Citations

Purpose To characterize reporting of P values, confidence intervals (CIs), and statistical power in health professions education research (HPER) through manual and computerized analysis of published research reports. Method The authors searched PubMed, Embase, and CINAHL in May 2016, for comparative research studies. For manual analysis of abstracts and main texts, they randomly sampled 250 HPER reports published in 1985, 1995, 2005, and 2015, and 100 biomedical research reports published in 1985 and 2015. Automated computerized analysis of abstracts included all HPER reports published 1970–2015. Results In the 2015 HPER sample, P values were reported in 69/100 abstracts and 94 main texts. CIs were reported in 6 abstracts and 22 main texts. Most P values (≥77%) were ≤.05. Across all years, 60/164 two-group HPER studies had ≥80% power to detect a between-group difference of 0.5 standard deviations. From 1985 to 2015, the proportion of HPER abstracts reporting a CI did not change significantly (odds ratio [OR] 2.87; 95% CI 1.04, 7.88) whereas that of main texts reporting a CI increased (OR 1.96; 95% CI 1.39, 2.78). Comparison with biomedical studies revealed similar reporting of P values, but more frequent use of CIs in biomedicine. Automated analysis of 56,440 HPER abstracts found 14,867 (26.3%) reporting a P value, 3,024 (5.4%) reporting a CI, and increased reporting of P values and CIs from 1970 to 2015. Conclusions P values are ubiquitous in HPER, CIs are rarely reported, and most studies are underpowered. Most reported P values would be considered statistically significant.

Purpose: To describe a novel endovascular bailout technique for successful completion of target vessel stenting during branched stent-graft repair of thoracoabdominal aortic aneurysms (TAAA) after encountering difficulties with standard catheterization techniques. Technique: Technical difficulties when using fenestrated and branched grafts should be expected, especially in difficult anatomy or when an off-the-shelf device (eg, standard 4-branch device) is used that does not perfectly “match” the anatomy. The “snare-ride technique” facilitates antegrade transaxillary side branch catheterization and stent placement during TAAA branched grafting using a snare via a transfemoral approach. The branch of the graft is catheterized from an axillary access. The respective target vessel is then catheterized via a femoral access. An Indy snare is advanced over the transfemoral wire and positioned near the entrance of the target vessel. The transaxillary wire inside the branch of the graft is then advanced, snared, and pushed inside the target vessel with the snare. The procedure is thereafter continued with antegrade bridging of the target vessel in routine fashion. Conclusion: The snare-ride technique can be a useful maneuver to catheterize target vessels with difficult anatomy in TAAA branched stent-graft repair. Early experience shows safety and feasibility.

Background: There is growing interest in white matter (WM) imaging with positron emission tomography (PET). Objectives: We studied the association of cognitive function in late multiple sclerosis (MS) with cortical and WM Pittsburgh compound-B PET (PiB-PET) binding. Methods: In the population-based Mayo Clinic Study of Aging, 24 of 4869 participants had MS (12 underwent PiB-PET). Controls were age and sex matched (5:1). We used automated or semi-automated processing for quantitative image analyses and conditional logistic regression for group differences. Results: MS patients had lower memory ( p = 0.03) and language ( p = 0.02) performance; smaller thalamic volumes ( p = 0.003); and thinner temporal ( p = 0.001) and frontal ( p = 0.045) cortices on magnetic resonance imaging (MRI) than controls. There was no difference in global cortical PiB standardized uptake value ratios between MS and controls ( p = 0.35). PiB uptake was lower in areas of WM hyperintensities compared to normal-appearing white matter (NAWM) in MS ( p = 0.0002). Reduced PiB uptake in both the areas of WM hyperintensities ( r = 0.65; p = 0.02) and NAWM ( r = 0.69; p = 0.01) was associated with decreased visuospatial performance in MS. Conclusion: PiB uptake in the cortex in late MS is not different from normal age-matched controls. PiB uptake in the WM in late MS may be a marker of the large network structures’ integrity such as those involved in visuospatial performance.

Purpose Factors contributing to early mortality after initiation of treatment of metastatic colorectal cancer are poorly understood. Materials and Methods Data from 22,654 patients enrolled in 28 randomized phase III trials contained in the ARCAD (Aide et Recherche en Cancérologie Digestive) database were pooled. Multivariable logistic regression models for 30-, 60-, and 90-day mortality were constructed, including clinically and statistically significant patient and disease factors and interaction terms. A calculator (nomogram) for 90-day mortality was developed and validated internally using bootstrapping methods and externally using a 10% random holdout sample from each trial. The impact of early progression on the likelihood of survival to 90 days was examined with time-dependent Cox proportional hazards models. Results Mortality rates were 1.4% at 30 days, 3.4% at 60 days, and 5.5% at 90 days. Among baseline factors, advanced age, lower body mass index, poorer performance status, increased number of metastatic sites, BRAF mutant status, and several laboratory parameters were associated with increased likelihood of early mortality. A multivariable model for 90-day mortality showed strong internal discrimination (C-index, 0.77) and good calibration across risk groups as well as accurate predictions in the external validation set, both overall and within patient subgroups. Conclusion A validated clinical nomogram has been developed to quantify the risk of early death for individual patients during initial treatment of metastatic colorectal cancer. This tool may be used for patient eligibility assessment or risk stratification in future clinical trials and to identify patients requiring more or less aggressive therapy and additional supportive measures during and after treatment.

Abstract Cancer development is a complex process driven by inherited and acquired molecular and cellular alterations. Prevention is the holy grail of cancer elimination, but making this a reality will take a fundamental rethinking and deep understanding of premalignant biology. In this Perspective, we propose a national concerted effort to create a Precancer Atlas (PCA), integrating multi-omics and immunity – basic tenets of the neoplastic process. The biology of neoplasia caused by germline mutations has led to paradigm-changing precision prevention efforts, including: tumor testing for mismatch repair (MMR) deficiency in Lynch syndrome establishing a new paradigm, combinatorial chemoprevention efficacy in familial adenomatous polyposis (FAP), signal of benefit from imaging-based early detection research in high-germline risk for pancreatic neoplasia, elucidating early ontogeny in BRCA1-mutation carriers leading to an international breast cancer prevention trial, and insights into the intricate germline-somatic-immunity interaction landscape. Emerging genetic and pharmacologic (metformin) disruption of mitochondrial (mt) respiration increased autophagy to prevent cancer in a Li-Fraumeni mouse model (biology reproduced in clinical pilot) and revealed profound influences of subtle changes in mt DNA background variation on obesity, aging, and cancer risk. The elaborate communication between the immune system and neoplasia includes an increasingly complex cellular microenvironment and dynamic interactions between host genetics, environmental factors, and microbes in shaping the immune response. Cancer vaccines are in early murine and clinical precancer studies, building on the recent successes of immunotherapy and HPV vaccine immune prevention. Molecular monitoring in Barrett's esophagus to avoid overdiagnosis/treatment highlights an important PCA theme. Next generation sequencing (NGS) discovered age-related clonal hematopoiesis of indeterminate potential (CHIP). Ultra-deep NGS reports over the past year have redefined the premalignant landscape remarkably identifying tiny clones in the blood of up to 95% of women in their 50s, suggesting that potentially premalignant clones are ubiquitous. Similar data from eyelid skin and peritoneal and uterine lavage fluid provide unprecedented opportunities to dissect the earliest phases of stem/progenitor clonal (and microenvironment) evolution/diversity with new single-cell and liquid biopsy technologies. Cancer mutational signatures reflect exogenous or endogenous processes imprinted over time in precursors. Accelerating the prevention of cancer will require a large-scale, longitudinal effort, leveraging diverse disciplines (from genetics, biochemistry, and immunology to mathematics, computational biology, and engineering), initiatives, technologies, and models in developing an integrated multi-omics and immunity PCA – an immense national resource to interrogate, target, and intercept events that drive oncogenesis. Cancer Res; 77(7); 1510–41. ©2017 AACR.

OBJECTIVESurgery for brain aneurysms is technically demanding. In recent years, the process to learn the technical skills necessary for these challenging procedures has been affected by a decrease in the number of surgical cases available and progressive restrictions on resident training hours. To overcome these limitations, surgical simulators such as cadaver heads and human placenta models have been developed. However, the effectiveness of these models in improving technical skills is unknown. This study assessed concurrent and predictive validity of brain aneurysm surgery simulation in a human placenta model compared with a “live” human brain cadaveric model.METHODSTwo human cadaver heads and 30 human placentas were used. Twelve neurosurgeons participated in the concurrent validity part of this study, each operating on 1 human cadaver head aneurysm model and 1 human placenta model. Simulators were evaluated regarding their ability to simulate different surgical steps encountered during real surgery. The time to complete the entire aneurysm task in each simulator was analyzed. The predictive validity component of the study involved 9 neurosurgical residents divided into 3 groups to perform simulation exercises, each lasting 6 weeks. The training for the 3 groups consisted of educational video only (3 residents), human cadaver only (3 residents), and human placenta only (3 residents). All residents had equivalent microsurgical experience with superficial brain tumor surgery. After completing their practice training, residents in each of the 3 simulation groups performed surgery for an unruptured middle cerebral artery (MCA) aneurysm, and their performance was assessed by an experienced vascular neurosurgeon who watched the operative videos.RESULTSAll human cadaver heads and human placentas were suitable to simulate brain aneurysm surgery. In the concurrent validity portion of the experiment, the placenta model required a longer time (p < 0.001) than cadavers to complete the task. The placenta model was considered more effective than the cadaver model in simulating sylvian fissure splitting, bipolar coagulation of oozing microvessels, and aneurysm neck and dome dissection. Both models were equally effective in simulating neck aneurysm clipping, while the cadaver model was considered superior for simulation of intraoperative rupture and for reproduction of real anatomy during simulation. In the predictive validity portion of the experiment, residents were evaluated for 4 tasks: sylvian fissure dissection, microvessel bipolar coagulation, aneurysm dissection, and aneurysm clipping. Residents trained in the human placenta simulator consistently had the highest overall performance scores when compared with those who had trained in the cadaver model and those who had simply watched operative videos (p < 0.001).CONCLUSIONSThe human placenta biological simulator provides excellent simulation for some critical tasks of aneurysm surgery such as splitting of the sylvian fissure, dissection of the aneurysm neck and dome, and bipolar coagulation of surrounding microvessels. When performing surgery for an unruptured MCA aneurysm, residents who had trained in the human placenta model performed better than residents trained with other simulation scenarios/models. In this age of reduced exposure to aneurysm surgery and restrictions on resident working hours, the placenta model is a valid simulation for microneurosurgery with striking similarities with real surgery.

675 Background: Recent retrospective analysis of CALGB/SWOG 80405 showed that left-sided colon cancers (LCC) respond differently to biological therapy compared with right-sided tumors. However, differences between rectal cancers (RC) and LCC remain undefined. Herein, we report our exploration of differences between these two groups. Methods: Individual patient data from 4182 patients (pts) with metastatic colorectal cancers, enrolled onto 8 first-line randomized trials, were pooled. Only pts with tumor locations that were clearly defined as LCC (splenic flexure to sigmoid) or RC were included in this analysis. Differences in pt characteristics and disease factors according to LCC vs. RC were identified. The prognostic effect of primary tumor location on OS and PFS was quantified via multivariable Cox proportional hazards modeling stratified by treatment arm within each study and adjusting for age, sex, performance status, and prior surgery. Results: In total, 2,479 (59%) pts with LCC and 1,703 (41%) pts with RC were identified. Pts with RC, compared with LCC, were more likely to be male (68% vs. 62%, p < 0.001), have lung metastases (mets) (56% vs. 37%, p < 0.001), and have 2 or more metastatic sites (64% vs. 60%, p < 0.02), whereas pts with LCC were more likely to have liver mets (84% vs. 76%, p < 0.001). RC had a greater frequency of KRAS mutations (41% vs. 37%, p = 0.04) than LCC but there were no differences in the frequency of BRAF mutations (5% vs. 4%, p = 0.2). In multivariable analysis, no differences in OS or PFS were observed between pts with LCC vs. RC. While risk of death did not differ by primary tumor location, across all pts with LCC or RC, those with liver mets had a 17% increased risk of death compared to those with lung mets (HR = 1.17, p = 0.03) after adjusting for effects of other variables. Forthcoming prognostic analysis of LCC vs. RC within grouped backbone treatments (e.g., FOLFOX and FOLFIRI) is underway. Conclusions: Tumors arising in the rectum may carry clinical and molecular features that are distinct from LCC. Further investigations are warranted to determine whether RC should be treated with the same chemo backbone and biological therapy as LCC.

255 Background: In a prior study, we found that 8 single nucleotide polymorphisms (SNPs) from 4 candidate hormone-related genes (JAK2, TRMT11, NKX3-1 and HSD17B12) were associated with overall survival (OS) in CRPC stage in a North American cohort of 519 subjects. We attempt to replicate these findings in an independent cohort of Portuguese patients. Methods: A hundred and forty CRPC stage patients in the new cohort were genotyped fort he candidate SNPs. The primary endpoint was overall survival (OS), defined as time from development of CRPC to death. For SNP level results we estimated hazard ratios (HR) and 95% confidence intervals (CI) under the dominant allele model using Cox regression and adjusted for age and Gleason score (GS). Results: The median age of the Portuguese cohort was 69 years (range 53-84). The GS distribution was 48% subjects with GS≥8; 35% with GS=7 and 17% with GS<7. Median time from castration resistance to death for the cohort was 2.2 years (IQ range: 0.8-3.4, 93 deaths). One of the 3 SNPs (rs2295005; C>G; MAF = 0.16) in the TRMT11gene was associated with OS after adjustment for age and GS: (dominant model p=0.05, HR=0.56; 95 CI=0.31-1.00). No other SNP was observed to have statistical significance with OS (Table 1). Conclusions: Variation in the TRMT11 gene is significantly associated with overall survival in patients with CRPC and warrants further validation as a potential prognostic biomarker. [Table: see text]