Discovery of a potent orally available pyrazolopyridone derivative as a novel selective bromodomain and extra-terminal domain (BET)-first bromodomain (BD1) inhibitor.

Clinical studies have shown that inhibitors of bromodomain and extra-terminal domain (BET) proteins, particularly BRD4, have antitumor activity and efficacy. The BET protein has two domains, BD1 and BD2, and we previously focused on BD1 and reported orally bioavailable BD1-selective inhibitors. In this study, we obtained a BD1 inhibitor, a more potent and highly selective pyrazolopyridone derivative 13a, and confirmed its in vivo efficacy.

Discovery of a potent, orally available furopyridine derivative as a novel selective bromodomain and extra-terminal domain (BET)-first bromodomain (BD1) inhibitor.

We explored novel immunosuppressive agents with immune tolerance using a phenotypic drug discovery strategy, focusing on costimulatory molecules in T cells, and obtained triazolothienodiazepine derivatives. Their mechanism of action is to inhibit the bromodomain and extra-terminal domain (BET) family, as we have previously reported. Selective inhibition of the first bromodomain (BD1) of the BET family is expected to exert antitumor and immunosuppressive effects, similar to BET inhibitors. This study identified furopyridine derivatives 7 and 8 with high BD1 inhibitory activity and high selectivity over BD2. Compound 7 was found to be orally bioavailable and exhibited anti-inflammatory activity in a lipopolysaccharide-induced model.

[A CASE OF DEXTRANOMER-HYALURONIC ACID COPOLYMER (Deflux®) IMPLANTS CALCIFICATION MIMICKING DISTAL URETERAL CALCULI].

Since 2011, endoscopic correction of vesicoureteral reflux using dextranomer-hyaluronic acid copolymer (Deflux®) has been widely accepted in Japan due to its safety and minimally invasive nature. However, long-term complications are unknown. We present a case of Deflux® implants calcification mimicking distal ureteral calculi in a 12-year-old boy with a history of Deflux® injection performed at three years of age for primary VUR. We should be aware of this complication to avoid misdiagnosis and unnecessary invasive examination such as radiological imaging or endoscopy.

[A CASE OF PARATESTICULAR FIBROUS HAMARTOMA OF INFANCY].

Fibrous hamartoma of infancy (FHI) is a rare, benign soft tissue tumor arising from subcutaneous tissue in children during the first two years of life. The tumor is commonly found in the axilla, shoulder and upper arm. Paratesticular FHI is extremely rare. To date, only a case of paratesticular FHI has been reported in Japan. We present a case of paratesticular FHI in an 11-month-old boy who eventually needed orchiectomy due to local recurrence one month after the excision of the tumor. Ten months postoperatively, there was no sign of recurrence.

Essential role for Toll-like receptor 7 (TLR7)-unique cysteines in an intramolecular disulfide bond, proteolytic cleavage and RNA sensing.

Toll-like receptor 7 (TLR7) an innate immune sensor for microbial RNA, erroneously responds to self-derived RNA. To avoid autoimmune responses, TLR7 is suggested to be silenced until the N-terminal half of the TLR7 ectodomain (TLR7N) is cleaved off. Resultant truncated TLR7 (TLR7C) is thought to signal microbial RNA. We here show that TLR7N remains associated with TLR7C through a disulfide bond. By N-terminal amino acid sequencing, TLR7C was found to start at 461E or 462A. The newly established monoclonal anti-TLR7N showed that endogenous TLR7 in bone marrow-derived dendritic cells was almost all cleaved and cleaved TLR7N remained in endolysosomes. TLR7N in endolysosomes was linked with TLR7C by a disulfide bond. In contrast, TLR9 did not have a disulfide bond between TLR9N and TLR9C fragments. Among the cysteines unique to the ectodomain of TLR7 but not TLR9 (Cys98, Cys445, Cys475 and Cys722), Cys98 in TLR7N and Cys475 in TLR7C were required for an intramolecular disulfide bond. These cysteines were also needed for proteolytic cleavage of and RNA sensing by TLR7, but not for TLR7 trafficking from endoplasmic reticulum to endosomes. No response was seen in TLR7 mutants lacking the proteolytic cleavage site or TLR7C alone. These results demonstrate requirement for proteolytic cleavage and TLR7N in TLR7 responses and indicate RNA sensing by TLR7N + TLR7C.

Augmentation Cystoplasty in a Girl With Early B-cell Factor 3 (EBF3)-Related Syndrome.

Early B-cell factor 3 (EBF3)-related syndrome, also known as hypotonia, ataxia, and delayed development syndrome (HADDS), is a recently recognized neurodevelopmental disorder frequently associated with bladder dysfunction. Despite bladder dysfunction possibly caused by detrusor sphincter dyssynergia, previous studies reported relatively accepted bladder compliance in patients with HADDS. We present the first case of bladder augmentation, in the English literature, in a girl with EBF3-related syndrome due to poor bladder compliance with clean intermittent catheterization and anticholinergic medication.

Unilateral renal agenesis and ipsilateral absence of the vas deferens in a cryptorchid infant with Klippel-Feil syndrome.

We report an exceedingly rare case of Klippel-Feil syndrome (KFS), compounded by ipsilateral absence of the vas deferens, renal agenesis, and diaphragmatic hernia. Unilateral absence of the vas deferens was found incidentally during orchidopexy. To the best of our knowledge, no case of unilateral absence of the kidney and vas deferens has been reported in children with KFS.

A Case of Solitary Kidney and Single-system Ectopic Ureter Draining Into the Vestibule in an Infant With Müllerian Duct Defect: Was the Bladder Missing?

We report a case of a solitary kidney and a single-system ectopic ureter draining into the vestibule in an infant with a Müllerian duct defect. Due to the absence of the upper vagina and uterus, an extremely underdeveloped bladder masqueraded as the vagina, and bladder agenesis was suspected preoperatively. Urinary continence was achieved using staged bladder surgery without augmentation or urinary diversion.

Prenatally diagnosed giant umbilical cord resulted from patent urachus in a monochorionic diamniotic twin with selective intrauterine growth restriction.

A long diffuse giant umbilical cord (GUC), caused by umbilical cord edema associated with a patent urachus, is an extremely rare anomaly. While patients with diffuse GUC appear to experience no significant complications and a good prognosis, little is known about their etiology and prenatal course. Here, we report the first case of prenatally diagnosed diffuse GUC resulted from patent urachus in a monochorionic diamniotic twin with selective intrauterine growth restriction. This case indicates that GUC is epigenetic and unrelated to multiple births.

Prenatally Detected Intrascrotal Testicular Teratoma in an Infant.

Although teratomas are the most common tumors in the testes of prepubertal children, prenatally detected testicular teratomas are extremely rare. To date, only 6 cases of prenatally detected testicular teratomas have been reported in the English literature. An intra-abdominal mass and an ipsilateral undescended testis were confirmed after birth in all 6 cases. Preservation of testicular tissue was not performed in any case. Herein, we report the first case of prenatally diagnosed intrascrotal testicular teratoma in an infant who underwent testis sparing surgery.

[MITOCHONDRIAL RESPIRATORY CHAIN DISORDERS WITH VESICOURETERAL REFLUX: A PEDIATRIC CASE REPORT].

Mitochondrial respiratory chain disorders (MRCD) constitute a highly heterogeneous group both with regard to clinical manifestations and underlying genetic/biochemical defects. Management of urological complications such as vesicoureteral reflux (VUR) has not been discussed in cases with MRCD. We report a pediatric case of MRCD with recurrent urinary tract infections (UTI) due to primary and secondary VUR.A 6-month-old boy with multiple malformations and a history of aspiration pneumonia was referred to our department for febrile UTI (fUTI). Voiding cystourethrography showed high-grade left VUR and a normal bladder. As a spontaneous resolution of VUR was not observed, he underwent left ureteral reimplantation concomitant with left orchidopexy at the age of 1 year and 7 months. Although he had fUTI immediately after surgery, no recurrence of the UTI occurred after discharge. At the age of 3 years, he had septic shock and cardiac arrest caused by aspiration pneumonia, as well as, encephalopathy following cardiopulmonary resuscitation. At this event, the diagnosis of MRCD was achieved by liver biopsy. Since the age of 4 years, he has had repeated fUTI. VCUG confirmed the bladder deformity and right VUR. He underwent vesico-cutaneostomy at the age of 6 years. The postoperative course was uneventful. No recurrence of UTI was observed at the one-year follow-up.

[CLINICAL AND IMAGING FINDINGS OF ACUTE EPIDIDYMITIS IN CHILDREN].

(Objective) The etiology of acute epididymitis in children remains poorly understood. Several studies have demonstrated that urine tests are negative in the majority of children with acute epididymitis, and the condition is self-limiting. The need for radiological evaluation of the urinary tract in children with acute epididymitis is still debatable. The aim of this study was to describe clinical and imaging findings in children with acute epididymitis. (Methods) We identified 47 children with acute epididymitis at our institute between 2017 and 2021.We retrospectively reviewed their clinical features and radiological and laboratory data. All children underwent ultrasonography of the kidney and urinary tract. (Results) Median patient age was 9 years (range, 6 months-16 years) and 60% of the cases occurred between the ages of 7 and 12 years. Thirteen children (28%) had a past history of genitourinary malformations. The common malformations were hypospadias in eight children and bladder dysfunction in three. Ultrasound revealed no new urinary tract abnormalities in the remaining 34 children. Urinalysis were performed in 27 children, nine of whom (33%) had pyuria. Urine culture was positive in two children. Of the nine children with genitourinary malformations, eight had pyuria. All 18 children without genitourinary malformations had a negative urinalysis except for one patient (p< 0.0001). (Conclusions) Acute epididymitis is a common cause of acute scrotum in pediatric patients. In this study, one-third of acute epididymitis cases presented pyuria, and about 30% had a past history of genitourinary malformations. The presence of pyuria was associated with a past history of genitourinary malformations. For children with no previous genitourinary malformations, routine use of ultrasound for the detection of urinary tract abnormalities is questionable due to the low yield.

Bladder Cancer in a Long-term Survivor of the Prune Belly Syndrome.

Prune belly syndrome (PBS) is a rare but morbid complexity of congenital anomalies that consists of abdominal wall defect, bilateral cryptorchidism, and urinary tract dilation. With the recent advances in perinatal care, the life expectancy of patients with PBS has improved. Although renal and sexual outcomes are frequently discussed in the literature, little is known about urinary tract malignancies in adulthood. Herein, we present a case of advanced bladder cancer in a 38-year-old man with PBS. To the best of our knowledge, a malignant tumor arising in a nondefunctionalized or nonaugmented bladder in patients with PBS has not been reported previously.

Unilateral Fibrous Hyperplasia of the Labium Majus in Pre- and Early Pubertal Girls: A Report on 3 Cases.

BACKGROUND: In recent years, certain prepubertal cases of asymmetric enlargement of the labium majus came to be recognized as a physiological condition in response to hormonal stimulation. However, there exist only scattered case reports or a few case series on this entity, with different terminology. CASE: We present 3 cases of unilateral asymptomatic swelling of the labium majus in otherwise healthy pre- and early pubertal girls. Physical examination revealed painless, fluctuating, nontender bulging that was recognized for a few years on one side of the labium majus. Ultrasound and magnetic resonance imaging showed increased labial soft tissue without any masses. In all cases, surgical excision was performed for cosmetic request. Histopathological diagnosis was fibrous hyperplasia of the labium majus in all cases. Recurrence occurred in one of 3 cases a year after surgery. SUMMARY AND CONCLUSION: Due to the site- and age-specific non-neoplastic physiological condition, we recommend prepubertal unilateral fibrous hyperplasia of the labium majus (PUFHLM), as the terminology accurately reflects this entity. For the differential diagnosis of genital disorders in children, recognition of PUFHLM is important to avoid unnecessary biopsy or invasive procedures. Surgical excision for cosmetic reasons should not be considered because of the benign nature of this entity and a high recurrence rate in childhood and early adolescence.

Histological analysis of testes in patients with 5 alpha-reductase deficiency type 2: Comparison with cryptorchid testes in patients without endocrinological abnormalities and a review of the literature.

As evidenced by the intact histology of the testes during infancy, testicular differentiation during the prenatal period occurs normally in individuals with 5 alpha-reductase type 2 deficiency (5αRD); however, a majority of these individuals suffer from azoospermia or oligospermia during adulthood, indicating that impaired spermatogenesis occurs postnatally. Although the accompanying cryptorchidism may be partly responsible for this process, the underlying mechanisms remain largely unknown. To address this issue, we retrospectively compared the histological findings of descended testes in a 3-mo-old patient and undescended testes in an 18-yr-old patient with 5αRD. In the latter, testicular histology was compared to that of cryptorchid testes obtained from five adolescent patients without endocrinological abnormalities. Histological findings of a 3-mo-old patient revealed normal number of germ cells with intact seminiferous tubules. In contrast, an 18-yr-old patient showed marked reduction in germ cell number and atrophic seminiferous tubules. The findings were very similar to those observed in cryptorchid testes without endocrinological abnormalities. These findings suggest that the decrease in germ cells in 5αRD patients may be at least partly caused by accompanying cryptorchidism. As the number of germ cells did not decrease during the infantile period, early orchiopexy is recommended to prevent a decrease in germ cell number and preserve fertility.

Successful separation of male pygopagus with anal canal and urethral reconstruction: a case report.

BACKGROUND: Pygopagus is a type of conjoined twin binding at the buttocks. Some cases of pygopagus involve the fusion of the gastrointestinal tract, urinary tract, and spinal cord. Few cases of male pygopagus have been reported; however, the prognosis after separation is unclear. Herein, we report a case of male pygopagus in which successful separation was performed with the reconstruction of the anal canal. CASE PRESENTATION: Twins with male pygopagus were born at 35 weeks by cesarean section. They shared a common anus, penis, and scrotum with four testes. The infants had normal defecation and urination after birth. The separation surgery was scheduled when they were 5 months. Two distinct anesthesia teams and four surgical teams (neurosurgery, pediatric urology, plastic surgery, and pediatric surgery) were involved in the multidisciplinary approach. After separating the spinal cord, we found that the anal canal and sphincter muscle complex were fused near the anal aperture, and we separated them. The fused penis and testis were separated and reconstructed using the same incisional line as the other separation, and the reconstructions of the anal canals with the sphincter muscle complex were completed. Both patients had an uneventful postoperative course. At 2 years of age, they could walk and defecate independently. In addition, they voided spontaneously without urinary incontinence at the time of 3 years and 11 months. CONCLUSIONS: Separation of the spinal cord with anal canal and urethral reconstruction is important for male pygopagus patients as it allows them to preserve their independent function.

Acquired undescended testes in boys with hypospadias.

PURPOSE: We determined the incidence of acquired undescended testes in boys with hypospadias. MATERIALS AND METHODS: We retrospectively reviewed the records of 566 boys with hypospadias who were referred to our outpatient clinic between January 2000 and September 2009. Acquired undescended testes were defined as testes that were documented at the bottom of the scrotum at least once after birth by the pediatric urologist at our institution but were subsequently documented to have moved from a satisfactory scrotal position by the same pediatric urologist or an equally experienced pediatric urologist. However, this definition did not include undescended testes after inguinoscrotal surgery. We excluded boys with gender development disorders with testicular dysgenesis, those who underwent bilateral inguinoscrotal surgery and those without congenital cryptorchidism who were followed less than 3 months. RESULTS: Of the 566 boys with hypospadias 100 met study exclusion criteria. Of the 466 boys included in analysis 29 (6.2%) had congenital cryptorchidism and 15 (3.2%) had acquired undescended testes. Urethroplasty was performed in 413 boys, including 91 with distal, 132 with mid and 181 with proximal hypospadias. The incidence of congenital cryptorchidism and acquired undescended testes in boys with proximal hypospadias was significantly higher than that in boys with other types of hypospadias (p = 0.03 and 0.001, respectively). CONCLUSIONS: Boys with proximal hypospadias are at a higher risk for acquired undescended testes than those with other mild types of hypospadias. Thus, testicular location should be monitored regularly until after puberty.

Positioning the instillation of contrast at the ureteral orifice cystography can be useful to predict postoperative contralateral reflux in children with unilateral vesicoureteral reflux.

The aim of the present study was to evaluate the usefulness of positioning the instillation of contrast at the ureteral orifice (PIC) cystography in prediction of postoperative contralateral reflux in patients with unilateral vesicoureteral reflux (VUR) undergoing ureteral reimplantation. Between January 2007 and March 2009, 34 children (20 boys and 14 girls) had antireflux surgery for unilateral primary VUR. This was diagnosed by conventional fluoroscopic voiding cystourethrography (VCUG) in all patients. After induction of general anesthesia, PIC cystography was carried out immediately before ureteral reimplantation by instilling contrast material at the ureteral orifice. Patients with positive PIC cystogram on the contralateral side underwent bilateral ureteral reimplantation via the Cohen technique. VCUG was repeated at 6-12 months postoperatively. Of the 34 patients, 16 (47%) showed VUR on the contralateral side on PIC cystography and underwent bilateral reimplantation. The remaining 18 patients (53%) with negative PIC cystogram underwent unilateral reimplantation, and no VUR was detected by postoperative VCUG in all ureters. None of the 34 patients had surgical complications or recurrent urinary tract infections. In conclusion, PIC cystography represents a useful tool to predict new onset contralateral VUR in patients with unilateral VUR on conventional VCUG.

Long-term outcome of ovotesticular disorder of sex development: a single center experience.

OBJECTIVES: To describe the clinical features of children with ovotesticular disorder of sex development (DSD) and to review cases of ovotesticular DSD in Japan. METHODS: Medical records of eight children diagnosed with ovotesticular DSD at our institute during the past 17 years were retrospectively evaluated. A review of 165 reported cases of ovotesticular DSD from Japanese institutions was carried out. RESULTS: Mean follow up was 8.2 years for six children, with two children lost to follow up. Mean age at first presentation was 2.4 months. All children were Japanese. The most common initial manifestation was ambiguous genitalia. The female:male ratio as the sex of rearing was 1:1. Gender reassignment, from male to female, was carried out in one child at 4-months-old. Genital surgery was always carried out in early childhood as per family desire. Appropriate gonadal tissue was preserved except for one child. No gonadal tumors were detected during follow up. Spontaneous pubertal development occurred in one boy. In reviewing Japanese data, the frequency of testes was higher than in other ethnicities and this was related to the higher incidence of 46,XY. CONCLUSIONS: According to our experience, most families in Japan desire early genital surgery in the case of ovotesticular DSD. Chromosomal and gonadal distributions in patients with ovotesticular DSD differ between Japanese and other ethnic groups. Treatment for these patients needs to be provided after considering the cultural and social backgrounds of DSD in Japan.