Citations

Abstract Background: Ovarian cancer is a leading cause of cancer-related death among women. In an effort to understand contributors to disease outcome, we evaluated single-nucleotide polymorphisms (SNP) previously associated with ovarian cancer recurrence or survival, specifically in angiogenesis, inflammation, mitosis, and drug disposition genes. Methods: Twenty-seven SNPs in VHL, HGF, IL18, PRKACB, ABCB1, CYP2C8, ERCC2, and ERCC1 previously associated with ovarian cancer outcome were genotyped in 10,084 invasive cases from 28 studies from the Ovarian Cancer Association Consortium with over 37,000-observed person-years and 4,478 deaths. Cox proportional hazards models were used to examine the association between candidate SNPs and ovarian cancer recurrence or survival with and without adjustment for key covariates. Results: We observed no association between genotype and ovarian cancer recurrence or survival for any of the SNPs examined. Conclusions: These results refute prior associations between these SNPs and ovarian cancer outcome and underscore the importance of maximally powered genetic association studies. Impact: These variants should not be used in prognostic models. Alternate approaches to uncovering inherited prognostic factors, if they exist, are needed. Cancer Epidemiol Biomarkers Prev; 22(5); 987–. ©2013 AACR.

We recently demonstrated a diurnal pattern to insulin action (i.e., insulin sensitivity [SI]) in healthy individuals with higher SI at breakfast than at dinner. To determine whether such a pattern exists in type 1 diabetes, we studied 19 subjects with C-peptide–negative diabetes (HbA1c 7.1 ± 0.6%) on insulin pump therapy with normal gastric emptying. Identical mixed meals were ingested during breakfast, lunch, and dinner at 0700, 1300, and 1900 h in randomized Latin square of order on 3 consecutive days when measured daily physical activity was equal. The triple tracer technique enabled measurement of glucose fluxes. Insulin was administered according to the customary insulin:carbohydrate ratio for each participant. Although postprandial glucose excursions did not differ among meals, insulin concentration was higher (P < 0.01) and endogenous glucose production less suppressed (P < 0.049) at breakfast than at lunch. There were no differences in meal glucose appearance or in glucose disappearance between meals. Although there was no statistical difference (P = 0.34) in SI between meals in type 1 diabetic subjects, the diurnal pattern of SI taken across the three meals in its entirety differed (P = 0.016) from that of healthy subjects. Although the pattern in healthy subjects showed decreasing SI between breakfast and lunch, the reverse SI pattern was observed in type 1 diabetic subjects. The results suggest that in contrast to healthy subjects, SI diurnal pattern in type 1 diabetes is specific to the individual and cannot be extrapolated to the type 1 diabetic population as a whole, implying that artificial pancreas algorithms may need to be personalized.

Background— Hemodynamic assessment after volume challenge has been proposed as a way to identify heart failure with preserved ejection fraction. However, the normal hemodynamic response to a volume challenge and how age and sex affect this relationship remain unknown. Methods and Results— Sixty healthy subjects underwent right heart catheterization to measure age- and sex-related normative responses of pulmonary capillary wedge pressure and mean pulmonary arterial pressure to volume loading with rapid saline infusion (100–200 mL/min). Hemodynamic responses to saline infusion in heart failure with preserved ejection fraction (n=11) were then compared with those of healthy young (<50 years of age) and older (≥50 years of age) subjects. In healthy subjects, pulmonary capillary wedge pressure increased from 10±2 to 16±3 mm Hg after ~1 L and to 20±3 mm Hg after ~2 L of saline infusion. Older women displayed a steeper increase in pulmonary capillary wedge pressure relative to volume infused (16±4 mm Hg·L −1 ·m 2 ) than the other 3 groups ( P ≤0.019). Saline infusion resulted in a greater increase in mean pulmonary arterial pressure relative to cardiac output in women compared with men regardless of age. Subjects with heart failure with preserved ejection fraction exhibited a steeper increase in pulmonary capillary wedge pressure relative to infused volume (25±12 mm Hg·L −1 ·m 2 ) than healthy young and older subjects ( P ≤0.005). Conclusions— Filling pressures rise significantly with volume loading, even in healthy volunteers. Older women and patients with heart failure with preserved ejection fraction exhibit the largest increases in pulmonary capillary wedge pressure and mean pulmonary arterial pressure.

OBJECTIVE Physical activity (PA), even at low intensity, promotes health and improves hyperglycemia. However, the effect of low-intensity PA captured with accelerometery on glucose variability in healthy individuals and patients with type 1 diabetes has not been examined. Quantifying the effects of PA on glycemic variability would improve artificial endocrine pancreas (AEP) algorithms. RESEARCH DESIGN AND METHODS We studied 12 healthy control subjects (five males, 37.7 ± 13.7 years of age) and 12 patients with type 1 diabetes (five males, 37.4 ± 14.2 years of age) for 88 h. Participants performed PA approximating a threefold increase over their basal metabolic rate. PA was captured using a PA-monitoring system, and interstitial fluid glucose concentrations were captured with continuous glucose monitors. In random order, one meal per day was followed by inactivity, and the other meals were followed by walking. Glucose and PA data for a total of 216 meals were analyzed from 30 min prior to meal ingestion to 270 min postmeal. RESULTS In healthy subjects, the incremental glucose area under the curve was 4.5 mmol/L/270 min for meals followed by walking, whereas it was 9.6 mmol/L/270 min (P = 0.022) for meals followed by inactivity. The corresponding glucose excursions for those with type 1 diabetes were 7.5 mmol/L/270 min and 18.4 mmol/L/270 min, respectively (P &lt; 0.001). CONCLUSIONS Walking significantly impacts postprandial glucose excursions in healthy populations and in those with type 1 diabetes. AEP algorithms incorporating PA may enhance tight glycemic control end points.

Abstract We determined the prognostic relevance of CD25 (IL-2 receptor-α) expression in 657 patients (≤ 60 years) with de novo acute myeloid leukemia (AML) treated in the Eastern Cooperative Oncology Group trial, E1900. We identified CD25POS myeloblasts in 87 patients (13%), of whom 92% had intermediate-risk cytogenetics. CD25 expression correlated with expression of stem cell antigen CD123. In multivariate analysis, controlled for prognostic baseline characteristics and daunorubicin dose, CD25POS patients had inferior complete remission rates (P = .0005) and overall survival (P < .0001) compared with CD25NEG cases. In a subset of 396 patients, we integrated CD25 expression with somatic mutation status to determine whether CD25 impacted outcome independent of prognostic mutations. CD25 was positively correlated with internal tandem duplications in FLT3 (FLT3-ITD), DNMT3A, and NPM1 mutations. The adverse prognostic impact of FLT3-ITDPOS AML was restricted to CD25POS patients. CD25 expression improved AML prognostication independent of integrated, cytogenetic and mutational data, such that it reallocated 11% of patients with intermediate-risk disease to the unfavorable-risk group. Gene expression analysis revealed that CD25POS status correlated with the expression of previously reported leukemia stem cell signatures. We conclude that CD25POS status provides prognostic relevance in AML independent of known biomarkers and is correlated with stem cell gene-expression signatures associated with adverse outcome in AML.

Although the quality of care delivered within the Florida Initiative for Quality Cancer Care practices seems to be high, several components of care were identified that warrant further scrutiny on a systemic level and at individual centers.

Abstract Background: Based on recent breast cancer literature, we hypothesized that there could be substantive differences in apparent efficacy estimates using a log-normal (LN) survival model rather than with standard Kaplan-Meier (K-M) or Cox model methods. While both Cox and LN survival analyses offer greater specification by individual patient characteristics, the LN model may more robustly estimate survival under model misspecification. Methods: We recently pooled data for 5 NCIC CTG primary breast cancer trials: MA.5, MA.12, MA.14, MA.21, and MA.27. The total patient count for patients who received at least 1 dose of trial therapy is 11,253. Compilation included definition of STEEP endpoints (C Hudis, JCO, 2008) and standardized factor categorizations. The primary endpoint is Breast Cancer Free Interval (BCFI) defined as the time from randomization until recurrence: first local invasive or DCIS; regional, or distant; contralateral invasive or DCIS; or death from breast cancer. We found substantive evidence of non-proportionality for 7 factors compiled for the meta-analyses. In this work, we fit multivariate Cox and LN models with these 7 factors, lymph node status and pathologic T status. We then compare BCFI efficacy estimates for patient and tumour characteristics at 1-, 3-, and 5-years obtained with K-M, Cox, and LN models. Results: There was evidence that the Cox assumption of proportional hazards was violated for 7 factors: age, menopausal status, hormone receptor status, anthracycline use, chemotherapy use, race, and ECOG performance status. Differences between models were intrinsically affected by timing and extent of non-proportionality; there was no consistent pattern. In particular, investigations to date indicate efficacy estimates with absolute differences between K-M, Cox and LN estimates which varied by time of assessment: at 1-year 0.0 to 6.7%, at 3-years 0.4 to 18.6%, and at 5-years 0.2 to 17.0%. BCFI estimates with the K-M were inconsistently closer to those with the LN or Cox model: for K-M to Cox at 1-year 0.4 to 5.2%, at 3-years 0.4 to 15%, at 5-years 0.4 to 14.3%; for K-M to LN at 1-year 0.0 to 6.7%, at 3-years 0.5 to 18.6%, at 5-years 0.2 to 17.0%; for Cox to LN at 1-year 0.8 to 1.8%, at 3-years 1.9 to 6.0%, at 5-years 0.6 to 5.7%. K-M and Cox models have step-wise adjustments at events for K-M and Cox, rather than smooth modeling with the LN. Discussion: Even with reasonably large population subgroups, there were substantive differences in apparent survival (0.0 to 18.6%) between K-M, Cox and LN model types. The magnitude of differences in survival estimates was large enough to be clinically relevant and warrant further consideration as we evaluate new therapies and prognostic/predictive factors. We will be statistically investigating framework robustness under differing levels of model misspecification. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-14-01.

Background. Physical activity is important for multiple aspects of health, for example, cancer prevention, metabolic disease treatment, cardiovascular health, and obesity management. Despite the improved capability of measuring physical activity in the research arena, the options are scarce and less reliable for measurements in free-living people. In this article, the authors tested the validity of a robust stand-alone patient-operated Accelerometer System that can measure physical activity and sedentariness in active people. Methods. Thirty subjects wore the Accelerometer System along with the validated physical activity monitoring system (PAMS) with different body postures and during graded walking at 7 velocities. Energy expenditure was measured using indirect calorimetry. Results. In all the 30 subjects, the Accelerometer System distinguished sedentary and walking activity reliably even with ½ mph increments in walking and was accurate and precise compared with PAMS, with an intraclass correlation coefficient ( r2 > .98). The Accelerometer System showed excellent sequential increases with increase in walking velocity and energy expenditure ( r2 > .9). Conclusion. A stand-alone Accelerometer System was accurate and reliable in measuring and quantifying physical activity in the laboratory setting.