Citations

Abstract This book comprises a collection of case studies of patients with acute and critical neurological disease, along with pertinent discussion of approaches to each particular condition. Case studies provide a way to examine how difficult it is to approach these patients situated in the neurosciences intensive care unit. Some patients need close observation and management of emerging problems, others need a neurosurgical intervention or a neurointerventional procedure, a few patients are in extremis. The examples provided in this book are quintessential to the practice of neurocritical care. Some are less common conditions that need to be recognized and appropriately treated. Another purpose of this book is to introduce the reader to the field of neurocritical care and to show what goes on. The book shows the complexity of care and urgent decision-making involved in treating patients who deteriorate. Practical suggestions are included for each topic it covers. Not only is treatment of serious neurological disorders discussed but also prognostication in practice and end-of-life care discussions. In some ways this book summarizes the entire spectrum of presenting acute illness and how best to intervene.

Circulating insulin‐like growth factors (IGFs) and their binding proteins (IGFBPs) are associated with prostate cancer. Using genetic variants as instruments for IGF peptides, we investigated whether these associations are likely to be causal. We identified from the literature 56 single nucleotide polymorphisms (SNPs) in the IGF axis previously associated with biomarker levels (8 from a genome‐wide association study [GWAS] and 48 in reported candidate genes). In ∼700 men without prostate cancer and two replication cohorts (N ∼ 900 and ∼9,000), we examined the properties of these SNPS as instrumental variables (IVs) for IGF‐I, IGF‐II, IGFBP‐2 and IGFBP‐3. Those confirmed as strong IVs were tested for association with prostate cancer risk, low (< 7) vs. high (≥ 7) Gleason grade, localised vs. advanced stage, and mortality, in 22,936 controls and 22,992 cases. IV analysis was used in an attempt to estimate the causal effect of circulating IGF peptides on prostate cancer. Published SNPs in the IGFBP1/IGFBP3 gene region, particularly rs11977526, were strong instruments for IGF‐II and IGFBP‐3, less so for IGF‐I. Rs11977526 was associated with high (vs. low) Gleason grade (OR per IGF‐II/IGFBP‐3 level‐raising allele 1.05; 95% CI: 1.00, 1.10). Using rs11977526 as an IV we estimated the causal effect of a one SD increase in IGF‐II (∼265 ng/mL) on risk of high vs. low grade disease as 1.14 (95% CI: 1.00, 1.31). Because of the potential for pleiotropy of the genetic instruments, these findings can only causally implicate the IGF pathway in general, not any one specific biomarker.

Abstract Background: The identification of organ-specific targetable signatures may help design more effective treatment for patients with metastatic breast cancer (MBC). We took a multi-OMIC approach to assess whether the AKT-mTOR pathway is globally activated during metastatic progression or whether it represents an organ-specific target. Methods: Snap frozen biopsies from 25 MBC patients enrolled in a prospective phase II trial were used. Sites of metastasis were classified as liver (n=8) and others (n=17), the latter including cutaneous, lung, lymph nodes, and intra-abdominal lesions. Signaling analysis of the 25 cases was performed using Reverse Phase Protein Microarray (RPPA) coupled with Laser Capture Microdissection. Activation of the AKT-mTOR pathway was quantified as phosphorylation of AKT (S473) and the mTOR target p70S6 (T389). Matched exome (WES) and RNASeq data were available for 17 of 25 patients, five with liver metastases. Sequencing data was processed using an in-house developed pipeline to identify somatic events including coding mutations, copy number alterations, gene fusions, and differential expression. Activation of the AKT-mTOR pathway and sequencing data were compared between hepatic and non-hepatic lesions using an integrated RPPA and genomic approach. Results: Among liver metastases, AKT was activated in 4 of the 8 (50.0%) patients, while 6 of the 8 cases (75.0%) showed activation of p70S6. Sequencing data revealed mutation of PIK3CA in 4 of the 5 liver metastases (80.0%). Three of the PIK3CA mutated specimens with catalytic domain mutations (codons 1023 and 147) demonstrated co-activation of AKT and p70S6, while the fourth case, containing a helical domain mutation (E542K), had activation of p70S6 only. The PIK3CA wild-type liver metastasis demonstrated low activation of AKT and p70S6. For non-hepatic metastases AKT was activated in 2 of the 17 cases (11.8%) and p70S6 in 5 of the 17 patients (29.4%). Discussion: Although these results need further validation, activation of the AKT-mTOR pathway appears to be a hepatic specific signature in MBC and could be used for the selection of targeted agents for hepatic lesions. Citation Format: Pierobon M, Wong S, Reeder A, Anthony SP, Robert NJ, Northfelt DW, Jahanzeb M, Vocila L, Wulfkuhle J, Dunetz B, Aldrich J, Byron S, Craig D, Liotta L, Petricoin EF, Carpten J. The AKT-mTOR pathway as a potential organ-specific drug target signature of hepatic metastases from breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-05-21.

Purpose To examine medical student attitudes toward cost-conscious care and whether regional health care intensity is associated with reported exposure to physician role-modeling behaviors related to cost-conscious care. Method Students at 10 U.S. medical schools were surveyed in 2015. Thirty-five items assessed attitudes toward, perceived barriers to and consequences of, and observed physician role-modeling behaviors related to cost-conscious care (using scales for cost-conscious and potentially wasteful behaviors; Cronbach alphas of 0.82 and 0.81, respectively). Regional health care intensity was measured using Dartmouth Atlas End-of-Life Chronic Illness Care data: ratio of physician visits per decedent compared with the U.S. average, ratio of specialty to primary care physician visits per decedent, and hospital care intensity index. Results Of 5,992 students invited, 3,395 (57%) responded. Ninety percent (2,640/2,932) agreed physicians have a responsibility to contain costs. However, 48% (1,1416/2,960) thought ordering a test is easier than explaining why it is unnecessary, and 58% (1,685/2,928) agreed ordering fewer tests will increase the risk of malpractice litigation. In adjusted linear regression analyses, students in higher-health-care-intensity regions reported observing significantly fewer cost-conscious role-modeling behaviors: For each one-unit increase in the three health care intensity measures, scores on the 21-point cost-conscious role-modeling scale decreased by 4.4 (SE 0.7), 3.2 (0.6), and 3.9 (0.6) points, respectively (all P < .001). Conclusions Medical students endorse barriers to cost-conscious care and encounter conflicting role-modeling behaviors, which are related to regional health care intensity. Enhancing role modeling in the learning environment may help prepare future physicians to address health care costs.

BACKGROUNDPrior studies have shown that a higher hospital volume or physician caseload is associated with better outcomes for complex and uncommon surgical procedures. Similar studies in the medical management of rare diseases such as hematologic cancers are limited. This retrospective, observational study using the US National Cancer Data Base determined the extent to which the number of new non‐Hodgkin lymphoma (NHL) patients treated annually at a treatment facility affected overall survival (OS).METHODSThere were 278,985 patients treated at 1151 facilities from 1998 to 2006. Treatment facilities were classified by quartiles based on the average number of new NHL patients seen annually: quartile 1 (Q1), 2 to 13 patients; quartile 2 (Q2), 14 to 20 patients; quartile 3 (Q3), 21 to 32 patients; and quartile 4 (Q4), 33 or more patients. The outcome of interest was OS according to facility volume.RESULTSThe unadjusted median OS was 61.8 months for Q1, 65.9 months for Q2, 71.4 months for Q3, and 83.6 months for Q4. A multivariate analysis that was adjusted for demographic (sex, age, race, and ethnicity), socioeconomic (income and insurance type), geographic (area of residence), disease‐specific (NHL subtype and stage), and facility‐specific factors (type and location) showed that the facility volume was associated with OS. Compared with patients at Q4 facilities, patients at lower quartile facilities had higher mortality (hazard ratio for Q3, 1.05 [95% confidence interval, 1.04‐1.06]; hazard ratio for Q2, 1.08 [95% confidence interval, 1.07‐1.10]; hazard ratio for Q1, 1.14 [95% confidence interval, 1.11‐1.17]).CONCLUSIONSNHL patients treated at higher volume facilities may survive longer than those treated at lower volume facilities. Further work is needed to understand the mechanisms of these differences and whether volume should be considered in the determination of referrals for NHL patients. Cancer 2016;122:2552–9. © 2016 American Cancer Society.

Abstract Background: Despite a large body of literature evaluating the association between recreational physical activity and epithelial ovarian cancer (EOC) risk, the extant evidence is inconclusive, and little is known about the independent association between recreational physical inactivity and EOC risk. We conducted a pooled analysis of nine studies from the Ovarian Cancer Association Consortium to investigate the association between chronic recreational physical inactivity and EOC risk. Methods: In accordance with the 2008 Physical Activity Guidelines for Americans, women reporting no regular, weekly recreational physical activity were classified as inactive. Multivariable logistic regression was utilized to estimate the ORs and 95% confidence intervals (CI) for the association between inactivity and EOC risk overall and by subgroups based upon histotype, menopausal status, race, and body mass index. Results: The current analysis included data from 8,309 EOC patients and 12,612 controls. We observed a significant positive association between inactivity and EOC risk (OR = 1.34; 95% CI, 1.14–1.57), and similar associations were observed for each histotype. Conclusions: In this large pooled analysis examining the association between recreational physical inactivity and EOC risk, we observed consistent evidence of an association between chronic inactivity and all EOC histotypes. Impact: These data add to the growing body of evidence suggesting that inactivity is an independent risk factor for cancer. If the apparent association between inactivity and EOC risk is substantiated, additional work via targeted interventions should be pursued to characterize the dose of activity required to mitigate the risk of this highly fatal disease. Cancer Epidemiol Biomarkers Prev; 25(7); 1114–24. ©2016 AACR.

Rationale: Coronary endothelial dysfunction (ED)—an early marker of atherosclerosis—increases the risk of cardiovascular events. Objective: We tested the hypothesis that cholesterol efflux capacity and high-density lipoprotein (HDL) particle concentration predict coronary ED better than HDL-cholesterol (HDL-C). Methods and Results: We studied 80 subjects with nonobstructive (<30% stenosis) coronary artery disease. ED was defined as <50% change in coronary blood flow in response to intracoronary infusions of acetylcholine during diagnostic coronary angiography. Cholesterol efflux capacity and HDL particle concentration (HDL-P IMA ) were assessed with validated assays. Cholesterol efflux capacity and HDL-P IMA were both strong, inverse predictors of ED ( P <0.001 and 0.005, respectively). In contrast, HDL-C and other traditional lipid risk factors did not differ significantly between control and ED subjects. Large HDL particles were markedly decreased in ED subjects (33%; P =0.005). After correction for HDL-C, both efflux capacity and HDL-P IMA remained significant predictors of ED status. HDL-P IMA explained cholesterol efflux capacity more effectively than HDL-C ( r =0.54 and 0.36, respectively). The efflux capacities of isolated HDL and serum HDL correlated strongly ( r =0.49). Conclusions: Cholesterol efflux capacity and HDL-P IMA are reduced in subjects with coronary ED, independently of HDL-C. Alterations in HDL-P IMA and HDL itself account for a much larger fraction of the variation in cholesterol efflux capacity than does HDL-C. A selective decrease in large HDL particles may contribute to impaired cholesterol efflux capacity in ED subjects. These observations support a role for HDL size, concentration, and function as markers—and perhaps mediators—of coronary atherosclerosis in humans.

Background BRCA1 interacting protein C-terminal helicase 1 (BRIP1) is one of the Fanconi Anaemia Complementation (FANC) group family of DNA repair proteins. Biallelic mutations in BRIP1 are responsible for FANC group J, and previous studies have also suggested that rare protein truncating variants in BRIP1 are associated with an increased risk of breast cancer. These studies have led to inclusion of BRIP1 on targeted sequencing panels for breast cancer risk prediction. Methods We evaluated a truncating variant, p.Arg798Ter (rs137852986), and 10 missense variants of BRIP1, in 48 144 cases and 43 607 controls of European origin, drawn from 41 studies participating in the Breast Cancer Association Consortium (BCAC). Additionally, we sequenced the coding regions of BRIP1 in 13 213 cases and 5242 controls from the UK, 1313 cases and 1123 controls from three population-based studies as part of the Breast Cancer Family Registry, and 1853 familial cases and 2001 controls from Australia. Results The rare truncating allele of rs137852986 was observed in 23 cases and 18 controls in Europeans in BCAC (OR 1.09, 95% CI 0.58 to 2.03, p=0.79). Truncating variants were found in the sequencing studies in 34 cases (0.21%) and 19 controls (0.23%) (combined OR 0.90, 95% CI 0.48 to 1.70, p=0.75). Conclusions These results suggest that truncating variants in BRIP1, and in particular p.Arg798Ter, are not associated with a substantial increase in breast cancer risk. Such observations have important implications for the reporting of results from breast cancer screening panels.

Abstract Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-stage approach to conduct genome-wide association studies for lung, ovary, breast, prostate, and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820 controls) to identify pleiotropic loci. Findings were replicated in independent association studies (55,789 cases, 330,490 controls). We identified a novel pleiotropic association at 1q22 involving breast and lung squamous cell carcinoma, with eQTL analysis showing an association with ADAM15/THBS3 gene expression in lung. We also identified a known breast cancer locus CASP8/ALS2CR12 associated with prostate cancer, a known cancer locus at CDKN2B-AS1 with different variants associated with lung adenocarcinoma and prostate cancer, and confirmed the associations of a breast BRCA2 locus with lung and serous ovarian cancer. This is the largest study to date examining pleiotropy across multiple cancer-associated loci, identifying common mechanisms of cancer development and progression. Cancer Res; 76(17); 5103–14. ©2016 AACR.