Comparison of traditional and closed loop vagus nerve stimulation for treatment of pediatric drug-resistant epilepsy: A propensity-matched retrospective cohort study.

OBJECTIVE: For epilepsy patients with drug-resistant, unresectable epilepsy, vagus nerve stimulation (VNS) is an option for seizure control. Approximately 40-70% of patients will achieve ≥50% seizure reduction with VNS. New closed loop VNS models detect ictal tachycardia and responsively stimulate the vagus nerve. The effectiveness of closed loop VNS compared to traditional VNS for pediatric epilepsy is unknown. METHODS: An 11-year retrospective electronic medical record review at Children's Hospital of Pittsburgh was performed. Patients with drug-resistant epilepsy who underwent VNS implantation were included. Patients were divided into groups based on VNS model: traditional versus closed loop. Those who transitioned from traditional to closed loop VNS were excluded. Given potential for selection bias, propensity scores matching was utilized to compare traditional to closed loop VNS patients. Patients with focal versus generalized epilepsy were also separately analyzed. The primary outcome was "VNS response", defined as at least 50% seizure frequency reduction from baseline. RESULTS: A total of 320 patients were included in this sample. The percentage of matched patients (total n = 220: n = 179 traditional VNS, n = 41 closed loop VNS) who responded to VNS after one year of therapy was 43% for traditional VNS and 39% for closed loop VNS (p = 0.64). After two years of therapy, a higher proportion of closed loop VNS patients than traditional VNS patients responded to VNS among all subgroups, though no differences were statistically significant (p>0.05). Notably, for those with generalized epilepsy, 73% of closed loop patients responded to VNS compared to only 46% of traditional patients (p = 0.10). After two years of VNS therapy, patients were taking approximately the same quantity of antiseizure medications as baseline (change of +0.074 +/- 0.90 ) with no difference between VNS models (p = 0.87). SIGNIFICANCE: Among pediatric patients with drug-resistant epilepsy, closed loop VNS trends towards a higher rate of VNS response after two years of treatment, especially among generalized epilepsy patients. Neither model of VNS allows patients to reduce antiseizure medication quantity after two years.

Use of letrozole after aromatase inhibitor-based therapy in postmenopausal breast cancer (NRG Oncology/NSABP B-42): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: The optimal duration of extended therapy with aromatase inhibitors in patients with postmenopausal breast cancer is unknown. In the NSABP B-42 study, we aimed to determine whether extended letrozole treatment improves disease-free survival after 5 years of aromatase inhibitor-based therapy in women with postmenopausal breast cancer. METHODS: This randomised, double-blind, placebo-controlled, phase 3 trial was done in 158 centres in the USA, Canada, and Ireland. Postmenopausal women with stage I-IIIA hormone receptor-positive breast cancer, who were disease-free after about 5 years of treatment with an aromatase inhibitor or tamoxifen followed by an aromatase inhibitor, were randomly assigned (1:1) to receive 5 years of letrozole (2·5 mg orally per day) or placebo. Randomisation was stratified by pathological node status, previous tamoxifen use, and lowest bone mineral density T score in the lumbosacral spine, total hip, or femoral neck. The primary endpoint was disease-free survival, defined as time from randomisation to breast cancer recurrence, second primary malignancy, or death, and was analysed by intention to treat. To adjust for previous interim analyses, the two-sided statistical significance level for disease-free survival was set at 0·0418. This study is registered with ClinicalTrials.gov, number NCT00382070, is active, and is no longer enrolling patients. FINDINGS: Between Sept 28, 2006, and Jan 6, 2010, 3966 patients were randomly assigned to receive letrozole (n=1983) or placebo (n=1983). Follow-up information was available for 3903 patients for the analyses of disease-free survival. Median follow-up was 6·9 years (IQR 6·1-7·5). Letrozole treatment did not significantly improve disease-free survival (339 disease-free survival events were reported in the placebo group and 292 disease-free survival events were reported in the letrozole group; hazard ratio 0·85, 95% CI 0·73-0·999; p=0·048). 7-year disease-free survival estimate was 81·3% (95% CI 79·3-83·1) in the placebo group and 84·7% (82·9-86·4) in the letrozole group. The most common grade 3 adverse events were arthralgia (47 [2%] of 1933 patients in the placebo group vs 50 [3%] of 1941 patients in the letrozole group) and back pain (44 [2%] vs 38 [2%]). The most common grade 4 adverse event in the placebo group was thromboembolic event (eight [<1%]) and the most common grade 4 adverse events in the letrozole group were urinary tract infection, hypokalaemia, and left ventricular systolic dysfunction (four [<1%] each). INTERPRETATION: After 5 years of aromatase inhibitor-based therapy, 5 years of letrozole therapy did not significantly prolong disease-free survival compared with placebo. Careful assessment of potential risks and benefits is required before recommending extended letrozole therapy to patients with early-stage breast cancer. FUNDING: National Cancer Institute, Korea Health Technology R&D Project, Novartis.

Low-Fidelity Haptic Simulation Versus Mental Imagery Training for Epidural Anesthesia Technical Achievement in Novice Anesthesiology Residents: A Randomized Comparative Study.

BACKGROUND: There are many teaching methods for epidural anesthesia skill acquisition. Previous work suggests that there is no difference in skill acquisition whether novice learners engage in low-fidelity (LF) versus high-fidelity haptic simulation for epidural anesthesia. No study, however, has compared the effect of LF haptic simulation for epidural anesthesia versus mental imagery (MI) training in which no physical practice is attempted. We tested the hypothesis that MI training is superior to LF haptic simulation training for epidural anesthesia skill acquisition. METHODS: Twenty Post-Graduate Year 2 (PGY-2) anesthesiology residents were tested at the beginning of the training year. After a didactic lecture on epidural anesthesia, they were randomized into 2 groups. Group LF had LF simulation training for epidural anesthesia using a previously described banana simulation technique. Group MI had guided, scripted MI training in which they initially were oriented to the epidural kit components and epidural anesthesia was described stepwise in detail, followed by individual mental rehearsal; no physical practice was undertaken. Each resident then individually performed epidural anesthesia on a partial-human task trainer on 3 consecutive occasions under the direct observation of skilled evaluators who were blinded to group assignment. Technical achievement was assessed with the use of a modified validated skills checklist. Scores (0-21) and duration to task completion (minutes) were recorded. A linear mixed-effects model analysis was performed to determine the differences in scores and duration between groups and over time. RESULTS: There was no statistical difference between the 2 groups for scores and duration to task completion. Both groups showed similarly significant increases (P = 0.0015) in scores over time (estimated mean score [SE]: group MI, 15.9 [0.55] to 17.4 [0.55] to 18.6 [0.55]; group LF, 16.2 [0.55] to 17.7 [0.55] to 18.9 [0.55]). Time to complete the procedure decreased similarly and significantly (P = 0.032) for both groups after the first attempt (estimated mean time [SE]: group MI, 16.0 [1.04] minutes to 13.7 [1.04] minutes to 13.3 [1.04] minutes; group LF: 15.8 [1.04] minutes to 13.4 [1.04] minutes to 13.1 [1.04] minutes). CONCLUSIONS: MI is not different from LF simulation training for epidural anesthesia skill acquisition. Education in epidural anesthesia with structured didactics and continual MI training may suffice to prepare novice learners before an attempt on human subjects.

An isoform of C/EBPß, LIP, regulates expression of the chemokine receptor CXCR4 and modulates breast cancer cell migration.

Metastasis is the primary cause of death in cancer patients. CXCR4/CXCL12 chemokine axis provides directional cues for breast cancer cells to metastasize to specific organs. Despite their potential clinical importance, how CXCR4 expression in breast cancer cells is regulated at the molecular level is not well understood. We identified an isoform of C/EBPß, liver-enriched inhibitory protein (LIP), as a previously unrecognized transcriptional regulator of CXCR4 in breast cancer cells. LIP up-regulated the transcription of CXCR4 through direct interaction with the CXCR4 promoter. The increase in CXCR4 mRNA was paralleled by an increased cell surface expression of the CXCR4, which in turn promoted CXCR4-mediated breast cancer cell migration. A significant positive correlation between LIP and CXCR4 expression was observed in stage III and IV human breast carcinoma specimens. Neuregulin 1 (or NRG1, hereafter referred to as heregulin) increased CXCR4 expression in breast cancer cells, and this coincided with increased LIP binding on the CXCR4 promoter. These findings may have important implications for understanding the molecular basis of CXCR4-mediated breast cancer cell metastasis and could potentially allow us to develop novel strategies to reduce morbidity and mortality in patients with metastatic breast cancer.

A new generalization of Weibull distribution with application to a breast cancer data set.

In this article, we propose a new generalization of the Weibull distribution, which incorporates the exponentiated Weibull distribution introduced by Mudholkar and Srivastava (IEEE Trans. Reliab. 1993; 42:299-302) as a special case. We refer to the new family of distributions as the beta-Weibull distribution. We investigate the potential usefulness of the beta-Weibull distribution for modeling censored survival data from biomedical studies. Several other generalizations of the standard two-parameter Weibull distribution are compared with regards to maximum likelihood inference of the cumulative incidence function, under the setting of competing risks. These Weibull-based parametric models are fit to a breast cancer data set from the National Surgical Adjuvant Breast and Bowel Project. In terms of statistical significance of the treatment effect and model adequacy, all generalized models lead to similar conclusions, suggesting that the beta-Weibull family is a reasonable candidate for modeling survival data.

Treatment of axillary lymph node-negative, estrogen receptor-negative breast cancer: updated findings from National Surgical Adjuvant Breast and Bowel Project clinical trials.

BACKGROUND: Results from three National Surgical Adjuvant Breast and Bowel Project sequentially conducted randomized trials of postoperative chemotherapy in women with estrogen receptor-negative tumors and negative axillary lymph nodes have demonstrated that a combination of methotrexate and 5-fluorouracil (MF) is more effective than surgery alone, that cyclophosphamide with MF (CMF) is more effective than MF, and that CMF and doxorubicin (Adriamycin) with cyclophosphamide (AC) are equally beneficial. This report presents updated findings from those trials, relates the results to age and menopausal status, and estimates the extent of progress made in treating such patients. METHODS: Patients were randomly assigned as follows: in B-13, 760 patients were assigned to surgery only or to MF; in B-19, 1095 patients were assigned to MF or CMF; in B-23, 2008 patients were assigned to CMF or AC. Recurrence-free survival (RFS) and overall survival (OS) were estimated according to age and menopausal status. Smoothed recurrence rates were used to evaluate patterns of recurrence as a continuous function of age. The Cox proportional hazards model was used to test for interactions between treatment and covariates and to estimate hazard ratios (HRs) for pairwise group comparisons. RESULTS: In B-13, through 16 years of follow-up, an overall benefit was seen with MF relative to surgery alone (RFS: HR = 0.59, 95% confidence interval [CI] = 0.44 to 0.78, P<0.001; OS: HR = 0.75, 95% CI = 0.58 to 0.98, P = 0.03). In B-19, through 13 years of follow-up, an overall benefit was seen for CMF relative to MF (RFS: HR = 0.59, 95% CI = 0.45 to 0.77, P<0.001; OS: HR = 0.71; 95% CI = 0.55 to 0.92; P = 0.01). In both trials, all age and menopausal groups demonstrated an RFS benefit, and most demonstrated an OS benefit. In B-23, through 8 years of follow-up, there were no statistically significant differences between the CMF and AC groups (RFS: HR = 1.00, 95% CI = 0.79 to 1.27, P = 0.97; OS, HR = 0.92, 95% CI = 0.73 to 1.17; P = 0.51). When women in the CMF or AC groups (B-19, B-23) were compared with those who were in the surgery-alone group (B-13), through 8 years of follow-up there was a 58% reduction in recurrence and a 40% reduction in mortality as a result of the chemotherapy. CONCLUSIONS: Outcomes in CMF- or AC-treated women with estrogen receptor-negative tumors and negative axillary lymph nodes were similar in all age groups. The decreased benefit from chemotherapy observed with increasing age was a result of a better outcome associated with advancing age in women who underwent surgery alone rather than a poorer outcome resulting from the use of chemotherapy.

Patterns of locoregional failure in patients with operable breast cancer treated by mastectomy and adjuvant chemotherapy with or without tamoxifen and without radiotherapy: results from five National Surgical Adjuvant Breast and Bowel Project randomized clinical trials.

PURPOSE: To assess patterns of locoregional failure (LRF) in lymph node-positive (LN+) breast cancer patients treated with mastectomy and adjuvant chemotherapy (+/- tamoxifen) and without postmastectomy radiotherapy (PMRT) in five National Surgical Adjuvant Breast and Bowel Project trials. PATIENTS AND METHODS: We examined 5,758 patients enrolled onto the B-15, B-16, B-18, B-22, and B-25 trials. Median follow-up time was 11.1 years. Distribution of pathologic tumor size was < or = 2 cm, 2.1 to 5 cm, and more than 5 cm in 30%, 52%, and 11% of patients, respectively. Distribution of the number of LN+ was one to three, four to nine, and > or = 10 in 51%, 32%, and 16% of patients, respectively. Ninety percent of patients received doxorubicin-based chemotherapy. RESULTS: The overall 10-year cumulative incidences of isolated LRF, LRF with or without distant failure (DF), and DF alone as first event were 12.2%, 19.8%, and 43.3%, respectively. Cumulative incidences for LRF as first event with or without DF for patients with one to three, four to nine, and > or = 10 LN+ were 13.0%, 24.4%, and 31.9%, respectively (P < .0001). For patients with a tumor size of < or = 2 cm, 2.1 to 5.0 cm, and more than 5.0 cm, these incidences were 14.9%, 21.3%, and 24.6%, respectively (P < .0001). Multivariate analysis showed age, tumor size, premenopausal status, number of LN+, and number of dissected LN as significant predictors for LRF as first event. CONCLUSION: In patients with large tumors and four or more LN+, LRF as first event remains a significant problem. Although PMRT is currently recommended for patients with four or more LN+, it may also have value in selected patients with one to three LN+. However, in the absence of a randomized trial examining the worth of radiotherapy in this group of patients, the value of PMRT remains unknown.