Citations

Abstract Accurate prediction of thrombosis in essential thrombocythemia (ET) provides the platform for prospective studies exploring preventive measures. Current risk stratification for thrombosis in ET is 2-tiered and considers low- and high-risk categories based on the respective absence or presence of either age > 60 years or history of thrombosis. In an international study of 891 patients with World Health Organization (WHO)–defined ET, we identified additional independent risk factors including cardiovascular risk factors and JAK2V617F. Accordingly, we assigned risk scores based on multivariable analysis–derived hazard ratios (HRs) to age > 60 years (HR = 1.5; 1 point), thrombosis history (HR = 1.9; 2 points), cardiovascular risk factors (HR = 1.6; 1 point), and JAK2V617F (HR = 2.0; 2 points) and subsequently devised a 3-tiered prognostic model (low-risk = < 2 points; intermediate-risk = 2 points; and high-risk = > 2 points) using a training set of 535 patients and validated the results in the remaining cohort (n = 356; internal validation set) and in an external validation set (n = 329). Considering all 3 cohorts (n = 1220), the 3-tiered new prognostic model (low-risk n = 474 vs intermediate-risk n = 471 vs high-risk n = 275), with a respective thrombosis risk of 1.03% of patients/y versus 2.35% of patients/y versus 3.56% of patients/y, outperformed the 2-tiered (low-risk 0.95% of patients/y vs high-risk 2.86% of patients/y) conventional risk stratification in predicting future vascular events.

OBJECTIVE To investigate the pharmacokinetics (PK), pharmacodynamics, and safety of single-dose RM-131 in type 2 diabetic patients with gastrointestinal cardinal symptoms (GCSI) and previously documented delayed gastric emptying (DGE). RESEARCH DESIGN AND METHODS In a randomized crossover study, 10 female patients received RM-131 (100 μg s.c.) or placebo and underwent scintigraphic gastric emptying (GE) and colonic filling at 6 h (CF6) of a solid-liquid meal administered 30 min postdosing. Adverse events, plasma glucose, and hormonal levels were assessed. GCSI daily diary (GCSI-DD) was completed during treatments. PK was assessed in this cohort and healthy volunteers (HVs). RESULTS At screening, HbA1c was 7.2 ± 0.4% (SEM) and total GCSI-DD score was 1.32 ± 0.21. RM-131 accelerated GE t1/2 of solids (P = 0.011); mean difference (Δ) in solid GE t1/2 was 68.3 min (95% CI 20–117) or 66.1%. There were numerical differences in GE lag time, CF6 solids, and GE t1/2 liquids (all P &lt; 0.14). With a significant (P &lt; 0.014) order effect, further analysis of the first treatment period (n = 5 per group) confirmed significant RM-131 effects on GE t1/2 (solids, P = 0.016; liquids, P = 0.024; CF6, P = 0.013). PK was similar in DGE patients and HVs. There were increases in 120-min blood glucose (P = 0.07) as well as 30–90-min area under the curve (AUC) levels of growth hormone, cortisol, and prolactin (all P &lt; 0.02) with single-dose RM-131. Only light-headedness was reported more on RM-131. CONCLUSIONS RM-131 greatly accelerates the GE of solids in patients with type 2 diabetes and documented DGE. PK is similar in diabetic patients and HVs.

Objective Pancreatic cysts are commonly detected in patients undergoing pancreatic imaging. Better approaches are needed to characterise these lesions. In this study we evaluated the utility of detecting mutant DNA in secretin-stimulated pancreatic juice. Design Secretin-stimulated pancreatic juice was collected from the duodenum of 291 subjects enrolled in Cancer of the Pancreas Screening trials at five US academic medical centres. The study population included subjects with a familial predisposition to pancreatic cancer who underwent pancreatic screening, and disease controls with normal pancreata, chronic pancreatitis, sporadic intraductal papillary mucinous neoplasm (IPMN) or other neoplasms. Somatic GNAS mutations (reported prevalence ∼66% of IPMNs) were measured using digital high-resolution melt-curve analysis and pyrosequencing. Results GNAS mutations were detected in secretin-stimulated pancreatic juice samples of 50 of 78 familial and sporadic cases of IPMN(s) (64.1%), 15 of 33 (45.5%) with only diminutive cysts (<5 mm), but none of 57 disease controls. GNAS mutations were also detected in five of 123 screened subjects without a pancreatic cyst. Among 97 subjects who had serial pancreatic evaluations, GNAS mutations detected in baseline juice samples predicted subsequent emergence or increasing size of pancreatic cysts. Conclusion Duodenal collections of secretin-stimulated pancreatic juice from patients with IPMNs have a similar prevalence of mutant GNAS to primary IPMNs, indicating that these samples are an excellent source of mutant DNA from the pancreas. The detection of GNAS mutations before an IPMN is visible suggests that analysis of pancreatic juice has the potential to help in the risk stratification and surveillance of patients undergoing pancreatic screening.

Abstract Pancreatic cancer is highly lethal with an estimated 5-year relative survival rate of less than 5%. A genome wide association study (GWAS) of pancreatic cancer (PanScan) conducted within the NCI Cohort Consortium and the Pancreatic Cancer Case-Control Consortium (PANC4) recently identified four common susceptibility loci for pancreatic cancer on chromosomes 1q32.1, 5p15.33, 9q34.2 and 13q22.1. To investigate how these germline variants influence pancreatic cancer risk, we are employing both genome wide and targeted approaches. For the former, we are characterizing the epigenome and transcriptome of pancreatic cell lines and tissue samples for genomic annotation and prioritization of methods to use in targeted approaches with the aim of directly linking pancreatic cancer risk variants to molecular phenotypes and mechanisms that underlie the association signals. As an example of our approach we will present results in a pancreatic cancer susceptibility locus on chromosome 1q32.2 marked by SNP (single nucleotide polymorphism) rs3790844. This SNP is located in the first intron of the NR5A2 gene that encodes a nuclear receptor of the Ftz-F1 family known to be involved in pancreatic development, cholesterol and bile acid homeostasis, steroidogenesis and cell proliferation. In ChIP-sequencing and MeDIP-chip experiments, we observed repressive histone modification marks (H3K27me3) and regions of DNA methylation in the NR5A2 gene locus in pancreatic cell lines whereas only a few weak positive histone modification marks were observed (H3K4me1 and H3K4me3). This pattern of epigenetic marks correlates well with low expression of NR5A2 in the same cell lines. Expression of the NR5A2 gene at the RNA level is high in normal pancreatic tissue samples as compared to stage I-III pancreatic adenocarcinoma, most islet cell and neuroendocrine tumors. Using immunohistochemistry, nuclear NR5A2 was detected in normal acinar cells and – at lower levels – in normal ductal cells. The protein was also expressed in low and high grade PanINs and in the majority of PDAC analyzed. Our analysis of the tissue specific expression of NR5A2 shows that it is mainly expressed in normal pancreas, colon, small intestine, liver and breast but detected at low levels or not at all in most other tissue types and cancer cell lines. Furthermore we have identified a novel NR5A2 transcript by rapid amplification of cDNA ends (RACE) and mapped a promoter in front of this transcript in the genomic region corresponding to first intron of the two annotated Refseq transcripts. Establishing a comprehensive catalog of epigenetic patterns coupled with targeted analysis to correlate risk variants to molecular phenotypes could provide functional plausibility for known pancreatic cancer association signals discovered by GWAS findings. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4965. doi:10.1158/1538-7445.AM2011-4965

Abstract Diagnosis of essential thrombocythemia (ET) has been updated in the last World Health Organization (WHO) classification. We developed a prognostic model to predict survival at diagnosis, named IPSET (International Prognostic Score for ET), studying patients with WHO-defined ET. Age 60 years or older, leukocyte count ≥ 11 × 109/L, and prior thrombosis significantly affected survival, by multivariable Cox regression. On the basis of the hazard ratio, we assigned 2 points to age and 1 each to leukocyte count and thrombosis. So, the IPSET model allocated 867 patients into 3 risk categories with significantly different survival: low (sum of points = 0; median survival not reached), intermediate (sum = 1-2; median survival 24.5 years), and high (sum = 3-4, median survival 13.8 years). The IPSET model was further validated in 2 independent cohorts including 132 WHO-defined ET and 234 Polycythemia Vera Study Group–defined ET patients. The IPSET model was able to predict the occurrence of thrombosis, and not to predict post-ET myelofibrosis. In conclusion, IPSET, based on age ≥ 60 years, leukocyte count ≥ 11 × 109/L, and history of thrombosis allows prognostic assessment of WHO-defined ET and the validation process makes IPSET applicable in all patients phenotypically appearing as ET.

AbstractIn the present study, we investigated disease characteristics and clinical outcome in young patients (< 40 years) with World Health Organization (WHO)–defined essential thrombocythemia (ET) compared with early/prefibrotic primary myelofibrosis (PMF) with presenting thrombocythemia. We recruited 213 young patients (median age, 33.6 years), ncluding 178 patients (84%) with WHO-defined ET and 35 patients (16%) showing early PMF. Median follow-up time was 7.5 years. A trend for more overall thrombotic complications, particularly arterial, was seen in early PMF compared with ET. Progression to overt myelofibrosis was 3% in ET and 9% in early PMF, but no transformation into acute leukemia was observed. Combining all adverse events (thrombosis, bleeding, and myelofibrosis), the rate was significantly different (1.29% vs 3.43% of patients/year, P = .01) in WHO-ET and early PMF, respectively. In multivariate analysis, early PMF and the JAK2V617F mutation emerged as independent factors predicting cumulative adverse events.

Abstract —At the community level, the effect of national programs in increasing hypertension awareness, prevention, treatment, and control is unclear. This study evaluated the degree of detection and control of high blood pressure in a random population-based sample of Olmsted County, Minnesota, residents ≥45 years old, of whom 636 subjects among 1245 eligible residents agreed to participate. Home interview and home and office measurements of blood pressure were used to estimate awareness, treatment, and control rates for hypertension in the community. Mean blood pressures (±SD) were 138/80±20/12 mm Hg for men and 137/76±23/11 mm Hg for women. The overall prevalence of hypertension was 53%. The percentage of subjects with treated and controlled hypertension was 16.6%. Thirty-nine percent of subjects were unaware of their hypertension. Despite clinical trial evidence of reduced morbidity and mortality with antihypertensive therapy, recently reported national data suggest a leveling-off trend for treatment and control of hypertension. This population-based study supports these observations and suggests that at a community level, hypertension awareness and blood pressure control rates are suboptimal, presumably because of decreased attention to the detection and control of hypertension.

Background —Atrial septal aneurysm (ASA) is a putative risk factor for cardioembolism. However, the frequency of ASA in the general population has not been adequately determined. Therefore, the frequency in patients with cerebral ischemic events, compared with the frequency in the general population, is poorly defined. We sought to determine the frequency of ASA in the general population and to compare the frequency of ASA in patients with cerebral ischemic events with the frequency in the general population. Methods and Results —The frequency of ASA in the population was determined in 363 subjects, a sample of the participants in the Stroke Prevention: Assessment of Risk in a Community study (control subjects), and was compared with the frequency in 355 age- and sex-matched patients undergoing transesophageal echocardiography in search of a cardiac source of embolism after a focal cerebral ischemic event. The proportion with ASA was 7.9% in patients versus 2.2% in control subjects ( P =0.002; odds ratio of ASA, 3.65; 95% CI, 1.64 to 8.13, in patients versus control subjects). Patent foramen ovale (PFO) was detected with contrast injections in 56% of subjects with ASA. The presence of ASA predicted the presence of PFO (odds ratio of PFO, 4.57; 95% CI, 2.18 to 9.57, in subjects with versus those without ASA). In 86% of subjects with ASA and cerebral ischemia, transesophageal echocardiography did not detect an alternative source of cardioembolism other than an associated PFO. Conclusions —The prevalence of ASA based on this population-based study is 2.2%. The frequency of ASA is relatively higher in patients evaluated with transesophageal echocardiography after a cerebral ischemic event. ASA is frequently associated with PFO, suggesting paradoxical embolism as a mechanism of cardioembolism. In patients with cerebral ischemia and ASA, ASA (with or without PFO) commonly is the only potential cardioembolic source detected with transesophageal echocardiography.

Background —Atherosclerosis of the thoracic aorta is associated with stroke. The association between hypertension, a major risk factor for stroke, and aortic atherosclerosis has not been determined in the general population. Methods and Results —Transesophageal echocardiography was performed in 581 subjects, a random sample of the Olmsted County (Minnesota) population aged ≥45 years participating in the Stroke Prevention: Assessment of Risk in a Community (SPARC) study. Blood pressure was assessed by multiple office measurements and 24-hour ambulatory blood pressure monitoring. The association between blood pressure variables and aortic atherosclerosis was evaluated by multiple logistic regression, adjusting for other associated variables. Among subjects with atherosclerosis, blood pressure variables associated with complex aortic atherosclerosis (protruding plaques ≥4 mm thick, mobile debris, or ulceration) were determined. Age and smoking history were independently associated with aortic atherosclerosis of any degree ( P ≤0.001) and with complex atherosclerosis ( P =0.002), whereas sex, diabetes mellitus, and body mass index were not. Multiple systolic and pulse pressure variables (office and ambulatory), but none of the diastolic blood pressure variables, were associated with atherosclerosis and complex atherosclerosis, adjusting for age and smoking. Among subjects with atherosclerosis, the odds of complex atherosclerosis increased as ambulatory out-of-bed systolic blood pressure increased (odds ratio 1.43 per 10 mm Hg increase, 95% CI 1.10 to 1.87) and with hypertension treatment, adjusting for age and smoking history. Conclusions —High blood pressure is independently associated with aortic atherosclerosis. Among subjects with atherosclerosis, high blood pressure is associated with complex atherosclerosis.