Prognostic value of pathologic fracture in patients with high grade localized osteosarcoma: A systemic review and meta‐analysis of cohort studies

Consensus has not been reached regarding the ability of pathologic fracture to predict local recurrence and survival in osteosarcoma. We aim to review the available evidence to examine the association between pathologic fracture and osteosarcoma prognosis. A comprehensive literature search for relevant studies published until March 2014 was performed using PubMed, Cochrane and Web of Science. The studies investigating pathologic fracture of osteosarcoma patients were systematically analyzed. The overall relative risk (RR) was estimated using a fixed‐effect model or random‐effect model according to heterogeneity between the trials. We included nine cohort studies involving 2,187 patients (311 with pathologic fracture and 1,876 without fracture) for the analysis of survival rate and local recurrence. Studies were assessed for quality using the Newcastle–Ottawa Assessment Scale. In the fixed‐effects model, the meta‐analysis showed that pathologic fracture in osteosarcoma patients predicted poor 3‐year overall survival (OS) (RR = 1.86, 95% CI: 1.37–2.53, p < 0.001) and 5‐year OS (RR = 1.34, 95% CI: 1.06–1.70, p = 0.016). Similarly, pathologic fracture was significantly correlated with worse 3‐year event free survival (EFS) (RR = 1.52, 95% CI: 1.21–1.92, p < 0.001) and 5‐year EFS (RR = 1.24, 95% CI: 1.03–1.49, p = 0.021), whereas no significant association was noted with local recurrence (RR = 1.30, 95% CI: 0.84–2.02, p = 0.233). The meta‐analysis confirmed that pathologic fracture in osteosarcoma was a prognostic marker for both OS and EFS but not for local recurrence. © 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:131–139, 2015.     

CD146 as a new marker for an increased chondroprogenitor cell sub‐population in the later stages of osteoarthritis

Cartilage‐derived mesenchymal stem cells (MSCs) have been isolated with different methods. In this study lateral and medial femoral condyles were respectively collected from patients with late‐stage osteoarthritis during the total knee arthroplasty. After digestion of the cartilage tissues with type II collagenase and analysis by fluorescence‐activated cell sorting (FACS) with CD146, a chondroprogenitor cell sub‐population were isolated and purified. The expression of other MSC‐associated markers in the CD146⁺ chondroprogenitors was analyzed by flow cytometry. Multi‐lineage differentiation capacity of CD146⁺ chondroprogenitors was compared with that of unsorted chondrocytes and adipose‐derived MSCs (ADMSCs). Higher percentage of CD146⁺ chondroprogenitors isolated from the medial femoral condyles was observed than that from the lateral. CD146⁺ chondroprogenitors expressed high levels of MSC‐specific surface antigens, and showed higher chondrogenesis capacity than ADMSCs and unsorted chondrocytes in a 3D cell pellet culture model. Thus CD146 might be a new cell surface marker for cartilage progenitor cell population in the late‐stage osteoarthritis. © 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:84–91, 2015.     

BMP2 Regulation of CXCL12 Cellular,Temporal, and Spatial Expression Is Essential During Fracture Repair

The cellular and humoral responses that orchestrate fracture healing are still elusive. Here we report that bone morphogenic protein 2 (BMP2)‐dependent fracture healing occurs through a tight control of chemokine C‐X‐C motif‐ligand‐12 (CXCL12) cellular, spatial, and temporal expression. We found that the fracture repair process elicited an early site‐specific response of CXCL12⁺‐BMP2⁺ endosteal cells and osteocytes that was not present in unfractured bones and gradually decreased as healing progressed. Absence of a full complement of BMP2 in mesenchyme osteoprogenitors (BMP2^cKO/+) prevented healing and led to a dysregulated temporal and cellular upregulation of CXCL12 expression associated with a deranged angiogenic response. Healing was rescued when BMP2^cKO/+ mice were systemically treated with AMD3100, an antagonist of CXCR4 and agonist for CXCR7 both receptors for CXCL12. We further found that mesenchymal stromal cells (MSCs), capable of delivering BMP2 at the endosteal site, restored fracture healing when transplanted into BMP2^cKO/+ mice by rectifying the CXCL12 expression pattern. Our in vitro studies showed that in isolated endosteal cells, BMP2, while inducing osteoblastic differentiation, stimulated expression of pericyte markers that was coupled with a decrease in CXCL12. Furthermore, in isolated BMP2^cKO/cKO endosteal cells, high expression levels of CXCL12 inhibited osteoblastic differentiation that was restored by AMD3100 treatment or coculture with BMP2‐expressing MSCs that led to an upregulation of pericyte markers while decreasing platelet endothelial cell adhesion molecule (PECAM). Taken together, our studies show that following fracture, a CXCL12⁺‐BMP2⁺ perivascular cell population is recruited along the endosteum, then a timely increase of BMP2 leads to downregulation of CXCL12 that is essential to determine the fate of the CXCL12⁺‐BMP2⁺ to osteogenesis while departing their supportive role to angiogenesis. Our findings have far‐reaching implications for understanding mechanisms regulating the selective recruitment of distinct cells into the repairing niches and the development of novel pharmacological (by targeting BMP2/CXCL12) and cellular (MSCs, endosteal cells) interventions to promote fracture healing. © 2015 American Society for Bone and Mineral Research.     

DEGS2 polymorphism associated with cognition in schizophrenia is associated with gene expression in brain

A genome-wide association study of cognitive deficits in patients with schizophrenia in Japan found association with a missense genetic variant (rs7157599, Asn8Ser) in the delta(4)-desaturase, sphingolipid 2 (DEGS2) gene. A replication analysis using Caucasian samples showed a directionally consistent trend for cognitive association of a proxy single-nucleotide polymorphism (SNP), rs3783332. Although the DEGS2 gene is expressed in human brain, it is unknown how DEGS2 expression varies during human life and whether it is affected by psychiatric disorders and genetic variants. To address these questions, we examined DEGS2 messenger RNA using next-generation sequencing in postmortem dorsolateral prefrontal cortical tissue from a total of 418 Caucasian samples including patients with schizophrenia, bipolar disorder and major depressive disorder. DEGS2 is expressed at very low levels prenatally and increases gradually from birth to adolescence and consistently expressed across adulthood. Rs3783332 genotype was significantly associated with the expression across all subjects (F_3,348=10.79, P=1.12 × 10⁻³), particularly in control subjects (F_1,87=13.14, P=4.86 × 10⁻⁴). Similar results were found with rs715799 genotype. The carriers of the risk-associated minor allele at both loci showed significantly lower expression compared with subjects homozygous for the non-risk major allele and this was a consistent finding across all diagnostic groups. DEGS2 expression showed no association with diagnostic status after correcting for multiple testing (P>0.05). Our findings demonstrate that a SNP showing genome-wide association study significant association with cognition in schizophrenia is also associated with regulation of DEGS2 expression, implicating a molecular mechanism for the clinical association.     

Efficacy of and Patient Compliance with a Ketogenic Diet in Adults with Intractable Epilepsy: A Meta-Analysis

Background and Purpose

Despite the successful use of a ketogenic diet in pediatric epilepsy, its application in adults has been limited. The aim of this meta-analysis was to summarize the findings of relevant published studies in order to identify the efficacy of and compliance with a ketogenic diet and its main subtypes (i.e., classic ketogenic diet and modified Atkins diet) in adults with intractable epilepsy, and to provide useful information for clinical practice.

Methods

Electronic searches of PubMed, EMBASE, Google Scholar, and the ISI Web of Science were conducted to identify studies of the efficacy of and patient compliance with a ketogenic diet in adults with intractable epilepsy; the included studies were reviewed. Meta-analyses were performed using STATA to determine combined efficacy rates and combined rates of compliance with the ketogenic diet and its main subtypes.

Results

In total, 12 studies qualified for inclusion, and data from 270 patients were evaluated.The results of the meta-analysis revealed combined efficacy rates of all types of ketogenic diet, a classical ketogenic diet, and a modified Atkins diet were 42%, 52%, and 34%, respectively; the corresponding combined compliance rates were 45%, 38%, and 56%.

Conclusions

The results indicate that a ketogenic diet is a promising complementary therapy in adult intractable epilepsy, and that while a classical ketogenic diet may be more effective, adult patients are likely to be less compliant with it than with a modified Atkins diet.