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Advances in the design of potential bone-selective drugs for the treatment of various bone-related diseases are creating exciting new directions for multiple unmet medical needs. For bone-related cancers, off-target/non-bone toxicities with current drugs represent a significant barrier to the quality of life of affected patients. For bone infections and osteomyelitis, bacterial biofilms on infected bones limit the efficacy of antibiotics because it is hard to access the bacteria with current approaches. Promising new experimental approaches to therapy, based on bone-targeting of drugs, have been used in animal models of these conditions and demonstrate improved efficacy and safety. The success of these drug-design strategies bodes well for the development of therapies with improved efficacy for the treatment of diseases affecting the skeleton. LINKED ARTICLES: This article is part of a themed issue on The molecular pharmacology of bone and cancer-related bone diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.9/issuetoc.

Next‐generation sequencing provides an opportunity to detect viral species from RNA‐seq data of human tissues, but existing computational approaches do not perform optimally on clinical samples. We developed a bioinformatic method called VirTect for detecting viruses in neoplastic human tissues using RNA‐seq data. Here, we used VirTect to analyze RNA‐seq data from 363 head and neck squamous cell carcinoma (HNSCC) patients and identified 22 human papillomavirus (HPV)‐induced HNSCCs. These predictions were validated by manual review of pathology reports on histopathologic specimens. VirTect showed better performance in recall and accuracy compared to the two existing prediction methods, VirusFinder and VirusSeq, in identifying viral sequences from RNA‐seq data. The majority of HPV carcinogenesis studies thus far have been performed on cervical cancer and generalized to HNSCC. Our results suggest that carcinogenesis of HPV‐induced HNSCC and other cases of HNSCC involve different genes, so understanding the underlying molecular mechanisms will have a significant impact on therapeutic approaches and outcomes. In summary, RNA‐seq together with VirTect can be an effective solution for the detection of viruses from tumor samples and can facilitate the clinicopathologic characterization of various types of cancers with broad applications for oncology.

An opportunistic infection (OI) is a disease of microbial cause or pathogenesis generally thought to occur in hosts with weakened immunity. Oral OIs are associated with many risk factors and pathogens. Causative organisms for oral OIs have unique modes of transmission. The clinical presentation of oral OIs is heterogeneous and diagnosis can be challenging. Therefore, laboratory identification of causative pathogens is useful for definitive diagnosis and targeted therapeutics, and can be achieved by biological, serologic, histologic, and/or molecular methods. Clinical risk assessment and history with review of systems, and accurate diagnosis, treatment, and follow-up, are essential.

Oral lichen planus (OLP) is a common chronic inflammatory disease affecting the oral mucosa. The pathogenesis of OLP is incompletely understood but is thought to be related to the immune system. As the oral cavity is a major reservoir and transmission gateway for bacteria, viruses, and fungi, the microbial composition of the oral cavity could play a role in the pathogenesis of OLP. However, due to limitations of analytic technology and incomplete knowledge of the microbial community in the oral cavity, it is not yet clear which pathogens are associated with OLP. Next-generation sequencing (NGS) is a powerful tool that can help to identify pathogens for many infectious diseases. In this study, we compared host cell gene expression profiles and microbial profiles from OLP patients and matched healthy individuals. We identified activation of the hepatocyte nuclear factor alpha (HNF4A) network in OLP patients and potential pathogens, includingCorynebacterium matruchotii, Fusobacterium periodonticum, Streptococcus intermedius, Streptococcus oralis, andPrevotella denticola. P. denticolais capable of activating the HNF4A gene network. Our findings shed light on the previously elusive association of OLP with various diseases like hepatitis, and indicate that OLP is a T-helper type 17 (Th17)-mediated mucosal inflammatory process. The molecular pathways and microbes identified here can inform future investigations into OLP pathogenesis and development of novel therapeutics for OLP treatment.

Studies of the potential role of bisphosphonates in dentistry date back to physical chemical research in the 1960s, and the genesis of the discovery of bisphosphonate pharmacology in part can be linked to some of this work. Since that time, parallel research on the effects of bisphosphonates on bone metabolism continued, while efforts in the dental field included studies of bisphosphonate effects on dental calculus, caries, and alveolar bone loss. While some utility of this drug class in the dental field was identified, leading to their experimental use in various dentrifice formulations and in some dental applications clinically, adverse effects of bisphosphonates in the jaws have also received attention. Most recently, certain bisphosphonates, particularly those with strong bone targeting properties, but limited biochemical effects (low potency bisphosphonates), are being studied as a local remedy for the concerns of adverse effects associated with other more potent members of this drug class. Additionally, low potency bisphosphonate analogs are under study as vectors to target active drugs to the mineral surfaces of the jawbones. These latter efforts have been devised for the prevention and treatment of oral problems, such as infections associated with oral surgery and implants. Advances in the utility and mechanistic understanding of the bisphosphonate class may enable additional oral therapeutic options for the management of multiple aspects of dental health.

Background Proliferative fasciitis is a benign and reactive lesion involving fibroblasts in the subcutaneous tissues and deep fascia, with a rare occurrence in the head and neck region. It is considered a variant of nodular fasciitis, which could involve trauma as an etiology. Proliferative fasciitis mostly occurs in adults, but cases in children have been reported. Clinically, it can present as an aggressive lesion with pain or no symptoms, mimicking sarcomas. Case Summary We report a case of a 53-year-old woman who presented to our clinic for an evaluation of a reddish lesion of the right mandibular gingiva around the molar areas with a relatively rapid onset. The patient had prediabetes with moderate oral hygiene and no other significant medical history.Intraoral examination revealed a poorly circumscribed gingival lesion on the posterior, Conclusions Because proliferative fasciitis has not been reported in the oral cavity, to our knowledge, and because it poses a diagnostic challenge and can mimic malignancies, it is essential to know the salient diagnostic features to avoid aggressive treatment in patients presenting with such lesions in the oral cavity.

The purpose of this systematic review and meta-analysis was to compare the prognosis of patients with p16 expressing oropharyngeal squamous cell cancers to patients with p16 non-expressing cancers. Clinical outcomes that were evaluated included overall survival, local recurrence, disease-free survival, disease-specific survival, and event-free survival. The following electronic databases were searched: Cochrane Library, MEDLINE (via Pubmed), and Web of Science. Publications were restricted to English language. Studies were limited to controlled clinical trials on the survival rates of patients with oropharyngeal tumors that were p16 expressing, compared to patients with p16 non-expressing tumors, and at least one clinical endpoint reported by trial authors (hazard ratios). Specific ascertainment criteria were applied for inclusion and exclusion of eligible studies. Data was independently extracted in duplicate. This systematic review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analysis PRISMA checklist. Risk of bias was assessed for all included studies, and disagreements between review authors were discussed until an agreement was reached. Eighteen studies were included for final review and meta-analysis. The subgroup meta-analyses, which included survival and recurrence data, showed significantly favorable outcomes for patients with p16 expressing tumors. There is strong evidence to support that patients with p16 expressing oropharyngeal squamous cell cancers have favorable clinical outcomes and prognosis.

The gold-standard periodontal probe is an aging tool that can detect periodontitis and monitor gingival health but is highly error-prone, does not fully characterize the periodontal pocket, and causes pain. Photoacoustic imaging is a noninvasive technique that can address these limitations. Here, a range of ultrasound frequencies between 16–40 MHz were used to image the periodontium and a contrast medium based on cuttlefish ink was used to label the pockets. A 40 MHz ultrasound frequency could spatially resolve the periodontal anatomy, including tooth, gum, gingival margin, and gingival thickness of tooth numbers 7–10 and 22–27. The photoacoustic-ultrasound measurements were more precise (0.01 mm) than those taken with physical probes by a dental hygienist. Furthermore, the full geometry of the pockets could be visualized with relative standard deviations of 10% (n = 5). This study shows the potential for non-invasive monitoring of periodontal health with photoacoustic-ultrasound imaging in the dental clinic. Keywords: Photoacoustic imaging, Periodontal disease, Diagnosis, Gingival thickness, Pocket depth, Periodontal charting, Melanin nanoparticles

The purpose of this systematic review with meta-analysis was to assess the effectiveness of dental interventions in preventing or reducing the incidence of medication-related osteonecrosis of the jaw (MRONJ) in cancer patients receiving antiresorptive therapy, compared to similar control groups receiving no intervention. Randomized controlled trials (RCT), case-controls and cohorts on cancer patients with primary outcome being the prevalence of MRONJ were included. Four electronic databases were searched (Cochrane Library, PubMed, EMBASE and Web of Science) up to February 12, 2018. A total of 409 abstracts were assessed and one case-control, one RCT and four cohort studies with 2332 cancer patients met our inclusion criteria. Risk of bias analysis followed Cochrane's handbook. Risk of bias was unclear for the case-control study and high risk for the RCT and all cohort studies. Five studies utilized preventive measures consisting of an initial examination and performing all necessary dental treatment before patients initiated antiresorptive therapy; one study used specialized post-extraction protocols utilizing plasma-rich in growth factors (PRGF) on cancer patients receiving antiresorptive therapy. Though dental preventive measures decreased MRONJ incidence by 77.3% in six studies with 2332 cancer patients (95% CI = 47.4–90.2%; p = .001) compared to control groups, quality of the evidence was low due to high or unclear risk of bias and the observational nature of five of the included studies. In conclusion, high-quality long-term prospective large sample size studies are needed to confirm these results due to high risk of bias and heterogeneous interventions. No funding.

Brain abscesses are rare but potentially deadly complications of odontogenic infections. This phenomenon has been described mainly in the form of case reports, as large-scale studies are difficult to perform. We compiled a total of 60 previously published cases of such a complication to investigate the predisposing factors, microbiology, and clinical outcomes of intracranial abscesses of odontogenic origin. A systematic review of the literature using the PubMed database was performed. Men accounted for 82.1% of cases, and the mean age was 42.1 years. Caries with periapical involvement and periodontitis were the two most common intra-oral sources, and wisdom tooth extraction was the most common preceding dental procedure. In 56.4% of cases, there were obvious signs of dental disease prior to development of intracranial infection. Commonly implicated microorganisms included Streptococcus viridans (especially the anginosus group), Actinomyces, Peptostreptococcus, Prevotella, Fusobacterium, Aggregatibacter actinomycetemcomitans and Eikenella corrodens. There was an 8.3% mortality rate. Intracranial abscesses can form anywhere within the brain, and appear unrelated to the side of dental involvement. This suggests that hematogenous spread is the most likely route of dissemination.

It is widely thought that inflammation and osteoclastogenesis result in hydroxyapatite (HA) resorption and sequestrum formation during osseous infections, and microbial biofilm pathogens induce the inflammatory destruction of HA. We hypothesized that biofilms associated with infectious bone disease can directly resorb HA in the absence of host inflammation or osteoclastogenesis. Therefore we developed an in vitro model to test this hypothesis.Customized HA discs were manufactured as a substrate for growing clinically relevant biofilm pathogens. Single-species biofilms of Streptococcus mutans, Staphylococcus aureus, Pseudomonas aeruginosa, and Candida albicans and mixed-species biofilms of C albicans plus S mutans were incubated on HA discs for 72 hours to grow mature biofilms. Three different non-biofilm control groups also were established for testing. HA discs were then evaluated by means of scanning electron microscopy, micro-computed tomography metrotomography, x-ray spectroscopy, and confocal microscopy with planimetric analysis. In addition, quantitative cultures and pH assessment were performed. Analysis of variance was used to test for significance between treatment and control groups.All investigated biofilms were able to cause significant (P.05) and morphologically characteristic alterations in HA structure as compared with controls. The highest number of alterations observed was caused by mixed biofilms of C albicans plus S mutans. S mutans biofilm incubated in medium with additional sucrose content was the most detrimental to HA surfaces among single-species biofilms.Our findings suggest that direct microbial resorption of bone is possible in addition to immune-mediated destruction, which has important translational implications for the pathogenesis of chronic bone infections and for targeted antimicrobial therapeutics.

Next generation sequencing (NGS) provides an opportunity to detect viral species from RNA-seq data on human tissues, but existing computational approaches do not perform optimally on clinical samples. We developed a bioinformatics method called VirTect for detecting viruses in neoplastic human tissues using RNA-seq data. Here, we used VirTect to analyze RNA-seq data from 363 HNSCC (head and neck squamous cell carcinoma) patients and identified 22 HPV-induced HNSCCs. These predictions were validated by manual review of pathology reports on histopathologic specimens. Compared to two existing prediction methods, VirusFinder and VirusSeq, VirTect demonstrated superior performance with many fewer false positives and false negatives. The majority of HPV carcinogenesis studies thus far have been performed on cervical cancer and generalized to HNSCC. Our results suggest that HPV-induced HNSCC involves unique mechanisms of carcinogenesis, so understanding these molecular mechanisms will have a significant impact on therapeutic approaches and outcomes. In summary, VirTect can be an effective solution for the detection of viruses with NGS data, and can facilitate the clinicopathologic characterization of various types of cancers with broad applications for oncology.Significance StatementWe developed a new bioinformatics tool, and reported the new inside of HPV carcinogenesis mechanism in HPV-induced head and neck squamous cell carcinoma (HNSCC). This novel bioin-formatics tool and the new knowledge of HPV-induced HNSCC will facilitate the development of target therapies for treating HNSCC.

// Andres Stucky 1 , Parish P. Sedghizadeh 1 , Susan Mahabady 1 , Xuelian Chen 1 , Cheng Zhang 1, 2 , Gang Zhang 1, 3 , Xi Zhang 1, 2 and Jiang F. Zhong 1 1 Division of Periodontology, Diagnostic Sciences and Dental Hygiene, and Division of Biomedical Sciences, Herman Ostrow School of Dentistry, University of Southern California, Los Angeles, CA, USA 2 Department of Hematology and Blood Transfusion, Xinqiao Hospital, Third Military Medical University, Chongqing, P. R. China 3 Department of Oral and Maxillofacial Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing, P. R. China Correspondence to: Andres Stucky, email: astucky@usc.edu Parish P. Sedghizadeh, email: sedghiza@usc.edu Xi Zhang, email: zhangxxi@sina.com Keywords: head and neck cancer, squamous cell carcinoma, HNSCC, single-cell genomics, circulating tumor cells Received: April 13, 2017 Accepted: May 10, 2017 Published: May 19, 2017 ABSTRACT Head and neck squamous cell carcinoma (HNSCC) incidence or rates have increased dramatically recently with little improvement in patient outcomes. There is an unmet need in HNSCC to develop reliable molecular markers capable of evaluating patient risks and advising treatments. This review focuses on recent developments in single-cell molecular analysis of cancer, and its applications for HNSCC diagnosis and treatments. For proof of concept, we examined gene expression levels of 62 patients with HNSCC, and correlate the gene expression profiles to single-cell gene expression profiles obtained from a pilot single-cell study of CCR5-positive breast carcinoma cells. The single-cell molecular analyses complemented the lysate data and reveals heterogeneity of oncogenesis pathways with the cancer cell population. Our single-cell molecular analysis indicated that molecular heterogeneity exists in HNSCC and should be addressed in treatment strategy of HNSCC. Single-cell molecular technology can have significant impact on diagnosis, therapeutic decision making, and prognosis of HNSCC.

Introduction The purpose of this study was to evaluate the number of roots and canal morphology of maxillary permanent first molars in a North American population. Methods Three hundred seventeen cases with bilateral maxillary first molars were included. All images from cone-beam computed tomography were carefully reviewed by 2 endodontists. Frequency of number of roots, presence of an additional mesiobuccal canal (MB2), and Vertucci canal type for each root were tabulated. Age, gender, and ethnicity differences were calculated with the χ 2 test. The intra-rater reliability was assessed by using the Cohen kappa statistic. Results The fused root rate was 0.9%. The occurrence of 3-rooted maxillary first molars differed between left and right sides ( P = .03). MB2 occurrence only showed statistically significant differences among age groups ( P = .005). In the mesiobuccal roots, the most common Vertucci classifications of canal types were type IV (2-2, 41.9%), type I (1, 28.3%), and type II (2-1, 26.3%). There was a statistically significant difference in Vertucci classification of canal type among 5 ethnic groups (African American, Asian, Hispanic, Other, and Non-Hispanic white, P Conclusions Cone-beam computed tomography facilitates the identification of root and canal configuration. The information gained about the tooth anatomy and canal morphology before treatment could potentially facilitate root canal therapy.

The connection between antiresorptive medications, like bisphosphonates and denosumab, and osteonecrosis of the jaw has been well studied in the literature. A 10-year retrospective case-control analysis of the patient population at the University of Southern California, Herman Ostrow School of Dentistry, found a robust population of patients of record with a history of bisphosphonate or denosumab use and a significant subset of those patients had medication-related osteonecrosis of the jaw (MRONJ). This study explores the demographic and clinical factors associated with risk for MRONJ in patients taking antiresorptive medications. Multivariate analysis indicated that patients at greatest risk were over 60 years of age, female sex, Asian race, had cancer as a comorbidity, had a history of tooth extraction, and also patients on long-term antiresorptive pharmacotherapy. The findings of this study should help guide clinicians to identify patients at high risk for MRONJ, and thus patients that would benefit from risk reduction and prevention protocols.

Introduction The purpose of this study was to evaluate the reliability and accuracy of cone-beam computed tomographic (CBCT) imaging against the histopathologic diagnosis for the differential diagnosis of periapical cysts (cavitated lesions) from (solid) granulomas. Methods Thirty-six periapical lesions were imaged using CBCT scans. Apicoectomy surgeries were conducted for histopathological examination. Evaluator 1 examined each CBCT scan for the presence of 6 radiologic characteristics of a cyst (ie, location, periphery, shape, internal structure, effects on surrounding structure, and perforation of the cortical plate). Not every cyst showed all radiologic features (eg, not all cysts perforate the cortical plate). For the purpose of finding the minimum number of diagnostic criteria present in a scan to diagnose a lesion as a cyst, we conducted 6 receiver operating characteristic curve analyses comparing CBCT diagnoses with the histopathologic diagnosis. Two other independent evaluators examined the CBCT lesions. Statistical tests were conducted to examine the accuracy, inter-rater reliability, and intrarater reliability of CBCT images. Results Findings showed that a score of ≥4 positive findings was the optimal scoring system. The accuracies of differential diagnoses of 3 evaluators were moderate (area under the curve = 0.76, 0.70, and 0.69 for evaluators 1, 2, and 3, respectively). The inter-rater agreement of the 3 evaluators was excellent (α = 0.87). The intrarater agreement was good to excellent (κ = 0.71, 0.76, and 0.77). Conclusions CBCT images can provide a moderately accurate diagnosis between cysts and granulomas.

Schaudinn C , Jaramillo D , Freire MO , SedghizadehPP , Nguyen A , Webster P , Costerton JW , Jiang C. Evaluation of a nonthermal plasma needle to eliminateex vivo biofilms in root canals of extracted human teeth.International Endodontic Journal. Aim To evaluate the efficacy of a nonthermal plasma(NTP) at atmospheric pressure on ex vivo biofilm inroot canals of extracted teeth.Methodology Intracanal contents from three teethwith root canal infections were collected, pooled andgrown in thirty-five microCT-mapped root canals ofextracted and instrumented human teeth. One groupof teeth was treated with NTP, another with 6%NaOCl and one set was left untreated. The intracanalcontents from twenty-seven teeth (nine teeth in eachgroup) were plated on agar and colony forming unitswere determined. Parametric test of one-way analysisof variance ( ANOVA ) was used to analyse statisticalsignificance. The remaining teeth were cut open,stained with LIVE/DEAD and examined with confo-cal laser scanning microscopy.Results The untreated root canals were coveredwith biofilm of varying thickness. Treatment withnonthermal plasma decreased the number of viablebacteria in biofilms by one order of magnitude, whilstthe NaOCl control achieved a reduction of more thanfour magnitudes. Both the NTP and the NaOCl treat-ment results were significantly different from the neg-ative control (P < 0.05).Conclusion The nonthermal plasma displayed anti-microbial activity against endodontic biofilms in rootcanals, but was not as effective as the use of 6%NaOCl.Keywords: biofilm, Endodontics, micro-CT, non-thermal plasma.

Background Oral mucositis occurs in patients undergoing chemoradiation for cancer treatment. It is believed that colonization of ulcerated mucosa by bacteria, fungi and virus results in secondary infections. The effect of chlorhexidine (CHX) on the incidence and severity of oral mucositis in cancer patients was evaluated in this review. Methods Studies were limited to randomized placebo-controlled trials. Three databases were searched: MEDLINE (via PubMed), Web of Science and the Cochrane Library up to May 25, 2016. Results Ninety-eight abstracts were evaluated by three independent reviewers. Twelve studies met the criteria for inclusion. Four of these studies were assessed at unclear risk of bias and eight of them at high risk. Of the 12 studies, 9 were included in two meta-analyses. Pooled results showed that chlorhexidine did not significantly reduce incidence of mucositis compared to placebo (p=0.129), nor chlorhexidine did significantly reduce the severity of mucositis (p=0.127), though subgroup analysis in the chemotherapy group showed a trend toward significance (p=0.054). Side-effects reported in the included studies were teeth staining and altered taste perception. Conclusions This systematic review found that chlorhexidine is not significantly effective in reducing the severity of mucositis (moderate quality of evidence) nor in preventing the incidence of mucositis (low quality of evidence). However, more studies are needed in patients receiving chemotherapy only, as a positive trend toward significance was found (p=.054). This article is protected by copyright. All rights reserved.

We hypothesized that patients with bisphosphonate (BP)-related osteonecrosis of the jaw (BRONJ) accumulate higher levels of BP in bone than those without BRONJ.Using the Pmetrics package and published data, we designed a population pharmacokinetic model of pamidronate concentration in plasma and bone and derived a toxic bone BP threshold of 0.2 mmol/L. With the model, and using patient individual BP duration and bone mineral content estimated from lean body weight, we calculated bone BP levels in 153 subjects.Mean bone BP in 69 BRONJ cases was higher than in 84 controls (0.20 vs 0.10 mmol/L, P0.001), consistent with the toxic bone threshold of 0.2 mmol/L. BRONJ was also associated with longer duration BP therapy (5.3 vs 2.7 years, P0.001), older age (76 vs 70 years, P0.001), and Asian race (49% vs 14%, P0.001).Our model accurately discriminated BRONJ cases from controls among patients on BP therapy.

Objective Bacterial biofilms play a role in the pathogenesis of bisphosphonate-related osteonecrosis of the jaw (BRONJ). The purpose of this preliminary study was to test the hypothesis that the extracellular filaments observed in biofilms associated with BRONJ contain electrically conductive nanowires. Study Design Bone samples of patients affected by BRONJ were evaluated for conductive nanowires by scanning electron microscopy (SEM) and conductive probe atomic force microscopy (CP-AFM). We created nanofabricated electrodes to measure electrical transport along putative nanowires. Results SEM revealed large-scale multispecies biofilms containing numerous filamentous structures throughout necrotic bone. CP-AFM analysis revealed that these structures were electrically conductive nanowires with resistivities on the order of 20 Ω·cm. Nanofabricated electrodes spaced along the nanowires confirmed their ability to transfer electrons over micron-scale lengths. Conclusions Electrically conductive bacterial nanowires to date have been described only in environmental isolates. This study shows for the first time that these nanowires can also be found in clinically relevant biofilm-mediated diseases, such as BRONJ, and may represent an important target for therapy.

Granular cell tumor (GCT) of the oral cavity is a benign lesion. Half of oral GCTs demonstrate pseudocarcinomatous hyperplasia (PCH) of the mucosa which can mimic invasive islands of oral squamous cell carcinoma (SCC). Such similarity can be confusing when diagnosing or evaluating the two conditions, potentially leading to misdiagnosis or misclassification. Indeed, several misdiagnosed cases of oral GCT have been reported in the literature as OSCC or malignant oral GCT that resulted in unnecessary aggressive treatment for the affected patients. The aim of this study was to investigate if the cytokeratin pattern of the PCH can help in differentiating GCT from oral SCC. To distinguish between these two entities, we examined 12 patient specimens of oral GCT-PCH and oral SCC histologically and via immunohistochemistry (IHC) for CK13, CK17 and P75. The results suggest that the cytokeratin profile of PCH is similar to that of oral SCC. Therefore, consideration of IHC findings for epithelial markers alone may lead to erroneous diagnosis; thus, the presence of the granular tumor underneath the PCH and its immunopositivity for P75 or other neural definition markers can be essential to identify the underlying tumor and exclude oral SCC. Finally we recommend more studies on the molecular biology of PCH to understand how it can mimic oral SCC histologically without harboring its malignant phenotype clinically, which could have significant translational potential for understanding invasive oral SCC.

Oral Diseases (2012) 18, 625–632 Non-exposed bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a newly reported complication arising from bisphosphonate therapy that presents with atypical symptoms and no apparent mucosal fenestration or exposure of necrotic bone. The clinical observation of the presence of necrotic bone underneath normal epithelial coverage was not conclusive for the diagnosis of BRONJ based on current guidelines established by the American Association of Oral and Maxillofacial Surgeons (AAOMS) and the American Society for Bone and Mineral Research (ASBMR), which specify the presence of clinically exposed necrotic bone for more than 8 weeks. Hence, the purpose of this review is to critically assess the current guidelines for diagnosis and management of BRONJ and propose a modified staging system and treatment guidelines to properly address the non-exposed variant of BRONJ lesions.

A recent paradigm shift in microbiology affects orthopaedic surgery and most other medical and dental disciplines because more than 65% of bacterial infections treated by clinicians in the developed world are now known to be caused by organisms growing in biofilms. These slime-enclosed communities of bacteria are inherently resistant to host defenses and to conventional antibacterial therapy, and these device-related and other chronic bacterial infections are unaffected by the vaccines and antibiotics that have virtually eliminated acute infections caused by planktonic (floating) bacteria. We examine the lessons that can be learned, within this biofilm paradigm, by the study of problems (e.g. non-culturability) shared by all biofilm infections and by the study of new therapeutic options aimed specifically at sessile bacteria in biofilms. Orthopaedic surgery has deduced some of the therapeutic strategies based on assiduous attention to patient outcomes, but much can still be learned by attention to modern research in related disciplines in medicine and dentistry. These perceptions will lead to practical improvements in the detection, management, and treatment of infections in orthopaedic surgery.

Microbial biofilms have been observed and described in bone specimens of patients with bisphosphonate (BP)-associated osteonecrosis of the jaw (BONJ) and investigators are more recently suggesting that this condition essentially represents an osteomyelitis of the jaw clinically, with greater susceptibility in some patients on BP therapy. This article explains the role of microbial biofilms in BONJ and also discusses associated factors in the disease pathogenesis, which include BP effects on bone remodeling, anti-angiogenesis, matrix necrosis, microcracks, soft tissue toxicity, and inflammation and wound healing. Recent findings suggest a key role for microbial biofilms in the pathogenesis of BONJ; this has important therapeutic implications because biofilm organisms represent a clinical target for prevention and treatment efforts aimed at reducing the significant morbidity and costs associated with this condition.

Of the approximately 8,400 children born each year in the US with cytomegalovirus (CMV)-induced birth defects, more than one third exhibit hypoplasia and hypocalcification of tooth enamel. Our prior studies indicated that CMV severely delayed, but did not completely interrupt, early mouse mandibular first molar morphogenesis in vitro. The aim of the present study was to examine the effects of CMV infection on progressive tooth differentiation and amelogenesis. Since initial CMV infection in human fetuses can occur at different developmental times, we varied the stage of initial viral infection (that is, Cap stage, Early Bell stage and Bell stage), as well as the duration of infection. CMV infection of embryonic mouse mandibular first molars in vitro induces tooth dysmorphogenesis and enamel defects in a developmental stage- and duration-dependent manner. Cap stage- and Early Bell stage-infected molars exhibit enamel agenesis and Bell stage-infected molars exhibit enamel hypoplasia. This viral-induced pathology is coincident with stage-dependent changes in Amelx, Enam and Dspp gene expression, distribution of amelogenin, enamelin and DSP proteins, cell proliferation localization and dedifferentiation of secretory ameloblasts. Importantly, our data indicate that specific levels of Amelx and Dspp gene expression define whether mouse CMV induces enamel agenesis or hypoplasia.

A novel coaxial tubular device capable of generating a 2.5 cm long pencil-like plasma plume in ambient atmosphere has recently been developed to disinfect root canal systems during endodontic treatment. Powered with short (≈100 ns), intense (6 kV) electric pulses at 1 kHz, the plasma dental probe is safe for operation, electromagnetic noise-free, with low power consumption (an average power of ≈1 W) and minimal heating of materials under treatment. It thus has the essential features required for oral and dental disinfection. In this communication, we present the design of the device and evidence that the plasma dental probe is effective for tooth surface disinfection. Scanning electron microscopy shows complete destruction of endodontic biofilms for a depth of 1 mm inside a root canal after plasma treatment for 5 min. Plasma emission spectroscopy identifies atomic oxygen as one of the likely active agents for the bactericidal effect.

Background Periodontitis is a classic example of biofilm-mediated diseases. Methods The authors reviewed selected publications in English-language peer-reviewed journals with respect to microbial biofilms, focusing on representative works that provided a historical to a contemporary perspective on periodontal oral biofilms in the larger context of biofilm microbiology. Results Developments in advanced microscopy and molecular microbiology have allowed scientists to examine and characterize microbial biofilm-mediated diseases, such as periodontitis, more accurately than in the past. Conclusions Periodontitis, like other biofilm infections, is refractory to antibiotic agents and host defenses because the causative microbes live in complex communities that persist despite challenges that range from targeted antibiotic agents to phagocytosis. Clinical Implications The regular delivery of nontargeted antibiofilm agents may be an effective strategy for treating biofilms, especially if these agents include oxidative agents that dissolve the biofilm matrix.

Background Initial reports of osteonecrosis of the jaw (ONJ) secondary to bisphosphonate (BP) therapy indicated that patients receiving BPs orally were at a negligible risk of developing ONJ compared with patients receiving BPs intravenously. The authors conducted a study to address a preliminary finding that ONJ secondary to oral BP therapy with alendronate sodium in a patient population at the University of Southern California was more common than previously suggested. Methods The authors queried an electronic medical record system to determine the number of patients with a history of alendronate use and all patients receiving alendronate who also were receiving treatment for ONJ. Results The authors identified 208 patients with a history of alendronate use. They found that nine had active ONJ and were being treated in the school's clinics. These patients represented one in 23 of the patients receiving alendronate, or approximately 4 percent of the population. Conclusions This is the first large institutional study in the United States with respect to the epidemiology of ONJ and oral bisphosphonate use. Further studies along this line will help delineate more clearly the relationship between oral BP use and ONJ. Clinical Implications The findings from this study indicated that even short-term oral use of alendronate led to ONJ in a subset of patients after certain dental procedures were performed. These findings have important therapeutic and preventive implications.

Objective. The aim of this report was to examine the oral cancer incidence by sex, race/ethnicity, and anatomical subsite. Study design. Data from the California Cancer Registry (CCR) were used to calculate the age-adjusted incidence rates of invasive oral squamous cell carcinoma (OSCC) by sex, race/ethnicity, and anatomical subsite among residents in California during 1988 to 2001. Results. Although non-Hispanic (NH) black men have the highest overall incidence rate for OSCC, NH whites and NH blacks have similar incidence patterns by subsite, but the male-to-female (M:F) rate ratio is higher among NH blacks. The OSCC incidence rates for Hispanics are much lower than those for NH whites and NH blacks and similar to those of Asians. The Asian ethnic groups display dramatic variations in terms of the subsite-specific incidence rates and M:F rate ratios. Conclusion. The findings illustrate the heterogeneity and complexity of oral cancer by anatomical location and the importance of cultural habits and behavioral factors in the development of oral cancer. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008;105:470-80)

Background Toxic epidermal necrolysis (TEN) is a rare and potentially fatal adverse dermatologic reaction, often secondary to drug intake. Methods and results We report a case of an adult male who developed TEN that was complicated by a sepsis-induced coma lasting a period of 3 months. Although the patient eventually recovered, severe oral mucosal involvement during the course of disease resulted in frenum-like fibrotic bands that connected movable oral mucosa (tongue and lips) to attached oral mucosa (gingiva). This complication was painful and also affected his ability to speak and maintain adequate oral hygiene, requiring surgical intervention to restore structure and function. Conclusions This oral manifestation in relation to TEN is rarely reported in the literature and represents a preventable complication.

Oral mucosal melanoma (OMM) is an extremely rare malignancy, accounting for < 0.5% of all melanomas and all oral malignancies. The rarity of OMM, the heterogeneity in clinical and histopathologic appearances, and the paucity of molecular and genetic studies to date have limited our knowledge of the etiopathogenesis of these cancers. A 39-year-old Hispanic male presented for evaluation of a large, pigmented, plaque-like and nodular growth of the maxillary gingival and palatal mucosa. On presentation, a presumptive clinical diagnosis of mucosal melanoma was made, which was confirmed by incisional biopsy with subsequent histopathologic evaluation. Macroscopically, the morphology and highly pigmented nature of the tumor was suggestive of a rarer subtype of melanoma known as animal-type melanoma, also referred to as pigmented epithelioid melanocytoma. However, microscopically, the tumor showed histopathologic features consistent with a high-grade acral (mucosal) lentiginous melanoma with overt cytomorphologic features of malignancy in addition to showing prominent pigment synthesis resembling animal-type melanoma. A detailed search of the literature did not identify a previous report of OMM with prominent pigment synthesis resembling animal-type melanoma. Identification of melanoma subtypes has specific implications for therapeutic approach, and thus their recognition is important to successful patient management.

Purpose Biofilm theory has emerged to explain the etiology of the chronic infections that have come to constitute between 65% to 80% of the microbial diseases treated by physicians in the developed world. The purpose of this article is to report for the first time the observation of multispecies microbial biofilms on affected bone in patients with osteonecrosis of the jaws (ONJ) secondary to bisphosphonate therapy. Patients and Methods A program has been established at the University of Southern California to monitor and evaluate patients with ONJ as a multidisciplinary collaboration between the School of Dentistry, Center for Biofilms, Center for Craniofacial Molecular Biology and the Keck School of Medicine. From this cohort, 4 patients with active ONJ who were scheduled for necessary treatment in the form of sequestrectomy gave informed consent for this study. Bone samples were evaluated using conventional histopathologic techniques and scanning electron microscopy, a technique applicable to biofilm characterization. Results Bone specimens from affected sites in all patients showed large areas occluded with biofilms comprising mainly bacteria, and occasionally yeast, embedded in extracellular polymeric substance. The number of bacterial morphotypes in the biofilms ranged from 2 to 15, and they included species from the genus Fusobacterium , bacillus, actinomyces, staphylococcus, streptococcus, Selenomonas , and 3 different types of treponemes. The yeast identified was consistent with Candida species. Co-aggregation was observed between different species within the biofilms. Conclusion These findings have important clinical and therapeutic implications and may suggest a role for microbial biofilms in the disease process of ONJ.

Alveolar ridge augmentation using intraoral autogenous block grafts to augment localized alveolar ridge defects before implant placement is a predictable method. However, large severely atrophic edentulous segments may require extraoral donor sites. The purpose of this study was to evaluate the effectiveness of using intraoral cortical block grafts in combination with particulate human mineralized allograft, in a "tenting" fashion, to augment large atrophic alveolar ridge defects for implant placement.This prospective case study evaluated augmentation in 10 consecutive patients with severely resorbed alveolar ridges missing a minimum of 4 adjacent teeth. Before augmentation, all grafted sites were deemed inadequate for placement of a standard 4-mm-diameter implant. Horizontal ridge augmentation was performed using autologous membranous cortical bone grafts from an oral donor site to tent out the soft tissue matrix and periosteum for the adjacent particulate allograft. The ridges were clinically evaluated 4 to 5 months after augmentation, and 42 implants were placed at that time.Implants were successfully placed at all grafted sites 4 to 5 months after the original graft date. Clinical evaluation of the grafted sites upon re-entry revealed uniform ridge anatomy. All edentulous segments had at least 2 implants placed of at least 4.0 mm diameter. In all, 42 implants were placed into grafted sites in the 10 patients. Implants were checked for osseointegration by using a counter torque of 35 N.cm. One implant failed to integrate. Mean follow-up was 22 months after implant placement. All augmented ridges had retained their functional and esthetic integrity at 1 year after original augmentation.Tenting of the periosteum and soft tissue matrix using a cortical bone block maintains space and minimizes resorption of the particulate allograft volume. In addition, bridging the cortical blocks with particulate bone avoids unaesthetic ridge defects between cortical block grafts in larger ridge defects. The result was a more uniform and esthetic alveolar ridge, capable of maintaining an implant-supported prosthesis. The technique offers predictable functional and esthetic reconstruction of large-volume defects without extensive amounts of autogenous bone. This offers a superior functional and esthetic result than with either cortical or particulate grafting alone.

Aim The objective of this report is to present the clinical experiences of several patients affected with osteonecrosis (ONJ) secondary to bisphosphonate (BP) therapy and to provide a discussion of the specific BPs implicated in this condition. Background ONJ secondary to BP therapy is becoming an increasingly reported complication following dental therapy. This is particularly true of surgical dental procedures such as extractions. BPs are a class of pharmaceuticals used in the treatment of numerous disorders affecting bone, including osteoporosis, cancer metastases to bone, hypercalcemia of malignancy, and multiple myeloma. Although ONJ is a more recently described phenomenon, it is an emerging problem that may be associated with significant morbidity such as oral dysfunction, impaired eating ability, pain, and compromised esthetics resulting in a poor quality of life in affected patients. Case Report This is a description of 13 patients affected with ONJ secondary to BP therapy managed at the Orofacial Pain & Oral Medicine Center, Special Patients Clinic, and Oral and Maxillofacial Surgery Clinic at the University of Southern California, School of Dentistry between October 2005 and April 2007, with a discussion of the specific BPs implicated in this condition, the clinical presentation, management, and follow-up. Summary Thorough reporting of every case of ONJ is important to help advance the understanding of this poorly understood condition. The authors’ approach to care represents a more conservative mode to management than previously described by many investigators. Citation Kumar SKS, Meru MC, Sedghizadeh PP. Osteonecrosis of the Jaws Secondary to Bisphosphonate Therapy: A Case Series. J Contemp Dent Pract 2008 January;(9)1:063-069.

ARONJ is defined as the persistence of exposed necrotic jawbone in the oral cavity for 8 weeks, despite adequate treatment, in a patient with current or previous history of ART and without local evidence of malignancy or prior radiotherapy to the affected region. The pathogenesis of ARONJ is multifactorial, and many risk factors have been associated with disease development and progression. Clinically, patients with ARONJ can be asymptomatic or may present with a wide range of signs and symptoms that are often inflammatory in nature. Radiologic examination is essential for accurate diagnosis and staging of ARONJ and for assessing the extent of disease. Many conditions can resemble ARONJ clinically, radiographically, and histopathologically; therefore, accurate clinical diagnosis should be predicated on careful correlation of medical and dental history, medication history, risk factors, presenting signs and symptoms, and examination and radiologic findings.

Objective Management of medication-related osteone-crosis of the jaw (MRONJ) with active infection can be a serious challenge for clinicians. Based on Association of Oral and Maxillofacial Surgeons (AAOMS) recommendations, we have tested a modified treatment protocol using topical minocycline. Study Design Five patients diagnosed with stage II or III MRONJ lesions were willing to consent to our protocol. In addition to conventional treatment as suggested by the AAOMS, such as, surgical debridement, chlorhexidine irrigation, and systemic antibiotics, we applied 10% minocycline to the lesions once a week for sustained local antibiotic delivery. Results All five patients reported pain relief after the first minocycline application. Complete healing occurred in three patients; case three healed completely after the third application, one case continues to improve toward resolution and one withdraws due to other non-relevant medical problem. Conclusions In this study, we are reporting favorable results using a modified protocol with topical minocycline to treat MRONJ lesions.

Peripheral ossifying fibroma (POF) is a common solitary gingival growth thought to arise from the periodontal ligament. Though the etiology of POF remains unknown, some investigators consider it an inflammatory or reactive process, while others suggest it is a neoplastic process. In this report, we present and discuss a unique case of multicentric POF, affecting the maxillary and mandibular gingiva of a 49-year-old Caucasian female with meticulous oral hygiene and routine dental care. Though biopsy samples from multiple sites revealed similar histopathologic features, consistent with POF, the fact that there was a multicentric presentation is a unique phenomenon for this lesion. Multicentric lesions presenting in the oral and maxillofacial region are not typical, but have been observed in conditions associated with known genetic mutations, such as nevoid basal cell carcinoma syndrome (multiple odontogenic keratocysts), multiple endocrine neoplasia type II (multiple neuromas), neurofibromatosis (multiple neurofibromas) and Gardner syndrome (multiple neoplasms). This case is the first one to demonstrate that there may be a multicentric variant of POF that has not been previously recognized, and given the clinical presentation and multifocal nature of disease, the lesions in this patient are likely the result of genetic mutation(s) that predisposes to gingival soft tissue overgrowths containing mineralized product.

Graft-versus-host disease (GVHD) is an untoward complication of bone marrow transplantation. It is characterized by an immune-mediated attack by donor immune cells against various host cells and tissues, a process which may be associated with significant morbidity in affected patients. Oral lesions are a common sequelae and can serve as a highly predictive index to the presence of systemic GVHD. The oral lesions of GVHD are clinically and histologically lichenoid in nature and can be a challenge in terms of management. Ulcerated and painful mucosal lesions may represent a significant impediment to normal eating habits and nutritional intake, necessitating appropriate diagnosis and treatment. Importantly, recent evidence has indicated that programmed cell death, or apoptosis, is the major constituent in the pathogenesis of GVHD. Apoptosis not only plays a major role in normal growth and ontogeny, but has been shown to contribute to a wide spectrum of both inflammatory and neoplastic disorders. Since knowledge of apoptotic molecular pathways is requisite for understanding GVHD, the purpose of this paper is to provide a fundamental overview of the predominant apoptotic mechanisms implicated in the pathogenesis of GVHD and to relate these findings to the oral complications of the disease. Finally, we will discuss management strategies for diagnosing and treating the oral lesions of GVHD. By explicating the molecular events in the apoptotic pathway, unique therapeutic and pharmacologic strategies for regulating apoptosis may be developed in the future, reducing the morbidity associated with conditions like GVHD.

Foreign bodies may be embedded in the oral cavity either by traumatic injury or iatrogenically. The commonly encountered iatrogenic foreign bodies are restorative materials like amalgam, obturation materials, broken instruments, needles, and impression materials. This paper describes an asymptomatic presentation of a foreign body in the oral mucosa which clinically appeared like a benign connective tissue tumor.

The histologic finding of a pagetoid epidermotropic growth pattern is associated with a variety of conditions that range from reactive to neoplastic in nature. Included among these conditions is the uncommon skin disorder pagetoid reticulosis. Pagetoid reticulosis may present clinically as a solitary, indolent plaque-like lesion. Conversely, it may manifest as a more generalized clinically aggressive disease. The generalized form may develop into systemic lymphoma, leading to severe morbidity and death. We present a case of pagetoid reticulosis of the perioral region, a rare anatomic site for this condition. Histopathologic and immunohistochemical findings were consistent with a diagnosis of isolated pagetoid reticulosis. This review discusses the nature of pagetoid reticulosis and addresses past and current concepts regarding the condition.

Celiac disease (CD) is a condition related to the small intestine's intolerance to gluten. The diagnosis of CD can be difficult, especially because patients may exhibit a wide spectrum of signs and symptoms. It is important to identify this disease process early because affected individuals have an increased risk for developing lymphoma of the gut. Our objective was to evaluate whether patients with CD have a significantly higher prevalence of recurrent aphthous stomatitis compared with the general population, as some investigators have speculated. Therefore, we screened 61 patients with diagnosed CD for the presence of, or a positive history of, aphthous ulcerations. We then statistically compared this data with a randomly selected control population, matched for age and gender, but without CD. Our results demonstrated no significant differences between groups for age, gender, or prevalence of recurrent aphthous stomatitis.

Introduction Gaucher disease is an autosomal recessive systemic condition, and the most common of the lysosomal storage disorders. It is characterized by lipid accumulation in certain cells and organs, particularly macrophages, which appear on light microscopy as ’Gaucher cells’ or vacuolated lipid-laden reticuloendothelial cells. Long bone involvement is common in Gaucher disease, whereas craniofacial bone involvement is extremely rare. Reports confirming the diagnoses of Gaucher disease involving craniofacial bones by histopathologic evidence are even rarer. Case presentation A 46-year-old Caucasian Ashkenazi Jewish woman with Gaucher disease presented with jawbone pain and lytic radiographic lesions of her mandible. Surgical biopsy of a mandibular lesion revealed Gaucher cells infiltrating the mandible, which correlated with radiographic and clinical findings, supporting a diagnosis of Gaucher disease with jawbone involvement. Conclusions Lysosomal storage diseases can have head and neck manifestations, and bone involvement in Gaucher disease is common. Therefore, careful consideration of signs and symptoms and medical history, with a thorough review of systems, is important when evaluating patients with lysosomal storage disorders to rule out head and neck involvement of disease. Biopsy may be warranted in some cases for more definitive diagnosis of painful jawbone lesions and to rule out other odontogenic and non-odontogenic conditions in the differential diagnosis.

Bisphosphonate (BP) drugs are a commonly prescribed group of medications used in the treatment of metabolic and oncologic bone disorders. The aim of this study was to conduct a systematic review in order to evaluate whether patients on BP therapy are appropriate candidates for dental implants as compared to patients not taking BP drugs with respect to successful implant osseointegration and the risk of developing bisphosphonate-related osteonecrosis of the jaw. Based on the current literature, a history of oral or intravenous BP use is not an absolute contraindication for dental implant placement, and dental implants can osseointegrate successfully in this patient population. Importantly, the studies currently available on this topic are of moderate to weak strength of evidence with inherent bias and limitations, and hence results must be interpreted in this context. Well-controlled studies with higher strength of evidence and larger population sizes are required to address this topic more accurately in the future.

Numb chin syndrome (NCS) is characterized by facial neuropathy along the distribution of the mental branch of the trigeminal nerve. We report a case of NCS in a 65 year old woman who initially presented to her dentist with nonspecific symptoms that she thought were related to a tooth infection. The patient was otherwise healthy and her medical history was significant for breast cancer treated 20 years prior; her cancer was thought to be in complete remission. Upon clinical examination and conventional dental radiography, no pathology was seen such as odontogenic, periodontal, or jawbone infection. Only paresthesia and hypoesthesia was noted unilaterally in her left chin, jaw and lower lip. A computed tomography scan was obtained for further evaluation and revealed lytic metastatic disease involving the right mandible at the level of the mandibular foramen; lytic lesions of the thoracic vertebrae and multiple pulmonary nodules were also noted. Oncologic referral was made immediately which confirmed a diagnosis of metastatic breast cancer. Familiarity with NCS is important for oral health care providers in order to identify etiology and differential diagnosis, as well as to provide appropriate referral and management.

Human papilloma virus (HPV) is a non-enveloped DNA virus that infects cutaneous and mucosal epithelial cells. Oral lesions of HPV can present as solitary or multifocal lesions, and multifocal lesions can represent a diagnostic challenge clinically with important medicolegal considerations in some cases. We report a unique case of a 12-year-old boy presenting with oral multifocal papillary mucosal lesions which upon biopsy was found to be consistent with a diagnosis of condyloma acuminatum or Heck’s disease histopathologically; in situ hybridization studies also confirmed positivity for low risk HPV subtypes in affected tissue. Based on the pathology results and our clinical protocols, we contacted social servicesto rule out the sexually transmitted disease condyloma. A final diagnosis of Heck’s disease was rendered after clinico-pathologic and social correlation. Cryotherapy with topical anesthesia was used to successfully treat the lesions with no evidence of recurrence on 6 month follow-up.