Immunohistopathological characterization and the impact of topical immunomodulatory therapy in oral chronic graft-versus-host disease: A pilot study.

OBJECTIVE: To characterize the immunohistopathological features of oral chronic graft-versus-host disease (cGVHD), and the impact of topical immunomodulatory therapy on the infiltrating cells. MATERIAL AND METHODS: Paired oral cGVHD biopsies obtained before (n = 12) and 1 month after treatment (n = 12) with topical dexamethasone (n = 8) or tacrolimus (n = 4) were characterized by immunohistochemistry using a panel of CD1a, CD3, CD4, CD8, CD20, CD31, CD62E, CD103, CD163, c-kit, and FoxP3. Controls included acute GVHD (aGVHD; n = 3), oral lichen planus (OLP; n = 5), and normal tissues (n = 5). RESULTS: Oral cGVHD specimens prior to treatment were mainly characterized by basal cell squamatization, lichenoid inflammation, sclerosis, apoptosis, and lymphocytic exocytosis. The infiltrating cells in oral cGVHD primarily consisted of CD3+ , CD4+ , CD8+ , CD103+ , CD163+ , and FoxP3+ cells, which were higher than in normal tissues. Topical dexamethasone or tacrolimus reduced neutrophilic exocytosis, basal cell squamatization, and lichenoid inflammation in oral cGVHD, and dexamethasone reduced the number of CD4+ and CD103+ cells. CONCLUSION: The high expression of CD3, CD4, CD8, CD103, CD163, and FoxP3 confirms that oral cGVHD is largely T-cell-driven with macrophage participation. The impact of topical immunomodulatory therapy was variable, reducing histological inflammatory features, but with a weak clinicopathological correlation. Topical dexamethasone reduced the expression of CD4 and CD103, which may offer novel therapeutic targets.

Oral mucous membrane pemphigoid and pemphigus vulgaris-a retrospective two-center cohort study.

OBJECTIVES: Few studies have compared oral mucous membrane pemphigoid (MMP) and pemphigus vulgaris (PV). Descriptive analysis of oral features, extent of extra-oral involvement, and management outcomes were performed. SUBJECTS AND METHODS: Patients with PV and MMP, the latter with exclusive oral involvement at first presentation, were included. RESULTS: There were 26 MMP (46%) and 31 PV (54%) patients. Desquamative gingivitis was evident in 84% of MMP cases compared to 28% of PV cases (P < 0.05). Non-gingival lesions were noted in 6% of MMP cases compared to 55% of PV cases (P < 0.01). Management of MMP consisted of only topical corticosteroids in 88% of cases while 12% of cases required concomitant systemic therapy. All PV cases (100%) required systemic therapy. No patients with MMP developed scarring or ocular lesions, and one patient (4%) developed cutaneous lesions. Five PV cases (16%) had oral cavity involvement only with three (60%) developing pharyngeal involvement and two (40%) developing cutaneous lesions on follow-up. CONCLUSION: Oral MMP presents primarily as desquamative gingivitis, infrequently involving extragingival sites, and is highly amenable to topical therapy, while PV is a systemic mucocutaneous disease with extensive non-gingival oral lesions that almost always requires systemic therapy.

Oral complications at 6 months after radiation therapy for head and neck cancer.

OBJECTIVE: To examine oral complications 6 months after modern radiation therapy (RT) for head and neck cancer (HNC). METHODS: Prospective multicenter cohort study of patients with HNC receiving intensity-modulated radiation therapy or more advanced RT. Stimulated whole salivary flow, maximal mouth opening, oral mucositis, oral pain, oral health-related quality of life (OH-QOL), and oral hygiene practices were measured in 372 subjects pre-RT and 216 subjects at 6 months from the start of RT. RESULTS: Mean stimulated whole salivary flow declined from 1.09 to 0.47 ml/min at 6 months (p < .0001). Mean maximal mouth opening reduced from 45.58 to 42.53 mm at 6 months (p < .0001). 8.1% of subjects had some oral mucositis at 6 months, including 3.8% with oral ulceration. Mean overall pain score was unchanged. OH-QOL was reduced at 6 months, with changes related to dry mouth, sticky saliva, swallowing solid foods, and sense of taste (p ≤ .0001). At 6 months, there was greater frequency of using dental floss and greater proportion using supplemental fluoride (p < .0001). CONCLUSIONS: Despite advances in RT techniques, patients with HNC experience oral complications 6 months after RT, with resulting negative impacts on oral function and quality of life.

Intraoral features and considerations in face transplantation.

Face transplantation (FT) is a unique and novel addition to the field of reconstructive surgery, which offers new hope to facially disfigured individuals. This review provides an overview of FT, including clinical indications, immunological principles, and functional outcomes, as well as an in-depth characterization of the intraoral hard and soft tissue findings in the six patients transplanted to date at Brigham and Women's Hospital in Boston, MA, USA. Six FT recipients underwent comprehensive clinical and radiographic evaluation to assess their intraoral status, function, and overall health. The extra- and intraoral soft tissue was assessed via quantitative sensory testing. The vitality of the transplanted dental hard tissue was evaluated with clinically available testing methods. Native teeth and prostheses were also assessed. Sensation of transplanted oral mucosa varied based on time elapsed from FT, ranging from minimal at 3 months post-FT, to nearly complete recovery by approximately 24 months. There was mixed success with the integration of donor teeth (Patients 1, 4 and 6), including associated occlusal discrepancies. Mucosal complications included constriction at the donor/recipient interface (Patients 2 and 5) and solitary episodes of mucosal rejection presenting as lichenoid inflammation (Patients 2 and 4). Face transplantation represents a pivotal moment in the history of reconstructive surgery and transplant medicine, providing new optimism to patients with gross facial deformities. This report highlights the successes of FT, but also the challenges of transplanting hard and soft tissues to restore complex stomatognathic function. Further attention directed toward comprehensive oral rehabilitation in FT will contribute to improved outcomes, with the ultimate goal of restoring and optimizing patient quality of life.

Oral chronic GVHD outcomes and resource utilization: a subanalysis from the chronic GVHD consortium.

OBJECTIVES: This study evaluated the extent to which oral chronic graft-versus-host disease (cGVHD) consensus assessments are predictive of management across institutions with and without oral medicine (OM) centers, and whether ancillary care guidelines are followed within clinical practice. METHODS: Longitudinal oral cGVHD data were abstracted from the cGVHD Consortium, and additional mouth-specific management data were analyzed across five transplant centers. RESULTS: Seventy-nine patients with 656 visits were observed for a median of 7.1 months with one visit per follow-up month. Ancillary therapies for oral cGVHD were prescribed for 67% of patients for a median of 0.46 months (per follow-up month) at OM centers and 0.78 months at non-OM centers. Patients treated with ancillary therapy were more likely to have an National Institutes of Health (NIH) mouth score of ≥1 (P < 0.001, odds ratio: 5.1) and mouth pain (P = 0.01, odds ratio: 2.6). The odds ratios of receiving ancillary therapy from OM experts were higher than transplant physicians (53%; P = 0.03). CONCLUSIONS: Oral cGVHD consensus assessments corresponding with ancillary therapy use were mouth pain and NIH mouth score, with higher odds ratios of receiving therapy from OM experts. Ancillary care guidelines for oral cGVHD are reflected in academic clinical practice with respect to utilization of recommended prescriptions.

Initial experience of dual maintenance immunosuppression with steroid withdrawal in vascular composite tissue allotransplantation.

Current immunosuppression in VCA is largely based on the experience in solid organ transplantation. It remains unclear if steroids can be reduced safely in VCA recipients. We report on five VCA recipients who were weaned off maintenance steroids after a median of 2 months (mean: 4.8 months, range 2-12 months). Patients were kept subsequently on a low dose, dual maintenance consisting of tacrolimus and mycophenolate mofetil/mycophenloic acid with a mean follow-up of 43.6 months (median = 40 months, range 34-64 months). Early and late acute rejections responded well to temporarily augmented maintenance, topical immunosuppression, and/or steroid bolus treatment. One late steroid-resistant acute rejection required treatment with thymoglobulin. All patients have been gradually weaned off steroids subsequent to the treatment of acute rejections. Low levels of tacrolimus (<5 ng/mL) appeared as a risk for acute rejections. Although further experience and a cautious approach are warranted, dual-steroid free maintenance immunosuppression appears feasible in a series of five VCA recipients.

Placebo effect in burning mouth syndrome: a systematic review.

Placebo controls play a critical role in the evaluation of any pharmacotherapy. This review surveys the placebo arm in 12 randomized controlled trials (RCTs) investigating burning mouth syndrome (BMS) and documents a positive placebo response in 6 of them. On average, treatment with placebos produced a response that was 72% as large as the response to active drugs. The lack of homogeneity in the use of placebos adds to the difficulty in comparing results and aggregating data. Future RCTs investigating BMS would benefit from larger sample sizes, adequate follow-up periods, and use of a standard placebo.

Resource utilization in cancer patients with bisphosphonate-associated osteonecrosis of the jaw.

BACKGROUND AND OBJECTIVE: Bisphosphonate-associated osteonecrosis of the jaw (BONJ) is an emerging oral complication that occurs most commonly in the setting of high-dose bisphosphonate therapy for cancer. The purpose of this study was to estimate the health care-related costs associated with a diagnosis of BONJ in patients with cancer evaluated and managed at one tertiary oral medicine practice. METHODS: This was a retrospective electronic medical record review of cancer patients with BONJ. All health care-related resources were abstracted using a structured chart abstraction tool; data captured included medications, imaging studies, laboratory investigations, procedures, and visits. Standardized references were used to assign costs in 2010 US dollars. RESULTS: Ninety-two cancer patients with BONJ were identified who were followed for a median of 12 months. The median cost of a case of BONJ was $1667 (interquartile range from $976 to $3350). Medication costs comprised the majority (42%) of the total costs, followed by procedural interventions (22%), clinic visits (19.5%), and imaging studies (13.8%). Patient factors associated with higher median costs included a greater number of involved oral quadrants and more advanced BONJ stage. CONCLUSION: There are considerable costs associated with the diagnosis and management of BONJ in patients with cancer, with medications accounting for nearly half of resource expenditures.

Defining the epidemiology of bisphosphonate-associated osteonecrosis of the jaw: prior work and current challenges.

UNLABELLED: Bisphosphonate-related osteonecrosis of the jaw (BONJ) is an adverse effect of bisphosphonate use with a poorly described epidemiology in osteoporosis patients. We examined the literature and two new cohorts for BONJ. The literature suggests an incidence rate of 0.028 % to 4.3 %. Our cohort studies found an incidence of 0.02 % (95 % CI 0.004 %-0.11 %). INTRODUCTION: We examined the epidemiology of BONJ associated with osteoporosis dosing of bisphosphonates. METHODS: First, we systematically searched the literature about osteoporosis BONJ. Identified studies were abstracted by two authors. Second, we attempted to estimate the relative risk of BONJ among bisphosphonate users with osteoporosis. Two different large insurance databases, one from 2005-2007 and another from 2007-2010, combined with medical record review, were searched. The older dataset did not include the International Classification of Diagnoses (ICD) diagnosis code for osteonecrosis of the jaw (ONJ; ICD 733.45). Incidence rates and relative risks were estimated using Cox regression. RESULTS: The literature review produced nine studies of varying quality. The incidence rates for BONJ among osteoporosis patients varied from 0.028 % to 4.3 %. Two prior studies estimated the relative risk of ONJ related to bisphosphonates and found odds ratios of 7.2 and 9.2. Our attempts to estimate the incidence rate of BONJ encompassed 41,957 in the dataset from 2005-2007 and 466,645 in a separate dataset from 2007-2010. From the older dataset, we found 51 potential cases of BONJ using a broad definition of possible ONJ. One case was confirmed by a dentist for a prevalence of 0.02 % (95 % CI 0.004 %-0.11 %) among bisphosphonate users. From the newer dataset, we found 13 possible cases, but none could be confirmed. Most subjects with the ONJ diagnosis code appeared to have had an osteoporosis-related fracture and not ONJ. CONCLUSIONS: The literature suggests a broad range of possible values for the prevalence of BONJ; our estimate fell within the range from prior literature.

Ninety-one osteoporosis patients affected with bisphosphonate-related osteonecrosis of the jaw: a case series.

Bisphosphonate (BP)-related osteonecrosis of the jaw (BRONJ) presents with necrotic bone in the mouth in the setting of BP exposure. It has been studied in cancer patients taking high-dose BP, but BRONJ has also been noted in patients taking lower-dose BP for osteoporosis. The purpose of this study was to characterize the phenotypes and outcomes in a large series of patients with osteoporosis and BRONJ in the setting of BP exposure. We conducted a retrospective case series. The sample was composed of subjects with BRONJ and osteoporosis. Subjects with a history of BP treatment for myeloma or metastatic cancer to the bones were excluded. Descriptive statistics were computed for the study variables. Ninety-one cases of BRONJ met the inclusion criteria. Subjects had a median age of 71 years and were predominantly female (94.5 %). The median time of BP exposure was 60 months (range 2-120). Most subjects were treated with alendronate (82.4 %). The mandible was involved more frequently (58.2 %) than the maxilla (37.3 %). Subjects commonly (65.9 %), but not universally, reported pain. For subjects with treatment outcome data (n = 0), most reported improvement (80.0 %). Although BRONJ is an uncommon condition, the absolute number of cases is fairly large due to the very large number of patients taking BPs for osteoporosis. The findings of this study confirm that BRONJ primarily affects the mandible, a substantial minority present without pain, and patients typically improve with treatment.

Dental Caries Postradiotherapy in Head and Neck Cancer.

BACKGROUND: Treatment for head and neck cancer (HNC) such as radiotherapy (RT) can lead to numerous acute and chronic head and neck sequelae, including dental caries. The goal of the present study was to measure 2-y changes in dental caries after radiotherapy in patients with HNC and test risk factors for caries increment. METHODS: Cancer and dental disease characteristics, demographics, and oral health practices were documented before and 6, 12, 18, and 24 mo after the start of RT for 572 adult patients with HNC. Patients were eligible if they were age 18 y or older, diagnosed with HNC, and planned to receive RT for treatment of HNC. Caries prevalence was measured as decayed, missing, and filled surfaces (DMFS). The association between change in DMFS and risk factors was evaluated using linear mixed models. RESULTS: On average, DMFS increased from baseline to each follow-up visit: 6 mo, +1.11; 12 mo, +2.47; 18 mo, +3.43; and 24 mo, +4.29 (P < 0.0001). The increase in DMFS during follow-up was significantly smaller for the following patient characteristics: compliant with daily fluoride use (P = 0.0004) and daily oral hygiene (brushing twice daily and flossing daily; P = 0.015), dental insurance (P = 0.004), and greater than high school education (P = 0.001). DMFS change was not significantly associated with average or maximum RT dose to the parotids (P > 0.6) or salivary flow (P > 0.1). In the subset of patients who had salivary hypofunction at baseline (n = 164), lower salivary flow at follow-up visits was associated with increased DMFS. CONCLUSION: Increased caries is a complication soon after RT in HNC. Fluoride, oral hygiene, dental insurance, and education level had the strongest association with caries increment after radiotherapy to the head and neck region. Thus, intensive oral hygiene measures, including fluoride and greater accessibility of dental care, may contribute to reducing the caries burden after RT in HNC. KNOWLEDGE TRANSFER STATEMENT: The results of this study can be used by clinicians when deciding how to minimize oral complications related to cancer therapy for patients with head and neck cancer. Identification of modifiable factors (e.g., oral hygiene and prescription fluoride compliance) associated with increased caries risk can minimize radiation caries burden.

Dental panoramic radiographic evaluation in bisphosphonate-associated osteonecrosis of the jaws.

OBJECTIVES: To determine the extent to which clinical and radiographic features of bisphosphonate-associated osteonecrosis of the jaw (BONJ) are correlated. DESIGN: Retrospective case review. METHODS: The records of 39 patients diagnosed with BONJ and examined by panoramic radiography were retrospectively evaluated. The arches were divided into sextants (n = 234) and evaluated for the following signs: sclerosis, surface irregularity, sockets, fragmentation and lysis. MAIN OUTCOME MEASURES: The McNemar, Kruskall-Wallis and equivalency tests were performed to analyze the association between clinical and radiographic signs and BONJ severity. RESULTS: Sixty-two out of 234 sextants were abnormal by clinical criteria and 61 out of 234 sextants demonstrated at least one radiographic abnormality. There was agreement between clinical and radiographic detection in 41 sextants. The data showed equivalency between BONJ diagnosis and both sclerosis and surface irregularity. The correlation between number of clinical sites and any radiographic finding was significant in the maxilla (P < 0.001) but not in the mandible (P = 0.178). The total number of radiographic signs per patient increased with BONJ stage. CONCLUSION: Focal panoramic radiographic findings of sclerosis and surface irregularity correlate with clinical sites of BONJ. This may be a useful and reliable tool to detect early changes of BONJ or to confirm a clinical diagnosis.

Influence of androgens on gene expression in the BALB/c mouse submandibular gland.

Androgens have profound effects on the murine submandibular gland. Our objective was to determine the nature and extent of androgen control of gene expression in the submandibular gland, and to explore the degree to which this might account for known sex differences. Orchiectomized male BALB/c mice were treated with placebo- or testosterone-containing hormone pellets for 14 days. Glands were collected, and total RNA was isolated. Samples were analyzed for differentially expressed mRNAs by CodeLink microarrays, and the data were evaluated with GeneSifter. Androgens significantly (p < 0.05) influenced the expression of over 1300 genes, and many (n = 366) of the genes differentially regulated by androgen treatment were also differentially expressed in males compared with the females in our previous study. These findings support our hypotheses that testosterone extensively influences gene expression in the male submandibular gland, and that many of the sex differences are due to androgens.

Sex-related differences in gene expression in salivary glands of BALB/c mice.

Sex-related differences exist in the structure and function of the major glands in a variety of species. Moreover, many of these variations appear to be unique to each tissue. We hypothesized that this sexual dimorphism is due, at least in part, to gland-specific differences in gene expression between males and females. Glands were collected from male and female BALB/c mice (n = 5/sex/experiment), and total RNA was isolated. Samples were analyzed for differentially expressed mRNAs with CodeLink microarrays, and data were evaluated by GeneSifter. Our results demonstrate that significant (P < 0.05) sex-related differences exist in the expression of numerous genes in the major salivary glands, and many of these differences were tissue-specific. These findings support our hypothesis that sex-related differences in the salivary glands are due, at least in part, to tissue-specific variations in gene expression.

Rheumatoid arthritis: a review and suggested dental care considerations.

BACKGROUND: Rheumatoid arthritis, or RA, is a chronic multisystem disease of presumed autoimmune etiology. It is estimated that arthritis and other rheumatic conditions affect 42.7 million Americans. Medical complications due to RA and its treatment may affect the provision of oral health care. METHODS: The authors undertook an extensive review of the English literature relating to RA and dental care. They used primarily MEDLINE searches, which included such key words as "rheumatoid arthritis" and "dental care" and subsequent appropriate subheadings. While the MEDLINE search spanned the years from 1975 to the present, the most recent literature was prioritized. Appropriate medical and dental textbooks were also used. The authors extrapolated information from selected texts based on its relevance to dentistry, oral health and the role of the dental provider in the overall treatment of RA patients. RESULTS: The authors reviewed nearly 200 articles and seven textbooks. Their determination of the texts' relevance to oral health care was based on content, significance, quality, journal in which articles were published and year of publication. Major features of RA--including its diagnosis, pathophysiology, clinical features and medical treatment--were identified, as well as complications due to treatment modalities and various related oral manifestations and conditions. CONCLUSIONS: Medical complications due to RA and its treatment can affect oral health care. Oral health care providers need to recognize and identify modifications of dental care based on the medical status of patients with RA. Furthermore, oral health care providers play an important role in the overall care of these patients as it release to early recognition, as well as control of the disease. CLINICAL IMPLICATIONS: In most patients with RA, the condition will necessitate few or no changes in routine dental care. However, considerations include the patient's ability to maintain adequate oral hygiene, xerostomia and its related complications, the patient's susceptibility to infections, impaired hemostasis, and untoward drug actions and interactions. Patients with RA may require antibiotic prophylaxis owing to joint replacement and/or immune suppression, glucocorticosteroid replacement therapy and modifications in oral hygiene procedures. Intra- and extraoral conditions such as ulcerations, gingival overgrowth, disease-associated periodontitis and temporomandibular pathology also need to be recognized.

Development of a local Physician Executive Leadership Program.

Dramatic changes are occurring at a rapid pace throughout the United States in virtually all aspects of health care delivery. Physicians, hospitals, consumer groups, and others are thus facing new and greater uncertainties and are forced to adapt to a continually shifting environment. Fundamental change of this magnitude has and will continue to result in the formation of new alliances and organizations within which physicians and others will be forced to function. To participate effectively in these processes of change and to maintain influence within these new organizations, physicians will need leadership and management skills. To address the challenges facing current physician leaders and the need to develop more effective leaders, Sharp HealthCare developed its Physician Executive Leadership Program. This article describes the program and summarizes some of the lessons learned regarding the training of physician executives and leaders in today's changing health care environment.

Physician acceptance of new medical information systems: the field of dreams.

Physicians often fail to embrace a complex information system, may not see its relevance to their practices, and are characteristically reluctant to invest the time and energy to be trained in its use. Why is widespread physician buy-in so difficult to achieve? From physicians overwhelmed with change to failing to begin with an adequate physician base of support, this article explores some of the reasons that physicians demonstrate little buy-in to this process and offers suggestions to help create a more successful implementation. Ways to build acceptance include acknowledging the importance of physicians as customers and training them early and often.

Marketing and the medical specialist in the managed care environment.

Marketing means more than just communicating or advertising to potential patients; marketing means identifying your customers and working to meet or exceed their expectations. There are five key areas of a marketing plan: (1) Establish the foundation, beginning with your mission statement; (2) Assess your marketing environment by internal and external research; (3) Target your efforts, looking at image and perception; (4) Develop your particular mix of product, price, place of distribution, and promotion; and (5) implement and evaluate your marketing process. This article discusses the importance of a marketing plan for the medical specialist and highlights the features unique to a practice working in a system of capitated reimbursement. Applying these principles will help to demonstrate added value, protect the fundamental role of the patient-physician relationship, ensure that our efforts are aligned with professional missions and goals, and ultimately increase profitability and professional success.

The courageous follower.

With the recent changes in the delivery of medical care in the United States, physicians are being thrust into new and unsettling roles. Many are finding themselves for the first time in the role of the follower, subject to myriad types of leadership. Leaders frequently complain that leading physicians is like "herding cats." What are the characteristics of followers? Do physicians make good followers? This article examines the role of the "cats"--what is effective followership, why physicians may fall short in followership skills, and how physicians might become better "followers."

Measurement of oral chronic GVHD: results from the Chronic GVHD Consortium.

Oral chronic GVHD (cGVHD) is a serious complication of alloSCT. Scales and instruments to measure oral cGVHD activity and severity have not been prospectively validated. The objective of this study was to describe the characteristics of oral cGVHD and determine the measures most sensitive to change. Patients enrolled in the cGVHD Consortium with oral involvement were included. Clinicians scored oral changes according to the National Institutes of Health (NIH) criteria, and patients completed symptom and quality-of-life measures at each visit. Both rated change on an eight-point scale. Of the 458 participants, 72% (n=331) had objective oral involvement at enrollment. Lichenoid change was the most common feature (n=293; 89%). At visits where oral change could be assessed, 50% of clinicians and 56% of patients reported improvement, with worsening reported in 4-5% for both the groups (weighted kappa=0.41). Multivariable regression modeling suggested that the measurement changes most predictive of perceived change by clinicians and patients were erythema and lichenoid, NIH severity and symptom scores. Oral cGVHD is common and associated with a range of signs and symptoms. Measurement of erythema and lichenoid changes and symptoms may adequately capture the activity of oral cGVHD in clinical trials but require prospective validation.