Current advances in BCG-unresponsive non-muscle invasive bladder cancer.

Introduction: The current first line therapy for high grade (HG) non-muscle invasive bladder cancer (NMIBC) is intravesical Bacillus Calmette-Guerin (BCG). Patients who recur or progress despite BCG are recommended to undergo radical cystectomy or participate in clinical trials. There is an urgent need for alternative therapies in the BCG-unresponsive NMIBC realm. Areas covered: We queried clinicaltrials.gov and pubmed.gov for current and recently completed early clinical trials pertaining to investigational agents used for the treatment of BCG-unresponsive NMIBC. These included intravesical chemotherapy, immunotherapy, vaccines, gene therapy, viruses, and agents used with novel drug delivery methods. In this article, we discuss the treatment guidelines for non-muscle invasive bladder cancer and therapeutic approaches under investigation in clinical trials. Expert opinion: The FDA is currently allowing single-arm studies as a pathway for approval in BCG-refractory patients with CIS. Although many agents are currently undergoing testing, none have been approved since Valrubicin. Hopefully, we will identify therapies sufficiently effective and durable to achieve FDA approval. Other considerations in this realm include the use of biomarkers in NMIBC to identify patients who will most likely respond to specific interventions. In addition, as systemic agents such as checkpoint inhibitors, are studied further, a multidisciplinary approach may be needed to treat this subset of patients.

Molecular Predictors of Complete Response Following Neoadjuvant Chemotherapy in Urothelial Carcinoma of the Bladder and Upper Tracts.

Urothelial carcinoma of the bladder (UCB) and upper tracts (UTUC) is often regarded as one entity and is managed generally with similar principles. While neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC) is an established standard of care in UCB, strong evidence for a similar approach is lacking in UTUC. The longest survival is seen in patients with complete response (pT0) on pathological examination of the RC specimen, but impact of delayed RC in nonresponders may be detrimental. The rate of pT0 following NAC in UTUC is considerably lower than that in UCB due to differences in access and instrumentation. Molecular markers have been evaluated to try to predict response to chemotherapy to reduce unnecessary treatment and expedite different treatment for nonresponders. A variety of potential biomarkers have been evaluated to predict response to cisplatin based chemotherapy including DNA repair genes (ATM, RB1, FANCC, ERCC2, BRCA1, and ERCC1), regulators of apoptosis (survivin, Bcl-xL, and emmprin), receptor tyrosine kinases (EGFR and erbB2), genes involved in cellular efflux (MDR1 and CTR1), in addition to molecular subtypes (Basal, luminal, and p53-like). The current state of the literature on the prediction of response to NAC based on the presence of these biomarkers is discussed in this review.

National comparison of oncologic quality indicators between open and robotic-assisted radical cystectomy.

INTRODUCTION: Despite increased adoption of robotic-assisted radical cystectomy (RARC), no national data have validated its oncologic efficacy compared to the "standard" open radical cystectomy (ORC). Positive surgical margins (PSM) and lymph node (LN) yield during radical cystectomy (RC) have an established relationship with bladder cancer outcomes. Here, we propose these 2 as quality indicators for RC and assess their differences to compare the oncologic efficacy between RARC and ORC. METHODS: Using the National Cancer Data Base for the years 2010 to 2012, all patients who underwent ORC or RARC were analyzed. Baseline demographic and cancer stage information were compared as well as unadjusted rates of PSM and LN yield. Survival effect of each indicator was assessed. Using propensity score adjustment, rates of PSM and LN yield were compared between RARC and ORC. RESULTS: A total of 12,036 patients are included who underwent RC, 20% (2,397) of which were performed robotically. Percentage RARC of total RC increased from 16.2% to 23.3% over the 3 study years. Compared to ORC, patients who underwent RARC were no different in age but were more often men (78.4% vs. 73.6%, P<0.001), had less-advanced cancer stage, and were more likely to have received neoadjuvant chemotherapy (20.9% vs. 14.5%, P<0.001). Most RARC procedures were performed at academic medical centers (66.1%). Unadjusted rates of PSM were lower in the RARC group (10.8% vs. 13.2%, P = 0.002) whereas median LN yield was higher in RARC patients (16 [interquartile range 9, 25] vs. 11 [interquartile range 5, 19], P<0.001). After propensity score covariate adjustment, there was no significant difference in PSM rate between RARC and ORC (-1.12% difference, [95% CI:-2.8, 0.32%]. However, RARC was associated with a higher node yield (+3.32 LN, [95% CI: 2.61, 4.03]) than ORC (P<0.001). CONCLUSION: The RARC is becoming more prevalent. In a national cohort, RARC was performed more often on men, with lower stage cancer, who were more likely to receive neoadjuvant chemotherapy. Controlling for these factors, RARC had comparable PSM rates but slightly higher LN yield than ORC.

Congenital Central Hypoventilation Syndrome: Neurocognition Already Reduced in Preschool-Aged Children.

BACKGROUND: Congenital Central Hypoventilation Syndrome (CCHS) is a rare neurocristopathy characterized by severe hypoventilation and autonomic dysregulation, with typical presentation in the neonatal period, and deficient cognitive skills in school-aged patients. We hypothesized that younger (preschool) children with CCHS would also show neurocognitive delay and that CCHS-related physiologic factors would impact neurocognitive test results. METHODS: We studied developmental (Bayley) test results collected during routine clinical care in 31 children (mean age 25.0 ± 8.5 months; range, 6-40 months) with PHOX2B mutation-confirmed CCHS by comparing them with the normative reference mean from the Bayley standardization sample; we also examined associations between Bayley scores and CCHS disease-related factors. RESULTS: Preschool patients with CCHS fell significantly below the normative mean of 100 on Bayley indices of mental (mean, 83.35 ± 24.75) and motor (mean, 73.33 ± 20.48) development (P < .001 for both). Significantly lower Bayley mental and motor scores were associated with severe breath-holding spells, prolonged sinus pauses, and need for 24 h/d artificial ventilation. Lower Bayley motor scores were also associated with seizures. Bayley scores differed among children with the three most common polyalanine repeat expansion mutation genotypes (mental, P = .001; motor, P = .006), being essentially normal in children with the 20/25 genotype but significantly lower in the other genotype groups (P < .05). CONCLUSIONS: These results confirm neurodevelopmental impairment of CCHS preschoolers, with severity related to physiologic compromise and PHOX2B genotype. These findings suggest that adverse effects begin early in the disease process, supporting the need for neurodevelopmental monitoring and intervention from early infancy.

Determining peripheral skin temperature: subjective versus objective measurements.

AIM: Diseases that affect peripheral vasculature or neurological function can manifest with peripheral skin temperature abnormalities. This pilot study investigates the accuracy of current physical examination techniques and determines whether a hand-held infrared device can be used to estimate peripheral skin temperature and detect temperature disparities. METHODS: Comparison between traditional physical examination of hands/feet by 30 healthcare professionals and a hand-held infrared device was made in 12 individuals (ages 4-25 years; 5 with disorders affecting peripheral skin temperature). Thermal camera measurements served as the reference temperature for comparison. RESULTS: A total of 231 extremity examinations by healthcare professionals were analysed. Healthcare professionals correctly identified subjects with colder or warmer than normal peripheral temperature. Hand-held device measurements were significantly different than reference measurements, with the size of the temperature difference diverging significantly between hands (1.20°C) and feet (0.78°C). When analysing temperature disparities, healthcare professionals identified fewer clinically significant disparities (≥3.0°C) than the hand-held device (76% vs. 99%). CONCLUSION: Although different from reference temperatures, the hand-held infrared device provided a more accurate and objective method than traditional physical exam in identifying peripheral skin temperature asymmetries that may be related to chronic paediatric illness.

Ultra percutaneous dilation tracheotomy vs mini open tracheotomy. A comparison of tracheal damage in fresh cadaver specimens.

BACKGROUND: To compare the ultra percutaneous dilation tracheostomy (PDT) and mini open techniques (MOT) in randomized fixed and fresh cadavers. Assess degrees of damage to tracheal cartilage and mucosa via tracheal lumen and external dissection. METHOD: Comparative cadaver study was performed, tracheostomy was placed in 36 cadavers (16 fixed, 20 fresh) from July 2004 to December 2004, in University of Alberta, Canada. PDT (size 7) were placed by intensivist and MOT (size 7) otolaryngologist. Both fixed and fresh cadavers were randomized. Evaluation was done according to gender, ease of landmark, mucosal and cartilage injuries. RESULTS: Significant differences in mucosal injury (7 of 9 in UPDT VS 0 of 7 in MOT, p value 0.008), and cartilage injury (8 of 9 in UPDT VS 1 of 7 in MOT p value 0.012) were seen in fixed cadavers; and in fresh cadavers, mucosal injury (5 of 10 in UPDT VS 0 of 10 in MOT, p value 0.043), and cartilage injury (5 of 10 in UPDT VS 0 of 10 in MOT, p value 0.043). CONCLUSIONS: PDT resulted in severe damage to mucosa and cartilage, that might contribute to subglottic stenosis preventing decannulation. Considering the injury, MOT has better outcome than UPDT.

Prospective, randomized, open-label trial comparing the safety, efficacy, and tolerability of an acne treatment regimen with and without a probiotic supplement and minocycline in subjects with mild to moderate acne.

BACKGROUND: Systemic antibiotics are an effective treatment for acne vulgaris. However, intolerable side effects may invariably occur. OBJECTIVE: To determine whether probiotics reduce the side effects imparted by systemic antibiotics while working synergistically with the latter in treating inflammatory acne. METHODS: Forty-five 18- to 35-year-old females were randomly assigned to one of three arms in this prospective, open-label study. Group A received probiotic supplementation, whereas group B received only minocycline. Group C was treated with both probiotic and minocycline. Clinical and subjective assessments were completed at baseline and during the 2-, 4-, 8-, and 12-week follow-up visits. RESULTS: All patients demonstrated a significant improvement in total lesion count 4 weeks after treatment initiation (p < .001), with continued improvement seen with each subsequent follow-up visit (p < .01). At the 8- and 12-week follow-up visits, group C had a significant decrease in total lesion count versus groups A (p < .001) and B (p < .01). Two patients (13%) from group B failed to complete the study secondary to vaginal candidiasis. CONCLUSION: Probiotics may be considered a therapeutic option or adjunct for acne vulgaris by providing a synergistic antiinflammatory effect with systemic antibiotics while also reducing potential adverse events secondary to chronic antibiotic use.