Outpatient-Based High-Volume Liposuction: A Retrospective Review of 310 Consecutive Patients.

BACKGROUND: Currently, the definition of large-volume liposuction is the removal of 5 L or more of total aspirate. Higher volumes of lipoaspirate come into consideration with higher BMIs, because more than 5 L is often required to achieve a satisfactory aesthetic result. The boundaries of what lipoaspirate volume is considered safe are based on historical opinion and are constantly in question. OBJECTIVES: Because to date there have been no scientific data available to support a specific safe maximum volume of lipoaspirate, the authors discuss necessary conditions for safe high-volume lipoaspirate extraction. METHODS: This retrospective study included 310 patients who had liposuction of ≥5 L over a 30-month period. All patients had 360° liposuction alone or in combination with other procedures. RESULTS: Patient ages ranged from 20 to 66 with a mean age of 38.5 (SD = 9.3). Average operative time was 202 minutes (SD = 83.1). Mean total aspirate was 7.5 L (SD = 1.9). An average of 1.84 L (SD = 0.69) of intravenous fluids and 8.99 L (SD = 1.47) of tumescent fluid were administered. Urine output was maintained above 0.5 mL/kg/hr. There were no major cardiopulmonary complications or cases requiring blood transfusion. CONCLUSIONS: High-volume liposuction is safe if proper preoperative, intraoperative, and postoperative protocols and techniques are employed. The authors believe that this bias should be modified and that sharing their experience with high-volume liposuction may help guide other surgeons to incorporate this practice with confidence and safety for better patient outcomes.

Ultrasound-guided Hydro-dissection Facilitates Tissue Expander Placement and Components Separation in Complex Ventral Hernia Repair.

Tissue expanders are known adjuncts in ventral hernia repair, used in a staged approach where tissue closure or coverage of the defect is preferred but inadequate. Placement of tissue expanders in the correct tissue plane can be difficult, especially in thin patients or with loss of domain. This case series describes a technique in which tissue expander placement is facilitated by ultrasound-guided hydro-dissection, following the placement of a transversus abdominis plane (TAP) block. In short, after induction of anesthesia, the same needle used for the ultrasound-guided TAP block can be repositioned by the anesthesiologist to instill tumescent solution into the fascial plane between the internal and external oblique muscles. This allows for identification of the fascial planes in the ensuing operation. Our technique may prove to be an alternative tool in the placement of tissue expanders for ventral hernia repair, or in other procedures requiring device placement.

A Combination of Allogeneic Stem Cells Promotes Cardiac Regeneration.

BACKGROUND: The combination of autologous mesenchymal stem cells (MSCs) and cardiac stem cells (CSCs) synergistically reduces scar size and improves cardiac function in ischemic cardiomyopathy. Whereas allogeneic (allo-)MSCs are immunoevasive, the capacity of CSCs to similarly elude the immune system remains controversial, potentially limiting the success of allogeneic cell combination therapy (ACCT). OBJECTIVES: This study sought to test the hypothesis that ACCT synergistically promotes cardiac regeneration without provoking immunologic reactions. METHODS: Göttingen swine with experimental ischemic cardiomyopathy were randomized to receive transendocardial injections of allo-MSCs + allo-CSCs (ACCT: 200 million MSCs/1 million CSCs, n = 7), 200 million allo-MSCs (n = 8), 1 million allo-CSCs (n = 4), or placebo (Plasma-Lyte A, n = 6). Swine were assessed by cardiac magnetic resonance imaging and pressure volume catheterization. Immune response was tested by histologic analyses. RESULTS: Both ACCT and allo-MSCs reduced scar size by -11.1 ± 4.8% (p = 0.012) and -9.5 ± 4.8% (p = 0.047), respectively. Only ACCT, but not MSCs or CSCs, prevented ongoing negative remodeling by offsetting increases in chamber volumes. Importantly, ACCT exerted the greatest effect on systolic function, improving the end-systolic pressure-volume relation (+0.98 ± 0.41 mm Hg/ml; p = 0.016). The ACCT group had more phospho-histone H3+ (a marker of mitosis) cardiomyocytes (p = 0.04), and noncardiomyocytes (p = 0.0002) than did the placebo group in some regions of the heart. Inflammatory sites in ACCT and MSC-treated swine contained immunotolerant CD3+/CD25+/FoxP3+ regulatory T cells (p < 0.0001). Histologic analysis showed absent to low-grade inflammatory infiltrates without cardiomyocyte necrosis. CONCLUSIONS: ACCT demonstrates synergistic effects to enhance cardiac regeneration and left ventricular functional recovery in a swine model of chronic ischemic cardiomyopathy without adverse immunologic reaction. Clinical translation to humans is warranted.

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

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).

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.

Firearm injuries due to legal intervention in children and adolescents: a national analysis.

BACKGROUND: Firearm injuries related to legal intervention have come under scrutiny because of recent events. METHODS: The Kids' Inpatient Database (1997-2012) was searched for firearm injuries due to legal interventions (International Classification of Diseases, ninth revision, Clinical Modification E970) requiring inpatient admission in children aged <20 y. Cases were weighted to provide national estimates. The Brady Campaign criteria were used to identify lenient versus strict gun law states. RESULTS: Overall, 275 cases were identified, with a 7.5% mortality rate. Incidence peaked at 1.0 per 100,000 admissions in 2006, significantly increased from a low 0.2 per 100,000 admissions in 1997, P < 0.001. Patients were predominantly male (97%). African Americans (44%) represented the largest racial group, followed by Hispanics (30%) and Caucasians (20%). Mean age was 17.5 ± 2.08 y. Patients were insured by Medicaid (33%) or a private payer (24%); the remainder (43%) was uninsured. Admissions most frequently occurred at urban teaching hospitals (81%). Cases occurred most frequently in the Southern United States (44%), followed by the Western United States (35%). Most patients presented to non-children's hospitals (97%). Mean hospital admission cost was 27,507 ± 40,197 USD, whereas mean charges amounted to 75,905 ± 116,622 USD. Cases mostly occurred in lenient (56%) gun law states, whereas the remainder occurred in strict (41%) and neutral (3%) states. When analyzed by race, Caucasians (16%) had a significantly higher mortality rate when compared with African Americans (5%), P = 0.03. CONCLUSIONS: An analysis of this very specific injury mechanism demonstrates important findings, which are difficult to collect from conventional data sources. Future research will contribute to the objective analysis of this politically charged subject.

Allogeneic Human Mesenchymal Stem Cell Infusions for Aging Frailty.

BACKGROUND: Impaired endogenous stem cell repair capacity is hypothesized to be a biologic basis of frailty. Therapies that restore regenerative capacity may therefore be beneficial. This Phase 1 study evaluated the safety and potential efficacy of intravenous, allogeneic, human mesenchymal stem cell (allo-hMSC)-based therapy in patients with aging frailty. METHODS: In this nonrandomized, dose-escalation study, patients received a single intravenous infusion of allo-hMSCs: 20-million (n = 5), 100-million (n = 5), or 200-million cells (n = 5). The primary endpoint was incidence of any treatment-emergent serious adverse events measured at 1 month postinfusion. The secondary endpoints were functional efficacy domains and inflammatory biomarkers, measured at 3 and 6 months, respectively. RESULTS: There were no treatment-emergent serious adverse events at 1-month postinfusion or significant donor-specific immune reactions during the first 6 months. There was one death at 258 days postinfusion in the 200-million group. In all treatment groups, 6-minute walk distance increased at 3 months (p = .02) and 6 months (p = .001) and TNF-α levels decreased at 6 months (p < .0001). Overall, the 100-million dose showed the best improvement in all parameters, with the exception of TNF-α, which showed an improvement in both the 100- and 200-million groups (p = .0001 and p = .0001, respectively). The 100-million cell-dose group also showed significant improvements in the physical component of the SF-36 quality of life assessment at all time points relative to baseline. CONCLUSIONS: Allo-hMSCs are safe and immunologically tolerated in aging frailty patients. Improvements in functional and immunologic status suggest that ongoing clinical development of cell-based therapy is warranted for frailty.

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.

Randomized Comparison of Allogeneic Versus Autologous Mesenchymal Stem Cells for Nonischemic Dilated Cardiomyopathy: POSEIDON-DCM Trial.

BACKGROUND: Although human mesenchymal stem cells (hMSCs) have been tested in ischemic cardiomyopathy, few studies exist in chronic nonischemic dilated cardiomyopathy (NIDCM). OBJECTIVES: The authors conducted a randomized comparison of safety and efficacy of autologous (auto) versus allogeneic (allo) bone marrow-derived hMSCs in NIDCM. METHODS: Thirty-seven patients were randomized to either allo- or auto-hMSCs in a 1:1 ratio. Patients were recruited between December 2011 and July 2015 at the University of Miami Hospital. Patients received hMSCs (100 million) by transendocardial stem cell injection in 10 left ventricular sites. Treated patients were evaluated at baseline, 30 days, and 3-, 6-, and 12-months for safety (serious adverse events [SAE]), and efficacy endpoints: ejection fraction, Minnesota Living with Heart Failure Questionnaire, 6-min walk test, major adverse cardiac events, and immune biomarkers. RESULTS: There were no 30-day treatment-emergent SAEs. Twelve-month SAE incidence was 28.2% with allo-hMSCs versus 63.5% with auto-hMSCs (p = 0.1004 for the comparison). One allo-hMSC patient developed an elevated (>80) donor-specific calculated panel reactive antibody level. The ejection fraction increased in allo-hMSC patients by 8.0 percentage points (p = 0.004) compared with 5.4 with auto-hMSCs (p = 0.116; allo vs. auto p = 0.4887). The 6-min walk test increased with allo-hMSCs by 37.0 m (p = 0.04), but not auto-hMSCs at 7.3 m (p = 0.71; auto vs. allo p = 0.0168). MLHFQ score decreased in allo-hMSC (p = 0.0022) and auto-hMSC patients (p = 0.463; auto vs. allo p = 0.172). The major adverse cardiac event rate was lower, too, in the allo group (p = 0.0186 vs. auto). Tumor necrosis factor-α decreased (p = 0.0001 for each), to a greater extent with allo-hMSCs versus auto-hMSCs at 6 months (p = 0.05). CONCLUSIONS: These findings demonstrated safety and clinically meaningful efficacy of allo-hMSC versus auto-hMSC in NIDCM patients. Pivotal trials of allo-hMSCs are warranted based on these results. (Percutaneous Stem Cell Injection Delivery Effects on Neomyogenesis in Dilated Cardiomyopathy [PoseidonDCM]; NCT01392625).

Treatment Options for Exposed Calvarium Due to Trauma and Burns.

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.

Pim1 Kinase Overexpression Enhances ckit+ Cardiac Stem Cell Cardiac Repair Following Myocardial Infarction in Swine.

BACKGROUND: Pim1 kinase plays an important role in cell division, survival, and commitment of precursor cells towards a myocardial lineage, and overexpression of Pim1 in ckit+ cardiac stem cells (CSCs) enhances their cardioreparative properties. OBJECTIVES: The authors sought to validate the effect of Pim1-modified CSCs in a translationally relevant large animal preclinical model of myocardial infarction (MI). METHODS: Human cardiac stem cells (hCSCs, n = 10), hckit+ CSCs overexpressing Pim1 (Pim1+; n = 9), or placebo (n = 10) were delivered by intramyocardial injection to immunosuppressed Yorkshire swine (n = 29) 2 weeks after MI. Cardiac magnetic resonance and pressure volume loops were obtained before and after cell administration. RESULTS: Whereas both hCSCs reduced MI size compared to placebo, Pim1+ cells produced a ∼3-fold greater decrease in scar mass at 8 weeks post-injection compared to hCSCs (-29.2 ± 2.7% vs. -8.4 ± 0.7%; p < 0.003). Pim1+ hCSCs also produced a 2-fold increase of viable mass compared to hCSCs at 8 weeks (113.7 ± 7.2% vs. 65.6 ± 6.8%; p <0.003), and a greater increase in regional contractility in both infarct and border zones (both p < 0.05). Both CSC types significantly increased ejection fraction at 4 weeks but this was only sustained in the Pim1+ group at 8 weeks compared to placebo. Both hCSC and Pim1+ hCSC treatment reduced afterload (p = 0.02 and p = 0.004, respectively). Mechanoenergetic recoupling was significantly greater in the Pim1+ hCSC group (p = 0.005). CONCLUSIONS: Pim1 overexpression enhanced the effect of intramyocardial delivery of CSCs to infarcted porcine hearts. These findings provide a rationale for genetic modification of stem cells and consequent translation to clinical trials.

Free Versus Pedicled TRAM Flaps: Cost Utilization and Complications.

INTRODUCTION: Conventionally, free transverse rectus abdominis myocutaneous (fTRAM) flap breast reconstruction has been associated with decreased donor site morbidity and improved flap inset. However, clinical success depends upon more sophisticated technical expertise and facilities. This study aims to characterize postoperative outcomes undergoing free versus pedicled TRAM (pTRAM) flap breast reconstruction. METHODS: Nationwide inpatient sample database (2008-2011) was reviewed for cases of fTRAM (ICD-9-CM 85.73) and pTRAM (85.72) breast reconstruction. Inclusion criteria were females undergoing pTRAM or fTRAM breast reconstruction; males were excluded. We examined demographics, hospital setting, insurance information, patient income, and comorbidities. Clinical endpoints included postoperative complications, length-of-stay (LOS), and total charges (TC). Bivariate/multivariate analyses were performed to identify independent risk factors associated with increased complications and resource utilization. RESULTS: Overall, 21,655 cases were captured. Seventy-percent were Caucasian, 95 % insured, and 72 % treated in an urban teaching hospital. There were 9 pTRAM and 6 fTRAM in-hospital mortalities. On bivariate analysis, the fTRAM cohort was more likely to be obese (OR 1.2), undergo revision (OR 5.9), require hemorrhage control (OR 5.7), suffer hematoma complications (OR 1.9), or wound infection (OR 1.8) (p < 0.003). The pTRAM cohort was more likely to suffer pneumonia (OR 1.6) and pulmonary embolism (OR 2.0) (p < 0.004). Reconstruction type did not affect risk of flap loss or seroma occurrence. TC were higher with fTRAM (p < 0.001). LOS was not affected by procedure type. On risk-adjusted multivariate analysis, fTRAM was an independent risk factor for increased LOS (OR 1.6), TC (OR 1.8), and postoperative complications (OR 1.3) (p < 0.001). CONCLUSION: Free TRAM has an increased risk of postoperative complications and resource utilization versus pTRAM on the current largest risk-adjusted analysis. Further analyses are required to elucidate additional factors influencing outcomes following these procedures. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the A3 online Instructions to Authors. www.springer.com/00266 .

Rebuilding the Damaged Heart: Mesenchymal Stem Cells, Cell-Based Therapy, and Engineered Heart Tissue.

Mesenchymal stem cells (MSCs) are broadly distributed cells that retain postnatal capacity for self-renewal and multilineage differentiation. MSCs evade immune detection, secrete an array of anti-inflammatory and anti-fibrotic mediators, and very importantly activate resident precursors. These properties form the basis for the strategy of clinical application of cell-based therapeutics for inflammatory and fibrotic conditions. In cardiovascular medicine, administration of autologous or allogeneic MSCs in patients with ischemic and nonischemic cardiomyopathy holds significant promise. Numerous preclinical studies of ischemic and nonischemic cardiomyopathy employing MSC-based therapy have demonstrated that the properties of reducing fibrosis, stimulating angiogenesis, and cardiomyogenesis have led to improvements in the structure and function of remodeled ventricles. Further attempts have been made to augment MSCs' effects through genetic modification and cell preconditioning. Progression of MSC therapy to early clinical trials has supported their role in improving cardiac structure and function, functional capacity, and patient quality of life. Emerging data have supported larger clinical trials that have been either completed or are currently underway. Mechanistically, MSC therapy is thought to benefit the heart by stimulating innate anti-fibrotic and regenerative responses. The mechanisms of action involve paracrine signaling, cell-cell interactions, and fusion with resident cells. Trans-differentiation of MSCs to bona fide cardiomyocytes and coronary vessels is also thought to occur, although at a nonphysiological level. Recently, MSC-based tissue engineering for cardiovascular disease has been examined with quite encouraging results. This review discusses MSCs from their basic biological characteristics to their role as a promising therapeutic strategy for clinical cardiovascular disease.

Rationale and design of the allogeneiC human mesenchymal stem cells (hMSC) in patients with aging fRAilTy via intravenoUS delivery (CRATUS) study: A phase I/II, randomized, blinded and placebo controlled trial to evaluate the safety and potential efficacy of allogeneic human mesenchymal stem cell infusion in patients with aging frailty.

Frailty is a syndrome associated with reduced physiological reserves that increases an individual's vulnerability for developing increased morbidity and/or mortality. While most clinical trials have focused on exercise, nutrition, pharmacologic agents, or a multifactorial approach for the prevention and attenuation of frailty, none have studied the use of cell-based therapies. We hypothesize that the application of allogeneic human mesenchymal stem cells (allo-hMSCs) as a therapeutic agent for individuals with frailty is safe and efficacious. The CRATUS trial comprises an initial non-blinded phase I study, followed by a blinded, randomized phase I/II study (with an optional follow-up phase) that will address the safety and pre-specified beneficial effects in patients with the aging frailty syndrome. In the initial phase I protocol, allo-hMSCs will be administered in escalating doses via peripheral intravenous infusion (n=15) to patients allocated to three treatment groups: Group 1 (n=5, 20 million allo-hMSCs), Group 2 (n=5, 100 million allo-hMSCs), and Group 3 (n=5, 200 million allo-hMSCs). Subsequently, in the randomized phase, allo-hMSCs or matched placebo will be administered to patients (n=30) randomly allocated in a 1:1:1 ratio to one of two doses of MSCs versus placebo: Group A (n=10, 100 million allo-hMSCs), Group B (n=10, 200 million allo-hMSCs), and Group C (n=10, placebo). Primary and secondary objectives are, respectively, to demonstrate the safety and efficacy of allo-hMSCs administered in frail older individuals. This study will determine the safety of intravenous infusion of stem cells and compare phenotypic outcomes in patients with aging frailty.

Pediatric papillary thyroid carcinoma: outcomes and survival predictors in 2504 surgical patients.

OBJECTIVE: To evaluate outcomes and predictors of survival of pediatric thyroid carcinoma, specifically papillary thyroid carcinoma. METHODS: SEER was searched for surgical pediatric cases (≤20 years old) of papillary thyroid carcinoma diagnosed between 1973 and 2011. Demographics, clinical characteristics, and survival outcomes were analyzed using standard statistical methods. All papillary types, including follicular variant, were included. RESULTS: A total of 2504 cases were identified. Overall incidence was 0.483/100,000 persons per year with a significant annual percent change (APC) in occurrence of 2.07 % from baseline (P < 0.05). Mean age at diagnosis was 16 years and highest incidence was found in white, female patients ages 15-19. Patients with tumor sizes <1 cm more likely received lobectomies/isthmusectomies versus subtotal/total thyroidectomies [OR = 3.03 (2.12, 4.32); P < 0.001]. Patients with tumors ≥1 cm and lymph node-positive statuses [OR = 99.0 (12.5, 783); P < 0.001] more likely underwent subtotal/total thyroidectomy compared to lobectomy/isthmusectomy. Tumors ≥1 cm were more likely lymph node-positive [OR = 39.4 (16.6, 93.7); p < 0.001]. Mortality did not differ between procedures. Mean survival was 38.6 years and higher in those with regional disease. Disease-specific 30-year survival ranged from 99 to 100 %, regardless of tumor size or procedure. Lymph node sampling did not affect survival. CONCLUSIONS: The incidence of pediatric papillary thyroid cancer is increasing. Females have a higher incidence, but similar survival to males. Tumors ≥1 cm were likely to be lymph node-positive. Although tumors ≥1 cm were more likely to be resected by subtotal/total thyroidectomy, survival was high and did not differ based on procedure.

Surgically Treated Pediatric Nonpapillary Thyroid Carcinoma.

Introduction This study aims to update outcomes and predictors of survival on pediatric thyroid carcinoma, specifically examining pediatric patients with nonpapillary thyroid carcinoma who underwent surgical resection. Methods Surveillance, epidemiology, and end results database were searched for pediatric cases (< 20 years old) of surgically treated nonpapillary thyroid carcinoma diagnosed from 1973 to 2011. Demographics, clinical characteristics, and survival outcomes were analyzed using standard statistical methods. All follicular, medullary, Hürthle-cell, and nonencapsulated sclerosing carcinoma types were included. Results A total of 493 cases were identified. The overall incidence was 0.096/100,000 persons per year. The mean age at diagnosis was 15 years and highest incidence was found in whites, females, and patients aged 15 to 19 years. Most patients had localized (60%) or regional disease (35%) and only 38% received radiation (any type). Subtotal/total thyroidectomy was the most common procedure performed (83%) and 47% had lymph node sampling. The most common histologies were follicular (54%) and medullary (28%). Most tumors were > 2cm in size (63%). Overall 30-year survival was 91% but higher for females (94%, p = 0.02) and for local disease (92%). Disease-specific survival was highest for those with no lymph node sampling and negative lymph nodes. On multivariate analysis for medullary type only stage was an independent prognostic indicator of survival. Gender, age, tumor size, histology, and disease extent were not associated with an increased risk of mortality. Conclusions Incidence of pediatric nonpapillary thyroid cancer is low. Females have a higher incidence but similar survival to males. Stage is the only independent prognostic indicator of survival for patients with medullary thyroid cancer.

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. Significance: Preclinical and clinical studies on cell-based therapy for cardiovascular disease have shown inconsistent results, in part because of variations in study-specific dosages and/or routes of administration (ROA). Future preclinical studies and smaller clinical trials implementing cell-dose and ROA comparisons are warranted before proceeding to pivotal trials.

Synergistic Effects of Combined Cell Therapy for Chronic Ischemic Cardiomyopathy.

BACKGROUND: Both bone marrow-derived mesenchymal stem cells (MSCs) and c-kit(+) cardiac stem cells (CSCs) improve left ventricular remodeling in porcine models and clinical trials. Using xenogeneic (human) cells in immunosuppressed animals with acute ischemic heart disease, we previously showed that these 2 cell types act synergistically. OBJECTIVES: To more accurately model clinical applications for heart failure, this study tested whether the combination of autologous MSCs and CSCs produce greater improvement in cardiac performance than MSCs alone in a nonimmunosuppressed porcine model of chronic ischemic cardiomyopathy. METHODS: Three months after ischemia/reperfusion injury, Göttingen swine received transendocardial injections with MSCs alone (n = 6) or in combination with cardiac-derived CSCs (n = 8), or placebo (vehicle; n = 6). Cardiac functional and anatomic parameters were assessed using cardiac magnetic resonance at baseline and before and after therapy. RESULTS: Both groups of cell-treated animals exhibited significantly reduced scar size (MSCs -44.1 ± 6.8%; CSC/MSC -37.2 ± 5.4%; placebo -12.9 ± 4.2%; p < 0.0001), increased viable tissue, and improved wall motion relative to placebo 3 months post-injection. Ejection fraction (EF) improved (MSCs 2.9 ± 1.6 EF units; CSC/MSC 6.9 ± 2.8 EF units; placebo 2.5 ± 1.6 EF units; p = 0.0009), as did stroke volume, cardiac output, and diastolic strain only in the combination-treated animals, which also exhibited increased cardiomyocyte mitotic activity. CONCLUSIONS: These findings illustrate that interactions between MSCs and CSCs enhance cardiac performance more than MSCs alone, establish the safety of autologous cell combination strategies, and support the development of second-generation cell therapeutic products.

Injury patterns and outcomes following pediatric bicycle accidents.

OBJECTIVES: Other than automobiles, bicycles are connected to more pediatric injuries than any other consumer product. Whereas characterization of injury patterns following motor vehicle accidents has led to safety initiatives and treatment guidelines, knowledge related to bicyclist injuries is lacking. Our purpose is to identify major injury patterns and outcomes associated with pediatric bicycle accidents. METHODS: From January 2000 to December 2012, 1934 consecutive pediatric admissions (≤17 years) at a level I trauma center were retrospectively reviewed for mechanism injury, demographics, and outcomes. Parametric data were analyzed with student's t test and are presented as mean ± standard deviation. Nonparametric data were analyzed with Mann-Whitney-U test and are presented as median (interquartile range). Analysis was performed to recognize injury patterns and outcomes significantly associated with bicycle related accidents. RESULTS: 80 pediatric patients were admitted following bicycle related trauma (4% of all pediatric trauma admissions). The cohort was age 11 ± 4 years, ISS 11 ± 10, 48% black, and 81% male. Injury patterns included 21% isolated head, 21% isolated abdominal, 13% isolated extremity, and 34% multiple injuries. 5% were age 0-4 years, 35% were age 5-9 years, 45% were 10-14 years, and 15% were 15-17 years (p < 0.001). 16% required operative intervention (6% abdominal, 9% orthopedic, 1% vascular). Children under age 6 required an abdominal operation 20% of the time. Length of stay was 2 (4) days with a mortality of 2.5%. CONCLUSIONS: Pediatric bicycle accidents more commonly occur in male children aged 10-14 years. Orthopedic injury is the most frequent overall indication for surgery, yet the youngest children more often required an abdominal operation. LEVEL OF EVIDENCE: Level III.