Targeted Inhibition of CD133+ Cells in Oral Cancer Cell Lines

Resistance to treatment and the appearance of secondary tumors in head and neck squamous cell carcinomas (HNSCC) have been attributed to the presence of cells with stem-cell-like properties in the basal layer of the epithelium at the site of the lesion. In this study, we tested the hypothesis that these putative cancer stem cells (CSC) in HNSCC could be specifically targeted and inhibited. We found that 9 of 10 head and neck tumor biopsies contained a subpopulation of cells that expressed CD133, an unusual surface-exposed membrane-spanning glycoprotein associated with CSC. A genetically modified cytolethal distending toxin (Cdt), from the periodontal pathogen Aggregatibacter actinomycetemcomitans , was conjugated to an anti-human CD133 monoclonal antibody (MAb). The Cdt-MAb complex preferentially inhibited the proliferation of CD133+ cells in cultures of established cell lines derived from HNSCC. Inhibition of the CD133+ cells was rate- and dose-dependent. Saturation kinetics indicated that the response to the Cdt-MAb complex was specific. Healthy primary gingival epithelial cells that are native targets of the wild-type Cdt were not affected. Analysis of these data provides a foundation for the future development of new therapies to target CSC in the early treatment of HNSCC. Abbreviations: Cdt, cytolethal distending toxin; CSC, cancer stem cells; HNSCC, head and neck squamous cell carcinoma; MAb, monoclonal antibody. © 2011 International & American Associations for Dental Research

Adjuncts for the evaluation of potentially malignant disorders in the oral cavity

BACKGROUND: Oral squamous cell carcinoma is the most common manifestation of malignancy in the oral cavity. Adjuncts are available for clinicians to evaluate lesions that seem potentially malignant. In this systematic review, the authors summarized the available evidence on patient-important outcomes, diagnostic test accuracy (DTA), and patients' values and preferences (PVPs) when using adjuncts for the evaluation of clinically evident lesions in the oral cavity. TYPES OF STUDIES REVIEWED: The authors searched for preexisting systematic reviews and assessed their quality using the Assessing the Methodological Quality of Systematic Reviews tool. The authors updated the selected reviews and searched MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials to identify randomized controlled trials and DTA and PVPs studies. Pairs of reviewers independently conducted study selection, data extraction, and assessment of the certainty in the evidence by using the Grading of Recommendations Assessment, Development and Evaluation approach. RESULTS: The authors identified 4 existing reviews. DTA reviews included 37 studies. The authors retrieved 7,534 records, of which 9 DTA and 10 PVPs studies were eligible. Pooled sensitivity and specificity of adjuncts ranged from 0.39 to 0.96 for the evaluation of innocuous lesions and from 0.31 to 0.95 for the evaluation of suspicious lesions. Cytologic testing used in suspicious lesions appears to have the highest accuracy among adjuncts (sensitivity, 0.92; 95% confidence interval, 0.86 to 0.98; specificity, 0.94; 95% confidence interval, 0.88 to 0.99; low-quality evidence). CONCLUSIONS AND PRACTICAL IMPLICATIONS: Cytologic testing appears to be the most accurate adjunct among those included in this review. The main concerns are the high rate of false-positive results and serious issues of risk of bias and indirectness of the evidence. Clinicians should remain skeptical about the potential benefit of any adjunct in clinical practice

The assessment of health policy changes using the time-reversed crossover design.

The time-reversed crossover design is a quasi-experimental design which can be applied to evaluate the impact of a change in health policy on a large population. This design makes use of separate sampling and analysis strategies to improve the validity of conclusions drawn from such an evaluation. The properties of the time-reversed crossover design are presented including the use of stratification on outcome in the sampling stage, which is intended to improve external validity. It is demonstrated that, although this feature of the design introduces internal validity threats due to regression toward the mean in extreme-outcome strata, these effects can be measured and eliminated from the test of significance of treatment effects. Methods for within- and across-stratum estimation and hypothesis-testing are presented which are similar to those which have been developed for the traditional two-period crossover design widely used in clinical trials. The procedures are illustrated using data derived from a study conducted by the United Mine Workers of America Health and Retirement Funds to measure the impact of cost-sharing on health care utilization among members of its health plan

World Workshop on Oral Medicine VII:Immunobiologics for Salivary Gland Disease in Sjögren’s Syndrome: A Systematic Review

Objective: This systematic review evaluated the efficacy of immunobiologics for the management of oral disease in Sj\uf6gren's syndrome (SS). Materials and Methods: MEDLINE\uae, Embase, Scopus, and the Cochrane Library were searched for evidence on the use of immunobiologics for management of glandular disease in SS. Primary outcomes were xerostomia and salivary gland dysfunction, assessed via visual analogue scales, disease-specific scales for SS, measurement of salivary flow, ultrasound data, and quality of life measures. Results: Seventeen studies (11 randomized controlled trials and 6 observational studies) met inclusion criteria. Rituximab showed efficacy in improving salivary gland function but not xerostomia. Abatacept showed promise in improving both xerostomia and salivary flow. Belimumab exhibited long-term improvement of salivary flow and subjective measures. The novel agent CFZ533 improved both disease activity and patient-reported indexes. Conclusions: There is strong evidence pointing to the efficacy of rituximab in the management of oral disease in SS. Future controlled trials may elucidate the efficacy of belimumab and abatacept. The new drug CFZ533 is a promising alternative for the management of SS and its salivary gland involvement. In considering these agents, the promise of efficacy must be balanced against the harmful effects associated with biologic agents

Toxicities and Early Outcomes in a Phase 1 Trial of Photodynamic Therapy For Premalignant and Early Stage Head and Neck Tumors

Objectives Management of early superficial lesions in the head and neck remains complex. We performed a phase 1 trial for high-grade premalignant and early superficial lesions of the head and neck using photodynamic therapy (PDT) with Levulan (ALA). Materials and methods Thirty-five subjects with high grade dysplasia, carcinoma in situ, or microinvasive (⩽1.5 mm depth) squamous cell carcinoma were enrolled. Cohorts of 3–6 patients were given escalating intraoperative light doses of 50–200 J/cm2 4–6 h after oral administration of 60 mg/kg ALA. Light at 629–635 nm was delivered in a continuous (unfractionated) or fractionated (two-part) schema. Results PDT was delivered to 30/35 subjects, with 29 evaluable. There was one death possibly due to the treatment. The regimen was otherwise tolerable, with a 52% rate of grade 3 mucositis which healed within several weeks. Other toxicities were generally grade 1 or 2, including odynophagia (one grade 4), voice alteration (one grade 3), and photosensitivity reactions. One patient developed grade 5 sepsis. With a median follow-up of 42 months, 10 patients (34%) developed local recurrence; 4 of these received 50 J/cm2 and two each received 100, 150, and 200 J/cm2. Ten (34%) patients developed recurrence adjacent to the treated field. There was a 69% complete response rate at 3 months. Conclusions ALA-PDT is well tolerated. Maximum Tolerated Dose appears to be higher than the highest dose used in this study. Longer followup is required to analyze effect of light dose on local recurrence. High marginal recurrence rates suggest use of larger treatment fields