Citations

Poly(GP) proteins are a promising pharmacodynamic marker for developing and testing therapeutics for treating C9ORF72 -associated amyotrophic lateral sclerosis.

184 Background: While evidence of the challenges of cancer caregiving has been growing, scant research addresses the experience of partners of young adults with cancer. These individuals and their relationships may be particularly vulnerable to stress, especially when managing the complexity of cancer care and survivorship with their partner. We sought to evaluate psychosocial concerns and mental health in the partners of young survivors of early stage breast cancer (BC). Methods: We invited partners of young women w/BC diagnosed at age ≤ 40 yrs enrolled in a prospective cohort study to participate in a one-time survey evaluating psychosocial concerns including quality of life, coping, social support, financial insecurity, partnership concerns, parenting concerns, anxiety and depression. Logistic regression was used to explore predictors of anxiety (score > 8 on Hospital Anxiety and Depression Scale (HADS)). Results: Most respondents (284/289) were male, with median age 43 yrs (range 27-65). The median time of survey completion was 62 months (range 16 -114) after their partner’s dx. Respondents were mostly white (93%), working full time (94%), and college educated (78%); 29% reported some financial stress, 74% were parenting children < 18 yrs, and 32% reported at least a fair amount of relationship concern. 42% (106/250) had anxiety (39/289 respondents (13%) had incomplete/missing HADS). In univariable analyses, lower education, working full time, parenting concerns, insufficient social support and maladaptive coping were associated (p < .05) with anxiety. In the multivariable model, only maladaptive coping remained significantly associated with anxiety (p < .01, OR = 2.32 (95% CI: 1.22, 4.39)). Conclusions: Partners of young BC survivors who used less constructive/more maladaptive coping strategies experience negative mental health outcomes after tx has ended. Caregivers’ anxiety may have implications for both their own and survivors’ health and QOL. Future interventions might focus on the development of constructive coping strategies to enhance adjustment and role effectiveness in dealing with the impact of cancer.

Abstract Rationale The release of eosinophil granule proteins in the lungs of patients with asthma has been dogmatically linked with lung remodeling and airway hyperresponsiveness. However, the demonstrated inability of established mouse models to display the eosinophil degranulation occurring in human subjects has prevented a definitive in vivo test of this hypothesis. Objectives To demonstrate in vivo causative links between induced pulmonary histopathologies/lung dysfunction and eosinophil degranulation. Methods A transgenic mouse model of chronic T-helper cell type 2–driven inflammation overexpressing IL-5 from T cells and human eotaxin 2 in the lung (I5/hE2) was used to test the hypothesis that chronic histopathologies and the development of airway hyperresponsiveness occur as a consequence of extensive eosinophil degranulation in the lung parenchyma. Measurement and Main Results Studies targeting specific inflammatory pathways in I5/hE2 mice surprisingly showed that eosinophil-dependent immunoregulative events and not the release of individual secondary granule proteins are the central contributors to T-helper cell type 2–induced pulmonary remodeling and lung dysfunction. Specifically, our studies highlighted a significant role for eosinophil-dependent IL-13 expression. In contrast, extensive degranulation leading to the release of major basic protein-1 or eosinophil peroxidase was not causatively linked to many of the induced pulmonary histopathologies. However, these studies did define a previously unappreciated link between the release of eosinophil peroxidase (but not major basic protein-1) and observed levels of induced airway mucin. Conclusions These data suggest that improvements observed in patients with asthma responding to therapeutic strategies ablating eosinophils may occur as a consequence of targeting immunoregulatory mechanisms and not by simply eliminating the destructive activities of these purportedly end-stage effector cells.

Objectives To examine associations between adiposity and adiposity change (loss, stable, gain) and subsequent longitudinal cognitive performance in African Americans in mid and late life. Design Cohort study using linear mixed models. Setting Genetic Epidemiology Network of Arteriopathy. Participants African‐American sibships with hypertension in Jackson, Mississippi (N = 1,108). Measurements Waist circumference and body mass index ( BMI ) were measured at two examinations 5 years apart. Stable adiposity was defined as values within 5% of the first measure. A composite cognitive Z ‐score was derived from individual cognitive test Z ‐scores at two study visits 6 years apart. Results Larger waist circumference was associated with greater rate of cognitive decline during follow‐up (beta = −0.0009 per year, P = .001); BMI , change in waist circumference, and change in BMI were not associated with rate of decline. Loss of adiposity in midlife was associated with higher cognitive Z ‐scores in middle‐aged individuals, and loss of adiposity in late life was associated with lower Z ‐scores in older adults ( P = .01 for interaction between waist circumference and age; P = .04 for interaction between BMI and age). Simultaneous inclusion of waist circumference and BMI in the cross‐sectional model suggested an association between larger waist circumference and poorer cognitive performance (beta = −0.009, P = .006) and between higher BMI and better cognitive performance (beta = 0.014, P = .06). Conclusion The results suggested a differential pattern of the relationship between adiposity and cognition according to age (mid‐ or late life) and regional distribution of adiposity.

Objective Sudden cardiac arrest (SCA) is the most devastating outcome in hypertrophic cardiomyopathy (HCM). We evaluated repolarisation features on the surface electrocardiogram (ECG) to identify the potential risk factors for SCA. Methods Data was collected from 52 patients with HCM who underwent implantable cardioverter defibrillator (ICD) implantation. Leads V2 and V5 from the ECG closest to the time of ICD implant were utilised for measuring the Tpeak-Tend interval (Tpe), QTc, Tpe/QTc, T-wave duration and T-wave amplitude. The presence of the five traditional SCA-associated risk factors was assessed, as well as the HCM risk-SCD score. Results 16 (30%) patients experienced aborted cardiac arrest over 8.5±4.1 years, with 9 receiving an ICD shock and 7 receiving ATP. On univariate analysis, T-wave amplitude was associated with appropriate ICD therapy (HR per 0.1 mV 0.79, 95% CI 0.56 to 0.96, p=0.02). Aborted SCA was not associated with a greater mean QTc duration, Tpeak-Tend interval, T-wave duration, or Tpe/QT ratio. Multivariate analysis (adjusting for cardinal HCM SCA-risk factors) showed T-wave amplitude in Lead V2 was an independent predictor of risk (adjusted HR per 0.1 mV 0.74, 95% CI 0.57 to 0.97, p=0.03). Addition of T-wave amplitude in Lead V2 to the traditional risk factors resulted in significant improvement in risk stratification (C-statistic from 0.65 to 0.75) but did not improve the performance of the HCM SCD-risk score. Conclusions T-wave amplitude is a novel marker of SCA in this high risk HCM population and may provide incremental predictive value to established risk factors. Further work is needed to define the role of repolarisation abnormalities in predicting SCA in HCM.

Purpose Follicular lymphoma (FL) is an indolent cancer, with effective but rarely curative treatment options. As a standard study end point for first-line FL therapy, progression-free survival (PFS) requires extended follow-up (median PFS, > 7 years). To provide patients with earlier access to newer therapies, an earlier end point to expedite clinical trials is needed. Our objective was to formally assess the complete response rate at 30 months (CR30) after initiation of induction therapy as a potential surrogate end point for PFS in first-line FL therapy. Patients and Methods We analyzed individual patient data from 13 randomized multicenter trials of induction and maintenance regimens in first-line FL therapy published after 1990 and with sufficient data to evaluate whether CR30 could predict treatment effects on PFS. Correlation of the CR30 odds ratio with the PFS hazard ratio was evaluated by both linear regression (R2WLS) and bivariate copula (R2Copula) models. Prespecified criteria for surrogacy required either R2WLS or R2Copula ≥ 0.80, with a lower-bound 95% CI > 0.60. Results Data from eight induction and five maintenance randomized trials in 3,837 evaluable patients were analyzed. The prespecified surrogacy threshold was met, with an R2WLS of 0.88 (95% CI, 0.77 to 0.96) and an R2Copula of 0.86 (95% CI, 0.72 to 1.00). Multiple sensitivity and supplemental analyses supported the robustness of the findings. A minimum 11% absolute improvement in CR30 from a 50% control rate predicted a significant treatment effect on PFS (hazard ratio, 0.69). Conclusion This large, prospective, pooled analysis of randomized chemotherapy, immunotherapy, and chemoimmunotherapy trials demonstrates that CR30 is a surrogate end point for PFS in first-line FL treatment trials. Use of this end point may expedite therapeutic development with the intent of bringing novel therapies to this patient population years before PFS results are mature.