Chemotherapy enriches for an invasive triple-negative breast tumor cell subpopulation expressing a precursor form of N-cadherin on the cell surface.

BACKGROUND: Although most triple-negative breast cancer (TNBC) patients initially respond to chemotherapy, residual tumor cells frequently persist and drive recurrent tumor growth. Previous studies from our laboratory and others' indicate that TNBC is heterogeneous, being composed of chemo-sensitive and chemo-resistant tumor cell subpopulations. In the current work, we studied the invasive behaviors of chemo-resistant TNBC, and sought to identify markers of invasion in chemo-residual TNBC. METHODS: The invasive behavior of TNBC tumor cells surviving short-term chemotherapy treatment in vitro was studied using transwell invasion assays and an experimental metastasis model. mRNA expression levels of neural cadherin (N-cadherin), an adhesion molecule that promotes invasion, was assessed by PCR. Expression of N-cadherin and its precursor form (pro-N-cadherin) was assessed by immunoblotting and flow cytometry. Pro-N-cadherin immunohistochemistry was performed on tumors obtained from patients pre- and post- neoadjuvant chemotherapy treatment. RESULTS: TNBC cells surviving short-term chemotherapy treatment exhibited increased invasive behavior and capacity to colonize metastatic sites compared to untreated tumor cells. The invasive behavior of chemo-resistant cells was associated with their increased cell surface expression of precursor N-cadherin (pro-N-cadherin). An antibody specific for the precursor domain of N-cadherin inhibited invasion of chemo-resistant TNBC cells. To begin to validate our findings in humans, we showed that the percent cell surface pro-N-cadherin (+) tumor cells increased in patients post- chemotherapy treatment. CONCLUSIONS: TNBC cells surviving short-term chemotherapy treatment are more invasive than bulk tumor cells. Cell surface pro-N-cadherin expression is associated with the invasive and chemo-resistant behaviors of this tumor cell subset. Our findings indicate the importance of future studies determining the value of cell surface pro-N-cadherin as: 1) a biomarker for TNBC recurrence and 2) a therapeutic target for eliminating chemo-residual disease.

Preoperative or postoperative radiotherapy versus surgery alone for retroperitoneal sarcoma: a case-control, propensity score-matched analysis of a nationwide clinical oncology database.

BACKGROUND: Recruitment into clinical trials for retroperitoneal sarcoma has been challenging, resulting in termination of the only randomised multicentre trial in the USA investigating perioperative radiotherapy. Nonetheless, use of radiotherapy for retroperitoneal sarcoma has increased over the past decade, substantiated primarily by its established role in extremity sarcoma. In this study, we used a nationwide clinical oncology database to separately compare overall survival for patients with retroperitoneal sarcoma who had surgery and preoperative radiotherapy or surgery and postoperative radiotherapy versus surgery alone. METHODS: We did two case-control, propensity score-matched analyses of the National Cancer Data Base, which included adult patients with retroperitoneal sarcoma who were diagnosed from 2003 to 2011. Patients were included if they had localised, primary retroperitoneal sarcoma. Patients were classified into three groups based on use of radiotherapy: preoperative radiotherapy, postoperative radiotherapy, and no radiotherapy (surgery alone). Patients were excluded if they received both preoperative radiotherapy and postoperative radiotherapy, or if they received intraoperative radiotherapy. Parallel propensity score-matched datasets were created for patients who received preoperative radiotherapy versus those who received no radiotherapy and for patients who received postoperative therapy versus those who received no radiotherapy. Propensity scores were calculated with logistic regression, with multiple imputation and backwards elimination, with a significance level to stay of 0·05. Matching was done with a nearest-neighbour algorithm and matched 1:2 for the preoperative radiotherapy dataset and 1:1 for the postoperative radiotherapy dataset. The primary objective of interest was overall survival for patients who received preoperative radiotherapy or postoperative radiotherapy compared with those who received no radiotherapy within the propensity score-matched datasets. FINDINGS: 9068 patients were included in this analysis: 563 in the preoperative radiotherapy group, 2215 in the postoperative radiotherapy group, and 6290 in the no radiotherapy group. Matching resulted in two comparison groups (preoperative radiotherapy vs no radiotherapy, and postoperative radiotherapy vs no radiotherapy) with negligible differences in all demographic, clinicopathological, and treatment-level variables. In the matched case-control analysis for preoperative radiotherapy median follow-up time was 42 months (IQR 27-70) for the preoperative radiotherapy group versus 43 months (25-64) for the no radiotherapy group; median overall survival was 110 months (95% CI 75-not estimable) versus 66 months (61-76), respectively. In the matched case-control analysis for postoperative radiotherapy median follow-up time was 54 months (IQR 32-79) for patients in the postoperative radiotherapy group and 47 months (26-72) for patients in the no radiotherapy group; median overall survival was 89 months (95% CI 79-100) versus 64 months (59-69), respectively. Both preoperative radiotherapy (HR 0·70, 95% CI 0·59-0·82; p<0·0001) and postoperative radiotherapy (HR 0·78, 0·71-0·85; p<0·0001) were significantly associated with improved overall survival compared with surgery alone. INTERPRETATION: To the best of our knowledge, this is the largest study to date of the effect of radiotherapy on overall survival in patients with retroperitoneal sarcoma. Radiotherapy was associated with improved overall survival compared with surgery alone when delivered as either preoperative radiotherapy or postoperative radiotherapy. Together with the results from the ongoing randomised EORTC trial (62092-22092; NCT01344018) investigating preoperative radiotherapy for retroperitoneal sarcoma pending, these data might provide additional support for the increasing use of radiotherapy for patients with retroperitoneal sarcoma undergoing surgical resection. FUNDING: Department of Surgery, Duke University School of Medicine.

Efficacy of a Nurse-Delivered Intervention to Prevent and Delay Postpartum Return to Smoking: The Quit for Two Trial.

INTRODUCTION: Most pregnant women who quit smoking return to smoking postpartum. Trials to prevent this return have been unsuccessful. We tested the efficacy of a nurse-delivered intervention in maintaining smoking abstinence after delivery among pregnant women who quit smoking that was tailored on their high risk of relapse (eg, had strong intentions to return). METHODS: We recruited 382 English-speaking spontaneous pregnant quitters from 14 prenatal clinics and randomized them to receive either a smoking abstinence booklet plus newsletters about parenting and stress (control) or a nurse-delivered smoking abstinence intervention that differed in intensity for the high and low risk groups. Our primary outcome was smoking abstinence at 12 months postpartum. RESULTS: Using intent-to-treat analyses, there was a high rate of biochemically validated smoking abstinence at 12 months postpartum but no arm differences ( CONTROL: 36% [95% confidence interval [CI]: 29-43] vs. INTERVENTION: 35% [95% CI: 28-43], P = .81). Among women at low risk of returning to smoking, the crude abstinence rate was significantly higher in the control arm (46%) than in the intervention arm (33%); among women at high risk of returning to smoking, the crude abstinence rate was slightly lower but not different in the control arm (31%) than in the intervention arm (37%). CONCLUSIONS: Low-risk women fared better with a minimal intervention that focused on parenting skills and stress than when they received an intensive smoking abstinence intervention. The opposite was true for women who were at high risk of returning to smoking. Clinicians might need to tailor their approach based on whether women are at high or low risk of returning to smoking. IMPLICATIONS: Results suggest that high-risk and low-risk women might benefit from different types of smoking relapse interventions. Those who are lower risk of returning to smoking might benefit from stress reduction that is devoid of smoking content, whereas those who are higher risk might benefit from smoking relapse prevention.

Baseline Prostate Atrophy is Associated with Reduced Risk of Prostate Cancer in Men Undergoing Repeat Prostate Biopsy.

PURPOSE: We evaluated whether the presence and severity of baseline prostate atrophy in men with initial biopsy negative for prostate cancer was associated the risk of subsequent prostate cancer detection in a clinical trial with scheduled study mandated biopsies. MATERIALS AND METHODS: We retrospectively analyzed the records of 3,084 men 50 to 75 years old with prostate specific antigen between 2.5 and 10 ng/ml, and a prior negative biopsy in the placebo arm of the REDUCE (Reduction by Dutasteride of Prostate Cancer Events) study who completed at least 1 per-protocol biopsy. Prostate cancer (defined as present or absent) and prostate atrophy (graded as absent, mild or moderate/marked) was assessed by central pathology review. The association of baseline atrophy with positive 2 and 4-year repeat biopsies was evaluated with logistic regression, controlling for baseline covariates. RESULTS: Baseline prostate atrophy was detected in 2,143 men (70%) and graded as mild and moderate/marked in 1,843 (60%) and 300 (10%) baseline biopsies, respectively. Patients with atrophy were older and had a larger prostate, and more acute and chronic prostate inflammation. At 2-year biopsy the prostate cancer incidence was 17% (508 cases). Baseline atrophy was significantly associated with lower prostate cancer risk (univariable and multivariable OR 0.60, 95% CI 0.50-0.74 and OR 0.67, 95% CI 0.54-0.83, p <0.001, respectively) at the 2-year biopsy. These results were similar at the 4-year biopsy (univariable and multivariable OR 0.70, 95% CI 0.53-0.93 and OR 0.72, 95% CI 0.53-0.97, p = 0.03, respectively). Relative to no atrophy the prostate cancer risk at the 2-year repeat biopsy was lower for mild atrophy (OR 0.69, 95% CI 0.55-0.86) and moderate/marked atrophy (OR 0.51, 95% CI 0.34-0.76, each p <0.001). CONCLUSIONS: Baseline prostate atrophy in men with a prostate biopsy negative for prostate cancer was independently associated with subsequent lower prostate cancer detection.

Steps to Health employee weight management randomized control trial: short-term follow-up results.

OBJECTIVE: To present the short-term follow-up findings of the Steps to Health study, a randomized trial to evaluate the effectiveness of two employee weight management programs offered within Duke University and the Health System. METHODS: A total of 550 obese (body mass index, ≥30 kg/m2) employees were randomized 1:1 between January 2011 and June 2012 to the education-based Weight Management (WM) or the WM+ arm, which focused on behavior modification. Employees were contacted to complete a follow-up visit approximately 14 months after baseline. RESULTS: There were no clinically, or statistically, meaningful differences between arms, but there were modest reductions in body mass index, and positive, meaningful changes in diet and physical activity for both arms. CONCLUSIONS: The modest positive effects observed in this study may suggest that to achieve weight loss through the workplace more intensive interventions may be required.

A multicenter phase I dose escalation trial to evaluate safety and tolerability of intra-arterial temozolomide for patients with advanced extremity melanoma using normothermic isolated limb infusion.

BACKGROUND: L-phenylalanine mustard (LPAM) has been the standard for use in regional chemotherapy (RC) for unresectable in-transit melanoma. Preclinical data demonstrated that regional temozolomide (TMZ) may be more effective. METHODS: Patients with AJCC Stage IIIB or IIIC extremity melanoma who failed previous LPAM-based RC were treated with TMZ via isolated limb infusion (ILI) according to a modified accelerated titration design. Drug pharmacokinetic (PK) analysis, tumor gene expression, methylation status of the O6-methylguanine methyltransferase (MGMT) promoter, and MGMT expression were evaluated. Primary objectives were to (1) determine dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of TMZ via ILI and (2) explore biomarker correlates of response. RESULTS: 28 patients completed treatment over 2.5 years at 3 institutions. 19 patients were treated at the MTD defined as 3,200 mg/m(2) [multiplied by 0.09 (arm), 0.18 (leg)]. Two of five patients had DLTs at the 3,600 mg/m(2) level while only grade 1 (n = 15) and grade 2 (n = 4) clinical toxicities occurred at the MTD. At 3-month post-ILI, 10.5 % (2/19) had CR, 5.3 % (1/19) had PR, 15.8 % (3/19) had SD, and 68.4 % (13/19) had PD. Neither PK parameters of TMZ nor MGMT levels were associated with response or toxicity. CONCLUSION: In this first ever use of intra-arterial TMZ in ILI for melanoma, the MTD was determined. While we could not define a marker for TMZ response, the minimal toxicity of TMZ ILI may allow for repeated treatments to increase the response rate as well as clarify the role of MGMT expression.

Efficacy of a couple-based randomized controlled trial to help Latino fathers quit smoking during pregnancy and postpartum: the Parejas trial.

BACKGROUND: Although many Latinos in the United States smoke, they receive assistance to quit less often than non-Latinos. To address this disparity, we recruited Latino couples into a randomized controlled trial and provided a smoking cessation program during a teachable moment, when men's partners were pregnant. METHODS: We compared two interventions: (i) written materials plus nicotine replacement therapy (NRT) to (ii) materials, NRT, and couple-based counseling that addressed smoking cessation and couples communication. We recruited 348 expectant fathers who smoked via their pregnant partners from county health departments. Our primary outcome was 7-day point prevalence smoking abstinence and was collected from November 2010 through April 2013 and analyzed in February 2014. RESULTS: We found high rates of cessation but no arm differences in smoking rates at the end of pregnancy (0.31 vs. 0.30, materials only vs. counseling, respectively) and 12 months after randomization (postpartum: 0.39 vs. 0.38). We found high quit rates among nondaily smokers but no arm differences (0.43 vs. 0.46 in pregnancy and 0.52 vs. 0.48 postpartum). Among daily smokers, we found lower quit rates with no arm differences but effects favoring the intervention arm (0.13 vs. 0.16 in pregnancy and 0.17 vs. 0.24 postpartum). CONCLUSIONS: A less intensive intervention promoted cessation equal to more intensive counseling. Postpartum might be a more powerful time to promote cessation among Latino men. IMPACT: Less intensive interventions when delivered during teachable moments for Latino men could result in a high smoking cessation rate and could reduce disparities.

Predictors of pregnant quitters' intention to return to smoking postpartum.

INTRODUCTION: Although many pregnant women quit smoking, most return to smoking postpartum. Returning to smoking is strongly related to women's stated intention about smoking during pregnancy. We examined factors related to women's intention to return to smoking to improve intervention trials. METHODS: We report cross-sectional baseline data from a randomized controlled trial to prevent postpartum return to smoking. Women (n = 382; 98% consent rate) were English-speaking women who smoked at least 100 cigarettes in their lifetimes and at least 5 cigarettes a day prior to becoming pregnant. We fit logistic regression models to test whether women's intention to return to smoking was associated with demographic and smoking factors such as race, parity, and smoker self-identity. RESULTS: Forty-three percent of women had a strong intention of returning to smoking. Factors independently associated with intending to return to smoking were: stating they did not want to be currently pregnant (OR = 2.1, CI = 1.1-3.9), reporting being abstinent for fewer days (OR = 0.8, CI = 0.7-0.9), being less concerned about the harmful effects of smoking to themselves (OR = 1.6, CI = 0.9-2.8), viewing quit as temporary (OR = 2.1, CI = 1.2-3.6), and self-identifying selves as smokers (OR = 8.7, CI = 5.0-15.2). CONCLUSIONS: Although some factors related to intention to return to smoking were unchangeable, it might be possible to attempt to change women's attribution of why they quit to be more permanent and to have them change their self-identity to be a "nonsmoker" from a "smoker who is not currently smoking." Helping women have stronger intentions to stay quit could promote less return to smoking postpartum.

Local recurrence after surgery for non-small cell lung cancer: a recursive partitioning analysis of multi-institutional data.

OBJECTIVE: To define subgroups at high risk of local recurrence (LR) after surgery for non-small cell lung cancer using a recursive partitioning analysis (RPA). METHODS: This Institutional Review Board-approved study included patients who underwent upfront surgery for I-IIIA non-small cell lung cancer at Duke Cancer Institute (primary set) or at other participating institutions (validation set). The 2 data sets were analyzed separately and identically. Disease recurrence at the surgical margin, ipsilateral hilum, and/or mediastinum was considered an LR. Recursive partitioning was used to build regression trees for the prediction of local recurrence-free survival (LRFS) from standard clinical and pathological factors. LRFS distributions were estimated with the Kaplan-Meier method. RESULTS: The 1411 patients in the primary set had a 5-year LRFS rate of 77% (95% confidence interval [CI], 0.74-0.81), and the 889 patients in the validation set had a 5-year LRFS rate of 76% (95% CI, 0.72-0.80). The RPA of the primary data set identified 3 terminal nodes based on stage and histology. These nodes and their 5-year LRFS rates were as follows: (1) stage I/adenocarcinoma, 87% (95% CI, 0.83-0.90); (2) stage I/squamous or large cell, 72% (95% CI, 0.65-0.79); and (3) stage II-IIIA, 62% (95% CI, 0.55-0.69). The validation RPA identified 3 terminal nodes based on lymphovascular invasion (LVI) and stage: (1) no LVI/stage IA, 82% (95% CI, 0.76-0.88); (2) no LVI/stage IB-IIIA, 73% (95% CI, 0.69-0.80); and (3) LVI, 58% (95% CI, 0.47-0.69). CONCLUSIONS: The risk of LR was similar in the primary and validation patient data sets. There was discordance between the 2 data sets regarding the clinical factors that best segregate patients into risk groups.

The steps to health employee weight management randomized control trial: rationale, design and baseline characteristics.

BACKGROUND: The workplace can be an important setting for addressing obesity. An increasing number of employers offer weight management programs. PURPOSE: Present the design, rationale and baseline characteristics of the Steps to Health study (STH), a randomized trial to evaluate the effectiveness of two preexisting employee weight management programs offered at Duke University and Medical Center. METHODS: 550 obese (BMI ≥30) employee volunteers were randomized 1:1 to two programs. Baseline data, collected between January 2011 and July 2012, included height/weight, accelerometry, workplace injuries, health care utilization, and questionnaires querying socio-cognitive factors, perceptions of health climate, physical activity, and dietary intake. In secondary analyses participants in the two programs will also be compared to a non-randomized observational control group of obese employees. RESULTS: At baseline, the mean age was 45 years, 83% were female, 41% white, and 53% black. Mean BMI was 37.2. Participants consumed a mean of 2.37 servings of fruits and vegetables per day (in the past week), participated in 11.5 min of moderate-to-vigorous physical activity, and spent 620 min being sedentary. CONCLUSION: STH addresses the need for evaluation of worksite interventions to promote healthy weight. In addition to having direct positive effects on workers' health, worksite programs have the potential to increase productivity and reduce health care costs.

Cost-effectiveness of BRCA1 and BRCA2 mutation testing to target PARP inhibitor use in platinum-sensitive recurrent ovarian cancer.

OBJECTIVES: (1) To determine whether use of a PARP inhibitor or (2) BRCA1/2 mutation testing followed by a PARP inhibitor for test positives is potentially cost-effective for maintenance treatment of platinum-sensitive recurrent high-grade serous ovarian cancer. METHODS: A modified Markov decision analysis compared 3 strategies: (1) observe; (2) olaparib to progression; (3) BRCA1/2 mutation testing; treat mutation carriers with olaparib to progression. Progression-free survival and rates of adverse events were derived from a phase 2 randomized trial. Key assumptions are as follows: (1) 14% of patients harbor a BRCA1/2 mutation; (2) progression-free survival of individuals treated with olaparib is improved for BCRA1/2 carriers compared with noncarriers (estimated hazard ratio, approximately 0.4). Costs derived from national data were assigned to treatments, adverse events, and BRCA1/2 test. Monte Carlo probabilistic sensitivity analysis was performed. RESULTS: Global olaparib was the most effective strategy, followed by BRCA1/2 testing and no olaparib. BRCA1/2 testing had an incremental cost-effectiveness ratio (ICER) of $193,442 per progression-free year of life saved (PF-YLS) compared to no olaparib, whereas global olaparib had an ICER of $234,128 per PF-YLS compared to BRCA1/2 testing. At a 52% lower-than-baseline olaparib cost estimate of $3000 per month, BRCA1/2 testing became potentially cost-effective compared with observation, with an ICER of $100,000 per PF-YLS. When strategy (1) was removed from the analysis, BRCA1/2 testing was the preferred strategy. CONCLUSIONS: The use of maintenance olaparib in women with high-grade serous ovarian cancer is not cost-effective regardless of whether BRCA1/2 testing is used to direct treatment. However, BRCA1/2 testing is a preferred strategy compared to global maintenance olaparib alone.

Assessment of the impact of adjunctive proactive telephone counseling to promote smoking cessation among lung cancer patients' social networks.

PURPOSE: When a patient is diagnosed with lung cancer, members of his/her social network may be more likely to engage in smoking cessation efforts. Proactive telephone counseling combined with a tailored self-directed intervention may be more effective at promoting smoking cessation than a tailored self-directed intervention alone. DESIGN: Randomized controlled trial. SETTING: Four clinical sites. SUBJECTS: Current smokers who are family members and close friends of patients with lung cancer. INTERVENTION: Six counselor-initiated counseling calls using motivational interviewing techniques and focusing on teaching adaptive coping skills based on the transactional model of stress and coping along with tailored self-directed materials (including nicotine patches, if not contraindicated) (n  =  245) vs. tailored self-directed materials (including nicotine patches, if not contraindicated) (n  =  251). MEASURES: Participants were surveyed at baseline and at 2 weeks, 6 months, and 12 months postintervention. The outcome was 7-day point prevalent abstinence. ANALYSIS: The objective of this study was to test for arm differences in smoking cessation rates at 2 weeks and 6 months postintervention (primary) and at 12 months postintervention (secondary). RESULTS: We found no overall effect of the proactive intervention on cessation rates. Among younger participants (age <50), the cessation rate in the intervention group was higher than in the control group at 2 weeks postintervention (16% vs. 4%, p  =  .046). For older participants (age >50), there were no group differences. CONCLUSION: Proactive telephone counseling focusing on adaptive coping skills was difficult to implement among smokers in lung cancer patients' social network. Although this study did not demonstrate any added benefit to cessation rates, this null finding may be a result of an intervention that was weaker than intended, owing to difficulties in completing the counseling phone calls. We discuss lessons learned and areas for future research in this special population.

The impact of initial fludarabine therapy on transformation to Richter syndrome or prolymphocytic leukemia in patients with chronic lymphocytic leukemia: analysis of an intergroup trial (CALGB 9011).

The impact of initial fludarabine therapy on transformation to Richter syndrome (RS) or prolymphocytic leukemia (PLL) in patients with chronic lymphocytic leukemia (CLL) is uncertain. We studied the outcomes of 521 patients with CLL who were randomized to initial fludarabine (F), chlorambucil (C) or F + C therapy on an intergroup trial (CALGB 9011). RS developed in 34 (7%) patients and PLL in 10 (2%). RS and PLL occurred in 14 (7%) and three (2%) of 188 patients randomized to F; nine (5%) and four (2%) of 191 patients treated with C; and 11 (8%) and three (2%) of 142 receiving F + C, respectively. Four percent of the 206 patients with Rai stage III/IV developed PLL, compared to only 1% of the 315 patients with Rai stage I/II (p = 0.02). Initial fludarabine therapy in patients with CLL did not impact transformation to RS or PLL, nor were any other baseline characteristics predictive for such transformation in this series.

Parent-focused change to prevent obesity in preschoolers: results from the KAN-DO study.

OBJECTIVE: The study presents the immediate post-intervention results of Kids and Adults Now - Defeat Obesity!, a randomized controlled trial to enhance healthy lifestyle behaviors in mother-preschooler (2-5 years old) dyads in North Carolina (2007-2011). The outcomes include change from baseline in the child's diet, physical activity and weight, and in the mother's parenting behaviors, diet, physical activity, and weight. METHOD: The intervention targeted parenting through maternal emotion regulation, home environment, feeding practices, and modeling of healthy behaviors. 400 mother-child dyads were randomized. RESULTS: Mothers in the intervention arm, compared to the control arm, reduced instrumental feeding (-0.24 vs. 0.01, p<0.001) and TV snacks (-.069 vs. -0.24, p=0.001). There were also improvements in emotional feeding (p=0.03), mother's sugary beverage (p=0.03) and fruit/vegetable (p=0.04) intake, and dinners eaten in front of TV (p=0.01); these differences were not significant after adjustment for multiple comparisons. CONCLUSION: KAN-DO, designed to maximize the capacity of mothers as agents of change, improved several channels of maternal influence. There were no group differences in the primary outcomes, but differences were observed in the parenting and maternal outcomes and there were trends toward improvement in the preschoolers' diets. Long-term follow-up will address whether these short-term trends ultimately improve weight status.

Prospective trial of synchronous bevacizumab, erlotinib, and concurrent chemoradiation in locally advanced head and neck cancer.

PURPOSE: We assessed the safety and efficacy of synchronous VEGF and epidermal growth factor receptor (EGFR) blockade with concurrent chemoradiation (CRT) in locally advanced head and neck cancer (HNC). EXPERIMENTAL DESIGN: Newly diagnosed patients with stage III/IV HNC received a 2-week lead-in of bevacizumab and/or erlotinib, followed by both agents with concurrent cisplatin and twice daily radiotherapy. Safety was assessed using Common Toxicity Criteria version 3.0. The primary efficacy endpoint was clinical complete response (CR) rate after CRT. RESULTS: Twenty-nine patients enrolled on study, with 27 completing therapy. Common grade III toxicities were mucositis (n = 14), dysphagia (n = 8), dehydration (n = 7), osteoradionecrosis (n = 3), and soft tissue necrosis (n = 2). Feeding tube placement was required in 79% but no patient remained dependent at 12-month posttreatment. Clinical CR after CRT was 96% [95% confidence interval (CI), 82%-100%]. Median follow-up was 46 months in survivors, with 3-year locoregional control and distant metastasis-free survival rates of 85% and 93%. Three-year estimated progression-free survival, disease-specific survival, and overall survival rates were 82%, 89%, and 86%, respectively. Dynamic contrast enhanced MRI (DCE-MRI) analysis showed that patients who had failed had lower baseline pretreatment median K(trans) values, with subsequent increases after lead-in therapy and 1 week of CRT. Patients who did not fail had higher median K(trans) values that decreased during therapy. CONCLUSIONS: Dual VEGF/EGFR inhibition can be integrated with CRT in locally advanced HNC, with efficacy that compares favorably with historical controls albeit with an increased risk of osteoradionecrosis. Pretreatment and early DCE-MRI may prospectively identify patients at high risk of failure.

Predictors of postpartum weight change among overweight and obese women: results from the Active Mothers Postpartum study.

BACKGROUND: The postpartum period may be critical for the development of midlife obesity. Identifying factors associated with postpartum weight change could aid in targeting women for healthy lifestyle interventions. METHODS: Data from Active Mothers Postpartum (AMP), a study of overweight and obese postpartum women (n=450), were analyzed to determine the effect of baseline characteristics, breastfeeding, diet, physical activity, and contraception on weight change from 6 weeks to 12, 18, and 24 months postpartum. The repeated measures mixed model was used to test the association of these effects with weight change. RESULTS: Although mean weight loss was modest (0.49 kg by 24 months), the range of weight change was striking (+21.5 kg to -24.5 kg, standard deviation [SD] 7.4). Controlling only for baseline weight, weight loss was associated with breastfeeding, hormonal contraception, lower junk food and greater healthy food intake, and greater physical activity. Only junk food intake and physical activity were significant after controlling for all other predictors. CONCLUSIONS: Eating less healthy foods and being less physically active put overweight and obese women at risk of gaining more weight after a pregnancy.

Phase II trial of dasatinib in patients with metastatic breast cancer using real-time pharmacodynamic tissue biomarkers of Src inhibition to escalate dosing.

PURPOSE: A phase II study of dasatinib, an inhibitor of multiple oncogenic tyrosine kinases including Src, was conducted to evaluate 16-week progression-free rate and tolerability in patients with previously treated metastatic breast cancer (MBC). Real-time assessment of potential tissue biomarkers of Src inhibition was used to optimize dosing. EXPERIMENTAL DESIGN: Eligibility criteria required that patients have measurable MBC, biopsiable tumor, and unlimited prior therapies. For the analysis of change in protein biomarkers of Src inhibition, focal adhesion kinase, paxillin, and p-Src, patients underwent metastatic biopsies at baseline and 4 weeks. Patients who tolerated the starting dose of dasatinib (50 or 70 mg orally twice daily) for the first 28-day cycle, and displayed suboptimal Src inhibition, were escalated to a higher dose (70 or 100 mg). RESULTS: The trial was closed early with 31 patients because of a statistical boundary that required at least 4 (13%) patients without disease progression to continue accrual. These 31 patients had a median of 2 prior lines of chemotherapy for MBC. The most notable toxicity was pleural effusions in 16 patients (52%). Twenty patients had evaluable metastatic biopsies. None of the tumors showed the predefined optimal level of Src inhibition at week 4. CONCLUSIONS: Single-agent dasatinib did not exhibit significant antitumor activity in patients with heavily pretreated MBC. There were no clinically meaningful decreases before and after dasatinib exposure between exploratory tissue biomarkers of Src inhibition which may be attributable to challenges in defining biomarker endpoints for multitargeted tyrosine kinase inhibitors.

Proactive recruitment of cancer patients' social networks into a smoking cessation trial.

BACKGROUND: This report describes the characteristics associated with successful enrollment of smokers in the social networks (i.e., family and close friends) of patients with lung cancer into a smoking cessation intervention. METHODS: Lung cancer patients from four clinical sites were asked to complete a survey enumerating their family members and close friends who smoke, and provide permission to contact these potential participants. Family members and close friends identified as smokers were interviewed and offered participation in a smoking cessation intervention. Repeated measures logistic regression model examined characteristics associated with enrollment. RESULTS: A total of 1062 eligible lung cancer patients were identified and 516 patients consented and completed the survey. These patients identified 1325 potentially eligible family and close friends. Of these, 496 consented and enrolled in the smoking cessation program. Network enrollment was highest among patients who were white and had late-stage disease. Social network members enrolled were most likely to be female, a birth family, immediate family, or close friend, and live in close geographic proximity to the patient. CONCLUSIONS: Proactive recruitment of smokers in the social networks of lung cancer patients is challenging. In this study, the majority of family members and friends declined to participate. Enlisting immediate female family members and friends, who live close to the patient as agents to proactively recruit other network members into smoking cessation trials could be used to extend reach of cessation interventions to patients' social networks. Moreover, further consideration should be given to the appropriate timing of approaching network smokers to consider cessation.

Kids and adults now! Defeat Obesity (KAN-DO): rationale, design and baseline characteristics.

BACKGROUND: Prevention of childhood obesity is a public health priority. Parents influence a child's weight by modeling healthy behaviors, controlling food availability and activity opportunities, and appropriate feeding practices. Thus interventions should target education and behavioral change in the parent, and positive, mutually reinforcing behaviors within the family. METHODS: This paper presents the design, rationale and baseline characteristics of Kids and Adults Now! - Defeat Obesity (KAN-DO), a randomized controlled behavioral intervention trial targeting weight maintenance in children of healthy weight, and weight reduction in overweight children. 400 children aged 2-5 and their overweight or obese mothers in the Triangle and Triad regions of North Carolina are randomized equally to control or the KAN-DO intervention, consisting of mailed family kits encouraging healthy lifestyle change. Eight (monthly) kits are supported by motivational counseling calls and a single group session. Mothers are targeted during a hypothesized "teachable moment" for health behavior change (the birth of a new baby), and intervention content addresses: parenting skills ((e.g., emotional regulation, authoritative parenting), healthy eating, and physical activity. RESULTS: The 400 mother-child dyads randomized to trial are 75% white and 22% black; 19% have a household income of $30,000 or below. At baseline, 15% of children are overweight (85th-95th percentile for body mass index) and 9% are obese (≥ 95th percentile). CONCLUSION: This intervention addresses childhood obesity prevention by using a family-based, synergistic approach, targeting at-risk children and their mothers during key transitional periods, and enhancing maternal self-regulation and responsive parenting as a foundation for health behavior change.

Chemoimmunotherapy with fludarabine and rituximab produces extended overall survival and progression-free survival in chronic lymphocytic leukemia: long-term follow-up of CALGB study 9712.

PURPOSE: The addition of rituximab to fludarabine-based regimens in chronic lymphocytic leukemia (CLL) has been shown to produce high response rates with extended remissions. The long-term follow-up of these regimens with respect to progression, survival, risk of secondary leukemia, and impact of genomic risk factors has been limited. METHODS: We report the long-term follow-up of the chemoimmunotherapy trial CALGB 9712 from the Cancer and Leukemia Group B, for which treatment regimen was previously reported, to examine end points of progression-free survival (PFS), overall survival (OS), impact of genomic features, and risk of therapy-related myeloid neoplasm (t-MN). RESULTS: A total of 104 patients were enrolled on this study and now have a median follow-up of 117 months (range, 66 to 131 months). The median OS was 85 months, and 71% of patients were alive at 5 years. The median PFS was 42 months, and 27% were progression free at 5 years. An estimated 13% remained free of progression at almost 10 years of follow-up. Multivariable models of PFS and OS showed that immunoglobulin heavy chain variable region mutational status was significant for both, whereas cytogenetic abnormalities were significant only for OS. No patient developed t-MN before relapse. CONCLUSION: Long-term follow-up of CALGB 9712 demonstrates extended OS and PFS with fludarabine plus rituximab. Patients treated with fludarabine plus rituximab administered concurrently or sequentially have a low risk of t-MN. These long-term data support fludarabine plus rituximab as one acceptable first-line treatment for symptomatic patients with CLL.