Citations

AbstractBackgroundLess is known about the genetic basis of Alzheimer's disease (AD) in African Americans (AAs) than in non‐Hispanic whites.MethodsWhole exome sequencing (WES) was performed on seven AA AD cases. Disease association with potentially AD‐related variants from WES was assessed in an AA discovery cohort of 422 cases and 394 controls. Replication was sought in an AA sample of 1037 cases and 1869 controls from the Alzheimer Disease Genetics Consortium (ADGC).ResultsForty‐four single nucleotide polymorphisms (SNPs) from WES passed filtering criteria and were successfully genotyped. Nominally significant (P < .05) association to AD was observed with two African‐descent specific AKAP9 SNPs in tight linkage disequilibrium: rs144662445 (P = .014) and rs149979685 (P = .037). These associations were replicated in the ADGC sample (rs144662445: P = .0022, odds ratio [OR] = 2.75; rs149979685: P = .0022, OR = 3.61).ConclusionsBecause AKAP9 was not previously linked to AD risk, this study indicates a potential new disease mechanism.

Background: Clinical decision support (CDS) for primary care has been shown to improve delivery of preventive services. However, there is little evidence for efficiency of physicians due to CDS assistance. In this article, we report a pilot study for measuring the impact of CDS on the time spent by physicians for deciding on preventive services and chronic disease management. Methods: We randomly selected 30 patients from a primary care practice, and assigned them to 10 physicians. The physicians were requested to perform chart review to decide on preventive services and chronic disease management for the assigned patients. The patients assignment was done in a randomized crossover design, such that each patient received 2 sets of recommendations—one from a physician with CDS assistance and the other from a different physician without CDS assistance. We compared the physician recommendations made using CDS assistance, with the recommendations made without CDS assistance. Results: The physicians required an average of 1 minute 44 seconds, when they were they had access to the decision support system and 5 minutes when they were unassisted. Hence the CDS assistance resulted in an estimated saving of 3 minutes 16 seconds (65%) of the physicians’ time, which was statistically significant ( P < .0001). There was no statistically significant difference in the number of recommendations. Conclusion: Our findings suggest that CDS assistance significantly reduced the time spent by physicians for deciding on preventive services and chronic disease management. The result needs to be confirmed by performing similar studies at other institutions.

Abstract Background This study aimed to have international experts converge on a harmonized definition of whole hippocampus boundaries and segmentation procedures, to define standard operating procedures for magnetic resonance (MR)‐based manual hippocampal segmentation. Methods The panel received a questionnaire regarding whole hippocampus boundaries and segmentation procedures. Quantitative information was supplied to allow evidence‐based answers. A recursive and anonymous Delphi procedure was used to achieve convergence. Significance of agreement among panelists was assessed by exact probability on Fisher's and binomial tests. Results Agreement was significant on the inclusion of alveus/fimbria ( P = .021), whole hippocampal tail ( P = .013), medial border of the body according to visible morphology ( P = .0006), and on this combined set of features ( P = .001). This definition captures 100% of hippocampal tissue, 100% of Alzheimer’s disease‐related atrophy, and demonstrated good reliability on preliminary intrarater (0.98) and inter‐rater (0.94) estimates. Discussion Consensus was achieved among international experts with respect to hippocampal segmentation using MR resulting in a harmonized segmentation protocol.

Abstract Background Proteins pathogenic in Alzheimer's disease (AD) were extracted from neurally derived blood exosomes and quantified to develop biomarkers for the staging of sporadic AD. Methods Blood exosomes obtained at one time‐point from patients with AD (n = 57) or frontotemporal dementia (FTD) (n = 16), and at two time‐points from others (n = 24) when cognitively normal and 1 to 10 years later when diagnosed with AD were enriched for neural sources by immunoabsorption. AD‐pathogenic exosomal proteins were extracted and quantified by enzyme‐linked immunosorbent assays. Results Mean exosomal levels of total tau, P‐T181‐tau, P‐S396‐tau, and amyloid β 1–42 (Aβ1–42) for AD and levels of P‐T181‐tau and Aβ1–42 for FTD were significantly higher than for case‐controls. Step‐wise discriminant modeling incorporated P‐T181‐tau, P‐S396‐tau, and Aβ1–42 in AD, but only P‐T181‐tau in FTD. Classification of 96.4% of AD patients and 87.5% of FTD patients was correct. In 24 AD patients, exosomal levels of P‐S396‐tau, P‐T181‐tau, and Aβ1–42 were significantly higher than for controls both 1 to 10 years before and when diagnosed with AD. Conclusions Levels of P‐S396‐tau, P‐T181‐tau, and Aβ1–42 in extracts of neurally derived blood exosomes predict the development of AD up to 10 years before clinical onset.

Abstract Metformin is a bi-guanidine employed in treating Type II diabetes. Epidemiologic studies have suggested that diabetics receiving metformin vs thialidizones or insulin have a lower incidence of cancer. In addition, metformin decreases levels of AMPK and IGF1; encouraging its use in both cancer prevention and therapy settings. Most preclinical studies with metformin have employed cell culture or xenografts. We examined its efficacy in multiple in situ animal cancer models. The preventive effect of Metformin administered by gavage or in the diet, at roughly the human equivalent dose (HED), was determined in four standard animal models: (1) methylnitrosourea (MNU)-induced ER+ mammary cancers; (2) MMTV-Neu ER− mammary cancers; (3) hydroxybutyl(butyl)nitrosamine (OH-BBN) induced urinary bladder cancers; and (4) Min mouse model of intestinal tumorigenesis. In the MNU model, Metformin (150 or 50 mg/Kg BW/day) was ineffective as a preventive dose; decreasing neither tumor multiplicity nor latency. Furthermore, both doses increased final tumor weights in treated rats. PK studies at the higher dose of Metformin (150 mg/kg BW/day) showed serum levels slightly higher than humans taking 1.5 g per day. In the MMTV-Neu model, dietary metformin (1200 PPM in diet) decreased the latency of tumor development as well as slightly, but insignificantly, increasing the final tumor multiplicity. Metformin (1200 ppm in diet) in the Min mouse model marginally increased the multiplicity of intestinal adenomas. In contrast, the NSAID naproxen (400 ppm in diet) examined simultaneously in the min mouse strongly inhibited adenoma development. Metformin (150 mg/Kg BW/day) in the OH-BBN induced model of urinary bladder cancer failed to significantly reduce bladder cancers despite relatively high levels of Metformin in the urine. In the MNU model, when rats were placed on a high fat diet to induce a pre-diabetic state, we observed roughly a 20% decrease in tumor multiplicity in the metformin treated rats (P&gt; 0.10). In contrast, tamoxifen and Targretin (an RXR agonist) that were used as positive controls were highly effective in rats on a high fat diet. Metformin didn't decrease tumorigenesis in these standard models, but actually increased tumor formation (incidence, multiplicity, weight) in three of the four models at their HED. These results should particularly discourage any large phase clinical trials in individuals without insulin resistance. The final study certainly raises the question whether the agent might be effective in animals that are diabetic or show insulin resistance Citation Format: Clinton J. Grubbs, Margie L. Clapper, Joel M. Reid, Vernon E. Steele, Ronald A. Lubet. Metformin promotes tumorigenesis in animal models of cancer prevention. [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 2273. doi:10.1158/1538-7445.AM2013-2273

Abstract Enzymatic degradation of hyaluronan (HA), a key component of the extracellular matrix (ECM), can enhance tumor perfusion, improve delivery of chemotherapeutics, and enhance the effects of anti-tumor agents. HA accumulation has been correlated with local invasion, the presence of distal metastasis, higher tumor grade, and poorer overall survival. PEGPH20, a pegylated form of recombinant human hyaluronidase PH20, is an investigational therapeutic agent under clinical development for the treatment of patients with solid tumors that may accumulate HA. Preclinical studies have demonstrated that sustained HA removal, accomplished with PEGPH20, inhibits tumor growth and enhances chemotherapeutic activity in HA-rich xenografts and genetically engineered mouse tumor models. Twenty-six patients with advanced solid tumors were enrolled in a Phase 1 multi-center trial. Patients received weekly or twice weekly doses of IV PEGPH20 (0.5 - 5 μg/kg) for the first 4-week cycle, followed by once-weekly dosing for the subsequent 4-week cycles. Serial blood samples were drawn from each patient, and plasma concentrations were measured by an ultrasensitive hyaluronidase activity assay to assess PEGPH20 pharmacokinetics (PK). Plasma levels of HA catabolites were measured using a quantitative HPLC method to characterize PEGPH20 pharmacodynamics (PD). Other measures of PD activity were evaluated in selected patients, including DCE-MRI, DW-MRI, 18FDG-PET, textural analysis on CT, and histochemical staining of HA in tumor biopsies collected both before and after PEGPH20 treatment. Peak plasma PEGPH20 concentrations increased with dose, and plasma pharmacokinetics (PK) were well described by a linear PK model. Pre-treatment plasma HA levels were typically &lt;1 μg/mL and increased in a dose-dependent fashion after PEGPH20 treatment. Increased plasma HA corresponded with decreased HA staining in patients with available tumor biopsies. DCE-MRI analysis indicated early (24-48 hr) and rapid increase in tumor perfusion compared to baseline in 4 patients with serial MRI assessments. Pharmacodynamic activity was also demonstrated when pre-treatment 18FDG-PET scans were compared with images collected at scheduled times after PEGPH20 dosing. Reduction in FDG uptake exceeding 25% was demonstrated in 3 of 4 patients after one cycle of treatment, consistent with a partial metabolic response. These data are consistent with the mechanism of action reported in preclinical models, and results support continued evaluation of PEGPH20 in combination with anti-tumor agents via modification of the ECM. Citation Format: Ping Jiang, Daniel C. Maneval, Ramesh K. Ramanathan, Jeffrey R. Infante, Mitesh Borad, Alberto Bessudo, Patricia LoRusso, Barry J. Sugarman, Deborah Carson, Marie A. Printz, Curtis B. Thompson, Paneer Selvam, Joy Zhu, Ronald Korn, H Michael Shepard, Gregory I. Frost. Phase 1 pharmacodyamic activity of multiple-dose PEGylated hyaluronidase PH20 (PEGPH20) in patients with solid tumors. [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 3375. doi:10.1158/1538-7445.AM2013-3375

We treated 26 eyes of 25 young patients having a mean age of 30 years with intravitreal vascular endothelial growth factor (VEGF) inhibitor for choroidal new vessel (CNV) formation overlying choroidal osteoma over a mean follow-up of 26 months. Mean number of injections was 2.4 at 6 months, 3.2 at 12 months, and 5.5 at 24 months. CNV was subfoveal in 14 eyes, juxtafoveal in 5, extrafoveal in 5, and peripapillary in 2. By paired comparison, mean decrease from baseline was 119.7 microns at 6 months (n=15;P=0.001), 105.3 microns at 1 year (n=10;P=0.03), and 157.6 microns at 2 years (n=7;P=0.08). BCVA improved by 3.3 lines at 6 months after therapy (n=26;P<0.001), 2.8 lines (n=20;P=0.01) at 1 year, and 3.1 lines (n=13;P=0.049) at 2 years. We conclude that intravitreal anti-VEGF injections improve vision in majority of eyes with CNV from choroidal osteoma.