Hemodynamics of the oral mucosa during cooling: A crossover clinical trial.

Objective: Oral cryotherapy is used to prevent the onset of oral mucositis, a common and debilitating adverse effect following cancer chemotherapy. A protective mechanism associated with oral cooling is thought to be mediated through reduced tissue microcirculation. The aim of the present study was to examine the underlying mechanism associated with oral mucosal cooling by measuring oral microcirculation and tissue oxygen saturation after cooling with ice chips (IC) and an intraoral cooling device (ICD). Study design: In a single-center randomized crossover study, 10 healthy volunteers were assigned (1:1) randomly to the order in which the two intraoral cooling procedures (IC/ICD) were to be commenced. On day 1, half of the study participants started with IC and then crossed over to intraoral cooling with the ICD on day 2, while the other half of the participants undertook the same two procedures in the reverse order. Total and functional capillary density (T/FCD) and tissue oxygen saturation (StO2) measurements were obtained at baseline and 30 min following oral cooling. Results: Following 30 min of oral cooling, a statistically significant difference was found for FCD between IC and ICD (percentage points; +2 vs. -13; p < 0.05). A statistically significant decrease in StO2 was observed with both IC and ICD (%; 13 vs. 10) after 30 min of cooling as compared to baseline (p < 0.05). As for the participants' preference the ICD was preferred over IC by 9 out of 10 participants (p = 0.021). Conclusions: Both microcirculation parameters and tissue oxygen saturation are altered in conjunction with oral cooling, indicating their potential mechanistic contribution towards cryoprevention of oral mucositis.

Cryopreventive temperatures prior to chemotherapy.

The superiority of oral cryotherapy (OC) for prevention of chemotherapy-induced oral mucositis (OM) has been demonstrated in several trials. In clinical settings, cooling is usually initiated prior to the chemotherapy infusion. It then continues during the infusion, and for a period after the infusion has been completed. While the cooling period post-infusion depends on the half-life of the chemotherapeutic drug, there is no consensus on when cooling should be initiated prior to the infusion. The lowest achieved temperature in the oral mucosa is believed to provide the best condition for OM prevention. Given this, it was of interest to investigate when along the course of intraoral cooling this temperature is achieved. In total, 20 healthy volunteers participated in this randomized crossover trial. Each subject attended three separate cooling sessions of 30 min each, with ice chips (IC) and the intraoral cooling device (ICD) set to 8 and 15 °C, respectively. At baseline and following 5, 10, 15, 20 and 30 min of cooling, intraoral temperatures were registered using a thermographic camera. The greatest drop in intraoral temperature was seen after 5 min of cooling with IC, ICD8°C and ICD15°C, respectively. A statistically significant difference, corresponding to 1.4 °C, was seen between IC and the ICD15°C (p < 0.05). The intraoral temperature further declined throughout the 30 min of cooling, showing an additional temperature reduction of 3.1, 2.2, and 1.7 °C for IC, ICD8°C and ICD15°C, respectively.

Moderate temperature reduction is sufficient for prevention of 5-fluorouracil-induced oral mucositis: an experimental in vivo study in rats.

PURPOSE: The current idea of how oral mucositis (OM) develops is primarily based on hypotheses and the early events which precede clinically established OM remain to be demonstrated. Cryotherapy (CT) continues to have considerable promise in clinical settings to reduce chemotherapy-induced OM. Although being effective, the knowledge is scarce regarding the ideal temperature for prevention of OM. Thus, the present study had two main objectives: (i) to develop an animal model to investigate the early events of OM; (ii) to study at what cooling temperature these early events could be abolished. METHODS: Male Sprague-Dawley rats were anaesthetized and given an intravenous bolus dose with the cytostatic drug fluorouracil (5-FU). During the first hour following injection with 5-FU, the oral cavity of the rats was cooled to a mucosal temperature at the range of 15-30 â—‹C, or left uncooled (35 â—‹C), serving as control. After 3-5 days, the rats were euthanized, and the buccal mucosa was excised. Subsequently, mucosal thickness and expression of IL-6 and TNF-α were analyzed with immunohistochemistry and enzyme-linked immunosorbent assay (ELISA). RESULTS: Five days following treatment with 5-FU, a statistically significant thickening of the oral mucosa occurred, and a distinct expression of both IL-6 and TNF-α were observed. The cryo-treated groups (15-30 °C) displayed statistically significantly thinner mucosa as compared to the control group (35 °C). The ELISA showed an increase in expression of the proinflammatory cytokines IL-6 and TNF-α in tissues exposed to 5-FU that were treated with increasing temperatures (15-30 °C). CONCLUSION: Bolus i.v. injection with 5-FU in rats can be used to create a functional animal model for chemotherapy-induced OM. Further, moderate temperature reduction is sufficient to reduce the early events which may precede clinically established OM.

Can cryoprevention of oral mucositis be obtained at a higher temperature?

OBJECTIVES: Ice chips (IC) have successfully been used to prevent the development of chemotherapy-induced oral mucositis (OM). Although effective, IC entails several shortcomings and may open avenues for systemic infections as the water used may be contaminated by microorganisms, which may jeopardise the medical rehabilitation of an already immunosuppressed patient. This study aimed to investigate the efficacy and tolerability profile of a novel intraoral cooling device (ICD). SUBJECTS AND METHODS: In total, 20 healthy volunteers were enrolled in this randomised crossover study. Intraoral temperatures were registered using an IR camera, at baseline and following 30 and 60 min of cooling with the ICD, set to 8 °C or 15 °C. Following each cooling session, tolerability was assessed using a questionnaire. RESULTS: A statistically significant difference in the intraoral temperature was observed using 8 °C compared with 15 °C, following both 30 (1.87 °C, p < 0.001) and 60 min (2.48 °C, p < 0.001) of cooling. Thus, the difference of the intraoral temperatures was less than the 7 °C difference between 8 °C and 15 °C. Furthermore, 60 min of cooling with 15 °C compared with 8 °C was better tolerated and preferred by 15 out of 20 participants (p < 0.001). CONCLUSION: Cooling was better tolerated when the ICD was set to 15 °C compared with 8 °C, although the difference in reduction of the intraoral mucosal temperature was marginal and may not affect cryoprevention of oral mucositis. CLINICAL RELEVANCE: The ICD has the potential to improve the care for patients with cancer at high risk of developing OM.

Oral lichen sclerosus: an overview and report of three cases.

Lichen sclerosus is an unusual, chronically relapsing mucocutaneous disease that usually afflicts the anogenital region. Oral lesions of lichen sclerosus are rare, with only 36 histologically verified cases reported to date. The classic histopathologic findings of oral lichen sclerosus include: an area of subepithelial hyalinization, loss of elastic fibres, and band-like mononuclear inflammatory infiltrate. Despite its rarity, oral lichen sclerosus should be included in the differential diagnosis of porcelain- or ivory-white macules. Here we present three new cases of oral lichen sclerosus. A review of these cases and the previously reported cases revealed that oral lichen sclerosus is slightly more common in women and can affect individuals of any age. Oral lesions of lichen sclerosus usually do not require treatment, except when there are significant symptoms or aesthetic complaint. Almost 50% of the patients with oral lichen sclerosus present with extraoral manifestations. Thus, referral to a dermatologist and a gynaecologist is advised. Although no cases of malignant transformation of oral lichen sclerosus have been reported, regular, long-term follow-up of patients with oral lichen sclerosus is indicated.

A mechanistic linkage between oral lichen planus and autoimmune thyroid disease.

OBJECTIVE: To determine the levels of antithyroid antibodies and thyroid hormones in the sera of patients with oral lichen planus (OLP), and to quantify the expression of thyroid proteins in OLP lesions. SUBJECTS AND METHODS: Venous blood samples were drawn from 110 patients with OLP who had no history of thyroid disease or levothyroxine supplementation (OLP+/LT4 -). A random population sample of 657 healthy subjects was used as the control group. Two additional groups were used as comparators. Immunohistochemical and qPCR analyses were performed on tissue specimens collected from the patients with OLP and thyroid disease and healthy subjects. RESULTS: No association was found between the presence of antithyroid antibodies and OLP. More patients in the OLP+/LT4 - group showed high levels of thyroid-stimulating hormone and low levels of free thyroxine than were seen in the control group. Thyroid-stimulating hormone receptor was more highly expressed in the OLP lesions of patients with thyroid disease than in the healthy oral mucosa. CONCLUSIONS: A significant number of patients with OLP who are not previously diagnosed with thyroid disease have thyroid parameters that are compatible with hypothyroidism. The expression of thyroid-stimulating hormone receptor in OLP lesions suggests that mechanisms related to autoimmune thyroid disease are involved in the aetiology of OLP.

Tissue-specific Differences in Immune Cell Subsets Located in the Naso-oropharyngeal-associated Lymphoid Tissues.

Defining the immune cells within the naso-oropharyngeal-associated lymphoid tissues would promote the development of efficient orally and nasally delivered immunotherapies. The aim was to compare murine antigen-presenting cells (APCs) and T cell subsets in the nose-associated lymphoid tissues (NALT), cervical lymph nodes (CLN), mesenteric lymph nodes (MLN) and peripheral lymph nodes (PLN) using flow cytometry and in vitro proliferation assays. Overall, the NALT contained a higher proportion of APCs and a lower proportion of T cells compared to the CLN, MLN and PLN. The APCs of the NALT more often belonged to the CD11c+ CD11b+ and the CD11cneg CD11b+ subsets as compared to the other sites. Both of these APC populations showed little sign of activation, that is low expression of the markers CD40, CD86 and IAd. Instead, the APCs of the NALT more often co-expressed CX3CR1 and CD206, markers associated with a tolerogenic function. No increase in the proportion of regulatory T cells was observed in the NALT. Instead, the T cells frequently exhibited a memory/effector phenotype, expressing the homing markers α4ß7, CCR4 and CCR9, but rarely the naïve phenotype cell surface marker CD45RB. In contrast, the T cells at the other sites were mostly of the naïve phenotype. In addition, cells from the NALT did not proliferate upon in vitro stimulation with Con A, whereas the cells from the other sites did. Taken together, these results suggest that the NALT is primarily an effector site rather than one for activation and differentiation, despite it being regarded as a site of induction.

Salivary levels of interleukin-8 and growth factors are modulated in patients with geographic tongue.

OBJECTIVES: The aim of the study was to determine the levels of salivary epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) as well as interleukin-8 (IL-8) in patients with geographic tongue (GT), as compared to control subjects. METHODOLOGY: An enzyme-linked immunosorbent assay was used to measure the levels of IL-8, EGF and VEGF in whole saliva samples collected from 34 patients with GT and 38 control subjects. The patients and controls were grouped and matched according to age, gender and the presence of systemic diseases, which are factors that may influence the levels of salivary biomarkers. RESULTS: All patients with GT displayed significantly higher levels of IL-8 than the controls (P < 0.001). The young female patients also showed reduced levels of EGF (P < 0.05) and VEGF (P < 0.05), as compared to the young male patients where no such differences were observed. Interestingly, high levels of IL-8 (P < 0.001) and VEGF (P < 0.05) were detected in the patients with GT who also suffered from hypertension. CONCLUSION: We consider IL-8 an inflammatory mediator, which contributes to the acute inflammatory response found in GT. EGF and VEGF also seem to be involved in the pathophysiology of GT.

Oral psoriasis-a diagnostic dilemma: a report of two cases and a review of the literature.

Whether psoriasis can manifest itself in the oral mucosa has been a matter of debate for many years. If an oral version of psoriasis exists, most researchers regard this manifestation as rare. The present report describes two patients who presented with lesions possibly related to cutaneous psoriasis. One patient had patchy erythematous lesions on the gingiva, and one had serpiginous lesions in the hard palate. We discuss these cases in relation to the existing literature, with special emphasis on the clinical and histopathologic criteria for the diagnosis of oral psoriasis.

Characterisation of a Swedish cohort with orofacial granulomatosis with or without Crohn's disease.

OBJECTIVE: To compare oral manifestations in a Swedish cohort of patients with orofacial granulomatosis with or without Crohn's disease and to assess NOD2 polymorphisms in the two groups. METHODS: Twenty-nine patients with orofacial granulomatosis were included. Demographics, disease history, clinical features and concurrent Crohn's disease were recorded. DNA was extracted from buccal swabs and examined for NOD2 variants Arg702Trp, Gly908Arg and Leu1007fsinsC, all previously linked to gastrointestinal Crohn's disease. RESULTS: Twelve of 29 patients were diagnosed with coexisting gastrointestinal Crohn's disease, and of whom 21 were males. Symptom duration was significantly longer for the orofacial granulomatosis group com-pared to the group with coexisting Crohn's disease (P < 0.0001). The orofacial granulomatosis patients also perceived their overall discomfort, aesthetic problems and social discomfort as more severe. No significant differences in the clinical presentation of oral lesions between the two groups were found. None of the patients with orofacial granulomatosis carried any of the NOD2 variations, whereas four of the 12 patients with coexisting Crohn's disease had a NOD2 variant (Arg702Trp). CONCLUSION: The two patient groups had similar phenotypic characteristics but seemed to have genotypic differences regarding NOD2. The Swedish cohort differed in their clinical characteristics from patients reported in other geographical regions.

Use of systemic medication in patients with oral lichen planus - a possible association with hypothyroidism.

BACKGROUND: Several drugs have been regarded as a possible aetiological factor for oral lichen planus (OLP). OBJECTIVE: To investigate the medication profile of patients with OLP and its possible association with the pathogenesis of OLP. METHODS: Data from 956 patients with OLP and 1029 controls were collected using a standardized registration method. All regular medications were recorded and classified according to the Anatomical Therapeutic Chemical Classification System. RESULTS: Patients with OLP used thyroid preparations (P < 0.001) and non-steroidal anti-inflammatory drugs (NSAIDs) (P < 0.01) in higher proportions compared to controls. A multivariate logistic regression model demonstrated that levothyroxine was associated with OLP (multivariate OR 3.39, 95% CI: 2.09-5.46, P < 0.001), even after controlling for confounders, including age, sex, smoking, allergies and systemic diseases. No statistical significance could be found between NSAIDs and OLP using the same model. CONCLUSION: In this study, the use of levothyroxine was associated with OLP, which in turn suggests a possible connection with hypothyroidism.

Langerhans cells and T cells sense cell dysplasia in oral leukoplakias and oral squamous cell carcinomas--evidence for immunosurveillance.

Leukoplakias (LPLs) are lesions in the oral mucosa that may develop into oral squamous cell carcinoma (OSCC). The objective of this study was to assess presence and distribution of dendritic Langerhans cells (LCs) and T cells in patients with LPLs with or without cell dysplasia and in oral squamous cell carcinoma (OSCC). Biopsy specimens from patients with leukoplakias (LPLs) with or without dysplasia and oral squamous cell carcinoma (OSCC) were immunostained with antibodies against CD1a, Langerin, CD3, CD4, CD8 and Ki67, followed by quantitative analysis. Analyses of epithelium and connective tissue revealed a significantly higher number of CD1a + LCs in LPLs with dysplasia compared with LPLs without dysplasia. Presence of Langerin + LCs in epithelium did not differ significantly between LPLs either with or without dysplasia and OSCC. T cells were found in significantly increased numbers in LPLs with dysplasia and OSCC. The number of CD4+ cells did not differ significantly between LPLs with and without dysplasia, but a significant increase was detected when comparing LPLs with dysplasia with OSCC. CD8+ cells were significantly more abundant in OSCC and LPLs with dysplasia compared with LPLs without dysplasia. Proliferating cells (Ki67+) were significantly more abundant in OSCC compared to LPLs with dysplasia. Confocal laser scanning microscopy revealed colocalization of LCs and T cells in LPLs with dysplasia and in OSCC. LCs and T cells are more numerous in tissue compartments with dysplastic epithelial cells and dramatically increase in OSCC. This indicates an ongoing immune response against cells with dysplasia.

Human papillomaviruses in oral carcinoma and oral potentially malignant disorders: a systematic review.

OBJECTIVES: Human papillomavirus (HPV) in oral carcinoma (OSCC) and potentially malignant disorders (OPMD) is controversial. The primary aim was to calculate pooled risk estimates for the association of HPV with OSCC and OPMD when compared with healthy oral mucosa as controls. We also examined the effects of sampling techniques on HPV detection rates. METHODS: Systematic review was performed using PubMed (January 1966-September 2010) and EMBASE (January 1990-September 2010). Eligible studies included randomized controlled, cohort and cross-sectional studies. Pooled data were analysed by calculating odds ratios, using a random effects model. Risk of bias was based on characteristics of study group, appropriateness of the control group and prospective design. RESULTS: Of the 1121 publications identified, 39 cross-sectional studies met the inclusion criteria. Collectively, 1885 cases and 2248 controls of OSCC and 956 cases and 675 controls of OPMD were available for analysis. Significant association was found between pooled HPV-DNA detection and OSCC (OR = 3.98; 95% CI: 2.62-6.02) and even for HPV16 only (OR = 3.86; 95% CI: 2.16-6.86). HPV was also associated with OPMD (OR = 3.87; 95% CI: 2.87-5.21). In a subgroup analysis of OPMD, HPV was also associated with oral leukoplakia (OR = 4.03; 95% CI: 2.34-6.92), oral lichen planus (OR = 5.12; 95% CI: 2.40-10.93), and epithelial dysplasia (OR = 5.10; 95% CI: 2.03-12.80). CONCLUSIONS: The results suggest a potentially important causal association between HPV and OSCC and OPMD.

Advancing oral medicine through informatics and information technology: a proposed framework and strategy.

The implementation of information technology in healthcare is a significant focus for many nations around the world. However, information technology support for clinical care, research and education in oral medicine is currently poorly developed. This situation hampers our ability to transform oral medicine into a 'learning healthcare discipline' in which the divide between clinical practice and research is diminished and, ultimately, eliminated. This paper reviews the needs of and requirements for information technology support of oral medicine and proposes an agenda designed to meet those needs. For oral medicine, this agenda includes analyzing and reviewing current clinical and documentation practices, working toward progressively standardizing clinical data, and helping define requirements for oral medicine systems. IT professionals can contribute by conducting baseline studies about the use of electronic systems, helping develop controlled vocabularies and ontologies, and designing, implementing, and evaluating novel systems centered on the needs of clinicians, researchers and educators. Successfully advancing IT support for oral medicine will require close coordination and collaboration among oral medicine professionals, information technology professionals, system vendors, and funding agencies. If current barriers and obstacles are overcome, practice and research in oral medicine stand ready to derive significant benefits from the application of information technology.

Microbial-associated oral lichenoid reactions.

OBJECTIVE: The objective of the present study was to compare a new type of symptomatic lichenoid reaction, specifically located on the mucosal side of the lips, and associated with microorganisms, with a matched group presenting with reticular oral lichen planus (OLP) of the buccal mucosa. PATIENTS AND METHODS: The mean age for both groups was 66 years with a predominance of women (62%). The lichenoid reaction group (n = 25) presented with a reticular reaction pattern embracing various degrees of erythema. Patients presenting with OLP had similar lesions confined to the buccal mucosa but not on the mucosal side of the lips. RESULTS: In both groups, 80% were on any type of medication. However, 56% of the patients with lichenoid reactions medicated with more than three drugs compared with 29% (P < 0.05) in the OLP group. The former group more often used medicaments prescribed for cardiovascular diseases (48%vs 25%). Twenty-two of the patients with lichenoid reactions were treated with chlorhexidine. In 80% of these patients (n = 18), the lesions improved or completely healed, indicating a microbial association. CONCLUSION: Lichenoid reactions present on the mucosal side of the lips may be initiated by microbial plaque precipitated on the buccal surfaces of the anterior teeth.

Langerhans cells from human oral epithelium are more effective at stimulating allogeneic T cells in vitro than Langerhans cells from skin.

This report is focused on the functional capacity of Langerhans cells (LC) in the epithelium of skin and oral mucosa, which both meet different antigenic challenges. The capacity of LC from human oral and skin epithelium to provide co-stimulatory signals to T cells in vitro was compared. LC in a crude suspension of oral epithelial cells had a significantly enhanced T cell co-stimulatory capacity compared to skin epithelial cells. This applied both to cultures with concanavalin A (con-A)-stimulated syngeneic T cells and to a mixed epithelial cell lymphocyte reaction involving allogeneic T cells. The co-stimulatory capacity of oral and skin epithelial cells was reduced by >70% if monoclonal antibodies against HLA-DR, -DP and -DQ were added to the cultures with allogeneic T cells, indicating the involvement of HLA class II expressing LC. Immunohistochemistry revealed that 6% of the epithelial cells were CD1a + LC in sections from both oral and skin epithelium. Interleukin (IL)-8 production was higher in cultures of oral epithelial cells and con-A stimulated T cells than in corresponding cultures with skin epithelial cells as accessory cells. The results suggest that LC in human oral epithelium are more efficient at stimulating T cells than those of skin.

T-cell costimulatory capacity of oral and skin epithelial cells in vitro: presence of suppressive activity in supernatants from skin epithelial cell cultures.

Oral Langerhans cells (LC) have better T-cell costimulatory capacity than skin LC. In this study factors affecting this capacity have been assessed in a mixed epithelial cell lymphocyte reaction (MELR) assay. Flow cytometry analysis of freshly recovered cells revealed major histocompatibility complex (MHC) class II molecule expression on 7.5% of the oral epithelial cells and 9.7% of the skin epithelial cells. Monoclonal anti class II antibodies significantly reduced the T-cell proliferation in the MELR. Pretreatment of skin epithelial cells with interleukin-1beta, tumour necrosis factor-alpha or interferon (IFN)-gamma did not affect the MELR proliferation, but incubation with IFNgamma significantly suppressed the T-cell response. Transfer of supernatants from cultures of skin epithelial cells and allogeneic T cells to cultures of oral epithelial cells and T cells resulted in a reduced T-cell proliferation while supernatants from oral epithelial cells and T cells did not reduce proliferation. The higher proliferation in cultures of T cells and oral epithelial cells than in cultures containing skin epithelial cells may be due to the presence of a suppressive factor in the skin epithelial cell suspensions.