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Objectives: The aim of the study was to investigate the association of surgical margin conditions, including positive specimen margins revised to negative relative to local recurrence, disease-free survival, and overall survival (OS) within a cohort of HPV-mediated oropharyngeal squamous cell carcinoma (OPSCC) who underwent en bloc resection via transoral robotic surgery (TORS). Materials and Methods: Retrospective cohort of patients with untreated HPV-mediated OPSCC cT1 or T2 undergoing TORS resection between October 2014 and March 2020. The methodologic description of our interdisciplinary institutional approach, number of cut-through margins (CTMs) during intraoperative consultation, percentage of final positive margin cases, and disease-free survival and OS stratified by margin status and margin tumor-free distance is identified. Results: 135 patients with primary cT1/T2 HPV-mediated OPSCC met inclusion criteria. Twenty-eight of 135 (20.7%) specimens revealed CTM and were revised during the same operative setting. Three of 135 (2.2%) surgical cases had positive final margin status. Local control rate was 97%. On univariate analysis, margin distance did not impact OS. CTM and final positive margins had lower OS than initially negative margins (p = 0.044). Pathologic N-stage significantly impacted OS (p < 0.001). Conclusions: High local control rate and low final positive margin status confound the study of specimen margin-based techniques in HPV-mediated OPSCC resected en bloc with TORS. Pathologic N-stage may impact OS more than margin status. Larger numbers are needed to confirm differences. [ABSTRACT FROM AUTHOR]

An emerging concept of cancer chemotherapy is that of chemosensitization. Most often applied to the treatment of drug-resistance cancers, chemosensitization has utility when such cancers are rendered drug sensitive through treatment with the sensitizing agent. A particularly striking example of chemosensitization is that encountered with the synthetic isoflavene phenoxodiol where patients with taxane- and/or platinum-resistant ovarian carcinoma once again become sensitive to these drugs following treatment with phenoxodiol. The latter appears to be a true chemosensitization in that the phenoxodiol need not be co-administered with the taxane or platinum drugs. Sensitivity is retained many weeks after the phenoxodiol has been cleared from the system. The response appears to be mediated through the primary drug target of phenoxodiol, a cancer-specific cell surface ECTO-NOX or ENOX protein designated tNOX (ENOX2). The ENOX protein family has been previously recognized as a hormetic target. The hypothesis under investigation is that chemosensitization and low dose synergies are most obvious in the hormetic range of concentrations and that the two phenomena, hormesis and chemosensitization, may be related mechanistically. Key words: ECTO-NOX, NADH oxidase, cancer, phenoxodiol, sulforaphane, paclitaxel, cisplatin, HeLa cells, ovarian carcinoma, INTRODUCTION Hormesis is a dose-response phenomenon characterized by low-dose stimulation and a high-dose inhibition (Fig. 1) [1,2]. Hormesis is most often observed in the context of a dose-time-response framework where [...]

Phenoxodiol, a synthetic isoflavene with clinical efficacy in the management of ovarian and other forms of human cancer, blocked the activity of a cancer-specific and growth-related cell surface ECTO-NOX protein with both oxidative (hydroquinone) and protein disulfide-thiol interchange activity designated tNOX. Purified recombinant tNOX bound phenoxodiol with high affinity (Kd of 50 nM). The tNOX protein appeared to be both necessary and sufficient for the cancer-specific cytotoxicity of phenoxodiol. Growth inhibition of fibroblasts from embryos of mice expressing a tNOX transgene, but not from wild-type mice, was inhibited by phenoxodiol followed by apoptosis. Both the oxidative and protein disulfide-thiol interchange activities that alternate to generate the complex set of oscillations with a period length of 22 min (24 min for the constitutive counterpart CNOX) that characterize ECTO-NOX proteins respond to phenoxodiol. Oxidation of NADH or reduced coenzyme Q10 was rapidly blocked by phenoxodiol. In contrast, the protein disulfidethiol interchange activity measured either by the restoration of activity to scrambled and inactive RNase or from the cleavage of dithiodipyridine (EC50 of 50 nM) was inhibited progressively over an interval of 60 min that spanned three cycles of activity. Inhibition of the latter paralleled the inhibition of cell enlargement and the consequent inability of inhibited cells to initiate traverse of the cell cycle. Activities of constitutive ECTO-NOX (CNOX) forms of either cancer or noncancer cells were unaffected by phenoxodiol to help explain how the cytotoxic effects of phenoxodiol may be restricted to cancer cells.