HIV Infection and Carotid Artery Intima-media Thickness: Pooled Analyses Across 5 Cohorts of the NHLBI HIV-CVD Collaborative.

BACKGROUND: Age and human immunodeficiency virus (HIV) treatment may affect the association of HIV infection with atherosclerosis. METHODS: We used identical carotid artery B-mode ultrasonographic methods in 5 cohorts participating in the National Heart, Lung, and Blood Institute HIV-CVD Collaborative to measure intima-media thickness of the right far wall of the common carotid artery (CCA-IMT) and carotid artery bifurcation (BIF-IMT) between 2010 and 2013. Participants aged 6-75 years were either HIV infected or uninfected. Linear regression assessed associations of CCA-IMT and BIF-IMT with HIV infection and cardiovascular disease risk factors, within age and HIV treatment groups. Adjustment variables included sex, race/ethnicity, smoking, height, weight, and use of antihypertensive and lipid-lowering drugs. RESULTS: We studied 867 HIV-infected and 338 HIV-uninfected male and 696 HIV-infected and 246 HIV-uninfected female participants. Among both middle-aged (30-49 years) and older adults (50-75 years), HIV-infected participants had CCA-IMT and BIF-IMT values that were similar to or lower than those in HIV-uninfected participants. In contrast, among those aged 6-29 years, HIV infection was associated with higher CCA-IMT and BIF-IMT values. Among HIV-infected participants, associations of higher systolic blood pressure and lower high-density lipoprotein cholesterol with Carotid artery intima-media thickness strengthened with age. CONCLUSIONS: The effects of HIV on carotid artery structure may differ across the lifespan, with traditional determinants of cardiovascular disease burden playing a larger role and HIV playing a lesser role in older adults than in young adults and children.

Prevalence and Correlates of Myocardial Scar in a US Cohort.

IMPORTANCE: Myocardial scarring leads to cardiac dysfunction and poor prognosis. The prevalence of and factors associated with unrecognized myocardial infarction and scar have not been previously defined using contemporary methods in a multiethnic US population. OBJECTIVE: To determine prevalence of and factors associated with myocardial scar in middle- and older-aged individuals in the United States. DESIGN, SETTING, AND PARTICIPANTS: The Multi-Ethnic Study of Atherosclerosis (MESA) study is a population-based cohort in the United States. Participants were aged 45 through 84 years and free of clinical cardiovascular disease (CVD) at baseline in 2000-2002. In the 10th year examination (2010-2012), 1840 participants underwent cardiac magnetic resonance (CMR) imaging with gadolinium to detect myocardial scar. Cardiovascular disease risk factors and coronary artery calcium (CAC) scores were measured at baseline and year 10. Logistic regression models were used to estimate adjusted odds ratios (ORs) for myocardial scar. EXPOSURES: Cardiovascular risk factors, CAC scores, left ventricle size and function, and carotid intima-media thickness. MAIN OUTCOMES AND MEASURES: Myocardial scar detected by CMR imaging. RESULTS: Of 1840 participants (mean [SD] age, 68 [9] years, 52% men), 146 (7.9%) had myocardial scars, of which 114 (78%) were undetected by electrocardiogram or by clinical adjudication. In adjusted models, age, male sex, body mass index, hypertension, and current smoking at baseline were associated with myocardial scar at year 10. The OR per 8.9-year increment was 1.61 (95% CI, 1.36-1.91; P < .001); for men vs women: OR, 5.76 (95% CI, 3.61-9.17; P < .001); per 4.8-SD body mass index: OR, 1.32 (95% CI, 1.09-1.61, P = .005); for hypertension: OR, 1.61 (95% CI, 1.12-2.30; P = .009); and for current vs never smokers: 2.00 (95% CI, 1.22-3.28; P = .006). Age-, sex-, and ethnicity-adjusted CAC scores at baseline were also associated with myocardial scar at year 10. Compared with a CAC score of 0, the OR for scores from 1 through 99 was 2.4 (95% CI, 1.5-3.9); from 100 through 399, 3.0 (95% CI, 1.7-5.1), and 400 or higher, 3.3 (95% CI, 1.7-6.1) (P ≤ .001). The CAC score significantly added to the association of myocardial scar with age, sex, race/ethnicity, and traditional CVD risk factors (C statistic, 0.81 with CAC vs 0.79 without CAC, P = .01). CONCLUSIONS AND RELEVANCE: The prevalence of myocardial scars in a US community-based multiethnic cohort was 7.9%, of which 78% were unrecognized by electrocardiography or clinical evaluation. Further studies are needed to understand the clinical consequences of these undetected scars.

Risk Factors for the Development and Progression of Thoracic Aorta Calcification: The Multi-Ethnic Study of Atherosclerosis.

RATIONALE AND OBJECTIVES: Vascular calcification independently predicts cardiovascular disease (CVD), and computed tomography (CT) is a useful tool to evaluate and quantify not only coronary but also thoracic aortic calcification (TAC). Previous TAC progression reports were limited to dialysis and renal transplant patients. This is the first study to evaluate TAC progression in a large multiethnic cohort without clinically evident CVD at entry. METHODS: Non-contrast-enhanced cardiac CTs were obtained in 5886 of 6814 Multi-Ethnic Study of Atherosclerosis (MESA) participants (mean age, 62 years; 48% males; 40% white, 27% black, 21% Hispanic, and 12% Chinese). Baseline and follow-up TAC scores were derived. RESULTS: Overall, 4308 (73%) participants had no detectable baseline TAC. Mean follow-up duration was 2.4 ± 0.8 years, during which 12% developed TAC. The overall incidence rate was 4.8%/year and was greater with age across gender and ethnic groups; TAC incidence was significantly lower in blacks than whites. After adjustment for follow-up duration, regression analyses showed age, systolic blood pressure, antihypertensives, and smoking were associated with incident TAC. A total of 1578 (27%) participants had TAC at baseline with a positive association between average annual TAC change and baseline age. Although the overall median change was 32.9 (-1.4 to 112.2) Agatston units, 27% showed an annual score change of ≥100 and blacks showed the lowest median across ethnic groups; 22.7 (-3 to 86.8). Age, systolic blood pressure, lipid-lowering medication, diabetes, and smoking were associated with TAC progression. CONCLUSIONS: In MESA, traditional CV risk factors were related to both TAC incidence and progression. Blacks had the lowest incidence and median change across ethnic groups, consistent with previous findings for coronary calcification.

Development of a new diabetes risk prediction tool for incident coronary heart disease events: the Multi-Ethnic Study of Atherosclerosis and the Heinz Nixdorf Recall Study.

OBJECTIVE: We develop a new diabetes CHD risk estimator using traditional risk factors plus coronary artery calcium (CAC), ankle-brachial index (ABI), high sensitivity C-reactive protein, family history of CHD, and carotid intima-media thickness and compared it with United Kingdom Prospective Diabetes study (UKPDS), Framingham risk and the NCEP/ATP III risk scores in type 2 diabetes mellitus (T2DM). METHODS AND RESULTS: We combined data from T2DM without clinical CVD in the Multi-Ethnic Study of Atherosclerosis (MESA) and the Heinz Nixdorf Recall Study (N = 1343). After a mean follow-up of 8.5 years, 85 (6.3%) participants had incident CHD. Among the novel risk markers, CAC best predicted CHD independent of the FRS [hazard ratio: HR (95% CI): log (CAC +25):1.69 (1.45-1.97), p < 0.0001; CAC categories: CAC ≤ 25 as reference, >25 and ≤125:2.29 (0.87-5.95), >125 and ≤400: 3.87 (1.57-9.57), >400: 5.97 (2.57-13.84), respectively). The MESA-HNR diabetes CHD risk score has better accuracy for the main outcome versus the FRS or UKPDS [area under curve (AUC) of 0.76 vs. 0.70 and 0.69, respectively; all p < 0.05]. The MESA-HNR risk score improved risk classification versus the FRS (net reclassification improvement (NRI) = 0.19 and integrated discrimination improvement (IDI) = 0.046, p < 0.05) and UKPDS (NRI = 0.215 and IDI = 0.046, p < 0.05). Compared with the ATP III guidelines, the MESA-HNR score has an NRI of 0.74 for the main outcome. CONCLUSIONS: This new CHD risk estimator has better discriminative ability for incident CHD than the FRS, UKPDS, and the ATP III/NCEP recommendations in a multi-ethnic cohort with T2DM.

Voxelwise single-subject analysis of imaging metabolic response to therapy in neuro-oncology.

F-18-Fluorodeoxyglucose positron emission tomography (FDG-PET) has been used to evaluate the metabolic response of metastatic brain tumors to treatment by comparing their tumor glucose metabolism before and after treatment. The standard analysis based on regions-of-interest has the advantage of simplicity. However, it is by definition restricted to those regions and is subject to observer variability. In addition, the observed changes in tumor metabolism are often confounded by normal changes in the tissue background, which can be heterogenous. We propose an analysis pipeline for automatically detecting the change at each voxel in the entire brain of a single subject, while adjusting for changes in the background. The complete analysis includes image registration, segmentation, a hierarchical model for background adjustment and voxelwise statistical comparisons. We demonstrate the method's ability to identify areas of tumor response and/or progression in two subjects enrolled in a clinical trial using FDG-PET to evaluate lapatinib for the treatment of brain metastases in breast cancer patients.

A phase II trial of capecitabine in combination with the farnesyltransferase inhibitor tipifarnib in patients with anthracycline-treated and taxane-resistant metastatic breast cancer: an Eastern Cooperative Oncology Group Study (E1103).

Capecitabine produces an objective response rate of up to 25% in anthracycline-treated, taxane-resistant metastatic breast cancer (MBC). The farnesyltransferase inhibitor tipifarnib inhibits Ras signaling and has clinical activity when used alone in MBC. The objective of this study was to determine the efficacy and safety of tipifarnib-capecitabine combination in MBC patients who were previously treated with an anthracycline and progressed on taxane therapy. Eligible patients received oral capecitabine 1,000 mg/m2 twice daily plus oral tipifarnib 300 mg twice daily on days 1-14 every 21 days. The primary endpoint was ORR. The trial was powered to detect an improvement in response rate from 25 to 40%. Among 63 eligible, partial response occurred in six patients (9.5%; 90% CI 4.2-17.9%), median progression-free survival was 2.6 months (95% CI 2.1-4.4), and median overall survival was 11.4 months (95% CI 7.7-14.0). Dose modifications were required for 43 patients (68%) for either tipifarnib and/or capecitabine. Grades 3 and 4 toxicities were seen in 30 patients (44%; 90% CI 44.4-67.0%) and 11 patients (16%; 90% CI 10.8-29.0%), respectively. The most common grade 3 toxicities included neutropenia, nausea, and vomiting; and the most common grade 4 toxicity was neutropenia (8 out of 11 cases). The tipifarnib-capecitabine combination is not more effective than capecitabine alone in MBC patients who were previously treated with an anthracycline and taxane therapy.

The impact of re-excision and residual disease on local recurrence after breast conservation treatment for patients with early stage breast cancer.

UNLABELLED: The current study examined the impact of re-excision and residual disease on local recurrence after breast conservation treatment for patients with negative margins. Patients with residual disease on re-excision had a higher local recurrence rate than other patients. However, with reasonably low local recurrence rates in all subgroups, neither re-excision nor residual disease on re-excision are contraindications for breast conservation treatment. PURPOSE: To evaluate the impact of re-excision and the presence of residual disease on local recurrence for patients who underwent breast conservation treatment (BCT) with negative final resection margins. METHODS: The records of 902 patients with stage I or II unilateral invasive breast cancer who had BCT were reviewed. The study cohort consisted of patients with negative final resection margins and was divided into 3 subgroups: (a) single excision (n = 332 [37%]), (b) re-excision with no residual disease in the re-excision specimen (n = 440 [49%]), and (c) re-excision with residual disease in the re-excision specimen (n = 130 [14%]). The median follow-up was 6.75 years. RESULTS: At 15 years, the rates of local failure were 10% for patients with a single excision, 10% for patients with a re-excision without residual disease, and 16% for patients with a re-excision with residual disease (P = .033). There were no significant differences between the 3 groups for overall survival, cause-specific survival, relapse-free survival, or freedom from distant metastases (all P ≥ .082). Multivariate analysis demonstrated an increased risk of local failure for patients with residual disease in the re-excision specimen that was borderline statistically significant (hazard ratio, 2.16; P = .061). CONCLUSIONS: Despite achieving negative final resection margins, the patients with residual disease in the re-excision specimen had a higher rate of local recurrence than patients who underwent single excision or patients without residual disease on re-excision. However, local recurrence was reasonably low in all 3 subgroups, and, therefore, neither re-excision nor residual disease represent contraindications for BCT.

Comparison of four early posttherapy imaging changes (EPTIC; RECIST 1.0, tumor shrinkage, computed tomography tumor density, Choi criteria) in assessing outcome to vascular endothelial growth factor-targeted therapy in patients with advanced renal cell carcinoma.

BACKGROUND: Vascular endothelial growth factor (VEGF)-targeted therapy has become standard treatment for patients with metastatic renal cell cancer (mRCC). Since these therapies can induce tumor necrosis and minimal tumor shrinkage, Response Evaluation Criteria in Solid Tumors (RECIST) may not be optimal for predicting clinical outcome. OBJECTIVE: To systematically determine the optimal early posttherapy imaging changes (EPTIC) to separate responders and nonresponders at the first posttreatment follow-up computed tomography (CT). DESIGN, SETTING, AND PARTICIPANTS: Seventy mRCC patients with 155 target lesions treated with first-line sunitinib, sorafenib, or bevacizumab at academic medical centers underwent contrast-enhanced thoracic and abdominal CT at baseline and first follow-up after therapy initiation (median: 78 d after therapy initiation; range: 31-223 d). MEASUREMENTS: Evaluations were performed according to (1) RECIST 1.0; (2) Choi criteria; (3) tumor shrinkage (TS) of ≥10% decrease in sum of the longest unidimensional diameter (SLD); and (4) 15% or 20% decrease in mean CT tumor density. Correlation with time to treatment failure (TTF) and overall survival (OS) were compared and stratified by response to each of the radiologic criteria. RESULTS AND LIMITATIONS: Eleven patients were considered responders by RECIST 1.0; 49 based on Choi criteria; 31 patients had ≥10% decrease in the SLD; and 36 and 32 patients had ≥15% and ≥20% decrease, respectively, in mean tumor density on CT. Only the threshold of 10% decrease in the SLD was statistically significant in predicting TTF (10.4 vs 5.1 mo; p=0.02) and OS (32.5 vs 15.8 mo; p=0.002). Receiver operating characteristic analysis yielded a 10% decrease in SLD as the optimal size change threshold for responders. The retrospective nature of the study and measurements by a single oncoradiologist are inherent limitations. CONCLUSIONS: In the retrospectively analyzed study population of mRCC patients receiving VEGF-targeted agents, a 10% reduction in the SLD on the first follow-up CT was an optimal early predictor of outcome.

Incidence of pulmonary embolism in oncologic outpatients at a tertiary cancer center.

BACKGROUND: Incidence of pulmonary embolism (PE) for different cancer types in oncology outpatients is unknown. The purposes of the current study is to determine the incidence of PE in oncology outpatients and to investigate whether the incidence for PE is higher in certain cancers. METHODS: A cohort of oncology outpatients who had imaging studies at Dana-Farber Cancer Institute, a tertiary outpatient cancer institute, from January 2004 through December 2009 was identified using research patient data registry. Radiology reports were reviewed to identify patients who developed PE. Incidences of PE in the total population and in each of 16 predefined cancer groups were calculated. Risk of PE for each cancer was compared using Fisher exact test. RESULTS: A total of 13,783 patients was identified, of which 395 (2.87%; 95% confidence interval [CI], 2.59-3.16) developed PE. The incidence of PE was highest in the central nervous system ([CNS] 12.90%; 95% CI, 8.45-18.59), hepatobiliary (6.85%; 95% CI, 3.33-12.24), pancreatic (5.81%; 95% CI, 3.59-8.84), and upper gastrointestinal (5.81%; 95% CI, 3.96-8.20) malignancies. The risk of PE was significantly higher for CNS (P < .0001; odds ratio [OR], 5.28), pancreatic (P = .0027; OR, 2.15), upper gastrointestinal (P = .0002; OR, 2.18), and lung/pleural malignancies (P = .0028; OR, 1.45). There was significantly lower risk of PE for hematologic (incidence, 1.16%; 95% CI, 0.79-1.64; P < .0001; OR, 0.35) and breast malignancies (incidence, 1.50%; 95% CI, 1.02-2.11; P < .0001; OR, 0.47). CONCLUSIONS: The incidence of PE in oncology outpatients in a tertiary cancer center during a 6-year period was 2.87%. CNS, pancreatic, upper gastrointestinal, and lung/pleural malignancies had a significantly higher risk for PE than other malignancies, whereas hematologic and breast malignancies had a significantly lower risk.

CT tumor volume measurement in advanced non-small-cell lung cancer: Performance characteristics of an emerging clinical tool.

RATIONALE AND OBJECTIVES: Determine inter- and intraobserver variability of computed tomography (CT) tumor volume measurements in advanced non-small-cell lung cancer (NSCLC) patients treated in a Phase II clinical trial using chest CT. MATERIALS AND METHODS: Twenty-three advanced NSCLC patients with a total of 53 measurable lung lesions enrolled in a Phase II, multicenter, open-label clinical trial of erlotinib were retrospectively studied with institutional review board approval. Two radiologists independently measured the tumor size, volume, and CT attenuation coefficient using commercially available volume analysis software. Concordance correlation coefficients (CCCs) and Bland-Altman plots were used to assess inter- and intraobserver agreement. RESULTS: High CCCs (0.949-0.990) were observed in all types of measurements for interobserver agreement. The 95% limits of agreements for volume, unidimensional, and bidimensional measurements were (-26.0%, 18.6%), (-23.1%, 24.4%), and (-34.0%, 48.6%), respectively. Volume measurement had slightly higher CCC and narrower 95% limits of agreement compared to uni- and bidimensional measurements. CCCs for intraobserver agreement were high (range, 0.946-0.996) with CCC for volume being slightly higher than CCCs of uni- and bidimensional measurements. The smaller the tumor volume was, the larger the interobserver difference of CT attenuation. Location, morphology, or adjacent atelectasis had no significant impact on inter- or intraobserver variability. CONCLUSION: CT tumor volume measurement in advanced NSCLC patients using clinical chest CT and commercially available software demonstrated high inter- and intraobserver agreement, indicating that the method may be used routinely in clinical practice.

The role of radiation therapy in malignant thymoma: a Surveillance, Epidemiology, and End Results database analysis.

INTRODUCTION: The potential benefits and long-term complications of radiotherapy treatment for malignant thymoma are unclear. This is a retrospective analysis of outcome in patients with malignant thymoma from the Surveillance, Epidemiology, and End Results database between 1973 and 2005. METHODS: Of the 1987 patients identified, 1334 were analyzed. Patients were categorized according to the Masaoka staging system as stage I to IIA, IIB or III to IV. The primary end points were overall survival, cardiac mortality, and the development of secondary malignancies. RESULTS: Patients received surgery and radiation (50%), surgery alone (26%), radiation alone (12%), or no treatment (12%). The median follow-up time for survivors was 65 months (range, 1-361 months). There was no significant increase in the 12-year cumulative incidence rate of death from heart disease (10.2% radiation versus 7.5% no radiation, p = 0.83) or incidence of secondary malignancies (11.7% versus 12.4%, p = 0.70) with radiation. Compared with surgery alone, adjuvant radiation significantly improved overall survival in patients with stage III to IV disease (p = 0.04) and demonstrated a nonsignificant trend in patients with stage IIB disease (p = 0.09). However, after excluding patients surviving less than 4 months to account for surgical mortality, the benefit with radiation was no longer significant (stage IIB: p = 0.45, stage III-IV: p = 0.44). CONCLUSIONS: Radiation does not seem to increase the risk of cardiac mortality or secondary malignancy in patients with malignant thymoma. Although the routine use of postoperative radiotherapy in malignant thymoma does not appear warranted, high-risk patients may benefit from adjuvant radiation. This study can help to design prospective trials to further establish the role of radiotherapy in malignant thymoma.

Multiplicity-calibrated Bayesian hypothesis tests.

When testing multiple hypotheses simultaneously, there is a need to adjust the levels of the individual tests to effect control of the family-wise error rate (FWER). Standard frequentist adjustments control the error rate but are typically both conservative and oblivious to prior information. We propose a Bayesian testing approach-multiplicity-calibrated Bayesian hypothesis testing-that sets individual critical values to reflect prior information while controlling the FWER via the Bonferroni inequality. If the prior information is specified correctly, in the sense that those null hypotheses considered most likely to be false in fact are false, the power of our method is substantially greater than that of standard frequentist approaches. We illustrate our method using data from a pharmacogenetic trial and a preclinical cancer study. We demonstrate its error rate control and power advantage by simulation.

Brachytherapy in the treatment of cholangiocarcinoma.

PURPOSE: To examine the role of brachytherapy in the treatment of cholangiocarcinomas in a relatively large group of patients. METHODS AND MATERIALS: Using the Surveillance, Epidemiology and End Results database, a total of 193 patients with cholangiocarcinoma treated with brachytherapy were identified for the period 1988-2003. The primary analysis compared patients treated with brachytherapy (with or without external-beam radiation) with those who did not receive radiation. To try to account for confounding variables, propensity score and sensitivity analyses were used. RESULTS: There was a significant difference between patients who received radiation (n = 193) and those who did not (n = 6859) with regard to surgery (p < 0.0001), race (p < 0.0001), stage (p < 0.0001), and year of diagnosis (p <0.0001). Median survival for patients treated with brachytherapy was 11 months (95% confidence interval [CI] 9-13 months), compared with 4 months for patients who received no radiation (p < 0.0001). On multivariable analysis (hazard ratio [95% CI]) brachytherapy (0.79 [0.66-0.95]), surgery (0.50 [0.46-0.53]), year of diagnosis (1998-2003: 0.66 [0.60-0.73]; 1993-1997: (0.96 [0.89-1.03; NS], baseline 1988-1992), and extrahepatic disease (0.84 [0.79-0.89]) were associated with better overall survival. CONCLUSIONS: To the authors' knowledge, this is the largest dataset reported for the treatment of cholangiocarcinomas with brachytherapy. The results of this retrospective analysis suggest that brachytherapy may improve overall survival. However, because of the limitations of the Surveillance, Epidemiology and End Results database, these results should be interpreted cautiously, and future prospective studies are needed.

Convergent evidence that choline acetyltransferase gene variation is associated with prospective smoking cessation and nicotine dependence.

The ability to quit smoking is heritable, yet few genetic studies have investigated prospective smoking cessation. We conducted a systems-based genetic association analysis in a sample of 472 treatment-seeking smokers of European ancestry after 8 weeks of transdermal nicotine therapy for smoking cessation. The genotyping panel included 169 single-nucleotide polymorphisms (SNPs) in 7 nicotinic acetylcholine receptor subunit genes and 4 genes in the endogenous cholinergic system. The primary outcome was smoking cessation (biochemically confirmed) at the end of treatment. SNPs clustered in the choline acetyltransferase (ChAT) gene were individually identified as nominally significant, and a 5-SNP haplotype (block 6) in ChAT was found to be significantly associated with quitting success. Single SNPs in ChAT haplotype block 2 were also associated with pretreatment levels of nicotine dependence in this cohort. To replicate associations of SNPs in haplotype blocks 2 and 6 of ChAT with nicotine dependence in a non-treatment-seeking cohort, we used data from an independent community-based sample of 629 smokers representing 200 families of European ancestry. Significant SNP and haplotype associations were identified for multiple measures of nicotine dependence. Although the effect sizes in both cohorts are modest, converging data across cohorts and phenotypes suggest that ChAT may be involved in nicotine dependence and ability to quit smoking. Additional sequencing and characterization of ChAT may reveal functional variants that contribute to nicotine dependence and smoking cessation.

Radiotherapy is associated with improved survival in adjuvant and palliative treatment of extrahepatic cholangiocarcinomas.

PURPOSE: Extrahepatic cholangiocarcinomas (EHC) are rare tumors of the biliary tree because of their low incidence, large randomized studies examining radiotherapy (RT) for EHC have not been performed. The purpose of this study was to examine the role of adjuvant and palliative RT in the treatment of EHC in a large patient population. METHODS AND MATERIALS: This was a retrospective analysis of 4,758 patients with EHC collected from the Surveillance, Epidemiology, and End Results database. The primary endpoint was overall survival. RESULTS: Patients underwent surgery (28.8%), RT (10.0%), surgery and RT (14.7%), or no RT or surgery (46.4%). The median age of the patient population was 73 years (range, 23-104), 52.5% were men, and 80.7% were white. The median overall survival time was 16 months (95% confidence interval [CI] 15-17), 9 months (95% CI 9-11), 9 months (95% CI 9-10), and 4 months (95% CI 3-4) for surgery and RT, surgery, RT, and no RT or surgery, respectively. The overall survival was significantly different between the surgery and surgery and RT groups (p < .0001) and RT and no RT or surgery groups (p < .0001) on the log-rank test. The propensity score-adjusted analyses of surgery and RT vs. surgery (hazard ratio, 0.94; 95% CI, 0.84-1.05) were not significantly different, but that for RT vs. no RT or surgery (hazard ratio, 0.61; 95% CI, 0.54-0.70) was significantly different. CONCLUSION: These results suggest that palliative RT prolongs survival in patients with EHC. The benefit associated with surgery and RT was significant on univariate analysis but not after controlling for potential confounders using the propensity score. Future studies should evaluate the addition of chemotherapy and biologic agents for the treatment of EHC.

Assessing the effects of lymphadenectomy and radiation therapy in patients with uterine carcinosarcoma: a SEER analysis.

OBJECTIVE: The purpose of this analysis is to determine the pathologic prognostic factors and treatment outcome of patients with carcinosarcoma of the uterus. METHODS: A retrospective analysis of data from the Surveillance, Epidemiology, and End Results program of the National Cancer Institute between January 1, 1988 and November 1, 2003 was conducted. A total of 1855 with AJCC Stages I-III disease were identified who received primary surgical treatment. Overall survival curves were constructed using Kaplan-Meier curves. Cox proportional hazards model was used to identify factors predictive of overall survival. RESULTS: AJCC stage of all patients was as follows: 65% Stage I (n=1099), 14% Stage II (n=245), 21% Stage III (n=353). 57% (n=965) patients underwent LND. The median number of lymph nodes removed was 12 (SD=10.2); 119 (14%) patients had positive lymph nodes. Five-year overall survival (OS), disease free survival, and median survival were significantly improved for patients receiving lymph node dissection (LND) as compared to patients that received no LND, irrespective of radiotherapy. Adjuvant radiation therapy had no improvement on overall survival regardless of LND. There was no overall survival benefit to the addition of radiotherapy regardless of whether patients underwent a lymph node dissection or not. Age, race, marital status, lymph node dissection and stage were predictive of survival on multivariate analysis. CONCLUSIONS: Lymphadenectomy is significantly associated with improved overall survival in patients with Stage I-III uterine carcinosarcoma compared to no lymphadenectomy. The use of adjuvant radiotherapy conferred no overall survival benefit.

Radiation therapy is associated with improved survival in the adjuvant and definitive treatment of intrahepatic cholangiocarcinoma.

PURPOSE: Intrahepatic cholangiocarcinomas (IHC) are rare tumors for which large randomized studies regarding the use of radiation are not available. The purpose of this study was to examine the role of adjuvant and definitive radiation therapy in the treatment of IHC in a large group of patients. METHODS AND MATERIALS: This is a retrospective analysis of 3,839 patients with IHC collected from the Surveillance, Epidemiology, and End Results (SEER) database. The primary endpoint was overall survival (OS). RESULTS: Patients received either surgery alone (25%), radiation therapy alone (10%), surgery and adjuvant radiation therapy (7%) or no treatment (58%). The median age of the patient population was 73 years (range, 22-102 years); 52% of patients were male and 81% were Caucasian. Median OS was 11 (95% confidence interval [CI], 9-13), 6 (95% CI, 5-6), 7 (95% CI, 6-8), and 3 months for surgery and adjuvant radiation therapy, surgery alone, radiation therapy alone, and no treatment, respectively. The OS was significantly different between surgery alone and surgery and adjuvant radiation therapy (p = 0.014) and radiation therapy alone and no treatment (p < 0.0001). Use of surgery and adjuvant radiation therapy conferred the greatest benefit on OS (HR = 0.40; 95% CI, 0.34-0.47), followed by surgery alone (hazard ratio [HR], 0.49; 95% CI, 0.44-0.54) and radiation therapy alone (HR, 0.68; 95% CI, 0.59-0.77) compared with no treatment, on multivariate analysis. Propensity score adjusted hazard ratios (controlling for age, race/ethnicity, stage, and year of diagnosis) were also significant (surgery and adjuvant radiation therapy vs. surgery alone (HR, 0.82; 95% CI, 0.70-0.96); radiation therapy alone vs. no treatment (HR, 0.67; 95% CI, 0.58-0.76)). CONCLUSIONS: The study results suggest that adjuvant and definitive radiation treatment prolong survival, although cure rates remain low. Future studies should evaluate the addition of chemotherapy and biologics to the treatment of IHC.

Relationship of biochemical outcome to percentage of positive biopsies in men with clinically localized prostate cancer treated with permanent interstitial brachytherapy.

OBJECTIVES: Recent studies have demonstrated that the percentage of positive prostate needle biopsies (PPBs) is an independent predictor of biochemical failure (BF) after radical prostatectomy and external beam radiotherapy. Few studies have confirmed this phenomenon in patients treated with permanent interstitial brachytherapy. We conducted an analysis to determine the clinical utility of the PPBs in predicting BF after permanent interstitial brachytherapy for patients with clinically localized prostate cancer. METHODS: The clinical and pathologic data from 245 hormone-naive patients with clinical Stage T1c-T2cNxM0 prostate cancer who had undergone permanent prostate brachytherapy from 1992 to 2002 at our institution were retrospectively evaluated. The PPBs, preimplant prostate-specific antigen, and biopsy Gleason score were evaluated as predictors of BF after brachytherapy. The risk of BF was calculated using logistic regression models. The time to BF was assessed using Cox proportional hazard models and Kaplan-Meier estimates. RESULTS: The median PPBs in our study cohort was 27%. The risk of BF was 10.9% for those with a PPBs less than the median versus 26.2% for those with a PPBs greater than the median. A PPBs greater than the median was an independent predictor of BF on multivariate analysis (relative risk 2.3, 95% confidence interval 1.21 to 4.39, P = 0.011). In the time-to-failure models, the PPBs, prostate-specific antigen level, and Gleason score were significantly associated with BF. CONCLUSIONS: Our data suggest that the PPBs is significantly associated with BF in patients undergoing permanent interstitial brachytherapy. The PPBs, along with the pretreatment prostate-specific antigen level and Gleason biopsy score, is a useful preoperative parameter in predicting for BF and the time to failure for patients treated with interstitial brachytherapy.

Identification of pharmacogenetic markers in smoking cessation therapy.

Pharmacogenetic clinical trials seek to identify genetic modifiers of treatment effects. When a trial has collected data on many potential genetic markers, a first step in analysis is to screen for evidence of pharmacogenetic effects by testing for treatment-by-marker interactions in a statistical model for the outcome of interest. This approach is potentially problematic because (i) individual significance tests can be overly sensitive, particularly when sample sizes are large; and (ii) standard significance tests fail to distinguish between markers that are likely, on biological grounds, to have an effect, and those that are not. One way to address these concerns is to perform Bayesian hypothesis tests [Berger (1985) Statistical decision theory and Bayesian analysis. New York: Springer; Kass and Raftery (1995) J Am Stat Assoc 90:773-795], which are typically more conservative than standard uncorrected frequentist tests, less conservative than multiplicity-corrected tests, and make explicit use of relevant biological information through specification of the prior distribution. In this article we use a Bayesian testing approach to screen a panel of genetic markers recorded in a randomized clinical trial of bupropion versus placebo for smoking cessation. From a panel of 59 single-nucleotide polymorphisms (SNPs) located on 11 candidate genes, we identify four SNPs (one each on CHRNA5 and CHRNA2 and two on CHAT) that appear to have pharmacogenetic relevance. Of these, the SNP on CHRNA5 is most robust to specification of the prior. An unadjusted frequentist test identifies seven SNPs, including these four, none of which remains significant upon correction for multiplicity. In a panel of 43 randomly selected control SNPs, none is significant by either the Bayesian or the corrected frequentist test.