Lisa Pappas

Effects of Body Size and Body Composition on Survival in Hemodialysis Patients

It is unclear whether increased muscle mass or body fat confer the survival advantage in hemodialysis patients with high body-mass index (BMI). Twenty-four-hour urinary creatinine (UCr) excretion was used as a measure of muscle mass. The outcomes of hemodialysis patients with high BMI and normal or high muscle mass (inferred low body fat) and high BMI and low muscle mass (inferred high body fat) were studied to study the effects of body composition on outcomes. In 70,028 patients who initiated hemodialysis in the United States from January 1995 to December 1999 with measured creatinine clearances reported in the Medical Evidence form, all-cause and cardiovascular mortality were examined in Cox and parametric survival models. When compared with normal BMI (18.5 to 24.9 kg/m(2)) group, patients with high BMI (> or = 25 kg/m(2)) had lower hazard of death (hazard ratio [HR], 0.85; P < 0.001). However, when compared with normal BMI patients with UCr >25th percentile (0.55 g/d), high BMI patients with UCr >0.55 g/d had lower hazard of all-cause (HR, 0.85; P < 0.001) and cardiovascular death (HR, 0.89; P < 0.001), and high BMI patients with UCr < or =0.55 g/d had higher hazard of all-cause death (HR, 1.14; P<0.001) and cardiovascular death (HR, 1.19; P <0.001). Both BMI and body composition are strong predictors of death. The protective effect conferred by high BMI is limited to those patients with normal or high muscle mass. High BMI patients with inferred high body fat have increased and not decreased mortality.

PAM50 Breast Cancer Subtyping by RT-qPCR and Concordance with Standard Clinical Molecular Markers

BackgroundMany methodologies have been used in research to identify the “intrinsic” subtypes of breast cancer commonly known as Luminal A, Luminal B, HER2-Enriched (HER2-E) and Basal-like. The PAM50 gene set is often used for gene expression-based subtyping; however, surrogate subtyping using panels of immunohistochemical (IHC) markers are still widely used clinically. Discrepancies between these methods may lead to different treatment decisions.MethodsWe used the PAM50 RT-qPCR assay to expression profile 814 tumors from the GEICAM/9906 phase III clinical trial that enrolled women with locally advanced primary invasive breast cancer. All samples were scored at a single site by IHC for estrogen receptor (ER), progesterone receptor (PR), and Her2/neu (HER2) protein expression. Equivocal HER2 cases were confirmed by chromogenic in situ hybridization (CISH). Single gene scores by IHC/CISH were compared with RT-qPCR continuous gene expression values and “intrinsic” subtype assignment by the PAM50. High, medium, and low expression for ESR1, PGR, ERBB2, and proliferation were selected using quartile cut-points from the continuous RT-qPCR data across the PAM50 subtype assignments.ResultsESR1, PGR, and ERBB2 gene expression had high agreement with established binary IHC cut-points (area under the curve (AUC) ≥ 0.9). Estrogen receptor positivity by IHC was strongly associated with Luminal (A and B) subtypes (92%), but only 75% of ER negative tumors were classified into the HER2-E and Basal-like subtypes. Luminal A tumors more frequently expressed PR than Luminal B (94% vs 74%) and Luminal A tumors were less likely to have high proliferation (11% vs 77%). Seventy-seven percent (30/39) of ER-/HER2+ tumors by IHC were classified as the HER2-E subtype. Triple negative tumors were mainly comprised of Basal-like (57%) and HER2-E (30%) subtypes. Single gene scoring for ESR1, PGR, and ERBB2 was more prognostic than the corresponding IHC markers as shown in a multivariate analysis.ConclusionsThe standard immunohistochemical panel for breast cancer (ER, PR, and HER2) does not adequately identify the PAM50 gene expression subtypes. Although there is high agreement between biomarker scoring by protein immunohistochemistry and gene expression, the gene expression determinations for ESR1 and ERBB2 status was more prognostic.

Impact of Timing of Initiation of Dialysis on Mortality

Previous studies showed that sicker patients were initiated on dialysis at higher GFR as estimated by the Modification of Diet in Renal Disease (MDRD) formula. It was previously shown that patients with low creatinine production were malnourished and had low serum creatinine levels and creatinine clearances (CrCl) but high MDRD GFR at initiation of dialysis. Therefore, a propensity score approach was used to examine the associations of MDRD GFR and measured CrCl at the initiation of dialysis with subsequent mortality. Baseline data and outcomes were obtained from the Dialysis Morbidity Mortality Study Wave II. Propensity scores for early initiation derived by logistic regression were used in Cox models to examine mortality. Each 5-ml/min increase in MDRD GFR at initiation of dialysis in the entire cohort was associated with increased hazard of death in multivariable Cox model (hazard ratio [HR] 1.14; P = 0.002). In the subgroup of patients with reported CrCl, higher MDRD GFR was associated with increased risk of death (for each 5-ml/min increase, HR 1.27; P < 0.001) but not CrCl (for each 5-ml/min increase, HR 0.98; P = 0.81). These divergent results might reflect erroneous GFR estimation by the MDRD formula. Furthermore, these data do not support earlier initiation of dialysis. Therefore, for patients without clinical indications for initiation of dialysis, the appropriate GFR level for initiation of dialysis is unknown.

Creatinine Production, Nutrition, and Glomerular Filtration Rate Estimation

This study examined the validity and clinical implications of the assumption of the Modification of Diet in Renal Disease Study (MDRD) formula that age, gender, race, and BUN account for creatinine production (CP). The relationships of MDRD GFR, CP, and nutrition were examined in 1074 Dialysis Morbidity and Mortality Study Wave II patients with reported measured creatinine clearances at initiation of dialysis. Age, gender, race, BUN, and serum creatinine (Scr) were used to calculate MDRD GFR. The measured 24-h urinary creatinine was used to estimate CP. In linear regression, Scr positively correlated with CP independent of age, gender, race, and BUN. Compared with the highest CP quartile, the lowest CP quartile had lower creatinine clearance (5.8 +/- 2.9 versus 11.3 +/- 3.4 ml/min, P <.01) despite lower Scr (5.8 +/- 2.6 versus 8.6 +/- 3.1 mg%, P <.01). There was an excellent correlation between the reciprocal of Scr and the MDRD GFR (r = 0.90). As a result, the MDRD GFR was higher in the lowest CP quartile (10.9 +/- 4.6 versus 7.6 +/- 2.4 ml/min, P <.01). Malnutrition (48% versus 26%, P <.01) was more common in the lowest CP quartile. Each 5-ml/min increase in MDRD GFR was associated with 21% higher odds of malnutrition (P = 0.046) in a multivariable logistic regression, which was abolished by controlling for CP. The fundamental assumption of the MDRD formula is invalid in patients with advanced renal failure, and the use of this formula in these patients might introduce biases.

Effect of Breast Conservation Therapy vs Mastectomy on Disease-Specific Survival for Early-Stage Breast Cancer

IMPORTANCE To our knowledge, there are no recent studies that directly compare survival after breast conservation therapy (BCT) vs mastectomy. OBJECTIVE To compare the breast cancer-specific survival rates of patients undergoing BCT, mastectomy alone, or mastectomy with radiation using a contemporary cohort of patients. DESIGN, SETTING, AND PARTICIPANTS We performed univariate, multivariate logistic regression, and propensity analyses to compare the hazard of death for female patients with early-stage invasive ductal carcinoma treated with BCT, mastectomy alone, or mastectomy with radiation during the period from 1998 to 2008. The data were extracted from the Surveillance, Epidemiology, and End Results database. Early-stage breast cancer was defined as having a tumor size of 4 cm or smaller with 3 or less positive lymph nodes. EXPOSURE Breast conservation therapy, mastectomy alone, or mastectomy with radiation. MAIN OUTCOMES AND MEASURES Hazard of death due to breast cancer for patients undergoing BCT, mastectomy alone, or mastectomy with radiation. RESULTS A total of 132,149 patients were included in this analysis. Breast conservation therapy was used to treat 70% of patients, mastectomy alone was used to treat 27% of patients, and mastectomy with radiation was used to treat 3% of patients. The 5-year breast cancer-specific survival rates of patients who underwent BCT, a mastectomy alone, or a mastectomy with radiation were 97%, 94%, and 90%, respectively (P < .001); the 10-year breast cancer-specific survival rates were 94%, 90%, and 83%, respectively (P < .001). Multivariate analysis showed that women undergoing BCT had a higher survival rate than those undergoing mastectomy alone (hazard ratio, 1.31; P < .001) or mastectomy with radiation (hazard ratio, 1.47; P < .001). When propensity score stratification was used, the effect of treatment method on survival was similar. CONCLUSIONS AND RELEVANCE Patients who underwent BCT have a higher breast cancer-specific survival rate compared with those treated with mastectomy alone or mastectomy with radiation for early-stage invasive ductal carcinoma. Further investigation is warranted to understand what may be contributing to this effect.

Survival of men with clinically localized prostate cancer treated with prostatectomy, brachytherapy, or no definitive treatment : Impact of age at diagnosis

The optimal treatment for men with early stage prostate cancer remains undefined. Survival of such patients after surgery, brachytherapy, or no definitive therapy was investigated specifically to determine the impact of age at diagnosis.

Malnutrition and Atherosclerosis in Dialysis Patients

Longitudinal associations of malnutrition with atherosclerotic events in uremia are unclear. In 50,732 incident Medicare dialysis patients who had normal (18.5 to 24.9 kg/m(2)), low (<18.5 kg/m(2)), or high (> or = 25 kg/m(2)) body mass index (BMI) and initiated dialysis in the United States from January 1995 to December 1999 with reported measured creatinine clearances and acute coronary syndrome (ACS; International Classification of Diseases, Ninth Revision codes 410.x and 411.x) were examined in parametric survival models. Normal BMI was the referent group. Twenty-four-hour urinary creatinine (UCr) was used as a measure of muscle mass. There were 7213 (14.2%) hospitalized ACS events, 1528 (22%) of which were fatal (death within 30 d). One-year post-ACS mortality was 48%. Low BMI (hazard ratio [HR], 0.89; P = 0.02] was associated with lower hazard, and UCr was not predictive (NS) of hospitalized ACS in multivariable model. Low BMI (NS) was not associated with a composite end point of hospitalized ACS/suspected out-of-hospital ACS death, whereas lowest UCr quartile was associated with higher hazard (HR, 1.14; P < 0.001). Low BMI (HR, 1.24; P < 0.001) and decrease in UCr (highest quartile reference, second quartile HR, 1.11 [P < 0.001]; third quartile HR, 1.24 [P < 0.001]; and fourth quartile HR, 1.43 [P < 0.001]) were associated with increased hazard of death. Hospitalized ACS events in dialysis patients carry very high immediate and long-term mortality. Positive longitudinal associations of malnutrition with documented hospitalized ACS events could not be demonstrated. Further longitudinal studies are warranted to provide definitive evidence of malnutrition as a uremic risk factor for atherosclerosis.

An analysis of immediate postmastectomy breast reconstruction frequency using the surveillance, epidemiology, and end results database

Abstract:  Mastectomy is used to treat one third of the nearly 180,000 women diagnosed with breast cancer in the United States annually. In this study, we use population‐level data from multiple years of the Surveillance, Epidemiology, End Results (SEER) database to further define patient, tumor, and geographic characteristics associated with immediate and early‐delayed breast reconstruction. Population level de‐identified data for the years 1998 to 2002 were extracted from the National Cancer Institute’s (NCI) SEER cancer database. All female patients who were treated with mastectomy for a diagnosis of ductal and/or lobular breast cancer (including Paget disease) were included. The primary end point of interest was odds of reconstruction. Multivariate analysis was performed to control for patient demographic and oncologic characteristics. A total of 52,249 patients met the inclusion criteria. Reconstruction was performed in 8,446 patients (16.2%). Odds of reconstruction varied by region from 0.60 (Seattle) to 2.81 (Atlanta). African Americans were noted to have a significantly lower likelihood of reconstruction when compared with Caucasian patients (OR 0.60 versus 1.00). Patients living in nonmetropolitan regions were also significantly less likely to undergo reconstruction. Receipt of radiation therapy was also negatively correlated with likelihood of reconstruction. In this multicenter, multiyear analysis of factors associated with immediate or early‐delayed reconstruction after mastectomy, we demonstrate that younger age, white race, metropolitan locale, and lower stage disease were all independently associated with higher likelihood of reconstruction. This information provides insight into breast reconstruction utilization and will help guide future studies to understand how these factors affect patient and physician decision‐making.

Patient preferences for in-center intense hemodialysis.

There is a lack of data on patient preferences for intense hemodialysis (IHD). In this study, we conducted a cross‐sectional survey to identify patient preferences and patient‐centered barriers for IHD. A questionnaire on preferences and anticipated barriers, anticipated benefits, and quality of life for three in‐center IHD schedules (daytime 2 hr six times/week [DHD], nocturnal 8 hr three times/week [ND3], and nocturnal 8 hr six times/week [ND6]) was administered to 100 chronic hemodialysis patients. A majority of patients (68%) were willing to undergo DHD for symptomatic benefits or increase in survival. An increase in energy level (94%) and improvement in sleep (57%) were the most common potential benefits that would justify DHD, but only 19% would undergo DHD for an increase in survival of ≤3 years. Only 20% and 7% would consider ND3 and ND6, respectively. The most common reported barriers were inadequate time for self (50%) and family (53%), followed by transportation difficulties (53%). Most patients would undergo DHD for symptomatic or survival benefits, but not ND3 or ND6. Disruption of personal time, however, is an important consideration. Success of DHD program would depend on arrangements for transportation to dialysis unit.

Prediction of 3-yr cadaveric graft survival based on pre-transplant variables in a large national dataset

Abstract: Pre‐ and post‐transplant predictive factors of graft survival for optimal and expanded criteria grafts have been studied in the past. The goal of our study was to evaluate the recent large set of United Network of Organ Sharing records (1990–1998) to generate a prediction algorithm of 3‐yr graft survival based on pre‐transplant variables alone. The dataset of patients with end‐stage renal disease and cadaveric kidney or kidney–pancreas transplantation (1990–1998) used in the study consisted of 37 407 records. Logistic regression (LM) and a tree‐based model (TBM) were used to identify predictors of 3‐yr allograft survival and to generate prediction algorithm. Donor and recipient demographic characteristics (age, race, and gender) and body mass index showed non‐linear, while human leukocyte antigen match showed strong linear relationships with 3‐yr graft survival. Prediction of the probability of graft survival from the model, achieved a good match with the observed survival of the separate dataset, with a correlation of r = 0.998 for LM and r = 0.984 for TBM. The positive predictive value (PV) of allograft survival with LM and TBM was 76.0% and the negative PV was 63 and 53.8% for LM and TBM, respectively. Both LM and the TBM can potentially be used in clinical practice for long‐term prediction of kidney allograft survival based on pre‐transplant variables.