Adverse Events of Everolimus in Patients with Tuberous Sclerosis Complex Treated for Renal Angiomyolipoma/Subependymal Giant Cell Astrocytoma.

Background: Although regarded as a potentially efficient approach to address tuberous sclerosis complex (TSC)-associated complications, the adverse event profile of everolimus has not yet been fully elucidated. The present study aimed to clarify the adverse event spectrum in patients with TSC who are using everolimus for common indications, in comparison to those who do not use everolimus. Materials and Methods: We recruited patients with TSC who were followed up annually at TSC integrated clinics or referred for medical assistance. Medical reviews and laboratory investigations were performed at baseline and annually by clinical physicians. The adverse events were assessed as per the National Cancer Institute Common Terminology Criteria for Adverse Events. Results: Common adverse events in everolimus users included hypercholesterolemia (55%), gingivostomatitis (50%), proteinuria (50%), and hyperglycemia (40%). Compared with everolimus nonusers, the occurrence of gingivostomatitis and proteinuria was significantly higher in everolimus users (gingivostomatitis, p=0.02; proteinuria, p=0.02). Among the everolimus users, 12 patients had level I CTCAE, and five had level II CTCAE. None of the everolimus users presented with CTCAE level III or higher. Conclusion: Patients with TSC who are everolimus users had a higher tendency to develop gingivostomatitis and proteinuria compared to nonusers. However, no differences were observed in the occurrence of other adverse events between everolimus users and nonusers.

SUMO1 and Defective Spermatozoa Correlate with Endogenous Hydrogen Peroxide and Live Birth Outcome in Intrauterine Insemination Cycles for Unexplained Infertility.

This study aimed to investigate the correlation between hydrogen peroxide (H2O2), small ubiquitin-like modifier molecules (SUMO), and pregnancy outcomes in couples with unexplained infertility (UI) undergoing intrauterine insemination (IUI) treatment. We prospectively collected semen samples from 56 couples with UI and divided the spermatozoa into motile and immotile fractions by density gradient centrifugation (DSC). Immunofluorescence staining was used to examine the immunostaining and localization of nuclear pore complex (NPC), SUMO1, and SUMO2/3 in spermatozoa. We detected H2O2 levels by chemiluminescence methods. We found that H2O2 levels correlated with NPC (neck) (r = 0.400) and NPC (tail) (r = 0.473) in motile sperm fractions. In immotile fractions, H2O2 positively correlated with NPC (tail) (r = 0.431) and SUMO1 (neck) (r = 0.282). Furthermore, the positive NPC (tail) group had a significantly lower live birth rate than the negative NPC group (17.9% = 5/28 vs. 42.9% = 12/28). In conclusion, H2O2 positively correlated with SUMO1 (neck) and NPC (tail) in human spermatozoa. The DSC may partially eliminate defective spermatozoa (positive NPC staining); however, if defective spermatozoa remain in the motile fraction, this scenario is associated with a low live birth rate following IUI treatment.

PNU-74654 Suppresses TNFR1/IKB Alpha/p65 Signaling and Induces Cell Death in Testicular Cancer.

Testicular cancer (TC) is a rare malignancy worldwide and is the most common malignancy in males aged 15-44 years. The Wnt/ß-catenin signaling pathway mediates numerous essential cellular functions and has potentially important effects on tumorigenesis and cancer progression. The search for drugs to inhibit this pathway has identified a small molecule, PNU-74654, as an inhibitor of the ß-catenin/TCF4 interaction. We evaluated the therapeutic role of PNU-74654 in two TC cell lines, NCCIT and NTERA2, by measuring cell viability, cell cycle transition and cell death. Potential pathways were evaluated by protein arrays and Western blots. PNU-74654 decreased cell viability and induced apoptosis of TC cells, with significant increases in the sub G1, Hoechst-stained, Annexin V-PI-positive rates. PNU-74654 treatment of both TC cell lines inhibited the TNFR1/IKB alpha/p65 pathway and the execution phase of apoptosis. Our findings demonstrate that PNU-74654 can induce apoptosis in TC cells through mechanisms involving the execution phase of apoptosis and inhibition of TNFR1/IKB alpha/p65 signaling. Therefore, small molecules such as PNU-74654 may identify potential new treatment strategies for TC.

High SPOCK1 Expression is Associated with Advanced Stage, T Value, and Gleason Grade in Prostate Cancer.

Prostate cancer (PCa) is a common malignancy in males and has a relatively slower progression than other cancers. Our goal was to evaluate the clinical role of SPARC (secreted protein acidic and cysteine rich, osteonectin), cwcv, and kazal-like domains' proteoglycan 1 (SPOCK1) in PCa. SPOCK1 expression was studied through the immunohistochemical staining of specimens from 71 patients with PCa. The correlation between SPOCK1 expression and clinicopathological features was quantitatively analyzed. We used Kaplan-Meier analysis and Cox proportional hazard models to analyze the prognostic value. Of 71 PCa patients, high SPOCK1 expression was more likely to be seen in those with an advanced stage (p = 0.018) of the disease and an advanced tumor (T) value (p = 0.014). Patients in Gleason grade groups 3 and 4 had significantly higher SPOCK1 expression (p = 0.044 and 0.003, respectively) compared to those of Gleason grade group 1. However, this trend was not observed in patients in Gleason grade group 5. For the survival analysis, although it was not statistically significant, patients with a high SPOCK1 expression had a shorter median overall survival (6.2 years) compared to those with low expression (7.8 years). High SPOCK1 expression may be related to advanced clinicopathological features and possibly a poor prognosis. Further analysis with a larger patient base would help clarify this issue.

Favorable mortality-to-incidence ratios of kidney Cancer are associated with advanced health care systems.

BACKGROUND: The advancements in cancer therapy have improved the clinical outcomes of cancer patients in recent decades. However, advanced cancer therapy is expensive and requires good health care systems. For kidney cancer, no studies have yet established an association between clinical outcome and health care disparities. METHODS: We used the mortality-to-incidence ratio (MIR) for kidney cancer as a marker of clinical outcome to compare World Health Organization (WHO) country rankings and total expenditures on health/gross domestic product (e/GDP) using linear regression analyses. RESULTS: We included 57 countries based on data from the GLOBOCAN 2012 database. We found that more highly developed regions have higher crude and age-standardized rates of kidney cancer incidence and mortality, but a lower MIR, when compared to less developed regions. North America has the highest crude rates of incidence, but the lowest MIRs, whereas Africa has the highest MIRs. Furthermore, favorable MIRs are correlated with countries with good WHO rankings and high e/GDP expenditures (p < 0.001 and p = 0.013, respectively). CONCLUSIONS: Kidney cancer MIRs are positively associated with the ranking of health care systems and health care expenditures.

Comparison of radiofrequency ablation versus laparoscopic adrenalectomy for benign aldosterone-producing adenoma.

PURPOSE: To retrospectively compare the safety and efficacy of radiofrequency ablation (RFA) with laparoscopic adrenalectomy (LA) in treating aldosterone-producing adenoma (APA) of the adrenal gland. MATERIALS AND METHODS: From September 2009 to September 2013, seven patients, diagnosed with unilateral adrenal APA and underwent computed tomography (CT)-guided percutaneous RFA, were recruited in this retrospective study. Eighteen unilateral adrenal APA with the same tumor size (<25 mm) who underwent LA during the same interval were enrolled as control group. Treatment success was defined as complete tumor ablation on follow-up CT scan and normalization of serum aldosterone-to-renin ratio. We also compared "normalization ability" between RFA group and LA group. Normalization ability was defined as reduction in blood pressure, decrease in number of antihypertensive medicine use, reduction in serum aldosterone, and increase in serum potassium level. RESULTS: There was no statistically significant demographic difference in both groups. The mean tumor size was 18 (8-25) mm in RFA and 19 (11-25) mm in LA groups, respectively. There was only one intra-procedure hypertensive crisis in the RFA group. No other complications needed further management in both groups. During an interval of 3-6 months of follow-up, the treatment success rate reached 100 % in the RFA group versus 94.4 % in the LA group. Normalization ability was statistically equivalent in the RFA and the LA group. Comparing with LA group, RFA group demonstrated with less post-operative pain (visual analog scale, 2.0 ± 1.16 vs. 4.22 ± 1.44, p < 0.001) and shorter operative time (105 ± 34 vs. 194 ± 58 min, p < 0.001). CONCLUSIONS: CT-guided percutaneous RFA is effective, safe and is a justifiable alternative for patients who are reluctant or unfit for laparoscopic surgery for the treatment of APA.

PBK/TOPK Expression Predicts Prognosis in Oral Cancer.

Oral cancer is a common cancer with poor prognosis. We evaluated the expression of PBK/TOPK (PDZ-binding kinase/T-LAK cell-originated protein kinase) and its prognostic significance in oral cancer. PBK/TOPK expression was measured by immunohistochemical staining of samples from 287 patients with oral cancer. The association between PBK/TOPK expression and clinicopathological features was analyzed. The prognostic value of PBK/TOPK for overall survival was determined by Kaplan-Meier analysis and Cox proportional hazard models. A high PBK/TOPK expression level was correlated with long overall survival. The prognostic role of PBK/TOPK expression was significant in young patients (p < 0.05), patients with smoking habits (p < 0.05), and late stage disease (p < 0.05). Our results suggest that PBK/TOPK expression is enhanced in oral cancer. High PBK/TOPK expression, either alone or in subgroups according to clinicopathological features, may serve as a favorable prognostic marker for patients with oral cancer.

The Prognostic Role of STEAP1 Expression Determined via Immunohistochemistry Staining in Predicting Prognosis of Primary Colorectal Cancer: A Survival Analysis.

STEAP1 (six transmembrane epithelial antigen of the prostate 1) is a transmembrane protein that functions as a potential channel or transporter protein. It is overexpressed in certain cancers and is viewed as a promising therapeutic target. However, the prognostic role of STEAP1 is still controversial, and no role for STEAP1 has yet been indicated in colorectal cancer. The aim of this study was to investigate the possible association of STEAP1 expression with colorectal cancer prognosis. STEAP1 expression was analyzed by immunohistochemical staining of a tissue array of 165 cancer specimens from primary colorectal cancer patients. The mean and medium follow-up times after surgery were 5.1 and 3.9 years, respectively. A total of 139 patients died during the 13 years of follow-up in the survey period. The prognostic value of STEAP1 with respect to overall survival was analyzed by Kaplan-Meier analysis and Cox proportional hazard models. In total, 164 samples displayed detectable STEAP1 expression in the cytoplasm and membrane. Low STEAP1 expression was correlated with poor overall survival (five-year survival: 33.7% vs. 57.0%, low expression vs. high expression, p = 0.020). Accordingly, multivariate analysis identified low STEAP1 expression as an independent risk factor (hazard ratio = 1.500, p = 0.018), especially in elderly patients or those with late stage cancers, late T values, and early N values. We suggest that analysis of STEAP1 expression by immunohistochemical staining could serve as an independent prognostic marker for colorectal patients. This finding should be validated by other investigative groups.

Adjuvant Chemotherapy in Patients with Locally Advanced Upper Tract Urothelial Carcinoma with or without Kidney Transplantation.

Background: The incidence of upper tract urothelial carcinoma (UTUC) is uniquely high in kidney transplant (KT) recipients in Taiwan. The evidence of adjuvant chemotherapy (AC) in UTUC is contradictory. We have sought to determine whether AC is associated with potential benefits related to locally advanced UTUC after KT. Methods: We retrospectively analyzed 134 patients with locally advanced UTUC (at least stage T2) and patients who were administrated AC after unilateral or bilateral nephroureterectomy with bladder cuff excision. Of these 134 patients, 57 patients fulfilled our inclusion criteria. We used 23 KT and 34 non-KT locally advanced UTUC patients for comparison. Results: The mean follow-up time was 52.35 ± 34.56 and 64.71 ± 42.29 months for the KT and non-KT groups, respectively. The five-year disease-free survival (DFS) and overall survival (OS) rates were 45.7% vs. 70.2% and 62.8% vs. 77.6%, for the KT and non-KT groups. The Kaplan-Meier curve and the log rank test revealed significant differences in the DFS and OS rates between the two groups, p = 0.015 and 0.036. The influence of chemotherapy on graft kidney function was mild. Only three in the KT group and two in the non-KT group developed > grade 2 nephrotoxicity. Conclusions: Our study suggested that KT patients with locally advanced UTUC who had been administered AC after surgery presented worse OS and DFS than non-KT patients. KT patients tolerated the AC course well, and their nephrotoxicity levels were mild and acceptable.

New Hydronephrosis in the Native Kidney Is Associated with the Development of De Novo Urinary Bladder Urothelial Carcinoma in Patients with Post-Kidney Transplantation.

Increased malignancy after kidney transplantation (KT) is by far the most troublesome issue. Among these malignancies, urothelial carcinoma (UC) incidence is uniquely high in Taiwan. We want to know whether routine sonography to detect native hydronephrosis is associated with the development of de novo urinary bladder urothelial carcinoma (UBUC) in post-KT recipients. From 2003 to 2018, we retrospectively analyzed 1005 KT patients, 58 of whom were subsequently diagnosed with UBUC. The association between new native hydronephrosis and post-KT UBUC was analyzed with univariate and multivariate logistic regression analyses and a Kaplan-Meier plot. We excluded cases of people who had upper urinary tract urothelial carcinoma (UTUC) and were diagnosed prior to UBUC. There were 612 males (60.9%) and 393 females (39.1%), with a mean age of 48.2 ± 12.0 years old at KT. The mean follow-up period was 118.6 ± 70.2 months, and the diagnosis of UBUC from KT to UBUC was 7.0 ± 5.1 years. New native kidney hydronephrosis occurred more frequently in the UBUC group (56.4% versus 6.4%, p < 0.001) than the non-UBUC group. Multivariate analysis disclosed that native hydronephrosis is the only statistically significant factor for UBUC, with an odds ratio of 16.03 (95% CI, 8.66-29.68; p < 0.001). UBUC in post-KT patients with native hydronephrosis also showed a tendency toward multifocal lesions upon presentation (47.8%). Post-KT UBUC is characterized by pathologically aggressive and multiple foci lesions. Native kidney hydronephrosis may be a deciding factor of post-KT UBUC.

Melatonin induces cell cycle arrest and suppresses tumor invasion in urinary bladder urothelial carcinoma.

Urinary bladder urothelial carcinoma (UBUC) encompasses about 90% of all bladder cancer cases, and the mainstream treatment is the transurethral resection of the bladder tumor followed by intravesical instillation. High rates of mortality, recurrence, and progression in bladder cancer have stimulated the search for alternative adjuvant therapies. The aim of this study was to investigate the potential of melatonin as adjuvant therapy in bladder cancer. Cell viability and clonogenic ability were assessed by an MTT assay and colony formation. Cell cycle and apoptosis analysis were performed by flow cytometry and Hoechst 33342 staining, while cell metastasis capacity was measured by wound healing and transwell assays. Potential mechanisms were investigated by an oncology array and verified via western blotting. The melatonin treatment significantly reduced T24 and UMUC3 bladder cancer cell proliferation and clonogenic ability. G1 arrest and sub-G1 accumulation in the T24 and UMUC3 cells led to cell proliferation suppression and cell death, and Hoechst 33342 staining further verified the apoptosis induction directly by melatonin. Moreover, melatonin weakened cell motility and invasiveness. Based on the oncology array results, we demonstrated that melatonin exerts its anti-cancer effect by down-regulating the HIF-1α and NF-κB pathways and downstream pathways, including Bcl-2, leading to cell cycle arrest and apoptosis induction in the UBUC cells. Overall, these findings support the potential of melatonin as adjuvant therapy in bladder cancer.

A 12-year-old boy with an infected ectopic ureter presenting with acute appendicitis-like symptoms and acute scrotum.

An ectopic ureter draining into the seminal vesicle or vas deferens in males is a very rare anomaly and is usually associated with renal dysplasia or agenesis. An ectopic ureter associated with a dysplastic kidney is not usually a suspected cause during clinical evaluation of children with abdominal pain. This report presents a rare case of an ectopic ureter associated with a dysplastic kidney with an acute infection in a previously healthy 12-year-old boy, demonstrated by magnetic resonance imaging. He presented with abdominal pain that mimicked acute appendicitis-like symptoms which was subsequently complicated by epididymitis manifesting as an acute scrotum. Clinicians should consider including an ectopic ureter in the differential diagnosis of children presenting with acute abdomen.

Motor and bladder dysfunctions in patients with vertebral fractures at the thoracolumbar junction.

OBJECTIVE: To present the motor deficits and type of neurogenic bladder dysfunction (NBD) in patients with vertebral fractures at thoracolumbar junction. METHODS: Fifty-two patients with single level vertebra fracture over T11-L2 with onset duration of longer than 3 years were enrolled. All participants provided basic demographic data, ambulatory status and received neurologic examination and urodynamic studies. The differences in distribution of NBD types, neurologic injury sites and functional walkers in patients with different levels of vertebral injury were analyzed. Receiver operating characteristic curve analysis was used to define the cutoff value of lower extremities motor score (LEMS) in functional walker and non-walker. RESULTS: Of the 52 patients, the injured levels were 3 (5.8%) in T11, 21 (40.4%) in T12, 22 (42.3%) in L1, and 6 (11.5%) in L2 vertebrae. Eight (15.4%) patients had upper lumbar cord lesions, 26 (50.0%) had epiconus and lumbar roots lesions, 18 (34.6%) had conus medullaris or/and cauda equina lesions. Mean LEMS was 0 ± 0, 5.4 ± 7.7, 11.1 ± 10.2, and 28.0 ± 11.0 for patients with T11, T12, L1, and L2 fractures, respectively. Patients with L2 fractures had higher LEMS than other levels (p < 0.001). The cutoff value of LEMS for functional walking was set at 20, and both the sensitivity and specificity was 100%. Thirty-one (59.6%) patients had spastic NBD, 18 (35.6%) had flaccid NBD, and 3 (5.8%) had mixed type NBD. Positive prediction value of ankle spasticity for bladder and sphincter spasticity was 95.2 and 100%, respectively. CONCLUSION: Half of the patients had epiconus lesion following thoracolumbar junction fracture, and they had a clinical presentation of flaccid legs and spastic NBD. Patients with L2 fracture had higher LEMS than patients with T11, T12, and L1 fracture. Patients whose LEMS was higher than 20 could all walk functionally. Fracture at the thoracolumbar junction may cause spastic, flaccid, or mixed type NBD, and urodynamic study is an essential tool for the correct diagnosis and management. Ankle spasticity has a high positive predictive value for spastic bladder or sphincter.

Value of Doppler ultrasonography in predicting deteriorating renal function after spinal cord injury.

PURPOSE: The authors sought to study the relationship between Doppler ultrasonography and deterioration of renal function in patients with spinal cord injury. MATERIALS AND METHODS: Nineteen patients who underwent follow-up with radioisotopic renography were evaluated. Median patient age was 50 [interquartile ratio (IQR) 35-57] years, and time since injury was 4.7 (IQR 1.3-9.2) years. Following Doppler ultrasound, patients were divided into groups based on baseline renal resistive index (RRI): normal RRI (≤ 0.7), group 1 (n=14); and abnormal RRI (> 0.7), group 2 (n=5), and were followed up with radioisotopic renography 1 or more years later. Annual change in effective renal plasma flow (ERPF) was analysed. RESULTS: The 38 kidneys (two for each patient) were stratified by initial RRI, with 28 in group 1 and ten in group 2. Result of univariate generalised estimation equation (GEE) analysis for the factors affecting the change in effective renal plasma flow (ERPF) indicated that the high RRI value (RRI > 0.7) correlated with the change in ERPF. ERPF value in group 2 was significantly decreased (p=0.01) by an average of 60.33 ml/min (standard error = 23.26). CONCLUSIONS: An RRI > 0.7 is a risk factor for future renal function deterioration in patients with spinal cord injury. Thus, annual Doppler ultrasonography to assess the RRI and the degree of hydronephrosis is recommended.

Bladder agenesis and bilateral ectopic ureters draining into the vagina in a female infant: demonstrated by MR imaging.

Complete agenesis of the bladder and urethra is an extremely rare congenital anomaly and most of these patients are stillborn or die during infancy. We report the case of a 1-month-old female infant with bladder and urethral agenesis who presented with bilateral dilated and tortuous ectopic ureters draining into the vagina diagnosed using MR imaging. Our patient was maintained on antibiotic prophylaxis and she remained well during the 3-year follow-up. MR imaging can be used as a valuable modality for genitourinary abnormalities, particularly in cases of inconclusive ultrasound or retrograde pyelography findings.

Concomitant Detrusor and External Urethral Sphincter Botulinum Toxin-A Injections in Male Spinal Cord Injury Patients with Detrusor Overactivity and Detrusor Sphincter Dyssynergia.

OBJECTIVE: To investigate the effects of concomitant injections of botulinum toxin-A (BoNT-A) into the detrusor and external urethral sphincter muscles in suprasacral spinal cord injured patients with detrusor overactivity and detrusor sphincter dyssynergia. DESIGN: An open treatment trial with pre- and posttreatment evaluations. SUBJECTS: Male suprasacral spinal cord injury patients (n = 20) with neurogenic detrusor overactivity and detrusor sphincter dyssynergia who emptied their bladder by reflex voiding and were unwilling to increase the frequency of intermittent catheterization. METHODS: Cystoscopic guidance of 200 U BoNT-A injections into the detrusor muscle and 100 U into external urethral sphincter muscles were applied. The urodynamic parameters, voiding diaries and quality of life scores using Urinary Distress Inventory, Short Form (UDI-6) and Incontinence Impact Questionnaire, Short Form (IIQ-7) were compared. RESULTS: All participants experienced a significant mean reduction in maximal detrusor pressure and maximal urethral pressure profile, and a mean significant increase in maximal cystometric bladder capacity 12 weeks after concomitant injections. Bladder diaries demonstrated persistently increased spontaneous voided volume, but no increase in post-void residual ratio, daily clean intermittent catheterization (CIC) frequency and diaper pad use from baseline to 24 weeks. UDI-6 scores were significantly improved at 4 and 12 weeks and IIQ-7 scores improved only at 12 weeks. CONCLUSION: Concomitant detrusor and external urethral sphincter BoNT-A injections may decrease detrusor and urethral pressure without increasing postvoid residual ratio and diaper pad use. For spinal cord injury patients with neurogenic detrusor overactivity and detrusor sphincter dyssynergia who are unwilling, or for whom it is inconvenient, to increase CIC frequency and who want to preserve spontaneous voiding, this treatment may provide an optional alternative.

Effective dose for kidney-ureter-bladder plain radiography, intravenous urography, and abdominal computed tomography scan: A phantom study.

Abdominal colic pain or hematuria is suspected to be caused by urinary tract stones. Commonly used X-ray examinations include kidney-ureter-bladder plain radiography (KUB), intravenous urography (IVU), and abdominal computed tomography (CT). In this study, a high-sensitivity thermoluminescent dosimeter (TLD) was embedded in a Rando phantom to directly measure organ dose and evaluate effective dose. During each experiment, 139 TLD measurement points that cover almost all organs (as recommended by the ICRP 103 report) were examined. Red bone-marrow and remainder tissues have a high tissue weighting factor (0.12), and they are widely distributed. In the phantom, 34 TLDs and 31 TLDs were embedded in the red bone-marrow and remainder tissues to improve the accuracy and representativeness of organ doses. The detailed organ dose distributions for KUB, IVU, and abdominal CT are presented. The effective doses for KUB and IVU were 0.22 and 1.51 mSv, respectively, and those for two abdominal CTs were 8.21 and 9.27 mSv. This experiment presents a conversion factor of 0.0177 mSv·mGy-1 cm-1 for the abdominal CT examination, which differs from most of the conversion factors obtained through the Monte Carlo simulation method.