Purpose Gliomas are known to induce local and systemic immunosuppression, inhibiting T cell-mediated cytotoxic responses to tumor growth. Tumor-associated macrophages are a significant component of the immune infiltrate in gliomas and may express immunosuppressive surface ligands, such as B7-H1. Experimental Design Tumor and peripheral blood samples from patients with glioblastoma (GBM) were analyzed by flow cytometry to evaluate the expression of B7-H1 in circulating and tumor-infiltrating macrophages. Human monocytes from healthy patients were stimulated with conditioned media from glioma cells to evaluate B7-H1 expression. Production of IL-10 by stimulated monocytes was measured by ELISA, and stimulation with IL-10 alone was evaluated for the ability to induce B7-H1 expression. The effect of inhibiting IL-10 and its receptor on glioma-induced B7-H1 expression in monocytes was evaluated. Results Circulating monocytes in patients with GBM had significantly increased expression of B7-H1 compared to healthy control patients. Tumor-associated macrophages from matched GBM tissue had even greater B7-H1 expression. Treatment of normal monocytes with glioma conditioned media could significantly increase B7-H1 expression. Stimulation of monocytes with conditioned media resulted in substantial production of IL-10 and upregulation of the IL-10 receptor. Stimulation of monocytes with IL-10 alone could significantly increase B7-H1 expression, sufficient to induce T cell apoptosis when co-cultured with stimulated monocytes. Inhibition of IL-10 and the IL-10 receptor could knock down the effect of glioma media on B7-H1 by greater than 50%. Conclusions Gliomas can upregulate B7-H1 expression in circulating monocytes and tumor-infiltrative macrophages through modulation of autocrine/paracrine IL-10 signaling, resulting in an immunosuppressive phenotype.

The HSPPC-96 vaccine is safe and warrants further study of efficacy for the treatment of recurrent GBM. Significant pretreatment lymphopenia may impact the outcomes of immunotherapy and deserves additional investigation.

BackgroundAllelopathy (negative, plant-plant chemical interactions) has been largely studied as an autecological process, often assuming simplistic associations between pairs of isolated species. The growth inhibition of a species in filter paper bioassay enriched with a single chemical is commonly interpreted as evidence of an allelopathic interaction, but for some of these putative examples of allelopathy, the results have not been verifiable in more natural settings with plants growing in soil.Methodology/Principal findingsOn the basis of filter paper bioassay, a recent study established allelopathic effects of m-tyrosine, a component of root exudates of Festuca rubra ssp. commutata. We re-examined the allelopathic effects of m-tyrosine to understand its dynamics in soil environment. Allelopathic potential of m-tyrosine with filter paper and soil (non-sterile or sterile) bioassays was studied using Lactuca sativa, Phalaris minor and Bambusa arundinacea as assay species. Experimental application of m-tyrosine to non-sterile and sterile soil revealed the impact of soil microbial communities in determining the soil concentration of m-tyrosine and growth responses.Conclusions/SignificanceHere, we show that the allelopathic effects of m-tyrosine, which could be seen in sterilized soil with particular plant species were significantly diminished when non-sterile soil was used, which points to an important role for rhizosphere-specific and bulk soil microbial activity in determining the outcome of this allelopathic interaction. Our data show that the amounts of m-tyrosine required for root growth inhibition were higher than what would normally be found in F. rubra ssp. commutata rhizosphere. We hope that our study will motivate researchers to integrate the role of soil microbial communities in bioassays in allelopathic research so that its importance in plant-plant competitive interactions can be thoroughly evaluated.

Object Craniopharyngiomas have a propensity to recur after resection, potentially causing death through their aggressive local behavior in their critical site of origin. Recent data suggest that subtotal resection (STR) followed by adjuvant radiotherapy (XRT) may be an appealing substitute for gross-total resection (GTR), providing similar rates of tumor control without the morbidity associated with aggressive resection. Here, the authors summarize the published literature regarding rates of tumor control with various treatment modalities for craniopharyngiomas. Methods The authors performed a comprehensive search of the English language literature to identify studies publishing outcome data on patients undergoing surgery for craniopharyngioma. Rates of progression-free survival (PFS) and overall survival (OS) were determined through Kaplan-Meier analysis. Results There were 442 patients who underwent tumor resection. Among these patients, GTR was achieved in 256 cases (58%), STR in 101 cases (23%), and STR+XRT in 85 cases (19%). The 2- and 5-year PFS rates for the GTR group versus the STR+XRT group were 88 versus 91%, and 67 versus 69%, respectively. The 5- and 10-year OS rates for the GTR group versus the STR+XRT group were 98 versus 99%, and 98 versus 95%, respectively. There was no significant difference in PFS (log-rank test) or OS with GTR (log-rank test). Conclusions Given the relative rarity of craniopharyngioma, this study provides estimates of outcome for a variety of treatment combinations, as not all treatments are an option for all patients with these tumors.

Some invasive plant species appear to strongly suppress neighbors in their nonnative ranges but much less so in their native range. We found that in the field in its native range in Mexico, the presence of Ageratina adenophora, an aggressive Neotropical invader, was correlated with higher plant species richness than found in surrounding plant communities where this species was absent, suggesting facilitation. However, in two nonnative ranges, China and India, A. adenophora canopies were correlated with much lower species richness than the surrounding communities, suggesting inhibition. Volatile organic compound (VOC) signals may contribute to this striking biogeographical difference and the invasive success of A. adenophora. In controlled experiments volatiles from A. adenophora litter caused higher mortality of species native to India and China, but not of species native to Mexico. The effects of A. adenophora VOCs on seedling germination and growth did not differ between species from the native range and species from the nonnative ranges of the invader. Litter from A. adenophora plants from nonnative populations also produced VOCs that differed quantitatively in the concentrations of some chemicals than litter from native populations, but there were no chemicals unique to one region. Biogeographic differences in the concentrations of some volatile compounds between ranges suggest that A. adenophora may be experiencing selection on biochemical composition in its nonnative ranges.

Purpose: Upregulation of programmed death-ligand 1 (PD-L1) on circulating and tumor-infiltrating myeloid cells is a critical component of GBM-mediated immunosuppression that has been associated with diminished response to vaccine immunotherapy and poor survival. Although GBM-derived soluble factors have been implicated in myeloid PD-L1 expression, the identity of such factors has remained unknown. This study aimed to identify factors responsible for myeloid PD-L1 upregulation as potential targets for immune modulation.Experimental Design: Conditioned media from patientderived GBM explant cell cultures was assessed for cytokine expression and utilized to stimulate na€ ve myeloid cells. Myeloid PD-L1 induction was quantified by flow cytometry. Candidate cytokines correlated with PD-L1 induction were evaluated in tumor sections and plasma for relationships with survival and myeloid PD-L1 expression. The role of identified cytokines on immunosuppression and survival was investigated in vivo utilizing immunocompetent C57BL/6 mice bearing syngeneic GL261 and CT-2A tumors.Results: GBM-derived IL6 was identified as a cytokine that is necessary and sufficient for myeloid PD-L1 induction in GBM through a STAT3-dependent mechanism. Inhibition of IL6 signaling in orthotopic murine glioma models was associated with reduced myeloid PD-L1 expression, diminished tumor growth, and increased survival. The therapeutic benefit of anti-IL6 therapy proved to be CD8 þ T-cell dependent, and the antitumor activity was additive with that provided by programmed death-1 (PD-1)-targeted immunotherapy.Conclusions: Our findings suggest that disruption of IL6 signaling in GBM reduces local and systemic myeloid-driven immunosuppression and enhances immune-mediated antitumor responses against GBM. Ã , P < 0.05; ÃÃ , P < 0.01; ÃÃÃ , P < 0.001; ÃÃÃÃ , P < 0.0001.Lamano et al. Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis):

We coordinated biogeographical comparisons of the impacts of an exotic invasive tree in its native and non-native ranges with a congeneric comparison in the non-native range. Prosopis juliflora is taxonomically complicated and with P. pallida forms the P. juliflora complex. Thus we sampled P. juliflora in its native Venezuela, and also located two field sites in Peru, the native range of Prosopis pallida. Canopies of Prosopis juliflora, a native of the New World but an invader in many other regions, had facilitative effects on the diversity of other species in its native Venezuela, and P. pallida had both negative and positive effects depending on the year, (overall neutral effects) in its native Peru. However, in India and Hawaii, USA, where P. juliflora is an aggressive invader, canopy effects were consistently and strongly negative on species richness. Prosopis cineraria, a native to India, had much weaker effects on species richness in India than P. juliflora. We carried out multiple congeneric comparisons between P. juliflora and P. cineraria, and found that soil from the rhizosphere of P. juliflora had higher extractable phosphorus, soluble salts and total phenolics than P. cineraria rhizosphere soils. Experimentally applied P. juliflora litter caused far greater mortality of native Indian species than litter from P. cineraria. Prosopis juliflora leaf leachate had neutral to negative effects on root growth of three common crop species of north-west India whereas P. cineraria leaf leachate had positive effects. Prosopis juliflora leaf leachate also had higher concentrations of total phenolics and L-tryptophan than P. cineraria, suggesting a potential allelopathic mechanism for the congeneric differences. Our results also suggest the possibility of regional evolutionary trajectories among competitors and that recent mixing of species from different trajectories has the potential to disrupt evolved interactions among native species.

Avoidance of facial nerve palsy is one of the major goals of vestibular schwannoma (VS) microsurgery. In this study, we examined the significance of previously implicated prognostic factors (age, tumor size, the extent of resection and the surgical approach) on post-operative facial nerve function. We selected all VS patients from prospectively collected database (1984–2009) who underwent microsurgical resection as their initial treatment for histopathologically confirmed VS. The effect of variables such as surgical approach, tumor size, patient age and extent of resection on rates facial nerve dysfunction after surgery, were analyzed using multivariate logistic regression. Patients with preoperative facial nerve dysfunction (House-Brackman [HB] score 3 or higher) were excluded, and HB grade of 1 or 2 at the last follow-up visit was defined as “facial nerve preservation.” A total of 624 VS patients were included in this study. Multivariate logistic regression analysis found that only pre-operative tumor size significantly predicted poorer facial nerve outcome for patients followed-up for ≥6 and ≥12 months (OR 1.27, 95% CI 1.09–1.49, p < 0.01; OR 1.35, 95% CI 1.10–1.67, P < 0.01, respectively). We found no significant relationship between facial nerve function and age, extent of resection, surgical approach, or tumor size (when extent of resection and surgical approach were included in the regression analysis). Because facial nerve palsy is a debilitating and psychologically devastating condition for the patient, we suggest altering surgical aggressiveness in patients with unfavorable tumor anatomy, particularly in cases with large tumors where overaggressive resection might subject the patient to unwarranted risk. Residual disease can be followed and controlled with radiosurgery if interval growth is noted.