Optimal cervical-ripening method for labor induction in Japan after the era of controlled-release dinoprostone vaginal insert.

OBJECTIVE: To investigate the predictive value of obstetric findings when using dinoprostone (prostaglandin E2 [PGE2]) vaginal inserts for cervical ripening, and to assess the optimal cervical-ripening method between PGE2 vaginal insert and/or cervical dilators. METHODS: This prospective observational study enrolled pregnant women who underwent cervical ripening for labor induction in 37-41 week' gestation in 2020. In evaluation 1, optimal obstetric findings predictive of rapid cervical ripening using PGE2 were assessed. In evaluation 2, the duration from PGE2 administration to labor onset and perinatal outcomes were compared between cases in which only PGE2 was used and cases that were treated with PGE2 after mechanical cervical dilators (Dilapan®) for extremely immature cervical ripening (uterine cervical os <2 cm). RESULTS: In evaluation 1, uterine dilatation before the use of a PGE2 vaginal insert was mostly correlated with the time from PGE2 administration to labor onset (r = -0.428, p < 0.001). When the uterine cervical os dilatation was ≥2 cm, a shorter time-to-labor onset was found. In addition, os dilatation, effacement, and station at the time of PGE2 vaginal insert removal also significantly progressed. In evaluation 2, the median duration from PGE2 administration to labor onset was 1740 min in cases where only PGE2 was used, and 610 min in those where PGE2 was used after mechanical cervical dilators (p = 0.011). CONCLUSION: PGE2 vaginal inserts are relatively effective when the uterine cervical os is ≥2 cm in diameter. However, in cases of extremely immature cervical-ripening, it was feasible to use PGE2 vaginal inserts before mechanical cervical dilatation.

Mailing human papillomavirus self-sampling kits to women under-screened for cervical cancer improved detection in cervical cancer screening in a general population study in Japan.

BACKGROUND: One cause of the increase in cervical cancer rates in Japan is the long-term stagnation in the cervical cancer screening consultation rate. Therefore, improving the screening consultation rate is of urgent concern to reduce cervical cancer incidence. Self-collected human papilloma virus (HPV) tests have been successfully adopted in several countries, such as the Netherlands and Australia, as a measure of individuals who have not undergone cervical cancer screening in national programs. This study aimed to verify whether self-collected HPV tests presented an effective countermeasure for individuals who had not undergone the recommended cervical cancer screenings. METHODS: This study was conducted from December 2020 to September 2022 in Muroran City, Japan. The primary evaluated endpoint was the percentage of citizens who underwent cervical cancer screening at a hospital with positive self-collected HPV test results. The secondary endpoint was the percentage of included participants who were diagnosed with cervical intraepithelial neoplasia (CIN) or higher among those who visited a hospital and underwent cervical cancer screening. RESULTS: The included study participants were 7,653 individuals aged 20-50 years with no record of previous cervical cancer examination in the past 5 years. We mailed these participants information on self-administered HPV tests as an alternative screening procedure and sent the kit to 1,674 women who requested the test. Among them, 953 returned the kit. Among the 89 HPV-positive individuals (positive rate, 9.3%), 71 (79.8%) visited the designated hospital for an examination. A closer examination revealed that 13 women (18.3% of hospital visits) had a CIN finding of CIN2 or higher, among whom one each had cervical cancer and vulvar cancer, eight presented with CIN3, and three presented with CIN2; two cases of invasive gynecologic cancer were also identified. CONCLUSIONS: We conclude that the self-collected HPV tests showed a certain efficacy as a measure of individuals who had not undergone the recommended cervical cancer screening. We devised ways to have the unexamined patients undergo HPV testing and ensure that HPV-positive individuals visited the hospital. Despite a few limitations, our findings suggest the effectiveness of this public health intervention.

Individualized management of vasa previa and neonatal outcomes.

OBJECTIVE: To describe our individualized management protocol for women with an antenatal diagnosis of vasa previa (VP) and to report maternal and neonatal outcomes in patients managed according to our protocol. METHODS: A retrospective study of prospectively collected data of antenatally diagnosed VP managed at our hospital between 2014 and 2021. Obstetric and neonatal outcomes were reviewed and analyzed. RESULTS: Fourteen cases of antenatally diagnosed VP in 5150 total deliveries were analyzed (0.3%) Five cases (36%) of VP were diagnosed during the routine fetal morphological ultrasound screening, and nine cases (64%) were referred to our hospital due to perinatal complications. There were nine cases that required hospitalization (due to fetal growth restriction [FGR] [1], preterm labor [3], patients' request [5]). The other five were asymptomatic. Eight patients were delivered by scheduled cesarean section at around 36 weeks and only three neonates were admitted to NICU with transient tachypnea of newborn. However, six patients required CS before the scheduled dates because of other complications (preterm labor [3], abnormal cardiotocogram patterns [1], FGR [1] and twin pregnancy [1]). Four neonates born by CS before their scheduled dates were admitted to NICU. No cases required prolonged hospitalization and there were no serious neonatal complications. CONCLUSION: Individualized management may lead to favorable outcomes with VP. Outpatient management may be considered in patients without risk factors. However, maternal hospitalization and earlier scheduled CS should be considered in symptomatic patients or those at risk for preterm delivery.

Human papillomavirus testing and cytology using physician-collected uterine cervical samples vs. self-collected vaginal samples and urine samples.

BACKGROUND: Human papillomavirus (HPV) testing using self-collected vaginal samples and urine samples is convenient and effective for improving the screening rate. But, to serve as an alternative cervical cancer screening technique, such tests must offer sensitivity equivalent to the HPV testing of physician-collected cervical samples. To examine the effectiveness of HPV testing using self-collected samples and urine samples, we compared the results of HPV testing using these samples with those of HPV testing using physician-collected samples and cytological examinations. METHODS: The study population included 300 women (age: 20-50 years) with abnormal cervical cytology. The results of HPV testing using self-collected samples and urine samples and physician-collected samples and cervical cytology were compared. RESULTS: For all HPV types, the κ-value was 0.773 for physician- and self-collected samples and 0.575 for physician-collected and urine samples. The κ-value for HPV type 16-positive samples was 0.988 for physician- and self-collected samples and 0.896 for physician-collected and urine samples. The κ-value for HPV type 18-positive samples was 0.856 for physician- and self-collected samples and 0.831 for physician-collected and urine samples. For other HPV types, the value was 0.809 for physician- and self-collected samples and 0.617 for physician-collected and urine samples. CONCLUSIONS: The obtained results were consistent between physician- and self-collected samples as well as between physician-collected and urine samples. Considering that the agreement rate was particularly high for the high-risk HPV types 16 and 18, HPV testing using physician-collected samples, self-collected samples, and urine samples was equally effective for the types with high carcinogenicity.

Girls and renal scarring as risk factors for febrile urinary tract infection after stopping antibiotic prophylaxis in children with vesicoureteral reflux.

PURPOSE: To clarify the incidence of and risk factors for febrile urinary tract infection in children with persistent vesicoureteral reflux (VUR) after the discontinuation of continuous antibiotic prophylaxis (CAP), retrospective chart review was performed. PATIENTS AND METHODS: Among children with primary VUR at 10 years of age or younger at presentation, those who had persistent VUR despite conservative management with CAP and who were subsequently followed after discontinuation of CAP were included. Kaplan-Meier curve and Cox's proportional hazard regression model were used for evaluation of the incidence of and risk factors for febrile urinary tract infection (fUTI) after stopping CAP. RESULTS: Among 144 children (99 boys and 45 girls), fUTI developed in 34. The 5-year fUTI-free rate after discontinuation of CAP was 69.4%. On multivariate analyses, girls (p = 0.008) and abnormalities on nuclear renal scans (p = 0.0019), especially focal defect (p = 0.0471), were significant factors for fUTI. Although the fUTI-free rate was not different between children who had no or 1 risk factor, it was significantly lower in children with 2 risk factors than in those with no or 1 risk factor. CONCLUSIONS: The present study revealed that girls and abnormal renal scan, especially focal defect, are risk factors for fUTI. Active surveillance without CAP for persistent VUR seems to be a safe option for children with no or 1 risk factor. Prophylactic surgery or careful conservative follow-up may be an option for girls with abnormal renal scan results if VUR persists under CAP.

Clinicopathological features of hepatocellular carcinoma with fatty change: Tumors with macrovesicular steatosis have better prognosis and aberrant expression patterns of perilipin and adipophilin.

The clinicopathological characteristics of steatosis in hepatocellular carcinoma (HCC) remain unclear. Here, we elucidate the features of macrovesicular steatosis (MaS) and microvesicular steatosis (MiS) in HCC and their relationships with background liver steatosis. A total of 165 HCC lesions were classified as MaS-HCC, MiS-HCC, or conventional HCC (cHCC) according to the cutoff value of 30% MaS or MiS in tumor cells. We analyzed the clinicopathological differences among these groups. MaS-HCC had less portal vein invasion, a higher proportion of HCC with intratumoral fibrosis, and a lower cumulative risk of recurrence than MiS-HCC or cHCC. Moreover, both MaS-HCC and MiS-HCC had lower incidences of hepatitis virus infection and higher levels of HbA1c than cHCC. Background liver steatosis was also higher in MaS-HCC than in cHCC. Immunohistochemical expression of perilipin (Plin1) and adipophilin (ADRP), major proteins expressed on lipid droplet membranes, revealed that almost all lipid droplets in HCC were Plin1 negative, whereas those in background liver were positive. In contrast, ADRP was expressed on lipid droplets in both HCC and background liver. We concluded that MaS-HCC and MiS-HCC were associated with metabolic abnormalities but exhibited different biologic behaviors. Furthermore, lipid droplets in HCC were pathophysiologically different from those in background liver.

Characterization of spatial distribution of tumor-infiltrating CD8+ T cells refines their prognostic utility for pancreatic cancer survival.

The abundance of cytotoxic T-cell infiltrates has important implications for patient outcome and therapeutic design for pancreatic ductal adenocarcinoma. However, intratumoral heterogeneity remains a challenge to understanding the complex immune microenvironment. We hypothesized that characterizing CD8+ cell distribution within pancreatic adenocarcinoma tissues might refine the prognostic value of tumor-infiltrating CD8+ lymphocytes. Using multiplex immunohistochemistry-based image analysis on whole-tissue sections of 214 pancreatic ductal adenocarcinomas, we measured CD8+ cell densities in the tumor center, the tumor margin, and the whole tumor, along with the proximity of CD8+ cells to carcinoma cells. Multivariable Cox regression analysis was performed to assess the associations of CD8+ cell densities with pancreatic cancer-specific survival, adjusting for clinicopathologic and immune-related features, including tumor expressions of TP53, SMAD4, and the programmed cell death 1 ligand 1 (CD274, PD-L1) and the extent of tertiary lymphoid structures. There was substantial heterogeneity in CD8+ cell density, with the mean density in the tumor center less than half that in the tumor margin. Tumor CD274 expression and extensive tertiary lymphoid structures were appeared to be associated with higher CD8+ cell density in the tumor margin (P = 0.037 and P = 0.005, respectively), but not with that in the tumor center (P > 0.50). The association of higher CD8+ cell density with prolonged survival was significant for the whole tumor (Ptrend = 0.009); however, the association was stronger for the tumor center (Ptrend = 0.002) and insignificant for the tumor margin (Ptrend = 0.07). Tumor cell-CD8+ cell distance correlated strongly with CD8+ cell density, whereas the density of CD8+ cells proximate to cancer cells exhibited no prognostic association. In conclusion, spatial computational analysis on pancreatic ductal adenocarcinoma reveals the prognostic validity of CD8+ cell density in the tumor center, where CD8+ cell infiltration is ununiformly restricted, likely suggesting pro-tumorigenic roles of the immunosuppressive tumor microenvironment of pancreatic cancer.

Risk factors affecting post-pubertal high serum follicle-stimulating hormone in patients with hypospadias.

PURPOSE: The factors affecting spermatogenesis in adulthood in patients with hypospadias (HS) are not clearly understood. In the present study, risk factors affecting post-pubertal high serum follicle-stimulating hormone (FSH) were evaluated in patients with HS. MATERIALS AND METHODS: Among those with a history of HS surgery, patients in whom endocrinological evaluation regarding pituitary-gonadal axis was performed at 15 years of age or older between March 2004 and April 2018 were enrolled in the present study. High serum FSH was defined as greater than 10 mIU/ml. The severity of HS was divided into mild and severe. Factors affecting the post-pubertal high serum FSH were estimated. RESULTS: Seventy-nine patients were included in the present study. The severity of HS was mild in 35 and severe in 44. History of undescended testis (UDT) was confirmed in 12. High serum FSH was detected in nine. On logistic regression model analysis, a history of UDT was the only significant factor for high serum FSH. The incidence of high serum FSH in patients with UDT was significantly higher than that in those without UDT (58.3% vs 7.5%, p < 0.01). When stratified by severity of HS and the presence of UDT, high serum FSH was detected in 70% in patients with severe HS and UDT, whereas less than 10% in other groups. CONCLUSIONS: A history of UDT was a significant factor for post-pubertal high serum FSH in patients with HS. Accordingly, the presence of UDT may be a marker for impaired spermatogenesis in patients with HS, especially in severe cases.

Late-onset visceral varicella-zoster virus infection presented as acute liver failure after allogeneic hematopoietic stem cell transplantation.

Although much less common than localized zoster, initial presentation of varicella-zoster virus (VZV) as visceral infection can occur especially after allogeneic hematopoietic stem cell transplantation (HSCT). We herein report a case of post-transplant visceral VZV infection presenting as fatal acute liver failure. It developed 4 years after allogeneic HSCT when a long-term prophylactic anti-VZV agent administration was discontinued. VZV should be listed as a causative pathogen of acute liver failure even years after allogeneic HSCT. Indication for, and duration of anti-VZV prophylaxis should be further investigated.

KRAS mutations in cell-free DNA from preoperative and postoperative sera as a pancreatic cancer marker: a retrospective study.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) has very poor prognosis despite existing multimodal therapies. This study aimed to investigate whether KRAS mutations at codons 12/13 in cell-free DNA (cfDNA) from preoperative and postoperative sera from patients with PDAC can serve as a predictive biomarker for treatment response and outcomes after surgery. METHODS: Preoperative and postoperative serum samples obtained from 45 patients with PDAC whom underwent curative pancreatectomy at our institution between January 2013 and July 2016 were retrospectively analysed. Peptide nucleic acid-directed PCR clamping was used to identify KRAS mutations in cfDNA. RESULTS: Among the 45 patients enrolled, 11 (24.4%) and 20 (44.4%) had KRAS mutations in cfDNA from preoperative and postoperative sera, respectively. Multivariate analysis revealed that KRAS mutations in postoperative serum (hazard ratio (HR)=2.919; 95% confidence interval (CI)=1.109-5.621; P=0.027) are an independent prognostic factor for disease-free survival. Furthermore, the shift from wild-type KRAS in preoperative to mutant KRAS in postoperative cfDNA (HR=9.419; 95% Cl=2.015-44.036; P=0.004) was an independent prognostic factor for overall survival. CONCLUSIONS: Changes in KRAS mutation status between preoperative and postoperative cfDNA may be a useful predictive biomarker for survival and treatment response.

Mesenchymal-epithelial transition of pancreatic cancer cells at perineural invasion sites is induced by Schwann cells.

Epithelial-mesenchymal transition (EMT) promotes invasion and metastasis of pancreatic ductal adenocarcinoma (PDAC). However, the importance of its reverse process, mesenchymal-epithelial transition (MET), for PDAC remains unclear. We aimed to characterize the histological finding "focal differentiation" in PDAC at perineural invasion sites in the context of MET and to investigate the role of Schwann cells in inducing tumor MET. Tumor differentiation and immunohistochemical expressions of E-cadherin, SMAD3, and vimentin at perineural invasion sites were examined in 168 PDAC tissues. Four PDAC cell lines were co-cultured with Schwann cells to investigate cell morphology, motility, or EMT-related markers using immunocytochemistry and quantitative PCR. Of 168 tumors, 124 (74%) showed focal differentiation with enhanced E-cadherin membrane expression (P < 0.001) and decreased nuclear accumulation of SMAD3 (P < 0.001). Among 115 PDACs harboring grade 1/2 tumor, tumors with focal differentiation showed worse survival compared to those without focal differentiation (P = 0.019). PDAC cells co-cultured with Schwann cells demonstrated a sheet-like appearance, increased E-cadherin expression, decreased expressions of SMAD3 and vimentin, and reduced cell motility. In conclusion, MET-like change is induced by Schwann cells, suggesting that Schwann cells contribute to PDAC colonization in pancreatic nerves through activating the MET machinery inside tumor cells in the pancreatic tumor microenvironment.

Prevalence and risk factors of testicular microlithiasis in patients with hypospadias: a retrospective study.

BACKGROUND: It has been described that the incidence of testicular microlithiasis is high in several congenital disorders which may be associated with testicular impairment and infertility. Several reports have shown that a prepubertal or pubertal hormonal abnormality in the pituitary-gonadal axis was identified in some patients with hypospadias that is one of the most common disorders of sex development. However, exact prevalence or risk factors of testicular microlithiasis in patients with hypospadias have not reported so far. In the present study, to clarify the prevalence and risk factors of testicular microlithiasis in patients with hypospadias, a retrospective chart review was performed. METHODS: Children with hypospadias who underwent testicular ultrasonography between January 2010 and April 2016 were enrolled in the present study. Severity of hypospadias was divided into mild and severe. The prevalence and risk factors of testicular microlithiasis or classic testicular microlithiasis were examined. RESULTS: Of 121 children, mild and severe hypospadias were identified in 66 and 55, respectively. Sixteen children had undescended testis. Median age at ultrasonography evaluation was 1.7 years old. Testicular microlithiasis and classic testicular microlithiasis were documented in 17 children (14.0%) and 8 (6.6%), respectively. Logistic regression analysis revealed that presence of undescended testis was only a significant factor for testicular microlithiasis and classic testicular microlithiasis. The prevalence of testicular microlithiasis or classic testicular microlithiasis was significantly higher in children with undescended testis compared to those without undescended testis (testicular microlithiasis; 43.8% versus 9.5% (p = 0.002), classic testicular microlithiasis; 37.5% versus 1.9% (p < 0.001). CONCLUSIONS: The current study demonstrated that the presence of undescended testis was only a significant risk factor for testicular microlithiasis or classic testicular microlithiasis in patients with hypospadias. As co-existing undescended testis has been reported as a risk factor for testicular dysfunction among patients with hypospadias, the current findings suggest that testicular microlithiasis in children with hypospadias may be associated with impaired testicular function. Conversely, patients with isolated HS seem to have lower risks for testicular impairment. Further investigation with longer follow-up will be needed to clarify these findings.

Impact of Preoperative Ultrasonographic Evaluation for Detection of a Viable Testis in Patients With a Unilateral Nonpalpable Testis.

OBJECTIVES: To investigate the impact of preoperative ultrasonography (US) for detecting a viable testis in patients with a unilateral nonpalpable testis. METHODS: Patients with a unilateral nonpalpable testis or unilateral palpable undescended testis who underwent preoperative US were enrolled. Patients were divided into 3 groups as follows: nonpalpable testis/no testis (n = 27), which included patients who had a unilateral nonpalpable testis with no viable testis detected at surgery; nonpalpable testis/viable testis (n = 10), which included patients who had a unilateral nonpalpable testis with a viable testis identified at surgery; and palpable undescended testis (n = 63), which included patients who had a unilateral palpable undescended testis. Preoperative US findings were compared among each group. RESULTS: The testicular volume on the contralateral descended side in the nonpalpable testis/no testis group was significantly greater than that in the nonpalpable testis/viable testis and palpable undescended testis groups. When a testicular volume of 0.54 mL was used as the cutoff value, the sensitivity, specificity, positive predictive value, and negative predictive value for the presence of the affected testis were 75.3%, 100%, 100%, and 60.0%, respectively. The testis on the affected side was detected in none of the nonpalpable testis/no testis group, 7 of the nonpalpable testis/viable testis group, and all of the palpable undescended testis group. When a visible testis on the affected side and a testicular volume of 0.54 mL or less were defined as positive, all patients in the nonpalpable testis/viable testis and palpable undescended testis groups had positive findings versus none in the nonpalpable testis/no testis group. CONCLUSIONS: Preoperative US provides valuable information for predicting the presence of a viable testis in patients with a unilateral nonpalpable testis by estimating both the unaffected testis and the affected side.

Concurrent presentation of an intraductal tubulopapillary neoplasm and intraductal papillary mucinous neoplasm in the branch duct of the pancreas, with a superior mesenteric artery aneurysm: a case report.

BACKGROUND: Since the concept of intraductal tubulopapillary neoplasm (ITPN) was introduced in the current World Health Organization classification of tumors, the number of reports of ITPN occurrence has increased gradually. However, ITPN is usually located in the main pancreatic duct, with few reports of a branch duct ITPN. As a result, imaging protocols for the diagnosis of a branch duct ITPN have not been established. CASE PRESENTATION: We report a case of a concurrent presentation of a branch duct ITPN and intraductal papillary mucinous neoplasm (IPMN) in the head of the pancreas, with a superior mesenteric artery (SMA) aneurysm. Initially, the cystic masses in the pancreatic head were diagnosed as branch duct IPMNs, with treatment consisting of a pylorus-preserving pancreaticoduodenectomy, in combination with an aneurysmectomy performed for treatment of the SMA aneurysm. Pathological examination confirmed these cysts were a combination of branch-type ITPN and IPMN. The patient recovered from the treatment without complication, with no evidence of recurrence over a period of 34 months post-surgery. CONCLUSION: This case report of a synchronous presentation of an ITPN and IPMN indicates the difficulty in differentiating these two types of neoplasms in the branch duct of the pancreatic head.

Prevalence of and risk factors for symptomatic urinary tract infection after endoscopic incision for the treatment of ureterocele in children.

OBJECTIVE: To clarify the impact of endoscopic incision (EI) for ureterocele as an initial procedure, by performing a retrospective chart review, focusing on the prevalence of and risk factors for symptomatic urinary tract infection (UTI) after EI. MATERIALS AND METHODS: In the present study we included children with ureterocele, managed between September 1994 and April 2016, who were observed conservatively without additional surgical management after EI. Ureterocele was categorized as intravesical or ectopic. Symptomatic UTI was defined as either recurrent non-febrile or febrile UTI. The prevalence of and risk factors for symptomatic UTI were analysed using Cox proportional hazard models or Kaplan-Meier curves, and the log-rank test. RESULTS: A total of 36 children met the inclusion criteria. The median age of the participants at EI was 8.9 months. Eleven children had symptomatic UTIs (febrile, n = 9; recurrent non-febrile, n = 2) during the median follow-up of 75.5 months. Initial symptomatic UTI in each child occurred <25 months after EI. The symptomatic UTI-free rate after EI was 65.6%. The risk factors for symptomatic UTI were female gender, duplex system, ectopic ureterocele, and unchanged hydronephrosis after EI. CONCLUSIONS: The present study determined the critical period and risk factors for symptomatic UTI after EI for the treatment of ureterocele. The results suggest that when conservative management is indicated after EI, patients, especially those with risk factors, should be followed carefully at least for 25 months after EI for symptomatic UTI.

Early hepatocellular carcinoma with high-grade atypia in small vaguely nodular lesions.

Multistep hepatocarcinogenesis progresses from dysplastic nodules to early hepatocellular carcinoma (eHCC) and to advanced HCC. The aim of the present study was to investigate the detailed histopathological features of eHCC. We investigated 66 small vaguely nodular lesions resected from 40 patients. The degree of cellular and structural atypia and stromal invasion were assessed. The immunohistochemical expression of HCC-related markers adenylate cyclase-associated protein 2 (CAP2), heat shock protein 70 (HSP70), Bmi-1, CD34 and h-caldesmon were evaluated. Of the 66 nodules, 10 were diagnosed as low-grade dysplastic nodules (LGDN), 10 as high-grade dysplastic nodules (HGDN) and 46 as eHCC. Among the 46 eHCC, 18 nodules (39.1%) showed marked stromal invasion and/or the presence of the scirrhous component and were subclassified as high-grade eHCC (HGeHCC). The remaining 28 eHCC, which lacked these features, were subclassified as low-grade eHCC (LGeHCC) and were examined further. HGeHCC showed high levels of cellular and structural atypia and large tumor size. The immunohistochemical expression of CAP2 and the area of sinusoidal vascularization showed increases from LGDN to HGeHCC. The density of arterial tumor vessels was high in HGeHCC compared with other nodule types. Cluster analysis of these parameters subclassified 65 nodules into HGeHCC-dominant, LGeHCC and HGDN-dominant, and LGDN-dominant groups. These results indicate the increased malignant potential of HGeHCC and suggest that it is already a transitional stage to advanced HCC. We consider that our grading classification system may be valuable for considering treatment strategies for eHCC around 2 cm in diameter.

Factors affecting post-pubertal penile size in patients with hypospadias.

OBJECTIVES: To evaluate actual post-pubertal penile size and factors affecting it in hypospadias patients, we retrospectively reviewed medical charts. PATIENTS AND METHODS: Hypospadias patients whose external genitalia were categorized into Tanner stage 5, and whose stretched penile length was evaluated at 15 years old or older from April 2008 to April 2015, were enrolled in the present study. Stretched penile length was measured by a single examiner. Actual post-pubertal stretched penile length and factors affecting the post-pubertal stretched penile length were estimated. Statistical analysis was performed using Mann-Whitney U test and univariate and multivariate linear regression models for the determination of independent factors. RESULTS: Thirty patients met the inclusion criteria. Median age at evaluation was 17.2 years. Thirteen and 17 had mild and severe hypospadias, respectively. Endocrinological abnormality was identified in 5. Multivariate analysis showed that the severity of hypospadias and endocrinological abnormality were significant factors affecting stretched penile length. Stretched penile length in 25 patients without endocrinological abnormality was significantly longer than that in those with endocrinological abnormality (p = 0.036). Among patients without endocrinological abnormality, stretched penile length in 13 with severe hypospadias was significantly shorter than that in 12 with mild hypospadias (p = 0.004). CONCLUSIONS: While the severity of hypospadias and endocrinological abnormality at post-pubertal evaluation were factors affecting post-pubertal penile size, stretched penile length in patients with severe hypospadias was shorter even in cases without endocrinological abnormality. These results suggest that severe hypospadias is not only a disorder of urethral development, but also a disorder of penile development.

Discovery of novel 2',4'-dimethyl-[4,5'-bithiazol]-2-yl amino derivatives as orally bioavailable TRPV4 antagonists for the treatment of pain: Part 2.

A series of 2',4'-dimethyl-[4,5'-bithiazol]-2-yl amino derivatives have been identified as selective TRPV4 antagonists that display inhibition potencies against 4α-phorbol 12,13-didecanoate (4αPDD), well known as a TRPV4 selective agonist and/or a hypotonicity. In particular, 9-(6-((2',4'-dimethyl-[4,5'-bithiazol]-2-yl)amino)nicotinoyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-one showed an analgesic effect in Freund's Complete Adjuvant (FCA) induced mechanical hyperalgesia model in guinea pig (reported in Part 1). However, there are some concerns such as species differences and the need for higher plasma exposure to achieve target efficacy for evaluation by an in vivo pain model. In this Letter, we report the resolution of some of the problems by further optimizing the chemical scaffold.

Discovery of novel 2',4'-dimethyl-[4,5'-bithiazol]-2-yl amino derivatives as orally bioavailable TRPV4 antagonists for the treatment of pain: Part 1.

A novel series of 2',4'-dimethyl-[4,5'-bithiazol]-2-yl amino derivatives were found by high throughput screening of the TRPV4 receptor, at which these compounds showed competitive antagonist potential against 4α-phorbol 12,13-didecanoate (4αPDD) as the selective TRPV4 agonist and showed excellent selectivity for TRPV1, N-type and L-type calcium ion channels, but poor ADME profile. In our SAR strategy, we found that the lead molecule 1 also having the unique 3-oxa-9-azabicyclo [3.3.1] nonan-7-one on the right part showed potent TRPV4 antagonist activity, good solubility at pH 6.8, good microsomal stability for human and better ADME profile including oral bioavailability. Moreover, compound 1 had an analgesic effect in Freund's Complete Adjuvant (FCA) induced mechanical hyperalgesia model in guinea pig. In this letter, we report a lead optimization process to identify the lead compound 1 (Fig. 1).

Endomyocardial fibrosis: missing tricuspid valve and Fontan-like circulation.

Endomyocardial fibrosis (EMF) is a progressive type of obliterative/restrictive cardiomyopathy characterized by fibrosis of the apical endomyocardium of the ventricles. Although the prognosis of EMF patients is poor in tropical regions, the exact clinical course and pathogenesis of patients with EMF are not known. Here, we report the rare case with EMF in the seventh decade, who showed the disappearance of papillary muscles, chordae tendineae, and part of the tricuspid valves due to massive right ventricular thrombus. Because of those unusual findings of the isolated RV involvement, we observed continuous forward pulmonary artery flow, as occurring in a Fontan circulation.