Linda J. Hazlett

VETERANS WITH CHRONIC LYMPHOCYTIC LEUKEMIA/SMALL LYMPHOCYTIC LYMPHOMA (CLL/ SLL) HAVE A MARKEDLY INCREASED RATE OF SECOND MALIGNANCY, WHICH IS THE MOST COMMON CAUSE OF DEATH

Patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) have an increased incidence of high-grade lymphoid malignancy. The risk of non-lymphoid second malignancy in this population is not well-defined to date. To test the hypothesis that patients with CLL/SLL have an increased risk of second malignancy, we studied the rate of second malignancy in 132 CLL/SLL patients and compared it to the rate of malignancy (excluding non-melanomatous skin cancer) in the Central Arkansas Veterans Healthcare System population of approximately 38,000 veterans over a period of 11.5 years. The rate of second malignancy, diagnosed concomitantly or after CLL/SLL, and the age-adjusted rate of malignancy calculated from tumor registry reports and demographic data, were used to calculate a Standardized Morbidity Ratio (SMR) with 95% confidence interval (CI). Twenty-one (16%) of the CLL/SLL patients had second malignancies (19 non-lymphoid, 1 Richters transformation and 1 Hodgkins disease), which were fatal in 15 (71%) patients. The SMR for the CLL/SLL population was 2.97 (95% CI 1.84 – 4.55) for second malignancy and 2.69 (95% CI 1.62 – 4.21) for non-lymphoid second malignancy. This study of a well-defined CLL/SLL population shows a significantly increased risk of second malignancy, which was the primary cause of death for 9% of all CLL/SLL patients (34% of all patient deaths).

Significance of Margin and Extent of Dysplasia in Loop Electrosurgery Excision Procedure Biopsies Performed for High-Grade Squamous Intraepithelial Lesion in Predicting Persistent Disease

CONTEXT High-grade squamous intraepithelial lesions (cervical intraepithelial neoplasia 2 and 3) are commonly treated with loop electrosurgery excision procedure (LEEP) biopsies. OBJECTIVE To highlight the significance of positive margins and extent of positive margins of the cervical LEEP biopsies in predicting the persistence of high-grade squamous intraepithelial lesion and to provide suggestions for reporting margins in cervical LEEP biopsies. DESIGN The pathology files at the University of Arkansas for Medical Sciences were searched for cervical intraepithelial neoplasia 2 and 3 treated by LEEP biopsy from 1990 to 2001. RESULTS A total of 489 LEEP biopsy specimens were retrieved and reviewed; 270 patients had follow-up within 1 year. The biopsy specimens of 110 patients showed positive endocervical margins. One hundred sixty specimens had negative ectocervical-endocervical margins. Follow-up of 54% of the cases with initial positive margins showed residual high-grade squamous intraepithelial lesions. This association was even greater when multiple blocks showed positive endocervical margins and in cases with positive deep margins. On the other hand, a negative margin predicted ability to completely remove the lesion in 95% of patients. CONCLUSION This study reiterates the significance of the evaluation of the margin, even in samples that were received as multiple fragments. Reporting of LEEP biopsy findings should include the extent of the dysplasia, the status of the ectocervical-endocervical margin, and the status of the deep margin.

Obesity Mediates the Association between Mediterranean Diet Consumption and Insulin Resistance and Inflammation in US Adults

Background: The inverse association between Mediterranean diet (Med-diet) consumption and insulin resistance or inflammatory markers is well known. However, the extent to which obesity may act directly on or mediate this association is unclear.Objective: We aimed to investigate whether the associations between Med-diet consumption and markers of insulin resistance and inflammation are mediated by body mass index (BMI) or waist circumference (WC) in a representative US population.Methods: We used cross-sectional data from 4700 adults aged 20-90 y without any previous diagnosis of cancer, cardiovascular disease, diabetes, or hypertension based on the NHANES III, 1988-1994. A Med-diet score (MDS) was created to assess adherence to the Med-diet. Linear regression models were fitted in conventional and causal mediation analyses comparing extreme MDS tertiles.Results: Compared with the lowest MDS tertile, the highest tertile of MDS was associated with a 0.77 lower BMI (in kg/m2; P = 0.004) and a 2.7 cm lower WC (P < 0.001) after multivariable adjustment. WC mediated the association of MDS with insulin resistance and glucose intolerance markers (log insulin, log homoeostasis model assessment of insulin resistance, fasting glucose, and glycated hemoglobin) and inflammatory markers (white blood cell count and fibrinogen), whereas BMI mediated the association between MDS and insulin resistance and glucose intolerance markers only (all P < 0.05). The mediated effects of WC were consistently greater than those of BMI for all markers in both conventional and causal mediation analyses. Furthermore, the association between MDS and fasting glucose was fully mediated by adiposity, especially by WC in men aged <45 y and in premenopausal women.Conclusion: Our results suggest that reducing abdominal obesity may play an important role in the pathway through which Med-diet consumption reduces insulin resistance and inflammation.

Association between Serum Antibodies to Oral Microorganisms and Hyperglycemia in Adults

We conducted a cross-sectional analysis to evaluate the relationship between serum antibody titers against 19 selected oral microorganisms and measures of hyperglycemia in a large, nationally representative data set. The study population consisted of 7,848 participants from the National Health and Nutrition Examination Survey III (1988-1994) who were at least 40 yrs old, with complete serum IgG antibody data against 19 oral microorganisms. The 19 antibody titers were grouped into 4 categories via cluster analysis—orange-red, yellow-orange, orange-blue, and red-green—named to reflect predominant antibody titers against microorganisms in Socransky’s classification scheme for oral microbes. Linear regression models weighted for complex survey design were used in which fasting blood glucose, fasting insulin, and HbA1c were outcomes and antibody cluster scores were exposures, adjusting for potential confounders. Higher orange-red cluster scores were associated with increased hyperglycemia, while higher orange-blue cluster scores were related with decreased hyperglycemia. A 1-unit-higher orange-red cluster score was associated with 0.46 mg/dL higher fasting blood glucose (p = .0038), and a 1-unit-higher orange-blue cluster score was associated with 0.34% lower HbA1c (p = .0257). Groups of antibody titers against periodontal microorganisms were associated with hyperglycemia independent of known risk factors.

Diet Quality and Mortality Risk in Metabolically Obese Normal-Weight Adults

OBJECTIVE To examine the associations among the Dietary Approaches to Stop Hypertension (DASH)-style diet, the Healthy Eating Index (HEI), and mortality risk in metabolically obese normal-weight (MONW) adults. PATIENTS AND METHODS Data were from normal-weight (body mass index of 18.5 to <25) adults aged 30 to 90 years at baseline in the Third National Health and Nutrition Examination Survey, October 18, 1988, through October 15, 1994, followed up for deaths (all-cause, cardiovascular, and cancer related) until December 31, 2011. A total of 2103 participants without known cardiovascular disease and cancer at baseline were included in this prospective cohort study. Metabolic obesity was defined as having 2 or more of the following: high glucose, blood pressure, triglyceride, C-reactive protein, and insulin resistance values and low high-density lipoprotein cholesterol levels; metabolic healthy status was defined as having 0 or 1 of these metabolic derangements. RESULTS During median follow-up of 18.6 years, there were 344 and 296 deaths in the MONW and metabolically healthy normal-weight (MHNW) phenotypes, respectively. In MONW individuals, a 1-SD increment in adherence to a DASH diet (2 points) or HEI (14 points) was significantly associated with reductions (17% [hazard ratio (HR), 0.83; 95% CI, 0.72-0.97] and 22% [HR, 0.78; 95% CI, 0.68-0.90], respectively) in the risk of all-cause mortality, after adjustment for potential confounders. The corresponding HRs for cardiovascular disease mortality were 0.72 (95% CI, 0.55-0.94) and 0.79 (95% CI, 0.65-0.97), respectively. In addition, reduction of cancer mortality was observed with 1-SD increment of HEI (HR, 0.63; 95% CI, 0.46-0.88). However, no association was observed in the MHNW phenotype. Sensitivity analyses suggested relationships robust to different definitions of MONW and also dose responses with the number of metabolic derangements. CONCLUSION Higher diet quality scores were associated with lower risk of mortality in normal-weight individuals with metabolic abnormalities.

Mediterranean diet and mortality risk in metabolically healthy obese and metabolically unhealthy obese phenotypes

Background:The Mediterranean diet has been consistently associated with reduced mortality risk. Few prospective studies have examined whether the benefits from a Mediterranean diet are equally shared by obese individuals with varying metabolic health.Objective:The objective of this study was to investigate the association between Mediterranean diet, metabolic phenotypes and mortality risk in a representative obese US population.Methods:Data from 1739 adults aged 20–88 years were analyzed from participants of the National Health and Nutrition Examination Survey III, 1988–1994 followed up for deaths until 31 December 2011 in a prospective cohort analysis. Mediterranean Diet Scores (MDS) were created to assess the adherence to Mediterranean diet. Participants were classified as metabolically healthy obese (MHO) phenotype (0 or 1 metabolic abnormality) or metabolically unhealthy obese (MUO) phenotype (two or more metabolic abnormalities), based on high glucose, insulin resistance, blood pressure, triglycerides, C-reactive protein and low high-density lipoprotein cholesterol.Results:The MHO phenotype (n=598) was observed in 34.8% (s.e., 1.7%) of those who were obese (mean body mass index was 33.4 and 34.8 in MHO and MUO phenotypes, respectively). During a median follow-up of 18.5 years, there were 77 (12.9%) and 309 (27.1%) deaths in MHO and MUO individuals, respectively. In MHO individuals, the multivariable-adjusted hazard ratio (HR) of all-cause mortality in the highest tertile compared with the first tertile of MDS was 0.44 (95% confidence interval (CI), 0.26–0.75; P for trend <0.001), after adjustment for potential confounders. A five-point (1 s.d.) increment in the adherence to MDS was associated with a 41% reduction in the risk of all-cause mortality (HR, 0.59; 95% CI, 0.37–0.94). Similar findings were obtained when we restricted our analyses to those with or without prevalent diabetes mellitus and hypertension. We did not observe mortality risk reduction in either individuals with MUO phenotype or all obese participants combined.Conclusions:Adherence to a Mediterranean dietary pattern appears to reduce mortality in the MHO phenotype, but not among the MUO phenotype in an obese population.

Relationship Between Serologic Markers of Periodontal Bacteria and Metabolic Syndrome and Its Components

BACKGROUND Periodontitis is a result of a complex biologic alteration of the periodontal microenvironment and a distributional shift of key periodontal pathogens. Metabolic syndrome (MetS), a complex cluster of cardiovascular risk factors, has been linked to periodontal diseases; however, the contribution of periodontal bacteria to systemic conditions remains unclear. METHODS The study population comprised 7,848 United States adults who participated in an interview, underwent a clinical oral-health examination, and had serum immunoglobulin G titers measured against 19 periodontal bacteria as part of the third National Health and Nutritional Examination Survey. The z-score antibody titers were clustered into four mutually exclusive groups and named after Socranskys classification of periodontal bacteria (Orange-Red, Red-Green, Yellow-Orange, and Orange-Blue). Survey logistic regression was used to investigate the independent associations between the cluster scores, and MetS and each component, including hypertension, hypertriglyceridemia, low high-density lipoprotein cholesterol, central obesity, and elevated fasting glucose. RESULTS The Orange-Red cluster score (that included Porphyromonas gingivalis and Prevotella spp.) was positively associated (odds ratio [OR] = 1.067, 95% confidence interval [CI] = 1.02 to 1.12) and the Orange-Blue cluster score (which included Actinomyces naeslundii and Eubacterium nodatum) was inversely associated (OR = 0.93, 95% CI = 0.88 to 0.97) with elevated fasting glucose (≥ 110 mg/dL) after adjustment for clusters and potential confounders. Neither MetS nor its other remaining MetS components were associated with a particular cluster score. CONCLUSIONS The associations between specific antibody clusters (Orange-Red and Orange-Blue) against periodontal bacteria and elevated plasma glucose were in qualitatively opposite directions after multivariable adjustment in a large, adult population. The periodontal bacterial profile was not found to be associated with metabolic control other than a very moderate association with elevated plasma glucose.

Antecedents and mediators of community connection in African American women with breast cancer.

Objective: To describe the theory of community connection defined as close relationships with women and men who are members of a neighborhood, a church, a work group, or an organization. Antecedent and mediator variables related to community connection are identified. Design/methods: A cross-sectional design was used to assess for relationships among theorized antecedents and mediators of community connection in a sample of 144 African American women aged 21 years and older (mean = 54.9) who had been diagnosed with invasive/infiltrating ductal carcinoma. Measurement and Analyses: Community connection was measured with the relational health indices-community subscale. Mediator analysis was conducted to assess significance of the indirect effects of the mediator variables, which were fear, breast cancer knowledge, and isolation. Results: Community connection was found to be associated with three of the four antecedents, cancer stigma, stress, and spirituality, but not associated with fatalism. Effects were mediated primarily through fear and isolation with isolation as was more dominant of the two mediators. Surprisingly, breast cancer knowledge showed no significant mediator role. Conclusions: The importance of isolation and fear as mediators of community connection is highlighted by this research. The study could serve as a model for other researchers seeking to understand connection in ethnic groups and communities.

A Multivariate Approach for Assessing Severity of Acute Graft-Versus-Host Disease in Bone Marrow Transplantation

Patients undergoing bone marrow transplantation are at high risk of developing acute graft-versus-host disease (GVHD) which is a primary limiting factor for this procedure inasmuch as it is responsible for high morbidity rates and is associated with poor survival outcome. To provide improved treatment assessment and better interpretation of clinical outcomes, we need a precise and objective assessment of GVHD. Severity of GVHD is commonly assessed using an imprecise categorical grading system that incorporates skin, gut and liver grades, as well as subjective assessment of clinical performance. These organ grades are based on arbitrary cutpoints of skin rash, diarrhoea volume and bilirubin level. The International Bone Marrow Transplant Registry proposed an alternative grading system based on different combinations of organ involvement and provided estimates of relative risk of treatment failure. On the basis of that work, we developed an empirical mathematical model that quantifies GVHD severity, and that uses continuous, rather than categorical, daily measurements for each organ system. We use model-predicted values as an index of severity for any combination of values. The proposed index allows a more precise comparison of GVHD profiles across different treatment protocols and also permits more refined analyses to address relationships between GVHD and clinical outcomes.

Factors Related to Coronary Heart Disease Risk Among Men: Validation of the Framingham Risk Score

Introduction Coronary heart disease (CHD) remains a leading cause of death in the United States. The Framingham Risk Score (FRS) was developed to help clinicians in determining their patients’ CHD risk. We hypothesize that the FRS will be significantly predictive of CHD events among men in the Aerobics Center Longitudinal Study (ACLS) population. Methods Our study consisted of 34,557 men who attended the Cooper Clinic in Dallas, Texas, for a baseline clinical examination from 1972 through 2002. CHD events included self-reported myocardial infarction or revascularization or death due to CHD. During the 12-year follow-up 587 CHD events occurred. Multivariable-adjusted hazard ratios generated from ACLS analysis were compared with the application of FRS to the Framingham Heart Study (FHS). Results The ACLS cohort produced similar hazard ratios to the FHS. The adjusted Cox proportional hazard model revealed that men with total cholesterol of 280 mg/dL or greater were 2.21 (95% confidence interval (CI), 1.59–3.09) times more likely to have a CHD event than men with total cholesterol from 160 through 199mg/dL; men with diabetes were 1.63 (95% CI, 1.35–1.98) times more likely to experience a CHD event than men without diabetes. Conclusion The FRS significantly predicts CHD events in the ACLS cohort. To the best of our knowledge, this is the first report of a large, single-center cohort study to validate the FRS by using extensive laboratory and clinical measurements.