Russell E. Christensen

Increased prevalence of bisphosphonate-related osteonecrosis of the jaw with vitamin D deficiency in rats.

Necrotic bone exposure in the oral cavity has recently been reported in patients treated with nitrogen‐containing bisphosphonates as part of their therapeutic regimen for multiple myeloma or metastatic cancers to bone. It has been postulated that systemic conditions associated with cancer patients combined with tooth extraction may increase the risk of osteonecrosis of the jaw (ONJ). The objective of this study was to establish an animal model of bisphosphonate‐related ONJ by testing the combination of these risk factors. The generation of ONJ lesions in rats resembling human disease was achieved under the confluence of intravenous injection of zoledronate (ZOL; 35 µg/kg every 2 weeks), maxillary molar extraction, and vitamin D deficiency [VitD(−)]. The prevalence of ONJ in the VitD(−)/ZOL group was 66.7%, which was significantly higher (p < .05, Fisher exact test) than the control (0%), VitD(−) (0%), and ZOL alone (14.3%) groups. Similar to human patients, rat ONJ lesions prolonged the oral exposure of necrotic bone sequestra and were uniquely associated with pseudoepitheliomatous hyperplasia. The number of terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate–biotin nick‐end label–positive (TUNEL+) osteoclasts significantly increased on the surface of post–tooth extraction alveolar bone of the VitD(−)/ZOL group, where sustained inflammation was depicted by [18F]fluorodeoxyglucose micro‐positron emission tomography (µPET). ONJ lesions were found to be associated with dense accumulation of mixed inflammatory/immune cells. These cells, composed of neutrophils and lymphocytes, appeared to juxtapose apoptotic osteoclasts. It is suggested that the pathophysiologic mechanism(s) underpinning ONJ may involve the interaction between bisphosphonates and compromised vitamin D functions in the realm of skeletal homeostasis and innate immunity.

MESENCHYMAL CHONDROSARCOMA OF THE JAWS

Abstract Mesenchymal chondrosarcoma is a rare malignant tumor with distinctive clinical and pathologic features. A thorough analysis of twenty-two cases of mesenchymal chondrosarcoma of the jaws in the world literature and of a current case reveals the following distinguishing features: (1) a dramatic predilection for occurrence in the second and third decades; (2) a high relative incidence in facial bones and ribs; (3) a distinct histology; and (4) poor prognosis. Reporting of this entity separately from ordinary chondrosarcomas of the jaws is encouraged, and reasons for inconsistency in the literature are discussed.

Extracondylar osteochondromas of the jaws

A review of the literature and the addition of two new cases have revealed that according to a histologic criterion there are presently twenty reported cases of osteochondroma of the jaws located outside the condyles. Although most of the extracondylar lesions have occurred on the coronoid process, cases are now reported on the maxilla and the body of the mandible. The clinical features of these lesions are compared with those located in the condyle, and the radiographic and surgical approaches of the extracondylar lesions are discussed.

The distribution of the antimicrobial protein, calprotectin, in normal oral keratinocytes.

Calprotectin is a heterodimeric peptide isolated from neutrophil cytosol that exhibits profound antimicrobial effects. Using monoclonal antibody MAC 387, calprotectin was found to be expressed in oral keratinocytes from normal, non-inflamed oral mucosa. Orthokeratinized sites including the attached gingiva and hard palate expressed low levels of calprotectin with a restricted pattern; immunoreactants were identified only within subcorneal keratinocytes. Parakeratinized mucosa from the lips, soft palate, tongue and buccal mucosa expressed calprotectin in a more widespread, yet variable pattern, immunoreactants being detectable in only a portion of the spinous layer in some cases whereas in others the pattern of expression was more topographically diffuse. Antigen was not detected in basilar and lower strata cells. Both cytoplasmic and nuclear decoration could be identified. The results indicate that oral mucosa harbours an antimicrobial deterrent to micro-organisms that may enhance the physical epithelial barrier of host defence.

Heterogeneous Nuclear Ribonucleoprotein G Shows Tumor Suppressive Effect against Oral Squamous Cell Carcinoma Cells

Purpose: Heterogeneous nuclear ribonucleoproteins (hnRNP) are nucleic acid binding proteins involved in RNA processing. We found that hnRNP G is expressed in normal human oral epithelial cells while frequently not found in the cells derived from human oral squamous cell carcinomas (HOSCC). The current study was designed to test the hypothesis that hnRNP G is a tumor suppressor. Experimental Design: We investigated the expression levels of hnRNP G protein in normal, precancerous, and malignant oral tissues by in situ immunohistochemistry. In addition, wild-type or mutant hnRNP G was ectopically overexpressed in HOSCC cells and their effects on cellular replication kinetics, colonogenic efficiency, anchorage-independent growth, and in vivo tumorigenicity were determined. Results:In situ immunohistochemical staining showed robust presence of hnRNP G in the basal cell layers of normal oral epithelium but the level of its staining was markedly reduced in dysplastic or cancerous tissues. Ectopic expression of wild-type hnRNP G in cancer cells lacking hnRNP G expression or containing mutant hnRNP G resulted in severe retardation of proliferation, reduction of colonogenic efficiency, loss of anchorage-independent growth, and reduction of in vivo tumorigenicity in immunocompromised mice. In addition, hnRNP G overexpression led to up-regulation of the expression of TXNIP, a cell cycle inhibitory gene, and significantly reduced the expression of the genes that promote cellular proliferation, such as EGR1, JUND, JUNB, FOS, FOSL1, ROS, and KIT. Conclusions: These results indicate that hnRNP G is a tumor suppressor against HOSCC but its mechanisms of action remain to be further investigated.

Characteristics and Prognostic Factors of Osteosarcoma of the Jaws: A Retrospective Cohort Study

IMPORTANCE Osteosarcoma of the jaws is rare and clinically distinct from osteosarcoma of the long bones of the body with different treatment and outcomes. The literature on these tumors is limited to case reports and small case series mostly from single institutions. We used data from the population-based national Surveillance, Epidemiology and End Results (SEER) cancer registry to determine the epidemiology and prognostic factors associated with osteosarcoma of the jaws. OBJECTIVE To investigate the epidemiologic characteristics and prognostic factors for survival in patients diagnosed with osteosarcoma of the jaws. DESIGN, SETTING, AND PARTICIPANTS A retrospective, population-based cohort study of 541 patients in the SEER tumor registry diagnosed with osteosarcoma of the jaws from 1973 through 2011 were reviewed. EXPOSURES Patients had been treated with surgery, radiation, both, or neither. MAIN OUTCOMES AND MEASURES Overall and disease-specific survival. RESULTS A total of 541 patients diagnosed with osteosarcoma of the jaws were identified (49.9% male and 50.1% female, with a mean age of 41.3 years). Kaplan-Meier analysis demonstrated an overall survival (OS) and disease-specific survival (DSS) of 53% and 62%, respectively, at 5 years and 35% and 54%, respectively, at 10 years. Multivariate Cox regression analysis revealed that independent predictors of OS and DSS included age at diagnosis (hazard ratio [HR], 1.03; 95% CI, 1.02-1.04 [P < .001] for OS; and HR, 1.03; 95% CI, 1.02-1.05 [P < .001] for DSS); stage at presentation (HR, 1.37; 95% CI, 1.10-1.71 [P = .006] for OS; and HR, 1.34; 95% CI, 1.01-1.76 [P = .04] for DSS); and surgical resection (HR, 0.31; 95% CI, 0.16-0.60 [P < .001] for OS; and HR, 0.22; 95% CI, 0.09-0.56 [P = .001] for DSS). Tumor size was not significant for OS (HR, 1.00; 95% CI, 1.00-1.01 [P = .11] but significant for DSS (HR, 1.01; 95% CI, 1.00-1.01 [P = .003]). CONCLUSIONS AND RELEVANCE To our knowledge, this is the largest study to date investigating prognostic factors for survival in patients diagnosed with osteosarcoma of the jaws. Determinants of survival include age at diagnosis, stage at presentation, tumor size, and surgical therapy. Radiation therapy was not associated with improved survival, reflecting the controversy surrounding its use in clinical literature.

Herpes simplex virus enhances the 7,12-dimethylbenz[a]anthracene (DMBA)-induced carcinogenesis and amplification and overexpression of c-erb-B-1 proto-oncogene in hamster buccal pouch epithelium☆

We studied the effects of herpes simplex virus type 1 (HSV-1) inoculation and topical 7,12-dimethylbenz[a]anthracene (DMBA) application, alone or in combination, on the carcinogenesis and on the amplification and expression of various cellular proto-oncogenes in hamster buccal pouch tissue. Topical DMBA treatment produced tumor formation in pouches, but HSV-1 inoculation, alone caused no neoplastic changes. In pouch tissues receiving both DMBA application and HSV-1 inoculation, the development of initial leukoplakia and tumor has hastened and enhanced in comparison with those receiving DMBA alone. Topical DMBA application to pouch tissue induced an amplification and an increase in the expression of cellular erb-B-1 (c-erb-B-1) proto-oncogene in the epithelial tissue, whereas repeated infection with HSV-1 alone did not. Topical DMBA combined with HSV-1 inoculation, however, resulted in greater amplification and expression of c-erb-B-1 proto-oncogene in the pouch epithelial tissue compared to the DMBA alone. These data indicate that HSV-1 inoculation significantly increases the carcinogenic activity of DMBA, in part, by probably enhancing DMBA-induced amplification and expression of c-erb-B-1 proto-oncogene in hamster buccal pouch tissue.

Glomangiosarcoma with metastasis to the maxilla

A thorough review of the literature disclosed very little information on glomangiosarcoma with no reported cases of verified metastases. We present a case which may be the first instance of oral metastatic glomangiosarcoma to be reported in the literature.

Psychoneuroimmunology in Oral Biology and Medicine

Abstract: Rheumatoid arthritis involves psychoneuroendocrine‐immunopathological comorbidities. In the stoma, patients with rheumatoid arthritis frequently show signs of periondontal disease consequent to elevated levels of crevicular proinflammatory cytokines. It is not clear whether rheumatoid arthritis may manifest in association with immunopathological manifestations of the oral soft mucosa. Oral lichen planus (OLP), first described by E. Wilson in 1859, is a T‐cell‐mediated inflammatory disease whose lesions characteristically lack B cells, plasma cells, immunoglobulin. or complement. It is increasingly well characterized and recognized as a model for psychoneuroimmunology research in oral biology and medicine. To date, we have shown an association between changes in hypothalamic‐pituitary‐adrenal (HPA) regulation, systemic markers of cellular immunity and mood states, with clinical stages of OLP (i.e., atrophic vs. erosive vs. bullous lesions). We report significant associations (p < 0.05) between the stage of OLP, HPA deregulation, and altered distribution and functional responses of naïve CD4+ cells. We emphasize the need to study in greater details the psychoneuroendocrine‐immune inter‐relationships in OLP, and we propose a novel neuroimmune hypothesis for OLP.

LCK, survivin and PI-3K in the molecular biomarker profiling of oral lichen planus and oral squamous cell carcinoma

T cell signaling is critical in oral lichen planus (OLP) based on the pathogenesis of this chronic inflammatory autoimmune mucocutaneous lesion. Lck plays a key role in T cell signaling; ultimately this signaling affects other targets such as PI-3K. Excessive activity in PI-3K inhibits apoptosis and promotes uncontrolled cell growth. Molecular biomarker profiling in OLP, Chronic Interface Mucosities (CIM), Epithelial Dysplasia (EpD) and Oral Squamous Cell Carcinoma (SCCA) with application of the principle of biomarker voting may represent a new frontier in the diagnosis, assessment and the arguable debate of OLP transformation to cancer. The presence of Lck, PI-3K and Survivin, a cancer specific anti-apoptotic protein was assessed, using immunohistochemistry and tissue micro-array on patient samples, in OLP, SCCA, CIM and EpD. Lck expression was very high in 78.6 % of OLP patients compared to 3.7% in SCCA; PI-3K was high in 63% of SCCA, 100% of EpD, and 35.7% OLP cases. Survivin was high in 64.3% of OLP cases, 96.3% of SCCA, and 100% of EpD. CIM cases may be slightly different molecularly to OLP. Taken together, our data suggest that biomarker protein voting can be effectively used to isolate high-risk OLP cases. Specifically, we show data with four remarkable cases demonstrating that molecular factors are predictive of histopathology. We conclude that it is safer to treat OLP as premalignant lesions, to adopt aggressive treatment measure in histopathologic described well and moderately differentiated SCCA, and to monitor progress of these diseases molecularly using individualized auto-proteomic approach. The use of Lck inhibitors in OLP management needs to be investigated in the future.