Publications by authors named "Ryuichi Mizuno"

142 Publications

Grading of Multifocal Prostate Cancer Cases in which the Largest Volume and the Highest Grade do Not Coincide within One Lesion.

J Urol 2021 Apr 5:101097JU0000000000001765. Epub 2021 Apr 5.

Keio University School of Medicine, Department of Urology.

Purpose: In general, the index lesion of prostate cancer has the largest tumor volume, the highest Grade Group (GG), and the highest stage (concordant cases). However these factors sometimes do not coincide within one lesion (discordant cases). In such discordant cases, the largest tumor may not be of biological significance and the secondary tumor may more greatly impact the prognosis.

Materials And Methods: We retrospectively reviewed the medical records of patients who underwent radical prostatectomy, and we identified 580 (85.3%) concordant cases and 100 (14.7%) discordant cases. The endpoint of this study was biochemical recurrence (BCR) and median follow-up was 4.2 years.

Results: Among discordant cases in which GGs of the largest tumor and the highest GG tumor differed, the majority (67 patients) had the largest tumor of GG 2 and we set them as the study cohort. On the other hand, we regarded 212 concordant cases with an index tumor of GG 2 as the control cohort. The study cohort comprised 48 (71.6%) patients with a secondary tumor of GG 3 and 19 (28.4%) with a secondary tumor of GG 4/5. Kaplan-Meier curves revealed that the 5-year BCR-free survival rates were 76%, and 67%, respectively. The 5-year BCR-free survival rate of the control cohort was 91%, which was significantly better than that of the study cohort (p=0.013 and 0.014, respectively).

Conclusions: Our study suggested that the prognosis of discordant cases is better determined by the secondary cancer lesion with the highest GG instead of the largest lesion.
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http://dx.doi.org/10.1097/JU.0000000000001765DOI Listing
April 2021

The Entire Intestinal Tract Surveillance Using Capsule Endoscopy after Immune Checkpoint Inhibitor Administration: A Prospective Observational Study.

Diagnostics (Basel) 2021 Mar 18;11(3). Epub 2021 Mar 18.

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan.

Background: Despite the proven efficacy of immune checkpoint inhibitors (ICIs) against various types of malignancies, they have been found to induce immune-related adverse events, such as enterocolitis; however, the clinical features of ICI-induced enterocolitis remain to be sufficiently elucidated, which is significant, considering the importance of early detection in the appropriate management and treatment of ICI-induced enterocolitis. Therefore, the current study aimed to determine the utility of capsule endoscopy as a screening tool for ICI-induced enterocolitis.

Methods: This single-center, prospective, observational study was conducted on patients with malignancy who received any ICI between April 2016 and July 2020 at Keio University Hospital. Next, second-generation capsule endoscopy (CCE-2) was performed on day 60 after ICI initiation to explore the entire gastrointestinal tract.

Results: Among the 30 patients enrolled herein, 23 underwent CCE-2. Accordingly, a total of 23 findings were observed in 14 (60.8%) patients at any portion of the gastrointestinal tract (7 patients in the colon, 4 patients in the small intestine, 2 patients in both the colon and the small intestine, and 1 patient in the stomach). After capsule endoscopy, 2 patients (8.7%) developed ICI-induced enterocolitis: both had significantly higher Capsule Scoring of Ulcerative Colitis than those who had not developed ICI-induced enterocolitis ( = 0.0455). No adverse events related to CCE-2 were observed.

Conclusions: CCE-2 might be a safe and useful entire intestinal tract screening method for the early detection of ICI-induced enterocolitis in patients with malignancies.
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http://dx.doi.org/10.3390/diagnostics11030543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8003297PMC
March 2021

Cranial nerve palsy caused by metastasis to the skull base in patients with castration-resistant prostate cancer: Three case reports.

IJU Case Rep 2021 Mar 21;4(2):108-111. Epub 2021 Jan 21.

Department of Urology Keio University School of Medicine Tokyo Japan.

Introduction: Skull base metastasis of prostate cancer associated with cranial nerve palsy is rare. We observed three patients with aggressive prostate cancer who experienced cranial nerve palsy.

Case Presentation: Case 1 was a 53-year-old patient who was treated with carboplatin and etoposide. He noticed sensory abnormalities on his left mouth edge. Head magnetic resonance imaging revealed skull base metastasis. Case 2 was a 50-year-old patient who received docetaxel. This patient exhibited ptosis of the left eye. Skull base metastasis was detected by magnetic resonance imaging. External beam radiation therapy was performed. Case 3 was a 64-year-old patient who was treated with docetaxel. He experienced ptosis of the right eye and diplopia. He was also treated with external beam radiation therapy.

Conclusion: External beam radiation therapy exhibited some efficacy against the symptoms, but skull base metastasis of treatment-resistant prostate cancer has poor prognosis. Three patients died within 3 months after symptoms occurred with or without external beam radiation therapy.
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http://dx.doi.org/10.1002/iju5.12255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7924080PMC
March 2021

Role of Previous Malignancy History in Clinical Outcomes in Patients with Initially Diagnosed Non-Muscle Invasive Bladder Cancer.

Ann Surg Oncol 2021 Mar 5. Epub 2021 Mar 5.

Department of Urology, Keio University School of Medicine, Tokyo, Japan.

Introduction: Our aim is to evaluate whether previous non-urothelial malignant history affects the clinical outcomes of patients with non-muscle invasive bladder cancer (NMIBC).

Patients And Methods: We identified 1097 cases treated by transurethral resection of bladder tumors for initially diagnosed NMIBC at our four institutions between 1999 and 2017. We compared clinical characteristics and outcomes between NMIBC patients with and without previous non-urothelial malignant history and investigated whether smoking status and treatment modality for previous cancer affected NMIBC outcomes.

Results: A total of 177 patients (16.1%) had previous non-urothelial malignant history (malignant history group). The 5-year recurrence-free survival rate and the 5-year progression-free survival rate in the malignant history group was 46.4% and 88.3%, respectively, which was significantly lower than that in the counterpart (60.2% p = 0.004, and 94.5% p = 0.002, respectively). A multivariate Cox regression analysis identified previous non-urothelial malignant history as an independent risk factor for tumor recurrence (p = 0.001) and stage progression (p = 0.003). In a subgroup of patients who were current smokers (N = 347), previous non-urothelial malignant history was associated with tumor recurrence and stage progression. In contrast, previous non-urothelial malignant history was not associated with tumor recurrence or stage progression in ex-smokers or non-smokers. In a subgroup analysis of NMIBC patients with previous prostate cancer history, those treated with androgen deprivation therapy had a significantly lower bladder tumor recurrence rate than their counterparts (p = 0.027).

Conclusions: Previous history of non-urothelial malignancy may lead to worse clinical outcome in patients with NMIBC, particularly current smokers.
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http://dx.doi.org/10.1245/s10434-021-09750-0DOI Listing
March 2021

Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma.

N Engl J Med 2021 03;384(9):829-841

From the Department of Medical Oncology, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, and Harvard Medical School, Boston (T.K.C.); the Department of Genitourinary Oncology, Barts Cancer Institute, Cancer Research UK Experimental Cancer Medicine Centre, Queen Mary University of London, Royal Free National Health Service Trust, London (T.P.); the Bradford Hill Clinical Research Center, Santiago, Chile (M.B.); the Department of Medical Oncology, Gustave Roussy, Villejuif, France (B.E.); the Department of Hemato-Oncology, Urologic Oncology Clinic, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City (M.T.B.), the Department of Medical Oncology, Centro Universitario contra el Cáncer, Hospital Universitario "Dr. José Eleuterio González," Universidad Autónoma de Nuevo León, Nuevo León (V.M.O.J.), and the Department of Medical Oncology, Hospital H+ Querétaro, Querétaro (J.P.F.) - all in Mexico; the Department of Outpatient Chemotherapy, Professor Franciszek Lukaszczyk Oncology Center, Bydgoszcz (B.Z.), and the Department of Clinical Oncology and Hematology, Regional Specialist Hospital, Biała Podlaska (J. Żołnierek) - both in Poland; the Division of Oncology, Department of Medicine, Siteman Cancer Center, Washington University School of Medicine, St. Louis (J.J.H.); Oncology Unit 1, Department of Oncology, Istituto Oncologico Veneto IRCCS, Padua (U.B.), the Department of Medical Oncology, Ospedale San Donato, Istituto Toscano i, Arezzo (A.H.), the Department of Internal Medicine, University of Pavia, Pavia (C.P.), and the University of Bari "A. Moro," Bari (C.P.) - all in Italy; the Department of Genitourinary Medical Oncology, M.D. Anderson Cancer Center, Houston (A.Y.S.); the Department of Medical Oncology, Vall d'Hebron Institute of Oncology, Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona (C.S.); the Department of Medical Oncology, Royal Brisbane and Women's Hospital, Herston, QLD (J.C.G.), and Cabrini Monash University Department of Medical Oncology, Cabrini Health, Malvern, VIC (D.P.) - both in Australia; the Oncology Research Center, Hospital São Lucas, Porto Alegre, Brazil (C.B.); Fundacion Richardet Longo, Instituto Oncologico de Cordoba, Cordoba (M.R.), and Instituto Multidisciplinario de Oncología, Clínica Viedma, Viedma (R.K.) - both in Argentina; the Division of Medical Oncology, Department of Internal Medicine, University of Colorado School of Medicine, Aurora (E.R.K.); the Departments of Urology and Molecular Oncology, Niigata University Graduate School of Medical and Dental Sciences, Niigata (Y.T.), and the Department of Urology, Keio University School of Medicine, Tokyo (R.M.) - both in Japan; the Department of Urology, Eberhard Karls University Tübingen, Tübingen, Germany (J.B.); the Departments of Clinical Research (J. Zhang.), Clinical Oncology (M.A.M.), Biostatistics (B.S.), and Health Economics and Outcomes Research (F.E.), Bristol Myers Squibb, Princeton, NJ; the Department of Clinical Oncology, Exelixis, Alameda, CA (G.M.S.); the Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD (A.B.A.); and the Department of Medicine, Memorial Sloan Kettering Cancer Center, New York (R.J.M.).

Background: The efficacy and safety of nivolumab plus cabozantinib as compared with those of sunitinib in the treatment of previously untreated advanced renal-cell carcinoma are not known.

Methods: In this phase 3, randomized, open-label trial, we randomly assigned adults with previously untreated clear-cell, advanced renal-cell carcinoma to receive either nivolumab (240 mg every 2 weeks) plus cabozantinib (40 mg once daily) or sunitinib (50 mg once daily for 4 weeks of each 6-week cycle). The primary end point was progression-free survival, as determined by blinded independent central review. Secondary end points included overall survival, objective response as determined by independent review, and safety. Health-related quality of life was an exploratory end point.

Results: Overall, 651 patients were assigned to receive nivolumab plus cabozantinib (323 patients) or sunitinib (328 patients). At a median follow-up of 18.1 months for overall survival, the median progression-free survival was 16.6 months (95% confidence interval [CI], 12.5 to 24.9) with nivolumab plus cabozantinib and 8.3 months (95% CI, 7.0 to 9.7) with sunitinib (hazard ratio for disease progression or death, 0.51; 95% CI, 0.41 to 0.64; P<0.001). The probability of overall survival at 12 months was 85.7% (95% CI, 81.3 to 89.1) with nivolumab plus cabozantinib and 75.6% (95% CI, 70.5 to 80.0) with sunitinib (hazard ratio for death, 0.60; 98.89% CI, 0.40 to 0.89; P = 0.001). An objective response occurred in 55.7% of the patients receiving nivolumab plus cabozantinib and in 27.1% of those receiving sunitinib (P<0.001). Efficacy benefits with nivolumab plus cabozantinib were consistent across subgroups. Adverse events of any cause of grade 3 or higher occurred in 75.3% of the 320 patients receiving nivolumab plus cabozantinib and in 70.6% of the 320 patients receiving sunitinib. Overall, 19.7% of the patients in the combination group discontinued at least one of the trial drugs owing to adverse events, and 5.6% discontinued both. Patients reported better health-related quality of life with nivolumab plus cabozantinib than with sunitinib.

Conclusions: Nivolumab plus cabozantinib had significant benefits over sunitinib with respect to progression-free survival, overall survival, and likelihood of response in patients with previously untreated advanced renal-cell carcinoma. (Funded by Bristol Myers Squibb and others; CheckMate 9ER ClinicalTrials.gov number, NCT03141177.).
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http://dx.doi.org/10.1056/NEJMoa2026982DOI Listing
March 2021

Site-specific differences in survival among upper and lower tract urothelial carcinoma patients treated with radical surgery.

Jpn J Clin Oncol 2021 Feb 16. Epub 2021 Feb 16.

Department of Urology, Keio University School of Medicine, Tokyo, Japan.

Background: It currently remains unclear whether the location of primary tumours affects the clinical outcomes of patients with locally advanced urothelial carcinoma in the urinary tract. The aim of the present study was to compare prognostic differences between bladder urothelial carcinoma and upper tract urothelial carcinoma, particularly pT3 or higher tumours.

Methods: In total, 307 patients with pT3 or higher urothelial carcinoma without distant metastasis who underwent radical cystectomy for bladder urothelial carcinoma (N = 127, 41.4%) or radical nephroureterectomy for upper tract urothelial carcinoma (N = 180, 58.6%) at Keio University Hospital and three affiliated hospitals between 1994 and 2017 were enrolled. Oncological outcomes were compared between bladder urothelial carcinoma and upper tract urothelial carcinoma using Cox regression analysis.

Results: Significantly higher rates of male patients, smokers, neoadjuvant chemotherapy, lymph node involvement and lymphovascular invasion were observed in the bladder urothelial carcinoma group. The incidence of regional lymph node or local recurrence was higher in patients with bladder urothelial carcinoma than in those with upper tract urothelial carcinoma, while that of lung metastasis was lower. In all patients, bladder urothelial carcinoma was independently associated with disease recurrence (hazard ratio (HR) 1.504, P = 0.035) in addition to neoadjuvant chemotherapy and lymphovascular invasion. Bladder urothelial carcinoma was also independently associated with cancer death (HR = 1.998, P = 0.002) as well as lymphovascular invasion. Following the exclusion of patients who received neoadjuvant chemotherapy, bladder urothelial carcinoma remained an independent risk factor for disease recurrence and cancer death (HR = 1.702, P = 0.010 and HR = 1.888, P = 0.013, respectively).

Conclusions: Bladder urothelial carcinoma may follow worse prognosis compared to upper tract urothelial carcinoma, particularly that with a high pathological stage.
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http://dx.doi.org/10.1093/jjco/hyab003DOI Listing
February 2021

Radiologic features of mixed epithelial and stromal tumors of the kidney: Hyperattenuating on unenhanced computed tomography and T2-hypointensity on magnetic resonance imaging.

Radiol Case Rep 2021 Apr 30;16(4):858-862. Epub 2021 Jan 30.

Department of Radiology, Keio University School of Medicine, 35, Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.

In the 2016 World Health Organization renal tumor classification, the mixed epithelial and stromal tumor family was introduced as a new entity. This family encompasses a spectrum of tumors, ranging from predominantly cystic tumors (adult cystic nephromas) to tumors that are variably solid (mixed epithelial and stromal tumors). The majority of previous studies incorporating "mixed epithelial and stromal tumor" in the titles were actually reports of imaging findings of adult cystic nephroma. Thus, the solid component of mixed epithelial and stromal tumors has not been well evaluated. In this study, we present 2 cases of mixed epithelial and stromal tumors, as defined by the 2016 World Health Organization classification, showing a predominantly solid component. The characteristic findings of the solid component of these tumors were T2-hypointensity on magnetic resonance imaging and hyperattenuation on unenhanced computed tomography. Angiomyolipoma with epithelial cysts and epithelioid angiomyolipoma should be considered in the differential diagnosis of mixed epithelial and stromal tumors.
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http://dx.doi.org/10.1016/j.radcr.2021.01.048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850961PMC
April 2021

Malignancy-associated membranous nephropathy with PLA2R double-positive for glomeruli and carcinoma.

CEN Case Rep 2021 May 3;10(2):281-286. Epub 2021 Jan 3.

Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.

Phospholipase A2 receptor (PLA2R) is the most common primary target antigen of idiopathic membranous nephropathy (MN) although PLA2R antibodies are also reported to be present in malignancy-associated MN. However, a case of PLA2R-positive MN secondary to PLA2R-positive carcinoma has not been reported. A 26-year-old Japanese woman presented with general fatigue, fever, and nonproductive cough. Computed tomography demonstrated a left kidney mass with pathologic diagnosis of Xp11.2 translocation renal cell carcinoma (RCC). After the second time of administration with Sunitinib, the patients exhibited significant proteinuria and hypoalbuminemia. Renal biopsy revealed a diagnosis of diffuse MN secondary to RCC. Immunofluorescence staining showed granular patterns positive for immunoglobulin (Ig) G, IgA, and C3c. PLA2R and IgG1-3 were positive, while IgG4 was negative. For the treatment of severe nephrotic syndrome, we attempted steroid therapy without any clinical improvement. Open nephrectomy was performed and surprisingly, RCC was stained for PLA2R with polarity for the basal side. At outpatient follow-up, 4 months after the operation, urinary protein had still persisted, although serum albumin was slightly increased. We report a case of PLA2R-positive MN secondary to PLA2R-positive RCC.
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http://dx.doi.org/10.1007/s13730-020-00556-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019443PMC
May 2021

Long-term follow-up comparing salvage radiation therapy and androgen-deprivation therapy for biochemical recurrence after radical prostatectomy.

Int J Clin Oncol 2021 Apr 2;26(4):744-752. Epub 2021 Jan 2.

Department of Urology, Keio University School of Medicine, Shinanomachi 35, Shinjuku-ku, Tokyo, 160-8582, Japan.

Background: The salvage treatments for biochemical recurrence (BCR) include local external beam radiation therapy (RT) and systemic androgen-deprivation therapy (ADT).

Methods: We reviewed patients who underwent radical prostatectomy (RP) and developed BCR at three institutions. After excluding patients whose nadir prostate-specific antigen (PSA) was higher than 0.2 ng/mL, those who received neoadjuvant/adjuvant therapy, and those whose BCR was not treated until their PSA exceeded 4.0 ng/mL, the remaining 335 patients comprised the cohort of this study. Salvage RT and ADT were performed for 154 and 181 patients, respectively. After the failure of salvage RT, all patients received subsequent ADT. The starting point of this study was the timing of BCR and the endpoint was the development of castration-resistant prostate cancer (CRPC).

Results: During the mean follow-up period of 8.5 years after BCR, CRPC was observed in 13 patients administered RT and 24 patients administered ADT. Kaplan-Meier curves demonstrated no significant difference in CRPC-free survival between the RT and ADT groups (10-year CRPC-free survival 89.9 vs. 86.3%, p = 0.199). On the other hand, we found a significant difference in CRPC-free survival between the RT and ADT groups in 50 high-risk patients with two risk factors of Grade Group ≥ 4 and PSA-doubling time  < 6 months (10-year CRPC-free survival 73.4 vs. 40.3%, p = 0.040).

Conclusion: This study revealed that salvage RT increases the CRPC-free survival rate compared with salvage ADT in high-risk patients with Grade Group ≥ 4 and PSA-doubling time < 6 months.
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http://dx.doi.org/10.1007/s10147-020-01839-yDOI Listing
April 2021

The clinicopathological characteristics of muscle-invasive bladder recurrence in upper tract urothelial carcinoma.

Cancer Sci 2021 Mar 11;112(3):1084-1094. Epub 2021 Jan 11.

Department of Urology, Keio University School of Medicine, Tokyo, Japan.

This study aimed to clarify the clinical characteristics and oncological outcomes of patients with upper tract urothelial carcinoma (UTUC) who developed muscle-invasive bladder cancer (MIBC) after radical nephroureterectomy (RNU). We identified 966 pTa-4N0-2M0 patients with UTUC who underwent RNU and clarified the risk factors for MIBC progression after initial intravesical recurrence (IVR). We also identified 318 patients with primary pT2-4N0-2M0 MIBC to compare the oncological outcomes with those of patients with UTUC who developed or progressed to MIBC. Furthermore, immunohistochemical examination of p53 and FGFR3 expression in tumor specimens was performed to compare UTUC of MIBC origin with primary MIBC. In total, 392 (40.6%) patients developed IVR after RNU and 46 (4.8%) developed MIBC at initial IVR or thereafter. As a result, pT1 stage on the initial IVR specimen, concomitant carcinoma in situ on the initial IVR specimen, and no intravesical adjuvant therapy after IVR were independent factors for MIBC progression. After propensity score matching adjustment, primary UTUC was a favorable indicator for cancer-specific death compared with primary MIBC. Subgroup molecular analysis revealed high FGFR3 expression in non-MIBC and MIBC specimens from primary UTUC, whereas low FGFR3 but high p53 expression was observed in specimens from primary MIBC tissue. In conclusion, our study demonstrated that patients with UTUC who develop MIBC recurrence after RNU exhibited the clinical characteristics of subsequent IVR more than those of primary UTUC. Of note, MIBC subsequent to UTUC may have favorable outcomes, probably due to the different molecular biological background compared with primary MIBC.
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http://dx.doi.org/10.1111/cas.14782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935810PMC
March 2021

Can random bladder biopsies be eliminated after bacillus Calmette-Guérin therapy against carcinoma in situ?

Int Urol Nephrol 2021 Mar 6;53(3):465-469. Epub 2020 Oct 6.

Department of Urology, Keio University School of Medicine, Shinanomachi 35, Shinjuku-ku, Tokyo, 1608582, Japan.

Purpose: Intravesical bacillus Calmette-Guérin (BCG) is the standard of care for bladder carcinoma in situ (CIS). The response to BCG therapy against CIS is generally assessed by random bladder biopsy (RBB). In this study, we examined the necessity of routine RBB after BCG therapy.

Methods: We retrospectively identified 102 patients who were initially diagnosed with CIS with or without papillary tumor and received subsequent 6-8-week BCG therapy. Thereafter, all patients underwent voiding cytology analysis, cystoscopy, and RBB to evaluate the effects of BCG therapy. We evaluated the association between clinical parameters (voiding cytology and cystoscopy findings) and the final pathological results by RBB specimens.

Results: According to the pathological results of RBB, 30 (29%) patients had BCG-unresponsive disease (remaining urothelial carcinoma was confirmed pathologically) and 20 were diagnosed with CIS. Positive/suspicious voiding cytology and positive cystoscopy findings were well observed in patients who had BCG-unresponsive disease compared with their counterparts (p = 0.116, and p < 0.001, respectively). The sensitivity (Sen.), specificity (Spe.), positive predictive value (PPV), and negative predictive value (NPV) of voiding cytology were 50%, 68%, 39%, and 77%, respectively. The values for cystoscopy findings were as follows: Sen.: 87%, Spe.: 57%, PPV: 46%, and NPV: 91%. The values for their combination (having either of them) were as follows: Sen.: 100%, Spe.: 44%, PPV: 43%, and NPV: 100%.

Conclusion: RBB after BCG therapy for patients with negative voiding cytology and negative cystoscopy may be omitted because their risk of BCG-unresponsive disease is significantly low (NPV: 100%).
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http://dx.doi.org/10.1007/s11255-020-02667-9DOI Listing
March 2021

Relationship between radiation doses and erectile function deterioration in patients with localized prostate cancer treated with permanent prostate brachytherapy.

Int J Urol 2020 Dec 6;27(12):1087-1093. Epub 2020 Sep 6.

Department of Urology, Keio University School of Medicine, Tokyo, Japan.

Objectives: To investigate the relationship between radiation doses in prostate brachytherapy and deterioration of erectile function in patients with localized prostate cancer.

Methods: A longitudinal survey study was carried out among 261 prostate cancer patients who received prostate brachytherapy. A total of 48 patients were potent at baseline and they did not receive any supplemental therapy preoperatively. Dosimetry parameters of the whole prostate gland, prostate apex, urethra and rectum were collected using the VariSeed 8.0 treatment planning system (Varian Medical Systems, Palo Alto, CA, USA). We carried out a logistic regression analysis to clarify the relationship between radiation doses and erectile function deterioration, which was assessed using the International Index of Erectile Function-15 questionnaire.

Results: The median patient age was 66 years (range 53-70 years) with a median follow-up time of 44 months (36-71 months). The mean total International Index of Erectile Function-15 score decreased from 49.9 at baseline to 34.7 after 12 months (P < 0.001), but gradually plateaued within 36 months. Erectile function deterioration was noted in 32 (66.7%) patients 36 months after prostate brachytherapy. In an analysis of risk factors for erectile function deterioration after prostate brachytherapy, age ≥70 years (P = 0.029), prostate V100 ≥95% (P = 0.024), apex V100 ≥95% (P = 0.024), apex V150 ≥70% (P = 0.009) and apex D90 ≥150 Gy (P = 0.011) correlated with erectile function deterioration. A multivariate analysis identified an age of ≥70 years (odds ratio 7.91, P = 0.024) and apex V150 ≥70% (odds ratio 7.75, P = 0.007) as independent risk factors for erectile function deterioration after prostate brachytherapy.

Conclusions: An excessive radiation dose, particularly to the prostate apex area, and an advanced age might have a negative impact on the preservation of potency after prostate brachytherapy.
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http://dx.doi.org/10.1111/iju.14358DOI Listing
December 2020

Significance of prophylactic urethrectomy at the time of radical cystectomy for bladder cancer.

Jpn J Clin Oncol 2021 Feb;51(2):287-295

Department of Urology, Keio University School of Medicine, Tokyo, Japan.

Background: Prophylactic urethrectomy at the time of radical cystectomy is frequently recommended for patients with bladder cancer at a high risk of urethral recurrence without definitive evidence. The present study attempted to clarify the survival benefits of performing prophylactic urethrectomy.

Methods: We identified 214 male patients who were treated by radical cystectomy with an incontinent urinary diversion in our seven institutions between 2004 and 2017. We used propensity score matching and ultimately identified 114 patients, 57 of whom underwent prophylactic urethrectomy (prophylactic urethrectomy group) and 57 who did not (non-prophylactic urethrectomy group).

Results: No significant differences were observed in the 5-year overall survival rate between the prophylactic urethrectomy and non-prophylactic urethrectomy groups in the overall. However, the local recurrence rate was significantly lower in the prophylactic urethrectomy group than in the non-prophylactic urethrectomy group (P = 0.015). In the subgroup of 58 patients with multiple tumours and/or concomitant carcinoma in situ at the time of transurethral resection of bladder tumour, the 5-year overall survival rate was significantly higher in the prophylactic urethrectomy group than in the non-prophylactic urethrectomy group (P = 0.021). A multivariate analysis revealed that performing prophylactic urethrectomy was the only independent predictor of the overall survival rate (P = 0.016). In those patients who were treated without neoadjuvant chemotherapy (n = 38), the 5-year overall survival rate was significantly higher in the prophylactic urethrectomy group than in the non-prophylactic urethrectomy group (P = 0.007).

Conclusions: Prophylactic urethrectomy at the time of radical cystectomy may have a survival benefit in patients with multiple tumours and/or concomitant carcinoma in situ, particularly those who do not receive neoadjuvant chemotherapy.
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http://dx.doi.org/10.1093/jjco/hyaa168DOI Listing
February 2021

Evaluation of Gleason Grade Group 5 in a Contemporary Prostate Cancer Grading System and Literature Review.

Clin Genitourin Cancer 2021 Feb 7;19(1):69-75.e5. Epub 2020 Aug 7.

Department of Urology, Keio University School of Medicine, Tokyo, Japan.

Introduction: The aim of this study was to validate contemporary grading systems, in particular, the Gleason grade group (GGG) 5.

Patients And Methods: We retrospectively reviewed the clinicopathologic data of 176 patients who underwent radical prostatectomy and whose pathologic results were GGG 4 or 5. The endpoints were biochemical recurrence (BCR) and castration-resistant prostate cancer (CRPC).

Results: The GGG 4 group was composed of 69 patients. The GGG 5 group consisted of 78 patients with GS 4+5 and 29 patients with GS 5+4 or higher. The 5-year BCR-free survival rates for men with GGG 4, GS 4+5, and GS 5+4 or higher were 59%, 54%, and 20%, respectively, and the 5-year CRPC-free survival rates were 98%, 100%, and 88%, respectively. Both the BCR- and CRPC-free survival rates were significantly higher in GS 4+5 than in GS 5+4 or higher (P < .001 and P = .002, respectively), but there were no significant differences between GGG 4 and GS 4+5 (P = .702 and P = .803, respectively). The multivariate analysis demonstrated that GS 5+4 or higher (hazard ratio, 3.4; P = .002) and lymphovascular invasion (hazard ratio, 3.4; P < .001) greatly affected BCR.

Conclusion: Our follow-up study revealed that men with GS 4+5 and those with GGG 4 had a similar prognosis. However, there was a significant discrepancy in prognosis between GS 4+5 and GS 5+4 or higher. This suggested that GGG 4 and 5 in the contemporary prostate cancer grading system should be reviewed. Furthermore, lymphovascular invasion may be useful to subgroup these pathologically high-risk patients.
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http://dx.doi.org/10.1016/j.clgc.2020.08.001DOI Listing
February 2021

Evaluating the Oncological Outcomes of Pure Laparoscopic Radical Nephroureterectomy Performed for Upper-Tract Urothelial Carcinoma Patients: A Multicenter Cohort Study Adjusted by Propensity Score Matching.

Ann Surg Oncol 2021 Jan 25;28(1):465-473. Epub 2020 Aug 25.

Department of Urology, Keio University School of Medicine, Tokyo, Japan.

Purpose: To evaluate the oncological feasibility of pure laparoscopic radical nephroureterectomy (p-LRNU) for upper tract urothelial carcinoma (UTUC) compared with conventional LRNU (c-LRNU) using a propensity-adjusted multi-institutional collaboration dataset.

Methods: Among the 503 UTUC patients who underwent RNU, we identified 219 who underwent c-LRNU (laparoscopic nephrectomy with open bladder cuff resection) and 72 who underwent p-LRNU (dissecting the kidney, ureter, and bladder cuff under complete laparoscopy). We adopted a propensity score (PS) matching method to achieve homogeneity with respect to patient backgrounds. PS matching-adjusted Cox-regression analysis was performed to evaluate the risk factors that influenced oncological outcomes.

Results: Sixty-eight p-LRNU and 68 c-LRNU patients were matched. Overall, 51 (37.0%) developed intravesical recurrence (IVR), 21 (15.4%) had disease recurrence, and 20 (14.7%) died. Patients who underwent p-LRNU had a significantly shorter operation time and less blood loss than those who underwent c-LRNU. Although no significant differences in 3-year recurrence-free survival were found between the two methods, atypical recurrence sites were observed in the p-LRNU group, including the brain, sigmoid colon, vagina, and peritoneum. Regarding IVR, the 3-year IVR-free survival rate was 41.8% in the p-LRNU group, which was significantly lower than that in the c-LRNU group (66.6%, p = 0.004). Multivariate analysis demonstrated that a history of bladder cancer, ureteral cancer, and p-LRNU were independent risk factors for subsequent IVR.

Conclusion: Although p-LRNU is less invasive, the current technique may increase the incidence of atypical disease recurrence and subsequent IVR due to extravesical and intravesical tumor dissemination.
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http://dx.doi.org/10.1245/s10434-020-09046-9DOI Listing
January 2021

Dehydroxymethylepoxyquinomicin, a novel nuclear factor-κB inhibitor, prevents the development of cyclosporine A nephrotoxicity in a rat model.

BMC Pharmacol Toxicol 2020 08 12;21(1):60. Epub 2020 Aug 12.

Department of Urology, Keio University School of Medicine, Tokyo, Japan.

Background: Cyclosporine A (CsA) is an essential immunosuppressant in organ transplantation. However, its chronic nephrotoxicity is an obstacle to long allograft survival that has not been overcome. Nuclear factor-κB (NF-κB) is activated in the renal tissue in CsA nephropathy. In this study, we aimed to investigate the effect of the specific NF-κB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), in a rat model of CsA nephrotoxicity.

Methods: We administered CsA (15 mg/kg) daily for 28 days to Sprague-Dawley rats that underwent 5/6 nephrectomy under a low-salt diet. We administered DHMEQ (8 mg/kg) simultaneously with CsA to the treatment group, daily for 28 days and evaluated its effect on CsA nephrotoxicity.

Results: DHMEQ significantly inhibited NF-κB activation and nuclear translocation due to CsA treatment. Elevated serum urea nitrogen and creatinine levels due to repeated CsA administration were significantly decreased by DHMEQ treatment (serum urea nitrogen in CsA + DHMEQ vs CsA vs control, 69 ± 6.4 vs 113.5 ± 8.8 vs 43.1 ± 1.1 mg/dL, respectively, p < 0.0001; serum creatinine in CsA + DHMEQ vs CsA vs control, 0.75 ± 0.02 vs 0.91 ± 0.02 vs 0.49 ± 0.02 mg/dL, respectively, p < 0.0001), and creatinine clearance was restored in the treatment group (CsA + DHMEQ vs CsA vs control, 2.57 ± 0.09 vs 1.94 ± 0.12 vs 4.61 ± 0.18 ml/min/kg, respectively, p < 0.0001). However, DHMEQ treatment did not alter the inhibitory effect of CsA on urinary protein secretion. The development of renal fibrosis due to chronic CsA nephrotoxicity was significantly inhibited by DHMEQ treatment (CsA + DHMEQ vs CsA vs control, 13.4 ± 7.1 vs 35.6 ± 18.4 vs 9.4 ± 5.4%, respectively, p < 0.0001), and these results reflected the results of renal functional assessment. DHMEQ treatment also had an inhibitory effect on the increased expression of chemokines, monocyte chemoattractant protein-1, and chemokine (c-c motif) ligand 5 due to repeated CsA administration, which inhibited the infiltration of macrophages and neutrophils into the renal tissue.

Conclusions: These findings suggest that DHMEQ treatment in combination therapy with CsA-based immunosuppression is beneficial to prevent the development of CsA-induced nephrotoxicity.
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http://dx.doi.org/10.1186/s40360-020-00432-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7424678PMC
August 2020

Optimal treatment strategy for paratesticular liposarcoma: retrospective analysis of 265 reported cases.

Int J Clin Oncol 2020 Dec 26;25(12):2099-2106. Epub 2020 Jul 26.

Department of Urology, Keio University School of Medicine, Shinanomachi 35, Shinjuku-ku, Tokyo, 160-8582, Japan.

Background: Liposarcoma is one of the most common subtypes of soft tissue sarcoma. Although the standard treatment for localized liposarcoma is surgical resection with negative margins, a treatment specific to paratesticular liposarcoma has yet to be quantitatively evaluated.

Methods: A systematic search of Medline, Web of Science, Embase, and Google was performed to find articles describing localized paratesticular liposarcoma published between 1979 and 2018 in English. The final cohort included 265 patients in 183 articles. The starting point was the time of surgical treatment, and the endpoint was the time of recurrence, including local recurrence, or distant metastasis.

Results: The median patient age was 62 years and the median tumor size was 9.5 cm. In total, 178 patients underwent high inguinal orchiectomy and 40 underwent simple tumorectomy. Based on the Kaplan-Meier curves, recurrence-free survival rates were significantly higher for those who underwent high inguinal orchiectomy than for those who underwent tumorectomy. Moreover, those with microscopic positive margins had a higher risk of recurrence than those with negative margins, but adjuvant radiation therapy after resection had no statistically significant effect on recurrence-free survival, even in subgroup analysis of patients with positive margins. Regarding the pathological subtypes, dedifferentiated, pleomorphic, and round-cell liposarcoma had a higher risk of recurrence than well-differentiated or myxoid liposarcoma. In the multivariate analysis, high inguinal orchiectomy greatly affected recurrence-free survival. The tumor size and histological subtype were independent risk factors for recurrence.

Conclusion: Complete resection with high inguinal orchiectomy is the optimal treatment for paratesticular liposarcoma.
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http://dx.doi.org/10.1007/s10147-020-01753-3DOI Listing
December 2020

Role of the MUC1-C oncoprotein in the acquisition of cisplatin resistance by urothelial carcinoma.

Cancer Sci 2020 Oct 11;111(10):3639-3652. Epub 2020 Aug 11.

Department of Urology, Keio University School of Medicine, Tokyo, Japan.

Mucin 1 C-terminal subunit (MUC1-C) has been introduced as a key regulator for acquiring drug resistance in various cancers, but the functional role of MUC1-C in urothelial carcinoma (UC) cells remains unknown. We aimed to elucidate the molecular mechanisms underlying the acquisition of cisplatin (CDDP) resistance through MUC1-C oncoprotein in UC cells. MUC1-C expression was examined immunohistochemically in tumor specimens of 159 UC patients who received CDDP-based perioperative chemotherapy. As a result, moderate to high MUC1-C expression was independently associated with poor survival in UC patients. Using human bladder cancer cell lines and CDDP-resistant (CR) cell lines, we compared the expression levels of MUC1-C, multiple drug resistance 1 (MDR1), the PI3K-AKT-mTOR pathway, and x-cystine/glutamate transporter (xCT) to elucidate the biological mechanisms contributing to the acquisition of chemoresistance. MUC1-C was strongly expressed in CR cell lines, followed with MDR1 expression via activation of the PI3K-AKT-mTOR pathway. MUC1-C also stabilized the expression of xCT, which enhanced antioxidant defenses by increasing intracellular glutathione (GSH) levels. MUC1 down-regulation showed MDR1 inhibition along with PI3K-AKT-mTOR pathway suppression. Moreover, it inhibited xCT stabilization and resulted in significant decreases in intracellular GSH levels and increased reactive oxygen species (ROS) generation. The MUC1-C inhibitor restored sensitivity to CDDP in CR cells and UC murine xenograft models. In conclusion, we found that MUC1-C plays a pivotal role in the acquisition of CDDP resistance in UC cells, and therefore the combined treatment of CDDP with a MUC1-C inhibitor may become a novel therapeutic option in CR UC patients.
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http://dx.doi.org/10.1111/cas.14574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541007PMC
October 2020

Significance of tumor microenvironment in acquiring resistance to vascular endothelial growth factor-tyrosine kinase inhibitor and recent advance of systemic treatment of clear cell renal cell carcinoma.

Pathol Int 2020 Oct 11;70(10):712-723. Epub 2020 Jul 11.

Department of Urology, Keio University School of Medicine, Tokyo, Japan.

The development of systemic therapies, including vascular endothelial growth factor-tyrosine kinase inhibitors (VEGF-TKI) and mammalian target of rapamycin (mTOR) inhibitors, represents a major breakthrough in the treatment of patients with renal cell carcinoma (RCC). However, inherent resistance is observed in some patients and acquired resistance commonly develops in many patients within several months of the initiation of systemic therapies. Since these treatments rarely cure patients, their aim is to suppress tumor progression and prolong survival. Therefore, the establishment of dependable criteria that predict responses and resistance to systemic therapies is clinically important, and the underlying molecular mechanisms also need to be elucidated for the future development of more effective therapies. We herein review recent advances in research on the molecular mechanisms underlying resistance, with a focus on morphological characteristics, tumor angiogenesis, and the tumor immune microenvironment in RCC and their relationships with VEGF-TKI treatments. Recent therapies using immune checkpoint inhibitors (ICI) and newly developed VEGF-TKI also appear to be effective for advanced RCC, with stable and durable responses to ICI being observed in some RCC patients. These new drugs and their outcomes have been briefly described.
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http://dx.doi.org/10.1111/pin.12984DOI Listing
October 2020

Multiple Immune-Related Adverse Events and Anti-Tumor Efficacy: Real-World Data on Various Solid Tumors.

Cancer Manag Res 2020 16;12:4585-4593. Epub 2020 Jun 16.

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.

Purpose: Immune checkpoint inhibitors (ICIs) have been approved for various types of cancer; however, they cause a broad spectrum of immune-related adverse events (irAEs). The association between the development of irAEs and the clinical benefit remains uncertain. We aimed to evaluate the association of irAEs and the treatment efficacy in real-world practice.

Patients And Methods: We conducted a retrospective study on patients with recurrent or metastatic non-small-cell lung cancer, malignant melanoma, renal cell carcinoma, or gastric cancer who received anti-PD-1/PD-L1 antibodies (nivolumab, pembrolizumab, or atezolizumab) at the Keio University Hospital between September 2014 and January 2019. We recorded treatment-related AEs from medical records and graded them using the Common Terminology Criteria for Adverse Events version 4. We performed an overall survival (OS) analysis using a Cox proportional hazards model and the shared frailty model.

Results: Of 212 patients eligible for this study, 108 experienced irAEs and 42 developed multiple irAEs. The median OS was significantly longer in the irAEs than in the no-irAE group (28.1 months vs 12.7 months; hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.33-0.73; P = 0.0004). Moreover, the OS of patients with multiple irAEs was significantly longer than that of patients with a single irAE (42.3 months vs 18.8 months; HR, 0.473; 95% CI, 0.346-0.647; P < 0.0001).

Conclusion: Our single-center retrospective study revealed a significant tendency associating the development of multiple irAEs with favorable prognoses.
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http://dx.doi.org/10.2147/CMAR.S247554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305832PMC
June 2020

External validation of the "optimal PSA follow-up schedule after radical prostatectomy" in a new cohort.

Int J Clin Oncol 2020 Jul 13;25(7):1393-1397. Epub 2020 Apr 13.

Department of Urology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.

Background: Biochemical recurrence (BCR) after radical prostatectomy (RP) is most commonly diagnosed by detecting an increase in asymptomatic prostate-specific antigen (PSA). We previously reported the "optimal PSA follow-up schedule after RP". The aim of this study was to confirm the usefulness and safety of that follow-up schedule in another cohort.

Methods: We retrospectively reviewed the clinicopathological data of 798 consecutive patients who underwent radical prostatectomy between 2009 and 2017. We examined all PSA values measured during follow-up. Furthermore, we estimated the PSA value when we observed the "optimal PSA follow-up schedule" at each timing in the virtual follow-up. BCR was defined as an elevation of PSA to greater than 0.2 ng/ml, and the ideal PSA range for detection of BCR was regarded to be 0.2-0.4 ng/ml.

Results: During the mean follow-up period of 5.8 years, BCR occurred in 115 (14.9%) patients and the frequency of virtual follow-up was significantly lower than the actual frequency. However, overlooking of BCR (detecting BCR when PSA exceeded 0.4 ng/ml) was observed in 17 patients, which is higher than the actual frequency of overlooking (12 patients). Therefore, we modified the follow-up schedule, which could achieve the lower follow-up frequency and a limited number of overlooking of BCR (7 patients).

Conclusion: This external validation study revealed that the "modified optimal PSA follow-up schedule after RP" can reduce the frequency of PSA measurement with a limited risk of overlooking BCR.
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http://dx.doi.org/10.1007/s10147-020-01676-zDOI Listing
July 2020

The pretreatment neutrophil-to-lymphocyte ratio is a novel biomarker for predicting clinical responses to pembrolizumab in platinum-resistant metastatic urothelial carcinoma patients.

Urol Oncol 2020 06 2;38(6):602.e1-602.e10. Epub 2020 Mar 2.

Department of Urology, Keio University School of Medicine, Tokyo, Japan.

Purpose: We investigated the relationship between pretreatment neutrophil-to-lymphocyte ratio (pre-NLR) levels just before the initiation of treatment with pembrolizumab and clinical outcomes in platinum-resistant metastatic urothelial carcinoma (UC) patients treated with pembrolizumab.

Methods: Our study population comprised 78 patients diagnosed with metastatic UC and treated with pembrolizumab after platinum-based chemotherapy at our institutions between December 2017 and April 2019. We examined the relationships between pre-NLR levels just before pembrolizumab treatment and clinical outcomes. A pre-NLR level of ≥3.35 was defined as elevated according to a calculation by a receiver-operating curve analysis.

Results: The high pre-NLR group consisted of 33 patients (42.3%). Overall, 29.5% of patients had a clinical response and the sum of the target lesion longest diameter was decreased in 18.8% of the high pre-NLR group, which was significantly lower than that in the low pre-NLR group (58.1%, P = 0.005). Six-month progression-free survival and cancer-specific survival rates for the high pre-NLR group were 9.1 and 58.0%, which were significantly lower than those for their counterpart (45.9 and 89.1%, P < 0.001 and P = 0.002, respectively). The pre-NLR level was an independent indicator of disease progression and cancer-specific death (P < 0.001 and P = 0.003). Furthermore, patients with a postpembrolizumab NLR level that had decreased ≥25% from the pre-NLR level had significantly lower disease progression and cancer-specific death rates than their counterparts (P = 0.01 and P = 0.022, respectively).

Conclusions: Elevated pre-NLR may be a novel biomarker for identifying poor responders to pembrolizumab among platinum-resistant metastatic UC patients.
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http://dx.doi.org/10.1016/j.urolonc.2020.02.005DOI Listing
June 2020

Editorial Comment.

J Urol 2020 06 5;203(6):1084. Epub 2020 Mar 5.

Department of Urology, Keio University School of Medicine, Tokyo, Japan.

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http://dx.doi.org/10.1097/JU.0000000000000523.01DOI Listing
June 2020

Appropriate timing for a biochemical evaluation after adrenalectomy for unilateral aldosterone-producing adenoma.

Clin Endocrinol (Oxf) 2020 06 3;92(6):503-508. Epub 2020 Mar 3.

Department of Urology, Keio University School of Medicine, Tokyo, Japan.

Context: The oversecretion of plasma aldosterone by unilateral aldosterone-producing adenoma (APA) can be cured by adrenalectomy. However, the time needed for the endocrine environment to normalize remains unclear.

Objective: To clarify adequate timing for a biochemical evaluation in unilateral APA patients after adrenalectomy.

Design And Patients: A total of 166 unilateral APA patients were retrospectively reviewed. We evaluated the plasma aldosterone concentration (PAC) (pg/mL), active renin concentration (ARC) (pg/mL), aldosterone-renin ratio (ARR; PAC/ARC), serum potassium concentration and estimated glomerular filtration rate (eGFR) at 1, 3 and 6 postoperation months (POM).

Results: PAC was significantly lower at 1POM than at presurgery (presurgery; 407.2, 1 POM; 90.0 pg/mL, P < .001). ARC did not increase from baseline at 1POM, but significantly increased at 3POM (presurgery; 4.43, 1POM; 4.87, 3POM; 11.3 pg/mL, P < .001). ARR significantly decreased at 1POM (presurgery; 146.9, 1 POM; 26.3, P < .001) although ARC did not increase at 1POM. Among the 34 patients who had hypokalaemia presurgery, it was resolved in 28 (82%) at 1POM and in all (100%) at 3POM. The biochemical outcomes at 1POM were 131 (79%) complete, 20 (12%) partial and 15 (9%) absent successes, while at 3POM, 147 (89%) were complete, 9 (5%) partial and 10 (6%) absent. Twenty-three (14%) patients were reclassified into different biochemical outcomes between 1 and 3POM, whereas only 5 (3%) changed between 3 and 6POM.

Conclusion: The appropriate timing for a biochemical evaluation of unilateral APA patients treated with laparoscopic adrenalectomy appears to be 3 months or more after surgery.
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http://dx.doi.org/10.1111/cen.14176DOI Listing
June 2020

Factors affecting renal function preservation among patients not achieving trifecta after laparoscopic partial nephrectomy for clinical T1a renal masses.

Asian J Endosc Surg 2020 Oct 9;13(4):526-531. Epub 2019 Dec 9.

Department of Urology, Keio University School of Medicine, Tokyo, Japan.

Introduction: The goal of partial nephrectomy for renal tumors is complete tumor removal with the preservation of renal function and no complications. Trifecta (total ischemia time < 25 minutes, negative surgical margins, and no surgical complications) is widely used to evaluate success after partial nephrectomy. We investigated factors affecting renal function preservation among patients not achieving trifecta after laparoscopic partial nephrectomy.

Methods: Sixty-six patients who underwent laparoscopic partial nephrectomy for clinical T1a renal masses between December 2006 and March 2016 were examined. We defined preserved renal function as the preservation of an estimated glomerular filtration rate ≥ 90% 1 year after surgery. We examined factors affecting renal function preservation among patients not achieving trifecta after laparoscopic partial nephrectomy.

Results: Thirty out of 66 patients (45%) did not achieve trifecta. In an evaluation of 66 patients, a multivariate analysis identified tumor size (P = .04) as an independent predictor affecting the achievement of trifecta. Tumor size was significantly smaller in the trifecta achievement group (1.9 ± 0.1 cm) than in the non-achievement group (2.2 ± 0.6 cm) (P = .04). We found that renal function was preserved 1 year after surgery in 14 out of the 30 patients not achieving trifecta. In univariate analysis, age (P = .01) was significantly associated with affecting the preservation of renal function among these patients. Patients with preserved renal function were significantly younger (47.8 ± 2.5 years) than those without (58.5 ± 2.9 years) (P = .01).

Conclusion: Renal function may be preserved in younger patients even if they do not achieve trifecta after partial nephrectomy for small renal masses.
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http://dx.doi.org/10.1111/ases.12776DOI Listing
October 2020

Usefulness of contrast-enhanced ultrasonography for diagnosis of renal cell carcinoma in dialysis patients: Comparison with computed tomography.

Medicine (Baltimore) 2019 Nov;98(47):e18053

Department of Radiology, Keio University School of Medicine, Tokyo.

Aims: To investigate the usefulness of contrast-enhanced ultrasonography for diagnosing renal cell carcinoma (RCC) in dialysis patients.

Material And Methods: Of 1301 dialysis patients who underwent abdominal computed tomography (CT) between January 2012 and March 2017, 19 were suspected to have solid renal lesions; of these patients, 18 gave consent for and underwent contrast-enhanced ultrasonography with perflubutane in addition to CT; 13 underwent dynamic contrast-enhanced CT, and 5, who could not be administered iodinated contrast media, underwent unenhanced CT. The final diagnoses were based on histopathological findings or the presence/absence of enlargement of the lesion during follow-up.

Results: Of the 19 lesions in 18 patients, 14 were diagnosed as RCC and 5 as benign cysts. CT facilitated accurate diagnosis in 10/19 lesions (52.6%) with obvious enhancement (≥20 Hounsfield units [HU]), while definitive diagnosis by CT was difficult in 9 lesions: 2 lesions showed ambiguous enhancement (10-20 HU), 1 lesion was an inflammatory cyst with obvious enhancement, and 6 lesions were assessed by unenhanced CT. Compared with CT, contrast-enhanced ultrasonography allowed more accurate diagnosis (McNemar test, P = .02) in 17/19 lesions (89.5%, 14 RCC and 3 cysts; including all lesions assessed by unenhanced CT and 2 with ambiguous enhancement on CT), with 1 false-positive (inflammatory cyst with hyper-enhancement) and 1 false-negative result due to deep location of the lesion.

Conclusions: Contrast-enhanced ultrasonography was useful for the diagnosis of RCC in dialysis patients with suspected solid renal lesions especially when contrast enhancement was not obvious on CT or contrast-enhanced CT could not be performed.
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http://dx.doi.org/10.1097/MD.0000000000018053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6882623PMC
November 2019

The efficacy of the TachoSil binding suturing technique in laparoscopic partial nephrectomy to prevent the development of pseudoaneurysm.

Asian J Surg 2020 Jun 16;43(6):668-675. Epub 2019 Oct 16.

Department of Urology, Keio University School of Medicine, Tokyo, Japan.

Objective: Our specific aim was to introduce the TachoSil binding suturing technique for renal cell carcinoma (RCC) patients when closing the parenchymal defect after tumor excision during laparoscopic partial nephrectomy (LPN), which is a novel technique for reducing the risk of developing subsequent pseudoaneurysm (PA).

Methods: We identified 113 pT1aN0M0 RCC patients who underwent LPN at our institution. Eighty-one (72%) patients underwent the suturing procedure without binding TachoSil, whereas 32 (28%) patients underwent renorraphy with the renal defect closed together with TachoSil. The vascular complications were evaluated by computed tomography or magnetic resonance imaging with enhanced contrast material at the first visit after LPN. We conducted Fischer's exact test to determine risk factors for transcatheter arterial embolization (TAE).

Results: The median age was 55 (36-86) years old and the median follow-up time was 65 (12-147) months. In the overall population, there were 11 (11%) patients who underwent TAE because they developed PA. All 11 patients exhibited the imaging findings of PA, and were all from the conventional suturing group. In contrast, no patients for whom the TachoSil binding method was used had any significant findings on imaging (14% vs. 0%). Based on the analysis to determine risk factors for TAE due to PA development, the TachoSil binding suturing technique was one of the significant indicators for reducing the risk of developing PA.

Conclusions: Our study demonstrated that the TachoSil binding suturing technique might reduce the development of PA after LPN. Prospective randomized study and comparison to the standard 2 or 3-layer renorrhaphy is needed to prove its actual value.
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http://dx.doi.org/10.1016/j.asjsur.2019.09.002DOI Listing
June 2020

Type of patients in whom biochemical recurrence after radical prostatectomy can be observed without salvage therapy.

World J Urol 2020 Jul 26;38(7):1749-1756. Epub 2019 Sep 26.

Department of Urology, Keio University School of Medicine, Shinanomachi 35, Shinjuku-ku, Tokyo, 160-8582, Japan.

Purpose: To examine the prognosis after BCR with and without salvage therapy, including radiation and/or androgen deprivation.

Methods: The study population consisted of 431 patients, all of whom underwent radical prostatectomy and developed BCR (PSA > 0.2 ng/mL). According to the two risk factors [Gleason score ≥ 8 and PSA-doubling time (DT) < 6 months], we divided the patients into two groups. The high/intermediate-risk group consisted of patients with both or one risk factor. On the other hand, patients with neither factor were in the low-risk group. We set the starting point at the timing of BCR, and the endpoints were development to castration-resistant prostate cancer (CRPC) and cancer-specific death.

Results: During the mean follow-up period of 8.3 years after BCR, CRPC was observed in 49 patients (11.4%), and 21 patients (4.9%) died due to prostate cancer. We first divided the 191 high/intermediate-risk patients according to the PSA level (PSA < 1.0 ng/mL, PSA 1.0-4.0, and PSA > 4.0 or no therapy) at the initiation of salvage therapy, including radiation and/or androgen deprivation. We found that delayed (PSA > 4.0 ng/mL) or no salvage therapy was significantly associated with CRPC and cancer-specific death. In the 240 low-risk patients, Kaplan-Meier curves demonstrated no significant difference in CRPC-free survival or cancer-specific survival within 10 years from the timing of BCR.

Conclusions: Observation after BCR without salvage therapy or delayed administration may be an option for low-risk patients with a Gleason score ≤ 7 and PSA-DT ≥ 6 months when their life expectancy is within 10 years.
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http://dx.doi.org/10.1007/s00345-019-02970-wDOI Listing
July 2020

A Novel Risk-based Approach Simulating Oncological Surveillance After Radical Nephroureterectomy in Patients with Upper Tract Urothelial Carcinoma.

Eur Urol Oncol 2020 12 6;3(6):756-763. Epub 2019 Aug 6.

Department of Urology, Keio University School of Medicine, Tokyo, Japan.

Background: The current guideline lacks evidence for creating individualized surveillance strategies for upper tract urothelial carcinoma (UTUC) patients after radical nephroureterectomy (RNU).

Objective: To create a novel risk model and to simulate individualized surveillance duration that dynamically illustrates the changing risk relationship of UTUC-related death and non-UTUC death, considering the impact of cigarette smoking.

Design, Setting, And Participants: This multicenter cohort study comprised 714 pTa-T4N0M0 UTUC patients, with a median follow-up duration of 65mo. There were 279 (39.1%) nonsmokers, 260 (36.4%) current smokers, and 175 (24.5%) ex-smokers.

Intervention: All patients underwent RNU.

Outcome Measurements And Statistical Analysis: The risks of UTUC death and non-UTUC death over time were estimated using parametric models for time to failure with Weibull distributions. Age-specific, stage-specific, and smoking status-specific surveillance durations were simulated based upon Weibull estimates.

Results And Limitations: The hazard rate (HR) of non-UTUC death gradually increased over time in all age groups regardless of the smoking status, whereas that of UTUC-related death decreased markedly according to the pathological T (pT) stage and was affected by the smoking status. Among current smokers, the baseline HR of UTUC-related death in pT3/4 was higher than that of pT ≤2 and remained high even 10yr after RNU. Among heavy smokers, the HR of UTUC-related death in all pT stages was highest at baseline and remained high after RNU, compared with nonsmokers, current smokers, or ex-smokers. We simulated specific time points when the risk of non-UTUC death was greater than that of UTUC-related death. Among patients ≥80yr of with pT3N0M0, the risk of non-UTUC death was greater than that of UTUC-related death 1yr after RNU in nonsmokers, but 7yr for heavy smokers.

Conclusions: Our result revealed that smokers bear a long-term risk burden of UTUC-related death more than the risk of non-UTUC death. For UTUC smokers, longer-term surveillance duration is recommended even in elderly stage.

Patient Summary: In the present study, we evaluated the risk transition of upper tract urothelial carcinoma (UTUC)-related death and non-cancer-related death over time. We found that smoking weighed a huge impact upon UTUC-related death compared with death from other cause, and therefore, we created a more individualized surveillance duration model.
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http://dx.doi.org/10.1016/j.euo.2019.06.021DOI Listing
December 2020