JoAnn Alvarez

Anti-Transforming Growth Factor ß Antibody Treatment Rescues Bone Loss and Prevents Breast Cancer Metastasis to Bone

Breast cancer often metastasizes to bone causing osteolytic bone resorption which releases active TGFβ. Because TGFβ favors progression of breast cancer metastasis to bone, we hypothesized that treatment using anti-TGFβ antibody may reduce tumor burden and rescue tumor-associated bone loss in metastatic breast cancer. In this study we have tested the efficacy of an anti-TGFβ antibody 1D11 preventing breast cancer bone metastasis. We have used two preclinical breast cancer bone metastasis models, in which either human breast cancer cells or murine mammary tumor cells were injected in host mice via left cardiac ventricle. Using several in vivo, in vitro and ex vivo assays, we have demonstrated that anti-TGFβ antibody treatment have significantly reduced tumor burden in the bone along with a statistically significant threefold reduction in osteolytic lesion number and tenfold reduction in osteolytic lesion area. A decrease in osteoclast numbers (p = 0.027) in vivo and osteoclastogenesis ex vivo were also observed. Most importantly, in tumor-bearing mice, anti-TGFβ treatment resulted in a twofold increase in bone volume (p<0.01). In addition, treatment with anti-TGFβ antibody increased the mineral-to-collagen ratio in vivo, a reflection of improved tissue level properties. Moreover, anti-TGFβ antibody directly increased mineralized matrix formation in calverial osteoblast (p = 0.005), suggesting a direct beneficial role of anti-TGFβ antibody treatment on osteoblasts. Data presented here demonstrate that anti-TGFβ treatment may offer a novel therapeutic option for tumor-induced bone disease and has the dual potential for simultaneously decreasing tumor burden and rescue bone loss in breast cancer to bone metastases. This approach of intervention has the potential to reduce skeletal related events (SREs) in breast cancer survivors.

The Comparative Harms of Open and Robotic Prostatectomy in Population Based Samples

PURPOSE Robotic assisted radical prostatectomy has largely replaced open radical prostatectomy for the surgical management of prostate cancer despite conflicting evidence of superiority with respect to disease control or functional sequelae. Using population cohort data, in this study we examined sexual and urinary function in men undergoing open radical prostatectomy vs those undergoing robotic assisted radical prostatectomy. MATERIALS AND METHODS Subjects surgically treated for prostate cancer were selected from 2 large population based prospective cohort studies, the Prostate Cancer Outcomes Study (enrolled 1994 to 1995) and the Comparative Effectiveness Analysis of Surgery and Radiation (enrolled 2011 to 2012). Subjects completed baseline, 6-month and 12-month standardized patient reported outcome measures. Main outcomes were between-group differences in functional outcome scores at 6 and 12 months using linear regression, and adjusting for baseline function, sociodemographic and clinical characteristics. Sensitivity analyses were used to evaluate outcomes between patients undergoing open radical prostatectomy and robotic assisted radical prostatectomy within and across CEASAR and PCOS. RESULTS The combined cohort consisted of 2,438 men, 1,505 of whom underwent open radical prostatectomy and 933 of whom underwent robotic assisted radical prostatectomy. Men treated with robotic assisted radical prostatectomy reported better urinary function at 6 months (mean difference 3.77 points, 95% CI 1.09-6.44) but not at 12 months (1.19, -1.32-3.71). Subjects treated with robotic assisted radical prostatectomy also reported superior sexual function at 6 months (8.31, 6.02-10.56) and at 12 months (7.64, 5.25-10.03). Sensitivity analyses largely supported the sexual function findings with inconsistent support for urinary function results. CONCLUSIONS This population based study reveals that men undergoing robotic assisted radical prostatectomy likely experience less decline in early urinary continence and sexual function than those undergoing open radical prostatectomy. The clinical meaning of these differences is uncertain and longer followup will be required to establish whether these benefits are durable.

The utility of Bayesian predictive probabilities for interim monitoring of clinical trials.

Background Bayesian predictive probabilities can be used for interim monitoring of clinical trials to estimate the probability of observing a statistically significant treatment effect if the trial were to continue to its predefined maximum sample size. Purpose We explore settings in which Bayesian predictive probabilities are advantageous for interim monitoring compared to Bayesian posterior probabilities, p-values, conditional power, or group sequential methods. Results For interim analyses that address prediction hypotheses, such as futility monitoring and efficacy monitoring with lagged outcomes, only predictive probabilities properly account for the amount of data remaining to be observed in a clinical trial and have the flexibility to incorporate additional information via auxiliary variables. Limitations Computational burdens limit the feasibility of predictive probabilities in many clinical trial settings. The specification of prior distributions brings additional challenges for regulatory approval. Conclusions The use of Bayesian predictive probabilities enables the choice of logical interim stopping rules that closely align with the clinical decision-making process.

Decreasing adrenergic or sympathetic hyperactivity after severe traumatic brain injury using propranolol and clonidine (DASH After TBI Study): study protocol for a randomized controlled trial

BackgroundSevere TBI, defined as a Glasgow Coma Scale ≤ 8, increases intracranial pressure and activates the sympathetic nervous system. Sympathetic hyperactivity after TBI manifests as catecholamine excess, hypertension, abnormal heart rate variability, and agitation, and is associated with poor neuropsychological outcome. Propranolol and clonidine are centrally acting drugs that may decrease sympathetic outflow, brain edema, and agitation. However, there is no prospective randomized evidence available demonstrating the feasibility, outcome benefits, and safety for adrenergic blockade after TBI.Methods/DesignThe DASH after TBI study is an actively accruing, single-center, randomized, double-blinded, placebo-controlled, two-arm trial, where one group receives centrally acting sympatholytic drugs, propranolol (1 mg intravenously every 6 h for 7 days) and clonidine (0.1 mg per tube every 12 h for 7 days), and the other group, double placebo, within 48 h of severe TBI. The study uses a weighted adaptive minimization randomization with categories of age and Marshall head CT classification. Feasibility will be assessed by ability to provide a neuroradiology read for randomization, by treatment contamination, and by treatment compliance. The primary endpoint is reduction in plasma norepinephrine level as measured on day 8. Secondary endpoints include comprehensive plasma and urine catecholamine levels, heart rate variability, arrhythmia occurrence, infections, agitation measures using the Richmond Agitation-Sedation Scale and Agitated Behavior scale, medication use (anti-hypertensive, sedative, analgesic, and antipsychotic), coma-free days, ventilator-free days, length of stay, and mortality. Neuropsychological outcomes will be measured at hospital discharge and at 3 and 12 months. The domains tested will include global executive function, memory, processing speed, visual-spatial, and behavior. Other assessments include the Extended Glasgow Outcome Scale and Quality of Life after Brain Injury scale. Safety parameters evaluated will include cardiac complications.DiscussionThe DASH After TBI Study is the first randomized, double-blinded, placebo-controlled trial powered to determine feasibility and investigate safety and outcomes associated with adrenergic blockade in patients with severe TBI. If the study results in positive trends, this could provide pilot evidence for a larger multicenter randomized clinical trial. If there is no effect of therapy, this trial would still provide a robust prospective description of sympathetic hyperactivity after TBI.Trial registrationClinicalTrials.gov NCT01322048

Racial variation in the quality of surgical care for bladder cancer

Differences in quality of care may contribute to racial variation in outcomes of bladder cancer (BCa). Quality indicators in patients undergoing surgery for BCa include the use of high‐volume surgeons and high‐volume hospitals, and, when clinically indicated, receipt of pelvic lymphadenectomy, receipt of continent urinary diversion, and undergoing radical cystectomy instead of partial cystectomy. The authors compared these quality indicators as well as adverse perioperative outcomes in black patients and white patients with BCa.

Variation in practices and attitudes of clinicians assessing PTSD‐related disability among veterans

One hundred thirty-eight Veterans Affairs mental health professionals completed a 128-item Posttraumatic Stress Disorder (PTSD) Practice Inventory that asked about their practices and attitudes related to disability assessment of PTSD. Results indicate strikingly wide variation in the attitudes and practices of clinicians conducting disability assessments for PTSD. In a high percentage of cases, these attitudes and practices conflict with best-practice guidelines. Specifically, 59% of clinicians reported rarely or never using testing, and only 17% indicated routinely using standardized clinical interviews. Less than 1% of respondents reported using functional assessment scales.

The Effectiveness of Baby Books for Providing Pediatric Anticipatory Guidance to New Mothers

OBJECTIVE: To assess whether embedding pediatric anticipatory guidance into books read to infants is an effective way to educate low-income, first-time mothers about injury-prevention and health-promotion practices. PATIENTS AND METHODS: Primiparous women (N = 168) were randomly assigned to 1 of 3 groups: an educational-book group; a noneducational-book group; or a no-book group. Knowledge of anticipatory-guidance topics regarding children from birth to 12 months of age (eg, injury prevention, parenting, nutrition) was assessed during the third trimester of pregnancy and again when infants were ∼2, 4, 6, 9, 12, and 18 months of age. RESULTS: Women in the educational-book group scored consistently higher on knowledge than did those in the other 2 groups. Those in the educational-book group were found to have significantly higher knowledge scores than those in both the noneducational-book group (effect size [ES]: 0.3, P < .001) and the no-book group (ES: 0.3, P < .001) in the longitudinal model. CONCLUSIONS: Books read by mothers to infants seem to be an effective way to provide anticipatory guidance to new mothers. However, future work is needed to determine if increased knowledge translates into safer and more developmentally appropriate parenting practices.

Baseline Predictors of Health-Related Quality of Life After Anterior Cruciate Ligament Reconstruction: A Longitudinal Analysis of a Multicenter Cohort at Two and Six Years

BACKGROUND Limited information exists regarding predictors of general quality of life following anterior cruciate ligament (ACL) reconstruction with up to six-year follow-up. We hypothesized that certain variables evaluated at the time of ACL reconstruction will predict the general quality of life as measured by the Short Form-36 (SF-36). METHODS All unilateral ACL reconstructions from 2002 to 2004 in patients currently enrolled in a prospective multicenter cohort were evaluated. Patients preoperatively completed the SF-36 validated outcome instrument. Surgeons documented intra-articular pathological conditions and treatment, as well as the ACL reconstruction surgical technique. At baseline and at a minimum of two and six years postoperatively, patients completed the SF-36. Longitudinal analysis was performed for the two-year and six-year end points. RESULTS Of the initial 1512 subjects, at least one follow-up questionnaire was obtained from 1411 subjects (93%). The cohort was 44% female, and the median patient age at enrollment was twenty-three years. The mean scores were 41.9 points for the Physical Component Summary (PCS) and 51.7 points for the Mental Component Summary (MCS) at baseline, 53.6 points for the PCS and 52.0 points for the MCS at two years, and 54.0 points for the PCS and 52.4 points for the MCS at six years. Significant predictors of a higher PCS score were a higher baseline PCS score, younger age, lower baseline body mass index, having >50% of the lateral meniscus excised, or having no treatment done on a lateral meniscal tear. In contrast, significant predictors of a lower PCS score were a shorter follow-up time since surgery, revision ACL reconstruction, smoking at baseline, fewer years of education, and chondromalacia of the lateral tibial plateau. The mean utility gained at six years after ACL reconstruction was 5.3 quality-adjusted life years (QALYs). CONCLUSIONS Large improvements in the PCS (with an effect size of 1.2) were noted at two years and were maintained at six years after ACL reconstruction. Lower education and smoking were significant predictors of lower PCS and MCS scores. ACL reconstruction resulted in a relatively high gain of QALYs.

Knowledge of diagnosis, treatment history, and risk of late effects among childhood cancer survivors and parents: The impact of a survivorship clinic

Childhood cancer survivors are at risk for treatment‐related adverse health outcomes, known as late effects. Through matched and longitudinal cohorts, we assessed the impact of survivorship care on patient and parent knowledge of treatment history and associated health risks.

Time course of arthralgia among women initiating aromatase inhibitor therapy and a postmenopausal comparison group in a prospective cohort.

More than 80,000 postmenopausal breast cancer patients in the United States each year are estimated to begin a 5‐year course of aromatase inhibitors (AIs) to prevent recurrence. AI‐related arthralgia (joint pain and/or stiffness) may contribute to nonadherence, but longitudinal data are needed on arthralgia risk factors, trajectories, and background in postmenopause. This study sought to describe 1‐year arthralgia trajectories and baseline covariates among patients with AI and a postmenopausal comparison group.