Citations

Abstract Introduction: Peripheral blood leukocyte (PBL) telomere length is associated with colon cancer (CC) risk, but the relationship of PBL telomere length to survival in CC patients receiving chemotherapy is unknown. Methods: We measured relative telomere length (RTL) by qPCR of PBL DNA from 2,748 cases (53% male, 85% white, median age 58 yrs) in the North American Phase III Intergroup Trial N0147 that compared disease-free survival (DFS) among completely resected Stage III CC treated with mFOLFOX6 +/- cetuximab. Tumor markers were assessed, and 12% were BRAF mutant; 35% Kras mutant, and 12% deficient mismatch repair (dMMR). Linear and non-linear prognostic associations of PBL RTL to the primary endpoint of DFS were assessed by Cox models. Optimal categories of RTL were developed using cumulative martingale residual plots, designated from shortest to longest RTL (Table 1). Results: Never smokers had longer PBL RTL (p = 0.0006) than past or current smokers. Those with diabetes mellitus (DM) had longer PBL RTL than those without DM (p = 0.0165). PBL RTL was not associated with any tumor markers (MMR status; p = 0.7174; BRAF mutant vs wild-type (wt); p =0.4039; Kras mutant vs wt; p= 0.1149). PBL RTL was significantly associated with DFS in a non-linear form (p = 0.0389). Cases in the longer RTL category had more favorable DFS than those with shorter or longest RTL, (Table), which remained after adjusting for age, sex , T/N stage, grade, tumor markers, and treatment (p = 0.0230). We observed no significant interaction (p = 0.1490) between RTL categories and treatment. Conclusion: We observed a non-linear association between RTL and DFS in stage III CC, suggesting that an optimal range telomere length can influence tumor behavior in CC patients. Future studies of telomere maintenance mechanisms may help to explain the association of RTL with improved DFS. RTL is associated with smoking and DM in CC cases but further studies are needed to determine if either tobacco use or DM affect survival from CC by modulating PBL telomere length. Citation Format: Nivedita Basu, Ruth A. Johnson, Qian Shi, Garth D. Nelson, Julie M. Cunningham, Richard M. Goldberg, Frank A. Sinicrope, Daniel J. Sargent, Steven R. Alberts, Gloria M. Petersen, Stephen N. Thibodeau, Halcyon G. Skinner, Kristin Litzelman, Songwon Seo, Russell J. Vanderboom, Ronald E. Gangnon, Corinne D. Engelman, David N. Rider, Lisa A. Boardman. Telomeres and survival in stage III colon cancers: Findings from NCCTG N0147 (Alliance) study. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5102. doi:10.1158/1538-7445.AM2014-5102

Abstract BACKGROUND. Proteosome inhibition is associated with induction of the proapoptotic BH3 protein NOXA. Therefore, we hypothesize that the combination of the irreversible proteosome inhibitor, carfilzomib, will cooperatively enhance apoptosis induction by the BH3 mimetic drug, ABT-263. Given that nononcogenic addiction to proteosome activity has been reported in KRAS mutant cells, we utilized isogenic colorectal cancer (CRC) cell lines in which the endogenous wild-type (wt) or mutant alleles had been inactivated through targeted homologous recombination. Since proteasome blockade results in proteotoxic stress, we determined whether an autophagy inhibitor can enhance chemosensitivity. EXPERIMENTAL METHODS. Isogenic KRAS mutant (MUT) CRC cells (HCT116, DLD1; obtained from B. Vogelstein, JHU) were incubated with carfilzomib (25,50nM) alone or combined with ABT-263 (1 µM) and apoptosis was measured by caspase cleavage and annexin V+ labeling. Synergy was measured by calculation of the combination index. Effect of carfilzomib on Bcl-2 family proteins was determined by immunoblotting. Interaction of NOXA with MCL-1 was examined by immunoprecipitation. Knockdown of NOXA was achieved by lentiviral shRNA. Cells were incubated with drugs alone or combined with chloroquine, and autophagy (LC3I/II conversion) and apoptosis were analyzed. RESULTS. Carfilzomib was shown to potently and synergistically enhance ABT-263-induced apoptosis (2-fold) in both KRAS MUT and wild type (WT) cell lines, with the effect being modestly higher in wild type cells, as shown by annexin V+ staining and caspase cleavage. Carfilzomib induced NOXA expression in both KRAS MUT and WT cells, and reduced MCL-1 expression. Induced NOXA was shown to bind and sequester MCL-1 proteins. Knockdown of NOXA attenuated drug-induced apoptosis. Autophagy inhibition by chloroquine accumulated LC3II, but only modestly increased carfilzomib-induced cell death. CONCLUSION. Irreversible proteasome inhibition by carfilzomib synergistically enhanced ABT-263-induced cell death that is mediated by NOXA upregulation and its sequestration/neutralization of MCL-1. The finding of similar efficacy in KRAS MUT vs WT cells suggests that this combination may represent a novel therapeutic strategy in this tumor subset. Citation Format: Shengbing Huang, Koichi Okamoto, Frank A. Sinicrope. Carfilzomib synergistically enhances ABT-263-induced apoptosis due to NOXA induction in KRAS wild type and mutant colorectal cancer cell lines. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 337. doi:10.1158/1538-7445.AM2014-337

The relation between somatosensory mechanisms and self-injury among children with neurologic impairments associated with developmental delay is not well understood. We evaluated the feasibility of procuring skin biopsies to examine epidermal nerve fiber density and reported self-injury. Following informed parental consent, epidermal skin biopsies were obtained from a distal leg site with no pre-existing skin damage from 11 children with global developmental delay (55% male; mean age = 36.8 months, 17-63 months). Visual microscopic examination and quantitative analyses showed extremely high epidermal nerve fiber density values for some children. Children with reported self-injury (5/11) had significantly ( P < .02) greater density values (138.8, standard deviation = 45.5) than children without self-injury (80.5, standard deviation = 17.5). Results from this novel immunohistologic analysis of skin in very young children with neurodevelopmental delays suggest it may be a useful tool to study peripheral innervation as a possible sensory risk factor for self-injury.

AbstractObjectivesChest pain is a common complaint to emergency departments (EDs) and clinical risk factors are used to predict which patients are at risk for worse outcomes and mortality. The goal was to assess the novel biomarker midregional proadrenomedullin (MR‐proADM) in prediction of mortality and major adverse cardiac events (MACE).MethodsThis was a subanalysis of the CHOPIN study, a 16‐center prospective trial that enrolled 2,071 patients presenting with chest pain within 6 hours of onset. The primary endpoint was 6‐month all‐cause mortality and the secondary endpoint was 30‐day and 6‐month MACE: ED visits or hospitalization for acute myocardial infarction, unstable angina, reinfarction, revascularization, and heart failure.ResultsMR‐proADM performed similarly to troponin (cTnI; c‐statistic = 0.845 and 0.794, respectively) for mortality prediction in all subjects and had similar results in those with noncardiac diagnoses. MR‐proADM concentrations were stratified by decile, and the cohort in the top decile had a 9.8% 6‐month mortality risk versus 0.9% risk for those in the bottom nine deciles (p < 0.0001). MR‐proADM, history of coronary artery disease (CAD), and hypertension were predictors of short‐term MACE, while history of CAD, hypertension, cTnI, and MR‐proADM were predictors of long‐term MACE.ConclusionsIn patients with chest pain, MR‐proADM predicts mortality and MACE in all‐comers with chest pain and has similar prediction in those with a noncardiac diagnosis. This exploratory analysis is primarily hypotheses‐generating and future prospective studies to identify its utility in risk stratification should be considered.

ObjectivesTo evaluate the differences in estimated glomerular filtration rate decline by urinary diversion type (incontinent diversion vs continent diversion) and preoperative estimated glomerular filtration rate among patients undergoing radical cystectomy and urinary diversion.MethodsWe evaluated 1383 patients treated with radical cystectomy between 1980–2006 who had a preoperative estimated glomerular filtration rate of 45‐89 mL/min/1.73 m2. Estimated glomerular filtration rate was estimated using Chronic Kidney Disease Epidemiology Collaboration equations, and patients were stratified by preoperative estimated glomerular filtration rate into chronic kidney disease 2 (estimated glomerular filtration rate 60–89 mL/min/1.73 m2) and chronic kidney disease 3a (estimated glomerular filtration rate 45–59 mL/min/1.73 m2). Multiple definitions of estimated glomerular filtration rate decline were evaluated: (i) 10‐point decline in estimated glomerular filtration rate; (ii) 20% decline in estimated glomerular filtration rate; and (iii) 10% decline in estimated glomerular filtration rate. Time to estimated glomerular filtration rate decline was compared using the Kaplan–Meier method stratified by diversion type. Cox regression models were used to evaluate the association of diversion type with estimated glomerular filtration rate decline risk.ResultsIn total, 74% (1021/1383) of patients underwent incontinent diversion and 26% (362/1383) underwent continent diversion. Preoperative chronic kidney disease 2 and chronic kidney disease 3a were noted among 59% and 41% of patients who underwent incontinent diversion, versus 74% and 26% with continent diversion. Median follow up after RC was 11.2 years. The rate of estimated glomerular filtration rate decline in patients with incontinent diversion versus continent diversion was similar when stratified by preoperative chronic kidney disease 2 and preoperative chronic kidney disease 3a, regardless of estimated glomerular filtration rate decline definition. On multivariable analysis, continent diversion was not associated with estimated glomerular filtration rate decline for patients with preoperative chronic kidney disease 3a.ConclusionsThe risk of estimated glomerular filtration rate decline over 10 years was not significantly different after incontinent diversion versus continent diversion among patients with preoperative chronic kidney disease 2 or chronic kidney disease 3a. Continent diversion does not appear to confer an independently increased risk of estimated glomerular filtration rate decline in patients with preoperative chronic kidney disease 3a.

Dynamic loading on articular joints is essential for the evaluation of the risk of the articulation degeneration associated with occupational activities. In the current study, we analyzed the dynamic constraint loading for the thumb during pipetting. The constraint loading is considered as the loading that has to be carried by the connective tissues of the joints (i.e., the cartilage layer and the ligaments) to maintain the kinematic constraints of the system. The joint loadings are solved using a classic free-body approach, using the external loading and muscle forces, which were obtained in an inverse dynamic approach combined with an optimization procedure in anybody. The constraint forces in the thumb joint obtained in the current study are compared with those obtained in the pinch and grasp tests in a previous study (Cooney and Chao, 1977, “Biomechanical Analysis of Static Forces in the Thumb During Hand Function,” J. Bone Joint Surg. Am., 59(1), pp. 27–36). The maximal compression force during pipetting is approximately 83% and 60% greater than those obtained in the tip pinch and key pinch, respectively, while substantially smaller than that obtained during grasping. The maximal lateral shear force is approximately six times, 32 times, and 90% greater than those obtained in the tip pinch, key pinch, and grasp, respectively. The maximal dorsal shear force during pipetting is approximately 3.2 and 1.4 times greater than those obtained in the tip pinch and key pinch, respectively, while substantially smaller than that obtained during grasping. Our analysis indicated that the thumb joints are subjected to repetitive, intensive loading during pipetting, compared to other daily activities.

Background and aim Although Non-steroidal anti-inflammatory drugs reduce colorectal adenoma burden in familial adenomatous polyposis (FAP), the utility of combining chemopreventive agents in FAP is not known. We conducted a randomised trial of celecoxib (CXB) versus CXB+diflouromethylornithine (DFMO) to determine the synergistic effect, if any. Methods The primary endpoint was % change in adenoma count in a defined field. Secondary endpoints were adenoma burden (weighted by adenoma diameter) and video review of entire colon/rectal segments. Adverse event (AEs) were monitored by National Cancer Institution toxicity criteria. Results 112 subjects were randomised: 60 men and 52 women at a mean age of 38 years. For the 89 patients who had landmark-matched polyp counts available at baseline and 6 months, the mean % change in adenoma count over the 6 months of trial was −13.0% for CXB+DFMO and −1.0% for CXB (p=0.69). Mean % change in adenoma burden was −40% (CXB+DFMO) vs −27% (CXB) (p=0.13). Video-based global polyp change was −0.80 for CXB+DFMO vs −0.33 for CXB (p=0.03). Fatigue was the only significant AE, worse on the CXB arm (p=0.02). Conclusions CXB combined with DFMO yielded moderate synergy according to a video-based global assessment. No significant difference in adenoma count, the primary endpoint, was seen between the two study arms. No evidence of DFMO-related ototoxicity was seen. There were no adverse cardiovascular outcomes in either trial arm and no significant increase in AEs in the CXB+DFMO arm of the trial. Differences in outcomes between primary and secondary endpoints may relate to sensitivity of the endpoint measures themselves. Trial registration number ClinicalTrials.gov number N01-CN95040.

ObjectiveTo review our experience with radical cystectomy for small cell carcinoma of the bladder, to compare outcomes with a cohort of patients with urothelial carcinoma, and to determine the effect of adjuvant chemotherapy and pathology re‐review in this setting.MethodsAmong 2427 patients who underwent radical cystectomy, 68 patients had small cell carcinoma of the bladder. Patients with small cell carcinoma of the bladder were compared with an unmatched cohort of 1146 patients with urothelial carcinoma, and were then matched (1:2) based on TNM stage. Survival was estimated using the Kaplan–Meier method, and Cox models were used to evaluate association of clinicopathological features with outcome.ResultsAmong the 68 small cell carcinoma of the bladder patients, 37 (54%) were found to have small cell carcinoma of the bladder only after pathology re‐review. Patients with small cell carcinoma of the bladder had a higher rate of advanced (pT3/4) tumor stage (84% vs 46%; P < 0.0001) and pN+ disease (37% vs 20%; P = 0.001) compared with patients with urothelial carcinoma. When matched for stage and lymph node status, no significant difference in 5‐year cancer‐specific survival was observed between the two groups (27% vs 29%; P = 0.64). Among small cell carcinoma of the bladder patients, those receiving adjuvant chemotherapy had improved 5‐year overall survival compared with patients who did not receive adjuvant chemotherapy (43% vs 20%; P = 0.03), and a trend toward superior cancer‐specific survival (40% vs 23%; P = 0.07).ConclusionsSmall cell carcinoma of the bladder is often an unrecognized pathological entity, which is associated with a higher rate of locally advanced and N+ disease. However, although when matched for pathological features, survival outcomes appear similar to urothelial carcinoma. Small cell carcinoma of the bladder patients receiving adjuvant chemotherapy had improved overall survival and cancer‐specific survival, and these results require further investigation.

Background: Vascular invasion (VI) is an important predictor of distant metastasis and possible radioactive iodine (RAI) benefit in follicular, Hürthle cell, and poorly differentiated thyroid carcinomas, but its role in well-differentiated papillary thyroid cancer (WDTC) remains unclear. Methods: Archived pathological material of all differentiated thyroid carcinoma patients undergoing primary surgical treatment at Memorial Sloan-Kettering Cancer Center between 1986 and 2003 was reviewed by two dedicated thyroid pathologists. Only WDTCs were included in the present study. Standard statistical methods were used to assess the relationship between VI and outcomes of interest, including 10-year disease-specific survival (DSS), regional recurrence-free survival (RRFS), and distant recurrence-free survival (DRFS). Results: VI was present in 47 of 698 WDTC (6.7%). VI was significantly associated with tumor size >4.0 cm, extrathyroidal extension, distant metastasis, and RAI treatment. On univariate analysis, VI was predictive of decreased 10-year DRFS, but not DSS or RRFS. On multivariate analysis, VI was not an independent predictor of DRFS. Univariate survival analysis of 422 RAI-naïve WDTC showed that both size >4 cm and VI were predictors of outcome, but only size remained independently predictive on multivariate analysis. Conclusion: The presence of VI is not an independent predictor of outcome in WDTC.