Urine miR-21-5p as a potential biomarker for predicting effectiveness of tadalafil in benign prostatic hyperplasia.

AIM: To investigate whether urine levels of miRNAs that regulate the function of endothelial cells are associated with effectiveness in benign prostatic hyperplasia (BPH) patients treated with a phosphodiesterase type 5 inhibitor, tadalafil. PATIENTS & METHODS: We measured urine levels of three miRNAs (miR-21-5p, miR-126-5p & miR-155-5p) in 55 BPH patients before and after tadalafil administration to understand its effectiveness. RESULTS: Baseline urine miR-21-5p level was an independent predictor of response to tadalafil in multivariate regression analysis (odds ratio: 0.28; 95% CI: 0.10-0.77; p = 0.014). Receiver operator curve analysis revealed that baseline urine miR-21-5p could serve as a predictor of response (area under curve: 0.85; 95% CI: 0.75-0.95; p < 0.001). CONCLUSION: Urine miR-21-5p could serve as a biomarker in predicting response of tadalafil for BPH.

Significance of twinkling artifact on ultrasound in the diagnosis of cystine urolithiasis.

Twinkling artifact (TA) refers to the finding characterized by both a high-echoic mass upon B-mode ultrasound (US) and turbulence-like signals over the entire mass without significant blood flow on color Doppler US. TA is a characteristic sign of urolithiasis, and there has been no previous report on this finding in the digestive tract. The authors recently encountered a 2-year 9-month-old boy with cystinuria presenting with an opacified abdominal mass. Although he was originally diagnosed as having calcified stool mass, the finding of TA upon US led to the correct diagnosis of huge urolith (4.2 cm in diameter) in the urinary bladder. Laparotomic stone removal was successfully conducted and the calculus was confirmed to be composed of cystine. The finding of TA upon US facilitates identification of the structure and location of the intra-abdominal mass.

[Validation of 2009 TNM classification based on a prognostic analysis of 350 patients treated for renal cell carcinoma].

PURPOSE: To validate 2009 TNM classification (7th edition) of renal cell carcinoma (RCC), we reevaluated our RCC database depends on 6th and 7th TNM staging and analyzed a prognostic divergence between subgroups. METHODS: A study population of 350 patients with RCC was retrospectively reviewed based on the TNM classification both 6th and 7th editions. Cause-specific survival (CSS) in each group was estimated using Kaplan-Meier method. RESULTS: Applying the new TNM system, 336 patients were divided into pT1a 131, pT1b 105, pT2a 31, pT2b 13, pT3 a 38, pT3b 3, pT3c 0, pT4 14. Previously pT3b-staged 11 cases with renal vein involvement without vena caval extension were included into pT3a. Due to the positive direct invasion into the adrenal gland, previously pT3-staged six patients were changed to pT4. Kaplan-Meier curves revealed no significant differences in CSS between each a/b subgroups from pT1 to pT3. Particularly, no significant statistical value was recognized between pT2a and pT2b subgroups. Patients with direct adrenal invasion tended to show a less favorable prognosis than those with invasion beyond Gerota. CONCLUSIONS: (1) pT2 subdivision does not affect prognostic value. (2) Population imbalance is enhanced due to the pT 3 reclassification. (3) Direct adrenal invasion is compatible with pT4 category.

Needle applicator displacement during high-dose-rate interstitial brachytherapy for prostate cancer.

PURPOSE: To introduce an effective ambulatory technique in high-dose-rate interstitial brachytherapy (HDR-ISBT) for prostate cancer, we investigated the displacement distance using our novel calculation method. METHODS AND MATERIALS: Sixty-four patients treated with HDR-ISBT as monotherapy were examined. Of these, 4, 17, and 43 patients were administered treatment doses of 38 Gy (3 days), 49 Gy (4 days), and 54 Gy (5 days), respectively. For dose administration, we used 776 flexible applicators with a removable template (ambulatory technique). Using CT images, we calculated the relative coordinates of the metal markers and applicators. From these coordinates, to analyze displacement during treatment, we measured the distance between the tip of the needle applicator and the center of gravity of the markers along the average applicator vector. RESULTS: The median displacement distance for all applicators was 7 mm (range, -14 to 24), and that of each treatment schedule was 4, 6, and 9 mm for 38, 49, and 54 Gy, respectively. Of the 776 applicators, displacement of >10 mm was seen in 198 (26%) applicators and >15 mm in 57 (7%) applicators. Body height (p<0.0001) and anticoagulant usage (p<0.0001) were significant factors influencing displacement. CONCLUSIONS: We investigated needle applicator displacement using our unique method. Additional cranial margins are necessary if there is no repositioning of the dwell position. CT scanning should be performed daily during treatment for checking the position of the applicator to detect and rectify the issue of displacement.

[Cryptorchidism and assisted reproductive technique].

The influence of cryptorchidism on male infertility is well-known. In this article the incidence of disturbance of spermatogenesis in cryptorchid patients and effect of assisted reproductive technique on such patients is reviewed.

New implant technique for separation of the seminal vesicle and rectal mucosa for high-dose-rate prostate brachytherapy.

PURPOSE: For safer treatment of seminal vesicles (SVs), we initiated a new technique using an anchor applicator for high-dose-rate interstitial brachytherapy (HDR-ISBT) of prostate cancer. METHODS AND MATERIALS: Between January 2004 and March 2005, 23 intermediate- to high-risk patients were treated with HDR-ISBT as monotherapy. Transrectal ultrasonography guided implantation of the treatment applicator in and around the prostate gland and proximal SV. We used an "anchor" applicator to prevent posterior displacement of the SV. After insertion of the anchor applicator, the actual treatment applicator was implanted at the best position for optimal SV coverage. SV coverage was analyzed using a dose-volume histogram. RESULTS: Implantation of the applicator on the posterior side of the SV was successful for 43 of 46 SVs (93%). The median percentage of the SVs receiving the prescribed dose was 41% (range 11-86%). Only one case of acute Grade 2 toxicity (3%) was seen. CONCLUSIONS: Our anchor applicator technique for HDR-ISBT can separate the SV from the rectum. This is the first report of dose-volume histogram analysis of the SV for HDR-ISBT.

Botryoid Wilms' tumor of the renal pelvis extending into the bladder.

We report a case of botryoid Wilms' tumor that occupied the renal pelvis and extended into the bladder. A 3-year-old boy was referred to us with a chief complaint of gross hematuria and micturition pain. Computed tomography showed tumor occupying the right renal pelvis and ureter and extending into the bladder. Right radical nephroureterectomy was performed. The resected specimen showed a botryoid sarcoma-like appearance, occupied the right renal pelvis and ureter, and protruded into the bladder. Histologic findings showed typical triphasic Wilms' tumor. Botryoid Wilms' tumor has been reported in only 16 cases in the literature and in only 3 cases extended into the bladder.

Urinary control after the definitive reconstruction of cloacal anomaly.

PURPOSE: Urinary control after definitive repair of a cloacal anomaly is difficult to achieve. The present report aims to describe the clinical course of urinary control, and the need for the management of bladder dysfunction after reconstruction. METHODS: The present consecutive series consisted of 11 girls who underwent definitive repair of cloacal anomalies over a period of 11 years. Eight patients were associated with hydrocolpos. Radiological examination included a plain X-ray radiograph of the lumbosacral spine and a voiding cystourethrography with or without a urodynamic study. RESULTS: Reconstruction of the cloaca was performed on patients aged between 1 and 3 years using a posterior sagittal approach. Vaginal reconstruction was carried out 13 times in 11 patients using tubularized vaginal flap, distal rectal segment, perineal skin flap, or total urogenital sinus mobilization. Cystostomy or vesicostomy was carried out in four newborns/infants. Another seven patients could void spontaneously but incompletely with residual urine. Occult spinal dysraphism was found in five patients and hemisacrum in two patients. After definitive reconstruction, most patients acquired an adequate to normal bladder volume for 1-year-olds. Normal detrusor-sphincter function was seen in three patients. Detrusor areflexia was seen in two patients who underwent in utero vesico-amniotic shunt. Detrusor underactivity was observed in six patients. Bladder compliance was good in all patients except for one. No patients in the present series showed persistent urinary incontinence from the bladder neck or urethral dysfunction. CONCLUSION: It is postulated that wetting after definitive repair may be the result of overflow incontinence and poor bladder contractility rather than sphincter injury. The main clinical characteristic of bladder dysfunction was a failure to empty. We could not define the exact etiology, but iatrogenic injury from extensive dissection can lead to the higher risks of peripheral nerve damage. Accomplishment of definitive repair involves not only anatomical reconstruction, but also postoperative urinary control, including the initiation of clean intermittent catheterizations under repeated urodynamic evaluations.

Pancreatic pseudocyst arising from ectopic pancreas and isolated intestinal duplication in mesocolon caused hydronephrosis in a girl with horseshoe kidney.

Ectopic pancreas is a relatively common congenital anomaly and is usually asymptomatic. Pancreatitis in the ectopic site and pseudocyst formation is extremely rare. To date, only 2 cases have been reported. We present a case of a 3-year-old girl with recurrent pancreatitis and unilateral hydronephrosis of the horseshoe kidney, which was produced by pancreatic pseudocyst arising from ectopic pancreas and isolated intestinal duplication in mesocolon. This is the first case of pancreatic pseudocyst that expanded to the retroperitoneal space and caused urinary tract obstruction.

Outcome of gonadotropin therapy for male hypogonadotropic hypogonadism at university affiliated male infertility centers: a 30-year retrospective study.

PURPOSE: Hypogonadotropic hypogonadism (HH) is an uncommon cause of male infertility. Even specialized centers see small numbers of patients and have little experience in restoring fertility in these patients. To explore the phenotypic heterogeneity and treatment outcome of HH, we summarized our 30-year experience. MATERIALS AND METHODS: Medical charts of 36 male patients (age range 11 to 42 years) with HH (81% primary, 19% secondary) treated at university affiliated male infertility centers were reviewed. Pubic hair stage, genital stage, testicular volume (TV), sexual function and sperm production were determined before and after human chorionic gonadotropin/human menopausal gonadotropin (hCG/hMG) treatment. Differences were analyzed statistically. RESULTS: The population was stratified according to initial TV into a small testis subset (TV less than 4 ml in 23) and a large testis subset (TV 4 ml or greater in 13). Comparison of these 2 subsets revealed significant differences in the incidence of cryptorchidism (39% vs 8%) and Kallmann's syndrome (22% vs 0%), pubic hair stage (1.3 +/- 0.5 vs 3.5 +/- 1.4), genital stage (1.2 +/- 0.4 vs 3.9 +/- 0.9) and TV (1.6 +/- 0.9 vs 7.5 +/- 3.5 ml). Long-term administration of hCG/hMG for 12 to 240 months (average 56 +/- 11) resulted in sperm production in only 36% of the small testis subjects but in 71% of the large testis subjects. CONCLUSIONS: Initial TV values provide insight into phenotypic variables such as time of onset and severity in patients with primary or secondary HH, and may predict sperm output in response to hCG/hMG therapy.

[Augmentation ureterocystoplasty in children: 7-years follow-up].

OBJECTIVES: We retrospectively reviewed our experience of augmentation ureterocystoplasty in children to evaluate its long-term results. MATERIALS AND METHODS: From February 1996 to March 1999 four children (2 boys and 2 girls) with neurogenic bladder had augmentation cystoplasty using dilated ureter in our institute. After trans-uretero-ureterostomy the lower two thirds of the unilateral ureter was used to perform the augmentation cystoplasty. Follow-up varied between 59 and 96 months (mean 85). RESULTS: In early post-operative period bladder volume and compliance increased from 96 (64-150) to 113 (40-220) ml and from 2.7 (1.3-5.8) to 4.5 (2.0-11.0) ml/H2O respectively. Incontinence was improved in all children and two had dry interval of 3-hour catheterization. Although bladder volume and compliance kept increasing gradually (239 (237-241) ml, 11.5 (5.7-18.5) ml/H2O respectively) over 5 years postoperatively, 2 elder patients had repeat augmentation cystoplasty using gastrointestinal tract because of hydronephrosis and deterioration of renal function. CONCLUSION: Our long-term result of ureterocystoplasty was no good. Ureter is not an ideal material to provide adequate bladder capacity and compliance for elder children unless their bladder becomes as large as that of adults early post-operatively.

Malignant retroperitoneal tumor arising in a multicystic dysplastic kidney of a girl with Schinzel-Giedion syndrome.

We report the first case of malignant retroperitoneal tumor arising in a multicystic dysplastic kidney of an 8-year-old girl with Schinzel-Giedion syndrome. Although conservative treatment has been regarded as the standard management for asymptomatic multicystic dysplastic kidney, prophylactic surgical removal should be considered for selected children with potential risk of malignancy.

[Differentiation of external genitalia and 5 alpha-reductase].

Sexual differentiation of the external genitalia depends on many factors such as genetic sex, gonadal sex or androgen action. Among them, 5 alpha-reductase plays an important role in androgen action: dihydrotestosterone(DHT) is produce from testosterone by 5 alpha-reductase and DHT binds the androgen receptor to induce the differentiation of the external genitalia. In this paper we reviewed on the mechanism of the differentiation of the external genitalia, especially on the relation with androgen action and 5 alpha-reductase.

[Decision-making process about sex assignment in the neonate with ambiguous genitalia].

Although diagnoses and etiologies of underlying disorders of sexual differentiation can be carefully delineated through biochemical, imagine, and chromosomal analyses, the decision-making process about sex assignment in the newborn with ambiguous genitalia is in a state of controversy. The conventional way for the approach to these neonates consists of 4 principles; 1) Urgency of diagnosis and sex assignment, so that early surgical reconstruction could obviate the fear of the parents with each diaper change. 2) Adequacy of the phallus as a male. 3) Fertility, especially 46XX female are sex assigned female because of potential fertility. 4) Cosmetic appearance of the reconstructed genitalia based on the recognition that external female genitalia are generally easier to construct than male. Contrary to these conventional methods, some researchers insist on flexibility in the clinical approach to provide the best possible outcome. It is getting apparent that the quantity, timing, and duration of androgen exposure will play a role in determining the degree of masculinization of the brain, which may potentially decide gender identity before 18 months of age or even in utero, and may influence the psychosexual development of the child. Flexibility in decision-making will allow for options not to remove any tissues including gonads and internal sex organs, or to reconstruct the genitalia until he or she is sure of the gender. This new approach must be proved in the future.

Effect of ureteral reimplantation on prevention of urinary tract infection and renal growth in infants with primary vesicoureteral reflux.

AIM: We retrospectively reviewed the results of ureteral reimplantation in infants with primary vesicoureteral reflux (VUR) to evaluate the effect on prevention of urinary tract infection (UTI) and renal growth. MATERIALS AND METHODS: From July 1991 to December 2001, a total of 205 infants (180 boys and 25 girls) with primary VUR underwent ureteral reimplantation at the Department of Urology, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan. Indications for surgery were high-grade reflux (grade IV-V), breakthrough UTI and non-compliance of medical treatment. Age at surgery raged from 1 to 11 months (mean, 6.4 months). Ureteral reimplantation was performed according to Cohen's method. Only two of 336 refluxing ureters required ureteral tailoring. Follow-up ranged from 12 to 110 months (mean, 64 months). Surgical outcome, frequency of UTI and individual renal growth measured by (99m)Tc-dimercaptosuccinic acid (DMSA) scintigraphy was evaluated. RESULTS: Postoperative ultrasound and voiding cystourethrography showed neither residual reflux nor ureterovesical obstruction. Contralateral low grade reflux occurred in six of 74 patients (8.1%) who had unilateral reflux preoperatively. After reimplantation, 10 patients documented 13 febrile UTI. Eleven of the 13 episodes occurred early in the postoperative period (<6 months). Frequency of febrile UTI reduced from 0.23538 before surgery to 0.00894 and 0.00081 per patient per month at 6 and 12 months after surgery, respectively. No development of renal scarring was seen in postoperative DMSA scan. Changes of differential renal function was <0.05 in all patients. CONCLUSION: The present results show ureteral reimplantation in infants is safe and very effective for the prevention of UTI. After surgical treatment in infancy, individual renal growth of children with primary VUR is stable.

Histological study of fetal kidney with urethral obstruction and vesicoureteral reflux: a consideration on the etiology of congenital reflux nephropathy.

PURPOSE: A recent subject of interest regarding reflux nephropathy is the presence of renal abnormalities in neonates and infants who have no history of urinary tract infections. Debates have centered on the etiology of this renal abnormality - congenital reflux nephropathy; regarding whether it is the result of abnormal ureteral budding or of back pressure effect from sterile reflux. We examined the renal pathology of fetuses with urethral obstruction and vesicoureteral reflux, and we suggest herein a possible etiology of congenital reflux nephropathy. METHODS: The renal pathology of seven autopsied fetuses with vesicoureteral reflux was studied. Reflux was demonstrated at autopsy by slow injection of contrast medium into the bladder. Severe urethral obstruction, either atresia or urethral valves, was evident in six of the subjects. RESULTS: In six subjects, abnormality of the urinary tracts was detected by prenatal ultrasonography. Of these six subjects, three revealed characteristics of prune belly syndrome. Reflux was graded as moderate in five subjects, and severe in two. In three subjects autopsied at 21 weeks gestation or earlier, the kidneys were well-developed with normal corticomedullary configuration, and nephrogenesis was retained. In three cases autopsied at over 25 weeks of gestation, the kidneys were grossly cystic, and the nephrogenic zone was completely absent. Contrast medium was observed not only in the dilated ducts and tubules, but also in the subcapsular cysts. Extravasation of the contrast medium was seen in the peritubular space. In the last subject with normal lower urinary tract, abnormal segments among normal cortical structures were observed. CONCLUSION: Our findings of renal pathology in fetuses with reflux are quite similar to those seen in fetal hydronephrosis. Back pressure from reflux probably damages the developing kidney leading to a degeneration of the ampullae and a reduction in the number of nephrons. Both dilatation of the collecting ducts and tubules, and extravasation of the urine may result in interstitial fibrosis. We postulate that one of the important etiologies of congenital reflux nephropathy may be the result of back pressure from sterile reflux.

Proliferation and differentiation of spermatogonial stem cells in the w/wv mutant mouse testis.

Mutations in the dominant-white spotting (W; c-kit) and stem cell factor (Sl; SCF) genes, which encode the transmembrane tyrosine kinase receptor and its ligand, respectively, affect both the proliferation and differentiation of many types of stem cells. Almost all homozygous W or Sl mutant mice are sterile because of the lack of differentiated germ cells or spermatogonial stem cells. To characterize spermatogenesis in c-kit/SCF mutants and to understand the role of c-kit signal transduction in spermatogonial stem cells, the existence, proliferation, and differentiation of spermatogonia were examined in the W/Wv mutant mouse testis. In the present study, some of the W/Wv mutant testes completely lacked spermatogonia, and many of the remaining testes contained only a few spermatogonia. Examination of the proliferative activity of the W/Wv mutant spermatogonia by transplantation of enhanced green fluorescent protein (eGFP)-labeled W/Wv spermatogonia into the seminiferous tubules of normal SCF (W/Wv) or SCF mutant (Sl/Sld) mice demonstrated that the W/Wv spermatogonia had the ability to settle and proliferate, but not to differentiate, in the recipient seminiferous tubules. Although the germ cells in the adult W/Wv testis were c-kit-receptor protein-negative undifferentiated type A spermatogonia, the juvenile germ cells were able to differentiate into spermatogonia that expressed the c-kit-receptor protein. Furthermore, differentiated germ cells with the c-kit-receptor protein on the cell surface could be induced by GnRH antagonist treatment, even in the adult W/Wv testis. These results indicate that all the spermatogonial stem cell characteristics of settlement, proliferation, and differentiation can be demonstrated without stimulating the c-kit-receptor signal. The c-kit/SCF signal transduction system appears to be necessary for the maintenance and proliferation of differentiated c-kit receptor-positive spermatogonia but not for the initial step of spermatogonial cell differentiation.

Surgical management of urinary incontinence in children with anatomical bladder-outlet anomalies.

BACKGROUND: Pediatric urinary incontinence secondary to anatomical anomalies of the bladder outlet is relatively rare, and there is no consensus on its surgical treatment. We reviewed the clinical courses and surgical management of children with this pathology. METHODS: From 1991 to 2001, we performed bladder neck reconstruction on seven children (three boys and four girls). The mean age at the first intervention was 7 years (range 5-12 years). The underlying diagnosis was bladder exstrophy in two children, pseudoureterocele-type ectopic ureter in three, bladder neck incompetence from unknown etiology in one boy with hypospadias, and bilateral single ectopic ureter associated with cloacal malformations in one child. Lower urinary tract was evaluated through various imagings, endoscopy, and urodynamic studies. RESULTS: The methods used to reconstruct the bladder neck was the Young-Dees-Leadbetter procedure (performed on four children); the Kropp procedure (two children); and the Pippi-Salle procedure (one child). Bladder augmentation with intestinal segment was performed on four children; Mitrofanoff continent stoma was created in all patients. Urethral catheterization could not be routinely used in all patients, because of pain, stricture, or complicated urethral anatomy. All patients achieved urinary continence. CONCLUSION: The treatment of pediatric urinary incontinence from anatomical anomalies is technically challenging. Depending on the underlying disorders and anatomy, one needs to decide which method of reconstruction to perform. It would be safer to employ simultaneous augmentation and to create catheterizable continent stoma.

Homeostatic regulation of germinal stem cell proliferation by the GDNF/FSH pathway.

Stem cell regulatory mechanisms are difficult to study because self-renewal and production of differentiated progeny, which are both strictly controlled, occur simultaneously in these cells. To focus on the self-renewal mechanism alone, we investigated the behavior of germinal stem cells (GSCs) in progeny-deficient testes with defective GSC differentiation. In these testes, we found that the proliferation of undifferentiated spermatogonia, some of which are GSCs, was accelerated by high concentrations of glial cell line-derived neurotrophic factor (GDNF). Furthermore, we found that follicle-stimulating hormone (FSH) stimulation via homeostatic control was one of the major regulators of GDNF concentration. These results suggest that in mammalian testes, GSC proliferation and population size are regulated homeostatically by the GDNF/FSH pathway.