Citations

We present the case of a 34-year-old woman with Klippel-Feil syndrome who developed progressive generalized dystonia of unclear etiology, resulting in intractable pain despite aggressive medical and surgical interventions. Ultimately, palliative sedation was required to relieve suffering. Herein, we describe ethical considerations including defining sedation, determining prognosis in the setting of an undefined neurodegenerative condition, and use of treatments that concurrently might prolong or alter end-of-life trajectory. We highlight pertinent literature and how it may be applied in challenging and unique clinical situations. Finally, we discuss the need for expert multidisciplinary involvement when implementing palliative sedation and illustrate that procedures and rules need to be interpreted to deliver optimal patient-centered plan of care.

Key PointsIn this first ALL GWAS in AYAs, we determined that inherited GATA3 variants strongly influence ALL susceptibility in this age group. These findings revealed similarities and differences in the genetic basis of ALL susceptibility between young children and AYAs.

AbstractRationale, aims and objectivesThis study was undertaken to assess the frequency of lipid screening in comparison with the United States Preventive Services Task Force guideline in a sample of family medicine patients. In addition, we sought to determine the association between testing frequency and achievement of lipid targets.MethodsA random sample was extracted from 271 patients from among all patients cared for in our Department of Family Medicine for whom lipid screening was ordered from March to September 2012 and who had ≥2 well‐defined cardiovascular risk factors. Lipid testing frequency was classified in three ways: semi‐annual or less often (0–12 tests over 6 years), annual or less often (0–6 tests), or biennial (0–3 tests).ResultsMultiple logistic regression analysis revealed that the predictors of lipid screening more often than semi‐annually were age ≥60 years [odds ratio (OR) = 3.7] and diabetes mellitus (DM) (OR = 30.6). Predictors of screening more often than annually were DM (OR = 4.3), hypertension (OR = 2.1), family history of premature coronary artery disease (OR = 5.6) and statin treatment (OR = 3.5). Lipid goal attainment was not associated with testing frequency except with regard to low‐density lipoprotein levels (P = 0.043, P < 0.001, P = 0.005, by semi‐annual, annual and biennial, respectively) and total cholesterol levels (P = 0.015, P = 0.025 by semi‐annual and annual, respectively).ConclusionsQuestionable high frequency of lipid testing was detected even when the more conservative approach of annual monitoring was assumed. Frequency of testing was not associated with goal attainment for most parameters. Physicians should request the lipid testing based on overall risk assessment and person variability in accordance with published guidelines.

BackgroundPast research has explored patients' expectations about the informed consent process. However, it is currently unknown if the complexity of the surgical procedure influences the type of anesthesia‐related risks that patients wish disclosed. This study explored fears of anesthesia‐related complications and whether these changed based on severity of surgery classification.MethodsPatients presenting to our pre‐operative evaluation clinic from February 2013 to May 2013 were asked to participate in a survey‐based study meant to evaluate their perception of five possible anesthetic risks (peripheral nerve injury, death, nausea and vomiting, heart attack and stroke) when confronted with differing levels of surgical severity.ResultsOne thousand surveys were administered, and 894 were returned for an overall response rate of 89%. Fear of death was the greatest concern as compared to the other risk factors independent of the severity of surgery. The level of fear for all risk factors, with the exception of stroke and heart attack, were dependent on the severity of surgery. Fear of death decreased as the severity of surgery decreased (major 46%, moderate 38%, minor 25%). For major surgery, the fear of perioperative death differed significantly with age (P < 0.001); specifically, with increasing age came a lessened fear of death.ConclusionAwareness by anesthesia providers of those fears that patients report may allow for a more personalized approach to providing information that may better allay anxiety. Further, these results may better tailor the informed consent process to one that meets particular patient concerns.

A large genotyping project within the Breast Cancer Association Consortium (BCAC) recently identified 41 associations between single nucleotide polymorphisms (SNPs) and overall breast cancer (BC) risk. We investigated whether the effects of these 41 SNPs, as well as six SNPs associated with estrogen receptor (ER) negative BC risk are modified by 13 environmental risk factors for BC. Data from 22 studies participating in BCAC were pooled, comprising up to 26,633 cases and 30,119 controls. Interactions between SNPs and environmental factors were evaluated using an empirical Bayes‐type shrinkage estimator. Six SNPs showed interactions with associated p ‐values ( p int ) <1.1 × 10 −3 . None of the observed interactions was significant after accounting for multiple testing. The Bayesian False Discovery Probability was used to rank the findings, which indicated three interactions as being noteworthy at 1% prior probability of interaction. SNP rs6828523 was associated with increased ER‐negative BC risk in women ≥170 cm (OR = 1.22, p = 0.017), but inversely associated with ER‐negative BC risk in women <160 cm (OR = 0.83, p = 0.039, p int = 1.9 × 10 −4 ). The inverse association between rs4808801 and overall BC risk was stronger for women who had had four or more pregnancies (OR = 0.85, p = 2.0 × 10 −4 ), and absent in women who had had just one (OR = 0.96, p = 0.19, p int = 6.1 × 10 −4 ). SNP rs11242675 was inversely associated with overall BC risk in never/former smokers (OR = 0.93, p = 2.8 × 10 −5 ), but no association was observed in current smokers (OR = 1.07, p = 0.14, p int = 3.4 × 10 −4 ). In conclusion, recently identified BC susceptibility loci are not strongly modified by established risk factors and the observed potential interactions require confirmation in independent studies.

Abstract Background: Genetic and environmental factors influence colorectal cancer (CRC) risk. Previous studies have provided additional etiologic insight by examining multiplicative gene-environment interactions for individual susceptibility loci. However, individual loci confer only modest risks, which may limit statistical power and clinical significance. A genetic risk score comprising known CRC loci may provide a more comprehensive assessment of risk. Further, there is a paucity of data on the role of additive gene-environment interactions, which may have greater public health implications than multiplicative interactions. We thus evaluated both additive and multiplicative interactions between a genetic risk score and 15 key environmental factors on risk of CRC. Methods: We conducted an analysis of 10,491 CRC cases and 10,725 controls of European ancestry in 7 cohort and 6 case-control studies participating in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) or Colon Cancer Family Registry (CCFR). To provide a global measure of genetic predisposition, information across multiple risk variants was combined by calculating a genetic risk score based on 24 polymorphisms near 21 genetic loci identified in previous genome-wide association studies. For the genetic score and environmental factors, the reference category corresponded to that associated with lower CRC risk. We tested for additive interactions by estimating relative excess risk due to interactions (RERIs) using logistic regression; for multiplicative interactions we used an empirical-Bayes approach. Nominal P values ≤ 0.05 were considered statistically significant. Results: After adjustment for age, sex, center, study, principal components, and total energy, as appropriate, we observed super-additive gene-environment interactions for CRC risk between the genetic risk score and body mass index (RERI=0.15; 95% CI: 0.00-0.31), ever smoking (RERI=0.14; 95% CI: 0.00-0.28), pack-years of smoking (RERI=0.23; 95% CI: 0.05-0.41), postmenopausal hormone therapy use (RERI=0.38; 95% CI: 0.17-0.59), and intake of processed meat (RERI=0.23; 95% CI: 0.06-0.40). Of the 15 environmental risk factors, 12 showed RERIs &gt; 0 – suggesting an overall trend toward super-additive interactions for these factors. In addition, we observed evidence of sub-multiplicative interactions for use of aspirin and non-steroidal anti-inflammatory drugs. There were no other statistically significant multiplicative interactions. Conclusions: We observed evidence for super-additive effects of genetic predisposition and environmental risk factors on risk of CRC. Our findings suggest that certain environmental risk factors have stronger effects on absolute risk among individuals with higher genetic risk of CRC. If confirmed in future studies, these results may have implications for targeted prevention strategies. Citation Format: Mengmeng Du, Sonja I. Berndt, Hermann Brenner, Bette J. Caan, Peter T. Campbell, Graham Casey, Andrew Chan, Jenny Chang-Claude, Stephen J. Chanock, Nilanjan Chatterjee, David V. Conti, David Duggan, Jane C. Figueiredo, Steven Gallinger, Jian Gong, Robert W. Haile, Tabitha A. Harrison, Richard B. Hayes, Michael Hoffmeister, John L. Hopper, Li Hsu, Thomas J. Hudson, Carolyn M. Hutter, Eric J. Jacobs, Mark A. Jenkins, Shuo Jiao, Laurence N. Kolonel, Peter Kraft, Loic Le Marchand, Mathieu Lemire, Yi Lin, Noralane M. Lindor, Polly A. Newcomb, John D. Potter, Robert E. Schoen, Fredrick R. Schumacher, Daniela Seminara, Martha L. Slattery, Stephen N. Thibodeau, Cornelia M. Ulrich, Aung Ko Win, Emily White, Brent W. Zanke, Ulrike Peters. Additive and multiplicative gene-environment interactions for colorectal cancer risk. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4831. doi:10.1158/1538-7445.AM2013-4831

Abstract CD36 is an endothelial cell (EC) receptor that mediates angiostatic activity and oxidative stress, which are important in ischemic disease and tumor progression. CD36 interacts with TSR domain proteins including thrombospondin-1. This results in a signal that is likely to initiate an antiangiogenic “switch," subsequently converting a growth factor-mediated proangiogenic response to an antiangiogenic response. However, in pathologic settings including malignant tumors, robust angiogenesis occurs despite the abundance of TSR-containing proteins in the microenvironment. This suggests that there is a mechanism by which TSR-mediated antiangiogenesis could be blunted via the localized downregulation of EC CD36 transcription. We previously reported that lysophosphatidic acid (LPA), a bioactive signaling phospholipid mediator, down-regulates microvascular EC (MVEC) CD36 transcription by protein kinase PKD-1 signaling via G protein coupled receptor LPA1,3. However, further elucidating the CD36 transcriptional mechanisms is critical to understanding the antiangiogenic switch. To this end, we recently discovered that obesity-derived LPA inhibited CD36 expression in tumor-associated ECs (TAECs). Similarly, inducing the constitutively active PKD-1 or PKD-CA expression also resulted in CD36 downregulation. Mechanistically, LPA treatment led to nuclear accumulation of PKD-1, HDAC7 and FoxO1. Furthermore, LPA-mediated PKD-1 signaling enhanced FoxO1-HDAC7 interaction in the nucleus. This interaction was attenuated with PKD-1 silencing. Intriguingly, doxycycline induced PKD-CA expression increased ephrin B2 expression and ERK activation, which are two critical “molecular signatures” involved in arteriogenesis. Functionally, FGF-2 induced a potent proangiogenic response even in the presence of TSP-1 in ECs pre-treated with LPA. Doxycycline induced PKD-CA expression stimulated robust arterial EC branching in a 3D spheroid assay. This angiogenic response was inhibited by a novel PKD-1 specific inhibitor. Moreover, in a mouse Lewis lung carcinoma model, we detected a minimal level of endothelial CD36 expression with robust tumor angiogenesis. The role of PKD-1 signaling in CD36 transcriptional repression and tumor arteriogenesis is a critical yet underexplored and underappreciated field. We propose that the LPA-PKD-FoxO1 signaling axis is essential for CD36 transcriptional repression and arteriogenic signaling and responses. The PKD-1 stimulated nuclear signaling network is critical to epigenetic suppression of CD36 transcription and silencing of CD36 antiangiogenic switch, subsequently turning on the angiogenic switch and stimulating the arteriogenic responses. Targeting the LPA-PKD1-FoxO1 signaling axis could have therapeutic potential in the ischemic disease and malignant tumors. Citation Format: Jacob D. Kohlenberg, Yiliang Chen, Brad Best, Peter Storz, Randall T. Peterson, Roy Silverstein, Bin Ren. A novel LPA-PKD1-FoxO1 pathway in endothelial cells provides an angiogenic switch via down-regulation of CD36 transcription and induction of arteriogenic responses . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-338. doi:10.1158/1538-7445.AM2013-LB-338