Multiscale quantification of morphological heterogeneity with creation of a predictor of longer survival in glioblastoma

Intratumor heterogeneity is a main cause of the dismal prognosis of glioblastoma (GBM). Yet, there remains a lack of a uniform assessment of the degree of heterogeneity. With a multiscale approach, we addressed the hypothesis that intratumor heterogeneity exists on different levels comprising traditional regional analyses, but also innovative methods including computer-assisted analysis of tumor morphology combined with epigenomic data. With this aim, 157 biopsies of 37 patients with therapy-naive IDH-wildtype GBM were analyzed regarding the intratumor variance of protein expression of glial marker GFAP, microglia marker Iba1 and proliferation marker Mib1. Hematoxylin and eosin stained slides were evaluated for tumor vascularization. For the estimation of pixel intensity and nuclear profiling, automated analysis was used. Additionally, DNA methylation profiling was conducted separately for the single biopsies. Scoring systems were established to integrate several parameters into one score for the four examined modalities of heterogeneity (regional, cellular, pixel-level and epigenomic). As a result, we could show that heterogeneity was detected in all four modalities. Furthermore, for the regional, cellular and epigenomic level, we confirmed the results of earlier studies stating that a higher degree of heterogeneity is associated with poorer overall survival. To integrate all modalities into one score, we designed a predictor of longer survival, which showed a highly significant separation regarding the OS. In conclusion, multiscale intratumor heterogeneity exists in glioblastoma and its degree has an impact on overall survival. In future studies, the implementation of a broadly feasible heterogeneity index should be considered.     

Interactions between cancer cells and immune cells drive transitions to mesenchymal-like states in glioblastoma

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Absence of FGFR3–TACC3 rearrangement in hematological malignancies with numerical chromosomal alteration

FGFR–TACC, found in different tumor types, is characterized by the fusion of a member of fibroblast grown factor receptor (FGFR) tyrosine kinase (TK) family to a member of the transforming acidic coiled-coil (TACC) proteins. Because chromosome numerical alterations, hallmarks of FGFR–TACC fusions are present in many hematological disorders and there are no data on the prevalence, we studied a series of patients with acute myeloid leukemia and myelodysplastic syndrome who presented numerical alterations using cytogenetic traditional analysis. None of the analyzed samples showed FGFR3–TACC3 gene fusion, so screening for this mutation at diagnosis is not recommended.     

Uptake of Adriamycin in tumour and surrounding brain tissue in patients with malignant gliomas

Summary Eight patients with malignant gliomas verified on CT scan, received an intravenous injection of 50 mg of Adriamycin R, 24 hours prior to surgical removal of the tumour. Peroperatively, both tumour and surrounding tissue specimens were obtained for determination of the tissue concentrations of Adriamycin and its reduced metabolite Adriamycinol. It was found that Adriamycin could be detected in tumour tissue from all patients. The concentration varied between 0,9 and 4,6 nmol/g tissue. In contrast, Adriamycin could only be detected in surrounding brain tissue from one patient.In anin vitro study a human malignant glioma cell line (U-251 MG) was exposed to various concentrations of Adriamycin for 24 hours. It was found that an intracellular drug concentration above 30 nmol/g cells caused a concentration dependent inhibition of cell growth. Thus, it is likely that the poor effect of Adriamycin on patients with malignant gliomas is due to an ineffective drug accumulation in the tumour tissue.     

Multidrug transport in human glioblastoma cells is inhibited by transforming growth factors type beta 1, beta 2, and beta 1.2

The transforming growth factors type beta 1, beta 2, and beta 1.2 suppress multidrug transport in human pat-1 glioblastoma cells and even in cells that strongly over-express mdr genes and are resistant to inhibition of multidrug transport by chemosensitizers. Thus, inhibition of multidrug transport by cytokines might be a new approach to increase cellular accumulation of chemotherapeutic agents in multidrug resistant glial tumor cells. Interestingly, a member of the more distantly related decapentaplegic subgroup of transforming growth factors, the bone morphogenetic protein BMP 2, did not inhibit multidrug transport.     

Spindle-cell glioblastoma or gliosarcoma?

'Gliosarcomas' have long been considered to be mixed gliomas and sarcomas. The present study failed to define criteria which clearly delineate 'gliosarcomas' from glioblastoma multiforme and suggests that 'gliosarcomas' should be considered as spindle cell glioblastomas. A total of six cases originally diagnosed as 'gliosarcomas' were compared with four cases of glioblastoma multiforme. No clinical or prognostic features were defined which would clearly separate 'gliosarcomas' from glioblastoma multiforme. Macroscopically, biopsies from 'gliosarcomas' ranged from firm, apparently well-circumscribed tumours to poorly circumscribed lesions with a soft consistency resembling glioblastoma multiforme. Histology revealed a continuous spectrum in which 'gliosarcomas' with large reticulin-rich areas of spindle cells merged with typical glioblastomas containing only small islands of spindle cells and reticulin staining. Immunocytochemistry for glial fibrillary acidic protein (GFAP); S100 protein and alpha-smooth muscle actin (ASMA) showed that the majority of cells in reticulin-poor areas of 'gliosarcoma' and glioblastomas expressed S100 protein and GFAP; many expressed ASMA and some expressed both GFAP and ASMA. Spindle cells in reticulin-rich areas of 'gliosarcomas' and glioblastomas most frequently expressed ASMA but many cells also expressed S100 protein and GFAP; some cells expressed both GFAP and ASMA. The results of this study and a review of the literature suggests that there is a clinical, radiological and pathological continuum with glioblastoma and 'gliosarcoma' at different ends of the spectrum. It is suggested, therefore, that most, if not all, 'gliosarcomas' be redesignated as spindle cell glioblastomas and not be considered as a mixture of glioma and sarcoma.     

加热及增加细胞内氧自由基水平对恶性胶质瘤细胞生物学特性的影响

本文就加热及同时增加细胞内氧自由基水平对恶性胶质瘤细胞存活、增殖和细胞间隙连结通讯的影响做初步观察。用Ｍ．Ｔ．Ｔ法测定胶质瘤细胞存活率；用Ｋｉ－６７抗增殖细胞核抗原单克隆抗体，通过免疫组织化学ＡＢＣ染色分析胶质瘤细胞的增殖活性；用划痕染料示踪技术观察胶质瘤细胞的细胞间隙连结通讯。结果表明，Ｈ２Ｏ２和３ＡＴ能增强加热对胶质瘤细胞存活与增殖的抑制作用，促进胶质瘤细胞间隙连结通讯的改善，存在着明显的剂量和时间效应。实验结果提示，通过内外源性增加胶质瘤细胞内的氧自由基水平，将有助于强化加热治疗胶质瘤效果，并可以减少加热的剂且，降低副作用。     

Glioblastoma multiforme of the hippocampus in advanced Alzheimer''s disease

An 87-year-old woman suffered from Alzheimer's disease diagnosed 6 years prior to her death. Autopsy showed in addition to far-advanced Alzheimer's disease, a large, partially necrotic glioblastoma occupying her right hippocampus. Occurrence of a glial neoplasm in Alzheimer's disease could well be coincidental, since both entities are fairly common in elderly individuals; it is however, uncommon for gliomas to centre on the hippocampus itself. For these reasons it is possible (although cannot be proven from a single case), that florid reactive gliosis commonly associated with Alzheimer's disease, may have played a role in eventually initiating neoplastic proliferation of astrocytes in this patient.     

紫外线照射充氧自血回输疗法治疗多形性红斑临床及甲皱微循环观察

采用紫外线充氧自血回输治疗多形性红斑的治疗组总有效率为１００％，对照组为４０％；甲皱微循环改善率治疗组为１００％，对照组为７５％，组间差异均有非常显著性（Ｐ＜０．０１）．观察证明，紫外线照射充氧自血回输疗法是治疗多形性红斑的一种好方法．     

Erythema multiforme during cytomegalovirus infection and oral therapy with terbinafine: a virus–drug interaction

The authors report a case of erythema multiforme in a 32-year-old woman who was also taking oral terbinafine for an onychomycosis. The patient data analysis showed serological positivity for cytomegalovirus (IgM and IgG) and hepatitis C virus and serological titre of antinuclear antibody was elevated. After a brief review of the literature the authors propose the possibility of virus-drug interaction as a model of adverse drug reactions.