A single-institution review of accelerated partial breast irradiation in patients considered "cautionary" by the American Society for Radiation Oncology.

BACKGROUND: The American Society for Radiation Oncology (ASTRO) issued a consensus statement in 2009 regarding patient selection for accelerated partial breast irradiation (APBI) following breast-conserving surgery (BCS) for breast cancer (BC). We reviewed our single-institution experience with APBI in patients considered "cautionary" by ASTRO to determine patterns of recurrence. METHODS: An institutional review board-approved, retrospective chart review was conducted from January 2004 to November 2009. We identified 106 "cautionary" patients with 109 BC. All patients were treated with BCS followed by APBI via balloon catheter brachytherapy. "Cautionary" criteria include patients aged 50-59 years, tumor size 2.1-3.0 cm, close margins (<2 mm), focal lymphovascular invasion, estrogen receptor (ER)-negative tumors, invasive lobular carcinoma, or ductal carcinoma in situ (DCIS) ≤ 3 cm. Rates of recurrence at any site were evaluated. RESULTS: Median follow-up was 3 years. There were 3 IBTR (2.8%) at a median of 3.2 years. The 3-year actuarial IBTR rate was 1.8%. Patients with ER-negative invasive cancers had a higher IBTR rate compared with ER-positive patients (11.8% vs. 2.2%), although this did not reach statistical significance (P = 0.18). There were no IBTR in 46 patients with DCIS. On univariate analysis, there was no association between "cautionary" criteria and risk of local, regional, or distant recurrence. CONCLUSIONS: Patients considered "cautionary" for APBI based on ASTRO guidelines had low rates of IBTR. ER-negative patients trended toward a higher IBTR rate with APBI compared with ER-positive patients. Longer follow-up is needed to establish the safety of APBI in "cautionary" patients.

A bootstrap test for comparing two variances: simulation of size and power in small samples.

An F statistic was proposed by Good and Chernick ( 1993 ) in an unpublished paper, to test the hypothesis of the equality of variances from two independent groups using the bootstrap; see Hall and Padmanabhan ( 1997 ), for a published reference where Good and Chernick ( 1993 ) is discussed. We look at various forms of bootstrap tests that use the F statistic to see whether any or all of them maintain the nominal size of the test over a variety of population distributions when the sample size is small. Chernick and LaBudde ( 2010 ) and Schenker ( 1985 ) showed that bootstrap confidence intervals for variances tend to provide considerably less coverage than their theoretical asymptotic coverage for skewed population distributions such as a chi-squared with 10 degrees of freedom or less or a log-normal distribution. The same difficulties may be also be expected when looking at the ratio of two variances. Since bootstrap tests are related to constructing confidence intervals for the ratio of variances, we simulated the performance of these tests when the population distributions are gamma(2,3), uniform(0,1), Student's t distribution with 10 degrees of freedom (df), normal(0,1), and log-normal(0,1) similar to those used in Chernick and LaBudde ( 2010 ). We find, surprisingly, that the results for the size of the tests are valid (reasonably close to the asymptotic value) for all the various bootstrap tests. Hence we also conducted a power comparison, and we find that bootstrap tests appear to have reasonable power for testing equivalence of variances.

Dabigatran and warfarin in vitamin K antagonist-naive and -experienced cohorts with atrial fibrillation.

BACKGROUND: The comparison of anticoagulants dabigatran and warfarin might be most equitable in vitamin K antagonist (VKA)-naive patients. METHODS AND RESULTS: Warfarin and 2 doses of dabigatran-110 mg BID (D110) and 150 mg BID (D150)-were compared in a balanced population of VKA-naive (≤62 days of lifetime VKA exposure, with 33% never prescribed a VKA) and VKA-experienced patients with atrial fibrillation (n=18 113). For VKA-naive and -experienced patients assigned warfarin, the time in therapeutic range (international normalized ratio 2.0 to 3.0) was 62% and 67%, respectively, and 61% and 66% for those never and ever prescribed a VKA. In VKA-naive patients, stroke and systemic embolism rates were 1.57%, 1.07%, and 1.69% per year for D110, D150, and warfarin, respectively. D110 was similar to warfarin (P=0.65); D150 was superior (P=0.005). Major bleeding rates were 3.11%, 3.34%, and 3.57% per year, respectively. D110 and D150 were similar to warfarin (P=0.19 and P=0.55). Intracranial bleeding rates were 0.19%, 0.33%, and 0.73% per year, respectively. D110 and D150 were lower than warfarin (P<0.001 and P=0.005). In VKA-experienced patients, stroke and systemic embolism rates were 1.51%, 1.15%, and 1.74% per year for D110, D150, and warfarin, respectively. D110 was similar to warfarin (P=0.32); D150 was superior (P=0.007). Major bleeding rates were 2.66%, 3.30%, and 3.57% per year, respectively. D110 was lower than warfarin (P=0.003); D150 was similar (P=0.41). Intracranial bleeding rates were 0.26%, 0.32%, and 0.79% per year, respectively. D110 and D150 were lower than warfarin (P<0.001 for both). Results were similar for patients never on a VKA. CONCLUSIONS: Previous VKA exposure does not influence the benefits of dabigatran at either dose compared with warfarin. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Unique identifier: NCT00262600.

Nanoparticle-delivered suicide gene therapy effectively reduces ovarian tumor burden in mice.

There is currently no effective therapy for patients with advanced ovarian cancer. To address the need for a more effective treatment for this deadly disease, we conducted preclinical tests in ovarian tumor-bearing mice to evaluate the therapeutic efficacy of using a cationic biodegradable poly(beta-amino ester) polymer as a vector for nanoparticulate delivery of DNA encoding a diphtheria toxin suicide protein (DT-A). The promoter sequences of two genes that are highly active in ovarian tumor cells, MSLN and HE4, were used to target DT-A expression to tumor cells. Administration of DT-A nanoparticles directly to s.c. xenograft tumors and to the peritoneal cavity of mice bearing primary and metastatic ovarian tumors resulted in a significant reduction in tumor mass and a prolonged life span compared to control mice. Minimal nonspecific tissue and blood chemistry toxicity was observed following extended treatment with nanoparticles. DT-A nanoparticle therapy suppressed tumor growth more effectively than treatment with clinically relevant doses of cisplatin and paclitaxel. Our findings suggest that i.p. administration of polymeric nanoparticles to deliver DT-A encoding DNA, combined with transcriptional regulation to target gene expression to ovarian tumor cells, holds promise as an effective therapy for advanced-stage ovarian cancer.

Tissue inhibitor of metalloproteinase-4 is elevated in early-stage breast cancers with accelerated progression and poor clinical course.

An increasing number of breast cancer patients are diagnosed with small, localized, early-stage tumors. These patients are typically thought to have a good prognosis for long-term disease-free survival, but epidemiological studies indicate that up to 30% may have a recurrence within 3 to 5 years of diagnosis. Identifying patients with a high risk of recurrence and/or progression is important because they could be more aggressively treated at diagnosis to improve their chances for disease-free survival. Recent evidence suggests that elevated levels of the matrix metalloproteinase inhibitor, tissue inhibitor of metalloproteinase (TIMP)-4, are associated with malignant progression of ductal carcinoma in situ, a precancerous lesion. To examine the association of TIMP-4 with survival outcomes, we conducted a retrospective immunohistochemical analysis of 314 cases from patients with early-stage disease, defined as tumors smaller than 2 cm and no spread to lymph nodes (tumor-node-metastasis staging: T1N0MX). We found that tumors with elevated levels of TIMP-4 were correlated with a reduced probability of long-term disease-free survival, especially in patients with estrogen receptor-negative tumors. Our findings prompt further evaluation of TIMP-4 as a simple prognostic marker that may help identify patients with early-stage breast cancer who could benefit from more aggressive treatment at diagnosis.