Samuel Golpanian

Effect of Aging on Human Mesenchymal Stem Cell Therapy in Ischemic Cardiomyopathy Patients

BACKGROUND The role of patient age in the efficacy of mesenchymal stem cell (MSC) therapy in ischemic cardiomyopathy (ICM) is controversial. OBJECTIVES This study sought to determine whether the therapeutic effect of culture-expanded MSCs persists, even in older subjects. METHODS Patients with ICM who received MSCs via transendocardial stem cell injection (TESI) as part of the TAC-HFT (Transendocardial Autologous Cells in Ischemic Heart Failure) (n = 19) and POSEIDON (Percutaneous Stem Cell Injection Delivery Effects on Neomyogenesis) (n = 30) clinical trials were divided into 2 age groups: younger than 60 and 60 years of age and older. Functional capacity was measured by 6-min walk distance (6MWD) and quality of life using the Minnesota Living With Heart Failure Questionnaire (MLHFQ) score, measured at baseline, 6 months, and 1 year post-TESI. Various cardiac imaging parameters, including absolute scar size, were compared at baseline and 1 year post-TESI. RESULTS The mean 6MWD was similar at baseline and increased at 1 year post-TESI in both groups: 48.5 ± 14.6 m (p = 0.001) for the younger and 35.9 ± 18.3 m (p = 0.038) for the older participants (p = NS between groups). The older group exhibited a significant reduction in MLHFQ score (-7.04 ± 3.54; p = 0.022), whereas the younger than 60 age group had a borderline significant reduction (-11.22 ± 5.24; p = 0.058) from baseline (p = NS between groups). Although there were significant reductions in absolute scar size from baseline to 1 year post-TESI, the effect did not differ by age. CONCLUSIONS MSC therapy with TESI in ICM patients improves 6MWD and MLHFQ score and reduces myocardial infarction size. Importantly, older individuals did not have an impaired response to MSC therapy.

Concise Review: Review and Perspective of Cell Dosage and Routes of Administration From Preclinical and Clinical Studies of Stem Cell Therapy for Heart Disease

An important stage in the development of any new therapeutic agent is establishment of the optimal dosage and route of administration. This can be particularly challenging when the treatment is a biologic agent that might exert its therapeutic effects via complex or poorly understood mechanisms. Multiple preclinical and clinical studies have shown paradoxical results, with inconsistent findings regarding the relationship between the cell dose and clinical benefit. Such phenomena can, at least in part, be attributed to variations in cell dosing or concentration and the route of administration (ROA). Although clinical trials of cell‐based therapy for cardiovascular disease began more than a decade ago, specification of the optimal dosage and ROA has not been established. The present review summarizes what has been learned regarding the optimal cell dosage and ROA from preclinical and clinical studies of stem cell therapy for heart disease and offers a perspective on future directions.

Rationale and design of the Percutaneous Stem Cell Injection Delivery Effects on Neomyogenesis in Dilated Cardiomyopathy (the POSEIDON-DCM study): a phase I/II, randomized pilot study of the comparative safety and efficacy of transendocardial injection of autologous mesenchymal stem cell vs. allogeneic mesenchymal stem cells in patients with non-ischemic dilated cardiomyopathy.

While accumulating clinical trials have focused on the impact of cell therapy in patients with acute myocardial infarction (MI) and ischemic cardiomyopathy, there are fewer efforts to examine cell-based therapy in patients with non-ischemic cardiomyopathy (NICM). We hypothesized that cell therapy could have a similar impact in NICM. The POSEIDON-DCM trial is a phase I/II trial designed to address autologous vs. allogeneic bone marrow-derived mesenchymal stem cells (MSCs) in patients with NICM. In this study, cells will be administered transendocardially with the NOGA injection-catheter system to patients (n = 36) randomly allocated to two treatment groups: group 1 (n = 18 auto-human mesenchymal stem cells (hMSC)) and group 2 (n = 18 allo-hMSCs). The primary and secondary objectives are, respectively, to demonstrate the safety and efficacy of allo-hMSCS vs. auto-hMSCs in patients with NICM. This study will establish safety of transendocardial injection of stem cells (TESI), compare phenotypic outcomes, and offer promising advances in the field of cell-based therapy in patients with NICM.

Dose Comparison Study of Allogeneic Mesenchymal Stem Cells in Patients With Ischemic Cardiomyopathy (The TRIDENT Study)

Rationale: Cell dose and concentration play crucial roles in phenotypic responses to cell-based therapy for heart failure. Objective: To compare the safety and efficacy of 2 doses of allogeneic bone marrow–derived human mesenchymal stem cells identically delivered in patients with ischemic cardiomyopathy. Methods and Results: Thirty patients with ischemic cardiomyopathy received in a blinded manner either 20 million (n=15) or 100 million (n=15) allogeneic human mesenchymal stem cells via transendocardial injection (0.5 cc per injection × 10 injections per patient). Patients were followed for 12 months for safety and efficacy end points. There were no treatment-emergent serious adverse events at 30 days or treatment-related serious adverse events at 12 months. The Major Adverse Cardiac Event rate was 20.0% (95% confidence interval [CI], 6.9% to 50.0%) in 20 million and 13.3% (95% CI, 3.5% to 43.6%) in 100 million (P=0.58). Worsening heart failure rehospitalization was 20.0% (95% CI, 6.9% to 50.0%) in 20 million and 7.1% (95% CI, 1.0% to 40.9%) in 100 million (P=0.27). Whereas scar size reduced to a similar degree in both groups: 20 million by −6.4 g (interquartile range, −13.5 to −3.4 g; P=0.001) and 100 million by −6.1 g (interquartile range, −8.1 to −4.6 g; P=0.0002), the ejection fraction improved only with 100 million by 3.7 U (interquartile range, 1.1 to 6.1; P=0.04). New York Heart Association class improved at 12 months in 35.7% (95% CI, 12.7% to 64.9%) in 20 million and 42.9% (95% CI, 17.7% to 71.1%) in 100 million. Importantly, proBNP (pro-brain natriuretic peptide) increased at 12 months in 20 million by 0.32 log pg/mL (95% CI, 0.02 to 0.62; P=0.039), but not in 100 million (−0.07 log pg/mL; 95% CI, −0.36 to 0.23; P=0.65; between group P=0.07). Conclusions: Although both cell doses reduced scar size, only the 100 million dose increased ejection fraction. This study highlights the crucial role of cell dose in the responses to cell therapy. Determining optimal dose and delivery is essential to advance the field, decipher mechanism(s) of action and enhance planning of pivotal Phase III trials. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02013674.

Allogeneic Mesenchymal Stem Cells Ameliorate Aging Frailty: A Phase II Randomized, Double-Blind, Placebo-Controlled Clinical Trial

Abstract Background Aging frailty, characterized by decreased physical and immunological functioning, is associated with stem cell depletion. Human allogeneic mesenchymal stem cells (allo-hMSCs) exert immunomodulatory effects and promote tissue repair. Methods This is a randomized, double-blinded, dose-finding study of intravenous allo-hMSCs (100 or 200-million [M]) vs placebo delivered to patients (n = 30, mean age 75.5 ± 7.3) with frailty. The primary endpoint was incidence of treatment-emergent serious adverse events (TE-SAEs) at 1-month postinfusion. Secondary endpoints included physical performance, patient-reported outcomes, and immune markers of frailty measured at 6 months postinfusion. Results No therapy-related TE-SAEs occurred at 1 month. Physical performance improved preferentially in the 100M-group; immunologic improvement occurred in both the 100M- and 200M-groups. The 6-minute walk test, short physical performance exam, and forced expiratory volume in 1 second improved in the 100M-group (p = .01), not in the 200M- or placebo groups. The female sexual quality of life questionnaire improved in the 100M-group (p = .03). Serum TNF-α levels decreased in the 100M-group (p = .03). B cell intracellular TNF-α improved in both the 100M- (p < .0001) and 200M-groups (p = .002) as well as between groups compared to placebo (p = .003 and p = .039, respectively). Early and late activated T-cells were also reduced by MSC therapy. Conclusion Intravenous allo-hMSCs were safe in individuals with aging frailty. Treated groups had remarkable improvements in physical performance measures and inflammatory biomarkers, both of which characterize the frailty syndrome. Given the excellent safety and efficacy profiles demonstrated in this study, larger clinical trials are warranted to establish the efficacy of hMSCs in this multisystem disorder. Clinical Trial Registration www.clinicaltrials.gov: CRATUS (#NCT02065245).

Growth Hormone–Releasing Hormone Agonists Reduce Myocardial Infarct Scar in Swine With Subacute Ischemic Cardiomyopathy

Background Growth hormone–releasing hormone agonists (GHRH‐As) stimulate cardiac repair following myocardial infarction (MI) in rats through the activation of the GHRH signaling pathway within the heart. We tested the hypothesis that the administration of GHRH‐As prevents ventricular remodeling in a swine subacute MI model. Methods and Results Twelve female Yorkshire swine (25 to 30 kg) underwent transient occlusion of the left anterior descending coronary artery (MI). Two weeks post MI, swine were randomized to receive injections of either 30 μg/kg GHRH‐A (MR‐409) (GHRH‐A group; n=6) or vehicle (placebo group; n=6). Cardiac magnetic resonance imaging and pressure–volume loops were obtained at multiple time points. Infarct, border, and remote (noninfarcted) zones were assessed for GHRH receptor by immunohistochemistry. Four weeks of GHRH‐A treatment resulted in reduced scar mass (GHRH‐A: −21.9±6.42%; P=0.02; placebo: 10.9±5.88%; P=0.25; 2‐way ANOVA; P=0.003), and scar size (percentage of left ventricular mass) (GHRH‐A: −38.38±4.63; P=0.0002; placebo: −14.56±6.92; P=0.16; 2‐way ANOVA; P=0.02). This was accompanied by improved diastolic strain. Unlike in rats, this reduced infarct size in swine was not accompanied by improved cardiac function as measured by serial hemodynamic pressure–volume analysis. GHRH receptors were abundant in cardiac tissue, with a greater density in the border zone of the GHRH‐A group compared with the placebo group. Conclusions Daily subcutaneous administration of GHRH‐A is feasible and safe in a large animal model of subacute ischemic cardiomyopathy. Furthermore, GHRH‐A therapy significantly reduced infarct size and improved diastolic strain, suggesting a local activation of the GHRH pathway leading to the reparative process.

Pediatric histiocytoses in the United States: incidence and outcomes

BACKGROUND Histiocytoses are rare disorders affecting the pediatric population. MATERIALS AND METHODS Surveillance, Epidemiology, and End Results database was searched for pediatric cases (<20 y old) of histiocytosis diagnosed between 1973 and 2010. Demographics, clinical characteristics, and survival outcomes were analyzed using standard statistical methods. Class I disease (Langerhans cell histiocytosis) and class III (malignant histiocytosis) were included in the data set. RESULTS A total of 828 cases were identified. Overall incidence was 0.142/100,000 persons per annum. Incidence was highest in younger children and those of Asian or Native American descent. Class III disease had a higher incidence versus class I. Adolescents tended to present with class III, whereas young children presented with class I. Disseminated disease was present in most cases of class III, whereas class I had more localized cases. Surgical excision was more likely to be performed in class I. Overall median survival was 349 mo. Patients 15-19 y old and children<1 y old had the worst outcomes. Class I had higher survival compared with class III, which had a median survival of 33 mo. Cases with hematologic spread carried the worst prognosis. Surgical excision conferred a survival advantage while radiation had no effect. Survival improved over the study period. Gender and race had no association with survival. CONCLUSIONS Class I disease had localized cases and showed benefit from surgical intervention. Class III disease had a higher incidence and was associated with disseminated disease and lower survival. Radiation therapy did not affect survival. Overall survival increased over the previous 40 y.

Deep inferior epigastric perforator versus free transverse rectus abdominis myocutaneous flap: Complications and resource utilization

Introduction Abdominal based breast reconstruction exists in a continuum from pedicled transverse rectus abdominis myocutaneous (TRAM) flap to deep inferior epigastric perforator (DIEP) free flap. DIEP flap has the advantage of complete rectus abdominis sparing during harvest, thus decreasing donor site morbidity. Aim of this study is to determine whether the surgical advantages of the DIEP flap impact postoperative outcomes versus the free TRAM flap (fTRAM). Methods We reviewed the Nationwide Inpatient Sample database (2010–2011) for all cases of DIEP and fTRAM breast reconstruction. Inclusion criteria were: female sex and patients undergoing DIEP or fTRAM total breast reconstruction. Male sex was excluded from the analysis. We examined demographic characteristics, hospital setting, insurance information, patient income, comorbidities, postoperative complications (including reoperation, hemorrhage, hematoma, seroma, myocardial infarction, pulmonary embolus, wound infection, and flap loss), length of stay, and total charges (TCs). Bivariate and multivariate analyses were performed to identify independent risk factors of increased length of stay and TCs. Results Fifteen thousand eight hundred thirty-six cases were identified. Seventy percent were white, 97% were insured, and 83% of patients were treated in an academic teaching hospital setting. No mortalities were recorded. The DIEP cohort was more likely to be obese (P = 0.001). Free TRAM cohort was more likely to suffer pneumonia (P < 0.001; odds ratio [OR], 3.7), wound infection (P = 0.001; OR, 1.7), and wound dehiscence (P < 0.001; OR, 4.3). Type of reconstruction did not appear to affect risk of revision, hemorrhage, hematoma, seroma, or flap loss. Total charges were higher in the DIEP group (P < 0.001). Multivariate analysis demonstrated that fTRAM was an independent risk factor for increased length of stay (P < 0.001; OR, 1.6), and DIEP was an independent risk factor for increased TCs (P < 0.01; OR, 1.5). There was no significant difference in postoperative complications. Conclusions The fTRAM cohort was more likely to develop surgical site complications and have an increased length of stay, but TCs were higher for the DIEP group.

Full-Thickness Skin Graft

Skin grafting for coverage of skin and/or tissue defects, secondary to trauma, infections, and neoplasms, is still a widely performed procedure by reconstructive surgeons today. While split-thickness skin grafts include the epidermis and varying amounts of dermis, full-thickness skin grafts consist of the epidermis and the entire underlying dermis. Full-thickness skin grafts are valuable for the reconstruction of certain soft tissue defects that require maintenance of functional and aesthetic integrity, such as the fingers or face. Donor sites may heal by primary closure or use of split-thickness skin grafts. Undeniably, full-thickness skin grafting bears its own risks of complications. The most significant involves the potential for graft contracture, poor graft survival, donor-site infections, and skin color mismatching. Overall, the procedure is a meticulous task that requires important postoperative observation and care. Restoration of function and cosmesis is considered a successful outcome for full-thickness skin grafting procedures.

Treatment Options for Exposed Calvarium Due to Trauma and Burns

Abstract Wounds involving the calvarium secondary to trauma or burns are rare. However, they can present with challenging potential clinical sequelae. A wide variety of reconstructive options have evolved over the last century. Technical aspects have progressively improved as well over time. For proper surgical restoration of function and cosmesis reconstructive surgeons must have a detailed understanding of both the scalp and skull anatomy. Several factors such as etiology of the injury, including whether or not calvarial bone defects exists or simply soft tissue loss, as well as size, local tissue environment and patient comorbidities play major roles in appropriate choice for reconstruction. Currently, there is no single treatment option for scalp or calvarial reconstruction after trauma or burns. However, reconstructive alternatives are constantly emerging with promising results.