PubMed · 12378727
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William I Wei. 2002-10-12. Commentary: Head and neck carcinomas in the developing world.. https://pubmed.ncbi.nlm.nih.gov/12378727/
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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.
It is still unknown what kinds of roles Epstein-Barr virus (EBV) infection that are highly specific to salivary gland lymphoepithelial carcinomas (LECs) play in their tumorigenesis. To clarify the significance of EBV in LECs, we paid particular attention to the LMP1 gene, which is responsible for triggering several pathways for activating transcription factors. Sixty-one cases of EBV positive LECs confirmed by PCR and in-situ hybridization were collected from various areas of the world and studied immunohistochemically for latent membrane protein-1. Furthermore, PCR for the LMP1 carboxyl (C)-terminus region was performed, and the PCR products were sequenced for detection of other mutational events. LMP1 gene products were immunohistochemically demonstrated in 51% of the cases, while PCR amplification of the LMP1 gene was successful in 41 cases (67%). Among them, a 30 bp deletion in the C-terminus of the LMP1 gene, which had been shown to be characteristic to EBV in Chinese nasopharyngeal carcinomas, was found in 20 cases (32%). Most of them were from Guangzhou, Chengdu and Taiwan, while most of the cases from Shanghai and other areas exhibited no 30 bp deletion. In addition, several point mutations including codon 338 of LMP1 were commonly shared by the cases with or without the 30 bp deletion. These results indicate that there are 2 major genomic variations of EBV infecting salivary gland LECs. The frequent mutational events in the C-terminus in addition to the 30 bp deletion also seem to be critical for the pathogenesis because such mutational events may possibly promote cellular proliferation.
PURPOSE: This report describes the dosimetric analyses of a Phase I/II protocol, designed to examine the capabilities of an institutionally developed intensity-modulated radiotherapy (IMRT) system with respect to dose escalation. The protocol employed stringent dosimetric guidelines in the treatment of locally advanced head-and-neck squamous cell carcinomas (HNSCC) with radiotherapy alone using IMRT and the simultaneous integrated boost (SIB) technique. METHODS AND MATERIALS: The first 14 patients enrolled on the protocol were included in this analysis. Escalating doses of 68.1 Gy (6 patients), 70.8 Gy (6 patients), and 73.8 Gy (2 patients) were delivered to the gross tumor volume (GTV) in 30 fractions. Simultaneously, constant dose coverage was given to the subclinical disease and the electively treated nodal regions, which received 60 Gy and 54 Gy, respectively, in all three cohorts. Parotid glands were spared to the degree possible without compromising target coverage. The following indices are reported for the GTV: (1) dose to specified percent volumes (e.g., D(98) and D(2)); (2) homogeneity index defined as the ratio (D(2) - D(98))/D(prescription); (3) biologically equivalent uniform dose (EUD); and (4) an index of conformality, PITV, defined as the ratio of volume enclosed within the prescribed isodose surface to the target volume. Treatments were planned and delivered with nine 6-MV photon beams using the multileaf collimator (MLC) "sliding window" technique. RESULTS: Mean doses to 98% of GTV were 68.4 Gy, 70.5 Gy, and 70.8 Gy, and average GTV dose homogeneity was 6.7%, 7.6%, and 8.8% for the three cohorts. The average doses to the parotid gland proximal to and distant from GTV were 41.3 Gy and 25.7 Gy, respectively. Dose distributions measured in phantom showed good agreement with calculations. CONCLUSIONS: Treatment of locally advanced HNSCC using SIB-IMRT as described is feasible. Treatment planning and delivery are safer and more efficient than with conventional three-dimensional processes. Predicted dose distributions can be accurately delivered with excellent conformality using dynamic MLC. At least one of the parotid glands can be adequately spared. Patient follow-up continues and will allow eventual quantitative correlation of delivered dose distributions with clinical outcomes.