Incorporating prior information with fused sparse group lasso: Application to prediction of clinical measures from neuroimages.

Predicting clinical variables from whole-brain neuroimages is a high-dimensional problem that can potentially benefit from feature selection or extraction. Penalized regression is a popular embedded feature selection method for high-dimensional data. For neuroimaging applications, spatial regularization using the ℓ1 or ℓ2 norm of the image gradient has shown good performance, yielding smooth solutions in spatially contiguous brain regions. Enormous resources have been devoted to establishing structural and functional brain connectivity networks that can be used to define spatially distributed yet related groups of voxels. We propose using the fused sparse group lasso (FSGL) penalty to encourage structured, sparse, and interpretable solutions by incorporating prior information about spatial and group structure among voxels. We present optimization steps for FSGL penalized regression using the alternating direction method of multipliers algorithm. With simulation studies and in application to real functional magnetic resonance imaging data from the Autism Brain Imaging Data Exchange, we demonstrate conditions under which fusion and group penalty terms together outperform either of them alone.

Problem-Solving Therapy for Older Adults at Risk for Depression: A Qualitative Analysis of the Depression in Later Life Trial.

OBJECTIVE: As a sequel to the Depression in Later Life trial of lay counselor-delivered problem-solving therapy for depression prevention among older adults in Goa, India, this qualitative study aimed to explore participant experiences to illuminate the reasons for the trial's positive findings and implications for further efforts at depression prevention in low-resource settings. METHODS: In-depth interviews were conducted with 19 participants (21% of those randomly assigned to the original intervention). Two independent raters coded the data and organized narratives according to broad themes. RESULTS: Most participants valued their relationship with the lay counselor, learned self-care strategies to cope with illnesses, and increased engagement in pleasurable social and physical activities. Some participants reported needing assistance with managing financial strain and family conflicts. CONCLUSIONS: The lay-counselor-delivered intervention was well received. The relationship with the counselor and behavioral activation toward better self-care and more-pleasurable activities may have been keys to the intervention's success.

Hemoglobin A1c Level and Cardiovascular Disease Incidence in Persons With Type 1 Diabetes: An Application of Joint Modeling of Longitudinal and Time-to-Event Data in the Pittsburgh Epidemiology of Diabetes Complications Study.

Type 1 diabetes (T1D) is associated with increased risk of cardiovascular disease (CVD), but hyperglycemia (measured by hemoglobin A1c (HbA1c) level), which characterizes T1D, has itself been an inconsistent predictor of CVD incidence. However, only baseline HbA1c or a summary measure (e.g., mean level over follow-up) is usually analyzed. Joint models allow simultaneous modeling of repeatedly measured longitudinal covariates, using random effects, and time-to-event data. We evaluated data from the Pittsburgh Epidemiology of Diabetes Complications Study, an ongoing prospective cohort study of childhood-onset T1D that has followed participants since 1986-1988 and has repeatedly found little association between baseline HbA1c or mean follow-up HbA1c and coronary artery disease incidence. Of 561 participants without CVD at baseline, 263 (46.9%) developed CVD over a period of 25 years (1986-2014). In joint models, each 1% unit increase in HbA1c trajectory was associated with a 1.26-fold increased risk of CVD (95% confidence interval: 1.07, 1.45), after adjustment for baseline levels of other CVD risk factors, and a 1.13-fold increased risk (95% confidence interval: 0.99, 1.32) after adjustment for updated mean levels of other CVD risk factors. These findings, which support the need for good glycemic control to prevent CVD in persons with T1D, underscore the importance of utilizing methods incorporating within-subject variation over time when analyzing and interpreting longitudinal cohort study data.

Risk factors for locoregional disease recurrence after breast-conserving therapy in patients with breast cancer treated with neoadjuvant chemotherapy: An international collaboration and individual patient meta-analysis.

BACKGROUND: Several studies have reported a high risk of local disease recurrence (LR) and locoregional disease recurrence (LRR) in patients with breast cancer after neoadjuvant chemotherapy (NCT) and breast-conserving therapy (BCT). The objective of the current study was to identify potential risk factors for LR and LRR after NCT and BCT. METHODS: Individual patient data sets from 9 studies were pooled. The outcomes of interest were the occurrence of LR and/or LRR. A 1-stage meta-analytic approach was used. Cox proportional hazards regression models were applied to identify factors that were predictive of LR and LRR, respectively. RESULTS: A total of 9 studies (4125 patients) provided their data sets. The 10-year LR rate was 6.5%, whereas the 10-year LRR rate was 10.3%. Four factors were found to be associated with a higher risk of LR: 1) estrogen receptor-negative disease; 2) cN + disease; 3) a lack of pathologic complete response in axilla (pN0); and 4) pN2 to pN3 disease. The predictive score for LR determined 3 risk groups: a low-risk, intermediate-risk, and high-risk group with 10-year LR rates of 4.0%, 7.9%, and 20.4%, respectively. Two additional factors were found to be associated with an increased risk of LRR: cT3 to cT4 disease and a lack of pathologic complete response in the breast. The predictive score for LRR determined 3 risk groups; a low-risk, intermediate-risk, and high-risk group with 10-year LRR rates of 3.2%, 10.1%, and 24.1%, respectively. CONCLUSIONS: BCT after NCT appears to be an oncologically safe procedure for a large percentage of patients with breast cancer. Two easy-to-use clinical scores were developed that can help clinicians to identify patients at higher risk of LR and LRR after NCT and BCT and individualize the postoperative treatment plan and follow-up. Cancer 2018;124:2923-30. © 2018 American Cancer Society.

Poor Prognosis After Second Locoregional Recurrences in the CALOR Trial.

BACKGROUND: Isolated locoregional recurrences (ILRRs) of breast cancer confer a significant risk for the development of distant metastasis. Management practices and second ILRR events in the Chemotherapy as Adjuvant for LOcally Recurrent breast cancer (CALOR) trial were investigated. METHODS: In this study, 162 patients with ILRR were randomly assigned to receive postoperative chemotherapy or no chemotherapy. Descriptive statistics characterize outcomes according to local therapy and the influence of hormone receptor status on subsequent recurrences. Competing risk regression models, Kaplan-Meier estimates, and Cox proportional hazards models were used to evaluate associations between treatment, site of second recurrence, and outcome. RESULTS: The median follow-up period was 4.9 years. Of the 98 patients who received breast-conserving primary surgery 89 had an ipsilateral-breast tumor recurrence. Salvage mastectomy was performed for 73 patients and repeat lumpectomy for 16 patients. Another eight patients had nodal ILRR, and one patient had chest wall ILRR. Among 64 patients whose primary surgery was mastectomy, 52 had chest wall/skin ILRR, and 12 had nodal ILRR. For 15 patients, a second ILRR developed a median of 1.6 years (range 0.08-4.8 years) after ILRR. All second ILRRs occurred for patients with progesterone receptor-negative ILRR. Death occurred for 7 (47 %) of 15 patients with a second ILRR and 19 (51 %) of 37 patients with a distant recurrence. As shown in the multivariable analysis, the significant predictors of survival after either a second ILRR or distant recurrence were chemotherapy for the primary cancer (hazard ratio [HR], 3.55; 95 % confidence interval [CI], 1.15-10.9; p = 0.03) and the interval (continuous) from the primary surgery (HR, 0.87; 95 % CI, 0.75-1.00; p = 0.05). CONCLUSIONS: Second ILRRs represented about one third of all recurrence events after ILRR, and all were PR-negative. These second ILRRs and distant metastases portend an unfavorable outcome.

Efficacy, safety, and tolerability of augmentation pharmacotherapy with aripiprazole for treatment-resistant depression in late life: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Treatment-resistant major depression is common and potentially life-threatening in elderly people, in whom little is known about the benefits and risks of augmentation pharmacotherapy. We aimed to assess whether aripiprazole is associated with a higher probability of remission than is placebo. METHODS: We did a randomised, double-blind, placebo-controlled trial at three centres in the USA and Canada to test the efficacy and safety of aripiprazole augmentation for adults aged older than 60 years with treatment-resistant depression (Montgomery Asberg Depression Rating Scale [MADRS] score of ≥15). Patients who did not achieve remission during a pre-trial with venlafaxine extended-release (150-300 mg/day) were randomly assigned (1:1) to the addition of aripiprazole (target dose 10 mg [maximum 15 mg] daily) daily or placebo for 12 weeks. The computer-generated randomisation was done in blocks and stratified by site. Only the database administrator and research pharmacists had knowledge of treatment assignment. The primary endpoint was remission, defined as an MADRS score of 10 or less (and at least 2 points below the score at the start of the randomised phase) at both of the final two consecutive visits, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00892047. FINDINGS: From July 20, 2009, to Dec 30, 2013, we recruited 468 eligible participants, 181 (39%) of whom did not remit and were randomly assigned to aripiprazole (n=91) or placebo (n=90). A greater proportion of participants in the aripiprazole group achieved remission than did those in the placebo group (40 [44%] vs 26 [29%] participants; odds ratio [OR] 2·0 [95% CI 1·1-3·7], p=0·03; number needed to treat [NNT] 6·6 [95% CI 3·5-81·8]). Akathisia was the most common adverse effect of aripiprazole (reported in 24 [26%] of 91 participants on aripiprazole vs 11 [12%] of 90 on placebo). Compared with placebo, aripiprazole was also associated with more Parkinsonism (15 [17%] of 86 vs two [2%] of 81 participants), but not with treatment-emergent suicidal ideation (13 [21%] of 61 vs 19 [29%] of 65 participants) or other measured safety variables. INTERPRETATION: In adults aged 60 years or older who do not achieve remission from depression with a first-line antidepressant, the addition of aripiprazole is effective in achieving and sustaining remission. Tolerability concerns include the potential for akathisia and Parkinsonism. FUNDING: National Institute of Mental Health, UPMC Endowment in Geriatric Psychiatry, Taylor Family Institute for Innovative Psychiatric Research, National Center for Advancing Translational Sciences, and the Campbell Family Mental Health Research Institute.

Design and Implementation of an Intervention Development Study: Retaining Cognition While Avoiding Late-Life Depression (ReCALL).

OBJECTIVE: To discuss the design, rationale, and implementation of an intervention development study addressing indicated and selective prevention of depression and anxiety in individuals 60 years and older with mild cognitive impairment (MCI) and in their caregivers. METHODS: In Phase I, now completed, we developed and standardized problem-solving therapy (PST) and the combined PST + moderate-intensity physical exercise (PE) intervention to be administered to participants with MCI and their caregivers together, dyadically, with both participants working with the same interventionist in the same therapy sessions. In Phase II we have been testing the interventions against enhanced usual care (EUC) and have addressed challenges to recruitment. Randomization was to one of three cells: PST + PE, PST, or EUC. RESULTS: Although we set out to intervene dyadically, many individuals with MCI lived alone or did not have a support person who could participate in the study with them. Consequently, we modified the study to include MCI participants with and without support persons. Ninety-four participants were enrolled: 20 with MCI together with their support persons (N = 20 dyads) and 54 MCI participants without accompanying support persons. Most participants have been satisfied with the usefulness of the interventions in managing stress and cognitive problems. CONCLUSION: PST and moderate-intensity PE are acceptable interventions for depression and anxiety prevention in older adults with MCI and their available caregivers.

A three-step estimation procedure using local polynomial smoothing for inconsistently sampled longitudinal data.

Parametric mixed-effects models are useful in longitudinal data analysis when the sampling frequencies of a response variable and the associated covariates are the same. We propose a three-step estimation procedure using local polynomial smoothing and demonstrate with data where the variables to be assessed are repeatedly sampled with different frequencies within the same time frame. We first insert pseudo data for the less frequently sampled variable based on the observed measurements to create a new dataset. Then standard simple linear regressions are fitted at each time point to obtain raw estimates of the association between dependent and independent variables. Last, local polynomial smoothing is applied to smooth the raw estimates. Rather than use a kernel function to assign weights, only analytical weights that reflect the importance of each raw estimate are used. The standard errors of the raw estimates and the distance between the pseudo data and the observed data are considered as the measure of the importance of the raw estimates. We applied the proposed method to a weight loss clinical trial, and it efficiently estimated the correlation between the inconsistently sampled longitudinal data. Our approach was also evaluated via simulations. The results showed that the proposed method works better when the residual variances of the standard linear regressions are small and the within-subjects correlations are high. Also, using analytic weights instead of kernel function during local polynomial smoothing is important when raw estimates have extreme values, or the association between the dependent and independent variable is nonlinear. Copyright © 2016 John Wiley & Sons, Ltd.

Association of Baseline Sleep Quality With Trajectories of Depressive Symptoms in Patients Undergoing Interferon Treatment.

OBJECTIVE: Some patients with hepatitis C starting interferon-α (IFN-α) therapy experience depression, although many patients do not develop depressive symptoms. We have found that poor sleep is associated with increased depressive symptoms on average. It is unknown whether this association holds generally or is driven by a specific, distinct subgroup. This investigation first determined whether patterns of change in depressive symptoms form clinically meaningful, distinct subgroups and then tested the extent to which sleep disturbances are associated with a less favorable depression trajectory. METHOD: Group-based trajectory modeling was used on 124 patients with hepatitis C who started IFN-α therapy. The Pittsburgh Sleep Quality Index (PSQI) assessed pretreatment sleep, the Beck Depression Inventory minus the sleep question assessed depression over time, and the Structured Clinical Interview for DSM-IV provided categorical diagnoses. RESULTS: Three distinct subgroups were found, where each subgroup shared similar patterns of depressive symptoms over time. The groups were characterized as "nondepressed," "slow increase," and "rapid increase." The nondepressed subgroup (44.4%) experienced low depressive symptoms with little change over time. In comparison, all rapid increasers (11.3%) were diagnosed as having a mood disorder by 12 weeks of treatment. The PSQI was strongly associated with group membership, where the odds of developing a rapid increase was elevated 39% for every unit-score increase in the PSQI compared with individuals who remained nondepressed (odds ratio = 1.39, 95% confidence interval = 1.07-1.80, adjusted for depression at baseline). CONCLUSIONS: Only a distinct subpopulation of people is notably vulnerable to a developing a rapid increase in depression symptoms during IFN-α therapy. This group may be identifiable by their markedly poor sleep before IFN-α therapy.

Longer lithium exposure is associated with better white matter integrity in older adults with bipolar disorder.

OBJECTIVES: Bipolar disorder (BD) is associated with cognitive dysfunction and structural brain abnormalities. In human and non-human studies, lithium has been related to neuroprotective and neurotrophic effects. We explored whether lithium treatment is related to better brain integrity and cognitive function in older adults with BD. METHODS: We examined cognitive and neuroimaging data in 58 individuals with BD [mean (standard deviation) age = 64.5 (9.8) years] and 21 mentally healthy comparators (controls) of similar age and education. Subjects received comprehensive neurocognitive assessment and structural brain imaging, examining total gray matter volume, overall white matter integrity (fractional anisotropy), and total white matter hyperintensity burden. RESULTS: In comparison to controls, subjects with BD had worse overall cognitive performance, lower total gray matter volume, and lower white matter integrity. Among subjects with BD, longer duration of lithium treatment was related to higher white matter integrity after controlling for age and vascular disease burden, but not with better cognitive performance. CONCLUSIONS: Lithium treatment appears to be related to better brain integrity in older individuals with BD, in particular, in those who take lithium long-term. While intriguing, these findings need to be confirmed in a larger sample.

Cue reactivity in converted and native intermittent smokers.

INTRODUCTION: Nondaily, or intermittent smokers (ITS), who constitute a substantial fraction of U.S. smokers, are thought to smoke in response to cues. Previous cue reactivity research showed no difference between ITS and daily smokers in response to cues. This report examines whether "converted" ITS (CITS) with a history of past daily smoking differ from "native" ITS (NITS) in craving and smoking in response to cues. METHODS: A total of 146 CITS (who previously smoked daily for at least 6 months) and 73 NITS participated. Participants were exposed to 5 active cues (smoking, alcohol, negative affect, positive affect, and smoking prohibitions) and a control neutral cue, in separate sessions. Changes in craving were assessed pre-post cue exposure. Smoking behavior (smoking [y/n], smoking latency, number of cigarettes, number of puffs, and increase in carbon monoxide [CO]) was observed. Analyses contrasted response to each active cue compared to the neutral cue and controlled for order effects and for time since last cigarette, which differed between groups. RESULTS: Regardless of cues, CITS reported higher craving and greater change in craving, were more likely to smoke, tended to progress faster to smoking, and showed greater increases in CO when they did smoke. NITS and CITS showed similar cue reactivity on most measures, though NITS took more puffs after viewing smoking cues (compared to neutral) than did CITS. CONCLUSIONS: Though CITS show some remnants of their history of daily smoking, CITS and NITS demonstrate similar cue reactivity, suggesting that they would not require different behavioral approaches to help them quit.

Chemotherapy for isolated locoregional recurrence of breast cancer (CALOR): a randomised trial.

BACKGROUND: Patients with isolated locoregional recurrences (ILRR) of breast cancer have a high risk of distant metastasis and death from breast cancer. We aimed to establish whether adjuvant chemotherapy improves the outcome of such patients. METHODS: The CALOR trial was a pragmatic, open-label, randomised trial that accrued patients with histologically proven and completely excised ILRR after unilateral breast cancer who had undergone a mastectomy or lumpectomy with clear surgical margins. Eligible patients were enrolled from hospitals worldwide and were centrally randomised (1:1) to chemotherapy (type selected by the investigator; multidrug for at least four courses recommended) or no chemotherapy, using permuted blocks, and stratified by previous chemotherapy, oestrogen-receptor and progesterone-receptor status, and location of ILRR. Patients with oestrogen-receptor-positive ILRR received adjuvant endocrine therapy, radiation therapy was mandated for patients with microscopically involved surgical margins, and anti-HER2 therapy was optional. The primary endpoint was disease-free survival. All analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00074152. FINDINGS: From Aug 22, 2003, to Jan 31, 2010, 85 patients were randomly assigned to receive chemotherapy and 77 were assigned to no chemotherapy. At a median follow-up of 4·9 years (IQR 3·6-6 ·0), 24 (28%) patients had disease-free survival events in the chemotherapy group compared with 34 (44%) in the no chemotherapy group. 5-year disease-free survival was 69% (95% CI 56-79) with chemotherapy versus 57% (44-67) without chemotherapy (hazard ratio 0·59 [95% CI 0·35-0·99]; p=0·046). Adjuvant chemotherapy was significantly more effective for women with oestrogen-receptor-negative ILRR (pinteraction=0·046), but analyses of disease-free survival according to the oestrogen-receptor status of the primary tumour were not statistically significant (pinteraction=0·43). Of the 81 patients who received chemotherapy, 12 (15%) had serious adverse events. The most common adverse events were neutropenia, febrile neutropenia, and intestinal infection. INTERPRETATION: Adjuvant chemotherapy should be recommended for patients with completely resected ILRR of breast cancer, especially if the recurrence is oestrogen-receptor negative. FUNDING: US Department of Health and Human Services, Swiss Group for Clinical Cancer Research (SAKK), Frontier Science and Technology Research Foundation, Australian and New Zealand Breast Cancer Trials Group, Swedish Cancer Society, Oncosuisse, Cancer Association of South Africa, Foundation for Clinical Research of Eastern Switzerland (OSKK), Grupo Español de Investigación en Cáncer de Mama (GEICAM), and the Dutch Breast Cancer Trialists' Group (BOOG).

Effect of occult metastases on survival in node-negative breast cancer.

BACKGROUND: Retrospective and observational analyses suggest that occult lymph-node metastases are an important prognostic factor for disease recurrence or survival among patients with breast cancer. Prospective data on clinical outcomes from randomized trials according to sentinel-node involvement have been lacking. METHODS: We randomly assigned women with breast cancer to sentinel-lymph-node biopsy plus axillary dissection or sentinel-lymph-node biopsy alone. Paraffin-embedded tissue blocks of sentinel lymph nodes obtained from patients with pathologically negative sentinel lymph nodes were centrally evaluated for occult metastases deeper in the blocks. Both routine staining and immunohistochemical staining for cytokeratin were used at two widely spaced additional tissue levels. Treating physicians were unaware of the findings, which were not used for clinical treatment decisions. The initial evaluation at participating sites was designed to detect all macrometastases larger than 2 mm in the greatest dimension. RESULTS: Occult metastases were detected in 15.9% (95% confidence interval [CI], 14.7 to 17.1) of 3887 patients. Log-rank tests indicated a significant difference between patients in whom occult metastases were detected and those in whom no occult metastases were detected with respect to overall survival (P=0.03), disease-free survival (P=0.02), and distant-disease-free interval (P=0.04). The corresponding adjusted hazard ratios for death, any outcome event, and distant disease were 1.40 (95% CI, 1.05 to 1.86), 1.31 (95% CI, 1.07 to 1.60), and 1.30 (95% CI, 1.02 to 1.66), respectively. Five-year Kaplan-Meier estimates of overall survival among patients in whom occult metastases were detected and those without detectable metastases were 94.6% and 95.8%, respectively. CONCLUSIONS: Occult metastases were an independent prognostic variable in patients with sentinel nodes that were negative on initial examination; however, the magnitude of the difference in outcome at 5 years was small (1.2 percentage points). These data do not indicate a clinical benefit of additional evaluation, including immunohistochemical analysis, of initially negative sentinel nodes in patients with breast cancer. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00003830.).

Craving in intermittent and daily smokers during ad libitum smoking.

INTRODUCTION: This study aimed to assess average and peak craving intensity among nondaily intermittent smokers (ITS) in smoking episodes and when not smoking compared to that of daily smokers (DS). METHODS: Two hundred and twelve ITS and 194 DS monitored their smoking and craving for 3 weeks using Ecological Momentary Assessment methods. Craving was assessed (0-100 scale) when subjects lit a cigarette and at random times when not smoking; 48,469 observations were analyzed using generalized estimating equations. RESULTS: ITS experienced craving, including intense craving; their 95th percentile intensity averaged 77.7 ± 22.5 out of 100 (higher among DS: 89.1 ± 14.5). ITS reported lower craving than DS, both when smoking and when not smoking. In both groups, craving was less intense when not smoking (DS: 71.1 ± 20.7 vs. 59.83 ± 21.97; ITS: 59.91 ± 23.03 vs. 26.63 ± 19.87), but the difference was significantly greater among ITS. Among ITS, the probability of smoking rose continuously as craving increased over the full range of the scale. In contrast, among DS the probability of smoking rose until the midpoint of the scale, after which the relationship flattened. Findings were mostly similar for ITS with and without a history of past daily smoking. CONCLUSIONS: ITS do experience craving, including intense craving. The relationship between craving and smoking is stronger among ITS because DS experience moderate craving even between cigarettes. In contrast, ITS appear to experience craving in limited situations associated with smoking, suggesting that their craving and smoking may be driven by transient cues rather than endogenous needs.

Additive effect of age on disability for individuals with spinal cord injuries.

OBJECTIVE: To examine the additive effect of age on disability for adults with spinal cord injury (SCI). DESIGN: Prospective cohort study. SETTING: SCI Model Systems. PARTICIPANTS: Individuals with SCI (median age at injury, 32 y; range, 6-88 y) with a discharge motor FIM score and at least 1 follow-up motor FIM score who also provided measures of other covariates (N=1660). Of the total sample, 79% were men, 72% were white, 16% had incomplete paraplegia, 33% had complete paraplegia, 30% had incomplete tetraplegia, and 21% had complete tetraplegia. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The primary study outcome was the motor subscale of the FIM. A mixed-models approach was used to examine the additive effect of age on disability for individuals with SCI. RESULTS: When controlling for motor FIM at discharge from rehabilitation, level and severity of injury, age at injury, sex, race, and the age × time interaction were not significant (P=.07). Age at the time of SCI was significantly associated with motor FIM (F1,238=22.49, P<.001). Two sensitivity analyses found significant interactions for both age × time (P=.03, P=.02) and age × time-square (P=.01, P=.006) models. Trajectory of motor FIM scores is moderated slightly by age at the time of injury. The older participants were at the time of injury, the greater the curvature and the more rapid decline were found in later years. CONCLUSIONS: These findings indicate that age moderately influences disability for some individuals with SCI: the older the age at the time of injury, the greater the influence age has on disability. The findings serve as an important empirical foundation for the evaluation and development of interventions designed to augment accelerated aging experienced by individuals with SCI.

Preliminary results of centralized HER2 testing in ductal carcinoma in situ (DCIS): NSABP B-43.

NSABP B-43 is the first prospective, randomized phase III multi-institution clinical trial targeting high-risk, HER2-positive DCIS. It compares whole breast irradiation alone with WBI given concurrently with trastuzumab in women with HER2-positive DCIS treated by lumpectomy. The primary aim is to determine if trastuzumab plus radiation will reduce in-breast tumor recurrence. HER2-positive DCIS was previously estimated at >50 %, occurring primarily in ER-negative, comedo-type DCIS of high nuclear grade. There has been no documented centralized multi-institutional HER2 analysis of DCIS. NSABP B-43 provides a unique opportunity to evaluate this in a large cohort of DCIS patients. Patients undergoing lumpectomy for DCIS without evidence of an invasive component are eligible. A central review of each patient's pure DCIS lesion is carried out by immunohistochemistry analysis. If the lesion is 2+, FISH analysis is performed. Patients whose tumors are HER2 3+ or FISH-positive are randomly assigned to receive two doses of trastuzumab during WBI or WBI alone. NSABP B-43 opened 11/9/08. As of 7/31/2013, 5,861 patients have had specimens received centrally, and 5,645 of those had analyzable blocks; 1,969 (34.9 %) were HER2 positive. A total of 1,428 patients have been accrued, 1,137 (79.6 %) of whom have follow-up information. The average follow-up time for the 1,137 patients is 23.3 months. No grade 4 or 5 toxicity has been observed. In NSABP B-43 the HER2-positive rate for pure DCIS among patients undergoing breast-preserving surgery is 34.9 %, lower than the previously reported rate. No trastuzumab-related safety signals have been observed. Interest in this trial has been robust.

Relationship between arm morbidity and patient-reported outcomes following surgery in women with node-negative breast cancer: NSABP protocol B-32.

BACKGROUND: The impact of arm morbidity following breast cancer surgery on patient-observed changes in daily functioning and health-related quality of life (HRQoL) has not been well-studied. OBJECTIVE: To examine the association of objective measures such as range of motion (ROM) and lymphedema, with patient-reported outcomes (PROs) in the arm and breast, upper extremity function, activities, and HRQoL. METHODS: The National Surgical Adjuvant Breast and Bowel Project Protocol B-32 was a randomized trial comparing sentinel node resection (SNR) with axillary dissection (AD) in women with node-negative breast cancer. ROM and arm volume were measured objectively. PROs included symptoms; arm function; limitations in social, recreational, occupational, and other regular activities; and a global index of HRQoL. Statistical methods included cross-tabulations and multivariable linear regression models. RESULTS: In all, 744 women provided at least 1 postsurgery assessment. About one-third of the patients experienced arm mobility restrictions. A similar number of patients avoided the use of the arm 6 months after surgery. Limitations in work and other regular activities were reported by about a quarter of the patients. In this multivariable analysis, arm mobility and sensory neuropathy were predictors of patient-reported arm function and overall HRQoL. Predictors for activity limitations also included side of surgery (dominant vs nondominant). Edema was not significant after adjustment for sensory neuropathy and ROM. LIMITATIONS: Arm mobility and edema were measured simultaneously only once during the follow-up (6 months). CONCLUSION: Clinical measures of sensory neuropathy and restrictions in arm mobility following breast cancer surgery are associated with self-reported limitations in activity and reductions in overall HRQoL.

An adaptive two-stage dose-response design method for establishing proof of concept.

We propose an adaptive two-stage dose-response design where a prespecified adaptation rule is used to add and/or drop treatment arms between the stages. We extend the multiple comparison procedures-modeling (MCP-Mod) approach into a two-stage design. In each stage, we use the same set of candidate dose-response models and test for a dose-response relationship or proof of concept (PoC) via model-associated statistics. The stage-wise test results are then combined to establish "global" PoC using a conditional error function. Our simulation studies showed good and more robust power in our design method compared to conventional and fixed designs.

Oral clodronate for adjuvant treatment of operable breast cancer (National Surgical Adjuvant Breast and Bowel Project protocol B-34): a multicentre, placebo-controlled, randomised trial.

BACKGROUND: Bisphosphonates are thought to act through the osteoclast by changing bone microenvironment. Previous findings of adjuvant clodronate trials in different populations with operable breast cancer have been mixed. The National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol B-34 aims to ascertain whether oral clodronate can improve outcomes in women with primary breast cancer. METHODS: NSABP B-34 is a multicentre, randomised, double-blind, placebo-controlled study in 3323 women with stage 1-3 breast cancer. After surgery to remove the tumour, patients were stratified by age, axillary nodes, and oestrogen and progesterone receptor status and randomly assigned in a 1:1 ratio to either oral clodronate 1600 mg daily for 3 years (n=1662) or placebo (1661). The primary endpoint was disease-free survival, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00009945. FINDINGS: Median follow-up was 90·7 months (IQR 82·7-100·0) and 3311 patients had data for this period. Disease-free survival did not differ between groups (286 events in the clodronate group vs 312 in the placebo group; hazard ratio 0·91, 95% CI 0·78-1·07; p=0·27). Moreover, no differences were recorded for overall survival (0·84, 0·67-1·05; p=0·13), recurrence-free interval (0·83, 0·67-1·04; p=0·10), or bone metastasis-free interval (0·77, 0·55-1·07; p=0·12). Non-bone metastasis-free interval was slightly increased with clodronate (0·74, 0·55-1·00; p=0·047). Analyses in women age 50 years or older on study entry showed benefits of clodronate for recurrence-free interval (0·75, 0·57-0·99; p=0·045), bone metastasis-free interval (0·62, 0·40-0·95; p=0·027), and non-bone metastasis-free interval (0·63, 0·43-0·91; p=0·014), but not for overall survival (0·80, 0·61-1·04, p=0·094). Adherence to treatment at 3 years was 56% for the clodronate group and 60% for the placebo group. Grade 3 or higher liver dysfunction was noted in 23 of 1612 patients in the clodronate group and 12 of 1623 patients in the placebo group; grade 3-4 diarrhoea was noted in 28 patients in the clodronate group and in ten in the placebo group. There was one possible case of osteonecrosis of the jaw in the clodronate group. INTERPRETATION: Findings of NSABP B-34 suggest that bisphosphonates might have anticancer benefits for older postmenopausal women. A meta-analysis of adjuvant bisphosphonate trials is suggested before recommendations for use in non-osteoporotic postmenopausal women with primary breast cancer are made. FUNDING: National Cancer Institute, Bayer Oy (formerly Schering Oy).

Early intervention to reduce the global health and economic burden of major depression in older adults.

Randomized trials for selective and indicated prevention of depression in both mixed-aged and older adult samples, conducted in high-income countries (HICs), show that rates of incident depression can be reduced by 20-25% over 1-2 years through the use of psychoeducational and psychological interventions designed to increase protective factors. Recurrence of major depression can also be substantially reduced through both psychological and psychopharmacological strategies. Additional research is needed, however, to address the specific issues of depression prevention in older adults in low- and middle-income countries (LMICs). The growing number of older adults globally, as well as workforce issues and the expense of interventions, makes it important to develop rational, targeted, and cost-effective risk-reduction strategies. In our opinion, one strategy to address these issues entails the use of lay health counselors (LHCs), a form of task shifting already shown to be effective in the treatment of common mental disorders in LMICs. We suggest in this review that the time is right for research into the translation of depression-prevention strategies for use in LMICs.