Copy Number Alterations and Methylation in Ewing's Sarcoma

Ewing's sarcoma is the second most common bone malignancy affecting children and young adults. The prognosis is especially poor in metastatic or relapsed disease. The cell of origin remains elusive, but the EWS-FLI1 fusion oncoprotein is present in the majority of cases. The understanding of the molecular basis of Ewing's sarcoma continues to progress slowly. EWS-FLI1 affects gene expression, but other factors must also be at work such as mutations, gene copy number alterations, and promoter methylation. This paper explores in depth two molecular aspects of Ewing's sarcoma: copy number alterations (CNAs) and methylation. While CNAs consistently have been reported in Ewing's sarcoma, their clinical significance has been variable, most likely due to small sample size and tumor heterogeneity. Methylation is thought to be important in oncogenesis and balanced karyotype cancers such as Ewing's, yet it has received only minimal attention in prior studies. Future CNA and methylation studies will help to understand the molecular basis of this disease

Experiment for cryogenic large-aperture intensity mapping: instrument design

The experiment for cryogenic large-aperture intensity mapping (EXCLAIM) is a balloon-borne telescope designed to survey star formation in windows from the present to z  =  3.5. During this time, the rate of star formation dropped dramatically, while dark matter continued to cluster. EXCLAIM maps the redshifted emission of singly ionized carbon lines and carbon monoxide using intensity mapping, which permits a blind and complete survey of emitting gas through statistics of cumulative brightness fluctuations. EXCLAIM achieves high sensitivity using a cryogenic telescope coupled to six integrated spectrometers employing kinetic inductance detectors covering 420 to 540 GHz with spectral resolving power R  =  512 and angular resolution ≈4  arc min. The spectral resolving power and cryogenic telescope allow the survey to access dark windows in the spectrum of emission from the upper atmosphere. EXCLAIM will survey 305  deg2 in the Sloan Digital Sky Survey Stripe 82 field from a conventional balloon flight in 2023. EXCLAIM will also map several galactic fields to study carbon monoxide and neutral carbon emission as tracers of molecular gas. We summarize the design phase of the mission

Overactive bladder and urgency urinary incontinence in men undergoing artificial urinary sphincter placement

Purpose To assess persistent and de novo rates of overactive bladder (OAB) and urgency urinary incontinence (UUI) in patients with incontinence after prostate treatment (IPT) focusing on differences between surgical intervention vs radiation. Methods We performed a retrospective review of 79 patients who underwent primary artificial urinary sphincter (AUS) placement and activation from a single surgeon between February 2012 and November 2017. Four patients with neurogenic bladder were excluded and two with insufficient follow‐up. The primary outcome measures were persistent OAB, persistent UUI, and pad usage before and after AUS placement. Results After activation of the AUS, 67% of non‐radiated patients had resolution of urgency incontinence vs only 31% of the radiated patients (P = .096). After activation of the AUS, resolution of OAB symptoms was more common in the non‐radiated group. We found 53% of the non‐radiated group vs only 22% of the radiated group had resolution of their urinary urgency (P = .045). Previous history of radiation was a risk factor for OAB after implantation of AUS (odds ratio [OR], 3.63; P = .010). Postoperative oral medical pharmacotherapy for OAB was higher in those with previous radiation vs those without prior radiation (66.7% vs 25.7%, P = .001). A history of OAB or UUI did not affect social continence after AUS placement. Conclusion Radiation is a risk for continued OAB after AUS activation. Appropriate counseling is necessary pre‐ and postoperatively to manage patient expectations and provide additional medical therapies. Mixed urinary incontinence or OAB symptoms should not exclude patients from undergoing AUS placement

Robotic intracorporeal orthotopic neobladder in the supine Trendelenburg position: a stepwise approach

Robotic radical cystectomy with urinary diversion has become increasingly utilized for the surgical management of bladder cancer. Orthotopic neobladder reconstruction is still performed worldwide primarily via an extracorporeal approach because of the difficulty associated with robotic intracorporeal reconstruction. The objective of this article is to demonstrate a stepwise approach for robotic intracorporeal neobladder in a standardized manner that adheres to the principles of open surgery

Pediatric Kidney Transplantation Outcomes in Children with Primary Urological Abnormalities Versus Nonurological Abnormalities: Long-Term Results

We assessed renal function, graft survival rates and the risk of graft loss in children based on etiology with a focus on differences between urological causes from congenital anomalies of the kidney and urinary tract vs other causes of end stage kidney disease. A retrospective chart review was performed including patients younger than 18 years who underwent kidney transplantation at our institution from December 1984 to November 2010 with the last followup recorded in March 2018. Patient clinical characteristics, demographics and end stage kidney disease etiology were recorded. Patients were divided into the 2 groups of urological (congenital anomalies of the kidney and urinary tract) vs nonurological based on end stage kidney disease etiology, and survival analysis was performed. Of 112 kidney transplant cases 90 (80.4%) were associated with nonurological causes and 22 (19.6%) with urological causes. Median (IQR) patient age at transplantation was 12 (7-15) years. Median graft survival time was not statistically different according to end stage kidney disease etiology (nonurological 12 years 95% CI 10.01-13.99 vs urological 16 years 95% CI 7.59-24.41, p=0.532). There was a significant risk of graft loss in patients with urinary tract infections after transplantation (HR 3.15, 95% CI 1.59-6.25, p=0.001). Children requiring transplantation due to urological causes have no disadvantage in graft survival compared to children with end stage kidney disease with other causes. Patients with urinary tract infection after transplantation had a higher rate of graft loss

Molecular inversion probe analysis detects novel copy number alterations in Ewing sarcoma

Ewing sarcoma (ES) is the second most common bone tumor in children and young adults, with dismal outcomes for metastatic and relapsed disease. To better understand the molecular pathogenesis of ES and to identify new prognostic markers, we used molecular inversion probes (MIPs) to evaluate copy number alterations (CNAs) and loss of heterozygosity (LOH) in formalin-fixed paraffin-embedded (FFPE) samples, which included 40 ES primary tumors and 12 ES metastatic lesions. CNAs were correlated with clinical features and outcome, and validated by immunohistochemistry (IHC). We identified previously reported CNAs, in addition to SMARCB1 (INI1/SNF5) homozygous loss and copy neutral LOH. IHC confirmed SMARCB1 protein loss in 7–10% of clinically diagnosed ES tumors in three separate cohorts (University of Utah [N = 40], Children's Oncology Group [N = 31], and University of Michigan [N = 55]). A multifactor copy number (MCN)-index was highly predictive of overall survival (39% vs. 100%, P < 0.001). We also identified RELN gene deletions unique to 25% of ES metastatic samples. In summary, we identified both known and novel CNAs using MIP technology for the first time in FFPE samples from patients with ES. CNAs detected by microarray correlate with outcome and may be useful for risk stratification in future clinical trials