A phase 1 open-label study to assess the relative bioavailability of TAK-931 tablets in reference to powder-in-capsule in patients with advanced solid tumors.

In this phase 1 open-label study, we assessed the relative bioavailability of a prototype tablet formulation of TAK-931, a cell division cycle 7 kinase inhibitor, in reference to the current powder-in-capsule (PIC) formulation in patients with advanced solid tumors for whom no effective standard treatment was available. Adult patients were randomized 1:1 in a crossover fashion to receive one dose of TAK-931 80 mg PIC on Day 1 and one dose of TAK-931 80 mg tablet on Day 3 (or the reverse sequence), followed by TAK-931 50 mg PIC once daily (QD) for 12 days starting from Day 5, before a 7-day rest period (Cycle 0). From Cycle 1, all patients received 50 mg PIC QD on Days 1-14 followed by a 7-day rest period. Twenty patients were enrolled. Median Tmax was achieved approximately 2 h post-dose of TAK-931 80 mg for both tablet and PIC. Geometric mean Cmax, AUC exposures, and T1/2z of TAK-931 were similar for both formulations. Geometric mean Cmax, AUClast, and AUCinf ratios were 0.936 (90% confidence interval [CI]: 0.808-1.084), 1.004 (90% CI: 0.899-1.120), and 1.007 (90% CI: 0.903-1.123), respectively, for TAK-931 tablet in reference to PIC. Discontinuation of TAK-931 due to treatment-emergent adverse events (TEAEs) occurred in 1 patient. Four (20%) patients experienced a serious TEAE; none were considered related to TAK-931. Pharmacokinetics and systemic exposure profiles were similar following administration of both formulations, supporting the transition from PIC to tablet in the clinical development of TAK-931. (Trial registration number ClinicalTrials.gov NCT03708211. Registration date October 12, 2018).

Examination of Knee Morphology After Secondary Ipsilateral ACL Injury Compared With Those That Have Not Been Reinjured: A Preliminary Study.

CONTEXT: Modifiable and nonmodifiable risk factors have been identified for sustaining a primary anterior cruciate ligament (ACL) injury; however, less research is available examining risk factors for a second injury. Identifying whether bony morphological factors are different (or more exaggerated) among those that experience a secondary ACL injury is critical to understanding if nonmodifiable risk factors are associated with a second injury. OBJECTIVE: To determine if bony morphology is different among those that experience a secondary ACL reinjury as compared with those that do not. DESIGN: Case-control. SETTING: University laboratory. PARTICIPANTS AND INTERVENTIONS: ACL participants were tracked after return to play following primary reconstruction, and if individuals experienced a second ipsilateral injury (ACLx2; n = 14, 8f/6m, 17.9 ± 4.0 y), the primary clinical MRI was analyzed for bony morphological risk factors. ACLx2 participants were matched to individuals (sex, age, height, graft, gender, and activity level) that had undergone reconstruction but did not experience reinjury (ACLx1, n = 14, 8f/6m, 18.7 ± 4.0 y). Ten controls were also enrolled (5m/5f, 20.8 ± 3.9 y) for the purposes of comparing the authors' ACL data against healthy knees. MAIN OUTCOME MEASURES: Lateral and medial posterior tibial slopes (LPTS, MPTS), notch shape index (NSI), and medial tibial plateau depth of concavity (MDC). RESULTS: All ACL-reconstructed patients (combined ACLx1 and ACLx2 group) had a steeper LPTS than controls (d = 0.87, 95% CI 0.11-1.60, P = .023); however, no difference in LPTS was found between ACLx1 and ACLx2 (P > .05). No differences in MPTS, NSI, and MDC were found between all ACL participants (combined ACLx2 and ACLx1) and controls or between ACLx1 and ACLx2 (P > .05). CONCLUSIONS: Compared to healthy individuals, a steeper LPTS is a common bony abnormality in all ACL-injured participants. Individuals that go on to experience a second ipsilateral ACL injury do not have more exaggerated bony morphology than those that do not suggesting that differences in modifiable risk factors at return to play may contribute to reinjury.

Penile myointimoma in children and adolescents: a clinicopathologic study of 5 cases supporting a distinct entity.

Penile myointimoma is a rare benign myointimal proliferation occurring exclusively within the corpus spongiosum of the glans penis and is most commonly described in adult patients. To date, there is only one reported series of 10 penile myointimomas plus one case report, representing a total of 8 adults and 3 children/adolescents. We report 5 penile myointimomas occurring in 5 patients less than 18 years of age (age range 4 to 15 y). All patients presented with a mass lesion on the glans penis ranging in size from 0.4 to 1.8 cm. All 5 lesions had the classic morphologic appearance: myointimal proliferation of the preexisting vascular spaces of the corpus spongiosum, creating a multinodular/plexiform architecture. Immunohistochemically, all stained cases showed strong cytoplasmic immunoreactivity for smooth muscle actin in the lesional cells and a collarette of native smooth muscle highlighted by desmin. None of the lesions appeared completely excised, but all 5 patients were clinically free of disease at last clinical follow-up (2 to 45 mo). In summary, we report only the second series of this distinctive, relatively rare myointimal proliferation within the corpus spongiosum of the glans penis, expand the number of published cases occurring in the pediatric/adolescent population, and confirm the benign clinical course after a marginal or incomplete excision.

Oral focal mucinosis: report of 15 cases and review of the literature.

AIMS: To describe 15 cases of oral focal mucinosis (OFM) and compare these to previously reported cases. METHODS: Cases diagnosed as OFM in the period 1981-2003-were reviewed. Clinical information provided at the time of submission of each specimen was retrieved and supplemented by additional clinical details provided by the respective clinician at the time of compilation of this paper. The literature was reviewed. RESULTS: OFM presented as an innocuous soft tissue swelling that may be either pedunculated or sessile. The gingiva was confirmed as the most common site for OFM, with a predominance of females affected. Microscopically, OFM is characterised by an area of myxoid tissue which is usually well-defined. The lesion is periodic acid-Schiff (PAS)-negative and alcian blue-positive, with pre-digestion with hyaluronidase preventing the alcian blue staining. As the differential diagnosis includes myxoid neural lesions, S100 staining is important in establishing the diagnosis, with cases of OFM being negative. CONCLUSIONS: The cause of OFM remains unknown. The cases presented in this paper bring OFM to the attention of anatomical pathologists when considering the differential diagnosis of myxoid lesions of the oral cavity.

The management of childhood urinary tract infections.

Urinary tract infections can result in significant morbidity and represent one of the most common urological conditions that the pediatrician and family practitioner encounter in the pediatric patient population. The prevalence of UTI in girls may be as high as 8.1%. UTIs also represent the most commonly identified serious bacterial infection in infants presenting with a febrile illness. Of febrile infants aged 2-3 months, 3-10% have a documented UTI. While the majority of the UTIs are not associated with any significant underlying conditions, the mere presence of a UTI is worrisome to most parents. An appropriate evaluation will determine which of these patients need referral. A brief summary is therefore presented to assist the primary care physician in the evaluation and management of childhood UTIs.

The management of childhood voiding dysfunction.

Wetting disorders in children can be frustrating for the patient, his parents and the physician caring for him. Although in most children the urinary incontinence will resolve with maturation, it is the persistent wetter that is brought in for management. There are two main categories of wetting disorders: those associated with neurological dysfunction of the lower urinary tract (neurogenic bladder) and those with normal neurological function (voiding dysfunction). This communication will be limited to the features, evaluation and management of voiding dysfunction.

Management of common disorders of the inguinal canal and scrotum in childhood and adolescence.

Primary care physicians, including family practitioners and pediatricians, frequently are consulted about children and adolescents with disorders of the inguinal canal and scrotum and are asked about the proper course of management, even if only to confirm an opinion of the surgical specialist. The purpose of this communication is to review the management of these conditions, including undescended testis, hydrocele and hernia, varicocele, testicular torsion, testicular trauma, epididymo-orchitis and scrotal edema.

Technique for repair of minimal distal balanitic hypospadias.

OBJECTIVES: Although not pernicious, minimal distal hypospadias is frequently obvious to parents, whose concern that their child be completely normal prompts their request for repair. A simple technique for the repair of this anomaly that results in an elliptical meatus is presented. METHODS: A total of 28 boys ranging in age from 3 to 100 months (mean 21.8) underwent a surgical technique in which the distal urethral plate was excised, followed by advancement of the meatus into the defect thus created. Only 5 boys (17.8%) underwent hypospadias repair as an isolated procedure. Other concomitantly repaired anomalies included hooded prepuce, phimosis, redundant prepuce after neonatal circumcision, ventral penile curvature, inguinal hernia, undescended testis, penile torsion, and meatal stenosis. RESULTS: All patients had healed well at a follow-up of 3 to 4 months (mean 3.2) and uniformly had an excellent cosmetic appearance with an elliptical meatus. CONCLUSIONS: We recommend a technique for the repair of minimal distal hypospadias, consisting of excision of the distal urethral plate with advancement of the dorsal lip of the meatus into the created defect, for its simplicity and resultant elliptical meatus.

A favorable experience with rotational flap techniques for fashioning the Firlit preputial collar.

PURPOSE: The Firlit collar technique for the approximation of the divergent inner leaf of the prepuce in operations to repair hypospadias and its variants are generally easily conceptualized and executed. However, in some cases the divergence is so great at the level of the corona that a simple approximation cannot be performed. Therefore, 2 techniques are described that facilitate completion of the Firlit collar in these instances. MATERIALS AND METHODS: A total of 101 boys 6 to 101 months old (mean 18.9) underwent formation of a Firlit collar between July 2003 and July 2004. Among the patients 69 had coronal or glanular hypospadias, 17 had a penile or a more proximal meatus and 15 had only a hooded prepuce. In 5 patients the divergence of the inner leaf of the prepuce precluded a simple midline approximation of the 2 halves. Two techniques of forming rotational flaps of the inner leaf were used to complete construction of the Firlit preputial collar. RESULTS: The techniques were used as described in 5 repairs, with excellent cosmetic results. CONCLUSIONS: Two rotational flap techniques for the repair of the widely divergent inner leaf of the prepuce associated with hypospadias and its variants are described and recommended for their simplicity and uniformly good results.

Buried penis: congenital syndrome of a short penile shaft and a paucity of penile shaft skin.

PURPOSE: The term "buried penis" has been applied to a variety of penile abnormalities and includes an apparent buried penis that is obvious at birth. The purpose of this study was to examine prospectively the congenital buried penis and to evaluate an operative technique for its management. MATERIALS AND METHODS: A total of 31 males 2 to 28 months old (mean age 12.3 months) with a congenital buried penis underwent surgical correction of the anomaly. Measurements were made of the penile shaft skin, inner leaf of the prepuce, glans length and stretched penile length. Observations of the subcutaneous tissue of the penis were made. The outer leaf of the prepuce was resected, following which covering of the penile shaft was accomplished with a combination of the penile shaft skin and the inner leaf of the prepuce. RESULTS: Stretched penile lengths ranged from 2.3 to 4.1 cm (mean 3.1). The glans length from the tip of the glans dorsally to the corona ranged from 0.9 to 1.6 cm (mean 1.2). The inner leaf of the prepuce ranged from 0.9 to 2.2 cm (mean 1.5) in length, while the dorsal penile skin lengths were 1 to 1.6 cm (mean 0.8). In all patients complete shaft coverage was accomplished using a combination of varying degrees of penile shaft skin and inner leaf of the prepuce. In no case was there a requirement for either unfurling of the inner and outer leaf of the prepuce or mobilization of scrotal flaps to accomplish shaft coverage. All patients healed well and have done well with a followup of 6 months to 1 year. CONCLUSIONS: Congenital buried penis is a syndrome consisting of a paucity of penile shaft skin and a short penile shaft. The anomaly may be successfully repaired by carefully preserving a length of inner leaf of the prepuce sufficient to cover, in some instances, the length of the penile shaft. Anchoring of the penile skin to the shaft is not recommended.

Cystic dysplasia of the testis with terminal ureterectasis and renal absence: evidence of involution of a dysplastic kidney?

Cystic dysplasia of the testis is a rare congenital anomaly, only 29 cases having been previously reported. We report a case of cystic dysplasia of the testis and absent ipsilateral kidney, but an ipsilateral ectatic terminal ureter, suggesting involution of a dysplastic kidney as a reason for the apparent renal agenesis.

Outcomes analysis of 64 consecutive open pediatric renal and upper ureteral operations.

OBJECTIVES: To report a recent consecutive series of children undergoing open renal and upper ureteral surgery that was analyzed for outcomes, particularly morbidity and length of stay. METHODS: A total of 64 children underwent open renal or upper ureteral surgery using an upper abdominal retroperitoneal approach. RESULTS: The mean operation time was 206 minutes, with a mean estimated blood loss of 20 mL. The mean analgesic dosage during the in-house postoperative period was 2.9 doses. The mean length of stay was 21.3 hours. A single complication occurred. One patient had a postoperative temperature of 38.6 degrees C, which was attributed to a pulmonary causation. CONCLUSIONS: For now, open surgery remains the standard approach for pediatric renal and upper ureteral anomalies and diseases with an expected postoperative result and course similar to that of laparoscopically performed procedures.

Extensive inflammatory eosinophilic bladder tumors in children: experience with three cases.

Eosinophilic cystitis, an uncommon lesion, is rare in children; < 25 cases have been reported. The intense inflammatory changes in the bladder wall associated with this lesion may produce heaped-up excrescences, which resemble vesical rhabdomyosarcoma. Our experience with 3 patients shows that the initial diagnosis of eosinophilic cystitis may not be easily made, and that the lesions produced may mask other disease processes. We alsoreport the fifth case of eosinophilic infiltration of the bladder occurring in association with chronic granulomatous disease.

Anuria due to bilateral ureteral obstruction by Aspergillus flavus in an adult male.

Mycelial clumps or bezoars (fungus balls) as a cause of upper urinary tract obstruction are rare, with fewer than 60 cases previously reported. Anuria due to bilateral ureteral obstruction with mycelial clumps is most rare. We report a man with bilateral ureteral obstruction by Aspergillus flavus and describe his diagnosis and treatment. It is remarkable that imaging modalities, including excretory urography, computed tomography, and retrograde ureteropyelography, did not identify filling defects to suggest a fungal causation of the ureteral obstruction, even in the presence of a rapidly progressing process. For this reason, one should consider a fungal infestation in high-risk patients with obstructive uropathy of unknown etiology.

Bilateral single ureteral ectopia in a boy.

Bilateral single ureteral ectopia is exceedingly rare, with fewer than 80 cases reported. Fewer than 20 cases have been reported in males. We describe a recent patient with bilateral single ureteral ectopia with bilateral megaureter and ureteral orifices opening into the prostatic urethra.

Extensive upper and mid ureteral loss in newborns: experience with reconstruction in 2 patients.

PURPOSE: We describe our experience with reconstruction of the ureter in 2 patients who sustained extensive upper and mid ureteral loss as newborns. MATERIALS AND METHODS: Two male patients, a 1-month-old and a neonate, sustained extensive ureteral loss due to candidal infection involving the retroperitoneum and ureter. The 1-month-old sustained a loss of the middle third of the ureter, and the neonate sustained a 3 cm. loss of the upper ureter. The first case was managed with a combination of renal mobilization and an extensive Boari flap, while the second was managed with renal mobilization and nephropexy with primary ureteropyelostomy. RESULTS: Both patients had a successful outcome with no evidence of anastomotic stenosis or obstruction. CONCLUSIONS: Extensive upper and middle third ureteral defects may be primarily bridged successfully in pediatric patients using the standard technique of renal mobilization combined with ureteropyelostomy and a Boari flap, respectively.

Scrotal enlargement in boys with a history of scrotal trauma: two unusual findings.

The presentation of a boy with an acutely painful scrotum is often associated with a history of trauma. Two recent patients with a history of scrotal trauma and an enlarged hemiscrotum were found on surgical exploration to have unusual causes for the scrotal enlargement. In the first case, there was bleeding from omentum in an incarcerated inguinal hernia, and in the second, there was bleeding into a scrotal cystic lymphangioma. Fewer than 40 cases of scrotal lymphangioma have been reported.