PubMed · 7285277
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H Nussbaum. 1981. Microscopic disease.. https://pubmed.ncbi.nlm.nih.gov/7285277/
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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.
BACKGROUND: The 5-year survival rate of patients with submucosal (sm) esophageal carcinoma continues to be much worse than that with intramucosal (m) lesions. The reasons are unclear, but matrix metalloproteinases (MMPs) and membrane type matrix metalloproteinases (MT-MMPs) are known to be involved in degradation of extracellular matrix macromolecules associated with tumor cell invasion. Expression of these enzymes may have some relation to the difference in survival between patients with sm and m esophageal carcinomas. METHODS: Surgical specimens from 148 primary esophageal squamous cell carcinomas were examined for expression of MMP-1, 2, 3, 7, and 9; tissue inhibitor of MMP (TIMP)-1 and 2; MT1-MMP; and MT2-MMP by immunohistochemical staining. The results were compared with tumor progression and other clinicopathologic parameters. Localization of gelatinase activity was also confirmed in carcinoma cells by in situ zymography. RESULTS: Expression of MMP-7 and 9, expression of MT1-MMP, and gelatinase activity were elevated in the carcinomas, correlating with depth of tumor invasion. Percentages of positive sm cases were 44.0%, 51.9%, and 52.0%, respectively, significantly higher than for the m cases. Percentages of venous invasion positive cases were 61.9%, 65.1%, and 65.1%, respectively. CONCLUSIONS: Expression of MMP-7 and 9 and MT1-MMP is closely associated with invasion depth and venous invasion in esophageal squamous cell carcinomas.
BACKGROUND: The current study was conducted to investigate retrospectively whether elective ipsilateral neck irradiation (EINI) is effective in controlling subclinical neck disease in patients with locally advanced (T3 and T4) nonmetastatic (N0, M0) squamous cell carcinoma (SCC) of the maxilla. METHODS: Between 1987 and 1993 a total of 44 patients were treated with EINI. The primary tumor bed was treated with 60 grays (Gy) in patients undergoing radical maxillectomy or with 66 Gy in patients undergoing partial maxillectomy. The ipsilateral upper and lower neck (down to the clavicle) was treated with either opposing anteroposterior-posteroanterior fields or appositional electron fields. The dose of elective neck radiotherapy was 50 Gy in 25 daily fractions. RESULTS: The 5-year and 10-year survival rates (with standard error [SE]) were 66% (SE 7%) and 60% (SE 8%), respectively, whereas the 5-year and 10-year recurrence free survival rates both were 64% (SE 7%). The 10-year local recurrence free survival rate was 69% (SE 7%), whereas the 10-year regional recurrence free survival rate was 94% (SE 4%). Of the 2 patients who developed a recurrence in the neck, 1 was salvaged successfully by surgery, producing an ultimate 10-year regional recurrence free survival rate of 97%. The 10-year distant metastasis free survival rate was 91% (SE 4%). CONCLUSIONS: The findings of the current study appear to suggest the potential efficacy of EINI in patients with locally advanced, nonmetastatic SCC of the maxilla and that the high rate of control of cervical lymph nodes may lead to better overall survival than that reported in the majority of the recent series.