Citations

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 DNA methylation profiles could signify the risk of prostate cancer and predict the progression of cancer before the appearance of clinical symptoms. Specific CpG sites methylation of genes identified in our study could be used to improve the sensitivity and specificity for early diagnosis and to predict the risk of prostate cancer recurrence. To identify methylation changes associated with prostate cancer, we measured gene methylation using the Infinium Human Methylation27 bead chips. Tissue DNA isolation and bisulfite conversion was done using ZR Genomic DNA kit and EZ methylation kit. The methylation27 microarrays was used to analyze methylation of 27,578 CpG sites of 14,495 genes in 198 tumor tissues and 40 matched normal tissues. Methylation data was processed using the Genome Studio software, differentially methylated genes identified using one-way analysis of variance, and correction for multiple testing done using the false discovery rate q-value. To identify putative diagnostic and prognostic biomarkers we performed four subgroup comparisons: tumor vs. matched normal, recurrent tumors vs. non-recurrent tumors, clinical recurrence vs. biochemical recurrence, and systemic recurrence vs. local recurrence. Clinicopathological and molecular features including patient preoperative PSA levels, Gelason score, TNM stage, GPSM, recurrence type, were also evaluated for subgroup discrimination. Discriminative subgroup candidate methlyation markers were selected using a p value &lt;0.05 and a mean difference between two contrast groups &gt;0.05. Between the tumor and matched normal tissue samples, 164 CpG sites representing 147 genes were identified as significantly differentially methylated (p&lt;9.99E-25, fold change&gt;2.0). Between recurrent tumor and non-recurrent tumor tissues there were 78 CpG sites representing 75 genes that were significantly differentially methylated (p &lt;0.002, fold change &gt;1.5). Between clinically recurrent and biochemically recurrent tumors, 16 CpG sites representing 16 genes were significantly differentially methylated (p &lt;0.05, fold change &gt;1.5). Between systemic recurrent and local recurrent tumors there were 73 CpG sites representing 68 genes that were significantly differentially methylated (p &lt;0.01, fold change &gt;1.5) Our analysis revealed differential methylation of the genes, implicating their role in prostate cancer development and progression. We demonstrated that the hypermethylation of genes could be used as a sensitive molecular tool in detection of prostate tumorigenesis and prediction of tumor progression. 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 109. doi:10.1158/1538-7445.AM2011-109

Abstract Background: Activation of oncology trials is a lengthy and complex process. Recent literature has identified numerous opportunities to improve activation timelines1, 2. The Multiple Myeloma Research Consortium (MMRC) has implemented several processes to identify and overcome myeloma clinical trial activation barriers within the consortium network of 14 North American cancer centers. We examined the impact of these processes preand post- implementation and also compared activation times with published clinical trial metrics data. Methods/Results: 12 MMRC-facilitated trials had sufficient trial data available for review within the study period of May 2006 to March 2009. Activation time was defined as the time from a center's receipt of the final clinical trial protocol from the sponsor, to the time the first patient was enrolled into a trial at any MMRC participating center. The earlier group (EG) of MMRC trials (n=7) required a mean of 257 calendar days for activation, comparable to the mean published data of 251 calendar days1. The more recent group (RG) of MMRC trials (n=5) required a mean of 158 calendar days for activation, representing a 38% shortening of activation time. Additionally, implementation of standardized processes and rigorous project management resulted in a reduction in activation times for all MMRC centers in a given trial from a mean of 7.5 months to a mean of 5.1 months. Improving the mean time of several several specific steps in the process including time to initial protocol review submission from receipt (EG=37 vs. RG=19 days), scientific review committee time (EG=98 vs. RG=55 days), and the time from trial opening to first patient dosed (EG=74 vs. RG=27 days) contributed to the overall decrease in activation times. The EG metrics data are comparable to published data1 for each process step. Conclusion: The MMRC member institutions have seen substantial improvements in trial activation times and are in the process of implementing additional processes to further improve protocol development and trial conduct metrics. The efficiencies and process improvements realized from application of rigorous MMRC project management resources and the standardization of contracting and other key activities may be applied in other areas of oncology clinical trials beyond multiple myeloma. With increasing numbers of new oncology agents to be evaluated and greater pressure on trial sponsors to introduce efficiencies into trial timelines, overcoming such barriers is of critical importance. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B58.

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.

Background —We tested sympathetic and cardiovagal baroreflex sensitivity during the placebo or “low-hormone” phase (LH) and 2 to 3 weeks later during the “high-hormone” phase (HH) of oral contraceptive (OC) use in 9 women. Methods and Results —Sympathetic baroreflex sensitivity was assessed by intravenous doses of sodium nitroprusside and phenylephrine and defined as the slope relating muscle sympathetic nerve activity (by microneurography) and diastolic blood pressure. Cardiovagal baroreflex sensitivity was defined as the slope relating R-R interval and systolic blood pressure. No difference was observed for resting muscle sympathetic nerve activity or plasma norepinephrine levels. However, sympathetic baroreflex sensitivity was greater and mean arterial pressure was higher during the LH than in the HH phase. Similarly, cardiovagal baroreflex sensitivity was greater in the LH than in the HH phase. Conclusions —Sympathetic and cardiovagal baroreflex sensitivities change during the 28-day course of OC use. Furthermore, changes in baroreflex sensitivity with OC differ from changes in baroreflex sensitivity during the normal menstrual cycle.

Background —The renin-angiotensin system regulates blood pressure through its effects on vascular tone, renal hemodynamics, and renal sodium and fluid balance. Methods and Results —Using data from a large population-based sample of 1488 siblings having a mean age of 14.8 years and belonging to the youngest generation of 583 randomly ascertained three-generation pedigrees from Rochester, Minn, we carried out variance components–based linkage analyses to evaluate the contribution of variation in four renin-angiotensin system gene regions (angiotensinogen, renin, angiotensin I–converting enzyme, and angiotensin II receptor type 1) to interindividual variation in systolic, diastolic, and mean arterial pressure. We rejected the null hypothesis that allelic variation in the region of the angiotensin-converting enzyme ( ACE ) gene does not contribute to interindividual blood pressure variability. After conditioning on measured covariates, variation in this region accounted for 0%, 13% ( P =0.04), and 16% ( P =0.04) of the interindividual variance in systolic, diastolic, and mean arterial pressures, respectively. These estimates were even greater in a subset of subjects with a positive family history of hypertension (0%, 29% [ P =0.005], and 32% [ P <0.005], respectively). In sex-specific analyses, genetic variation in the region of the ACE gene significantly influenced interindividual blood pressure variation in males (37% for SBP [ P =0.03], 38% for DBP [ P =0.04], and 53% for MAP [ P <0.005]) but not in females. Conclusions —Although it is possible that variation in a gene near the ACE gene may explain the observed results, knowledge about the physiological involvement of ACE in blood pressure regulation supports the proposition that the ACE gene itself influences blood pressure variability in a sex-specific manner.

Background The growth of the US cardiac transplant waiting list has outpaced the increase in donors, resulting in a widening gap between the number of waiting recipients and available donors. These trends have generated concern that longer waiting times may result in more patients deteriorating to urgent status and that transplanting only patients who are in an advanced state of decompensation will reduce posttransplant survival. Furthermore, the shortage of donors may result in extending the guidelines for donor acceptability to a degree that increases graft failure and posttransplant mortality. We measured these secular trends in the Cardiac Transplant Research Database to provide current data on time-dependent changes in US cardiac transplant practice and survival. Methods and Results At the time of this analysis, the Cardiac Transplant Research Database included all 2749 patients transplanted from January 1, 1990, to June 30, 1994, in the 25 participating transplant centers. During this 4.5-year period, the median waiting time for recipients who received a transplant increased from 2.7 to 3.5 months ( P <.0001), and the proportion of recipients whose status was urgent at transplantation increased from 41% to 60% ( P <.0001). Donor ischemic time increased from 150 to 166 minutes ( P <.0001), and the proportion of donors requiring pressor support increased from 68% to 85% ( P <.0001). Despite these changes in practice, the 1-year survival rate remained constant at 84% during this 4.5-year interval. There was no significant difference in 1-year survival rate between urgent status patients (83%) and nonurgent status patients (85%) ( P =.08). Conclusions The widening gap between the number of waiting recipients and the number of donors has resulted in a continuing trend toward transplanting urgent status recipients and to a liberalization of donor acceptance criteria. Despite these changes, posttransplant survival has remained constant.

Background —Our goal was to test sympathetic and cardiovagal baroreflex sensitivity and the transduction of sympathetic traffic into vascular resistance during the early follicular (EF) and midluteal (ML) phases of the menstrual cycle. Methods and Results —Sympathetic baroreflex sensitivity was assessed by lowering and raising blood pressure with intravenous bolus doses of sodium nitroprusside and phenylephrine. It was defined as the slope relating muscle sympathetic nerve activity (MSNA; determined by microneurography) and diastolic blood pressure. Cardiovagal baroreflex sensitivity was defined as the slope relating R-R interval and systolic blood pressure. Vascular transduction was evaluated during ischemic handgrip exercise and postexercise ischemia, and it was defined as the slope relating MSNA and calf vascular resistance (determined by plethysmography). Resting MSNA (EF, 1170±151 U/min; ML, 2252±251 U/min; P <0.001) and plasma norepinephrine levels (EF, 240±21 pg/mL; ML, 294±25 pg/mL; P =0.025) were significantly higher in the ML than in the EF phase. Furthermore, sympathetic baroreflex sensitivity was greater during the ML than the EF phase in every subject (MSNA/diastolic blood pressure slopes: EF, −4.15; FL, −5.42; P =0.005). No significant differences in cardiovagal baroreflex sensitivity or vascular transduction were observed. Conclusions —The present study suggests that the hormonal fluctuations that occur during the normal menstrual cycle may alter sympathetic outflow but not the transduction of sympathetic activity into vascular resistance.