Citations

Key PointsPhenotypic and genotypic profiling of MDM2 in DLBCL. MDM2 as a negative regulator of p53 tumor suppressor function.

Objective To assess recommendations for prostate‐specific antigen ( PSA ) screening in a national survey of radiation oncologists and urologists following the recent USA P reventive S ervices T ask F orce ( USPSTF ) grade D recommendation. Methods A random sample of 1366 radiation oncologists and urologists were identified from the A merican M edical A ssociation P hysician M asterfile. From N ovember 2011 to A pril 2012, a mail survey was sent to query PSA screening recommendations for men at average risk of prostate cancer for the following age groups: 40–49, 50–59, 60–69, 70–74, 75–79 and ≥80 years. Multivariable logistic regression was used to test for differences in PSA ‐based screening recommendations by physician characteristics. Results Response rates were similar at 52% for radiation oncologists and urologists ( P = 0.92). Overall, 51.5% of respondents recommended PSA ‐based screening for men aged 40–49 years, while nearly all endorsed it for those aged 50–74 years (96.1% for 50–59, 97.3% for 60–69, and 87.7% for 70–74 years). However, screening recommendations decreased to 43.9% and 12.8% for men aged 75–79 and ≥80 years, respectively. On multivariable analysis, urologists were more likely to recommend screening for men aged 40–49 (odds ratio [ OR ] 3.09; P < 0.001) and 50–59 years ( OR 3.81; P = 0.01), but less likely for men aged 75–79 ( OR 0.66; P = 0.01) and ≥80 years ( OR 0.45; P = 0.002) compared with radiation oncologists. Conclusion While radiation oncologists and urologists recommended PSA screening for men aged 50–69 years, there was less agreement about screening for younger (40–49 years old) and older (≥70 years) men at average risk for prostate cancer.

Objectives/Hypothesis Pediatric obstructive sleep apnea syndrome ( OSAS ) is a common disorder with serious clinical implications if left untreated. The recommended initial treatment for pediatric patients with obstructive sleep apnea syndrome ( OSAS ) is adenotonsillectomy. However, recent reports have shown variable surgical results with adenotonsillectomy in the treatment of pediatric OSAS . Study Design Prospective, controlled study. Methods From April 2007 to August 2010, 24 participants were assigned alternatively to either adenotonsillectomy with pillar suturing (intervention group) or adenotonsillectomy alone (control group). Result The average improvement in apnea hypopnea index ( AHI ) was 42.6% in the control group and 79.9% in the intervention group ( P =0.037). The success rate was 50% in the control group and 91.6% in the intervention group ( P =0.034). Six patients (50%) in the intervention group achieved complete resolution of pediatric OSAS , as defined by an AHI <1/hour, compared to 2 patients (16.7%) in the control group ( P =0.097). Conclusion Adenotonsillectomy with pillar suturing showed significant improvement in treating pediatric patients with OSAS compared to adenotonsillectomy alone. The procedure is simple and safe. Level of Evidence 4. Laryngoscope , 123:2574–2578, 2013

SummaryBackgroundNeuronal loss via apoptosis in CNS is the fundamental mechanism underlying various neurodegenerative diseases. Compounds with antiapoptotic property might have therapeutic effects for these diseases. In this study, bis(propyl)‐cognitin (B3C), a novel dimer that possesses anti‐AChE and anti‐N‐methyl‐d‐aspartate receptor activities, was investigated for its neuroprotective effect on K+ deprivation‐induced apoptosis in cerebellar granule neurons (CGNs).MethodsCerebellar granule neurons were switched to K+ deprived medium with or without B3C. 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium assay, fluorescein diacetate (FDA)/propidium iodide (PI) staining, Hoechst staining, and DNA laddering assays were applied to detect cytotoxicity and apoptosis. Additionally, the expression of p‐VEGFR‐2, p‐Akt, p‐glycogen synthase kinase 3β (GSK3β), and p‐extracellular signal‐regulated kinase (ERK) was examined in CGNs.ResultsSwitching CGNs to K+ deprived medium resulted in remarkable apoptosis, which could be substantially blocked by B3C treatment (IC50, 0.37 μM). Moreover, a rapid decrease in p‐Tyr1054‐VEGFR‐2 was observed after the switch. B3C significantly reversed the inhibition of p‐Tyr1054‐VEGFR‐2 as well as Akt and ERK pathways. VEGFR‐2 inhibitor PTK787/ZK222584, as well as PI3‐K inhibitor LY294002 and MEK inhibitor PD98059, each abolished the neuroprotective effect of B3C.ConclusionsOur results demonstrate that B3C blocks K+ deprivation‐induced apoptosis in CGNs through regulating VEGFR‐2/Akt/GSK3β and VEGFR‐2/ERK signaling pathways, providing a molecular insight into the therapeutic potential of B3C for the treatment of neurodegenerative diseases.

Abstract Purpose: We set out to identify Stearoyl-CoA desaturase 1 (SCD1) as a novel molecular target in clear cell renal cell carcinoma (ccRCC) and examine its role in tumor cell growth and viability in vitro and in vivo independently as well as in combination with current U.S. Food and Drug Administration (FDA)-approved regimens. Experimental Design: Patient normal and ccRCC tissue samples and cell lines were examined for SCD1 expression. Genetic knockdown models and targeted inhibition of SCD1 through use of a small molecule inhibitor, A939572, were analyzed for growth, apoptosis, and alterations in gene expression using gene array analysis. Therapeutic models of synergy were evaluated utilizing pharmacologic inhibition of SCD1 with the tyrosine kinase inhibitors (TKI) sunitinib and pazopanib, and the mTOR inhibitor temsirolimus. Results: Our studies identify increased SCD1 expression in all stages of ccRCC. Both genetic knockdown and pharmacologic inhibition of SCD1 decreased tumor cell proliferation and induced apoptosis in vitro and in vivo. Upon gene array, quantitative real-time PCR, and protein analysis of A939572-treated or SCD1 lentiviral knockdown samples, induction of endoplasmic reticulum stress response signaling was observed, providing mechanistic insight for SCD1 activity in ccRCC. Furthermore, combinatorial application of A939572 with temsirolimus synergistically inhibited tumor growth in vitro and in vivo. Conclusions: Increased SCD1 expression supports ccRCC viability and therefore we propose it as a novel molecular target for therapy either independently or in combination with an mTOR inhibitor for patients whose disease cannot be remedied with surgical intervention, such as in cases of advanced or metastatic disease. Clin Cancer Res; 19(9); 2368–80. ©2013 AACR.

Objective To describe the extent of use and in‐hospital outcomes of open and laparoscopic pyeloplasty for paediatric pelvi‐ureteric junction ( PUJ ) obstruction in the USA . Patients and Methods Using the 2004–2008 N ationwide I npatient S ample, we identified 4590 paediatric patients (≤18 years old) who underwent open or laparoscopic pyeloplasty for PUJ obstruction at 195 hospitals. Multivariable regression models were used to test the associations between hospital and patient covariates (age, gender, race, primary health insurance), type of admission (emergent vs elective), and hospital characteristics (teaching vs non‐teaching status; rural vs urban location) with complications, length of stay ( LOS ), and total hospitalization costs. Results During the 5‐year study interval, 4426 (96.4%) and 164 (3.6%) paediatric patients diagnosed with PUJ obstruction underwent open and laparoscopic pyeloplasty, respectively. The proportion of patients undergoing laparoscopic pyeloplasty gradually increased from 2.4% in 2004 to 4.4% in 2008, but this increase was not significant ( P = 0.22 for trend). On multivariable analysis, laparoscopic pyeloplasty was observed to have rates of postoperative complications (2.51 vs 5.00; P = 0.67), LOS (2.42 vs 2.75; P = 0.33) and total hospitalization cost ($9755 vs $8537; P = 0.24) similar to those of open pyeloplasty. Conclusions While laparoscopic pyeloplasty was generally an infrequent operation performed for paediatric PUJ obstruction during the period studied, this minimally invasive surgery provided similar outcomes in terms of in‐hospital complications, LOS and total hospitalization costs. The results of this study inform policymakers about the comparative effectiveness of laparoscopic and open pyeloplasty.

Key Points Lenalidomide consolidation repairs T-cell immune synapses in CLL patients. Lenalidomide consolidation improved the quality of response in CLL patients treated with chemoimmunotherapy.

What's known on the subject? and What does the study add? Variations in the type of urinary diversion exist for patients undergoing radical cystectomy. Although its use has been increasing from 2001 to 2008, patients who are older, female, and primary insured by Medicaid are less likely to receive continent diversions. Furthermore, patients treated surgically at high‐volume and teaching hospitals are more likely to receive continent diversions. Objective To describe the contemporary trends in urinary diversion among patients undergoing radical cystectomy ( RC ) for bladder cancer; and elucidate whether socioeconomic disparities persist in the type of diversion performed in the USA from a population‐based cohort. Patients and Methods Using the Nationwide Inpatient Sample, we identified patients who underwent RC for bladder cancer between 2001 and 2008. Multivariable regression models were used to identify patient and hospital covariates associated with continent urinary diversion and enumerate predicted probabilities for statistically significant variables over time. Results Overall, 55 635 (92%) patients undergoing RC for bladder cancer received incontinent urinary diversion, while 4552 (8%) patients received continent diversion from 2001 to 2008. Receipt of continent urinary diversion increased from 6.6% in 2001–2002 to 9.4% in 2007–2008 ( P < 0.001 for trend). Patients who were older (odds ratio [ OR ] 0.93; P < 0.001), female ( OR 0.52; P < 0.001) and insured by Medicaid ( OR 0.54; P = 0.002) were less likely to receive continent urinary diversion. However, patients treated at teaching ( OR 2.14; P < 0.001) and high‐volume hospitals ( OR 2.39; P = 0.04) had higher odds of continent urinary diversion. Predicted probabilities of continent diversion remained lower for female patients, Medicaid insurance status, and non‐teaching and medium/low‐volume hospitals over time. Conclusions In this nationally representative sample of hospitals from 2001 to 2008, the use of continent diversion in RC gradually increased. Although variations in urinary diversion exist by hospital teaching status, case volume, patient gender and primary health insurance, increased attention in expanding the use of continent diversions may help reduce these disparities for patients undergoing RC for bladder cancer.

ObjectiveChildren with childhood‐onset rheumatoid arthritis (RA) include those with rheumatoid factor or anti–citrullinated protein antibody–positive juvenile idiopathic arthritis. To test the hypothesis that adult‐onset RA–associated variants are also associated with childhood‐onset RA, we investigated RA‐associated variants at 5 loci in a cohort of patients with childhood‐onset RA. We also assessed the cumulative association of these variants in susceptibility to childhood‐onset RA using a weighted genetic risk score (wGRS).MethodsA total of 155 children with childhood‐onset RA and 684 healthy controls were genotyped for 5 variants in the PTPN22, TRAF1/C5, STAT4, and TNFAIP3 loci. High‐resolution HLA–DRB1 genotypes were available for 149 cases and 373 controls. We tested each locus for association with childhood‐onset RA via logistic regression. We also computed a wGRS for each subject, with weights based on the natural log of the published odds ratios (ORs) for the alleles investigated, and used logistic regression to test the wGRS for association with childhood‐onset RA.ResultsChildhood‐onset RA was associated with TNFAIP3 rs10499194 (OR 0.60 [95% confidence interval 0.44–0.83]), PTPN22 rs2476601 (OR 1.61 [95% confidence interval 1.11–2.31]), and STAT4 rs7574865 (OR 1.41 [95% confidence interval 1.06–1.87]) variants. The wGRS was significantly different between cases and controls (P < 2 × 10−16). Individuals in the third to fifth quintiles of wGRS had a significantly increased disease risk compared to baseline (individuals in the first quintile). Higher wGRS was associated with increased risk of childhood‐onset RA, especially among males.ConclusionThe magnitude and direction of the association between TNFAIP3, STAT4, and PTPN22 variants and childhood‐onset RA are similar to those observed in RA, suggesting that adult‐onset RA and childhood‐onset RA share common genetic risk factors. Using a wGRS, we have demonstrated the cumulative association of RA‐associated variants with susceptibility to childhood‐onset RA.