Abstract-Multipotent neural crest cells (NCCs) are a major extracardiac component of cardiovascular development.Although recognized as contributing cells to the arterial valves at early developmental stages, NCC persistence in the valves at later times or in the adult heart is controversial. We analyzed NCC persistence and contributions to both semilunar and atrioventricular (AV) valves in the mature heart. Two NCC-specific promoters driving Cre recombinase, Wnt1-Cre and P0-Cre, were mated with floxed reporter mice, R26R or CAG-CAT-EGFP, to map NCC fate. Hearts were analyzed before aorticopulmonary (AP) septation through adult stages. As previously demonstrated, strong NCC labeling was detected in ventral and dorsal outflow cushions before AP septation. In contrast to previous reports, we found that substantial numbers of labeled cells persisted in the semilunar valves in late fetal, neonatal, and adult hearts. Furthermore, NCCs were also found in the AV valves, almost exclusively in the septal leaflets. NCCs in the AV valves expressed melanocytic and neurogenic markers. However, cells labeled in the proximal cardiac conduction system exhibited neurogenic and gliagenic markers, whereas some NCCs expressed no differentiation specific markers. These results suggest that cardiac NCCs contribute to the mature valves and the cardiac conduction system and retain multipotent characteristics late in development.

BACKGROUNDBecause the efficacy and safety of pazopanib in Japanese patients with soft tissue sarcoma (STS) had not been evaluated previously in a large‐scale cohort, the authors investigated the efficacy and safety of pazopanib in 156 Japanese patients with relapsed STS. This was a retrospective study based on the collection of real‐life, postmarketing surveillance data.METHODSPatients received pazopanib with the objective of treating local recurrence (n = 20), metastasis (n = 104), and both (n = 32). The patient median age was 53.8 years. The primary objective of this study was to clarify the efficacy of pazopanib for patients with STS.RESULTSThe median treatment duration was 28.7 weeks, and the average dose intensity of pazopanib was 609 mg. Adverse events occurred in 127 patients (81.4%). In addition to the main common toxicities, such as hypertension and liver disorder, pneumothorax (n = 11) and thrombocytopenia (n = 16) also were observed. The median progression‐free survival for all patients was 15.4 weeks. The median progression‐free survival for patients with leiomyosarcoma, synovial sarcoma, undifferentiated pleomorphic sarcoma, and liposarcoma was 18.6 weeks, 16.4 weeks, 15.3 weeks, and 8 weeks, respectively. The median survival for all patients was 11.2 months. The median survival for patients with leiomyosarcoma, synovial sarcoma, undifferentiated pleomorphic sarcoma, and liposarcoma was 20.1 months, 10.6 months, 9.5 months, and 7.3 months, respectively.CONCLUSIONSThere were apparent differences in the efficacy of pazopanib treatment among histologic types of STS. Pazopanib treatment is a new treatment option; however, adverse events like pneumothorax and thrombocytopenia, which did not occur frequently in the PALETTE study (pazopanib for metastatic soft‐tissue sarcoma), should be taken into consideration. Cancer 2016;122:1408‐16. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.

Study DesignPreliminary clinical trial.PurposeTo determine the safety and initial efficacy of intradiscal injection of autologous platelet-rich plasma (PRP) releasate in patients with discogenic low back pain.Overview of LiteraturePRP, which is comprised of autologous growth factors and cytokines, has been widely used in the clinical setting for tissue regeneration and repair. PRP has been shown in vitro and in vivo to potentially stimulate intervertebral disc matrix metabolism.MethodsInclusion criteria for this study included chronic low back pain without leg pain for more than 3 months; one or more lumbar discs (L3/L4 to L5/S1) with evidence of degeneration, as indicated via magnetic resonance imaging (MRI); and at least one symptomatic disc, confirmed using standardized provocative discography. PRP releasate, isolated from clotted PRP, was injected into the center of the nucleus pulposus. Outcome measures included the use of a visual analog scale (VAS) and the Roland-Morris Disability Questionnaire (RDQ), as well as X-ray and MRI (T2-quantification).ResultsData were analyzed from 14 patients (8 men and 6 women; mean age, 33.8 years). The average follow-up period was 10 months. Following treatment, no patient experienced adverse events or significant narrowing of disc height. The mean pain scores before treatment (VAS, 7.5±1.3; RDQ, 12.6±4.1) were significantly decreased at one month, and this was generally sustained throughout the observation period (6 months after treatment: VAS, 3.2±2.4, RDQ; 3.6±4.5 and 12 months: VAS, 2.9±2.8; RDQ, 2.8±3.9; p<0.01, respectively). The mean T2 values did not significantly change after treatment.ConclusionsWe demonstrated that intradiscal injection of autologous PRP releasate in patients with low back pain was safe, with no adverse events observed during follow-up. Future randomized controlled clinical studies should be performed to systematically evaluate the effects of this therapy.

MRI shows features which were helpful for differentiating MPNST from NF.

Noonan syndrome (NS) is an autosomal dominant disorder characterized by a wide spectrum of defects, which most frequently include proportionate short stature, craniofacial anomalies, and congenital heart disease (CHD). NS is the most common nonchromosomal cause of CHD, and 80%-90% of NS patients have cardiac involvement. Mutations within the protein tyrosine phosphatase Src homology region 2, phosphatase 2 (SHP2) are responsible for approximately 50% of the cases of NS with cardiac involvement. To understand the developmental stage-and cell type-specific consequences of the NS SHP2 gain-of-function mutation, Q79R, we generated transgenic mice in which the mutated protein was expressed during gestation or following birth in cardiomyocytes. Q79R SHP2 embryonic hearts showed altered cardiomyocyte cell cycling, ventricular noncompaction, and ventricular septal defects, while, in the postnatal cardiomyocyte, Q79R SHP2 expression was completely benign. Fetal expression of Q79R led to the specific activation of the ERK1/2 pathway, and breeding of the Q79R transgenics into ERK1/2-null backgrounds confirmed the pathway's necessity and sufficiency in mediating mutant SHP2's effects. Our data establish the developmental stage-specific effects of Q79R cardiac expression in NS; show that ablation of subsequent ERK1/2 activation prevents the development of cardiac abnormalities; and suggest that ERK1/2 modulation could have important implications for developing therapeutic strategies in CHD.

BACKGROUND:The aim of this study was to determine whether circulating C-reactive protein (CRP) levels before treatment predict the overall survival and disease-free survival in soft tissue sarcoma patients. METHODS: A total of 102 primary soft tissue sarcoma patients from 2003 to 2009 were retrospectively reviewed. The CRP levels were obtained before treatment for all patients. The patients who presented with metastases at diagnosis were excluded from this study. RESULTS: Elevated CRP levels were seen in 18 patients. The tumor histological grade and American Joint Committee on Cancer stage in the patients with elevated CRP levels were significantly higher than those in patients with normal CRP levels. Patients with elevated CRP levels before initial treatment had a poorer overall survival than patients with normal CRP levels (P ¼ .01). The overall survival estimates at 3 and 5 years were 75.3% and 53.8%, respectively, versus 90.3% and 81.3%, respectively. Patients with elevated CRP levels before initial treatment had poorer event-free survival after initial treatment than patients with normal CRP levels (P < .001). The event-free survival estimates at 2 and 5 years were 53.2% and 33.2%, respectively, versus 83.2% and 81.3%, respectively. A multivariate analysis also showed the preoperative CRP level to be an independent predictor of events. CONCLUSIONS:The pretreatment serum CRP level may be a marker of aggressive tumor characteristics. Pretreatment elevated CRP levels were found to be a poor prognostic factor for overall survival in a univariate analysis, and for disease-free survival in a multivariate analysis, for soft tissue sarcoma patients.

BACKGROUND: The authors retrospectively evaluated the impact of lung radiofrequency (RF) ablation on survival in patients with lung metastases from musculoskeletal sarcomas. METHODS: Lung RF ablation was done under the real‐time computed tomography (CT) fluoroscopy. Safety, local tumor progression, and survival were evaluated in 2 institutions. RESULTS: Lung RF ablation was performed in 20 consecutive patients. The mean maximum tumor diameter was 14 ± 9 mm (range, 5‐40 mm) and the mean tumor number 7 ± 6 (range, 1‐18) per patient. Pneumothorax requiring chest tube placement developed in 24 of 63 RF sessions (38%). During the mean follow‐up period of 18 months (range, 7 months to 54 months), 9 of 20 patients died of lung tumor progression. The 1‐ and 3‐year survival rates from RF ablation were 58% (95% confidence interval [CI], 33.3‐82.6%) and 29% (95% CI, 0‐59.9%) with a median survival time of 12.9 months in all patients. Ablation of all lung tumors was the only significantly better prognostic factors in both the univariate analysis and the multivariate analyses. The 1‐ and 3‐year survival rates were 88.9% (95% CI, 69.3%‐100%) and 59.2% (95% CI, 10.2%‐100%) in 11 patients with complete tumor ablation. CONCLUSIONS: Lung RF ablation is a safe and useful therapeutic option for selected patients. (R#1) Prognostic factors identified in our study will help to stratify those patients who may benefit from lung RF ablation. Cancer 2009. © 2009 American Cancer Society.

A gain of function mutation in SHP2, a protein phosphatase encoded by PTPN11, causes Noonan syndrome (NS), which is characterized in part by developmental deficits in both the cardiac and skull fields. Previously, we found that expression of the mutated protein SHP2 Q79R in the heart led to a phenotypic presentation that mimicked some aspects of NS and that this was dependent upon activation of the ERK1/2 pathway. To understand the role that ERK1/2 signaling plays in skull development through signaling in the neural crest, we explored the consequences of Q79R expression in neural crest cells, which contribute to a subset of the bony and cartilaginous structures of the skull. Hyperactivation of ERK1/2 led to craniofacial defects that included smaller skull lengths, greater inner canthal distances, and taller frontal bone heights. In proportion to the smaller skull length, mandibular bone length was also reduced. Inhibition of ERK1/2 hyperactivity as a result of Q79R expression was achieved by injection of the MAPK/ ERK kinase inhibitor U0126 during pregnancy. The drug effectively decreased the severity of the craniofacial defects and restored normal skull shape and fontanelle closure. X-ray computer-assisted microtomography analysis of the head confirmed that decreasing ERK1/2 activity led to an abrogation of the craniofacial deficits and brain shape changes that presented in the mice. These data show that normal ERK1/2 signaling in the neural crest is imperative for normal craniofacial development and offer insight into how the heart and craniofacial developmental fields might be affected in some congenital syndromic presentations.congenital disease ͉ skull ͉ SHP2 ͉ neural crest