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Taiki Kato,1 Kentaro Mizuno,2 Hidenori Nishio,2 Yoshinobu Moritoki,1 Akihiro Nakane,1 Satoshi Kurokawa,1 Hideyuki Kamisawa,1 Tetsuji Maruyama,3 Takahiro Yasui,1 Yutaro Hayashi2 1Department of Nephro-urology, Nagoya City University Graduate School of Medical Sciences, Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Japan; 2Department of Pediatric Urology, Nagoya City University Graduate School of Medical Sciences, Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Japan; 3Department of Urology, Nagoya City East Medical Center, Wakamizu, Chikusa-ku, Nagoya, Japan Introduction: Lichen sclerosus (LS), or balanitis xerotica obliterans, is a chronic, inflammatory disease accompanied by cicatrizing skin conditions resulting in pathologic phimosis. LS can be detected clinically by the whitish appearance of the glans or the foreskin, thickened, nonretractable foreskin, dysuria, and spraying. However, diagnosis is confirmed histopathologically. Purpose: The aim of this study was to investigate whether LS can be diagnosed on the basis of clinical manifestation and symptoms. Patients and methods: A retrospective analysis was performed, which included boys referred to our institutions for phimosis evaluation between May 2001 and December 2016. Pediatric urologists clinically diagnosed LS preoperatively. Boys with voiding problems, recurrent balanoposthitis, or who were unresponsive to topical steroid treatment underwent surgical treatment. Patients who underwent religious circumcisions were not included. Results: Three-hundred twenty boys diagnosed with phimosis were identified, and 71 (22%) boys underwent surgery. Fifty-eight boys underwent complete or partial circumcision, and 13 boys underwent a dorsal slit or preputioplasty. Thirty foreskin samples were sent for histopathologic examination. Histopathologic evaluation showed evidence of LS in 13 of 30 (43%) circumcised boys, chronic inflammation in ten (33%), no abnormality in four (13%), dysplasia in two (7%), and acute inflammation in one (3%). In the 22 boys who were clinically diagnosed with LS, 13 patients had histopathologic evidence of LS (59%). Visually, eleven cases had whitish foreskins and 21 cases had thickened nonretractable foreskins, of which there were seven (64%) (P>0.05) and 12 (57%) (P0.2). Conclusion: It is difficult to reliably distinguish whether a patient has histopathological LS by clinical findings alone. Keywords: balanitis xerotica obliterans, lichen sclerosus, circumcision, histology, child

Introduction: Hemiscrotal agenesis is a rare scrotal developmental disorder. Orchiopexy on the opposite side of the scrotum with rugae or scrotoplasty combined with orchiopexy is usually performed as a surgical treatment for hemiscrotal agenesis with cryptorchidism. Till date, there are only eight published case studies of hemiscrotal agenesis., Case Presentation: A 6-year-old boy, who had been previously treated for infantile hemangiomas, was referred by a pediatrician to our hospital for the follow-up of hemiscrotal agenesis without cryptorchidism. Thermography demonstrated that the temperature of the right scrotal skin with no rugae was higher than that of the left scrotal skin with rugae. The patient's parent declined scrotoplasty because the hemiscrotal agenesis was to be followed up without scrotoplasty and scrotal ultrasonography revealed no abnormal findings in both testes., Conclusion: High-temperature environment may not impair the testicular growth in prepubertal hemiscrotal agenesis without cryptorchidism., Competing Interests: Kentaro Mizuno is the Deputy Editor of IJU Case Reports and a coauthor of this article. He was excluded from editorial decision‐making related to the acceptance and publication of this article. The other authors declare no conflict of interest., (© 2024 The Author(s). IJU Case Reports published by John Wiley & Sons Australia, Ltd on behalf of Japanese Urological Association.)

Objectives: The 2021 European Association of Urology-European Society for Paediatric Urology guidelines on Pediatric Urology recommended testis-sparing surgery (TSS) as the primary approach to treat prepubertal testicular tumors exhibiting favorable preoperative ultrasound diagnoses. However, prepubertal testicular tumors are rare and clinical data regarding them is limited. Here, we analyzed the surgical management of prepubertal testicular tumors based on cases observed over approximately 30 years., Methods: Data were retrospectively reviewed from medical records of consecutive patients aged <14 years with testicular tumors who received treatment at our institution between 1987 and 2020. We compared patients by their clinical characteristics, namely, those who underwent TSS versus radical orchiectomy (RO) and those who received surgery in 2005 onward versus prior to 2005., Results: We identified 17 patients, with a median age at surgery of 3.2 years (range 0.6-14.0) and a median tumor size of 15 mm (range 6-67). The tumor size was significantly smaller in patients who underwent TSS than in those who underwent RO (p = 0.007). Patients treated in 2005 onward were more likely to undergo TSS than those treated prior to 2005 (71% vs. 10%, respectively), without significant differences in tumor size or the rate of preoperative ultrasound. No TSS cases required conversion to RO., Conclusions: Recent improvements in ultrasound imaging technology allow for more accurate clinical diagnosis. Therefore, the indications of TSS for prepubertal testicular tumors can be judged based not only on the tumor size but also on the diagnosis of benign tumors by preoperative ultrasound., (© 2023 The Japanese Urological Association.)

Introduction: Primary obstructed non-refluxing megaureter, a type of congenitally dilated ureter, often resolves spontaneously. Surgery may be indicated in symptomatic cases; however, there are no reports of transvesicoscopic ureteral implantation and ureteroscopy for ureteral stones. Therefore, we describe the treatment of primary obstructed non-refluxing megaureter and ureteral calculi using this technique., Case Presentation: A 6-year-old Japanese girl was referred for abdominal pain and gross hematuria due to right megaureter with multiple stones in the renal lower-pole calyces and ureter. She was diagnosed with primary obstructed non-refluxing megaureter and ureterovesical junction obstruction. The stones were removed using mini-percutaneous nephrolithotomy and transvesicoureteroscopic surgery, respectively. A narrow segment of the right ureter was cut, and transvesicoscopic ureteral plication and reimplantation were performed. The procedures were successful without postoperative complications., Conclusion: Transvesicoscopic ureteral reimplantation with ureteroscopy may be a safe, effective and minimally invasive surgical option for ureterovesical junction obstruction with ureteral stones., Competing Interests: The authors declare no conflicts of interest., (© 2022 The Authors. IJU Case Reports published by John Wiley & Sons Australia, Ltd on behalf of Japanese Urological Association.)

Purpose: In cryptorchidism, germ cell development failure presents from infancy and may be reflected by altered hormonal levels produced by Sertoli cells. Our object was to assess for associations between serum hormone levels and testicular histopathology in cryptorchidism with an infertility risk according to the pretreatment undescended testicular positions., Materials and Methods: Prepubertal cryptorchid boys aged 7-91 (median 20) months who underwent orchidopexy between 2014 and 2019 were included (122 unilateral [median 19 months {range 7-91}], 23 bilateral [24 months {11-81}]). We evaluated the pretreatment testicular position and size; serum hormone levels; and the mean number of germ cells per tubule transverse section (G/T). We also performed a subgroup analysis of boys aged ≤24 months at orchidopexy., Results: Serum inhibin B levels and G/T were significantly lower in bilateral than in unilateral cryptorchid boys (median 96 [range 46-197] pg/ml vs 125 [21-354] pg/ml, p=0.026; 0.20 [0-2.59] vs 0.65 [0-4.55], p <0.001, respectively). Inhibin B/follicle-stimulating hormones (FSH) and anti-Müllerian hormone (AMH)/FSH ratios were positively correlated with G/T in bilateral cryptorchid boys aged ≤24 months (12, p=0.008 and p=0.019, respectively). Low inhibin B/FSH and AMH/FSH ratios and high FSH were predictors of impaired G/T as per receiver operating characteristic curves (p=0.019, p=0.004 and p=0.004, respectively), whereas in unilateral cryptorchid boys aged ≤24 months, serum hormone levels and G/T did not differ with the pretreatment testicular positions., Conclusions: In bilateral cryptorchid boys aged ≤24 months at orchidopexy, low inhibin B/FSH and AMH/FSH ratios may reflect impaired G/T and future infertility risk.

Background: Transverse testicular ectopia (TTE) is a rare anomaly in which both testes descend through a single inguinal canal into the same hemiscrotum. Although almost 20-50% of patients with TTE exhibit persistent Müllerian duct syndrome (PMDS) and many genetic analyses have been performed, no reports have described the genes contributing to TTE without PMDS. Here, we report two cases of TTE without PMDS using immunohistochemical staining and genetic analysis., Case Presentation: Two Asian patients with TTE without PMDS were subjected to orchiopexy. We performed testicular biopsies during operation and obtained blood samples before the operation. Testicular tissues were stained for c-kit, placental alkaline phosphatase (PLAP), and undifferentiated embryonic cell transcription factor 1 (UTF1) to evaluate the presence of intratubular malignant germ cells. Additionally, we performed polymerase chain reaction-based direct sequencing to identify single nucleotide polymorphisms in genes associated with regression of the Müllerian duct and testicular descent (that is, anti-Müllerian hormone [AMH], AMH receptor 2 [AMHR2], insulin-like 3 [INSL3], and relaxin family peptide receptor 2 [RXFP2]). The three-dimensional structures of proteins were predicted using SWISS-MODEL. In immunohistochemical analysis, c-kit and UTF1 were positive, whereas PLAP was negative in three testicular tissue samples from the two patients. These features were also detected on the unaffected side. In variant analysis, common missense variants in the AMH gene (g.365G>T; c.165G>T; p.Ser49Ile [rs10407022]) were observed. All variants in INSL3 and RXFP2 genes were intronic or silent., Conclusions: Because UTF1, a specific marker of spermatogonial stem cell activity, was expressed in both the affected and unaffected sides in the testicular tissues of two patients, the risk of malignancy may be high in these patients. Although the etiology of TTE without PMDS remains unclear, our variant analysis results were consistent with previous reports, and variants in the AMH gene (rs10407022) may contribute to the specific phenotype of TTE without PMDS.

Background: Most cases of antenatal the Society of Fetal Urology (SFU) grade 1or 2 hydronephrosis (HN) improve or resolve spontaneously with conservative treatment. However, there is no consensus on the duration of follow-up for cases of grade 1or 2 HN. The aim of this study was to determine the need for continuous follow-up period and new management of children with antenatal grade 1or 2 HN., Methods: Subjects underwent ultrasonographic assessment for HN according to the SFU classification. We retrospectively evaluated 112 patients with postnatal grade 1 HN and 69 with grade 2 HN using abdominal ultrasonography between January 2010 and December 2017. We examined the change in HN grade on repeat ultrasonography. Kaplan-Meier method was used to show the effect of HN grade on the rate of HN changes., Results: The mean follow-up duration was 44.9 ± 36.4 months (range 12-274). Initial SFU grade 1 HN disappeared in 47.0% of cases at 12 months, 66.4% at 24 months and 73.2% at 48 months. Initial SFU grade 2 HN showed improvement in grade in 74.7% of cases at 12 months, 88.3% at 24 months and 89.5% at 48 months. However, 14.6% of SFU grade 1 and 2.8% of SFU grade 2 cases increased in grade and of the 17 cases, 16 cases worsened within the first 6 months. No cases with increased grade required pyeloplasty. Initial disappearance and later reappearance of HN occurred in 40.5% of SFU grade 1 and 2 cases. The mean duration of later reappearance of HN was 39.1 ± 36.2 months (range 12-137). No cases showed reappearance of HN after more than 1 year., Conclusions: Ultrasonography within the first 6 months was necessary for management of children with antenatal grade 1or 2 HN, because some patients showed worsening. After that, it is considered safe to spread the follow-up interval for stable cases. Most cases of grade 1or 2 HN resolved spontaneously, however a few cases reappeared within 1 year. Therefore, ultrasonography after 1 year was necessary in children with HN that spontaneously disappeared. The appropriate time to end the follow-up was considered to have been after 1 year or more has passed since the disappearance was confirmed.

Background: Cryptorchidism is known to impair spermatogenesis. The blood-testis barrier (BTB) becomes defined in seminiferous tubules around puberty and provides a suitable environment for germ cells. Little is known about the BTB in undescended testes (UDT)., Objectives: To determine the role of BTB during puberty in UDT using a non-surgical cryptorchid rat model., Material and Methods: Unilateral cryptorchid male rats were intraperitoneally injected with non-steroidal antiandrogen during intrauterine development; the testes were harvested at 4, 5, and 6 weeks after birth. Testicular histology, expression levels of the BTB proteins (claudin-11, occludin, zonula occludens-1), and apoptotic cells were evaluated by immunohistochemistry, Western blotting, and TUNEL assay. The functionality of the BTB was investigated by electron microscopy using the lanthanum tracer method., Results: The testicular histology of undescended testes 6 weeks after birth showed maturation arrest at the spermatocyte level. The BTB protein distributions were altered in the UDT, with a noticeable difference in claudin-11(CLDN11) localization from 4 to 5 weeks after birth between control and UDT samples. BTB protein levels were similar. More apoptotic germ cells were detected in the adluminal compartment of tubules in the UDT than in the control testes. Electron microscopy showed that the lanthanum tracer was limited to the BTB of control testes, whereas it penetrated the BTB of UDT., Discussion: Here, loss of normal BTB function and impaired spermatogenesis were observed in UDT during puberty. CLDN11 is a pivotal tight junction protein belonging to the BTB. Tight junctions are considered as essential for normal spermatogenesis, and abnormal CLDN11 organization may cause UDT-associated male infertility., Conclusion: CLDN11 disorganization within the BTB may cause spermatogenic impairment, possibly by limiting the BTB function., (© 2020 American Society of Andrology and European Academy of Andrology.)

Background: Congenital anomalies of the kidney and urinary tract (CAKUT), such as renal dysplasia, hydronephrosis, or vesicoureteral reflux, are the most common causes of end-stage renal disease. However, the genetic etiology of CAKUT remains unclear. In this study, we performed whole exome sequencing (WES) to elucidate the genetic etiology of symptomatic CAKUT and CAKUT accompanied by cryptorchidism., Methods: Three patients with unilateral renal dysplasia accompanied by ipsilateral cryptorchidism were included in this analysis. Genomic DNA was extracted from peripheral blood, and WES was performed. Disease-specific single nucleotide polymorphisms (SNPs) were determined by comparison with the human genome reference sequence (hg19). Additionally, we searched for SNPs that were common to all three patients, with a particular focus on the coding regions of the target genes., Results: In total, 8710 SNPs were detected. Of the genes harboring these SNPs, 32 associated with renal or testicular development were selected for further analyses. Of these, eight genes (i.e., SMAD4, ITGA8, GRIP1, FREM1, FREM2, TNXB, BMP8B, and SALL1) carried a single amino acid substitution that was common to all three patients. In particular, SNPs in SMAD4 (His290Pro and His291Pro) have not been reported previously in patients with symptomatic CAKUT. Of the candidate genes, four genes (i.e., ITGA8, GRIP1, FREM1, and FREM2) were Fraser syndrome-related genes, encoding proteins that functionally converged on the glial cell-derived neurotrophic factor/RET/bone morphogenic protein (BMP) signaling pathways. As another candidate gene, the protein encoded by BMP8B activates the nuclear translocation of SMAD4, which regulates the expression of genes associated with the differentiation of primordial germ cells or testicular development. Additionally, BMP4, a member of the BMP family, regulates the interaction between metanephric mesenchyme and ureteric buds by suppressing GDNF., Conclusions: Taken together, our findings suggested that the development of the kidney and urinary tract is intimately linked with that of male reproductive organs via BMP/SMAD signaling pathways.

Robotic-assisted procedures are gaining traction as a viable form of minimally invasive surgery in the field of reconstructive surgery. In this article, the aim is to present our initial experience and clinical outcomes of robot-assisted laparoscopic pyeloplasty (RAL-P). We performed RAL-P in 22 patients for the management of ureteropelvic junction obstruction between December 2012 and August 2015. The da Vinci® S surgical system was utilized for all cases. All procedures were performed via a transperitoneal approach. We assessed perioperative outcomes, and furthermore, compared between pediatric and adult patients undergoing this procedure. Dismembered procedures were performed in 19 patients. Three patients underwent Y-V plasty, and two patients who experienced failure during the primary pyeloplasty had to undergo reoperation. Although the console time for pediatric patients was significantly shorter than that of adults (123.1 ± 18.3, 162.4 ± 23.9 min, respectively, p < 0.001), success rate was not significantly different between pediatric and adults (100 vs 90 %, p = 0.512). According to a comparison of surgical outcomes by age, the console time was significantly shorter in pediatric than in adult patients. This finding may be attributable to the differences in intraabdominal fatty tissues. Besides, RAL-P with Y-V plasty was applicable even for cases of failed pyeloplasty. In conclusion, the surgical outcomes of RAL-P were favorable and safe for both pediatric and adult patients, and comparable to findings of previous reports. To our knowledge, this is the first report of a case series of RAL-P in Japan.

Randall plaques (RPs) can contribute to the formation of idiopathic calcium oxalate (CaOx) kidney stones; however, genes related to RP formation have not been identified. We previously reported the potential therapeutic role of osteopontin (OPN) and macrophages in CaOx kidney stone formation, discovered using genome-recombined mice and genome-wide analyses. Here, to characterize the genetic pathogenesis of RPs, we used microarrays and immunohistology to compare gene expression among renal papillary RP and non-RP tissues of 23 CaOx stone formers (SFs) (age- and sex-matched) and normal papillary tissue of seven controls. Transmission electron microscopy showed OPN and collagen expression inside and around RPs, respectively. Cluster analysis revealed that the papillary gene expression of CaOx SFs differed significantly from that of controls. Disease and function analysis of gene expression revealed activation of cellular hyperpolarization, reproductive development, and molecular transport in papillary tissue from RPs and non-RP regions of CaOx SFs. Compared with non-RP tissue, RP tissue showed upregulation (˃2-fold) of LCN2, IL11, PTGS1, GPX3, and MMD and downregulation (0.5-fold) of SLC12A1 and NALCN (P<0.01). In network and toxicity analyses, these genes associated with activated mitogen-activated protein kinase, the Akt/phosphatidylinositol 3-kinase pathway, and proinflammatory cytokines that cause renal injury and oxidative stress. Additionally, expression of proinflammatory cytokines, numbers of immune cells, and cellular apoptosis increased in RP tissue. This study establishes an association between genes related to renal dysfunction, proinflammation, oxidative stress, and ion transport and RP development in CaOx SFs., (Copyright © 2016 by the American Society of Nephrology.)

Here, we report the case of a 62-year-old man with neuroblastoma, which is extremely rare in adults. His tumor was resected, but it recurred four months later. Radiotherapy reduced tumor size, and the patient remained in good health three years after surgical tumor removal. The residual tumor and the treatments administered to this patient were evaluated. We have also reviewed the literature.

Background: The most common pediatric renal neoplasm is Wilms tumor, but clear cell sarcoma of the kidney or synovial sarcoma of the kidney are also sometimes encountered. Accurate pathological diagnosis is important, because adjuvant therapies including chemotherapy and radiotherapy differ according to the pathological type., Case Presentation: A 9-year-old boy presented with a headache, and ultrasonography, computed tomography, and magnetic resonance imaging revealed a heterogeneous enhancement of soft tissue originating from the upper pole of the left kidney, measuring approximately 11.0 × 10.0 × 8.0 cm. A left radical nephrectomy was performed using an intraperitoneal approach through an anterior subcostal incision. Pathological examination suggested clear cell sarcoma of the kidney or synovial sarcoma of the kidney based on morphological and immunohistological features. Using genetic analysis, a final diagnosis of spindle cell pattern clear cell sarcoma of the kidney was made based on the absence of the SYT-SSX fusion gene. After adjuvant chemo-radiotherapy was administered, no recurrence or metastasis has been identified as of 60 months postoperatively., Conclusion: In this case, it was difficult to discriminate clear cell sarcoma of the kidney from synovial sarcoma of the kidney based on histopathological examination alone, and genetic analysis was required. Accurate pathological diagnosis of pediatric renal tumor is important for determining optimal treatment and preventing recurrence and metastasis.

Objectives: To report our initial experience with robot-assisted laparoscopic extravesical ureteral reimplantation using the ureteral advancement technique., Methods: A total of 15 ureters from nine patients (age range 2-25 years) underwent robot-assisted laparoscopic extravesical ureteral reimplantation for the management of vesicoureteral reflux. The reflux was classified as grade I in one ureter, grade II in two ureters, grade III in seven ureters, grade IV in three ureters and grade V in two ureters. One of the five female patients had a bilateral duplex system, and reflux was observed in all four ureters. The da Vinci surgical system was utilized. Ureteral advancement was carried out in all cases. We also compared the operative outcomes between conventional laparoscopic procedure and robotic surgery., Results: The console time was 211.5 ± 87.4 min (median ± standard deviation) in the bilateral cases and 144.0 ± 40.8 min in the unilateral cases. Urethral catheters were removed at one or two postoperative days. None of the patients suffered postoperative complications, such as urine leakage or urinary retention. Postoperative voiding cystourethrography showed that the reflux had been resolved in 14 of the 15 ureters (success rate 93.3%). In the remaining case, the reflux grade decreased from III to I. The operative outcomes of robotic surgery were favorable and safe compared with conventional laparoscopic procedure., Conclusions: Our preliminary results showed that robot-assisted laparoscopic surgery is a feasible and useful approach to extravesical ureteral reimplantation, even for patients with bilateral reflux., (© 2014 The Japanese Urological Association.)

Purpose: Although several genes, including the SRY gene, are involved in testicular differentiation, the entire mechanism of this differentiation remains unclear. We performed genome wide analysis in patients with 46,XX testicular disorders of sex development to comprehensively elucidate the mechanisms of testicular differentiation., Materials and Methods: Whole genomic DNA was extracted from the peripheral blood of 4 patients with 46,XX testicular disorders of sex development who were SRY negative. Genomic DNA was hybridized to a GeneChip® human mapping 250K array set. Compared to normal female data, we detected common loss of heterozygosity and copy number variation regions in 4 patients using Genotyping Console™ software., Results: Loss of heterozygosity was detected in 19 regions of 11 chromosomes. A total of 27 genes or nearby genomic areas were included in the applicable regions. Copy number loss was recognized in 13 regions of 10 chromosomes, and these regions included 55 genes. Copy number gain was detected in 6 regions of 4 chromosomes, which included the upstream region of the SOX3 gene., Conclusions: The regions with loss of heterozygosity did not contain genes associated with testicular differentiation. However, the upstream area of the SOX3 gene, which is located in Xq27.1, was included in the region of copy number gain. These results suggest that high expression of the SOX3 gene led to testicular differentiation despite SRY gene loss. As this applicable area is not within a coding region, genome wide analyses were valuable for detecting the novel regions associated with testicular differentiation., (Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: Gonocytes differentiate into spermatogonial stem cells, which make it possible to maintain spermatogenesis continuously throughout life. We previously reported attenuated spermatogonial stem cell activity in cryptorchid testes, which resulted in altered spermatogenesis and affected fertility. However, few groups have examined the differentiation process from gonocytes to spermatogonial stem cells. To clarify the underlying mechanisms comprehensively we performed microarray analysis to assess differential expression of transcripts between normal and undescended testes in juvenile rats., Materials and Methods: Using microarray analysis we compared whole mRNA expression of normal and cryptorchid testes in a rat model. We subsequently validated differential expression of candidate genes by real-time reverse transcriptase-polymerase chain reaction and performed immunohistochemistry. We also investigated the methylation status of histone H3K4 in cryptorchid testes and the GC-1 spermatogonial cell line., Results: We detected 24 up-regulated and 39 down-regulated genes. Of these genes Kdm5a expression was significantly higher in undescended testes. Immunohistochemistry showed that Kdm5a was localized in the nuclei of gonocytes, spermatogonia and spermatocytes. H3K4me2/me3 expression levels were decreased in undescended testes at 9 days postpartum. Furthermore, Kdm5a over expression in GC-1 cells led to increased expression of Esr2, Neurog3, Pou5f1, Ret and Thy1., Conclusions: Recent investigations revealed that not only genetic but also epigenetic regulation has a role in spermatogenesis. Kdm5a is likely involved in the transformation of gonocytes into spermatogonial stem cells by transcriptional regulation of specific genes via H3K4 histone modification. To our knowledge this is the first report of epigenetic analysis of germ cell differentiation during early spermatogenesis., (Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: We elucidated the mechanism of spermatogonial stem cell disturbance of cryptorchidism and investigated the expression of miRNAs and their target genes in undescended testes., Materials and Methods: Using microarray analysis we compared total miRNA expression in unilateral undescended testes with that in contralateral descended and normal testes in a rat model of cryptorchidism. The model was derived by administering flutamide to pregnant Sprague Dawley® rats. We identified mRNA targets of miRNAs by bioinformatic analysis, followed by in situ hybridization and immunohistochemistry to localize candidate miRNAs and mRNAs, respectively. We also investigated whether miRNAs could inhibit target protein expression in vitro., Results: Microarray analysis and subsequent quantitative reverse transcriptase-polymerase chain reaction showed that only miR-135a was expressed at a lower level in undescended testes. We identified its target as FoxO1, which is essential for stem cell maintenance. miR-135a and FoxO1 localized to spermatogonial stem cells. FoxO1 localized to the spermatogonial stem cell nucleus less frequently in undescended testes, indicating that the activity of FoxO1, which acts as a transcription factor, is altered in undescended testes. Finally, miR-135a transfection into spermatogonia in vitro resulted in down-regulation of FoxO1 expression., Conclusions: In cryptorchid testes there is a decreased number of spermatogonial stem cells in which FoxO1 is activated, indicating that failure of spermatogonial stem cell maintenance results in spermatogenesis alteration. We also noted interaction between miR-135a and FoxO1, and propose that miR-135a contributes to spermatogonial stem cell maintenance through modulation of FoxO1 activity., (Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Objective: To elucidate alternative pathways in testicular development, we attempted to clarify the genetic characteristics of SRY-negative XX testes., Materials and Methods: We previously reported 5 cases of SRY-negative 46,XX testicular disorders of sex development and demonstrated that coordinated expression of genes such as SOX9, SOX3, and DAX1 was associated with testicular development. We performed a case-control study between the aforementioned boy with 46,XX testicular disorders of sex development and an age-matched patient with hydrocele testis (46,XY). During their consecutive surgeries, testicular biopsy specimens were obtained. Genes with differential expression compared with XY testis were identified using polymerase chain reaction (PCR)-based subtractive hybridization and sequencing. For validation of differential gene expression, real-time RT-PCR was performed using gene-specific primers. The distribution of candidate proteins in the testicular tissue was clarified by immunohistochemistry in human and rodent specimens. Moreover, in vitro inhibitory assays were performed., Results: We identified 13 upregulated and 7 downregulated genes in XX testis. Among the candidate genes, we focused on ROCK1 (Rho-associated, coiled-coil protein kinase 1) in the upregulated gene group, because high expression in XX testis was validated by real-time RT-PCR. ROCK1 protein was detected in germ cells, Leydig cells, and Sertoli cells by immunohistochemistry. Moreover, the addition of specific ROCK1 inhibitor to Sertoli cells decreased SOX9 gene expression., Conclusion: On the basis of in vitro inhibitory assay, it is suggested that ROCK1 phosphorylates and activates SOX9 in Sertoli cells. Testes formation might be initiated by an alternative signaling pathway attributed to ROCK1, not SRY, activation in XX testes., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: To clarify whether spongioplasty decreases the complications rate and the degree of penile curvature in TIP urethroplasty., Methods: From 2007 to 2011, 47 patients underwent TIP repair. Thirty-seven underwent spongioplasty, while 10 did not because their bifurcated spongy tissues could be not clearly identified. We investigated whether spongioplasty reduced the incidencerates of complications such as urethrocutaneous fistula. We also evaluated whether spongioplasty contributed to resolving or decreasing penile curvature. In addition, we assessed how many of the patients that underwent spongioplasty did not have to undergo dorsal plication., Results: Among the 47 patients who underwent TIP repair, postoperative complications occurred in 3 (8%) of the 37 patients that underwent spongioplasty and 1 (10%) of the 10 who did not. Spongioplasty did not decrease the complications rate of TIP repair. As 15 of the 47 patients demonstrated a straight penis before spongioplasty, the effect of spongioplasty on the correction of penile curvature was analyzed in 32 patients. Dorsal plication was avoided in 19 patients (59%) because their penile curvature had been decreased to within the permissible range (<15°) by spongioplasty., Conclusion: We conclude that spongioplasty can not replace dartos flap coverage of the neourethra after TIP urethroplasty because it did not produce a significant reduction in the complications rate; however, spongioplasty could be used as an additional procedure because it reduced the degree of penile curvature and allowed dorsal plication to be avoided in more than half of the hypospadiac patients that displayed moderately severe curvature., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objectives: To identify the causes of vanishing testis besides vascular events secondary to testicular torsion., Methods: A total of 102 boys with vanishing testis were treated in our hospital from 1984 to 2011. Of these cases, 91 testicular nubbins were excised. Immunohistochemical analysis of testicular nubbins was carried out using anti-Wilms tumor 1 antibody, which is a stable marker of Sertoli cells. Reverse transcription polymerase chain reaction was also carried out using Wilms tumor 1-specific primers., Results: Most testicular nubbins were associated with inguinal lesion (51 patients, 56.0%). Light microscopy showed that 11 patients (12.5%) had seminiferous tubules (with germ cells in three patients [3.4%]), and 77 patients lacked seminiferous tubules, some of which had calcification (26 patients, 29.5%), and/or deposition of hemosiderin (21 patients, 23.9%). Immunohistochemical analysis showed Wilms tumor 1 expression not only in the Sertoli cells of the seminiferous tubules in the seminiferous tubule-positive patients, but also in the interstitium of testicular nubbins in the seminiferous tubule-negative patients. Reverse transcription polymerase chain reaction showed Wilms tumor 1 messenger ribonucleic acid expression in the testicular nubbins of both seminiferous tubule-positive and tubule-negative patients., Conclusions: The presence of Wilms tumor 1-positive cells in the interstitium of vanishing testis lacking seminiferous tubules suggests that the disturbance of testicular development after Sertoli cell differentiation and during testicular tubule formation might be involved in the etiology of vanishing testis., (© 2012 The Japanese Urological Association.)

Objective: To investigate the molecular aetiology of hypospadias during a critical developmental period by identifying differentially regulated genes in the tissues of individuals with hypospadias and comparing these genes with similar genes in the tissues of control individuals., Materials and Methods: Pregnant Sprague-Dawley rats were administered flutamide (7.5 mg) on gestational days 15-17 to produce hypospadiac pups. Dams were killed on gestational day 17, and the genital tubercles (GTs) of male pups were harvested. Gene expression of RNA isolated from the GTs was analysed using an oligonucleotide microarray containing 20,500 genes. The results of microarray analysis were confirmed using quantitative real-time PCR (qPCR). Protein expression levels were studied using Western blot analysis. The distribution of genes associated with GT development in rats was histologically examined. Prepuces harvested from patients with hypospadias and phimosis were immunohistochemically examined for gene distribution., Results: Of the 20, 500 genes, 23 annotated genes, including prolactin-induced protein (Pip), in the GTs of the hypospadiac rats were expressed at levels less than half of that of similar genes in the GTs of the control rats. Findings from qPCR and Western blot analysis revealed significantly lower Pip/PIP expression in the GTs of the hypospadiac rats than in those of the control rats. Immunohistochemical analysis revealed PIP expression in the prepuces of the GTs of the control and hypospadiac rats. PIP was expressed in the human prepuces of the patients with hypospadias and phimosis., Conclusions: Pip/PIP, expressed at low levels in the GTs of hypospadiac rats, may be associated with preputial development. This model can be useful to elucidate the molecular mechanisms underlying penile and urethral development as well as preputial development. Further studies should provide detailed information regarding the molecular aetiology of hypospadias., (© 2011 THE AUTHORS. BJU INTERNATIONAL © 2011 BJU INTERNATIONAL.)

Purpose: To elucidate the mechanism of infertility caused by cryptorchidism we focused on early stage spermatogenesis and spermatogonial stem cell activity in undifferentiated spermatogonia in cryptorchid testes., Materials and Methods: Histological findings and expression patterns of the stem cell marker undifferentiated embryonic cell transcription factor 1 were examined in a unilateral cryptorchid rat model. We removed unilateral descended testis and contralateral descended testis from cryptorchid and normal rats (control), respectively, 18 days postcoitum to 144 days postpartum., Results: In descended testes gonocyte differentiation into early A spermatogonia occurred at 9 days postpartum. However, this transformation was altered in undescended testes. Furthermore, the undifferentiated embryonic cell transcription factor 1 negative early A spermatogonia-to-positive early A spermatogonia ratio was significantly higher in the undescended testis group (mean ± SD 0.69 ± 0.04) than in the control (0.46 ± 0.10, p = 0.037) and descended testis (0.44 ± 0.05, p = 0.022) groups, indicating decreased early A spermatogonia with spermatogonial stem cell activity in cryptorchid testes., Conclusions: In cryptorchid testes the differentiation from gonocytes into early A spermatogonia and the stem cell activity of early A spermatogonia were altered during the early stage of spermatogenesis, suggesting that the loss of spermatogonial stem cell activity in cryptorchid rats resulted in altered spermatogenesis, thus interfering with fertility., (Copyright © 2012 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Objective: To assess the correlation between intratesticular pressure (ITP) after testicular torsion and subsequent testicular function using a rat model and to show that ITP at surgery is a useful predictor of future spermatogenesis., Materials and Methods: Fourteen rats were divided into a torsion group (n= 7) and a control group with sham operation (n= 7). Torsion was created by 720° rotation of the left testis in a counter-clockwise direction. Using a handheld compartment monitor, the ITP of the torsed testes was measured three times: before torsion (pre-torsion), just before torsion repair (pre-detorsion) and 5 min after torsion repair (post-detorsion). We evaluated the correlation between ITP and testicular weight, epididymal sperm count or pathological findings, such as the seminiferous tubule diameter (STD) and the modified Johnsen's score, 4 weeks after surgery., Results: Mean (se) pre-torsion, pre-detorsion and post-detorsion ITP values in the torsion group were 5.9 (2.5), 19.7 (10.7) and 8.2 (4.8) cm H(2) O, respectively. The ITP in torsed testes significantly increased after torsion (P < 0.01) and decreased after detorsion (P < 0.01). Strong correlations were observed between the reduction of ITP after detorsion and testicular weight (r= 0.87, P < 0.05), epididymal sperm count (r= 0.94, P < 0.05), STD (r= 0.87, P < 0.05) or the Johnsen's score (r= 0.99, P < 0.001)., Conclusion: A smaller reduction in ITP after detorsion can be a risk factor for subsequent disturbance of spermatogenesis, suggesting that ITP can be an index for determining whether the affected testis should be removed after testicular torsion., (© 2011 THE AUTHORS. BJU INTERNATIONAL © 2011 BJU INTERNATIONAL.)

Caudal regression syndrome (CRS) is a rare congenital vertebral anomaly, which occurs most often in combination with spinal cord malformations and morphologic dysfunctions of the lower extremities; these signs are useful for both patients and clinicians in the diagnosis of this syndrome. However, in certain cases, clinicians have failed to identify the syndrome due to the lack of apparent anomalies, resulting in the progression of renal dysfunction caused by neuropathic bladder when CRS is eventually identified. Here, we report a case of a 2-year-old girl who was referred to our hospital for vesicoureteral reflux. At examination, she presented no neurological symptoms; however, on cystourethrography and CT scanning we found that the sacral bone was absent, through which CRS was diagnosed. A urodynamic study indicated detrusor-sphincter dyssynergia, and clean intermittent catheterization was initiated. In the present report, we describe a case of CRS with no neurologic symptoms other than a neuropathic bladder. The lack of outward signs can result in delayed diagnosis. Thus, urological examinations, including a urodynamic study, might be the only clue for identifying an underlying neurologic injury involving the lower spinal cord.

The management of multicystic dysplastic kidney (MCDK) is controversial. There has been a shift from routine surgical removal to nonoperative management. However, recently, an argument has emerged with regard to the management of MCDK, with several studies recommending surgical removal. We report a case of pelvic MCDK that was diagnosed and subsequently removed by a laparoscopic procedure. A laparoscopic approach to the renal and pelvic areas is a minimally invasive, safe, and effective procedure to diagnose and treat MCDK. We believe that laparoscopic nephrectomy should be offered as a management option to the families of children with unilateral MCDK., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: Four disorders, including poor semen quality, testicular cancer, cryptorchidism and hypospadias, are thought to represent testicular dysgenesis syndrome and have been hypothesized to share a common etiology. We predicted testicular function in prepubertal boys with a history of cryptorchidism and/or hypospadias by measuring serum hormone levels., Materials and Methods: A total of 82 prepubertal boys who underwent orchiopexy and/or hypospadias repair in childhood were enrolled in the study. Patients were surgically treated for cryptorchidism (23 in group 1), hypospadias (49 in group 2), cryptorchidism and hypospadias (10 in group 3), and hydrocele testis (7 in control group 4). Serum hormones, including luteinizing hormone, follicle-stimulating hormone and total testosterone, were measured separately by age less than 12.5, 12.5 to 13.5 and greater than 13.5 years, and by Tanner pubertal stage., Results: Follicle-stimulating hormone in group 3 was significantly higher than in groups 1, 2 and 4 at ages 12.5 to 13.5 and greater than 13.5 years, and for Tanner stages 2 and 3 (p <0.05). However, luteinizing hormone and testosterone did not differ among the groups regardless of age or Tanner stage. Group 3 patients had significantly higher follicle-stimulating hormone regardless of the severity of cryptorchidism or hypospadias., Conclusions: Data suggest that testicular function in patients with cryptorchidism plus hypospadias is more severely impaired than that in patients with cryptorchidism or hypospadias, lending clinical support to the testicular dysgenesis syndrome hypothesis of a common origin., (Copyright © 2011 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Objectives: In hypospadia patients, the urethral plate and the underlying tissue were previously thought to be the main cause of penile curvature and, because of this, they used to be excised to correct the curvature. Currently, they are preserved as they are not thought to cause penile curvature anymore. The aim of the present histology study was to elucidate the characteristic structure of the tissue beneath the urethral plate., Methods: The experimental group consisted of 27 hypospadiac patients with moderately severe penile curvature, who underwent one-stage urethroplasty after dividing the urethral plate. Excised tissues were observed under light microscopy and transmission electron microscopy (TEM). Furthermore, the presence of collagen subtypes I, III and IV was examined with immunohistochemical staining and western blotting., Results: Light microscopy showed the existence of many massed and intertwined collagen fibers and vessels that resembled those of the cavernous sinus. TEM showed the existence of many collagen fibers, capillary vessels and other structures. Immunohistochemical staining showed collagen subtype I in the interfascicular space and collagen fibers were densely stained. Collagen subtype IV was found in the basement membrane of vessels, but collagen subtype III was not detected. The same results were obtained by western blotting., Conclusions: The tissue beneath the urethral plate was considered to originate from the corpus spongiosum penis. The distribution of collagen subtypes suggests that the presence of the tissue might affect ventral penile curvature. Long-term follow up is required after one-stage hypospadias repair with preservation of the urethral plate and the underlying tissue., (© 2011 The Japanese Urological Association.)

Purpose: We established a new strategy for nonpalpable testis, including intra-abdominal testis, testicular nubbins, and intracanalicular testis, to correct these conditions by laparoscopic procedures., Patients and Methods: Of the 53 boys (mean age, 24.5 months), nonpalpable testis was on the right side in 13, on the left in 34, and bilateral in 6. Three boys with nonpalpable testis involved contralateral palpable undescended testis. We applied only laparoscopic treatment without open inguinal incision for all cases. After laparoscopic orchiopexy and orchiectomy, we performed subsequent laparoscopic inguinal ring and/or peritoneal defect closure to prevent postoperative inguinal hernia formation, and concurrent laparoscopic repair for cases of contralateral undescended testes and open processus vaginalis under the same anesthesia., Results: All boys underwent laparoscopic treatment immediately after laparoscopic evaluation. We performed laparoscopic orchiopexy for 22 cases with intra-abdominal testes. Twenty-seven boys underwent laparoscopic groin exploration, and 24 underwent subsequent laparoscopic orchiectomy for testicular nubbins, and 3 underwent subsequent laparoscopic orchiopexy for intracanalicular testes. In two boys with testicular nubbin, an open processus vaginalis was present. Forty-nine boys underwent laparoscopic inguinal ring and/or peritoneal defect closure after orchiopexy or orchiectomy to prevent inguinal hernia formation or hydrocele testis. Concurrent laparoscopic contralateral inguinal closure was performed for two cases with opened contralateral processus vaginalis., Conclusions: Our new strategy is useful because all patients with nonpalpable testis could be treated successfully by only laparoscopic management, avoiding open inguinal incision, preventing inguinal hernia formation, and enabling the concurrent repair of contralateral undescended testis and open processus vaginalis.