KEAP1-NRF2 system regulates age-related spermatogenesis dysfunction.

Purpose: The average fatherhood age has been consistently increasing in developed countries. Aging has been identified as a risk factor for male infertility. However, its impact on various mechanisms remains unclear. This study focused on the KEAP1-NRF2 oxidative stress response system, by investigating the relationship between the KEAP1-NRF2 system and age-related changes in spermatogenesis. Methods: For examination of age-related changes, we used 10-, 30-, 60-, and 90-week-old mice to compare sperm count, sperm motility, and protein expression. For assessment of Keap1 inhibition, 85-week-old C57BL/6J mice were randomly assigned to the following groups: control and bardoxolone methyl (KEAP1 inhibitor). Whole-exome sequencing of a Japanese cohort of patients with non-obstructive azoospermia was performed for evaluating. Results: Sperm count decreased significantly with aging. Oxidative stress and KEAP1 expression in the testes were elevated. Inhibition of KEAP1 in aging mice significantly increased sperm count compared with that in the control group. In the human study, the frequency of a missense-type SNP (rs181294188) causing changes in NFE2L2 (NRF2) activity was significantly higher in patients with non-obstructive azoospermia than in healthy control group. Conclusions: The KEAP1-NRF2 system, an oxidative stress response system, is associated with age-related spermatogenesis dysfunction.

Evaluation of the efficacy of creatine chemical exchange saturation transfer imaging in assessing testicular maturity.

Purpose: Microscopic testicular sperm extraction is the most effective treatment for NOA, but the sperm retrieval rate is low and depends on testicular maturity. However, there are limited useful tests to assess testicular maturity. Chemical exchange saturation transfer (CEST) imaging is a new magnetic resonance imaging (MRI) technique that can image the distribution of trace substances in vivo. We focused on the potential role of creatine (Cr) in testes and hypothesized that Cr-CEST could indicate intratesticular spermatogenesis. Methods: We performed Cr-CEST by using 7T MRI on wild-type C57B6/J mice and several types of male infertility models such as Sertoli-cell only (SCO) (Kitw/Kitwv), maturation arrest (MA) (Zfp541 knockout mouse and Kctd19 knockout mouse), and teratozoospermia (Tbc1d21 knockout mouse). After performing Cr-CEST, histological analysis was performed. Results: The SCO and MA models showed decreased CEST signal intensity (p < 0.05), while no reduction was observed in the teratozoospermia model (p = 1.0). CEST signal intensity increased as the spermatogenesis stage progressed from the SCO model to the MA and teratozoospermia models. Furthermore, CEST signal intensity was reduced in 4-week-old wild-type mice with immature testes (p < 0.05). Conclusions: This study suggests that Cr-CEST evaluates intratesticular spermatogenesis noninvasively and provides a new therapeutic strategy for treating male infertility.

High performance of 5-aminolevulinic acid-induced fluorescent selective upper tract urinary cytology.

OBJECTIVES: To investigate the efficacy of selective upper tract urinary cytology using extracorporeal 5-aminolevulinic acid for the diagnosis of upper urinary tract urothelial carcinoma. METHODS: We evaluated 104 patients who underwent radical nephroureterectomy and were diagnosed pathologically as having upper urinary tract urothelial carcinoma between March 2013 and May 2019 in Osaka Rosai Hospital. Preoperatively, we collected upper tract urinary cytology from both sides, and compared the sensitivity and specificity between conventional urine cytology and 5-aminolevulinic acid-induced fluorescent urine cytology. RESULTS: The sensitivity of 5-aminolevulinic acid-induced fluorescent selective upper tract urinary cytology was significantly higher than conventional cytology (90.4% vs 66.3%, P < 0.001), whereas the specificity was equally high (100% vs 98.2%, P = 1.0). In more detailed analysis, the sensitivity of 5-aminolevulinic acid-induced fluorescent selective upper tract urinary cytology was significantly higher than that of conventional cytology unrelated to patients' age (<76 years: 90.2% vs 68.6%, P = 0.013; ≥76 years: 90.6% vs 64.2%, P = 0.021), sex (male: 89.2% vs 67.5%, P = 0.001; female: 95.2% vs 61.9%, P = 0.02) or pT stage (pT1 or less: 91.4% vs 69.0%, P = 0.005; pT2 or more: 89.1% vs 63.0%, P = 0.006), tumor grade (high grade: 91.0% vs 70.5%, P = 0.002; low grade: 88.5% vs 53.8%, P = 0.013), and tended to be more efficacious for tumors that could not be detected by imaging techniques (83.3% vs 50.0%, P = 0.075). CONCLUSIONS: 5-Aminolevulinic acid-induced fluorescent selective upper tract urinary cytology is more sensitive than conventional cytology for the diagnosis of upper urinary tract urothelial carcinoma, regardless of pT stage and tumor grade.

[Usefulness of Fluorescent Urine Cytology in the Diagnosis of Urothelial Carcinoma].

Five-aminolevulinic acid, an amino acid that is metabolized in the cytoplasm to become protoporphyrin IX, is used in photodynamic diagnosis in various carcinomas because it accumulates in higher concentrations in tumor tissue than in normal tissue. 5-Aminolevulinic acid-induced fluorescent urine cytology is more sensitive than conventional urine cytology only in low grade urothelial carcinoma (UC), but it showed a tendency for higher sensitivity in high grade UC. To increase the number of patients and reconsider our previous findings, we compared the sensitivity and specificity of preoperative urine cytology and fluorescent urine cytology in 343 patients diagnosed as having UCs pathologically (215 bladder cancers, 128 upper tract UCs) and 197 non-cancer patients at Osaka Rosai Hospital from March 2013 to December 2019. The sensitivities of fluorescent urine cytology and conventional urine cytology were 81.1% and 63.3% (p<0.001), respectively, and specificities were 92.9% and 93.9% (p=0.84), respectively. The sensitivity of fluorescent urine cytology was superior to that of conventional urine cytology in both low grade UC (76.8% vs 41.1%, p<0.001) and high grade UC (83.1% vs 74.0%, p=0.023).

[Late Recurrence of Seminoma Diagnosed by Endoscopic Ultrasound-Guided Fine Needle Aspiration in a Retroperitoneal Lymph Node].

The patient was a 43-year-old man. At 30 years of age, he underwent high-inguinal orchiectomy for a right testicular tumor and was diagnosed with seminoma pT1N0M0. The patient had been followed without additional treatment and had dropped out 7 years after surgery. At 43 years of age, abdominal ultrasonography performed for screening revealed a swollen 4 cm-wide intra-abdominal lymph node, and he was referred to our department. Abdominal contrast-enhanced computed tomography (CT) showed a mass with a 5 cm-wide contrast effect that contacted the anterior surface of the inferior vena cava from the duodenum to the aortic bifurcation. Histological examination by trans-duodenal ultrasound-guided fineneedle aspiration suggested late recurrence of seminoma. After receiving three courses of BEP (bleomycin, etoposide, and platinum) therapy, the patient underwent laparoscopic lymphadenectomy. Pathological examination showed no residual tumor, and the patient was free of recurrence at 13 months after surgery.

High diagnostic efficacy of 5-aminolevulinic acid-induced fluorescent urine cytology for urothelial carcinoma.

BACKGROUND: In general, urine cytology is often problematic because of its low sensitivity, especially for low-grade urothelial carcinoma (UC) in clinical practice. To improve the sensitivity, we focused on 5-aminolevulinic acid (5-ALA), because recent studies suggested that 5-ALA-induced urine cytology can be used for photodynamic diagnosis. In this study, we evaluated the diagnostic efficacy of 5-ALA-induced fluorescent urine cytology for UC. METHODS: We included in this study 318 patients comprising 158 non-cancer patients, 84 bladder tumor patients, and 76 upper urinary tract urothelial carcinoma (UUT-UC) patients treated in our institution from March 2013 to September 2018. Using the same voided urine sample, we compared sensitivity and specificity between conventional urine cytology and 5-ALA-induced fluorescent urine cytology. RESULTS: Overall, the sensitivity of 5-ALA-induced fluorescent urine cytology was significantly higher than that of conventional urine cytology (86.9% vs. 69.4%; p = 0.0002), and the specificity was equivalently high (96.2% vs. 95.6%; p = 1.0). In subgroup analysis, the high sensitivity of 5-ALA-induced fluorescent urine cytology was also detected regardless of age, sex, and tumor type. However, in terms of stage and grade, differences were only detected in patients with less than pTa stage (89.2% vs. 52.1%; p = 0.0001) and low-grade tumor (91.5% vs. 51.1%; p < 0.0001). CONCLUSIONS: 5-ALA-induced fluorescent urine cytology was significantly more effective for UC diagnosis when compared with the conventional cytology, especially in patients with low-stage and low-grade tumors. These findings indicate that 5-ALA-induced fluorescent urine cytology may potentially be a very useful tool for clinical use.

[A Case Report : Primary Urothelial Carcinoma of the Prostate Producing Interleukin-6 Detected from a Fever].

A 72-year-old man visited a hospital because of a fever and fatigue. His fever persisted and computed tomography revealed a tumor of the prostate. The patient was referred to our hospital with a suspicion of prostate cancer. The blood test showed increased serum C-reactive protein (CRP) level without any infectious findings. Tumor markers including prostate specific antigen were within the normal range and urine cytology was negative. Prostate needle biopsy revealed urothelial carcinoma. No tumor was detected in other areas of the urinary tract. Therefore we diagnosed the patient with primary urothelial carcinoma of the prostate, cT3N0M0. Serum interleukin-6 (IL-6) elevated up to 68 ng/ml. We were not able to detect any metastatic lesions and performed radical cystoprostatectomy and ileal conduit. Serum CRP and IL-6 levels decreased and the fever declined. There has been no relapse 52 months after the surgery.

[Renal Pelvic Cancer with Delayed Diagnosis Due to Left Renal Injury : A Case Report].

We report a case of renal pelvic cancer found after left renal trauma. A 63-year-old man was admitted to our hospital because of gross hematuria after he had fallen down the stairs two days earlier. He had asymptomatic severe anemia (Hb : 3. 6 g/dl). Abdominal computed tomography (CT) scan revealed bilateral ureteropelvic stones, bilateral severe hydronephrosis and hematoma of the left upper renal pelvis. We diagnosed him with left renal pelvic hemorrhage by trauma, and transcatheter arterial embolization (TAE) was performed. After TAE, gross hematuria improved, but some hematuria continued to be noted. We suspected malignancy, and examined the patient with contrast-enhanced CT, transurethral resection and retrograde pyelography combined with urine cytology in the upper urinary tract, all with no evidence of malignancy. However, four months after the left renal injury, follow-up CT revealed multiple metastatic lesions. We performed a left nephrectomy, and the resulting pathological diagnosis was invasive urothelial carcinoma with squamous differentiation of the renal pelvis. We performed 7 courses of chemotherapy, but the multiple metastatic lesions progressed, and he died of the disease 19 months after the operation.

[Penile Tuberculosis : A Case Report].

A 66-year-old man presented with a chief complaint of glans penis pain, induration, and discharge of pus. He was prescribed a course of antibiotics, but the condition persisted despite treatment. Thus, we differrentially diagnosed the patient with penile tuberculosis and pyoderma gangrenosum, and performed a biopsy of the penis. The biopsy result was thickening of the horny layer epidermis with only a foreign body granuloma composed of inflammatory cells, and did not lead to a definitive diagnosis. Thoraca-abdominal computed tomography revealed axillary lymphadenopathy with necrosis. Suspecting tuberculosis lymphadenitis, we performed T-spot and QuantiFERONtests. The result was T-spot negative and QuantiFERONpositive, so we diagnosed the patient with penile tuberculosis, and started antituberculosis medication. In about half a year after the start of treatment the symptoms subsided, and lymphadenopathy showed reduction.

[Solitary Fibrous Tumor in the Retroperitoneum : A Case Report].

A 55-year-old man was diagnosed with an abdominal tumor and referred to our department. Abdominal contrast-enhanced computed tomography revealed a 15-cm tumor in the retroperitoneum. The inferior vena cava was compressed ventrally, the right ureter laterally, and the right kidney toward the head. Part of the tumor was situated on the dorsal side of the abdominal aorta. A preoperative diagnosis of neurogenic tumor or a type of sarcoma was made. We performed en bloc resection of the tumor. The right kidney was also resected. We exfoliated between the tumor and inferior vena cava without temporary interruption. The final diagnosis was a solitary fibrous tumor. The patient received no adjuvant therapy. Neither recurrence nor metastasis has been detected for 8 months postoperatively.

Preoperative Immunonutrition Significantly Reduced Surgical Site Infection After Urinary Diversion for Invasive Bladder Cancer: A Retrospective Cohort Study.

BACKGROUND: Radical cystectomy and ileal conduit have a high incidence of surgical site infection. In this study, we evaluated the effects of preoperative immunonutrition on its incidence following these procedures. MATERIALS AND METHODS: We retrospectively enrolled 86 patients who underwent radical cystectomy and ileal conduit at our hospital between 2014 October and 2021 July. They were sequentially divided into the Immunonutrition group (n = 43) and Control group (n = 43). Patients in the Immunonutrition group drank 4 packs of IMPACT (Nestle, Japan) per day for 5 days before surgery. IMPACT contains arginine and eicosapentaenoic acid. We compared levels of plasma arginine and eicosapentaenoic acid before and after surgery and the rate of surgical site infection between the groups. Factors related to surgical site infection were analyzed using univariate and multivariable logistic regression analysis. RESULTS: No statistically significant differences were observed in patient characteristics between the groups except for surgical operative method (P < .001) and transfusion (P = .009). Levels of plasma arginine and eicosapentaenoic acid were significantly increased the day before surgery in the immunonutrition group (P < .001). However, the levels of plasma arginine on the day after surgery did not vary significantly between the groups. The incidence of surgical site infection was significantly lower in the immunonutrition group (P = .014). Multivariate analyses showed a significant association of surgical site infection with immunonutrition (OR = 0.14, CI 0.03-0.72, P = .019) and with ASA classification (OR = 4.76, CI 1.23-18.40, P = .024). CONCLUSIONS: Preoperative immunonutrition significantly reduced the incidence of surgical site infection following radical cystectomy and ileal conduit.

Recurrent urinary retention due to clots caused by a congenital renal arteriovenous malformation that forms a complex vascular network: Report of two cases.

INTRODUCTION: Repeated urinary retention due to clots caused by congenital renal arteriovenous malformation is rare. CASE PRESENTATION: A 40-year-old woman (case 1) and a 66-year-old man (case 2) experienced recurrent urinary retention due to clots. Neither patient had a history of renal trauma nor was taking any medications. Contrast-enhanced abdominal computed tomography revealed a large hematoma in the renal pelvis and ureter with no masses, stones, or vascular lesions and only dilated blood vessels in the arterial phase in case 1. Angiography of the kidney in both patients revealed an arteriovenous malformation, and embolization of the arteries feeding the arteriovenous malformation was performed. Soon after embolization, hematuria disappeared completely with no recurrence for 5 years in case 1 and 2 years in case 2. CONCLUSION: Congenital renal arteriovenous malformation should be considered as a cause of recurrent clot retention, and angiographic embolization of the feeding arteries can be an effective treatment.

Localization and potential role of prostate microbiota.

Introduction: We aimed to clarify the presence and localization of the prostate microbiota and examine its association with benign prostate enlargement (BPE). Methods: The microbiota of prostate tissues and catheterized urine from 15 patients were analyzed by 16S metagenomic analysis and compared to show that the prostate microbiota was not a contaminant of the urinary microbiota. Fluorescence in situ hybridization (FISH) and in situ hybridization (ISH) using the specific probe for eubacteria was performed on prostate tissue to show the localization of bacteria in the prostate. The BPE group was defined as prostate volume ≥30 mL, and the non-BPE group as prostate volume <30 mL. The microbiota of the two groups were compared to clarify the association between prostate microbiota and BPE. Results: Faith's phylogenetic diversity index of prostate tissue was significantly higher than that of urine (42.3±3.8 vs 25.5±5.6, P=0.01). Principal coordinate analysis showed a significant difference between the microbiota of prostate tissue and catheterized urine (P<0.01). FISH and ISH showed the presence of bacteria in the prostatic duct. Comparison of prostate microbiota between the BPE and non-BPE groups showed that the Chao1 index of the BPE group was significantly lower than that of the latter [142 (50-316) vs 169 (97-665), P=0.047] and the abundance of Burkholderia was significantly higher in the BPE group than in the latter. Conclusions: We demonstrated that the prostate microbiota was located in the prostatic duct and reduced diversity of prostate microbiota was associated with BPE, suggesting that prostate microbiota plays a role in BPE.

Complete remission of metastatic renal cell carcinoma to the bone with sunitinib.

Target agents such as tyrosine kinase inhibitors have improved renal cell carcinoma (RCC) patient outcomes. However, complete remission (CR) with target agents is rare. Furthermore, CR of bone metastasis is much less common. We report a case of CR in bone and lung metastatic RCC. Radical nephrectomy was performed first, and clear cell RCC was diagnosed. Thereafter, sunitinib was started, and bone and lung metastases resolved entirely after 8 months of treatment. Sunitinib therapy was discontinued after 2 years because of the adverse event of proteinuria. However, the patient has remained in CR for over 1 year after sunitinib cessation.

[CLINICAL STUDY OF INTEGRATED URINARY CARE TO SUPPORT SELF-RELIANCE AGAINST URINARY DYSFUNCTION WITH INVOLVEMENT BY UROLOGISTS].

(Purpose) We reviewed 207 patients with urinary dysfunction who were managed by voiding care team at Osaka Rosai Hospital between November 2016 and June 2018. (Materials & methods) The study involved 112, 32, 24, 19, 10, 7, and 3 patients in the Urology, Orthopedics, Surgery, Internal Medicine, Neurosurgery, and Otorhinolaryngology departments, respectively. The average age was 72.7 years, ranging from 27 to 94 years, and the patients were170 males and 37 females. The average body mass index was 23.3, ranging from 11.6 to 43.7. The degree of activity of daily life (ADL) was distributed from J (independent ADL) to C (bedridden), and consisted of 132 in J category, 23 in A, 28 in B, 24 in C. Forty-seven patients had diabetes mellitus (DM), 36 had a cranial nerve disease, 25 had a history of urinary retention, 17 had indwelling urethral catheters on admission, 53 had an emergency hospital admission, and 174 underwent ≥1 operations during admission. (Results & conclusions) Among the 112 patients treated in the Urology department, 60 underwent robot-assist radical prostatectomy (RARP), 36 transurethral resection of prostate (TUR-P) and Holmium laser enucleation of the prostate (HoLEP), and 16 other procedures. A total of 93% were indwelling urethral catheter free, and 92% were pad-free (≤1 pad per day) at 1 year. In contrast, only 66% of the 95 patients in other departments were indwelling urethral catheter free at 1 year and were indwelling urethral catheter-free within 100 days, except for only one patient. The self-reliant voiding rate, including patients who have their indwelling urethral catheter removed or managed clean intermittent self-catheterization, was 91% at 1 year. A univariate analysis indicated that an ADL of J, independent ambulation, self-care/undiapered, self-reliant voiding score ≤4 (on a scale from 0 to 10, with higher score indicating a poorer ADL), and a urinary function ≤4 (on a scale from 0 to 10, with a higher score indicating greater urinary dysfunction) were significantly associated with freedom from urethral catheter. A multivariate analysis with Cox's proportional hazard model revealed a urinary function of ≤4 to be an independent good prognosticator for being catheter-free. Furthermore, a univariate analysis indicated that ADL J, a scheduled hospital admission, ≥1 operations during admission, independent ambulation, self-care/independent portable toilet, self-care/undiapered, self-reliant voiding score (≤4), and a urinary function of ≤4 were significantly associated with the acquisition of self-reliant voiding. A multivariate analysis with Cox's proportional hazard model revealed a self-reliant voiding of ≤4 to be an independent good prognosticator for self-reliant voiding. (Conclusions) Achieving freedom from an indwelling urethral catheter and acquiring a self-reliant voiding function are suggested to be very important for integrated urinary care.

Renal cell carcinoma in a horseshoe kidney treated with robot-assisted partial nephrectomy.

Horseshoe kidney is one of the most common congenital renal fusion anomalies and the incidence of renal cell carcinoma in horseshoe kidney is predicted to be approximately 5.2/100000 individuals. Because horseshoe kidney merges malformations and vascular changes, open surgery is the standard for treatment. There are no reports of robot-assisted partial nephrectomy (RAPN) for renal cell carcinoma in horseshoe kidney. We describe for the first time the safety and the utility of RAPN in a horseshoe kidney with renal cell carcinoma.

Liposarcoma of the spermatic cord associated with scrotum lipoma: A case report and review of the literature.

Liposarcoma of the spermatic cord is a rare disease and often mistakenly diagnosed as inguinal hernia, hydrocele, and lipoma. We report the case of a 58-year-old man who presented with persistent discomfort and swelling on the left inguinal region. He was diagnosed with left scrotum lipoma when he was 12 years old. He underwent high orchiectomy and wide resection of the inguinal tumor. Histopathological examination revealed a well-differentiated liposarcoma of the spermatic cord with negative resection margin and scrotum lipoma. To our knowledge, this is the first report of liposarcoma of the spermatic cord with scrotum lipoma in English literature.

A Rare Case of Vascular Leiomyosarcoma Originating from a Branch Vessel of the External Iliac Vein.

Leiomyosarcoma arising from the external iliac vein is uncommon. This is a report of a 51-year-old Japanese man with venous leiomyosarcoma originating from a branch vessel of the left external iliac vein. The tumor was found during a medical examination, and the patient had no symptoms. Computed tomography showed a 72 × 49 mm mass adjacent to the left external iliac vein. The tumor was resected en-block along with ligation of the external iliac vein due to strong adhesion with the tumor. Histological examination showed venous leiomyosarcoma, and its origin was thought to be a branch vessel of the left external iliac vein. The patient has remained free from recurrence at 30 months after surgery.