Publications by authors named "Norio Nonomura"

375 Publications

Health-related quality of life in testicular cancer survivors in Japan: A multi-institutional, cross-sectional study using the EORTC QLQ-TC26.

Urology 2021 Mar 27. Epub 2021 Mar 27.

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

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

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

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

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

Editorial Comment from Dr Hatano and Dr Nonomura to Temporal trends in the incidence of distant-stage bladder cancer among young individuals.

Int J Urol 2021 Mar 28. Epub 2021 Mar 28.

Department of Urology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.

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http://dx.doi.org/10.1111/iju.14559DOI Listing
March 2021

Monotherapy With Anti-CD70 Antibody Causes Long-Term Mouse Cardiac Allograft Acceptance With Induction of Tolerogenic Dendritic Cells.

Front Immunol 2020 19;11:555996. Epub 2021 Feb 19.

Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan.

Allograft rejection has been an obstacle for the long-term survival of patients. CD70, a tumor necrosis factor (TNF) family member critically expressed on antigen-presenting cells and strongly but transiently up-regulated during lymphocyte activation, represents an important co-stimulatory molecule that induces effective T cell responses. We used a mouse heterotopic cardiac transplantation model to evaluate the effects of monotherapy with the antibody targeting mouse CD70 (FR70) on transplantation tolerance and its immunoregulatory activity. FR70-treated C3H recipient mice permanently accepted B6 fully mismatched cardiac allografts. Consistent with the graft survival, the infiltration of CD8 T cells in the graft was reduced, dendritic cells were differentiated into a tolerogenic status, and the number of regulatory T cells was elevated both in the graft and the recipient's spleen. In addition, naïve C3H given an adoptive transfer of spleen cells from the primary recipients with FR70 treatment accepted a heart graft from a matching B6 donor but not third-party BALB/c mice. Our findings show that treatment with FR70 induced regulatory cells and inhibited cytotoxic T cell proliferation, which led to long-term acceptance of mouse cardiac allografts. These findings highlight the potential role of anti-CD70 antibodies as a clinically effective treatment for allograft rejection.
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http://dx.doi.org/10.3389/fimmu.2020.555996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961176PMC
February 2021

Proteomic analysis of urinary and tissue-exudative extracellular vesicles to discover novel bladder cancer biomarkers.

Cancer Sci 2021 Mar 15. Epub 2021 Mar 15.

Department of Urology, Osaka University Graduate School of Medicine, Suita, Japan.

Proteomic analysis of urinary extracellular vesicles (EVs) is a powerful approach to discover potential bladder cancer (BCa) biomarkers, however urine contains numerous EVs derived from the kidney and normal urothelial epithelium, which can obfuscate information related to BCa cell-derived EVs. In this study, we combined proteomic analysis of urinary EVs and tissue-exudative EVs (Te-EVs), which were isolated from culture medium of freshly resected viable BCa tissues. Urinary EVs were isolated from urine samples of 11 individuals (7 BCa patients and 4 healthy individuals), and Te-EVs were isolated from 7 BCa tissues. We performed tandem mass tag (TMT)-labeling liquid chromatography (LC-MS/MS) analysis for both urinary EVs and Te-EVs and identified 1960 proteins in urinary EVs and 1538 proteins in Te-EVs. Most of the proteins identified in Te-EVs were also present in urinary EVs (82.4%), with 55 of these proteins showing upregulated levels in the urine of BCa patients (fold change > 2.0; P < .1). Among them, we selected 22 membrane proteins as BCa biomarker candidates for validation using selected reaction monitoring/multiple reaction monitoring (SRM/MRM) analysis on urine samples from 70 individuals (40 BCa patients and 30 healthy individuals). Six urinary EV proteins (heat-shock protein 90, syndecan-1, myristoylated alanine-rich C-kinase substrate (MARCKS), MARCKS-related protein, tight junction protein ZO-2, and complement decay-accelerating factor) were quantified using SRM/MRM analysis and validated as significantly upregulated in BCa patients (P < .05). In conclusion, the novel strategy that combined proteomic analysis of urinary EVs and Te-EVs enabled selective detection of urinary BCa biomarkers.
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http://dx.doi.org/10.1111/cas.14881DOI Listing
March 2021

High detection rate in [F]PSMA-1007 PET: interim results focusing on biochemical recurrence in prostate cancer patients.

Ann Nucl Med 2021 Apr 4;35(4):523-528. Epub 2021 Mar 4.

Institute for Radiation Sciences, Osaka University, Osaka, Japan.

Objective: F-labeled prostate-specific membrane antigen (PSMA) ligand, [F]PSMA-1007, has the benefit of a higher synthetic yield and minimal excretion in the urine. High detection efficacy was reported in biochemical recurrence (BCR) of prostate cancer after radical prostatectomy. Thus, we evaluated the preliminary diagnostic utility of [F]PSMA-1007 PET in patients with prostate cancer, focusing on the BCR which is not detected on conventional imaging.

Methods: We enrolled a total of 28 patients (age 51-79 years) with BCR of prostate cancer. BCR was defined as a continuous increase in PSA after radical prostatectomy or radiation therapy without any apparent recurrent lesions on conventional diagnostic imaging (CT and bone scintigraphy). PSMA-PET scanning was performed approximately 60 min after intravenous injection of [F]PSMA-1007 (259 ± 37 MBq). PSMA-PET images were evaluated for lesion detection as well as its relation to PSA values and location.

Results: Abnormal uptake, which was suspected to be recurrence or metastasis, was detected in 92.9% (26/28) of patients with BCR. The SUVmax was 8.4 ± 6.4 in local recurrence, 11.5 ± 11.8 in pelvic lymph nodes (LN), and 4.1 ± 1.6 in bone metastasis. The detection rates were 66.7% in the PSA group-1 (0.1-0.5 ng/mL), 85.7% in the PSA group-2 (0.5-1.0 ng/mL), and 100% in the PSA group-3 (above 1.0 ng/mL). Among the PET-positive BCR patients (n = 26), local recurrence was detected in 57.7% (15/26), pelvic LN in 42.3% (11/26), and bone metastasis in 15.4% (4/26). In 53% (8/15) of BCR patients who were suspected of local recurrence, focal uptake was detected adjacent to the bladder on [F]PSMA-1007 PET. This suggested the significant advantage of having minimal physiological urine excretion.

Conclusions: [F]PSMA-1007 PET showed a high detection rate in recurrent and metastatic lesions. In patients with BCR, its high detection led to suitable treatment strategies, such as salvage radiation therapy or surgical removal of recurrent lymph nodes.

Trial Registration: (UMIN Clinical Trials Registry) UMIN000037697.
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http://dx.doi.org/10.1007/s12149-021-01602-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7981319PMC
April 2021

Urinary Extracellular Vesicles: Ultracentrifugation Method.

Methods Mol Biol 2021 ;2292:173-181

Department of Urology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.

Recently, urinary extracellular vesicles (EVs) have garnered interest as a potential source of noninvasive biomarkers of diseases related to urinary organs (kidney, bladder, urethra, and prostate).Ultracentrifugation is considered the gold standard method for isolation of EVs. However, the precipitates after ultracentrifugation steps are usually contaminated with soluble proteins, such as the Tamm-Horsfall protein (uromodulin).Therefore, ultracentrifugation on a sucrose-deuterium oxide (DO) cushion for purer EV isolation is performed to remove these proteins. In addition, as a nonultracentrifugation method for EV isolation, we have also adopted the phosphatidylserine (PS) affinity method, which is a novel method for EV purification using the T-cell immunoglobulin domain and the mucin domain-containing protein 4 (Tim4).Here, we describe an ultracentrifugation protocol based on a sucrose-DO cushion and the PS affinity method protocol for the isolation of urinary EVs.
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http://dx.doi.org/10.1007/978-1-0716-1354-2_15DOI Listing
April 2021

Serum core-type fucosylated prostate-specific antigen index for the detection of high-risk prostate cancer.

Int J Cancer 2021 Feb 16. Epub 2021 Feb 16.

Department of Urology, Osaka University Graduate School of Medicine, Suita, Japan.

It is known that core-type fucosylation is higher in prostate cancer cells than in other cancer cell types and is associated with high-risk prostate cancer. Here, we developed an automated microcapillary electrophoresis-based immunoassay system for measuring serum core-type fucosylated prostate-specific antigen (PSA) and evaluated whether the serum fucosylated PSA index (FPI) can detect high-risk prostate cancer. Core-type fucosylated-free PSA was measured by our automated microcapillary electrophoresis-based immunoassay system with Pholiota squarrosa lectin. The FPI was calculated from total PSA and the percentage of fucosylated-free PSA. The optimum model to predict Gleason grade (GG) ≥2 was constructed by multivariate logistic regression analysis. Discrimination was assessed by determining the area under the receiver operator characteristic curve (AUC). The study included 252 men who underwent prostate needle biopsy due to elevated serum PSA levels (4-20 ng/mL), including 138 with GG ≥2. A higher FPI was significantly associated with GG (P < .0001). Multivariate logistic regression analysis showed that age, prostate volume and FPI were significant predictors of GG ≥2. The AUC of FPI and the model were 0.729 (95% confidence interval [CI]: 0.668-0.790) and 0.837 (95% CI: 0.788-0.886), respectively, compared to 0.629 (95% CI: 0.561-0.698) for PSA. Decision curve analysis showed the superior benefit of FPI and the model when compared to PSA. In a cohort with serum PSA levels <20 ng/mL, FPI could differentiate high-risk prostate cancer from biopsy-negative or low-risk prostate cancer. Therefore, FPI could be a useful adjunct in prostate biopsy counseling for men with abnormal PSA levels.
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http://dx.doi.org/10.1002/ijc.33517DOI Listing
February 2021

Peripheral T cell receptor repertoire features predict durable responses to anti-PD-1 inhibitor monotherapy in advanced renal cell carcinoma.

Oncoimmunology 2021 Jan 19;10(1):1862948. Epub 2021 Jan 19.

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

Immune checkpoint inhibitors (ICIs) offer significant clinical benefits to a subset of cancer patients via the induction of a systemic T cell-mediated anti-cancer immune response. Thus, the dynamic characterization of T cell repertoires in the peripheral blood has the potential to demonstrate noninvasive predictive biomarkers for the clinical efficacy of ICIs. In this study, we collected tumor tissues and peripheral blood samples from 25 patients with advanced kidney cancer before anti-programmed cell death protein 1 (PD-1) treatment and 1, 3, and 6 months after treatment initiation. Furthermore, we applied a next-generation sequencing approach to characterize T cell receptor (TCR) alpha and beta repertoires. TCR repertoire analysis revealed that the responders to anti-PD-1 showed an expansion of certain T cell clones even in the blood, as evidenced by the significant decrease in the TCR diversity index and increase in the number of expanded TCR clonotypes 1 month after treatment. Interestingly, these expanded TCR clonotypes in the peripheral blood were significantly shared with tumor-infiltrating T cells in responders, indicating that they have many circulating T cells that may recognize cancer antigens. Expression analysis also revealed that 1 month after treatment, T cells from the peripheral blood of responders showed significantly elevated transcriptional levels of , and , markers of cancer-associated antigen-specific T cells. Altogether, we propose that global TCR repertoire analysis may allow identifying early surrogate biomarkers in the peripheral blood for predicting clinical responses to anti-PD-1 monotherapy.
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http://dx.doi.org/10.1080/2162402X.2020.1862948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833759PMC
January 2021

[AN ADULT MALE CASE OF CRYPTORCHIDISM CONCOMITANT WITH HYPOGONADOTROPIC HYPOGONADISM WHO UNDERWENT hCG THERAPY AND SHOWED A SPONTANEOUS DESCENT OF THE TESTIS].

Nihon Hinyokika Gakkai Zasshi 2020 ;111(1):30-33

Department of Urology, Osaka University Graduate School of Medicine.

A 32-year-old Japanese man was referred to our hospital with a chief complaint of the delayed puberty with having been aware of it since he was in his teens. Physical examination demonstrated the small penis, the impalpable left testis, and the atrophic right testis in the scrotum. Abdominal magnetic resonance imaging showed the left testis of 8 mm in the external inguinal ring. Endocrinological blood tests revealed that testosterone and luteinizing hormone were 0.34 ng/mL and 1 mIU/mL, respectively, leading to a diagnosis of the left cryptorchidism with hypogonadotropic hypogonadism. The hCG therapy was initiated, resulting in the increased volume and spontaneous descent into the scrotum of the left testis after 6 months of the treatment. The hCG therapy could be an alternative treatment for surgery for cryptorchidism with hypogonadism in adults.
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http://dx.doi.org/10.5980/jpnjurol.111.30DOI Listing
February 2021

The prognostic impact of immune-related adverse events in metastatic renal cell carcinoma patients treated with nivolumab: a real-world multi-institutional retrospective study.

Int J Clin Oncol 2021 Jan 20. Epub 2021 Jan 20.

Department of Urology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.

Background: Recent studies have shown that immune-related adverse events (irAEs) caused by immune checkpoint inhibitors (ICIs) were correlated with favorable clinical outcome in patients with melanoma. However, in metastatic renal cell carcinoma (mRCC) patients, there have been few reports about the correlation between irAEs and clinical efficacy of anti-programmed cell death protein-1 (PD-1) therapy.

Methods: We retrospectively investigated 160 mRCC patients who started nivolumab monotherapy between September 2016 and July 2019. IrAEs were defined as patients' AEs having a potential immunological basis that required close follow-up, or immunosuppressive therapy. We compared the data of patients who received nivolumab into two groups based on the occurrence of irAEs and assessed clinical efficacy in both groups.

Results: Of all mRCC patients, 47 patients (29.4%) developed irAEs. In patients who developed irAEs, the objective response rate and disease control rate were 38.8% and 77.6%, which were significantly higher when compared to that in patients without irAEs (p = 0.012 and p < 0.001, respectively). Furthermore, the incidence of irAEs was significantly associated with an increase in progression-free survival (PFS) [Hazard ratio (HR) = 0.4867; p = 0.0006] and overall survival (OS) (HR = 0.526; p = 0.0252). Importantly, PFS and OS seemed to be similar in patients who discontinued treatment because of irAEs and in those who did not discontinue because of irAEs (p = 0.36 and p = 0.35, respectively).

Conclusion: Development of irAEs strongly correlates with clinical benefit for mRCC patients receiving nivolumab monotherapy in real-world settings.
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http://dx.doi.org/10.1007/s10147-021-01872-5DOI Listing
January 2021

Editorial Comment to Relationship between serum zinc concentration and semen quality in newly-wed men.

Int J Urol 2021 03 19;28(3):293-294. Epub 2020 Dec 19.

Department of Urology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.

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http://dx.doi.org/10.1111/iju.14477DOI Listing
March 2021

Cumulative cancer incidence and mortality after kidney transplantation in Japan: A long-term multicenter cohort study.

Cancer Med 2021 Apr 13;10(7):2205-2215. Epub 2020 Dec 13.

Department of Urology, Osaka University Graduate School of Medicine, Suita Osaka, Japan.

Kidney transplantation is the most promising treatment to improve mortality and life quality in end-stage kidney disease; however, cancer remains a leading cause of death. Several factors including immunosuppressants might be associated with a gradual increase in cumulative cancer incidence after kidney transplantation. Risk factors for cancer and overall and cancer-specific survival were analyzed in 1973 kidney transplant recipients from three study institutions in Japan. The 5-, 10-, 20-, and 30-year overall and cancer-specific survival rates were 93.3%, 88.4%, 78.0%, and 63.6% and 99.4%, 98.0%, 95.3%, and 91.7%, respectively. The overall survival rate was significantly higher and the graft survival rate was significantly lower in recipients without cancer than in those with cancer. Older recipient age, longer dialysis duration before kidney transplantation, and history of transfusion were significant predictors of cancer. Dialysis duration before kidney transplantation was a prognostic factor of overall survival rate. Regarding cancer-specific survival rates, older recipient age and dialysis duration before kidney transplantation were prognostic factors of worse cancer-specific survival rates. The type of immunosuppressant was not associated with an increased cancer rate. Aggressiveness of immunosuppressant regimens or potent immunosuppressants might improve graft survival rate while inducing de novo cancer after kidney transplantation. Older age and longer dialysis duration before kidney transplantation were risk factors of cancer-specific survival rate.
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http://dx.doi.org/10.1002/cam4.3636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982608PMC
April 2021

Bladder urothelium converts bacterial lipopolysaccharide information into neural signaling via an ATP-mediated pathway to enhance the micturition reflex for rapid defense.

Sci Rep 2020 12 3;10(1):21167. Epub 2020 Dec 3.

Department of Neuroscience and Cell Biology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan.

When bacteria enter the bladder lumen, a first-stage active defensive mechanism flushes them out. Although urinary frequency induced by bacterial cystitis is a well-known defensive response against bacteria, the underlying mechanism remains unclear. In this study, using a mouse model of acute bacterial cystitis, we demonstrate that the bladder urothelium senses luminal extracellular bacterial lipopolysaccharide (LPS) through Toll-like receptor 4 and releases the transmitter ATP. Moreover, analysis of purinergic P2X and P2X receptor-deficient mice indicated that ATP signaling plays a pivotal role in the LPS-induced activation of L6-S1 spinal neurons through the bladder afferent pathway, resulting in rapid onset of the enhanced micturition reflex. Thus, we revealed a novel defensive mechanism against bacterial infection via an epithelial-neural interaction that induces urinary frequency prior to bacterial clearance by neutrophils of the innate immune system. Our results indicate an important defense role for the bladder urothelium as a chemical-neural transducer, converting bacterial LPS information into neural signaling via an ATP-mediated pathway, with bladder urothelial cells acting as sensory receptor cells.
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http://dx.doi.org/10.1038/s41598-020-78398-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713076PMC
December 2020

Successful recovery from coronavirus disease 2019 in a living kidney transplant recipient using low-dose methylprednisolone.

IJU Case Rep 2020 Oct 5. Epub 2020 Oct 5.

Department of Urology Osaka General Medical Cancer Osaka City Osaka Japan.

Introduction: The data of immunosuppressive therapy management on solid organ transplant recipients with coronavirus disease 2019 are insufficient. We report a kidney transplant recipient who developed coronavirus disease 2019 pneumonia, with successful management of low-dose mPSL.

Case Presentation: A 36-year-old man, who underwent living kidney transplantation 1.5 year prior, developed fever. After 10 days, he developed dyspnea, and his blood oxygen levels decreased. Computed tomography showed pulmonary ground-glass shadow on both lungs, and the coronavirus disease 2019 real-time polymerase chain reaction test was positive. After reducing the immunosuppressive agents, the C-reactive protein levels continued elevating, and the pulmonary shadow spread. Subsequently, low-dose methylprednisolone (40 mg/day) was administered for 4 days and his C-reactive protein and blood oxygen levels increased and improved, respectively. The coronavirus disease 2019 real-time polymerase chain reaction test was negative and the pulmonary shadow disappeared.

Conclusion: Low-dose methylprednisolone may prevent the development of severe coronavirus disease 2019.
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http://dx.doi.org/10.1002/iju5.12226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7675346PMC
October 2020

Recurrence of Proliferative Glomerulonephritis with Monoclonal Immunoglobulin G Deposits with a Striated Ultrastructure.

Nephron 2020 23;144 Suppl 1:43-48. Epub 2020 Nov 23.

Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan.

A 64-year-old man with nephrotic syndrome was admitted to another hospital where his renal biopsy revealed membranoproliferative glomerulonephritis (MPGN) with monoclonal immunoglobulin (Ig) G, subclass 1, κ light chain (IgG1κ) deposition on immunofluorescence (IF). Proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) was suspected due to monoclonal IgG1κ deposits and the absence of hematological abnormalities. However, the typical PGNMID phenotype was not observed by electron microscopy. Instead, an organized and striated muscle-like structure was observed in the subendothelial space. Since a 2-year treatment with immunosuppressants did not improve his proteinuria, a second biopsy was performed at our hospital. It showed an MPGN-like phenotype; however, monoclonal Ig deposits on IF were no longer observed. One year after the second biopsy, he developed ESRD. Thus, he underwent living kidney transplantation from his wife. Allograft biopsy was performed as proteinuria was observed 3 months after transplantation, which again showed an MPGN-like phenotype with monoclonal IgG1κ deposits. The observed electron-dense deposits were similar to those in the native biopsies. Accordingly, the patient was diagnosed with recurrent MPGN. Adding methylprednisolone pulse therapy to conventional immunosuppressants did not improve the patient's renal function or proteinuria. He died of Legionella pneumonia 8 months after transplantation. Considering the patient's histological findings of MPGN with monoclonal IgG1κ deposits and early recurrence of glomerulonephritis after transplantation, he was diagnosed with PGNMID with novel electron-dense deposits.
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http://dx.doi.org/10.1159/000512330DOI Listing
November 2020

Efficacy of prophylactic selective arterial embolization for renal angiomyolipomas: identifying predictors of 50% volume reduction.

CVIR Endovasc 2020 Nov 21;3(1):84. Epub 2020 Nov 21.

Department of Diagnostic and Interventional Radiology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, Japan.

Background: Transcatheter arterial embolization (TAE) has been widely performed for renal angiomyolipomas (AMLs) as prophylaxis or emergency treatment. On the other hand, mammalian target of rapamycin (mTOR) inhibitors have recently been used for tuberous sclerosis (TSC)-related AMLs, and no comparison between the effectiveness of mTOR inhibitors versus prophylactic selective TAE has yet been performed. Therefore, the purpose of this study was to evaluate the efficacy of TAE for AML tumor volume reduction and predictors of tumor volume decrease over 50%, with reference to the EXIST-2 trial.

Methods: A total of 44 patients who underwent 48 prophylactic embolization procedures for 50 AMLs in a single institution between 2004 and 2018 were included. Indications for TAE of AMLs were tumor size ≥4 cm or aneurysm ≥5 mm in diameter on contrast-enhanced computed tomography (CECT). Microspheres, ethanol, and micro-coils were used as embolic agents. The percentage volume reduction from before TAE to the minimum volume during follow-up after TAE was calculated, and predictors for 50% volume reduction were identified by univariate and multivariate binary logistic regression analyses.

Results: The technical success rate was 100% (50 of 50). No severe acute complications related to the procedure were encountered. Tumor volume reduction of ≥50% was observed in 35/50 AMLs. There was a significant difference in the rate of tumor volume reduction of 50% between the presence and absence of an aneurysm ≥5 mm and between tumor diameter ≥ 70 mm and < 70 mm on univariate analysis. On multivariate analysis, tumor diameter < 70 mm was the only independent predictor of significant tumor volume reduction after TAE.

Conclusion: Prophylactic selective TAE for AMLs has good tumor-reduction effects, especially for AMLs with tumor diameter < 70 mm.
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http://dx.doi.org/10.1186/s42155-020-00179-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7679424PMC
November 2020

Duodenal Adenocarcinoma Mimicking Metastasis of Prostate Cancer on 18F-Prostate-Specific Membrane Antigen-1007 PET/CT.

Clin Nucl Med 2021 Jan;46(1):49-51

Urology, Graduate School of Medicine, Osaka University, Osaka, Japan.

A 76-year-old man with dyspnea (initial prostate-specific antigen [PSA]: 216 ng/mL) underwent F-FDG PET/CT, with uptake in the prostate, lymph nodes, fifth thoracic vertebra (T5), and cricoid cartilage. A biopsy revealed prostate adenocarcinoma (Gleason score 4 + 5, cT4 N1 M1). On initiation of combined androgen blockade therapy, PSA value decreased. However, 4 years later, in a castration-resistant state (PSA 2.14 ng/mL), CT and bone scintigraphy revealed a duodenal tumor and T5 metastasis. F-prostate-specific membrane antigen-1007 PET/CT showed uptake in the already known T5 metastasis (SUVmax, 33.55) and even in the duodenal tumor (16.55). The latter was histologically diagnosed as duodenal adenocarcinoma.
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http://dx.doi.org/10.1097/RLU.0000000000003400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722462PMC
January 2021

Validation study of the Japanese version of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Testicular Cancer 26 for patients with testicular cancer.

Int J Urol 2021 Feb 10;28(2):176-182. Epub 2020 Nov 10.

Department of, Departments of, Urology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.

Objective: To validate the Japanese version of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Testicular Cancer 26 in Japanese-speaking testicular cancer survivors.

Methods: A total of 200 testicular cancer survivors were recruited at eight high-volume institutions in Japan. The participants completed the Japanese version of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Testicular Cancer 26, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 and the International Index of Erectile Function 15 questionnaires. A total of 40 participants completed a retest of the questionnaires 2 weeks after the first response. The psychometric properties of the Japanese version including test-retest reliability, internal consistency and concurrent validity were evaluated.

Results: The mean age at response was 43 years (range 22-74 years), and the mean period after treatment was 77 months (range 0-416 months). The response rate for each item, except sexual function, was high, and the percentage of missing values was less than 3.5%. For test-retest reliability, seven of 12 scales met the criteria (intraclass correlation 0.70-0.86). For internal consistency, four of seven scales met the criteria (Cronbach's alpha 0.62-0.91). For concurrent validity, treatment side effects of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Testicular Cancer 26 were related to some domains of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30. The sex-related subscales of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Testicular Cancer 26 were moderately correlated with some International Index of Erectile Function 15 domains.

Conclusions: The psychometric properties of the Japanese version are equivalent to the properties of the original European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Testicular Cancer 26. The Japanese version of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Testicular Cancer 26 questionnaire is a useful tool to assess the health-related quality of life of testicular cancer patients.
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http://dx.doi.org/10.1111/iju.14422DOI Listing
February 2021

Efficacy of a Si-based agent against developing renal failure in a rat remnant kidney model.

Biochem Biophys Res Commun 2020 12 31;533(4):698-703. Epub 2020 Oct 31.

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

Chronic renal failure is exacerbated by oxidative stress, and this condition is difficult to treat in advanced stages. Because of the lack of effective treatments, the disease is a global public health concern. We developed a Si-based agent that continuously generates hydrogen for more than 24 h by reacting with water under conditions similar to those in the gastrointestinal tract. Given the efficacy of hydrogen in the treatment of conditions associated with oxidative stress, we examined whether the Si-based agent had beneficial effects on the development of renal failure. The Si-based agent was orally administered to rats that were developing renal failure. Rats underwent 5/6 nephrectomy to establish a remnant kidney model. Specifically, on day -7, rats underwent right 2/3 nephrectomy, followed by light nephrectomy on day 0. Starting on day -3, the rats were administered a control or Si-based agent-containing diet for 8 weeks. Compared with the findings in control rats, the Si-based agent greatly suppressed the increases of both serum creatinine and urinary protein levels. All analyzed parameters of oxidative stress were significantly suppressed in the Si-based agent groups. Histopathological examination illustrated that glomerular hypertrophy was suppressed by the treatment. Quantitative real-time reverse transcription-polymerase chain reaction revealed that sirtuin 1 and heme oxygenase-1 expression was increased in the Si-based agent groups, suggesting improved antioxidant activity and reduced hypoxia. In addition, caspase-3 and interleukin-6 expression was suppressed in the Si-based agent groups, indicating the alleviation of apoptosis and inflammation. In conclusion, oral administration of a Si-based agent resulted in renoprotective effects, presumably by suppressing oxidative stress via hydrogen generation.
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http://dx.doi.org/10.1016/j.bbrc.2020.10.067DOI Listing
December 2020

Clinical Efficacy of Intravenous Immunoglobulin for BK Polyomavirus-Associated Nephropathy After Living Kidney Transplantation.

Ther Clin Risk Manag 2020 8;16:947-952. Epub 2020 Oct 8.

Department of Urology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.

Purpose: BK polyomavirus (BKPyV)-associated nephropathy (BKPyVAN) is one of the most difficult infections to be treated after kidney transplantation. Although patients with BKPyVAN usually received a reduction of immunosuppressive agents, the majority of these patients undergo the loss of the graft kidney without any effective treatment afterward. Therefore, development of more effective therapy for BKPyVAN is eagerly expected.

Patients And Methods: Among patients who underwent a kidney transplantation between January 2016 and April 2019 at our hospital, there were five cases of BKPyVAN. After the initial diagnosis, all patients discontinued administration of mycophenolate mofetil (MMF), which was not enough to diminish decoy cells in urine cytology test. Therefore, all patients received additional intravenous immunoglobulin (IVIG) (100 mg/kg/day) therapy for five days and were evaluated for the therapeutic effect of IVIG with immunohistochemical examination using re-biopsy samples of the graft kidney.

Results: After IVIG therapy, 2 cases showed negative decoy cells in urine and 3 cases showed a drastic decrease of plasma BK virus load. Importantly, simian virus (SV) 40 large T antigens diminished after IVIG administration in all cases, which degraded polyomavirus nephropathy classification.

Conclusion: Although it is difficult to treat BKPyVAN after kidney transplant, IVIG therapy was considered to a promising treatment to improve severity of BKPyVAN especially in cases that dose reduction of immunosuppressive agents was ineffective.
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http://dx.doi.org/10.2147/TCRM.S273388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549878PMC
October 2020

Fragmentation of cell-free DNA is induced by upper-tract urothelial carcinoma-associated systemic inflammation.

Cancer Sci 2021 Jan 12;112(1):168-177. Epub 2020 Nov 12.

Department of Urology, Osaka University Graduate School of Medicine, Suita, Japan.

Reliable biomarkers for upper-tract urothelial carcinoma (UTUC) have yet to be found. Plasma cell-free DNA (cfDNA) has been clinically applied as a minimally invasive blood biomarker for various types of cancer. We investigated the utility of plasma cfDNA as a blood biomarker in UTUC patients. The fragment size of plasma cfDNA was shorter and the concentration of plasma cfDNA was higher in UTUC patients than in healthy controls. The fragment size of plasma cfDNA had a moderate accuracy of diagnosing UTUC (area under the curve [AUC] = 0.72), and multivariate analysis indicated that the fragment size of plasma cfDNA was significantly associated with the presence of UTUC (odds ratio = 0.807, 95% confidence interval [CI] 0.653-0.955, P = .024). Furthermore, we found that the size of plasma cfDNA shortens alongside disease progression (P < .001). The fragment size of plasma cfDNA in UTUC patients may be an auxiliary tool for the diagnosis of UTUC patients. We also found a high correlation between the fragmentation of plasma cfDNA and serum levels of three inflammatory cytokines (TNFα [r = -.837], interleukin-6 [IL-6] [r = -.964], interleukin-1 receptor antagonist [IL-1ra] [r = -.911]), which were reported to associate with poor prognosis. Also, we found that the proportion of short fragments of cfDNA was significantly increased in the supernatant of peripheral blood mononuclear cells (PBMCs) from healthy controls cultured in media containing TNFα. These results supposed that cancer-associated systemic inflammation, especially tumor necrosis factor-α (TNFα), may contribute to the fragmentation of plasma cfDNA in UTUC patients.
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http://dx.doi.org/10.1111/cas.14679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780031PMC
January 2021

Resumption of anti-programmed cell death 1 monotherapy for severe immune-related adverse events experienced patient with renal cell carcinoma.

IJU Case Rep 2020 Sep 25;3(5):176-179. Epub 2020 Jun 25.

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

Introduction: Combined anti-cytotoxic-T-lymphocyte antigen 4 and programmed cell death 1 blockade induced high rates of immune-related adverse events in patients with renal cell carcinoma. However, the safety of reinitiating anti-programmed cell death 1 monotherapy for patients who discontinued combination therapy due to immune-related adverse events is largely unknown.

Case Presentation: We report the case of 74-year-old man who received combination therapy with anti-cytotoxic-T-lymphocyte antigen 4 and programmed cell death 1 inhibitors for advanced renal cell carcinoma. After three cycles of combination therapy, he complained severe immune-related adverse events including grade 3 nausea and anorexia, and grade 3 diarrhea, leading to discontinuation of the therapy. He started readministration of anti-programmed cell death 1 monotherapy at 41 weeks after discontinuation due to the new lung metastatic lesion. Importantly, he experienced only grade 1 diarrhea, which can be controlled with prednisolone.

Conclusion: The readministration of anti-programmed cell death 1 monotherapy with close monitoring can be an acceptable treatment even after discontinuation of combination therapy.
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http://dx.doi.org/10.1002/iju5.12173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469840PMC
September 2020

Impact of Immunoglobulin M-Type Donor-Specific Human Leukocyte Antigen-Antibody Levels in Supernatants from Cultured Peripheral Blood Mononuclear Cells as Predictors of Antibody-Mediated Rejection.

Pathogens 2020 Sep 5;9(9). Epub 2020 Sep 5.

Department of Renal Transplantation, Kansai Medical Hospital, Osaka 560-0083, Japan.

Background: Antibody-mediated rejection (AMR) is a crucial barrier in the long-term prognosis of transplant recipients.

Methods: Peripheral blood mononuclear cells (PBMCs) were collected from kidney allograft recipients ( = 41) and cultured in vitro for 1 week. Furthermore, the supernatants of the cultured PBMCs were analyzed by Luminex single-antigen beads.

Results: Analyses using Luminex single-antigen beads revealed the presence of immunoglobulin (Ig) G donor-specific anti-HLA antibodies (DSAs) was detected in the supernatants of cultured PBMCs collected more frequently than IgM in DSA-sensitized patients with AMR, and IgM were detectable in patients with stable graft function mainly and several IgM DSAs were detectable in the supernatants of the cultured PBMCs before detecting the IgG levels in sera. We also found that the DSA-specific IgM-secreting memory B cells (mBCs) were more sensitive to the chronic use of immunosuppressive agents than to the IgG-secreting mBCs.

Conclusions: In the transplant recipients, the assessment of supernatants of cultured PBMCs provide more details of immune reactions than the commonly used method that directly measures IgG DSA levels in patient sera and some IgM DSA detection may be a better predictor of IgG DSAs production, which may cause AMR and enable early intervention, in initial stages of AMR development.
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http://dx.doi.org/10.3390/pathogens9090733DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7559903PMC
September 2020

A Potential Mechanism of Anticancer Immune Response Coincident With Immune-related Adverse Events in Patients With Renal Cell Carcinoma.

Anticancer Res 2020 Sep;40(9):4875-4883

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

Background/aim: Some reports showed encouraging efficacy of immune checkpoint inhibitors among patients who experienced immune-related adverse events (irAEs). Thus, characterization of T-cell repertoire and immune signatures in peripheral blood mononuclear cells (PBMCs) and tumors before and after immune checkpoint inhibitors treatment should contribute to better understanding of irAE-provoked anticancer immune responses.

Materials And Methods: We applied expression analysis of immune-related genes and T-cell receptor sequencing in tumor and PBMCs from five patients with renal cell carcinoma before combined immunotherapy and at the onset of severe irAEs.

Results: We found that the cluster of differentiation 8 (CD8)/forkhead box P3(FOXP3), granzyme B(GZMB)/CD3, perforin 1(PRF1)/CD3 and programmed cell death 1(PD1)/CD8 expression ratios were significantly elevated in PBMCs at the onset of irAEs. In addition, we found expansion of certain T-cell clones in metastatic tissue after irAEs, which were already increased in peripheral blood at the onset of irAEs.

Conclusion: irAE-provoked T-cells may also circulate and attack distant tumors, leading to durable response in patients with irAEs.
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http://dx.doi.org/10.21873/anticanres.14490DOI Listing
September 2020

Mutational Landscape and Environmental Effects in Bladder Cancer.

Int J Mol Sci 2020 Aug 23;21(17). Epub 2020 Aug 23.

Department of Urology, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan.

Bladder cancer is the most common cancer of the urinary tract. Although nonmuscle-invasive bladder cancers have a good prognosis, muscle-invasive bladder cancers promote metastases and have a poor prognosis. Comprehensive analyses using RNA sequence of clinical tumor samples in bladder cancer have been reported. These reports implicated the candidate genes and pathways that play important roles in carcinogenesis and/or progression of bladder cancer. Further investigations for the function of each mutation are warranted. There is suggestive evidence for several environmental factors as risk factors of bladder cancer. Environmental factors such as cigarette smoking, exposure to chemicals and gases, bladder inflammation due to microbial and parasitic infections, diet, and nutrition could induce several genetic mutations and alter the tumor microenvironment, such as immune cells and fibroblasts. The detailed mechanism of how these environmental factors induce carcinogenesis and/or progression of bladder cancer remains unclear. To identify the relationship between the mutations and the lifestyle could be useful for prevention and treatment of bladder cancer.
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http://dx.doi.org/10.3390/ijms21176072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7503658PMC
August 2020

Application of Anti-Inflammatory Agents in Prostate Cancer.

J Clin Med 2020 Aug 18;9(8). Epub 2020 Aug 18.

Department of Urology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.

Chronic inflammation is a major cause of human cancers. The environmental factors, such as microbiome, dietary components, and obesity, provoke chronic inflammation in the prostate, which promotes cancer development and progression. Crosstalk between immune cells and cancer cells enhances the secretion of intercellular signaling molecules, such as cytokines and chemokines, thereby orchestrating the generation of inflammatory microenvironment. Tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) play pivotal roles in inflammation-associated cancer by inhibiting effective anti-tumor immunity. Anti-inflammatory agents, such as aspirin, metformin, and statins, have potential application in chemoprevention of prostate cancer. Furthermore, pro-inflammatory immunity-targeted therapies may provide novel strategies to treat patients with cancer. Thus, anti-inflammatory agents are expected to suppress the "vicious cycle" created by immune and cancer cells and inhibit cancer progression. This review has explored the immune cells that facilitate prostate cancer development and progression, with particular focus on the application of anti-inflammatory agents for both chemoprevention and therapeutic approach in prostate cancer.
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http://dx.doi.org/10.3390/jcm9082680DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464558PMC
August 2020

Diagnostic Accuracy of F-PSMA-1007 PET/CT Imaging for Lymph Node Staging of Prostate Carcinoma in Primary and Biochemical Recurrence.

J Nucl Med 2021 02 17;62(2):208-213. Epub 2020 Aug 17.

Department of Nuclear Medicine, University Hospital, Heidelberg, Germany

Prostate-specific membrane antigen (PSMA)-ligand PET/CT is performed on patients with prostate cancer to stage the disease initially or to identify sites of recurrence after definitive therapy. On the basis of clinical results, F-PSMA-1007 is a promising PSMA PET tracer, but detailed histologic confirmation has been lacking. Ninety-six patients with prostate cancer underwent F-PSMA-1007 PET/CT followed by either radical prostatectomy with lymphadenectomy or salvage lymphadenectomy. The histologic findings of PSMA PET-positive nodes were analyzed retrospectively. A lesion-based and patient-based analysis was performed comparing all positive lesions and only lesions larger than 3 mm on histopathology. Of the patients, 90.6% received F-PSMA-1007 PET/CT for staging before the primary treatment, whereas 9.4% underwent imaging for biochemical recurrence. In 34.4% of the cohort, positive lymph nodes were present on imaging. In total, 1,746 lymph nodes were dissected in 96 patients. F-PSMA-1007 PET had a lesion-based sensitivity of 81.7%, a specificity of 99.6%, a positive predictive value of 92.4%, and a negative predictive value of 98.9% for detecting positive lymph nodes larger than 3 mm. In the analysis of all malignant nodes regardless of size, the overall sensitivity, specificity, positive predictive value, and negative predictive value on lesion-based analysis were 71.2%, 99.5%, 91.3%, and 97.9%, respectively. The patient-based analysis showed a sensitivity of 85.9% and a specificity of 99.5% for lymph nodes larger than 3 mm. F-PSMA-1007 PET/CT reliably detects malignant lymph nodes and has an exceptional specificity of more than 99% for nodal metastases.
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http://dx.doi.org/10.2967/jnumed.120.246363DOI Listing
February 2021

Failure to achieve castrate level of serum testosterone during luteinizing hormone-releasing hormone agonist therapy in a patient with prostate cancer.

Anticancer Drugs 2020 11;31(10):1099-1102

Departments of Urology.

We report the failure to achieve castrate level of serum testosterone during luteinizing hormone-releasing hormone agonist therapy in a patient with prostate cancer. A 76-year-old man was admitted to our hospital for evaluation of an elevated serum prostate specific antigen (PSA) level (191.10 ng/ml) in August 2011. He was diagnosed with T3aN0M1b prostate adenocarcinoma. A combined androgen blockade using luteinizing hormone-releasing hormone agonist (the 1-month depot of leuprorelin acetate) and antiandrogen was administered. Due to liver dysfunction, antiandrogens, both bicalutamide and flutamide, were stopped. The 1-month depot was switched to the 3-month depot in May 2013, but the patient complained of induration and abscess at the infection site. Leuprorelin acetate was replaced by goserelin acetate. Because no adverse event appeared after injection of the 1-month depot of goserelin acetate, the 3-month depot was administered in October 2013. The PSA level increased gradually, and the testosterone level was greater than 50 ng/dl, that is, above castrate range. The 3-month depot of both leuprorelin acetate and goserelin acetate was not effective for this patient. For this reason, the 1-month depot of leuprorelin acetate was started resulting in a rapid decrease in PSA and testosterone levels. Thereafter, androgen depriving therapy could be continued. Androgen deprivation therapy is the standard treatment for patients with advanced prostate cancer and luteinizing hormone-releasing hormone aims to suppress serum testosterone to castrate range. We recommend assessing the serum testosterone levels during luteinizing hormone-releasing hormone agonist therapy for monitoring treatment efficacy and verifying progression when the PSA level increases.
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http://dx.doi.org/10.1097/CAD.0000000000000986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566291PMC
November 2020

Novel hydrogen-producing Si-based agent reduces oxidative stress, and improves sperm motility and in vitro fertilization rate in varicocoele.

Andrology 2021 01 9;9(1):376-383. Epub 2020 Sep 9.

Department of Urology, Osaka University Graduate School of Medicine, Suita, Japan.

Background: Varicocoele-induced male infertility potentially involves oxidative stress. Although varicocoelectomy is recommended for varicocoele patients presenting abnormal semen findings, no pharmacotherapeutic methods currently exist. We have recently developed a silicon-based agent that produces hydrogen by the reaction with water.

Objectives: This study aimed to investigate the therapeutic effects of oral administration of a Si-based agent on varicocoele rat.

Materials And Methods: Twenty-one rats were divided into four groups: varicocoele + normal diet (n = 5), varicocoele + Si-based agent-supplemented diet (n = 6), sham + normal diet (n = 5), and sham + Si-based agent-supplemented diet (n = 5). All rats were euthanized four weeks after surgery.

Results: The mean left epididymal sperm motility was 74.4% in the sham group, 72.3% in the sham + Si group, 57.6% in the varicocoele group, and 66.9% in the varicocoele + Si group. Epididymal sperm motility was significantly lower in the varicocoele group, but was significantly higher upon Si-based agent ingestion (P < .01). The mean left testicular weight, Johnsen's score, and left epididymal sperm concentration did not differ significantly between groups. The 8-OHdG concentration and DNA fragmentation rate were significantly increased in the varicocoele group, but were significantly decreased in the Si-based agent intake group (P < .01). Additionally, the IVF rate was significantly lower in the varicocoele group (26.3%) compared with the sham group (73.4%; P < .01), and was significantly higher in the varicocoele + Si group (51.8%) compared with the varicocoele group (P < .05), indicating that the Si-based agent improves IVF rates.

Discussion And Conclusion: Oral intake of the silicon-based agent improves epididymal sperm motility and in vitro fertilization rates through hydrogen production and subsequent reduction of oxidative stress. Considering the lack of effective noninvasive methods, this Si-based agent is potentially applicable for treating varicocoele-induced abnormal semen parameters.
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http://dx.doi.org/10.1111/andr.12890DOI Listing
January 2021