Intramyocardial cell-based therapy with Lomecel-B during bidirectional cavopulmonary anastomosis for hypoplastic left heart syndrome: the ELPIS phase I trial.

Aims: Hypoplastic left heart syndrome (HLHS) survival relies on surgical reconstruction of the right ventricle (RV) to provide systemic circulation. This substantially increases the RV load, wall stress, maladaptive remodelling, and dysfunction, which in turn increases the risk of death or transplantation. Methods and results: We conducted a phase 1 open-label multicentre trial to assess the safety and feasibility of Lomecel-B as an adjunct to second-stage HLHS surgical palliation. Lomecel-B, an investigational cell therapy consisting of allogeneic medicinal signalling cells (MSCs), was delivered via intramyocardial injections. The primary endpoint was safety, and measures of RV function for potential efficacy were obtained. Ten patients were treated. None experienced major adverse cardiac events. All were alive and transplant-free at 1-year post-treatment, and experienced growth comparable to healthy historical data. Cardiac magnetic resonance imaging (CMR) suggested improved tricuspid regurgitant fraction (TR RF) via qualitative rater assessment, and via significant quantitative improvements from baseline at 6 and 12 months post-treatment (P < 0.05). Global longitudinal strain (GLS) and RV ejection fraction (EF) showed no declines. To understand potential mechanisms of action, circulating exosomes from intramyocardially transplanted MSCs were examined. Computational modelling identified 54 MSC-specific exosome ribonucleic acids (RNAs) corresponding to changes in TR RF, including miR-215-3p, miR-374b-3p, and RNAs related to cell metabolism and MAPK signalling. Conclusion: Intramyocardially delivered Lomecel-B appears safe in HLHS patients and may favourably affect RV performance. Circulating exosomes of transplanted MSC-specific provide novel insight into bioactivity. Conduct of a controlled phase trial is warranted and is underway.Trial registration number NCT03525418.

Results and insights from a phase I clinical trial of Lomecel-B for Alzheimer's disease.

HYPOTHESIS: We hypothesized that Lomecel-B, an allogeneic medicinal signaling cell (MSC) therapeutic candidate for Alzheimer's disease (AD), is safe and potentially disease-modifying via pleiotropic mechanisms of action. KEY PREDICTIONS: We prospectively tested the predictions that Lomecel-B administration to mild AD patients is safe (primary endpoint) and would provide multiple exploratory indications of potential efficacy in clinical and biomarker domains (prespecified secondary/exploratory endpoints). STRATEGY AND KEY RESULTS: Mild AD patient received a single infusion of low- or high-dose Lomecel-B, or placebo, in a double-blind, randomized, phase I trial. The primary safety endpoint was met. Fluid-based and imaging biomarkers indicated significant improvement in the Lomecel-B arms versus placebo. The low-dose Lomecel-B arm showed significant improvements versus placebo on neurocognitive and other assessments. INTERPRETATION: Our results support the safety of Lomecel-B for AD, suggest clinical potential, and provide mechanistic insights. This early-stage study provides important exploratory information for larger efficacy-powered clinical trials.

Allogeneic mesenchymal stem cell therapy: A regenerative medicine approach to geroscience.

Extraordinary advances in medicine and public health have contributed to increasing life expectancy worldwide. However, health span-"healthy aging"-has paradoxically lagged to parallel this increase. Consequently, aging-associated illnesses, such as Alzheimer's disease and aging frailty, are having a growing impact on patients, their families, and entire health-care systems. Typically, such disorders have been treated as isolated disease entities. However, the inextricable links between aging-associated disorders and the aging process itself have become increasingly recognized, leading to formation of the field of geroscience. The geroscience concept is that treating the aging process itself should lead to treatment and prevention of aging-related disorders. However, the aging process is complex, dictated by highly interrelated pleiotropic processes. As such, therapeutics with pleiotropic mechanisms of action (either alone, or as part of combinatorial strategies) will be required for preventing and treating both aging and related disorders. Mesenchymal stem cells (MSCs) have multiple mechanisms of action that make these highly promising geroscience therapeutic candidates. These cells have a high safety profile for clinical use, are amenable to allogeneic use since tissue-type matching is not required, and can have sustained activity after transplantation. Herein, we review preclinical and clinical data supporting the utility of allogeneic MSCs as a geroscience therapeutic candidate.

Trastuzumab-induced cardiotoxicity.

PURPOSE/OBJECTIVES: To review trastuzumab-related cardiotoxic effects in the breast cancer adjuvant setting, present a system for pretreatment screening for cardiovascular risk factors, describe monitoring recommendations, provide a tool to facilitate adherence to monitoring guidelines, and discuss implications for patient education. DATA SOURCES: Literature regarding cardiotoxicity and trastuzumab in breast cancer. DATA SYNTHESIS: Trastuzumab was approved in 2006 for use in the adjuvant setting. A small percentage of women (approximately 4%) developed heart failure during or after treatment. However, the trials excluded women with cardiac disease. Current screening for cardiotoxicity relies on sequential left ventricular function measurements with either echocardiography or multigated acquisition scanning at baseline and every three months. Treatment modifications are recommended if changes from baseline are detected. Long-term and late effects have yet to be determined. CONCLUSIONS: Although a small number of women experienced cardiotoxicity in the adjuvant setting, an increase may be seen because women with preexisting heart disease receive this treatment. Guidelines and tools will be helpful for appropriate and consistent screening of cardiac risk factors and disease prior to initiation of trastuzumab and for monitoring during and after administration. IMPLICATIONS FOR NURSING: Nurses are instrumental in assessing, monitoring, and treating women receiving trastuzumab. Implementing guidelines to promote adherence to recommended monitoring is important in the early detection of cardiotoxicity in this population. Educating women about their treatment and side effects is an important aspect of care.

Measurement of the risk for substance use disorders: phenotypic and genetic analysis of an index of common liability.

The inability to quantify the risk for disorders, such as substance use disorders (SUD), hinders etiology research and development of targeted intervention. Based on the concept of common transmissible liability to SUD related to illicit drugs, a method enabling quantification of this latent trait has been developed, utilizing high-risk design and item response theory. This study examined properties of a SUD transmissible liability index (TLI) derived using this method. Sons of males with or without SUD were studied longitudinally from preadolescence to young adulthood. The properties of TLI, including its psychometric characteristics, longitudinal risk assessment and ethnic variation, were examined. A pilot twin study was conducted to analyze the composition of TLI's phenotypic variance. The data suggest that TLI has concurrent, incremental, predictive and discriminant validity, as well as ethnic differences. The data suggest a high heritability of the index in males. The results suggest applicability of the method for genetic and other etiology-related research, and for evaluation of individual risk.

Predictors of enrollment into a familial cancer registry by individuals at high risk for BRCA1/2.

BACKGROUND: Registries of individuals at risk for hereditary cancer syndromes are an invaluable resource for cancer research, yet little is known about the predictors of enrollment in hereditary cancer registries. We sought to identify the factors that characterize individuals who enroll versus those who decline participation in a Familial Cancer Registry (FCR). We also sought to identify the factors associated with provision of a blood sample to the FCR. METHODS: Participants (n = 549) had a 10% or greater prior probability of having a BRCA1/2 mutation or were members of a family with a known BRCA1/2 mutation. RESULTS: Of 549 participants, 81.1% (n = 445) enrolled in the FCR and 18.9% (n = 104) declined. Independent significant predictors of FCR participation included: lower anxiety (odds ratio(0.5 SD), 0.83; 95% confidence interval, 0.73-0.95) and being unaffected with breast or ovarian cancer (odds ratio, 0.52; 95% confidence interval, 0.39-0.67). Of the 445 FCR participants, 80.4% provided a blood sample whereas 19.6% declined, with blood sample provision predicted by being employed full time (odds ratio, 1.68; 95% confidence interval, 1.31-2.16). CONCLUSION: These findings have implications for the generalizability of results from research using hereditary cancer registry samples. Individuals who are affected with breast/ovarian cancer and have more anxiety are less likely to enroll in a hereditary cancer registry. Clinically, these results indicate that cancer registry enrollment strategies could benefit from the use of tailored approaches to increase the enrollment of individuals that are less likely to participate.