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Malignancy Grade (malignancy + grade)
Selected AbstractsMaternal embryonic leucine zipper kinase transcript abundance correlates with malignancy grade in human astrocytomasINTERNATIONAL JOURNAL OF CANCER, Issue 4 2008Suely K.N. Marie Abstract We have performed cDNA microarray analyses to identify gene expression differences between highly invasive glioblastoma multiforme (GBM) and typically benign pilocytic astrocytomas (PA). Despite the significant clinical and pathological differences between the 2 tumor types, only 63 genes were found to exhibit 2-fold or greater overexpression in GBM as compared to PA. Forty percent of these genes are related to the regulation of the cell cycle and mitosis. QT-PCR validation of 6 overexpressed genes: MELK, AUKB, ASPM, PRC1, IL13RA2 and KIAA0101 confirmed at least a 5-fold increase in the average expression levels in GBM. Maternal embryonic leucine zipper kinase (MELK) exhibited the most statistically significant difference. A more detailed investigation of MELK expression was undertaken to study its oncogenic relevance. In the examination of more than 100 tumors of the central nervous system, we found progressively higher expression of MELK with astrocytoma grade and a noteworthy uniformity of high level expression in GBM. Similar level of overexpression was also observed in medulloblastoma. We found neither gene promoter hypomethylation nor amplification to be a factor in MELK expression, but were able to demonstrate that MELK knockdown in malignant astrocytoma cell lines caused a reduction in proliferation and anchorage-independent growth in in vitro assays. Our results indicate that GBM and PA differ by the expression of surprisingly few genes. Among them, MELK correlated with malignancy grade in astrocytomas and represents a therapeutic target for the management of the most frequent brain tumors in adult and children. © 2007 Wiley-Liss, Inc. [source] Expression profiling of Wilms tumors reveals new candidate genes for different clinical parametersINTERNATIONAL JOURNAL OF CANCER, Issue 8 2006B. Zirn Abstract Wilms tumor is the most frequent renal neoplasm in children, but our understanding of its genetic basis is still limited. We performed cDNA microarray experiments using 63 primary Wilms tumors with the aim of detecting new candidate genes associated with malignancy grade and tumor progression. All tumors had received preoperative chemotherapy as mandated by the SIOP protocol, which sets this study apart from related approaches in the Unites States that are based on untreated samples. The stratification of expression data according to clinical criteria allowed a rather clear distinction between different subsets of Wilms tumors. Clear-cut differences in expression patterns were discovered between relapse-free as opposed to relapsed tumors and tumors with intermediate risk as opposed to high risk histology. Several differentially expressed genes, e.g.TRIM22, CENPF, MYCN, CTGF, RARRES3 and EZH2, were associated with Wilms tumor progression. For a subset of differentially expressed genes, microarray data were confirmed by real-time RT-PCR on the original set of tumors. Interestingly, we found the retinoic acid pathway to be deregulated at different levels in advanced tumors suggesting that treatment of these tumors with retinoic acid may represent a promising novel therapeutic approach. © 2005 Wiley-Liss, Inc. [source] VEGF concentration from plasma-activated platelets rich correlates with microvascular density and grading in canine mast cell tumour spontaneous modelJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 3 2009R. Patruno Abstract Canine cutaneous mast cell tumour (CMCT) is a common cutaneous tumour in dog, with a higher incidence than in human. CMCT is classified in three subgroups, well and intermediately differentiated (G1 and G2), corresponding to a benign disease, and poorly differentiated (G3), corresponding to a malignant disease, which metastasize to lymph nodes, liver, spleen and bone marrow. In this study, we have evaluated serum (S), platelet-poor plasma (P-PP), plasma-activated platelet rich (P-APR) and cytosol vascular endothelial growth factor (VEGF) concentrations, microvascular density (MVD) and mast cell density (MCD) in a series of 86 CMCTs and we have correlated these parameters with each other, by means of ELISA detection of VEGF and immunohistochemistry. Results show that VEGF level from cytosol P-APR and MVD were significantly higher in G3 CMCTs as compared to G1 or G2 subgroups. Moreover, a significantly strong correlation among VEGF levels from P-PAR and cytosol, MVD and MCD was found in G3 subgroup. Because VEGF levels from P-APR well correlated with MVD and malignancy grade in CMCT, we suggest that VEGF might be secreted from MCs and it may be a suitable surrogate inter-species angiogenetic markers of tumour progression in CMCT. Finally, CMCT seems to be a useful model to study the role of MCs in tumour angiogenesis and inhibition of MCs degranulation or activation might be a new anti-angiogenic strategy worthy to further investigations. [source] A quantitative co-localization analysis of large unspliced tenascin-CL and laminin-5/,2-chain in basement membranes of oral squamous cell carcinoma by confocal laser scanning microscopyJOURNAL OF ORAL PATHOLOGY & MEDICINE, Issue 1 2007Marcus Franz Background:, A structural interaction of the oncofetal large tenascin-C splice variants (Tn-CL) and the ,2-chain of laminin-5 (Ln-5/,2) was recently demonstrated in oral squamous cell carcinoma (OSCC). In situ different patterns of co-localization and co-deposition of both proteins could be detected. Especially the co-localization in re-established basement membrane (BM) structures seemed to be biologically meaningful within the process of tumour progression. Methods:, The amount of Tn-CL incorporated in reorganized OSCC BM structures at the tumour margins was investigated by a laser scanning microscopy-based quantitative co-localization analysis. Results:, In the BM of normal oral mucosa no Tn-CL could be detected. In dysplastic and neoplastic oral mucosa a distinct co-localization of Tn-CL and Ln-5/,2 in the BM region could be observed. The extent of Tn-CL arrangement into reorganized BM structures correlated with malignancy grade. Conclusions:, The results suggest at first, a modulation of carcinomatous BM structures by the inclusion of oncofetal matrix proteins during tumour progression and secondly, the BM incorporation of the adhesion-modulating molecule Tn-CL as a pre-invasive structural phenomenon in OSCC. [source] Immunohistochemical evidence of PTEN in oral squamous cell carcinoma and its correlation with the histological malignancy grading systemJOURNAL OF ORAL PATHOLOGY & MEDICINE, Issue 7 2002Cristiane Helena Squarize Abstract PTEN is a tumor suppressor gene that encodes a dual phosphatase protein capable of modulating membrane receptors and interaction of the cell and extracellular stimuli. PTEN regulates cell physiology such as division, differentiation/apoptosis and also migration and adhesion. The expression of PTEN was evaluated by immunohistochemistry in OSCC and compared to a well-established histological malignancy grading system. The well-differentiated OSCC were 59.1% and poorly differentiated were 40.9%. According to PTEN expression, the cases were 45.5% positive (the entire tumor showed stained), 22.7% mixed (both negative and positive cells were present) and 31.8% negative (no staining was seen in the tumor cells). PTEN expression in OSCC was related to the malignancy grade (P < 0.0005). Aggressive tumors with a high score of malignancy did not express PTEN, and clearly, the PTEN expression was present in the epithelium adjacent to the tumor. Negative cells were in the invasion border of the tumor. This result suggests that PTEN is related to histologic pattern and biological behavior of OSCC and may be a used as a prognostic marker in the future. The role of PTEN during carcinogenesis and as a biomarker should be further investigated. [source] Polyploidy in atypical grade II choroid plexus papilloma of the posterior fossaNEUROPATHOLOGY, Issue 3 2009María Sol Brassesco Cytogenetic studies of choroid plexus tumors, particularly for atypical choroid plexus papillomas, have been rarely described. In the present report, the cytogenetic investigation of an atypical choroid plexus papilloma occurring at the posterior fossa of a 16-year-old male is described. Comparative genome hybridization analysis demonstrated gains of genetic material from almost all chromosomes. Chromosome losses involved 19p, regional losses at chromosome X and loss of chromosome Y. The presence of polyploid cells was confirmed by fluorescence in situ hybridization analysis with probes directed to centromeric regions. Furthermore, the microscopic analysis of cultures showed nuclear buds, nucleoplasmic bridges, and micronuclei in 23% of tumor cells suggesting the presence of complex chromosomal abnormalities. Previous cytogenetic studies on choroid plexus papillomas showed either normal, hypodiploid or hyperdiploid karyotypes. To the best of our knowledge, this is the first report of polyploidy in choroid plexus papilloma of intermediate malignancy grade. Although the mechanisms beneath such genome duplication remain to be elucidated, the observed abnormal nuclear shapes indicate constant restructuring of the tumor's genome and deserves further investigation. [source] Vascular endothelial growth factor expression in oligodendrogliomas: a correlative study withSainte-Anne malignancy grade, growth fractionand patient survivalNEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 4 2000P. Varlet Microangiogenesis is a delayed but crucial event in the malignant progression of oligodendrogliomas. Accord-ingly, in the new Sainte-Anne grading system of oligodendrogliomas, endothelial hyperplasia and contrast enhancement, both being indicators of microangiogenesis, are key criteria for the distinction of grade A from grade B tumours. Vascular endothelial growth factor (VEGF) is a potent angiogenic factor: a strong correlation between VEGF expression, Sainte-Anne malignancy grade and patient outcome might thus be expected. In order to assess this hypothesis, VEGF immunostaining was performed in a series of 34 oligodendrogliomas that included 11 grade B and 23 grade A, of which nine became grade B during the study period (mean clinical and imaging follow-up: 41 months). VEGF expression correlated strongly with Sainte-Anne tumour grade (P < 0.001), and inversely with patient survival (P < 0.001) and recurrence-free survival (P = 0.002). One hundred per cent of grade B but only 17% of grade A were VEGF-positive. By contrast, the MIB-1 labelling index did not correlate with VEGF expression, total survival or recurrence-free survival. In accordance with the grading system, this study showed that, in oligodendrogliomas, VEGF expression and microangiogenesis are progression-related phenomena that confer on these tumours a growth advantage by presumably reducing hypoxia-induced apoptotic cell death. These findings might have important implications in the future for the indication and timing of anti-angiogenic therapies. [source] Metabolic differences between primary and recurrent human brain tumors: a 1H NMR spectroscopic investigationNMR IN BIOMEDICINE, Issue 6 2005Fritz-Georg Lehnhardt Abstract High-resolution proton magnetic resonance spectroscopy was performed on tissue specimens from 33 patients with astrocytic tumors (22 astrocytomas, 11 glioblastomas) and 13 patients with meningiomas. For all patients, samples of primary tumors and their first recurrences were examined. Increased anaplasia, with respect to malignant transformation, resulting in a higher malignancy grade, was present in 11 recurrences of 22 astrocytoma patients. Spectroscopic features of tumor types, as determined on samples of the primary occurrences, were in good agreement with previous studies. Compared with the respective primary astrocytomas, characteristic features of glioblastomas were significantly increased concentrations of alanine (Ala) (p,=,0.005), increased metabolite ratios of glycine (Gly)/total creatine (tCr) (p,=,0.0001) and glutamate (Glu)/glutamine (Gln) (p,=,0.004). Meningiomas showed increased Ala (p,=,0.02) and metabolite ratios [Gly, total choline (tCho), Ala] over tCr (p,=,0.001) relative to astrocytomas, and N -acetylaspartate and myo-inositol were absent. Metabolic changes of an evolving tumor were observed in recurrent astrocytomas: owing to their consecutive assessments, more indicators of malignant degeneration were detected in astrocytoma recurrences (e.g. Gly, p,=,0.029; tCho, p,=,0.034; Glu, p,=,0.015; tCho/tCr, p,=,0.001) in contrast to the comparison of primary astrocytomas with primary glioblastomas. The present investigation demonstrated a correlation of the tCho-signal with tumor progression. Significantly elevated concentrations of Ala (p,=,0.037) and Glu (p,=,0.003) and metabolite ratio tCho/tCr (p,=,0.005) were even found in recurrent low-grade astrocytomas with unchanged histopathological grading (n,=,11). This may be related to an early stage of malignant transformation, not yet detectable morphologically, and emphasizes the high sensitivity of 1H NMR spectroscopy in elucidating characteristics of brain tumor metabolism. Copyright © 2005 John Wiley & Sons, Ltd. [source] Allelic Gain and Amplification on the Long Arm of Chromosome 17 in Anaplastic MeningiomasBRAIN PATHOLOGY, Issue 2 2002Rainer Büschges Using comparative genomic hybridization (CGH) we have previously identified amplification at 17q21-qter as a common aberration in anaplastic meningiomas but not in atypical or benign meningiomas (19). To define the amplified genomic region, we analyzed 44 meningeal tumors, including 7 benign meningiomas of World Health Organization (WHO) grade I, 19 atypical meningiomas (WHO grade II) and 18 anaplastic meningiomas (WHO grade III) at 46 chromosome 17 loci (including 42 17q loci). In line with the CGH data we found evidence of increased numbers of alleles on 17q. The incidence rose with malignancy grade, culminating at 61% (11 of 18 cases) in the anaplastic meningioma group. The majority of cases showing increased allele numbers had, on average, low-level allelic gains (relative increase in allele dosage of 2- to 5-fold). Amplification of alleles (defined here as an average relative increase in allele dosage of more than 5 times) was detected in 2 anaplastic meningiomas. The amplification patterns in these tumors defined a number of common regions of amplification/increased allele copy number, the best defined include one between D17S790 and D17S1607 and one between D17S1160 and PS6K. Real-time PCR analysis of the PS6K candidate gene revealed no high-level amplification despite this affecting adjacent loci. Our findings are fundamental for the identification of the gene(s) in 17q22-q23 that is (are) the target(s) for increased copy number in anaplastic meningiomas and possibly other tumor types. [source] Improved prediction of recurrence after curative resection of colon carcinoma using tree-based risk stratificationCANCER, Issue 5 2004Martin Radespiel-Tröger M.D. Abstract BACKGROUND Patients who are at high risk of recurrence after undergoing curative (R0) resection for colon carcinoma may benefit most from adjuvant treatment and from intensive follow-up for early detection and treatment of recurrence. However, in light of new clinical evidence, there is a need for continuous improvement in the calculation of the risk of recurrence. METHODS Six hundred forty-one patients with R0-resected colon carcinoma who underwent surgery between January 1, 1984 and December 31, 1996 were recruited from the Erlangen Registry of Colorectal Carcinoma. The study end point was time until first locoregional or distant recurrence. The factors analyzed were: age, gender, site in colon, International Union Against Cancer (UICC) pathologic tumor classification (pT), UICC pathologic lymph node classification, histologic tumor type, malignancy grade, lymphatic invasion, venous invasion, number of examined lymph nodes, number of lymph node metastases, emergency presentation, intraoperative tumor cell spillage, surgeon, and time period. The resulting prognostic tree was evaluated by means of an independent sample using a measure of predictive accuracy based on the Brier score for censored data. Predictive accuracy was compared with several proposed stage groupings. RESULTS The prognostic tree contained the following variables: pT, the number of lymph node metastases, venous invasion, and emergency presentation. Predictive accuracy based on the validation sample was 0.230 (95% confidence interval [95% CI], 0.227,0.233) for the prognostic tree and 0.212 (95% CI, 0.209,0.215) for the UICC TNM sixth edition stage grouping. CONCLUSIONS The prognostic tree showed superior predictive accuracy when it was validated using an independent sample. It is interpreted easily and may be applied under clinical circumstances. Provided that their classification system can be validated successfully in other centers, the authors propose using the prognostic tree as a starting point for studies of adjuvant treatment and follow-up strategies. Cancer 2004;100:958,67. © 2004 American Cancer Society. [source] Revisiting the value of assessing the mitotic rate of choroidal melanomaACTA OPHTHALMOLOGICA, Issue 2009SE COUPLAND Purpose To re-evaluate mitotic rate (MR) as an indicator of malignancy grade in uveal melanoma (UM) and as a predictor for UM-related mortality. Methods UM patients treated 1993-2006 by local resection or enucleation were included. Data on largest basal diameter (LBD), ciliary body involvement, extraocular extension, cell type, closed loops, MR per 40/HPF, cytogenetics were collected. Mortality data were obtained from NHS Cancer Registry. Results 918 patients (520 M; 398 F) had median age of 64.6 yrs with a median follow-up of 3.46 yrs (range 0.02-13). The UM had mean diameter of 14.9 mm with ciliary body involvement in 43.0%, epithelioid cells in 63.3%, closed loops in 41.2%, extraocular spread in 11.3%. Cytogenetics in 337 patients showed disomy 3 and 8 in 27%, monosomy 3 in 10.7%, chromosome 8 gains in 24.0%, both these abnormalities in 38.3%. The median MR was 3(range 0-61, SD 6). High MR correlated with ciliary body involvement (p = 0.001), epithelioid cells(p = 0.009), closed loops(p<0.0001), extraocular spread(p=0.027) & monosomy 3(p<0.0001;Mann-Whitney). MR also correlated with LBD(p=0.0001; t-test). Metastatic death occurred in 243 patients (26.7%). Kaplan-Meier analysis showed MR >4/40 HPF to be associated with increased 10-year metastatic mortality from 32.5 (95% confidence intervals [CI] 25.7-39.3) to 65.5 (95% CI 55-7-75.4; log rank statistic 53.28, p<0.0001). Cox multivariate analysis showed MR to be an independent predictive factor for metastatic death (p<0.0001). MR was predictive of metastatic death also in patients without detectable monosomy 3 (Log rank statistic 10.38, p = 0.002). Conclusion MR correlates with other known risk factors for metastatic death and independently predicts mortality even when cytogenetics show disomy 3. [source] Frequent promoter hypermethylation of Wnt pathway inhibitor genes in malignant astrocytic gliomasINTERNATIONAL JOURNAL OF CANCER, Issue 11 2010Silke Götze Abstract Aberrant activation of wingless (Wnt) signaling is involved in the pathogenesis of various cancers. Recent studies suggested a role of Wnt signaling in gliomas, the most common primary brain tumors. We investigated 70 gliomas of different malignancy grades for promoter hypermethylation in 8 genes encoding members of the secreted frizzled-related protein (SFRP1, SFRP2, SFRP4, SFRP5), dickkopf (DKK1, DKK3) and naked (NKD1, NKD2) families of Wnt pathway inhibitors. All tumors were additionally analyzed for mutations in exon 3 of the ,-catenin gene (CTNNB1). While none of the tumors carried CTNNB1 mutations, we found frequent promoter hypermethylation of Wnt pathway inhibitor genes, with at least one of these genes being hypermethylated in 6 of 16 diffuse astrocytomas (38%), 4 of 14 anaplastic astrocytomas (29%), 7 of 10 secondary glioblastomas (70%) and 23 of 30 primary glioblastomas (77%). Glioblastomas often demonstrated hypermethylation of 2 or more analyzed genes. Hypermethylation of SFRP1, SFRP2 and NKD2 each occurred in more than 40% of the primary glioblastomas, while DKK1 hypermethylation was found in 50% of secondary glioblastomas. Treatment of SFRP1-, SFRP5-, DKK1-, DKK3-, NKD1- and NKD2 -hypermethylated U87-MG glioblastoma cells with 5-aza-2,-deoxycytidine and trichostatin A resulted in increased expression of each gene. Furthermore, SFRP1 -hypermethylated gliomas showed significantly lower expression of the respective transcripts when compared with unmethylated tumors. Taken together, our results suggest an important role of epigenetic silencing of Wnt pathway inhibitor genes in astrocytic gliomas, in particular, in glioblastomas, with distinct patterns of hypermethylated genes distinguishing primary from secondary glioblastomas. [source] | ||||||||||||||||||||||