%, and 10.0%; PSA responses at 12 weeks were 48.1%, 14.3%, and 10.0%; the median progression-free survival was 3, 1, and 1 month; and the median overall survival was 19, 11, and 6 months, respectively, for the first-, second-, and third-line settings. The only patient who achieved exceptional and durable PSA response in the third-line setting had a deleterious germline BRCA2 mutation (5645C>A). The adverse event profile was favorable.

Conclusion: CP shows moderate efficacy against CRPC in the first-line setting, but shows little effect in the third-line setting. CP after docetaxel and cabazitaxel may be recommended in selected patients with CRPC with homology-directed repair gene defects.
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http://dx.doi.org/10.1016/j.clgc.2019.04.017DOI Listing
October 2019

Analytical performance of a new automated chemiluminescent magnetic immunoassays for soluble PD-1, PD-L1, and CTLA-4 in human plasma.

Sci Rep 2019 07 12;9(1):10144. Epub 2019 Jul 12.

Kyoto University Institute for Advanced Study, Kyoto, Japan.

Current clinically approved biomarkers for the PD-1 blockade cancer immunotherapy are based entirely on the properties of tumour cells. With increasing awareness of clinical responses, more precise biomarkers for the efficacy are required based on immune properties. In particular, expression levels of immune checkpoint-associated molecules such as PD-1, PD-L1, and CTLA-4 would be critical to evaluate the immune state of individuals. Although quantification of their soluble form leased from the membrane will provide quick evaluation of patients' immune status, available methods such as enzyme-linked immunosorbent assays to measure these soluble factors have limitations in sensitivity and reproducibility for clinical use. To overcome these problems, we developed a rapid and sensitive immunoassay system based on chemiluminescent magnetic technology. The system is fully automated, providing high reproducibility. Application of this system to plasma of patients with several types of tumours demonstrated that soluble PD-1, PD-L1, and CTLA-4 levels were increased compared to those of healthy controls and varied among tumour types. The sensitivity and detection range were sufficient for evaluating plasma concentrations before and after the surgical ablation of cancers. Therefore, our newly developed system shows potential for accurate detection of soluble PD-1, PD-L1, and CTLA-4 levels in the clinical practice.
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http://dx.doi.org/10.1038/s41598-019-46548-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6626008PMC
July 2019

[A Case of Late Onset Nivolumab-Induced Interstitial Nephritis in a Patient with Metastatic Renal Cell Carcinoma].

Hinyokika Kiyo 2019 May;65(5):157-161

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

A 43-year-old man underwent nephrectomy for right renal cell carcinoma (cT3aN0M1 (PUL), clear cell carcinoma). Thereafter, he was treated with sunitinib for lung metastases as the first-line therapy for three months. Because lung metastases progressed and new bone metastases appeared, nivolumab was started for the second-line treatment. Although the cancer progression was suppressed by multidisciplinary treatment combined with systemic immunotherapy and local radiation therapy, he developed severe acute kidney injury with cortical swelling after eighteen months of nivolumab treatment. A diagnosis of acute interstitial nephritis induced by nivolumab was made based on biopsy findings. Treatment with prednisolone (1.0 mg/kg daily) led to a rapid improvement in renal function. We must consider the possibility of immunerelated adverse events, especially nivolumab-induced acute kidney injury, even after long-term treatment.
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http://dx.doi.org/10.14989/ActaUrolJap_65_5_157DOI Listing
May 2019

Development and Validation of a Novel Prognostic Model for Predicting Overall Survival in Treatment-naïve Castration-sensitive Metastatic Prostate Cancer.

Eur Urol Oncol 2019 05 23;2(3):320-328. Epub 2018 Nov 23.

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

Background: There has been growth in the treatment options for castration-sensitive metastatic prostate cancer (mPCa), but without clear guidance for risk stratification.

Objective: To identify clinical parameters associated with overall survival (OS) and establish a prognostic model for use with treatment-naïve castration-sensitive mPCa.

Design, Setting, And Participants: A retrospective review of 304 patients treated at Kyoto University Hospital was performed. A prognostic model was created using clinical parameters associated with OS. The model was externally validated in an independent cohort of 520 patients.

Outcome Measurements And Statistical Analysis: Multivariable analysis was performed to identify the clinical parameters associated with OS. Risk scores were calculated using Cox proportional hazards analysis for each combination of risk factors, and patients were grouped into categories based on those scores.

Results And Limitations: Over 80% of the cohort had a Gleason sum score ≥8. The median OS was 53mo among patients with CHAARTED high-volume PCa (n=172) and 131mo among those with low-volume PCa (n=100). Independent factors associated with OS were extent of disease score ≥2 or the presence of liver metastasis; lactate dehydrogenase >250U/L; and a primary Gleason score of 5. The median OS for the high-, intermediate-, and low-risk groups according to the new model were 28mo, 59mo, and not reached, respectively; the corresponding values in the validation cohort were 41mo, 63mo, and not reached. Harrell's C-index was 0.649.

Conclusions: Our simple and reproducible prognostic model for treatment-naïve castration-sensitive mPCa could aid in risk stratification and treatment selection.

Patient Summary: We identified clinical parameters associated with prognosis in castration-sensitive metastatic prostate cancer and established a reproducible prognostic model that could be used to guide treatment decisions.
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http://dx.doi.org/10.1016/j.euo.2018.10.011DOI Listing
May 2019

Ten-year outcomes of high-dose intensity-modulated radiation therapy for nonmetastatic prostate cancer with unfavorable risk: early initiation of salvage therapy may replace long-term adjuvant androgen deprivation.

Int J Clin Oncol 2019 Oct 31;24(10):1247-1255. Epub 2019 May 31.

Department of Radiation Oncology and Image-Applied Therapy, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.

Background: The optimal timing of salvage androgen deprivation therapy (ADT) following definitive radiation therapy for prostate cancer (PCa) is unknown. This study evaluated the efficacy of early initiation of salvage-ADT (S-ADT) based on predetermined timing among patients with unfavorable PCa treated with high-dose intensity-modulated radiation therapy (IMRT).

Materials And Methods: High-risk (HR) and very-high-risk (VHR) PCa patients treated with IMRT at our institution between September 2000 and December 2010 were analyzed retrospectively. Treatment consisted of high-dose IMRT (78 Gy/39 fractions) combined with 6 months of neoadjuvant-ADT (NA-ADT). S-ADT was initiated when prostate-specific antigen levels exceeded 4.0 ng/mL.

Results: In total, 268 (184 HR and 84 VHR) patients were analyzed. The median follow-up period was 114.4 months. The 10-year overall survival (OS), PCa-specific survival (PCSS), biochemical failure (BF), and clinical failure (CF) rates were 82.8%, 97.1%, 27.3%, and 12.8% among the HR PCa patients and 79.4%, 87.9%, 56.2%, and 26.7% among the VHR PCa patients (p = 0.839, = 0.0377, < 0.001, and < 0.001), respectively. The 10-year cumulative incidence rates of urinary and rectal (grades 2-3) toxicities were 22.6% and 5.8%, respectively. No grade 4 or higher toxicities were observed.

Conclusion: High-dose IMRT combined with short-term NA-ADT resulted in long-term disease-free status, with acceptable morbidity among approximately three-fourths of the HR PCa patients and nearly half of the VHR PCa patients. Moreover, excellent survival outcomes were achieved by the early S-ADT initiation. This approach may be a promising alternative to uniform provision of long-term ADT.
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http://dx.doi.org/10.1007/s10147-019-01478-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736780PMC
October 2019

Incidence, features, and prognosis of immune-related adverse events involving the thyroid gland induced by nivolumab.

PLoS One 2019 14;14(5):e0216954. Epub 2019 May 14.

Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Background: Blocking the PD-1 pathway induces immune-related adverse events (irAEs) which often involve the thyroid gland (thyroid irAEs). Clinical features of a thyroid irAE including its predictability and relationship to prognosis remain to be elucidated.

Methods: Two hundred consecutive patients treated with nivolumab at Kyoto University Hospital between September 1, 2014 and August 31, 2017 were included in a retrospective cohort study. We systematically determined and classified subclinical and overt thyroid irAEs based on data collected of serum free T4 and TSH levels. Baseline characteristics and detailed clinical data were analyzed, and analyses of overall survival (OS) excluded patients censored within 1 month from the first administration of nivolumab.

Results: Sixty-seven patients (33.5%) developed thyroid irAEs and these were divided into a subclinical thyroid irAE group (n = 40, 20.0%) and an overt thyroid irAE group (n = 27, 13.5%). Patients with thyroid uptake of FDG-PET before treatment showed high incidences of overt thyroid irAE (adjusted odds ratio 14.48; 95% confidence interval [CI] 3.12-67.19), while the same relationship was not seen with subclinical thyroid irAE. Regarding the total cohort, the thyroid irAE (+) group had a significantly longer median OS than the thyroid irAE (-) group (16.1 versus 13.6 months, hazard ratio [HR] 0.61; 95% CI 0.39-0.93). In 112 non-excluded patients with lung cancer, the thyroid irAE (+) group similarly had a longer median OS than the thyroid irAE (-) group (not reached versus 14.2 months, HR 0.51; 95% CI 0.27-0.92). However, this observation was not seen in 41 non-excluded patients with malignant melanoma (12.0 versus 18.3 months, HR 1.54; 95% CI 0.67-3.43).

Conclusions: By thyroid uptake of FDG-PET, overt thyroid irAEs could be predicted before nivolumab therapy. Thyroid irAEs related to good prognosis in lung cancer but might be inconclusive in malignant melanoma.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0216954PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6516638PMC
January 2020

Downregulation of RalGTPase-activating protein promotes invasion of prostatic epithelial cells and progression from intraepithelial neoplasia to cancer during prostate carcinogenesis.

Carcinogenesis 2019 Dec;40(12):1535-1544

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

RalGTPase-activating protein (RalGAP) is an important negative regulator of small GTPases RalA/B that mediates various oncogenic signaling pathways in various cancers. Although the Ral pathway has been implicated in prostate cancer (PCa) development and progression, the significance of RalGAP in PCa has been largely unknown. We examined RalGAPα2 expression using immunohistochemistry on two independent tissue microarray sets. Both datasets demonstrated that the expression of RalGAPα2 was significantly downregulated in PCa tissues compared to adjacent benign prostatic epithelia. Silencing of RalGAPα2 by short hairpin RNA enhanced migration and invasion abilities of benign and malignant prostate epithelial cell lines without affecting cell proliferation. Exogenous expression of wild-type RalGAP, but not the GTPase-activating protein activity-deficient mutant of RalGAP, suppressed migration and invasion of multiple PCa cell lines and was phenocopied by pharmacological inhibition of RalA/B. Loss of Ralgapa2 promoted local microscopic invasion of prostatic intraepithelial neoplasia without affecting tumor growth in a Pten-deficient mouse model for prostate tumorigenesis. Our findings demonstrate the functional significance of RalGAP downregulation to promote invasion ability, which is a property necessary for prostate carcinogenesis. Thus, loss of RalGAP function has a distinct role in promoting progression from prostatic intraepithelial neoplasia to invasive adenocarcinoma.
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http://dx.doi.org/10.1093/carcin/bgz082DOI Listing
December 2019
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