Biomedical subjects

Andrey Korshunov

Publications and source records attributed to Andrey Korshunov.

12 recordsLinked to original sources

PubMed2026

Primary mismatch repair deficient glioma, IDH-wildtype and H3-wildtype: A giant cell tumor with potential for long-term survival occurring at all ages.

BACKGROUND: Replication repair deficiency is associated with increased risk of developing malignant gliomas. The aim of this study was to investigate primary mismatch repair deficient gliomas (PMMRDGs), a group of IDH-wildtype and H3-wildtype gliomas that is enriched among patients with CMMRD and Lynch syndrome. METHODS: We investigated how PMMRDGs differ from other gliomas with respect to DNA methylation profile, genomic alterations, histopathology, and clinical outcomes. RESULTS: PMMRDGs occur in pediatric, adolescents and the elderly, falling in two related methylation clusters and are characterized by a high frequency of replication repair deficiency. Histology showed multinucleated giant cells, and immunohistochemistry demonstrated loss of MMR protein expression. Survival analysis revealed long-term survival in patients with high mutational burden (>50 mut/Mb) and an intact chromosome 9p region, which was validated in an independent reference cohort. CONCLUSIONS: Overall, our findings indicate that PMMRDGs represent a distinct type of IDH-wildtype gliomas with potential for long-term survival likely driven by immune activation.

Humans↗

PubMed2004

Microarray-based screening for molecular markers in medulloblastoma revealed STK15 as independent predictor for survival.

Medulloblastoma, a primitive neuroectodermal tumor of the cerebellum, is one of the most common central nervous system malignancies of childhood. Despite aggressive multimodal therapy, including surgery, irradiation, and chemotherapy, 5-year survival rates have only approached 50-60%. To identify potential candidate genes that predict for overall survival (OS), we performed a gene expression profiling analysis in 35 newly diagnosed medulloblastoma neoplasms. Subsequently, the nine most promising candidate genes were analyzed by immunohistochemistry and fluorescence in situ hybridization on tumor tissue microarrays representing a series of 180 tumors. We found 54 genes in which expression levels predicted for unfavorable survival in medulloblastoma. In line with the gene expression profiling analysis, a positive staining for STK15 (P = 0.0006), stathmin 1 (P = 0.001), and cyclin D1 (P = 0.03) was associated with an unfavorable OS, whereas cyclin B1, DAXX, Ki-67, MYC, NRAS, and p53 showed no statistical significant effect. In comparison to clinically defined parameters such as gender, age, metastatic stage, extent of tumor resection, application of chemotherapy, and tumor grade, positive staining for STK15 was identified as an independent prognostic factor for OS (P = 0.026). Moreover, additional gene copy numbers of MYC (P = 0.003) and STK15 (P = 0.05) predicted for poor survival. The combination of gene expression profiling with tissue microarray experiments allowed the identification of a series of candidate genes that predicts for survival in medulloblastoma. Of the results highlighted by the various data analysis procedures, genes associated with cell proliferation (cyclin D1), transcription (MYC), and especially mitosis (stathmin 1, STK15) appear particularly intriguing with respect to medulloblastoma pathomechanism.

Adolescent↗

PubMed2004

The histologic grade is a main prognostic factor for patients with intracranial ependymomas treated in the microneurosurgical era: an analysis of 258 patients.

BACKGROUND: Ependymomas account for 3-5% of all intracranial malignancies and occur most often in children and young adults. These neoplasms continue to generate considerable controversy with regard to their rational clinical management. It has been shown that the histologic classification of ependymoma is a significant predictor of clinical outcome in patients with ependymoma. METHODS: Ependymomas from 258 patients who underwent microsurgery at a single institution were evaluated histologically to elucidate the prognostic utility of a recently proposed grading scheme. Pathologic and clinical data then were compared using univariate and multivariate analyses. RESULTS: Increasing grade of ependymoma malignancy was found to be associated strongly and independently with worse clinical outcomes in terms of both event-free survival and overall survival. The effect of radiotherapy also was found to be related to histologic grade and was more beneficial for patients who had anaplastic ependymomas and had undergone complete tumor removal. CONCLUSIONS: The application of a uniform diagnostic criteria for grading ependymomas highlighted the key role of tumor histology in clinical outcome in a cohort of patients who were treated in the microsurgical era. The recently proposed grading scheme is likely to be practically useful, reproducible, and clinically applicable.

Adolescent↗

PubMed2003

Immunohistochemical analysis of p16INK4a, p14ARF, p18INK4c, p21CIP1, p27KIP1 and p73 expression in 271 meningiomas correlation with tumor grade and clinical outcome.

Routine pathological examination cannot distinctively predict the clinical course of meningiomas because even histologically benign tumors may recur after gross total resection. Numerous efforts have been made for the evaluation of different immunohistochemical assays in meningioma prognosis. We investigated the prognostic significance of p16INK4a, p14ARF, p18INK4c, p21CIP1, p27KIP1 and p73 expression by immunohistochemical analysis of 271 meningiomas. All tumors were additionally stained for the proliferation markers Ki-67 and DNA topoisomerase II alpha (TopoIIalpha). Significant differences between the number of p16INK4a-, p18INK4c- and p21CIP1-positive cases were noted among the 3 grades of meningiomas. p16INK4a- and p21CIP-positive tumors were found to prevail among benign meningiomas, whereas p18INK4c immunostaining was closely associated to anaplastic meningiomas. The number of p16INK4a- and p21CIP-positive cases was significantly lower in the cohort of recurrent meningiomas. In contrast, p18INK4c-positive cases were clustered among recurrent meningiomas regardless of tumor grade. Immunoreactivity of p14ARF, p27KIP1 and p73 did not show any differences between meningiomas of various histology and clinical outcomes. Multivariate analysis revealed that only tumor grade and TopoIIalpha index are independent criteria for predicting meningioma recurrence. Thus, the immunohistochemical assessment of p16INK4a, p14ARF, p18INK4c, p21CIP1, p27KIP1 and p73 expression in meningiomas does not appear to provide prognostically useful information. Further studies are needed to identify more reliable prognostic markers and to address in more detail the role of cell cycle aberrations in these tumors.

Adult↗

PubMed2003

Gene expression patterns in ependymomas correlate with tumor location, grade, and patient age.

To elucidate the molecular events responsible for tumorigenesis and progression of ependymomas, we analyzed molecular alterations on the gene expression level in a series of newly diagnosed ependymal neoplasms (n = 39). To this aim, tumor RNA was hybridized to microarrays comprising 2600 different genes with relevance to mitosis, cell-cycle control, oncogenesis, or apoptosis. For CLU, IGF-2, and RAF-1, which are apparent candidate genes because they had been previously described to be involved in tumorigenesis of other human malignancies, we found a high expression on the mRNA as well as the protein level. We identified gene expression signatures for the differentiation of tumors with respect to location, grade, and patient age. Spinal ependymomas were characterized by high-expression levels of HOXB5, PLA2G, and CDKN2A and tumors in young patients (< or =16 years of age) by high-expression levels of LDHB and STAM. Notably, we were able to classify supratentorial grade II and III tumors with 100% accuracy, whereas this did not apply for infratentorial ependymomas. The similar gene expression patterns of grade II and III infratentorial malignancies suggest that grade III tumors may develop through a secondary multistep transformation process involving genes that are related to cell proliferation (LDHA, cyclin B, MAT2A) or tumor suppression (PTEN). In summary, our results provide new insight in the biochemical pathways particularly intriguing in the pathomechanism of ependymomas and suggest that this entity comprises molecularly distinct diseases.

Adolescent↗

PubMed2002

Immunohistochemical markers for prognosis of cerebral glioblastomas.

Glioblastoma is the commonest neuroectodermal tumor and the most malignant in the range of cerebral astrocytic gliomas. The prognostic utility of various biological markers for glioblastomas has been broadly tested but the results obtained are regarded as controversial. In the present study, 302 glioblastoma specimens were studied to evaluate a possible association between clinical outcome and expression of some immunohistochemical variables. Furthermore, tumors examined were subdivided on the three cytological subsets--small-cell (SGB), pleomorphic-cell (PGB) and gemistocytic (GGB). Immunohistochemical variables differed between various subsets: the number of p53-positive tumors was found to be prevailed among the PGB, whereas the number of tumors with EGFR and mdm2 positivity was significantly greater in SGB. GGB contained significantly lowest mean proliferating cell nuclear antigen (PCNA) labeling index (LI), greater number of p21ras positive cases, and higher mean apoptotic index (AI). Survival time in patients with SGB, EGFR and mdm2-positivity and PCNA LI >40% was found to be significantly shorter, whereas presence of p21ras and AI >0.5% were associated with prolonged survival. Multivariate analysis revealed that survival time is associated with SGB, EGFR-positivity, and AI (p = 0.0023, p = 0.0035 and p = 0.0029 respectively). We conclude that although some immunohistochemical variables were found to be significant for glioblastoma outcome, they appear to be closely related to biology of single cytological subsets. Furthermore, these variables exhibited no prognostic value when they were analyzed within each cytological subset separately. Therefore, the glioblastoma subdivision on three cytological subsets proposed by us is carrying some element of rationality but, undoubtedly, requires further prospective studies.

Adult↗

PubMed2002

Immunohistochemical markers for prognosis of ependymal neoplasms.

Intracranial ependymomas are the third most common primary brain tumor in children. Although clinical and histological criteria for ependymoma prognosis are recognized, studies have reported contradictory results. Prognostic significance based on immunohistochemistry of ependymomas has been reported in a few studies. One-hundred and twelve patients with intracranial ependymomas were examined retrospectively for immunoexpression of various tumor-associated antigens and apoptosis. The results demonstrated significant preponderance of expression of the tenascin, vascular endothelial growth factor protein (VEGF), epidermal growth factor (EGFR) and p53 protein in high-grade tumors. Also high-grade ependymomas revealed more prominent labeling indices (LI) for proliferative marker Ki-S1 and apoptotic index (AI), and lower LI for cyclin-dependent kinase inhibitors p27/Kipl and pl4ARF. For low-grade ependymomas the progression-free survival time (PFS) was found to be significantly shorter for Ki-S1 LI > 5%, and for tenascin, VEGF and EGFR positivity. For high-grade ependymomas PFS was found to be significantly reduced for p27 LI < 20%, p14ARF LI < 10%, for p53 positivity, and for AI < 1%. The CART modeling process exhibited five final groups of ependymoma patients (1) low-grade and tenascin-negative; (2) low-grade and tenascin-positive; (3) high-grade and p53-negative with p14 LI > 0%; (4) high-grade with combination of either p53 positivity and p14 LI > 10% or p53 negativity and p14 LI < 10%; (5) high-grade and p53-positive with pl4 LI < 10%. In summary, some immunohistochemical variables were found to be the strong predictors of ependymoma recurrence and they seem to be useful for assessing individual tumor prognosis in routinely processed biopsy specimens together with tumor grade. For histologically benign ependymomas immunohistochemical study should be focused on Ki-S1, tenascin, EGFR and VEGF evaluation, whereas p53 expression and number of p27, p14 and ISEL-positive nuclei will be of value in determining PFS from high-grade ependymomas.

Adolescent↗

PubMed2002

Immunohistochemical markers for prognosis of average-risk pediatric medulloblastomas. The effect of apoptotic index, TrkC, and c-myc expression.

Medulloblastomas (MB) are the most common central nervous system malignancies in children. Numerous publications describe certain efforts to identify predictive value of various patterns of MB pathology and immunohistochemistry but received data appear to be controversial. In the present study, the apoptotic index (AI) and immunoexpression of TrkC, and c-myc proteins were investigated in biopsy samples from 68 MB with an average clinical risk to determine their prognostic utility in this tumor category. The number of cases with AI > 1.5% was significantly greater in the group of tumors in patients with recurrent MB and the mean AI was significantly higher in this group -4.7% vs. 1.1%. Furthermore, the number of tumors with AI > 1.5% was greater in the group of tumors in deceased patients and the mean Al was also higher in this group -4.6% vs. 1.2%. Immunoreactivity of the c-myc and TrkC did not show any differences between groups of patients with various clinical outcomes. A close association between Al as a continuous variable and the progression-free and overall survival was found. We found no any differences in survival times for c-myc and TrkC immunoreactivity. Multivariate revealed analysis that AI is a single significant prognostic factor for MB survival. Perhaps, investigations of c-myc and TrkC mRNA levels should be useful for clinical purposes, but in order to introduce these biomolecular markers in clinical protocols its distinct prognostic significance needs to be proved by prospective studies.

Adolescent↗

PubMed2002

Immunohistochemical markers for prognosis of anaplastic astrocytomas.

Among the entire spectrum of astrocytic neoplasms, just anaplastic astrocytoma (or grade III astrocytoma) appears to be a more enigmatic tumor entity with vague criteria for pathological diagnosis, unclear biological behavior and diverse clinical outcome. Attempts have been made to identify biological markers that would be useful in prediction of prognosis of anaplastic astrocytomas but the results obtained are controversial. In the present study, survival data on 63 patients with anaplastic astrocytoma were studied to evaluate a possible association between clinical outcome and expression of some immunohistochemical variables. Both the progression-free (PFS) and overall (OS) survival times were significantly reduced for patients older than 45 years, for anaplastic astrocytomas containing multiple mitoses, for Ki-67 LI > 5%, for cyclin A LI > 4% and for PTEN-negative tumors. We found no differences in survival times in patients with or without p53 immunoreactivity and also in cases with different values of p16 and p27 immunostaining. Multivariate analysis revealed that risk of tumor progression and death is independently associated with tumors containing multiple mitoses and for PTEN-negative tumors. According to the data from the CART modeling, tumors were subdivided based on the three following subsets: (1) Anaplastic astrocytomas with solitary mitosis. (2) Anaplastic astrocytomas with multiple mitoses and PTEN positivity. (3) Anaplastic astrocytomas with multiple mitoses and PTEN negativity. Thus, the results obtained reveal the advantage of combined approach including evaluation of routine histological parameters and immunohistochemical variables for further clinical subdivision of anaplastic astrocytomas.

Adult↗

PubMed2002

Immunohistochemical markers for prognosis of oligodendroglial neoplasms.

Despite numerous previous studies, oligodendrogliomas continue to generate considerable controversy in the identification of prognostic factors, including single histopathological patterns, and grade of tumor malignancy. The prognostic significance of various pathological and immunohistochemical factors has been intensively examined but numerous studies have yielded conflicting results. In the present study, biopsy samples of 123 oligodendrogliomas were examined immunohistochemically to evaluate a possible association between expression of various tumor-associated antigens and clinical outcome. Both the progression-free and overall survival times were significantly reduced for high-grade tumors, for Ki-S1 labeling index (LI) > 10%, for p27 LI < 20% and for p18, p53, and vascular endothelial growth factor (VEGF)-positive tumors. For low-grade tumors survival rates were significantly reduced for p27 LI less than 20%, whereas high-grade oligodendrogliomas with Ki-S1 LI greater than 10%, and with p18 positivity revealed significantly shortened survival times. We found no differences in survival times in patients with or without p 14ARF, p21, mdm2, and pRb immunoreactivity. Multivariate analysis revealed that risk of oligodendroglioma progression is associated with high-grade tumors, with Ki-S1 LI > 10%, and with p27 LI < 20%; whereas risk of death is associated with high-grade tumors, with Ki-S1 LI > 10%, and with p18 positivity. CART modeling process identified four final groups of oligodendroglioma patients: (1) thirty-nine patients with low-grade tumors and p27 LI > 20%; (2) twenty patients with low-grade tumors and p27 LI < 20%; (3) thirty-four patients with high-grade tumors and Ki-S1 LI < 10%; and (4) thirty patients with high-grade tumors and Ki-S1 LI >10%. In summary, both the p27 and Ki-S1 scores were found to be the strong predictors of oligodendroglioma outcome together with the WHO tumor grade and they seem to be useful for assessing individual prognosis in routinely processed specimens.

Adult↗

PubMed2002

Immunohistochemical analysis of p18INK4C and p14ARF protein expression in 117 oligodendrogliomas: correlation with tumor grade and clinical outcome.

OBJECTIVE: To investigate immunoexpression of 2 cyclin-dependent kinase inhibitors, p18INK4C (p18) and p14ARF (p14), in oligodendrogliomas and to evaluate the possible association with tumor grade and clinical outcome. DESIGN: One hundred seventeen specially selected cases of cerebral oligodendrogliomas were studied retrospectively. Tumor specimens were immunohistochemically examined with antibodies to p18INK4C (118.2) and p14ARF (FL-132) proteins. A computerized color image analyzer was used to count immunostained nuclei. RESULTS: p18 nuclear immunoexpression was found in 57 (49%) of the oligodendrogliomas we studied. p18 immunoreactivity exhibited a clear tendency to elevate with increasing tumor grade, and the mean p18 labeling index was 9.7% for low-grade (World Health Organization [WHO] grade II) and 19.2% for high-grade (WHO III) tumors. p14-immunopositive nuclei were found in 87 (74%) tumors, and p14 immunoreactivity showed no correlation with oligodendroglioma histological malignancy. Survival times were significantly reduced for p18-positive tumors, and risk of death was independently associated with p18 expression (hazard ratio = 2.48; P =.01). There was no difference in survival times in patients with or without p14 immunoreactivity. CONCLUSIONS: p18 protein expression is closely associated with malignant oligodendrogliomas and worse clinical outcome. It seems unlikely that p14 immunohistochemistry will be of value in assessing individual prognosis for these tumors.

Adult↗

PubMed2002

DNA topoisomerase II-alpha and cyclin A immunoexpression in meningiomas and its prognostic significance: an analysis of 263 cases.

CONTEXT: Routine pathologic examination cannot distinctively predict the clinical course of meningiomas because even histologically benign tumors may recur after gross total resection. Therefore, numerous efforts have been made to evaluate the meningioma growth fraction and its prognostic value. However, a universally applicable proliferative marker for meningioma outcome is not yet a reality. OBJECTIVE: To investigate the prognostic utility of 3 proliferative markers, namely, Ki-67, DNA topoisomerase II-alpha (topoII), and cyclin A in a representative series of intracranial meningiomas. DESIGN: Two hundred sixty-three adult patients with intracranial meningiomas (208 benign, 42 atypical, and 13 anaplastic) were studied retrospectively. Tumor specimens were immunohistochemically examined with antibodies to Ki-67 (MM-1), topoII, and cyclin A. A computerized color image analyzer was used to count immunostained nuclei. RESULTS: The topoII and cyclin A scores exhibited a close correlation with Ki-67 immunostaining. Significant differences between the indices for all 3 markers were noted among the 3 grades of meningiomas. The scores for all 3 markers were significantly different between recurrent and nonrecurrent meningiomas, including benign tumors that were treated with gross total resection. Recurrence-free survival was significantly reduced for cases with a Ki-67 labeling index (LI) of 4.4% or greater, a topoII LI of 3.2% or greater, and a cyclin A LI of 3.1% or greater. Multivariate analysis revealed that the risk of recurrence for the entire meningioma cohort was significantly associated with tumor grade (hazard ratio = 2.7; P =.004), topoII LI of 3.2% or greater (hazard ratio = 5.5; P <.001), and a cyclin A LI of 3.1% or greater (hazard ratio = 2.4; P =.01). CONCLUSIONS: There is a close correlation in the expression of these 3 proliferative markers in meningiomas, and all of the markers showed a significant association with tumor grade, recurrence rate, and recurrence-free survival. Consequently, in addition to Ki-67, immunoexpression of topoII and cyclin A is available for predicting meningioma recurrence. Moreover, the topoII and cyclin A staining scores were found to be more sensitive predictors for meningioma progression than Ki-67 and, therefore, either of these 2 markers may prove to be clinically informative and useful.

Adult↗