PubMed · 8536193
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D W Lewis. 1995. Diagnostic tests.. https://pubmed.ncbi.nlm.nih.gov/8536193/
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We previously reported a novel association between CDKN2A nonpromoter methylation and transcription (ARF/INK4a) in human papillomavirus associated oropharyngeal tumors. In this study we assessed whether nonpromoter CDKN2A methylation in laryngeal squamous cell carcinomas (LXSCC) conferred a similar association with transcription that predicted patient outcome. We compared DNA methylation and ARF/INK4a RNA expression levels for the CDKN2A locus using the Illumina HumanMethylation27 beadchip and RT-PCR in 43 LXSCC tumor samples collected from a prospective study of head and neck cancer patients treated at Montefiore Medical Center (MMC). Validation was performed using RNAseq data on 111 LXSCC tumor samples from the Cancer Genome Atlas (TCGA). The clinical relevance of combined nonpromoter CDKN2A methylation and transcription was assessed by multivariate Cox regression for locoregional recurrence on a subset of 69 LXSCC patients with complete clinicopathologic data from the MMC and TCGA cohorts. We found evidence of CDKN2A nonpromoter hypermethylation in a third of LXSCC from our MMC cohort, which was significantly associated with increased ARF and INK4a RNA expression (Wilcoxon rank-sum, P = 0.007 and 0.003, respectively). A similar association was confirmed in TCGA samples (Wilcoxon rank-sum test P < 0.0001 for ARF and INK4a). Patients with CDKN2A hypermethylation or high ARF/INK4a expression were significantly less likely to develop a locoregional recurrence compared to those with neither of the features, independent of other clinicopatholgic risk factors (adjusted hazard ratio=0.21, 95% confidence interval:0.05-0.81). These results support the conclusion that CDKN2A nonpromoter methylation is associated with increased ARF and INK4a RNA expression, and improved locoregional control in LXSCC.
The purpose of this study was to investigate the expression of vascular endothelial growth factor (VEGF) -C in human esophageal squamous cell carcinomas to elucidate its role in lymph node metastasis and tumor progression. The expression of VEGF-C and flt-4 genes was examined in 5 esophageal carcinoma cell lines, 12 fresh biopsy specimens and 48 archival surgical specimens of human esophageal carcinoma tissues by RT-PCR and immunohistochemistry. Immunohistochemistry using antibodies against CD34 (endothelial cell specific) was also carried out and microvessels were quantified by counting vessels in a 200x field in the most vascular area of the tumor. Of the 5 human esophageal carcinoma cell lines, 4 constitutively expressed VEGF-C mRNA. In 8 (66.7%) of 12 cases, VEGF-C mRNA was detected in only tumor tissues but not in normal mucosa by RT-PCR. There was a significant relationship between VEGF-C and flt-4 mRNA expression. Out of the 48 surgical specimens of esophageal carcinomas, 19 (39.6%) and 10 (20.8%) exhibited intense VEGF-C immunoreactivity in the cytoplasm of many cancer cells and the stromal cells, respectively. In contrast, Flt-4 was mainly expressed on the lymphatic endothelial cells. Normal and dysplastic esophageal squamous epithelium exhibited no or faint cytoplasmic staining of VEGF-C. VEGF-C expression correlated with depth of tumor invasion, tumor stage, venous invasion, lymphatic invasion and lymph node metastasis. Vessel count was significantly higher in the VEGF-C positive tumors than in the negative tumors. These results overall suggest that VEGF-C may play a role in tumor progression via lymphangiogenesis and angiogenesis in human esophageal carcinoma.
PURPOSE: To assess whether incorporation of measurements of surviving fraction at 2 Gy (SF(2)) and colony-forming efficiency (CFE) into a tumor control probability (tcp) model increases their prognostic significance. METHODS AND MATERIALS: Measurements of SF(2) and CFE were available from a study on carcinoma of the cervix treated with radiation alone. These measurements, as well as tumor volume, dose, and treatment time, were incorporated into a Poisson tcp model (tcp(alpha,rho)). Regression analysis was performed to assess the prognostic power of tcp(alpha,rho) vs. the use of either tcp models with biologic parameters fixed to best-fit estimates (but incorporating individual dose, volume, and treatment time) or the use of SF(2) and CFE measurements alone. RESULTS: In a univariate regression analysis of 44 patients, tcp(alpha,rho) was a better prognostic factor for both local control and survival (p < 0.001 and p = 0.049, respectively) than SF(2) alone (p = 0.009 for local control, p = 0.29 for survival) or CFE alone (p = 0.015 for local control, p = 0.38 for survival). In multivariate analysis, tcp(alpha,rho) emerged as the most important prognostic factor for local control (p < 0.001, relative risk of 2.81). After allowing for tcp(alpha,rho), CFE was still a significant independent prognostic factor for local control, whereas SF(2) was not. The sensitivities of tcp(alpha,rho) and SF(2) as predictive tests for local control were 87% and 65%, respectively. Specificities were 70% and 77%, respectively. CONCLUSIONS: A Poisson tcp model incorporating individual SF(2), CFE, dose, tumor volume, and treatment time was found to be the best independent prognostic factor for local control and survival in cervical carcinoma patients.