Citations

Since the late 1990s, there has been a steady decline in cancer-related mortality, in part related to the introduction of so-called targeted therapies. Intended to interfere with a specific molecular pathway, these therapies have, paradoxically, led to a number of effects off their intended cancer tissue or molecular targets. The latest examples are tyrosine kinase inhibitors targeting the Philadelphia Chromosome mutation product, which have been associated with progressive atherosclerosis and acute vascular events. In addition, agents designed to interfere with the vascular growth factor signaling pathway have vascular side effects ranging from hypertension to arterial events and cardiomyocyte toxicity. Interestingly, the risk of cardiotoxicity with drugs such as trastuzumab is predicted by preexisting cardiovascular risk factors and disease, posing the question of a vascular component to the pathophysiology. The effect on the coronary circulation has been the leading explanation for the cardiotoxicity of 5-fluorouracil and may be the underlying the mechanism of presentation of apical ballooning syndrome with various chemotherapeutic agents. Classical chemotherapeutic agents such as cisplatin, often used in combination with bleomycin and vinca alkaloids, can lead to vascular events including acute coronary thrombosis and may be associated with an increased long-term cardiovascular risk. This review is intended to provide an update on the evolving spectrum of vascular toxicities with cancer therapeutics, particularly as they pertain to clinical practice, and to the conceptualization of cardiovascular diseases, as well. Vascular toxicity with cancer therapy: the old and the new, an evolving avenue.

ObjectiveIt is unclear whether isolated cutaneous lupus erythematosus (CLE) affects cardiovascular risk. We estimated the cumulative incidence and mortality of cardiovascular diseases in a population‐based CLE cohort and compared the risk with a matched non‐CLE cohort.MethodsAll incident cases of CLE in Olmsted County, Minnesota, between 1965 and 2005 were followed until December 2013. The cumulative incidence of cerebrovascular accidents (CVAs [including stroke and transient ischemic attack]), ischemic heart disease (IHD [including coronary artery disease, myocardial infarction, and angina pectoris]), heart failure, and peripheral arterial disease (PAD) was derived and compared to an age‐, sex‐, and calendar year–matched non‐CLE cohort using Cox models.ResultsThere were 155 patients with CLE (mean ± SD age at diagnosis 48 ± 16 years, 65% female, mean ± SD BMI 26.3 ± 7.1 kg/m2, 40% smokers, 9% with diabetes mellitus). During a median followup of 14.6 years, 41 CLE patients had cardiovascular events (15 patients with CVAs, 32 patients with IHD), with a 20‐year cumulative incidence of 31.6%. As compared to non‐CLE subjects, the risk of CVAs (smoking‐adjusted hazard ratio [HR] 2.97 [95% confidence interval (95% CI) 1.13–7.78]) and PAD (HR 2.06 [95% CI 0.99–4.32]) was increased in patients with CLE, but the risk of IHD was not increased (HR 0.94 [95% CI 0.57–1.54]). There was no increase in cardiovascular mortality (HR 1.68 [95% CI 0.76–3.75]). The magnitude of risk for any cardiovascular outcome was not significantly influenced by the extent of cutaneous involvement.ConclusionCLE may be associated with an increased risk of CVAs and PAD, but not IHD. Factors contributing to increased CVA risk in patients with CLE merit evaluation.

Abstract During the past decade, a conceptual shift occurred in the field of Alzheimer's disease (AD) considering the disease as a continuum. Thanks to evolving biomarker research and substantial discoveries, it is now possible to identify the disease even at the preclinical stage before the occurrence of the first clinical symptoms. This preclinical stage of AD has become a major research focus as the field postulates that early intervention may offer the best chance of therapeutic success. To date, very little evidence is established on this “silent” stage of the disease. A clarification is needed about the definitions and lexicon, the limits, the natural history, the markers of progression, and the ethical consequence of detecting the disease at this asymptomatic stage. This article is aimed at addressing all the different issues by providing for each of them an updated review of the literature and evidence, with practical recommendations.

AbstractIntroductionThe genetics underlying posterior cortical atrophy (PCA), typically a rare variant of Alzheimer's disease (AD), remain uncertain.MethodsWe genotyped 302 PCA patients from 11 centers, calculated risk at 24 loci for AD/DLB and performed an exploratory genome‐wide association study.ResultsWe confirm that variation in/near APOE/TOMM40 (P = 6 × 10−14) alters PCA risk, but with smaller effect than for typical AD (PCA: odds ratio [OR] = 2.03, typical AD: OR = 2.83, P = .0007). We found evidence for risk in/near CR1 (P = 7 × 10−4), ABCA7 (P = .02) and BIN1 (P = .04). ORs at variants near INPP5D and NME8 did not overlap between PCA and typical AD. Exploratory genome‐wide association studies confirmed APOE and identified three novel loci: rs76854344 near CNTNAP5 (P = 8 × 10−10 OR = 1.9 [1.5–2.3]); rs72907046 near FAM46A (P = 1 × 10−9 OR = 3.2 [2.1–4.9]); and rs2525776 near SEMA3C (P = 1 × 10−8, OR = 3.3 [2.1–5.1]).DiscussionWe provide evidence for genetic risk factors specifically related to PCA. We identify three candidate loci that, if replicated, may provide insights into selective vulnerability and phenotypic diversity in AD.

BACKGROUND: Delayed-release oral mesalamine 2.4 g/day to 4.8 g/day has been shown to be effective in treating mildly to moderately active ulcerative colitis (UC), but it is unknown whether an initial dose of 4.8 g/day is more effective than 2.4 g/day in patients with mildly to moderately active UC and in the subgroup with moderate disease.PATIENTS AND METHODS: A six-week, multicentre, randomized, double-blind, controlled trial assessing the safety and clinical efficacy of a new dose (ASCEND I) of medication randomly assigned 301 adults with mildly to moderately active UC to delayed-release oral mesalamine 2.4 g/day (400 mg tablet [n=154]) or 4.8 g/day (800 mg tablet [n=147]). The primary efficacy end point was overall improvement (ie, treatment success), defined as complete remission or response to therapy from baseline to week 6. Primary safety end points were adverse events and laboratory evaluations. Data were also analyzed separately for the prespecified subgroup of patients with moderate UC at baseline.RESULTS: Treatment success was not statistically different between the treatment groups at week 6; 51% of the group (77 of 150) who received delayed-release oral mesalamine 2.4 g/day and 56% of the group (76 of 136) who received 4.8 g/day reached the efficacy end point (P=0.441). Among the moderate disease subgroup, however, the higher initial dose was more effective; 57% of patients (53 of 93) given delayed-release oral mesalamine 2.4 g/day and 72% of patients (55 of 76) given 4.8 g/day achieved treatment success (P=0.0384). Both regimens were well tolerated.CONCLUSIONS: Delayed-release oral mesalamine is an effective and well-tolerated initial therapy in patients with mildly to moderately active UC, and a 4.8 g/day dose may enhance treatment success rates in patients with moderate disease compared with mesalamine 2.4 g/day.

Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are the most prevalent types of primary liver cancer. These malignancies have limited treatment options, resulting in poor patient outcomes. Metabolism reprogramming, including increased de novo lipogenesis, is one of the hallmarks of cancer. Fatty acid synthase (FASN) catalyzes the de novo synthesis of long‐chain fatty acids from acetyl‐coenzyme A and malonyl‐coenzyme A. Increased FASN expression has been reported in multiple tumor types, and inhibition of FASN expression has been shown to have tumor‐suppressing activity. Intriguingly, we found that while FASN is up‐regulated in human HCC samples, its expression is frequently low in human ICC specimens. Similar results were observed in mouse ICC models induced by different oncogenes. Ablating FASN in the mouse liver did not affect activated AKT and Notch (AKT/Notch intracellular domain 1) induced ICC formation in vivo. Furthermore, while both HCC and ICC lesions develop in mice following hydrodynamic injection of AKT and neuroblastoma Ras viral oncogene homolog oncogenes (AKT/Ras), deletion of FASN in AKT/Ras mice triggered the development almost exclusively of ICCs. In the absence of FASN, ICC cells might receive lipids for membrane synthesis through exogenous fatty acid uptake. In accordance with the latter hypothesis, ICC cells displayed high expression of fatty acid uptake‐related proteins and robust long‐chain fatty acid uptake. Conclusion: Our data demonstrate that FASN dependence is not a universal feature of liver tumors: while HCC development is highly dependent of FASN and its mediated lipogenesis, ICC tumorigenesis can be insensitive to FASN deprivation; our study supports novel therapeutic approaches to treat this pernicious tumor type with the inhibition of exogenous fatty acid uptake. (Hepatology 2016;63:1900‐1913)

Background: Delivering specialty care remotely directly into people's homes can enhance access for and improve the healthcare of individuals with chronic conditions. However, evidence supporting this approach is limited. Materials and Methods: Connect.Parkinson is a randomized comparative effectiveness study that compares usual care of individuals with Parkinson's disease in the community with usual care augmented by virtual house calls with a Parkinson's disease specialist from 1 of 18 centers nationally. Individuals in the intervention arm receive four virtual visits from a Parkinson's disease specialist over 1 year via secure, Web-based videoconferencing directly into their homes. All study activities, including recruitment, enrollment, and assessments, are conducted remotely. Here we report on interest, feasibility, and barriers to enrollment in this ongoing study. Results: During recruitment, 11,734 individuals visited the study's Web site, and 927 unique individuals submitted electronic interest forms. Two hundred ten individuals from 18 states enrolled in the study from March 2014 to June 2015, and 195 were randomized. Most participants were white (96%) and college educated (73%). Of the randomized participants, 73% had seen a Parkinson's disease specialist within the previous year. Conclusions: Among individuals with Parkinson's disease, national interest in receiving remote specialty care directly into the home is high. Remote enrollment in this care model is feasible but is likely affected by differential access to the Internet.