Lack of Prognostic Significance of Survivin in Pediatric Medulloblastoma (original) (raw)
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Survivin is a negative prognostic marker in medulloblastoma
Neuropathology and Applied Neurobiology, 2005
J. Pizem , A. Cör, L. Zadravec-Zaletel and M. Popovic (2005) Neuropathology and Applied Neurobiology 31, 000-000 Survivin is a negative prognostic marker in medulloblastoma Survivin is a member of the inhibitor of apoptosis protein family, which is over-expressed in many human cancers. Our aim was to analyse survivin expression in medulloblastoma, its association with aberrant activation of the WNT (wingless) pathway and to test the prognostic significance of survivin expression.
Survivin Expression in Medulloblastoma: A Possible Marker for Survival
Pathology & Oncology Research, 2012
Medulloblastomas are highly invasive tumors which are generally disseminated at the time of diagnosis. High and continued morbidity and mortality have prompted the search for new biologic markers that might be used for targeted therapy to minimise treatment related side effects. In this work, we studied the positive expression of survivin in medulloblastoma and investigated its relation to clinical, pathologic data and survival. Tumor tissue specimens from 47 patients with medulloblastoma who underwent primary surgical treatment from June 2002 to June 2006 at the Mansoura university hospital, Egypt were collected. Paraffin sections of all samples were submitted for immunohistochemistry using anti-survivin antibody. The relation between the percentage of positive survivin cells with clinical, pathological and survival data was evaluated Results: In 47 cancer tissue specimens, one case large-cell-anaplastic (1.12 %), tweleve cases desmoplastic (25.53 %) and 34 cases classic medulloblastomas (72.34 %). The immunohistochemical expression of survivin was nulear with moderate intensity. It does not correlate with either age or sex. There was a significant negative correlation of survivin expression with survival (p<0.001), where negative survivin immunostaining was associated with prolonged overall and disease free survival, while survivin expression was associated with shortened survival. Conclusion: Survivin expression correlate with the clinical outcome with poor prognosis and could be a potential predictive factor for recurrence or metastasis.
Survivin expression in glioblastomas correlates with proliferation, but not with apoptosis
Anticancer research
Survivin is expressed in proliferating tissues and in tumors. It is a member of the inhibitory apoptosis protein (IAP) family known to regulate mitosis and to inhibit apoptosis. It has therefore been regarded as a target for therapies. In malignant gliomas it increases with malignancy, even though in glioblastomas it does not seem to correlate with outcome. Survivin was immunohistochemically studied in 39 selected viable glioblastoma areas belonging to 20 cases which were assayed for apoptosis, using a TUNEL assay, caspase-3, poly(ADP-ribose)polymerase 1 (PARP-1), Bid (BH3-interacting domain death agonist) and with the proliferation index Ki-67/MIB-1 and mitotic index (MI). A positive linear correlation was found between the survivin labelling index (LI) and the Ki-67/MIB-1 LI and MI. No inverse correlation was found with apoptosis. This double behavior can be attributed to mechanisms mediating survivin activity, either as a mitosis regulator and apoptosis inhibitor, and should be t...
Journal of Pediatric Hematology/Oncology, 2006
Alterations in apoptotic mechanisms favoring cell survival may be vital for modifying tumor behavior. Survivin, an inhibitor of apoptosis, and caspase 8, a proapoptotic enzyme, are key players in cellular apoptotic mechanisms. We investigated whether the levels of survivin and caspase 8 and the ratio between these 2 apoptotic factors correlate with tumor biology and predicts outcome in patients with neuroblastoma. Survivin and caspase 8 levels were quantified in 38 primary tumor specimens and analyzed individually and in relation to each other. High survivin expression and high survivin:caspase 8 ratios were associated with MYCN amplification, unfavorable histology, and high-risk group of disease (P<0.0008). High survivin mRNA levels were associated with worse overall survival (P = 0.02) although the median follow up was only 22.6 months with a range of 1 day to 3.3 years. Low caspase 8 expression was associated with stage 4 disease, high-risk group, MYCN amplification, and unfavorable histology. Although the survivin:caspase 8 ratio was associated with these risk factors, the ratio did not improve the predictive value of survivin alone in this small series. Quantifying multiple apoptotic genes in neuroblastoma may supplement current risk stratification. Moreover, categorizing aberrant apoptotic gene expression in neuroblastoma may translate into novel therapeutic targets.
Neuroscience Letters, 2004
In order to look for genetic markers helpful for the biological risk stratification of medulloblastomas (MBs) we assayed by real-time PCR expression levels of the following genes: MATH1, encoding a critical transcription factor for the differentiation of cerebellar granular cells (CGCs); PEDF, that encodes a trophic factor for CGCs and is located in a region of frequent allelic imbalance in MBs; and BIRC5, encoding the antiapoptotic protein survivin, usually overexpressed in malignancies. Expression levels of TRKC, higher in MBs with a more favorable prognosis, were also studied. Twenty-three patients were considered: MATH1 expression was strong in 14/23 and undetectable in the others. PEDF was up-regulated in 8/23, TRKC in 9/23, and BIRC5 in 23/23. MATH1 expression was significantly correlated with adult age (p < 0.0001), tumor location in hemispheres rather than the vermis (p < 0.0004), and PEDF and TRKC up-regulation (p < 0.008 and p < 0.04, respectively). During development MATH1 is selectively expressed in the external germinal layer (EGL) of the cerebellum. Thus, MATH1 expression identifies a subgroup of MBs that derive from the EGL and arise during adult age into cerebellar hemispheres. MATH1 mRNA-positive MBs express high levels of PEDF and show a trend towards longer survival, in agreement with increased expression of TRKC. BIRC5 expression, which is strong in all MBs and absent in normal cerebellum, lacks any prognostic value but could be explored for selective targeting of therapeutic factors to MBs. (G. Finocchiaro). size more frequently than others and a review of a large series of patients indicated that anaplasia, identified in 24% of the cases, is significantly associated with shorter survival . Medulloblastomas with extensive nodularity, on the other hand, have a more favorable prognosis . The impact of molecular prognostic markers increased in recent years. High levels of TRKC expression have been associated with a good clinical outcome , while loss of heterozygosity (LOH) on the short arm of chromosome 17, increased expression of the ErbB2 receptor and c-Myc amplification are associated with diminished survival . More recently the technology of DNA microarray has been used for gene expression profiling and prediction of clinical outcome of medulloblastomas . New markers 0304-3940/$ -see front matter
Prognostic significance of apoptosis in medulloblastoma
Neuroscience Letters, 2005
Activation of the sonic hedgehog (SHH) signalling pathway, which is involved in the formation of a significant proportion of medulloblastomas, is characterised by up-regulation and nuclear localisation of downstream transcription factor Gli1. Our aim was to analyse Gli1 expression by immunohistochemistry in a large group of medulloblastomas, to assess possible correlations with WNT (wingless) pathway activation and poly(ADP-ribose) polymerase-1 (PARP1) expression, previously shown to be associated with SHH pathway activation in a mouse model of medulloblastoma. We analysed expression and localisation of Gli1, b-catenin and PARP1 by immunohistochemistry in a series of 65 consecutive medulloblastomas. Gli1 was positive in 40 (61.5%) medulloblastomas, as revealed by either strong (21 cases) or mild (19 cases) nuclear reaction in more than 50% of tumour cells. Nuclear positivity for PARP1 was noted in all 65 cases, ranging from 46% to 100% (mean 80%) but was not correlated with Gli1 positivity. Gli1 was positive in 9 of 11 cases with nuclear localisation of b-catenin, signifying concurrent activation of SHH and WNT pathways. Overall survival of patients with strong nuclear reaction to Gli1 was better compared with patients with Gli1-negative medulloblastomas. Immunohistochemical detection of Gli1 could be useful in identifying medulloblastomas with SHH pathway activation. As revealed by nuclear reaction to Gli1, the SHH pathway is activated in approximately 60% of medulloblastomas. In some medulloblastomas, both SHH and WNT appear to be activated. PARP1 is highly expressed in medulloblastomas. It might be useful as a target to increase the effectiveness of current treatment modalities.
Survivin and gliomas: A literature review
Oncology Letters, 2016
Gliomas are the most common primary brain tumor, the diagnosis of which is challenging. In this respect, the use of immunohistochemical proliferation markers may aid diagnosis; survivin, also known as Baculoviral IAP Repeat Containing 5, is one such marker. Survivin is a unique member of the inhibitors of apoptosis protein gene family, and is known for its dual function as an apoptosis inhibitor and mitosis regulator. Furthermore, survivin has been demonstrated to be overexpressed in a number of malignancies. The purpose of the present literature review was to gain an overview of studies published on the diagnostic and/or prognostic use of survivin in gliomas. Using PubMed, 19 studies matching the inclusion criteria were ultimately included in the present review. The majority of the studies identified revealed that survivin was significantly associated with other proliferation markers, histological malignancy grade, and inversely associated with prognosis. However, there were a number of inconsistencies between studies, which suggests a requirement for standardization of immunohistochemical procedures.
Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia, 2011
Medulloblastomas (MB) are highly aggressive primitive neuroectodermal tumors (PNET) usually located in the posterior fossa. Current treatment for MBs, which includes a combination of surgery, chemotherapy and radiation, remain challenging especially in younger patients. However, advances in the understanding of regulatory pathways in cerebellar development have elucidated possible areas of dysfunction involved in tumorigenesis. Multiple studies have demonstrated the importance of the sonic hedgehog, Wnt, and Notch pathways in MB pathogenesis at the molecular level. While staging and prognosis are often based on the Chang classification system, future algorithms will involve identifying molecular markers in order to allow for more specific risk stratifications of various MB subtypes and provide improved correlation with staging and prognosis. Future development of novel therapies that target the heterogeneity of MB and are tailored to the tumor's unique molecular profile may yie...
PloS one, 2016
Medulloblastoma (MB) is the most common pediatric primary malignant brain tumor. Approximately one-third of MB patients succumb to treatment failure and some survivors suffer detrimental side effects. Hence, the purpose of this study is to explore new therapeutic regimens to overcome chemotherapeutic agent resistance or reduce chemotherapy-induced toxicity. We detected the expression of inhibitors of apoptosis proteins (IAPs) in MB and CD133+ MB cell lines and MB tissues using immunoblotting and immunohistochemical staining. The antitumor effects of inhibitors against IAPs on MB or CD133+ MB cells were evaluated by MTT assay, Annexin V/PI analysis, and caspase-3/7 activity. Autophagy was assessed by the conversion of light chain (LC) 3-I to LC3-II and Cyto-ID autophagy detection kit. MB cells showed higher expression of IAPs compared to normal astrocytes and normal brain tissues. Conventional chemotherapeutic agents combined with small-molecule IAP inhibitors (LCL161 or LBW242) show...