Objectives To develop a model using radiomic features extracted from MR images to distinguish radiation necrosis from tumor progression in brain metastases after Gamma knife radiosurgery. Methods We retrospectively identified 87 patients with pathologically confirmed necrosis (24 lesions) or progression (73 lesions), and calculated 285 radiomic features from 4 MR sequences (T1, T1 post-contrast, T2, and fluid-attenuated inversion recovery) obtained at 2 follow-up time points per lesion per patient. Reproducibility of each feature between the two time points was calculated within each group to identify a subset of features with distinct reproducible values between two groups. Changes in radiomic features from one time point to the next (delta radiomics) were used to build a model to classify necrosis and progression lesions. Results A combination of 5 radiomic features from both T1 post-contrast and T2 MR images were found to be useful in distinguishing necrosis from progression lesions. Delta radiomic features with a RUSBoost ensemble classifier had an overall predictive accuracy of 73.2% and an area under the curve value of 0.73 in leave-one-out cross-validation. Conclusions Delta radiomic features extracted from MR images have potential for distinguishing radiation necrosis from tumor progression after radiosurgery for brain metastases.
Using immunohistochemistry, we studied the IgG subclass distribution of the anti-Hu antibody in serum, nervous system, and tumor of patients with anti-Hu-associated paraneoplastic encephalomyelitis/sensory neuropathy (PEM/PSN). The nervous system was also examined for deposits of complement and the distribution and type of inflammatory cells. IgG1 and IgG3 were the predominant isotypes of the anti-Hu IgG in serum, nervous system, and tumor. A few patients also had anti-Hu IgG2, but this isotype was not consistently present in all the regions of the nervous system studied. There was no correlation between neurologic symptoms and specific anti-Hu isotype, nor was there evidence that different anti-Hu isotypes recognized specific brain regions. Although IgG1 and IgG3 can activate complement, only weak complement reactivity was found, and that only in a few areas of the nervous system. This finding, in addition to the absence of natural killer (NK) cells, suggested that complement-mediated toxicity and antibody-dependent cell cytotoxicity mediated by NK cells are not pathogenic in PEM/PSN. Inflammatory infiltrates included CD19+ (B cells) and CD4+ (helper/inducer) cells in the perivascular spaces, and lymphocytes bearing CD8+CD11b- markers (cytotoxic T cells) in the interstitial spaces. Infiltrates of EBM11+ (monocyte/macrophage) cells were identified in the perivascular spaces (macrophage phenotype) and in those interstitial regions (microglial phenotype) with severe pathologic changes. The ability of the IgG1 and IgG3 isotypes to bind Fc receptors may have played a role in the recruitment of these monocyte/macrophage cells.(ABSTRACT TRUNCATED AT 250 WORDS)
The second messenger cAMP is proapoptotic for numerous cell types, but the mechanism for this proapoptotic action is not defined. Here, we use murine CD4 ؉ /CD8 ؉ S49 lymphoma cells and isolated thymocytes to assess this mechanism. In WT Apoptosis, programmed cell death, contributes to a variety of cellular processes that include embryonic development, tissue homeostasis, and immune responses. Apoptosis can be stimulated by a variety of "death stimuli," including DNA damage, oxidative stress, hormones, cytokines, and drugs and is often targeted in cancer therapy. The second messenger cAMP has cell type-dependent effects on apoptosis (as recently reviewed (1)), being anti-apoptotic in certain cell types (e.g. neutrophils (2), eosinophils (3), hepatocytes (4), gastrointestinal epithelial cells (5), and several others) whereas having proapoptotic actions in other types of cells (e.g. cardiac myocytes (6) and certain lymphoid cells (7), in particular poorly differentiated lymphoblastic cells (8, 9)). Hematological malignancies, including large B cell lymphoma and chronic lymphocytic leukemia, are associated with a deficiency in apoptosis (10, 11). We and others have implicated the cAMP/PKA pathway as a promising one to enhance killing of lymphoma and leukemia cells (7,8,(12)(13)(14). Despite the proapoptotic ability of cAMP/PKA, the mechanisms for this action are poorly defined.Using murine S49 lymphoma cells, CD4 ϩ /CD8 ϩ T cells that undergo growth arrest in the G 1 phase of the cell cycle and apoptosis in response to cAMP-promoted activation of PKA 2 (15), we identified mRNAs that differ between WT and kin-S49 cells, which lack PKA (16). In other studies, we showed that expression of certain apoptotic pathway members are differentially regulated in WT and cAMP-deathless (D-) S49 cells (7, 12), a clonal isolate that undergoes G 1 arrest but is resistant to cAMP/PKA-promoted apoptosis (17).The proapoptotic protein Bim, a BH3-only Bcl family member protein, shows a pronounced difference in expression between 12), with Bim expression being higher and longer in the WT cells treated with a cAMP analog or with a -adrenergic agonist; moreover, increase in cAMP does not increase Bim expression in kin-cells (7,12). Bim triggers apoptosis by promoting the release of cytochrome C from mitochondria. However, Bim may not be sufficient for inducing apoptosis, which can involve other BH3-only proteins (18). Multiple Bim isoforms exist (19), certain of which have been implicated in promoting T cell and B cell apoptosis (20). In this study, we used S49 cells (WT, D-, and kin-mutants) and CD4 ϩ / CD8 ϩ thymocytes isolated from WT and Bim Ϫ/Ϫ mice to test whether Bim mediates cAMP/PKA-promoted apoptotic cell death in CD4 ϩ /CD8 ϩ cells. EXPERIMENTAL PROCEDURESMaterials-WT, kin-, and D-S49 cells were obtained from the University of San Francisco cell culture facility. 8-(4-chlorophenylthio)-adenosine-3Ј,5Ј-cyclic monophosphate (CPTcAMP) was obtained from Sigma-Aldrich. BimL cDNA was purchased from Addgene (21). Protease inhibitor m...
Sarcoidosis-lymphoma syndrome is a well-established syndrome where sarcoidosis is followed by the development of a lymphoproliferative disease such as non-Hodgkin's lymphoma (NHL). Here we report two patients with NHL who developed sarcoidosis subsequent to the diagnosis of lymphoproliferative disease. In both cases, chemotherapeutic treatment had already been initiated or was completed when sarcoidosis occurred. In these patients, sarcoidosis may have been triggered by immunologic aberrations induced by antineoplastic therapy or as a consequence of an underlying immunologic disturbance associated with the lymphoma. When a suspected relapse of lymphoma presents with signs and symptoms compatible with sarcoidosis, this rare immunologic disorder has to be ruled out by careful clinical and histopathologic analysis to prevent mistreatment.
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