Ideal Cohort Research Articles

Brain Metastases in Women with Inflammatory Breast Cancer (IBC): Incidence, Treatment and Outcome.

Abstract Background: Brain metastases are an uncommon metastatic recurrence site in breast cancer with a median incidence of approximately 6% in unselected populations. Inflammatory breast cancer (IBC) is an aggressive disease associated with dismal outcome. The purpose of this study was to determine the incidence of and survival following brain metastases among women with IBC.Material and Methods: Two hundred and six women with newly diagnosed stage III or IV IBC diagnosed between the period of between 2003 and 2008 were identified in a prospectively maintained IBC database at the MD Anderson Cancer Center. Cumulative incidence of brain metastases was computed. Cox proportional hazards models were fitted to explore factors that predict for the development of brain metastases. Survival was computed using the Kaplan-Meier product limit method.Results: Median follow-up was 20 months. Eighty three (40.3%) women had de-novo stage IV disease and 123 (59.7%) had stage III disease at diagnosis. Thirty-three (16%) patients developed brain metastases with a cumulative incidence at 1 and 3 years of 2.7% and 22% respectively. Eleven (5.3%) patients developed brain metastases as the first site of recurrence with cumulative incidence at 1 and 3 years of 1.6% and 6.7% respectively. In the multivariable model, no specific factor was observed to be significantly associated with time to brain metastases, including HER-2 status. Median overall survival for the whole cohort was not reached. 3-year overall survival for the whole cohort was 78% (95% CI 69%-86%). Median survival following a diagnosis of brain metastases for all women who developed brain metastases or those who developed brain metastases as the first site of recurrence was 6 months.Conclusion: In this single-institutional study, women with IBC demonstrated a high early incidence of brain metastases associated with poor survival. As such IBC may be an ideal cohort to target screening procedures for brain metastases and/or enrollment of these women in clinical trials evaluating additional adjuvant preventive strategies. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2102.

A Population-Based, Longitudinal Study of Erectile Dysfunction and Future Coronary Artery Disease

The prevalence of erectile dysfunction (ED) increases with age. It occurs in 5% to 10% of men aged 40 years and 40% to 60% of men aged 70 years. There are a number of pathophysiologic links between ED and atherosclerotic vascular diseases and its presence may be a precursor of coronary artery disease (CAD) and cerebrovascular disease. Two prior studies found an association between ED and the risk of future cardiac events but both had deficiencies in design. This population-based, prospective cohort study investigated the association between the presence of ED and the risk of development of future CAD and the role of age among a cohort of men followed from 1996 to 2005. Biennial screening was carried out during the study period in a random sample of 1402 community-dwelling men with a regular sexual partner and without known CAD for the presence of ED. Time-dependent bivariate and multivariate Cox proportional hazards regression models were used to assess the association between ED and CAD and the role of age. At baseline, the prevalence of ED was 2.4% in men aged 40 years, 5.6% in men aged 50 years, 17.0% among men aged 60 years, and 38.8% in men aged 70 years or older. For men without ED at baseline, the CAD incidence rates per 1000 person-years were 0.94 for men aged 40 years, 5.09 for men aged 50 years, 10.72 for men aged 60 years, and 23.30 for men aged 70 years or older. In contrast, among men with ED at baseline, the CAD incidence rates per 1000 person-years were much higher: 48.52 for men aged 40 years, 27.15 for men aged 50 years, 23.97 for men aged 60 years, and 29.63 for men aged 70 years or older. These findings add to accumulating evidence supporting the concept that ED and CAD are differing manifestations of a common underlying vascular pathology. ED among younger men but not older men appears to be associated with a marked increase in the risk of future cardiac events and to have prognostic importance. The investigators believe that young men with ED could be an ideal cohort for clinical trials of cardiovascular disease prevention.

Survival among women with triple receptor-negative breast cancer and brain metastases

BackgroundThe purpose of this study was to determine the incidence of and survival following brain metastases among women with triple receptor-negative breast cancer. Patients and methodsIn all, 679 patients with nonmetastatic triple receptor-negative breast cancer diagnosed from 1980 to 2006 were identified. Cumulative incidence of brain metastases was computed. Cox proportional hazards models were fitted to explore factors that predict for development of brain metastases. Survival was computed using the Kaplan–Meier product limit method. ResultsMedian follow-up was 26.9 months. In all, 42 (6.2%) patients developed brain metastases with a cumulative incidence at 2 and 5 years of 5.6% [95% confidence interval (CI) 3.8% to 7.9%] and 9.6% (95% CI 6.8% to 13%), respectively. A total of 24 (3.5%) patients developed brain metastases as the first site of recurrence with cumulative incidence at 2 and 5 years of 2.0% (95% CI 2.6% to 6.0%) and 4.9% (95% CI 3.2% to 7.0%), respectively. In the multivariable model, no specific factor was observed to be significantly associated with time to brain metastases. Median survival for all patients who developed brain metastases and those who developed brain metastases as the first site of recurrence was 2.9 months (95% CI 2.0–7.6 months) and 5.8 months (95% CI 1.7–11.0 months), respectively. ConclusionIn this single-institutional study, patients with nonmetastatic triple receptor-negative breast tumors have a high early incidence of brain metastases associated with poor survival and maybe an ideal cohort to target brain metastases preventive strategies.

Big School, Small School: (Re)Testing Assumptions about High School Size, School Engagement and Mathematics Achievement

In an effort to increase both adolescents' engagement with school and academic achievement, school districts across the United States have created small high schools. However, despite the widespread adoption of size reduction reforms, relatively little is known about the relationship between size, engagement and outcomes in high school. In response, this article employs a composite measure of engagement that combines organizational, sociological, and psychological theories. We use this composite measure with the most recent nationally-representative dataset of tenth graders, Educational Longitudinal Study: 2002, (N = 10,946, 46% female) to better assess a generalizable relationship among school engagement, mathematics achievement and school size with specific focus on cohort size. Findings confirm these measures to be highly related to student engagement. Furthermore, results derived from multilevel regression analysis indicate that, as with school size, moderately sized cohorts or grade-level groups provide the greatest engagement advantage for all students and that there are potentially harmful changes when cohorts grow beyond 400 students. However, it is important to note that each group size affects different students differently, eliminating the ability to prescribe an ideal cohort or school size.

Survival among women with triple receptor-negative breast cancer and brain metastases.

Abstract Abstract #6077 Background
 The purpose of this study was to determine the incidence of brain metastases in a cohort of women with early stage triple-receptor negative breast cancer and to evaluate the survival outcomes of these patients.
 Method
 Six hundred and seventy nine patients with early stage triple-receptor negative breast cancer diagnosed between 1980 and 2006 were identified. Cumulative incidence of brain metastases at 2- and 5-years following a diagnosis of early-stage triple receptor-negative breast cancer considering death as a competing risk was computed. Time to brain metastases was computed from the date of breast cancer diagnosis to the date of development of brain metastases. Cox proportional hazards models, adjusted for various patient and tumor characteristics, were then fitted to explore factors that could predict for the subsequent development of brain metastases in this cohort. Survival following a diagnosis of brain metastases was measured from the date of brain metastases diagnosis to the date of death from any cause. All survival outcomes were computed using the Kaplan – Meier product limit method and compared across groups using log rank statistic.
 Results
 Median age was 50 years (range 22 to 97 years) and median follow-up was 26.9 months (range 1.1 to 321.3 months. Overall 42 (6.2%) patients developed brain metastases of whom 16 (38.1%) had 3 brain lesions or less, 19 (45.2%) had more than 3 brain lesions and number of brain lesions was unknown in 7 (16.7%) patients. Overall cumulative incidence at 2- and 5-years was 5.6% (95% CI 3.8%-7.9%) and 9.6% (95% CI 6.8% - 13%) respectively. Twenty –four (3.5%) patients developed brain metastases as the first site of recurrence with cumulative incidence at 2- and 5-years observed to be 2.0% (95% CI 2.6% -6.0%) and 4.9% (95% CI 3.2%-7.0%) respectively. In the multivariable model factors such as age at primary tumor diagnosis, initial clinical stage, histological tumor grade, number of lymph nodes examined and tumor lymph-vascular invasion were not significantly associated with time to brain metastases. For the whole group of patients who developed brain metastases median survival was 2.9 months (95% CI 2.0 – 7.6 months). Among those who developed brain metastases as the first site of recurrence median survival was 5.8 months (95% CI 1.7 – 11.0 months).
 Conclusion
 Data from published studies have reported a 5-year cumulative incidence of brain metastases of approximately 5 % in an unselected breast cancer population. In our large single institutional study patients with triple-receptor-negative breast tumors we report higher early cumulative incidence compared to historical controls associated with poor survival. Patients with triple-receptor negative breast tumors may be an ideal cohort to target brain metastases preventive strategies. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6077.

The NICE guidelines - should they apply to military personnel?

Introduction/aims: To assess if lower third molars, in military patients referred to RAF Brize Norton are extracted in accordance with the NICE guidelines. These military personnel have high levels of dental care available to them and generally have good plaque control and periodontal health, making them an ideal cohort to study the important risk factors for caries development in the lower second molar. Clearly, dental pain in deployed military personnel can impact on military effectiveness.

Understanding secondary databases: a commentary on “Sources of bias for health state characteristics in secondary databases”

Understanding secondary databases: a commentary on “Sources of bias for health state characteristics in secondary databases”

Polycystic ovary syndrome, a pathway to type 2 diabetes

Numerous studies have established a relation between insulin resistance (IR) and polycystic ovary syndrome (PCOS), a highly prevalent (5% to 10%) endocrine metabolic dysfunction in premenopausal women. Even though this syndrome was described in 1935 by Stein and Leventhal, it remains a matter of great controversy and interest due to its heterogeneity and complex physiopathology, which has opened a debate as to whether it is a single or a multiple disorder. Currently there are two definitions; one was proposed by the National Institute of Health Consensus Conference (1990), which defined PCOS as the presence of hyperandrogenism and oligo-ovulation in the absence of other specific causes of ovarian, adrenal, or hypophyseal origin, and the other was proposed by the Rotterdam ESHRE/ASRM Consensus Conference (2003), which defined PCOS as an ovarian dysfunction characterized by hyperandrogenism and polycystic ovarian morphology. Most women with PCOS (60% to 80%) exhibit peripheral IR, which affects predominantly muscle and adipose tissue, and a compensatory hyperinsulinemia that can be manifested independent of obesity. IR plus pancreatic -cell dysfunction constitute a frequent comorbidity in these patients and play a major role in the long-term metabolic consequences of the syndrome, among which type 2 diabetes and cardiovascular disease should be highlighted. More than 40% of these patients develop glucose intolerance and 16% develop type 2 diabetes at the end of the fourth decade of life. Moreover, it has been demonstrated that coronary disease is more frequent in women with PCOS and that the risk of developing a myocardial infarction is seven times higher than in normal women. These important findings recently led Reaven to incorporate PCOS into the syndrome X [1], or Reaven’s plurimetabolic syndrome, with its other components (type 2 diabetes, arterial hypertension, dyslipidemia, etc.); as a consequence, PCOS, which was initially described as a distinctly reproductive disorder, is currently defined as a mainly endocrine metabolic disorder. Therefore, according to these arguments, it is evident that PCOS should be considered a public health problem that affects a woman beyond her reproductive function but nevertheless leads her to consult a physician at a young age, thus offering us the valuable opportunity for the early detection of associated metabolic abnormalities. Due to the high prevalence of affected women, several years ago it was postulated that this syndrome might have a genetic basis. This has been evaluated in different populations through phenotypic and family aggregation studies. Most of this research has been conducted in relation to hyperandrogenism or ovarian morphology as assessed by ultrasound, and a high frequency of PCOS in mothers and sisters of these patients has been established. A scarce (limited) number of studies has evaluated the metabolic compromise in other family members of women with PCOS; one suggested that first-degree relatives of patients with PCOS exhibit high insulin levels and another suggested that -cell dysfunction in families of women with PCOS is a heritable trait. According to my experience and that of my colleagues, a first study on family aggregation, based on personal interviews with healthy women, women with PCOS, and their parents, we established that the probability that a family member (brothers, sisters, parents, and grandparents) of a woman with PCOS would develop type 2 diabetes is significantly higher than in a family member of a control woman. To confirm this finding, we designed a second study in which we evaluated glucose tolerance, IR, and frequency of type 2 diabetes in 120 parents of healthy women and in 200 parents of women with PCOS. These data [2] suggest that parents of women with PCOS exhibit IR and type 2 diabetes more frequently than do those of healthy women, thus constituting a highrisk group but an ideal cohort to detect and prevent the development of type 2 diabetes. This apparently simple concept is of utmost importance because it means that patients with PCOS, due to their genetic charge, have a higher probability of developing a metabolic pathology and, hence, constitute a high-risk population. In addition, PCOS

National patterns of use and effectiveness of angiotensin-converting enzyme inhibitors in older patients with heart failure and left ventricular systolic dysfunction.

Although ACE inhibitors are underprescribed for heart failure, factors associated with their use are not well described. Furthermore, the effectiveness of ACE inhibitors has been questioned in some populations, potentially contributing to underuse. Our objectives were to assess the correlates of ACE inhibitor use and the relationship between ACE inhibitor prescription and mortality in older patients with heart failure. We studied a national sample aged > or =65 years who had survived hospitalization for heart failure between April 1998 and March 1999 or July 2000 and June 2001, restricting the analysis to patients with left ventricular systolic dysfunction and without a documented contraindication to use of ACE inhibitors (n=17 456). Factors associated with ACE inhibitor prescription at discharge and the relationship between ACE inhibitor prescription and death within 1 year were assessed with hierarchical logistic models. Secondary analyses assessed therapeutic substitution with angiotensin receptor blockers (ARBs). ACE inhibitors were prescribed to only 68% of this ideal cohort, and 76% received either an ACE inhibitor or an ARB. Patient, physician, and hospital factors were weak predictors of prescription, except for serum creatinine (RR for 133 to 221 micromol/L=0.87, 95% CI 0.85 to 0.89; RR for > or =222 micromol/L=0.53, 95% CI 0.49 to 0.57 compared with < or =132 micromol/L). ACE inhibitor prescription was associated with lower crude 1-year mortality (33.0% versus 42.1%, P<0.001), lower risk of death after adjustment (RR 0.86, 95% CI 0.82 to 0.90), and lower mortality regardless of patient gender, age, race, or serum creatinine level. ACE inhibitors were widely underprescribed despite evidence of a favorable impact on survival in a broad range of patients with heart failure. These results emphasize the importance of ongoing efforts to translate clinical trial results into practice.

Does Makeham make sense?

Numerical modeling was used to explore the behavior of ideal cohorts obeying the Gompertz-Makeham (GM) law of mortality (-dn/dt 1/n(t) = C + lambda egammat) supplemented with the Strehler-Mildvan (SM) correlation (ln lambda = A - Bgamma) and to show how changes in the age-independent parameter C will produce an apparent SM correlation if C is ignored in mortality data treatment as in the case of the so-called longitudinal gompertzian analysis of historical changes in human mortality patterns. The essential difference between the Makeham term C and Gompertz term lambda e(gammat) has been suggested to be not that the latter is age-dependent whereas the former is not, but that C comprises the contributions of inherently irresistible stresses to mortality, whereas lambda e(gammat) comprises the contributions of resistible stresses and shows how changes in the resistance to them are translated into changes in mortality. This assumption was used to show by modeling how the transition of stresses from irresistible to resistible may result in decreased late survivorship as the cost of increased early survivorship, in line with the antagonistic pleiotropy theory of aging. On the whole, the modeling suggests that the GM equation is not only a mathematical tool for treatment of mortality data but that it also has a fundamental biological significance, and its Makeham term C should not be ignored in any analysis of mortality data.

Prevalence of Type II diabetes mellitus and insulin resistance in parents of women with polycystic ovary syndrome.

Insulin resistance with increased risk of Type II (non-insulin-dependent) diabetes is a common feature of polycystic ovary syndrome (PCOS). To investigate antecedents of metabolic disorders in family members of patients with PCOS, we evaluated glucose tolerance and insulin resistance in parents of patients with PCOS compared to parents of healthy women. A total of 200 parents of women with clinical and hormonal evidence of PCOS (PCOSp) and 120 parents of healthy normally cycling women (HWp) were studied. A 75-g OGGT was performed and subjects were classified according to the World Health Organization (WHO) criteria (1999). Serum glucose and insulin were measured before the glucose load and 30, 60 and 120 min after. C-peptide and sex hormone-binding globulin were also determined before the glucose load. Insulin resistance was assessed by HOMA model and ISI composite. The prevalence of Type II diabetes was 1.89-(1.06-3.38)-fold higher in PCOSp compared to HWp. Insulin resistance, evaluated by HOMA(IR)and ISI composite was also significantly higher in the PCOSp group compared to the HWp group. After both study groups were distributed by sex, and adjusted by age and BMI, the metabolic parameters were still significantly different between PCOSp and HWp. The data suggest that parents of PCOS women exhibit insulin resistance and Type II diabetes more frequently than those of healthy women, thus constituting a high-risk group but an ideal cohort to detect and prevent the development of Type II diabetes.

Three-dimensional conformal radiotherapy and dose escalation: Where do we stand?

Three-dimensional conformal radiotherapy is an effective means of delivering high doses of radiation with enhanced precision. Several institutions have gained substantial experience using this modality for patients with clinically localized prostate cancer. Reports from these centers have demonstrated not only excellent tolerance despite the administration of higher radiation doses, but improved biochemical and local control outcomes as well. Meticulous attention to treatment technique and dose volume histogram analysis are critical for the safe implementation of these higher doses. The emergence of intensity-modulated treatment planning has provided the opportunity at our institution to further escalate the radiation dose to 86.4 Gy while still respecting the surrounding normal tissue tolerance. Phase I studies will need to continue to define more clearly the maximal dose of radiation that can be delivered safely with this modality. Current studies indicate a direct correlation between dose and prostate-specific antigen (PSA) relapse-free survival response for patients with intermediate and high-risk prognostic features. These patients likely represent the ideal cohort for future studies designed to investigate the impact of dose on biochemical and disease-free survival outcome.

Heart failure treatment with angiotensin-converting enzyme inhibitors in hospitalized Medicare patients in 10 large states. The Large State Peer Review Organization Consortium

Angiotensin-converting enzyme (ACE) inhibitors have been proved to reduce mortality, rates of hospitalization, and disease progression in patients with heart failure. Investigators have suggested that ACE inhibitors are underused in heart failure. We examined the use of ACE inhibitors and the documentation of cardiac ejection fractions (EFs) in Medicare patients admitted to acute care hospitals with a principal diagnosis of heart failure. A random sample of at least 600 medical records in each of 10 populous states was retrospectively abstracted by peer review organizations. A total of 6749 records were reviewed of patients aged 65 years and older who were discharged in 1993 and 1994. The review tool was adapted from the Heart Failure Guidelines disseminated by the Agency for Health Care Policy and Research. An ideal candidate cohort was created of patients most likely to benefit from ACE inhibitors on the basis of their EF values (< 40%), renal function, absence of hyperkalemia, and absence of other contraindications. Fifty-five percent (95% confidence interval, 54%-56%) of patients received ACE inhibitors at discharge. In the ideal candidate group, 73% (95% confidence interval, 71%-75%) of patients received ACE inhibitors at discharge. The oldest group was least likely to have ACE inhibitors prescribed at discharge. The EF was documented in 59% (95% confidence interval, 58%-60%) of records. Medicare chart review suggests under-use of ACE inhibitors in up to one quarter of patients who have no clear contraindications. A substantial number of patients without documented EF are also likely to benefit from the use of ACE inhibitors.

Searching for the Ideal Cohort

Searching for the Ideal Cohort

Possible risk of endometriosis for Seveso, Italy, residents: an assessment of exposure to dioxin.

A recent study by Rier et al. showed that rhesus monkeys exposed daily for 4 years to 5 or 25 ppt of dioxin in food develop endometriosis, with incidence and severity related to dose. We aimed to determine whether the total time-integrated dioxin exposure of a human population could be comparable to that of Rier's monkeys. We selected a sample of residents of Seveso, Italy, who were acutely exposed to high levels of dioxin following an accident in 1976. We conducted a toxicokinetic analysis which takes into account species and exposure differences in dose and timing between humans and monkeys. The area under the time-concentration curve for dioxin in fat, which corresponds to cumulative exposure over time, ranges for some of the most heavily exposed Seveso residents from approximately 1.7 x 10(6) ppt-days to 1.1 x 10(8) ppt-days. These values exceed in all cases the values for the monkeys exposed to 25 ppt or 5 ppt. Given their exposure, the Seveso population should be an ideal epidemiologic cohort to rule out or confirm whether exposure to dioxin leads to an increased risk of endometriosis in humans.

Possible Risk of Endometriosis for Seveso, Italy, Residents: An Assessment of Exposure to Dioxin

A recent study by Rier et al. showed that rhesus monkeys exposed daily for 4 years to 5 or 25 ppt of dioxin in food develop endometriosis, with incidence and severity related to dose. We aimed to determine whether the total time-integrated dioxin exposure of a human population could be comparable to that of Rier's monkeys. We selected a sample of residents of Seveso, Italy, who were acutely exposed to high levels of dioxin following an accident in 1976. We conducted a toxicokinetic analysis which takes into account species and exposure differences in dose and timing between humans and monkeys. The area under the time-concentration curve for dioxin in fat, which corresponds to cumulative exposure over time, ranges for some of the most heavily exposed Seveso residents from approximately 1.7 x 10(6) ppt-days to 1.1 x 10(8) ppt-days. These values exceed in all cases the values for the monkeys exposed to 25 ppt or 5 ppt. Given their exposure, the Seveso population should be an ideal epidemiologic cohort to rule out or confirm whether exposure to dioxin leads to an increased risk of endometriosis in humans.