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Tissue factor expression predicts outcome in children with neuroblastoma: A retrospective study.

ABSTRACT: Previous studies have revealed that the processes of tumor angiogenesis, metastasis and invasiveness are highly dependent on components of the blood coagulation cascade. Tissue factor (TF) is one of the key proteins in coagulation. Cumulative evidence suggested that in addition to its role in coagulation, TF regulates intracellular signaling pathways that serve an important role in angiogenesis, tumor development and metastasis. In the present study, TF expression in neuroblastoma as well as its association with tumor stage, pathology and outcome were assessed. A total of 40 formalin-fixed paraffin-embedded tissues were evaluated for TF expression by immunohistochemical analysis. Results revealed that TF expression was positive in 75% of the analyzed tumor tissues. No significant association between TF expression and sex, age, tumor stage or disease pathology was observed. MYCN proto-oncogene bHLH transcription factor (MYCN) was upregulated in 45% (n=18) of the study cases. Positive TF expression was observed in 94.4% of patients (n=17) with upregulated MYCN, while 59% of patients (n=13) with normal MYCN showed positive TF expression (P<0.05). TF expression was a significant outcome predictor for patients; 18/30 patients (60%) with positive TF expression succumbed to the disease during the study period. In conclusion, TF may be a promising prognosis indicator for neuroblastoma. Future studies to determine how TF affects the progression and outcome of neuroblastoma, as well as to investigate its potential role as a therapeutic target, are required.

SUBMITTER: Sherief LM

PROVIDER: S-EPMC6876335 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Tissue factor expression predicts outcome in children with neuroblastoma: A retrospective study.

Sherief Laila M LM Hassan Tamer H TH Zakaria Marwa M Fathy Manar M Eshak Elia A EA Bebars Marwa A MA Esh Asmaa A

Oncology letters 20191030 6

Previous studies have revealed that the processes of tumor angiogenesis, metastasis and invasiveness are highly dependent on components of the blood coagulation cascade. Tissue factor (TF) is one of the key proteins in coagulation. Cumulative evidence suggested that in addition to its role in coagulation, TF regulates intracellular signaling pathways that serve an important role in angiogenesis, tumor development and metastasis. In the present study, TF expression in neuroblastoma as well as its ...[more]

PMID: 31807159

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Project description:BackgroundNeuroblastoma is the most common pediatric extracranial tumor with varied prognoses, but the survival of treated refractory or relapsing patients remains poor.ObjectiveThis analysis presents the outcomes of children with neuroblastoma undergoing MIBG therapy in Poland in 2006-2019.Study designA retrospective cohort of 55 patients with refractory or relapsed neuroblastoma treated with I-131 MIBG in Poland in 2006-2019 was analyzed. The endpoints were overall survival (OS), event-free survival (EFS), cumulative incidence (CI) of second cancers and CI of hypothyroidism. Survival curves were estimated using the Kaplan-Meier method and compared between the cohorts by the log-rank test. Cox modeling was adopted to estimate hazard ratios for OS and EFS, considering factors with P < 0.2.ResultsFifty-five patients with a median age of 78.4 months (range 18-193) with neuroblastoma underwent one or more (4 patients) courses of MIBG I-131 therapy. Fifteen patients were not administered chemotherapy, 3 children received standard-dose chemotherapy, and 37 patients were administered high-dose chemotherapy (HDCT) (busulfan-melphalan in 24 and treosulfan-based in 12 patients). Forty-six patients underwent stem cell transplantation, with autologous (35 patients), haploidentical (6), allogeneic (4), and syngeneic grafts (1). The median time from first MIBG therapy to SCT was 22 days. Children with relapsing tumors had inferior OS compared to those with primary resistant disease (21.2% vs 58.7%, p=0.0045). Survival was better in patients without MYCN gene amplification. MIBG therapy was never curative, except in patients further treated with HDCT with stem cell rescue irrespective of the donor type. 31 patients were referred for immune therapy after MIBG therapy, and the 5-year OS in this group was superior to the untreated children (55.2% vs 32.7%, p=0.003), but the difference in the 5-year EFS was not significant (25.6% vs 32.9%, p=ns). In 3 patients, a second malignancy was diagnosed. In 19.6% of treated children, hypothyroidism was diagnosed within 5 years after MIBG therapy.ConclusionMIBG therapy can be incorporated into the therapeutic strategy of relapsed or resistant neuroblastoma patients as preconditioning with HDCT rather than stand-alone therapy. Follow-up is required due to the incidence of thyroid failure and risk of second cancers.

Project description:More accurate prognostic assessment of patients with neuroblastoma is required to better inform the choice of risk-related therapy. The aim of this study is to develop and validate a gene-expression signature to improve outcome prediction.59 genes were selected using an innovative data-mining strategy, and were profiled in the largest neuroblastoma patient series (n=579) to date using real-time quantitative PCR starting from only 20 ng of RNA. A multigene-expression signature was built using 30 training samples, tested on 313 test samples, and subsequently validated in a blind study on an independent set of 236 tumours.The signature has a performance, sensitivity, and specificity of 85.4% (95% CI 77.7-93.2), 84.4% (66.5-94.1), and 86.5% (81.1-90.6), respectively, to predict patient outcome. Multivariate analysis indicates that the signature is a significant independent predictor of overall survival and progression-free survival after controlling for currently used risk factors: patients with high molecular risk have a higher risk of death from disease and higher risk of relapse or progression than patients with low molecular risk (odds ratio 19.32 [95% CI 6.50-57.43] and 3.96 [1.97-7.97] for overall survival and progression-free survival, respectively, both p<0.0001). Patients at an increased risk of an adverse outcome can also be identified in the current treatment groups, showing the potential of this signature for improved clinical management. These results were confirmed in the validation study, in which the signature was also independently statistically significant in a model adjusted for MYCN status, age, International Neuroblastoma Staging System stage, ploidy, International Neuroblastoma Pathology Classification grade of differentiation, and mitosis karyorrhexis index (odds ratios between 4.81 and 10.53 depending on the model for overall survival and 3.68 [95% CI 2.01-6.71] for progression-free survival).The 59-gene expression signature is an accurate predictor of outcome in patients with neuroblastoma. The signature is an independent risk predictor, identifying patients with an increased risk of poor outcome in the current clinical-risk groups. The method and signature is suitable for routine laboratory testing, and should be evaluated in prospective studies.The Belgian Foundation Against Cancer, the Children Cancer Fund Ghent, the Belgian Society of Paediatric Haematology and Oncology, the Belgian Kid's Fund and the Fondation Nuovo-Soldati (JV), the Fund for Scientific Research Flanders (KDP, JH), the Fund for Scientific Research Flanders, the Institute for the Promotion of Innovation by Science and Technology in Flanders, Strategisch basisonderzoek, the Fondation Fournier Majoie pour l'Innovation, the Instituto Carlos III, the Italian Neuroblastoma Foundation, the European Community under the FP6, and the Belgian programme of Interuniversity Poles of Attraction.

Project description:BackgroundChromosome 1 open reading frame 63 (C1orf63) is located on the distal short arm of chromosome 1, whose allelic loss has been observed in several human cancers. C1orf63 has been reported to be up-regulated in IL-2-starved T lymphocytes, which suggests it might be involved in cell cycle control, a common mechanism for carcinogenesis. Here we investigated the expression and clinical implication of C1orf63 in breast cancer.MethodsParaffin-embedded specimens, clinicopathological features and follow-up data of the breast cancer patients were collected. Publicly available microarray and RNA-seq datasets used in this study were downloaded from ArrayExpress of EBI and GEO of NCBI. KM plotter tool was also adopted. The expression of C1orf63 and CDK10, one known cell cycle-dependent tumor suppressor in breast cancer, was assessed by immunohistochemistry. Western blotting was performed to detect C1orf63 protein in human breast cancer cell lines, purchased from the Culture Collection of the Chinese Academy of Sciences, Shanghai.ResultsIn a group of 12 human breast tumors and their matched adjacent non-cancerous tissues, C1orf63 expression was observed in 7 of the 12 breast tumors, but not in the 12 adjacent non-cancerous tissues (P < 0.001). Similar results were observed of C1orf63 mRNA expression both in breast cancer and several other cancers, including lung cancer, prostate cancer and hepatocellular carcinoma. In another group of 182 breast cancer patients, C1orf63 expression in tumors was not correlated with any clinicopathological features collected in this study. Survival analyses showed that there was no significant difference of overall survival (OS) rates between the C1orf63 (+) group and the C1orf63 (-) group (P = 0.145). However, the analyses of KM plotter displayed a valid relationship between C1orf63 and RFS (relapse free survival)/OS (P < 0.001; P = 0.007). Notablely, in breast cancers with advanced TNM stages (III ~ IV) among these 182 patients, C1orf63 expression was an independent prognostic factor predicting better clinical outcome (HR: 0.41; 95 % CI: 0.17 ~ 0.97; P = 0.042). Additionally, we found that CDK10 mRNA expression was positively correlated with C1orf63, which was consistent with the relationship of protein expression between C1orf63 and CDK10 (r s = 0.391; P < 0.001).ConclusionsCompared to adjacent non-cancerous tissues, C1orf63 expression was elevated in tumor tissues. However, C1orf63 predicts better prognosis for breast cancers with advanced TNM stage, and the underlying mechanism is unknown. In addition, C1orf63 is correlated with the cell cycle related gene, CDK10.

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Tissue factor expression predicts outcome in children with neuroblastoma: A retrospective study.

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Tissue factor expression predicts outcome in children with neuroblastoma: A retrospective study.

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