Durability of Response to Primary Chemoablation of Low-Grade Upper Tract Urothelial Carcinoma Using UGN-101, a Mitomycin-Containing Reverse Thermal Gel: OLYMPUS Trial Final Report.

PURPOSE: Our goal was to evaluate long-term safety and durability of response to UGN-101, a mitomycin-containing reverse thermal gel, as primary chemoablative treatment for low-grade upper tract urothelial carcinoma. MATERIALS AND METHODS: In this open-label, single-arm, multicenter, phase 3 trial (NCT02793128), patients ≥18 years of age with primary or recurrent biopsy-proven low-grade upper tract urothelial carcinoma received 6 once-weekly instillations of UGN-101 via retrograde catheter to the renal pelvis and calyces. Those with complete response (defined as negative ureteroscopic evaluation, negative cytology and negative for-cause biopsy) 4-6 weeks after the last instillation were eligible for up to 11 monthly maintenance instillations and were followed for ≥12 months with quarterly evaluation of response durability. Durability of complete response was determined by ureteroscopic evaluation; duration of response was estimated by the Kaplan-Meier method. Treatment-emergent adverse events (TEAEs) were monitored. RESULTS: Of 71 patients who initiated treatment, 41 (58%) had complete response to induction therapy and consented to long-term followup; 23/41 patients (56%) remained in complete response after 12 months (95% CI 40, 72), comprising 6/12 (50%) who did not receive any maintenance instillations and 17/29 (59%) who received ≥1 maintenance instillation. Kaplan-Meier analysis of durability was estimated as 82% (95% CI 66, 91) at 12 months. Ureteric stenosis was the most frequently reported TEAE (31/71, 44%); an increasing number of instillations appeared to be associated with increased incidence of urinary TEAEs. CONCLUSIONS: Durability of response to UGN-101 with or without maintenance treatment is clinically meaningful, offering a kidney-sparing therapeutic alternative for patients with low-grade disease.

Primary chemoablation of low-grade upper tract urothelial carcinoma using UGN-101, a mitomycin-containing reverse thermal gel (OLYMPUS): an open-label, single-arm, phase 3 trial.

BACKGROUND: Most patients with low-grade upper tract urothelial cancer are treated by radical nephroureterectomy. We aimed to assess the safety and activity of a non-surgical treatment using instillation of UGN-101, a mitomycin-containing reverse thermal gel. METHODS: In this open-label, single-arm, phase 3 trial, participants were recruited from 24 academic sites in the USA and Israel. Patients (aged ≥18 years) with primary or recurrent biopsy-proven, low-grade upper tract urothelial cancer (measuring 5-15 mm in maximum diameter) and an Eastern Cooperative Oncology Group performance status score of less than 3 (Karnofsky Performance Status score >40) were registered to receive six instillations of once-weekly UGN-101 (mitomycin 4 mg per mL; dosed according to volume of patient's renal pelvis and calyces, maximum 60 mg per instillation) via retrograde catheter to the renal pelvis and calyces. All patients had a planned primary disease evaluation 4-6 weeks after the completion of initial therapy, in which the primary outcome of complete response was assessed, defined as negative 3-month ureteroscopic evaluation, negative cytology, and negative for-cause biopsy. Activity (complete response, expected to occur in >15% of patients) and safety were assessed by the investigator in all patients who received at least one dose of UGN-101. Data presented are from the data cutoff on May 22, 2019. This study is registered with ClinicalTrials.gov, NCT02793128. FINDINGS: Between April 6, 2017, and Nov 26, 2018, 71 (96%) of 74 enrolled patients received at least one dose of UGN-101. 42 (59%, 95% CI 47-71; p<0·0001) patients had a complete response at the primary disease evaluation visit. The median follow-up for patients with a complete response was 11·0 months (IQR 5·1-12·4). The most frequently reported all-cause adverse events were ureteric stenosis in 31 (44%) of 71 patients, urinary tract infection in 23 (32%), haematuria in 22 (31%), flank pain in 21 (30%), and nausea in 17 (24%). 19 (27%) of 71 patients had study drug-related or procedure-related serious adverse events. No deaths were regarded as related to treatment. INTERPRETATION: Primary chemoablation of low-grade upper tract urothelial cancer with intracavitary UGN-101 results in clinically significant disease eradication and might offer a kidney-sparing treatment alternative for these patients. FUNDING: UroGen Pharma.

Phase II Trial of Neoadjuvant Systemic Chemotherapy Followed by Extirpative Surgery in Patients with High Grade Upper Tract Urothelial Carcinoma.

PURPOSE: Data supporting neoadjuvant chemotherapy of high grade upper tract urothelial carcinoma are scant. In this multi-institution, prospective, phase II trial we investigated pathological complete responses after neoadjuvant chemotherapy of high grade upper tract urothelial carcinoma. MATERIALS AND METHODS: Patients with high grade upper tract urothelial carcinoma in whom nephroureterectomy was planned were assigned to 4 neoadjuvant chemotherapy cycles of accelerated methotrexate, vinblastine, doxorubicin and cisplatin in those with baseline creatinine clearance greater than 50 ml per minute or gemcitabine and carboplatin in those with creatinine clearance 30 to 50 ml per minute or less. The study primary end point was a pathological complete response (ypT0N0). The accrual goal was 30 patients per arm. An 18% pathological complete response was considered worth further study while a 4% pathological complete response would not have justified pursuing this regimen. With 28 eligible patients per arm success was defined as 3 or more pathological complete responses (10.7%) in a given arm. Secondary end points included safety, renal function and oncologic outcomes. RESULTS: A total of 30 patients enrolled in the accelerated methotrexate, vinblastine, doxorubicin and cisplatin arm from 2015 to 2017. Six patients enrolled in the gemcitabine and carboplatin arm, which closed due to poor accrual. Of the 29 patients eligible for accelerated methotrexate, vinblastine, doxorubicin and cisplatin, including 23 men and 6 women with a median age of 65 years (range 40 to 84), 80% completed all planned treatments, 3 (10.3%) achieved ypT0N0 and 1 achieved ypT0Nx for a pathological complete response in 13.8% (90% CI 4.9-28.8). In 1 patient receiving accelerated methotrexate, vinblastine, doxorubicin and cisplatin nephroureterectomy was deferred due to grade 4 sepsis. The grade 3-4 toxicity rate was 23% in the accelerated methotrexate, vinblastine, doxorubicin and cisplatin arm with no grade 5 event. CONCLUSIONS: Accelerated methotrexate, vinblastine, doxorubicin and cisplatin neoadjuvant chemotherapy in patients with high grade upper tract urothelial carcinoma and creatinine clearance greater than 50 ml per minute was safe and demonstrated predefined activity with a 14% pathological complete response rate. Final pathological stage ypT1 or less in more than 60% of patients is encouraging. Together the results of this prospective trial support the use of neoadjuvant chemotherapy in eligible patients with high grade upper tract urothelial carcinoma.

ICUD-SIU International Consultation on Bladder Cancer 2017: management of non-muscle invasive bladder cancer.

PURPOSE: To provide a summary of the Third International Consultation on Bladder Cancer recommendations for the management of non-muscle invasive bladder cancer (NMIBC). METHODS: A detailed review of the literature was performed focusing on original articles for the management of NMIBC. An international committee assessed and graded the articles based on the Oxford Centre for Evidence-based Medicine system. The entire spectrum of NMIBC was covered such as prognostic factors of recurrence and progression, risk stratification, staging, management of positive urine cytology with negative white light cystoscopy, indications of bladder and prostatic urethral biopsies, management of Ta low grade (LG) and high risk tumors (Ta high grade [HG], T1, carcinoma in situ [CIS]), impact of BCG strain and host on outcomes, management of complications of intravesical therapy, role of alternative therapies, indications for early cystectomy, surveillance strategies, and new treatments. The working group provides several recommendations on the management of NMIBC. RESULTS: Recommendations were summarized with regard to staging; management of primary and recurrent LG Ta and high risk disease, positive urine cytology with negative white light cystoscopy and prostatic urethral involvement; indications for timely cystectomy; and surveillance strategies. CONCLUSION: NMIBC remains a common and challenging malignancy to manage. Accurate staging, grading, and risk stratification are critical determinants of the management and outcomes of these patients. Current tools for risk stratification are limited but informative, and should be used in clinical practice when determining diagnosis, surveillance, and treatment of NMIBC.

External Validation of Bladder Cancer Predictive Nomograms for Recurrence, Cancer-Free Survival and Overall Survival following Radical Cystectomy.

PURPOSE: We externally validated 3 previously published nomograms to predicting recurrence, and cancer specific and overall survival following radical cystectomy and pelvic lymph node dissection for urothelial carcinoma of the bladder. MATERIALS AND METHODS: Two surgeons from a single institution performed a total of 197 consecutive radical cystectomies and pelvic lymph node dissections for bladder cancer from January 2003 to September 2009. A total of 23 patients were excluded from analysis. Examined parameters were those used in the original nomograms, including patient age, gender, pathological T stage, N stage, tumor grade, presence of carcinoma in situ and lymphovascular invasion, neoadjuvant chemotherapy, adjuvant chemotherapy and adjuvant radiation therapy. Nomogram predictions were compared to actuarial outcomes and predictive accuracy was quantified using measures of discrimination and calibration. RESULTS: At the time of analysis 34 patients had experienced recurrence, of whom 28 died of disease and 6 were currently alive with disease. Discrimination at 2, 5 and 8 years was 0.776, 0.809 and 0.794 for recurrence, 0.822, 0.840 and 0.849 for cancer specific survival, and 0.812, 0.820 and 0.825, respectively, for overall survival. Calibration plots revealed nomogram overestimation of all 3 end points. CONCLUSIONS: Nomograms for bladder cancer recurrence, cancer specific survival and overall survival following radical cystectomy and pelvic lymph node dissection performed well in our series with accuracy comparable to that in the original series. The use of nomogram predictions should be further explored in clinical trials to assess the impact on patient care in clinical practice.

Usefulness of transurethral biopsy for staging the prostatic urethra before radical cystectomy.

PURPOSE: We determined the likelihood that transurethral resection biopsy of the prostatic urethra adjacent to the verumontanum would detect prostatic involvement of urothelial carcinoma in patients with bladder carcinoma. MATERIALS AND METHODS: We compared precystectomy transurethral resection biopsy specimens of the prostatic urethra with those of the matched radical cystoprostatectomy in 272 patients with urothelial carcinoma of the bladder. All prostates were evaluated by whole mount step sections. RESULTS: Prostatic involvement by urothelial carcinoma was detected by transurethral resection biopsy or radical cystoprostatectomy in 101 patients (37.1%). Transurethral resection biopsy detected urothelial carcinoma in 72 cases with 71.3% sensitivity and 100% specificity. The overall accuracy of transurethral resection biopsy to detect urothelial carcinoma of the prostate was 89% (positive and negative predictive values 100% and 86%, respectively). Invasive prostatic urothelial carcinoma arising from the prostatic urethra was detected by transurethral resection biopsy in 21 of 26 patients (81%) while prostatic carcinoma in situ was detected in 39 of 52 (75%). Transurethral resection biopsy detected prostatic invasive urothelial carcinoma resulting from transmural invasion of a bladder tumor in 4 of 15 patients. CONCLUSIONS: Prostatic involvement by urothelial carcinoma of the bladder was found in 37.1% of patients. Transurethral resection biopsy missed most tumors resulting from transmural invasion of the bladder primary lesion. Carcinoma in situ and invasive urothelial carcinoma arising from the prostatic urethra were detected in most cases. Transurethral resection biopsy of the prostatic urethra can complement staging and support clinical decision making with respect to neoadjuvant chemotherapy and planning for an orthotopic neobladder.

Significance of lymphovascular invasion in organ-confined, node-negative urothelial cancer of the bladder: data from the prospective p53-MVAC trial.

OBJECTIVES: To investigate the association between lymphovascular invasion (LVI) and clinical outcome in organ-confined, node-negative urothelial cancer of the bladder (UCB) in a post hoc analysis of a prospective clinical trial. To explore the effect of adjuvant chemotherapy with methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) on outcome in the subset of patients whose tumours exhibited LVI. PATIENTS AND METHODS: Surgical and tumour factors were extracted from the operative and pathology reports of 499 patients who had undergone radical cystectomy (RC) for pT1-T2 N0 UCB in the p53-MVAC trial (Southwest Oncology Group 4B951/NCT00005047). The presence or absence of LVI was determined by pathological examination of transurethral resection or RC specimens. Variables were examined in univariate and multivariate Cox proportional hazards models for associations with time to recurrence (TTR) and overall survival (OS). RESULTS: Among 499 patients with a median follow-up of 4.9 years, a subset of 102 (20%) had LVI-positive tumours. Of these, 34 patients had pT1 and 68 had pT2 disease. LVI was significantly associated with TTR with a hazard ratio (HR) of 1.78 [95% confidence interval (CI) 1.15-2.77; number of events (EV) 95; P = 0.01) and with OS with a HR of 2.02 (95% CI 1.31-3.11; EV 98; P = 0.001) after adjustment for pathological stage. Among 27 patients with LVI-positive tumours who were randomised to receive adjuvant chemotherapy, receiving MVAC was not significantly associated with TTR (HR 0.70, 95% CI 0.16-3.17; EV 7; P = 0.65) or with OS (HR 0.45, 95% CI 0.11-1.83; EV 9; P = 0.26). CONCLUSIONS: Our post hoc analysis of the p53-MVAC trial revealed an association between LVI and shorter TTR and OS in patients with pT1-T2N0 disease. The analysis did not show a statistically significant benefit of adjuvant MVAC chemotherapy in patients with LVI, although a possible benefit was not excluded.

Erectile dysfunction as a marker for cardiovascular disease diagnosis and intervention: a cost analysis.

INTRODUCTION: Erectile dysfunction (ED) is a risk factor for cardiovascular disease (CVD). We examine the costs of screening men with ED for CVD risk factors and the cost savings of treating these at risk men. AIM: This study aims to evaluate the effect of screening men presenting with ED for CVD risk factors and to determine the cost effectiveness of this screening protocol. METHODS: The known incidence and prevalence of ED and CVD, the rate of undiagnosed CVD, and the effects of CVD treatment were used to model the change in prevalence of acute CVD events and ED as a function of the number of men with ED and CVD. The cost savings associated with reduction in acute cardiovascular (CV) events and ED prevalence was estimated over 20 years. MAIN OUTCOME MEASURES: Acute CVD event rate reduction and associated cost savings were modeled over 20 years. RESULTS: The relative risk of ED in men with CVD is 1.47 and the coprevalence of both ED and CVD was estimated at 1,991,520 men. Approximately 44% of men with CVD risk factors are unaware of their risk. If all men presenting with ED were screened for CVD, 5.8 million men with previously unknown CVD risk factors would be identified over 20 years, costing $2.7 billion to screen. Assuming a 20% decrease in CV events as a result of screening and treatment, 1.1 million cardiovascular events would be avoided, saving $21.3 billion over 20 years. Similarly, 1.1 million cases of ED would be treated, saving $9.7 billion. Together, the reduction in acute CVD and ED treatment cost would save $28.5 billion over 20 years. CONCLUSIONS: Screening for CVD in men presenting with ED can be a cost-effective intervention for secondary prevention of both CVD and, over the longer term, ED.

Three differentiation states risk-stratify bladder cancer into distinct subtypes.

Current clinical judgment in bladder cancer (BC) relies primarily on pathological stage and grade. We investigated whether a molecular classification of tumor cell differentiation, based on a developmental biology approach, can provide additional prognostic information. Exploiting large preexisting gene-expression databases, we developed a biologically supervised computational model to predict markers that correspond with BC differentiation. To provide mechanistic insight, we assessed relative tumorigenicity and differentiation potential via xenotransplantation. We then correlated the prognostic utility of the identified markers to outcomes within gene expression and formalin-fixed paraffin-embedded (FFPE) tissue datasets. Our data indicate that BC can be subclassified into three subtypes, on the basis of their differentiation states: basal, intermediate, and differentiated, where only the most primitive tumor cell subpopulation within each subtype is capable of generating xenograft tumors and recapitulating downstream populations. We found that keratin 14 (KRT14) marks the most primitive differentiation state that precedes KRT5 and KRT20 expression. Furthermore, KRT14 expression is consistently associated with worse prognosis in both univariate and multivariate analyses. We identify here three distinct BC subtypes on the basis of their differentiation states, each harboring a unique tumor-initiating population.

Maternal thyroid hormones during pregnancy, childhood adiposity and cardiovascular risk factors: the Generation R Study.

OBJECTIVE: Variation in maternal thyroid function during early pregnancy may permanently affect childhood growth and cardiovascular development. We examined the associations of early pregnancy maternal TSH and free T4 (FT4) levels with childhood growth, body composition and cardiovascular characteristics. METHODS: We performed a population-based prospective cohort study among 5646 mothers and their children. Maternal thyroid parameters were assessed in early pregnancy (median: 13·2 weeks; 95% range: 9·7-17·6 weeks). Childhood growth was repeatedly measured from birth to 6 years. At the age of 6 years, childhood body mass index (BMI), total body and abdominal fat distribution, blood pressure and left ventricular mass were measured. RESULTS: Maternal thyroid parameters were not consistently associated with childhood length and weight growth characteristics. Lower maternal TSH levels were associated with lower childhood BMI, total fat mass, abdominal subcutaneous fat mass area and diastolic blood pressure (P-values <0·05), but not with preperitoneal abdominal fat mass area, systolic blood pressure or left ventricular mass. Higher maternal FT4 levels were associated with lower childhood BMI, abdominal subcutaneous and preperitoneal fat mass area (P for trends <0·05), but not with other cardiovascular characteristics. Clinically maternal hypothyroid or hyperthyroid statuses were not associated with childhood growth, body fat or cardiovascular outcomes. CONCLUSIONS: Maternal thyroid function during early pregnancy may influence childhood body composition and cardiovascular development. Further studies are needed to replicate these findings and to examine the influence of maternal thyroid hormone levels during pregnancy on long-term growth and cardiovascular development in the offspring.

Testosterone replacement therapy in patients with prostate cancer after radical prostatectomy.

PURPOSE: Testosterone replacement therapy in men with prostate cancer is controversial, with concern that testosterone can stimulate cancer growth. We evaluated the safety and efficacy of testosterone in hypogonadal men with prostate cancer treated with radical prostatectomy. MATERIALS AND METHODS: We performed a review of 103 hypogonadal men with prostate cancer treated with testosterone after prostatectomy (treatment group) and 49 nonhypogonadal men with cancer treated with prostatectomy (reference group). There were 77 men with low/intermediate (nonhigh) risk cancer and 26 with high risk cancer included in the analysis. All men were treated with transdermal testosterone, and serum hormone, hemoglobin, hematocrit and prostate specific antigen were evaluated for more than 36 months. RESULTS: Median (IQR) patient age in the treatment group was 61.0 years (55.0-67.0), and initial laboratory results included testosterone 261.0 ng/dl (213.0-302.0), prostate specific antigen 0.004 ng/ml (0.002-0.007), hemoglobin 14.7 gm/dl (13.3-15.5) and hematocrit 45.2% (40.4-46.1). Median followup was 27.5 months, at which time a significant increase in testosterone was observed in the treatment group. A significant increase in prostate specific antigen was observed in the high risk and nonhigh risk treatment groups with no increase in the reference group. Overall 4 and 8 cases of cancer recurrence were observed in treatment and reference groups, respectively. CONCLUSIONS: Thus, testosterone therapy is effective and, while followed by an increase in prostate specific antigen, does not appear to increase cancer recurrence rates, even in men with high risk prostate cancer. However, given the retrospective nature of this and prior studies, testosterone therapy in men with history of prostate cancer should be performed with a vigorous surveillance protocol.

Research Note: Corn energy and nutrient utilization by broilers as affected by geographic areas and carbohydrases.

Two experiments (Exp.) were conducted to evaluate the effects of exogenous carbohydrases on nutrient and energy utilization of corn with different compositions by broilers. In Exp. 1, a total of 448 Cobb 500 male chicks were distributed in a 2 × 4 factorial arrangement (corn from regions geographically located in the North or South of Brazil × 4 carbohydrases supplementation), with 8 replicate cages of 7 birds each. In Exp. 2, 672 Cobb 500 male chicks were fed 12 experimental feeds, in a 3 × 4 factorial arrangement [3 corn endosperm compositions (waxy, semi-dent, or semi-flint) × 4 carbohydrases], with 8 replicate cages of 7 birds. Birds were fed semi-purified test diets with 95.9% corn from d 14 to 24 in both studies. In Exp. 1, α-amylase, ß-xylanase, or carbohydrase complex (cellulase, glucanase, and xylanase) were added to the diet. In Exp. 2, α-amylase, ß-xylanase, or α-amylase + ß-xylanase were supplemented. Digestibility of DM, N, ether extract (EE), Ca, and P as well as AME, AMEn, and IDE were determined. In Exp. 2, jejunal starch digestibility was determined on d 24. Data were subjected to analysis of variance and means were compared by Tukey test (P ≤ 0.05). Corn from the North origin had higher AME, AMEn, and digestibility of DM and N compared to the South (P ≤ 0.05). Amylase supplementation led to increases of 3% in AME and 2% in N digestibility when compared to the non-supplemented feeds (P ≤ 0.01). In Exp. 2, the highest ME values and EE digestibility were observed in the semi-flint corn compared to the waxy, whereas the semi-dent presented the highest digestibility of N and starch. Corn diets supplemented with amylase + xylanase had improvements of 2.5% AMEn and 3% starch digestibility. In conclusion, energy and nutrient utilization of corn by broilers depend on the region where it was grown. Corn genetics, expressed by the endosperm composition, and carbohydrase supplementation influenced energy and nutrient utilization by broilers.

Incidental detection of FGFR3 fusion via liquid biopsy leading to earlier diagnosis of urothelial carcinoma.

The rising utilization of circulating tumor DNA (ctDNA) assays in Precision Oncology may incidentally detect genetic material from secondary sources. It is important that such findings are recognized and properly leveraged for both diagnosis and monitoring of response to treatment. Here, we report a patient in whom serial cell-free DNA (cfDNA) monitoring for his known prostate adenocarcinoma uncovered the emergence of an unexpected FGFR3-TACC3 gene fusion, a BRCA1 frameshift mutation, and other molecular abnormalities. Due to the rarity of FGFR3 fusions in prostate cancer, a workup for a second primary cancer was performed, leading to the diagnosis of an otherwise-asymptomatic urothelial carcinoma (UC). Once UC-directed treatment was initiated, the presence of these genetic abnormalities in cfDNA allowed for disease monitoring and early detection of resistance, well before radiographic progression. These findings also uncovered opportunities for targeted therapies against FGFR and BRCA1. Overall, this report highlights the multifaceted utility of longitudinal ctDNA monitoring in early cancer diagnosis, disease prognostication, therapeutic target identification, monitoring of treatment response, and early detection of emergence of resistance.

Pelvic lymph node dissection for prostate cancer: frequency and distribution of nodal metastases in a contemporary radical prostatectomy series.

PURPOSE: We determined the frequency and distribution of metastases to pelvic lymph nodes in a contemporary American radical prostatectomy series. MATERIALS AND METHODS: In 642 consecutive patients with clinically localized prostate cancer treated by a single surgeon between 2002 and 2009 pelvic lymph nodes were removed and submitted to the pathologist in separate packets (external iliac, obturator and hypogastric). We assessed the total number of nodes and the number with metastases in each packet. RESULTS: Complete pathological information was available for 427 patients, who had a median of 16 lymph nodes removed. Of the patients 35 (8.2%) had lymph node metastases, including 1.7% with low, 8.6% with intermediate and 23.9% with high risk cancer. Of those with nodal metastases 24 (69%) had positive lymph nodes in only 1 of the 3 areas, including the external iliac in 4 (11%), the obturator in 9 (26%) and the hypogastric in 11 (31%). Only 37% of the patients had positive nodes only in the external iliac area above the obturator nerve while 60% and 49% had at least 1 positive node in the obturator and the hypogastric area, respectively. Of the patients 80% had only 1 (49%) or 2 (31%) positive nodes. CONCLUSIONS: In contemporary American patients with clinically localized prostate cancer lymph node metastases were found more often and frequently exclusively in the obturator and hypogastric areas than in the external iliac area. Pelvic lymph node dissection limited to the external iliac area above the obturator nerve would identify and remove lymph node metastases in only a third of the patients with positive nodes found at full pelvic lymph node dissection.

Urine survivin as a diagnostic biomarker for bladder cancer: a systematic review.

What's known on the subject? and What does the study add? Although many tests for identifying patients with new or recurrent bladder cancer have been used, a reliable method has yet to be established. Recently, increasing attention has focused on the role of survivin in bladder cancer detection. Because urine survivin tests have better sensitivity than cytology, urine survivin could potentially replace routine cytology and might be used as an adjunct method for cystoscopy. However, the clinical utility of urine survivin as a bladder tumour marker identified in the present study remains to be elucidated. To determine the clinical utility of urine survivin as a bladder tumour marker we systematically reviewed the available evidence. A comprehensive literature review was performed, from August 1997 to March 2011, using three search engines in English including PubMed, Cochrane Library, and SCOPUS. Two reviewers independently evaluated both trial eligibility and methodological quality and data extraction. We included studies that evaluated urine survivin, used cystoscopy and/or histopathology as the reference standard, and allowed the construction of a 2 × 2 contingency table. Bivariate random effect meta-analyses were used to calculate the summary estimated of sensitivity and specificity and to construct a summary receiver-operating characteristics curve of urine survivin tests. In all, 14 studies were included in the present review; two studies had two subsets of data. There were 2051 subjects, including 1038 in the case group and 1013 in the control group, and heterogeneity was present among diagnostic studies. The pooled sensitivity and specificity for urine survivin tests were 0.772 (95% confidence interval [CI] 0.745-0.797) and 0.918 (95% CI 0.899-0.934), respectively. The area under the curve of urine survivin tests was 0.9392. When a subgroup analysis with six studies was performed, urine survivin tests had better sensitivity than cytology, but did not match cytology for specificity. The clinical utility of urine survivin as a bladder tumour marker identified in the present study remains to be elucidated.

Combining imaging and ureteroscopy variables in a preoperative multivariable model for prediction of muscle-invasive and non-organ confined disease in patients with upper tract urothelial carcinoma.

OBJECTIVE: To create a preoperative multivariable model to identify patients at risk of muscle-invasive (pT2+) upper tract urothelial carcinoma (UTUC) and/or non-organ confined (pT3+ or N+) UTUC (NOC-UTUC) who potentially could benefit from radical nephroureterectomy (RNU), neoadjuvant chemotherapy and/or an extended lymph node dissection. PATIENTS AND METHODS: We retrospectively analysed data from 324 consecutive patients treated with RNU between 1995 and 2008 at a tertiary cancer centre. Patients with muscle-invasive bladder cancer were excluded, resulting in 274 patients for analysis. Logistic regression models were used to predict pT2+ and NOC-UTUC. Pre-specified predictors included local invasion (i.e. parenchymal, renal sinus fat, or periureteric) on imaging, hydronephrosis on imaging, high-grade tumours on ureteroscopy, and tumour location on ureteroscopy. Predictive accuracy was measured by the area under the curve (AUC). RESULTS: The median follow-up for patients without disease recurrence or death was 4.2 years. Overall, 49% of the patients had pT2+, and 30% had NOC-UTUC at the time of RNU. In the multivariable analysis, only local invasion on imaging and ureteroscopy high grade were significantly associated with pathological stage. AUC to predict pT2+ and NOC-UTUC were 0.71 and 0.70, respectively. CONCLUSIONS: We designed a preoperative prediction model for pT2+ and NOC-UTUC, based on readily available imaging and ureteroscopic grade. Further research is needed to determine whether use of this prediction model to select patients for conservative management vs RNU, neoadjuvant chemotherapy, and/or extended lymphadenectomy will improve patient outcomes.

Infant prostatic Rhabdomyosarcoma: A diagnostic and therapeutic challenge.

The following case report describes a case of prostatic rhabdomyosarcoma in a 6-month-old male who presented with urinary retention and constipation. MRI showed a prostatic mass that was displacing the rectum and bladder, leading to bladder outlet obstruction. A suprapubic tube was placed for urinary diversion and a transvesical approach was used for tissue diagnosis. Biopsy confirmed the diagnosis of prostatic rhabdomyosarcoma. Patient underwent chemotherapy regiment with VAC (vincristine, actinomycin D and cyclophosphamide) and subsequently ifosfamide and doxorubicin. Eventually, due to tumor progression, the patient underwent a radical cystoprostatectomy with pelvic lymph node dissection and ileal conduit.

Prefrontal Cortex and Hippocampus Inflammation in Mice Fed High-Carbohydrate or High-Fat Diets.

We previously reported that a high-carbohydrate diet (HCD) induced systemic inflammation and higher gene expression of proinflammatory mediators in the liver, skeletal muscle, and brain than a high-fat diet (HFD). However, the differences between the groups were less pronounced in the brain. In this study, we extended the evaluation of inflammation to specific areas of the brain. In this study, we evaluated the gene expression of caspase 2, caspase 3, caspase 9, cyclooxygenase-2 (Cox 2), inducible nitric oxide synthase (iNOS), interleukin (IL), IL-6, IL-1ß, IL-10, IL-4, tumor necrosis factor-alpha (TNF-α), integrin subunit alpha m (Itgam), S100 protein (S100), allograft inflammatory factor 1 (Aif1), and glial fibrillary acidic protein (Gfap) in the prefrontal cortex and hippocampus of male Swiss mice that were fed with HCD or HFD for 8 weeks. The HCD group exhibited higher IL-1ß expression, whereas the HFD group showed higher TNF-α expression in the prefrontal cortex. In the hippocampus, TNF-α expression was higher in the HFD group. IL-1ß and TNF-α are proinflammatory cytokines that have been associated with impaired brain function and numerous brain disorders. Our results indicate that both HCD and HFD promote prefrontal cortex inflammation; however, the hippocampus seems more sensitive to a HFD than HCD.