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  • 1
    Publication Date: 2018-06-16
    Description: Purpose: The cross-talk between tumor cells, myeloid cells, and T cells can play a critical role in tumor pathogenesis and response to immunotherapies. Although the etiology of mesothelioma is well understood, the impact of mesothelioma tumor cells on the surrounding immune microenvironment is less well studied. In this study, the effect of the mesothelioma tumor microenvironment on circulating and infiltrating granulocytes and T cells is investigated. Experimental Design: Tumor tissues and peripheral blood from mesothelioma patients were evaluated for presence of granulocytes, which were then tested for their T-cell suppression potential. Different cocultures of granulocytes and/or mesothelioma tumor cells and/or T cells were set up to identify the mechanism of T-cell inhibition. Results: Analysis of human tumors showed that the mesothelioma microenvironment is enriched in infiltrating granulocytes, which inhibit T-cell proliferation and activation. Characterization of the whole blood at diagnosis identified similar, circulating, immunosuppressive CD11b + CD15 + HLADR – granulocytes at increased frequency compared with healthy controls. Culture of healthy-donor granulocytes with human mesothelioma cells showed that GM-CSF upregulates NOX2 expression and the release of reactive oxygen species (ROS) from granulocytes, resulting in T-cell suppression. Immunohistochemistry and transcriptomic analysis revealed that a majority of mesothelioma tumors express GM-CSF and that higher GM-CSF expression correlated with clinical progression. Blockade of GM-CSF with neutralizing antibody, or ROS inhibition, restored T-cell proliferation, suggesting that targeting of GM-CSF could be of therapeutic benefit in these patients. Conclusions: Our study presents the mechanism behind the cross-talk between mesothelioma tumors and the immune microenvironment and indicates that targeting GM-CSF could be a novel treatment strategy to augment immunotherapy in patients with mesothelioma. Clin Cancer Res; 24(12); 2859–72. ©2018 AACR .
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
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  • 2
    Keywords: OPTIMIZATION ; CANCER ; SYSTEM ; ACCURACY ; RADIATION-THERAPY ; PARAMETERS ; GLAND ; electromagnetic tracking ; MOVING TARGETS ; INTERPLAY
    Abstract: BACKGROUND AND PURPOSE: Scanned-beam interplay with the intrafraction target motion may result in dose deterioration in particle therapy. The magnitude of this effect and the possibilities to mitigate it were investigated for carbon ion prostate treatments. METHODS AND MATERIALS: For 12 prostate cases, 9 carbon ion treatment plans were prepared using 3 scanned-beam settings (spot sizes of 6, 7 and 9 mm and, respectively, raster pitches of 2, 2 and 3 mm) for 3 planning margins (3, 6 and 9 mm). Plans were recomputed in presence of 5 intrafraction prostate motion scenarios with and without intra-beam motion compensation. RESULTS: For 6 mm margin and 7 mm spot, the median (max) CTV D(95%) change was -0.2 (-2.6) pp (percentual points) with pure drift motion, -3.8 (-6.0) pp and -2.8 (-3.1) pp in transient motion scenarios and -4.8 (-7.7) pp and -1.8 (-5.7) pp in mixed motion scenarios. No particular raster setting brought distinct advantage, while planning margin expansion showed statistically significant effects for drift-dominated scenarios. Intra-beam motion compensation yielded improved CTV coverage. CONCLUSION: Intrafraction prostate motion can lead to marked target coverage deterioration, dependent on individual motion patterns, which can be only partially avoided through planning-time countermeasures. Among possible delivery-time countermeasures, intra-beam motion compensation is capable of improving target coverage.
    Type of Publication: Journal article published
    PubMed ID: 24833557
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  • 3
    ISSN: 1365-2559
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Morphometric methods were applied to predict the clinical course of individual patients with breast cancer. Measurement of tumour diameter, assessment of mitotic and cellular indices, and quantitative microscopy of nuclear features were assessed together with nuclear features and histological grades. Of the tumours from 78 patients investigated, 42 had died from metastases within 6.5 years (‘non-survivors’), while the other 36 were alive and well without evidence of metastases at the end of the follow-up period (minimum 6.5 years) (‘survivors’). If the tumours of the 42 non-survivors are compared with those of 36 survivors, there are many reproducible significant differences, the most important being cellularity index and mitotic activity index, followed by quantitative microscopical nuclear parameters and nuclear and histological grade. Discriminant analysis, of the quantitative microscopical data alone showed 82% of all patients to be correctly classified as survivor or non-survivor. By contrast with the axillary lymph node invasion status alone, or the tumour diameter and axillary lymph node status together, 59% and 64% of the patients were predicted correctly as survivor or non-survivor. With a more realistic statistical approach of discriminant analysis, 78% of the patients were classified correctly with quantitative microscopy, in place of 54% with the axillary lymph node status, 56% with the TNM-system and 64% with a combination of TNM system and nuclear and histological grade. Morphometry thus seems possible to predict the outcome of individual patients more accurately than with the usual staging/grading methods. This technique might therefore prove to be useful in the selection of patients for adjuvant chemotherapy.
    Type of Medium: Electronic Resource
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  • 4
    Electronic Resource
    Electronic Resource
    Amsterdam : Elsevier
    Experimental Cell Research 70 (1972), S. 13-16 
    ISSN: 0014-4827
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology , Medicine
    Type of Medium: Electronic Resource
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