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2.  Bone Mesenchymal Stem Cells with Growth Factors Successfully Treat Nonunions and Delayed Unions 
HSS Journal  2015;11(2):104-111.
Background
While the gold standard of treatment of nonunion is open autologous bone grafting, studies have shown that injecting bone marrow aspirate concentrates (BMAC) is effective in treating tibial nonunions with fracture gaps less than 5 mm.
Questions/Purposes
We aim to demonstrate that combining BMAC with osteoinductive agents can effectively treat delayed or nonunion regardless of fracture gap size, nonunion site, or osteoinductive agent used.
Methods
In this non-randomized retrospective-prospective cohort study, 49 patients with tibial nonunion met the inclusion criteria and underwent BMAC injection with demineralized bone matrix (DBM) and/or recombinant human bone morphogenic protein-2 (rhBMP-2). Radiologic healing of the fracture was the primary outcome. Patients were followed until radiographic union was achieved or another procedure was performed. Radiographic healing was defined as bridging of three out of four cortices on anteroposterior and lateral films.
Results
There was no difference in the healing rate (p = 0.81) between patients with fracture gaps less than and greater than 5 mm. On multivariate analysis, the use of rhBMP-2 was associated with a lower healing rate compared to DBM (p = 0.036). Patients who underwent early intervention (within 6 months of fixation) had higher union rates (p = 0.04).
Conclusion
This study shows that percutaneous BMAC injection combined with either DBM and/or rhBMP-2 is a safe and effective treatment for delayed or nonunion regardless of the fracture gap size or fracture site. DBM may be superior to rhBMP-2 in this procedure.
Electronic supplementary material
The online version of this article (doi:10.1007/s11420-015-9432-1) contains supplementary material, which is available to authorized users.
doi:10.1007/s11420-015-9432-1
PMCID: PMC4481261  PMID: 26140028
modified Hernigou technique; nonunion; delayed union; BMAC (concentrated autogenous iliac crest bone marrow aspirate); demineralized bone matrix; bone morphogenic protein
4.  IT-17ONO-AE3-208 INHIBITS MYELOID-DERIVED SUPPRESSOR CELLS AND GLIOMA GROWTH 
Neuro-Oncology  2014;16(Suppl 5):v113.
Myeloid-Derived Suppressor Cells (MDSCs) heavily infiltrate in a variety of solid tumors and suppress anti-tumor T-cell activity. Our recent studies have demonstrated the ability of monocytic, Ly6C+ MDSCs to promote glioma growth through the activation of cyclooxygenase (COX)-2 pathway, which is responsible for plostaglandin-synthesis. ONO-AE3-208 is an antagonist of the prostaglandin E (EP)-4 receptor, which is an important positive feedback regulator of the COX-2 pathway. We thus examined the ability of ONO-AE3-208 to suppress MDSC activity in gliomas. ONO-AE3-208 treatment in mice bearing established GL261-quad glioma in the brain resulted in complete and persistent rejection of the tumors. Flow cytometric analysis revealed that gliomas in the ONO-AE3-208-treated mice were infiltrated by fewer numbers of Ly6C+ MDSCs compared with non-treated animals. We subsequently isolated glioma-infiltrating Ly6C+ MDSCs by flow-sorting to address their functions. RT-PCR analysis revealed that the Ly6C+ MDSCs derived from ONO-AE3-208 treated mice expressed lower levels of the Arg1 and Cox2 expression compared to control animals. Consistently, brain infiltrating leukocytes in ONO-AE3-208 treated tumor-bearing mice demonstrated enhanced Ifng expression compared with control mice, suggestive of enhanced T-cell activity. Importantly, ONO-AE3-208 inhibited glioma growth and promoted immune activity in 2 additional murine glioma models: the Sleeping Beauty de novo glioma model and the SB28 glioma cell line model. Our data demonstrate that ONO-AE3-208 may be useful in the treatment of glioma patients to suppress Ly6C+ MDSCs and promote anti-tumor immunity.
doi:10.1093/neuonc/nou258.15
PMCID: PMC4218233
5.  IT-33USE OF IFN-ALPHA AND POLY-ICLC AS CHEMOKINE MODULATORS FOR IMMUNOTHERAPY IN GLIOMAS 
Neuro-Oncology  2014;16(Suppl 5):v117.
Chemokines are known to play an integral role in the cellular trafficking of the immune system, which has important implications in immunotherapy of cancers. Expression of CXCL10/IP10 and CCL5/RANTES has been shown to correlate with increased infiltration of effector T cells and natural killer (NK) cells; conversely expression of CCL22/MDC has been associated with suppression of the adaptive immune response through recruitment of regulatory T cells. Our study evaluated the effects of polyinosinic polycytidylic acid stabilized with lysine and carboxymethylcellulose (poly-ICLC) and IFN-alpha individually and in combination on the expression of chemokines in glioma tissue samples and in glioma cell lines cocultured with myeloid cells to simulate the tumor microenvironment. We found that IFNα as a single agent produced the greatest increase in the expression of CCL5 and CXCL10 while minimizing the expression of CCL22. The addition of poly-ICLC further increased expression of CCL5 and CXCL10. Patient glioma samples had heterogeneous chemokine expression but demonstrated a similar pattern of expression of chemokines to the coculture and cell lines examined. Our findings support the use of IFN-alpha with poly-ICLC as a potential immunotherapy adjuvant for patients with gliomas.
doi:10.1093/neuonc/nou258.31
PMCID: PMC4218251
6.  NI-70STEREOTACTIC BIOPSY WITH AND WITHOUT INTRAOPERATIVE MRI 
Neuro-Oncology  2014;16(Suppl 5):v153-v154.
BACKGROUND: Intraoperative magnetic imaging (iMRI) has been described as a useful adjunct for stereotactic brain biopsy, however, there is limited data demonstrating how this technology performs compared to biopsies done without intraoperative imaging. OBJECTIVE: To compare the results of stereotactic biopsies done with "conventional frameless stereotaxy" with those done using iMRI guidance. METHODS: A retrospective review of 93 frameless stereotactic brain biopsies from 91 patients was done. 21 cases had surgery with iMRI (PoleStar N20, Medtronic Surgical Technologies) and in 72 cases the StealthStation (Medtronic) was used. We analyzed the surgery time, lesion cross sectional area, and diagnostic yield of biopsies. RESULTS: All but one patient in the iMRI group had a diagnosis made by biopsy. The one exception was in a patient who received steroids before surgery, and in whom lesion reduction raised suspicion for lymphoma. Of biopsies performed without iMRI, 6 out of 72 patients (8.3%) did not get a diagnosis (in 3 because of inadequate sample size). These results approached significance (P = 0.58). There was 1 mortality from an iMRI biopsy case, however the iMRI itself was not utilized in this case to confirm cannula placement due to contact of the cannula with the gantry. Use of iMRI for biopsies resulted in longer surgery times compared to cases without its use; median times of 1.83 and 1.2 hours were found respectively (P < 0.001). Another consideration in our experience is that iMRI guided biopsies generally were smaller lesions with a median axial cross-sectional area of 7.8 cm, where cases without iMRI had a median axial cross-sectional area of 9.36 cm. CONCLUSION: Stereotactic biopsy with iMRI is more likely to yield a diagnosis than surgery done without iMRI. The extra time required - slightly over a half hour - is justified by this improved yield.
doi:10.1093/neuonc/nou264.68
PMCID: PMC4218398
7.  The COPD genetic association compendium: a comprehensive online database of COPD genetic associations 
Human Molecular Genetics  2009;19(3):526-534.
Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide. COPD is thought to arise from the interaction of environmental exposures and genetic susceptibility, and major research efforts are underway to identify genetic determinants of COPD susceptibility. With the exception of SERPINA1, genetic associations with COPD identified by candidate gene studies have been inconsistently replicated, and this literature is difficult to interpret. We conducted a systematic review and meta-analysis of all population-based, case–control candidate gene COPD studies indexed in PubMed before 16 July 2008. We stored our findings in an online database, which serves as an up-to-date compendium of COPD genetic associations and cumulative meta-analysis estimates. On the basis of our systematic review, the vast majority of COPD candidate gene era studies are underpowered to detect genetic effect odds ratios of 1.2–1.5. We identified 27 genetic variants with adequate data for quantitative meta-analysis. Of these variants, four were significantly associated with COPD susceptibility in random effects meta-analysis, the GSTM1 null variant (OR 1.45, CI 1.09–1.92), rs1800470 in TGFB1 (0.73, CI 0.64–0.83), rs1800629 in TNF (OR 1.19, CI 1.01–1.40) and rs1799896 in SOD3 (OR 1.97, CI 1.24–3.13). In summary, most COPD candidate gene era studies are underpowered to detect moderate-sized genetic effects. Quantitative meta-analysis identified four variants in GSTM1, TGFB1, TNF and SOD3 that show statistically significant evidence of association with COPD susceptibility.
doi:10.1093/hmg/ddp519
PMCID: PMC2798725  PMID: 19933216

Results 1-7 (7)