Efficacy of a novel device for cryoprevention of oral mucositis: a randomized, blinded, multicenter, parallel group, phase 3 trial.

Cryoprevention (CP) using ice (IC) is an effective strategy to prevent chemotherapy-induced oral mucositis (OM). However, the use of IC may cause adverse reactions and requires water of safe quality to minimize risk of serious infections. This randomized, blinded, parallel group, phase 3 trial was conducted in five Scandinavian centers. Eligible patients were diagnosed with multiple myeloma or lymphoma, scheduled to receive conditioning with high-dose chemotherapy prior to autologous hematopoietic stem cell transplantation (ASCT). Patients were assigned to cooling with IC or a novel intraoral cooling device (ICD). The primary outcome was the highest OM score during the study period, expressed as peak value on the Oral Mucositis Assessment Scale (OMAS-total). When the entire study population (n = 172) was analyzed for peak OMAS-total, the two cooling methods were equally effective. However, when the lymphoma group was analyzed separately, the ICD significantly reduced the peak OMAS-total score to a greater extent compared to IC (x̄ ± SD; 1.77 ± 1.59 vs. 3.08 ± 1.50; p = 0.047). Combined with existing evidence, the results of the present trial confirm that CP is an effective method to prevent OM. ClinicalTrials.gov. NCT03203733.

A family-based genome-wide association study of recurrent aphthous stomatitis.

OBJECTIVES: The aetiology of recurrent aphthous stomatitis (RAS) remains unknown. Individuals may share features of genetic susceptibility, and there may also be a hereditary component. The aim was to identify patterns of association and segregation for genetic variants and to identify the genes and signalling pathways that determine the risk of developing RAS, through a family-based genome-wide association study (GWAS). SUBJECTS AND METHODS: DNA was extracted from buccal swabs of 91 individuals in 16 families and analysed in an Illumina core exome single nucleotide polymorphism (SNP) array. A family-based association test (dFAM) was used to derive SNP association values across all chromosomes. RESULTS: None of the final 288,452 SNPs reached the genome-wide significant threshold of 5 × 10-8 . The most significant pathways were the Ras and PI3K-Akt signalling pathways, pathways in cancer, circadian entrainment and the Rap 1 signalling pathway. CONCLUSIONS: This confirms that RAS is not monogenic but results as a consequence of interactions between multiple host genes and possibly also environmental factors. The present approach provides novel insights into the mechanisms underlying RAS and raises the possibility of identifying individuals at risk of acquiring this condition.

Increased levels of calprotectin in the saliva of patients with geographic tongue.

OBJECTIVE: We investigated whether patients with geographic tongue have increased salivary levels of calprotectin and whether there is a correlation between the salivary levels of calprotectin and interleukin 8 (IL-8), which is another marker of inflammation. METHODS: Twenty-three patients diagnosed with geographic tongue and 32 control subjects without oral mucosal lesions were included in the study. The patients with geographic tongue were classified based on clinical appearance and number of oral lesions. ELISAs were used to determine the levels of calprotectin and IL-8 in whole saliva samples. RESULTS: There was a statistically significant increase in the salivary output of calprotectin in patients with geographic tongue compared with the healthy controls (62 ± 9,1 vs. 37,5 ± 4,7 µg/min; p = .0134). Furthermore, the levels of calprotectin correlated positively with the number of oral lesions in patients with geographic tongue. There was also a significant and positive correlation between the salivary levels of calprotectin and IL-8, both for the patients with geographic tongue and the controls. CONCLUSION: This study supports the notion that GT is an inflammatory disease, in which the activation of neutrophils and production of calprotectin in the saliva may play roles in its pathogenesis.

Reduced sialyl-Lewisx on salivary MUC7 from patients with burning mouth syndrome.

We analysed and compared MUC7 O-glycosylation and inflammatory biomarkers in saliva from female patients with burning mouth syndrome (BMS) and gender/age-matched controls. Oligosaccharides from salivary MUC7 from BMS and controls were released. Inflammatory mediators were measured by multiplex proximity extension assay. Presence of sialyl-Lewisx (Si-Lex) epitope on MUC7 was confirmed using Western blot. MUC7 O-glycans and measured inflammatory biomarkers were found to be similar between BMS and controls. However, oligosaccharides sialyl-Lewisx (Si-Lex) was found to be reduced in samples from BMS patients. Positive correlation (combined patients and controls) was found between levels of C-C motif chemokine 19 (CCL-19) and the amount of core-2 oligosaccharides on MUC7 as well as fractalkine (CX3CL1) and level of sialylation. Patients with BMS were shown to represent a heterogeneous group in terms of inflammatory biomarkers. This indicates that BMS patients could be further stratified on the basis of low-level inflammation. The results furthermore indicate that reduced sialylation of MUC7, particularly Si-Lex, may be an important feature in patients with BMS. However, the functional aspects and potential involvement in immune regulation of Si-Lex remains unclear. Our data suggests a chemokine driven alteration of MUC7 glycosylation.

Saliva on the oral mucosa and whole saliva in women diagnosed with burning mouth syndrome.

OBJECTIVE: The aim of the study was to examine mucosal saliva and unstimulated (UWS) and stimulated (SWS) whole saliva secretion rates and associated factors, in 56 female patients diagnosed with BMS and age-matched control women. MATERIAL AND METHODS: Mucosal saliva was assessed using the Periotron® method and blood flow using laser Doppler flowmetry. Diseases, drug usage and xerostomia were registered using questionnaires. RESULTS: The patients with BMS displayed less lingual and whole saliva, and more hyposalivation, xerostomia diseases/disorders and drug usage, compared to the controls. Only a low SWS and xerostomia differed after adjusting for drugs and systemic diseases. Regression analyses suggested an importance of saliva affecting drugs for saliva on the tongue and for SWS, and the total number of drugs used for UWS. Lingual saliva and UWS were also associated with systemic diseases in the patients. Xerostomia was significantly associated with drug use and whole saliva for all subjects but not in separate analyses of the groups. CONCLUSION: Less saliva in patients with BMS could be related to more systemic diseases and medication and not to the syndrome per se. Xerostomia in the patients was not related to any of these factors.

Cooling of the oral mucosa to prevent adverse effects of chemotherapeutic agents: An in vitro study.

BACKGROUND: The cytotoxic effect of chemotherapeutic agents to the oral mucosa, as a side effect of cancer treatment, is a major problem. Cooling the oral mucosa using ice chips in conjunction with chemotherapy is known to reduce the severity of oral mucositis. However, although the use of ice chips is of clinical value, this method of cooling has inherent problems including discomfort for the patient, non-uniformity and fluctuations in cooling temperature throughout the oral cavity. Furthermore, despite being used clinically, it is not known what reduction in temperature is required to prevent oral mucositis. The aim of this study was therefore to determine in vitro if the cytotoxic effect of 5-fluorouracil (5-FU) on the oral mucosa could be reduced by lowering the temperature during chemotherapeutic treatment. METHODS: Tissue-engineered oral mucosal (TEOM) models were incubated at 20, 25, 30 or 35°C for 30 minutes followed by exposure to a clinically relevant concentration of 5-FU (162 µg/mL) for 2 hours and compared with untreated models (35°C). Cell viability and inflammatory cytokine production (IL-6 and TNF-α) were measured using PrestoBlue® and ELISA, respectively. RESULTS: TEOM models incubated at 20°C showed an increased cell viability and had a reduced IL-6 and TNF-α production compared to models treated with 5-FU incubated at 35°C. CONCLUSION: This study demonstrates a reduced cytotoxic effect to the TEOM by reducing the temperature of the tissue during chemotherapy treatment and suggests that decreasing the temperature to 20°C could have clinical advantages.

Clinical characterization of women with burning mouth syndrome in a case-control study.

OBJECTIVE: Burning mouth syndrome (BMS) is a chronic orofacial pain disorder that is defined by a burning sensation in the oral mucosa. The aim of this study was to investigate the underlying factors, clinical characteristics and self-reported oral and general health factors associated with BMS. MATERIAL AND METHODS: Fifty-six women with BMS (mean age: 67.7) and their age-matched controls were included in the study. A general questionnaire, an OHRQL index and BMS-specific questionnaires were used. Each subject underwent an oral examination. RESULTS: The mean severity of the BMS symptoms (VAS, 0-100) was 66.2 (SD 19.7). Overall, 45% of the patients reported taste disturbances. More of the patients than the controls rated their general health, oral health and life situation as 'less satisfactory'. The patients also reported more frequently on-going medications, diseases/disorders, xerostomia, allergy and skin diseases. Except for more bruxofacets among the patients, there were no significant differences regarding signs of parafunction. In a multiple logistic regression analysis, xerostomia and skin diseases showed the strongest prediction for BMS and no significant effect was found for medication, allergy or bruxofacets. CONCLUSIONS: Skin diseases and xerostomia but not parafunction were strongly associated with BMS. Our findings provide the basis for additional studies to elucidate the causal factors of BMS.

Correction to: Innovative intraoral cooling device better tolerated and equally effective as ice cooling.

Unfortunately, the online published article has error in Table 1. The correct Table 1 is given in the following page.

Mutations in the genes for keratin-4 and keratin-13 in Swedish patients with white sponge nevus.

BACKGROUND: White sponge nevus is a rare autosomal dominant disorder that affects the non-keratinised stratified squamous epithelium. Mutations in the genes that encode mucosa-specific keratin-4 and keratin-13 are strongly linked to the manifestation of white sponge nevus. This study involved mutational analysis of the genes encoding keratin-4 and keratin-13 in two Swedish families with white sponge nevus. METHODS: The diagnosis of white sponge nevus was based on disease history, clinical characteristics of the lesions and, in the majority of the cases, histopathological examination. Samples were collected from the affected buccal mucosa using buccal swabs. DNA was subsequently extracted and amplified using touchdown-PCR. The keratin-4 and keratin-13 genes were sequenced, and a genetic analysis was performed. RESULTS: A novel heterozygous missense mutation was identified in exon 1A of the keratin-4 gene in Family 2. In addition, previously reported heterozygous missense mutations were identified in the keratin-4 (E449K, A72V, Q156R, R208H) and keratin-13 (L115P) genes in both families. CONCLUSION: We describe a novel heterozygous missense mutation in the keratin-4 gene of a Swedish family with white sponge nevus. Our results support the notion that mutations in keratin-4 and keratin-13 are the underlying cause of white sponge nevus.

Innovative intraoral cooling device better tolerated and equally effective as ice cooling.

PURPOSE: Most of the patients who receive myeloablative therapy prior to stem cell transplantation develop oral mucositis (OM). This adverse reaction manifests as oral mucosal erythema and ulcerations and may require high doses of morphine for pain alleviation. OM may also interfere with food intake and result in weight loss, a need for parenteral nutrition, and impaired quality of life. To date, there have been very few studies of evidence-based interventions for the prevention of OM. Cryotherapy, using ice chips, has been shown to reduce in an efficient manner the severity and extent of OM, although clinical applications are still limited due to several shortcomings, such as adverse tooth sensations, problems with infectious organisms in the water, nausea, and uneven cooling of the oral mucosa. The present proof-of-concept study was conducted to compare the tolerability, temperature reduction, and cooling distribution profiles of an intra-oral cooling device and ice chips in healthy volunteers who did not receive myeloablative treatment, and therefore, did not experience the symptoms of OM. METHODS: Twenty healthy volunteers used the cooling device and ice chips for a maximum of 60 min each, using a cross-over design. The baseline and final temperatures were measured at eight intra-oral locations using an infra-red thermographic camera. The thermographic images were analysed using two digital software packages. A questionnaire was used to assess the tolerability levels of the two interventions. RESULTS: The intra-oral cooling device was significantly better tolerated than the ice-chips (p = 0.0118). The two interventions were equally effective regarding temperature reduction and cooling distribution. CONCLUSIONS: The intra-oral cooling device shows superior tolerability in healthy volunteers. Furthermore, this study shows that temperature reduction and cooling distribution are achieved equally well using either method.

Lingual microbiota profiles of patients with geographic tongue.

Geographic tongue (GT) is an oral mucosal lesion that affects the tongue. The association between GT and the bacterial colonization profiles of the tongue is not clear. Lingual swabs were collected from lesion sites and healthy sites of 35 patients with GT (19 males and 16 females; Mage = 54.3 ± 16.1 years) and 22 controls (12 males and 10 females; Mage = 56.3 ± 15.8 years). Bacterial DNA was extracted and sequenced by next-generation sequencing. At the phylum level, Fusobacteria were significantly less abundant, while Spirochaetes were significantly more abundant in GT patients compared to controls. At the operational taxonomic units level, multivariate analysis revealed distinct clusters for the three groups based on the lingual microbiota composition. Acinetobacter and Delftia were significantly associated with GT lesion and healthy sites. However, Microbacterium, Leptospira, Methylotenera, and Lactococcus were significantly associated with GT lesion sites. Additionally, Mogibacterium and Simonsiella were significantly associated with GT healthy sites and controls. The changes in the lingual microbiota profiles of patients with GT imply a shift in the lingual bacterial ecology. However, it remains unknown if this shift is a consequence of the lesions or of factors associated with the initiation and progression of the disease.

Immunohistopathology of the Newly Discovered Giant Papillae Tongue Disorder in Organ-Transplanted Children.

BACKGROUND: Giant papillae tongue disorder (GPTD) is a newly discovered, long-lasting clinical disorder that may develop in organ-transplanted pediatric recipients. The key feature of this disorder is the unique tongue lesion, which comprises swollen fungiform papillae. The aim of this study was to characterize the immunohistopathology of this novel inflammatory condition. METHODS: Six organ transplanted children with GPTD were included in the study. Routine histopathology and immunohistochemical stainings for CD3, CD4, CD8, CD25, FOXP3, CD20, CD138, CD68, CD1a, CD15, CD23, and mast cell tryptase were performed. RESULTS: Immunohistochemical analyses of the oral lesions revealed a subepithelial infiltrate that was primarily composed of CD3- and CD4-positive T cells, CD20-expressing B cells, macrophages, and CD138-positive plasma cells. The CD20-positive cells did not display the typical B cell morphology, having in general a more dendritic cell-like appearance. The CD138-expressing plasma cells were distinctly localized as a dense infiltrate beneath the accumulation of T cells and B cells. Increased numbers of CD1a-expressing Langerhans cells were detected both in the epithelium and connective tissue. Because no granulomas were observed and only single lesional eosinophils were detected, GPTD does not resemble a granulomatous or eosinophilic condition. CONCLUSIONS: We describe for the first time the immunopathological characteristics of a novel inflammatory disorder of the oral cavity, which may develop after solid organ transplantation in children.

The engagement of oral-associated lymphoid tissues during oral versus gastric antigen administration.

The role of oral-associated lymphoid tissues during induction of oral tolerance still remains elusive. Therefore, the aim was to compare T-cell activation and induction of tolerance to ovalbumin (OVA) presented through either of two routes; deposited into the oral cavity, or the stomach, thereby bypassing the oral cavity. OVA was administered by the oral or gastric route to BALB/c mice that had received OVA-specific DO11.10+ CD4(+) T cells, stained with CellTrace(™) Violet dye, through intravenous injection. Proliferating OVA-specific T cells were detected in the nose-associated lymphoid tissues (NALT) and the cervical, mesenteric and peripheral lymph nodes at different time-points following OVA exposure. OVA-specific T-cell proliferation was initially observed in the NALT 1 hr after oral, but not gastric, administration. However, at day 1, proliferation at this site was also detected after gastric administration and profound proliferation was observed at all sites by day 4. For the oral route the degree of proliferation observed was lower in the peripheral lymph nodes by day 4 compared with the other sites. These results demonstrate a similar activation pattern achieved by the two routes. However, the NALT distinguishes itself as a site of rapid T-cell activation towards fed antigens irrespective of feeding regimen. To evaluate induction of tolerance a semi-effective OVA dose was used, to detect differences in the degree of tolerance achieved. This was performed in a model of OVA-induced airway hypersensitivity. No differences in tolerance induction were observed between the two administration routes.

Does Crohn's Disease with Concomitant Orofacial Granulomatosis Represent a Distinctive Disease Subtype?

BACKGROUND: Although orofacial granulomatosis (OFG) may present as a separate clinical entity, it often seems in conjunction with various systemic diseases, of which Crohn's disease (CD) is one of the most common. The aim of this study was to investigate whether CD with concomitant OFG represents a distinctive disease subtype. METHODS: Twenty-one patients with CD and concomitant OFG (CD+OFG group) were included in the study. As the reference group, a cohort of 39 patients with CD but without OFG (CD-R group) was used. Demographic data and clinical characteristics were recorded at the time of diagnosis. The 2 groups were compared using multivariate analyses. RESULTS: The percentage of patients with intestinal inflammation in the upper gastrointestinal tract was significantly higher in the CD+OFG group, as compared with the CD-R group (81% versus 33%; P < 0.001). Furthermore, ileocolonic inflammation was significantly more common in the CD+OFG patients (81% versus 46%; P = 0.013). In addition, perianal disease was more frequently observed in the CD+OFG group (48% versus 18%; P = 0.033). Significantly more patients showed evidence of granulomas in the primary endoscopy in the CD+OFG group than in the CD-R group (81% versus 38%; P = 0.003). CONCLUSION: The data from this study suggest that the presence of CD in conjunction with OFG represents a distinctive subphenotype of CD that is characterized by extensive inflammation, perianal disease, and pronounced granuloma formation in the intestine.

Oral medicine (stomatology) across the globe: birth, growth, and future.

Oral medicine (stomatology) is a recognized and increasingly important dental specialty in many parts of the world that recognizes and fosters the interplay between medical health and oral health. Its dental activities rely greatly on the underlying biology of disease and evidence-based outcomes. However, full recognition of the importance of oral medicine to patient care, research, and education is not yet totally universally acknowledged. To address these shortcomings, we outline the birth, growth, and future of oral medicine globally, and record identifiable past contributions to the development of the specialty, providing an accurate, unique, and valuable resource on oral medicine. Although it was challenging to gather the data, we present this information as a review that endeavors to summarize the salient points about oral medicine, based on MEDLINE, other internet searches, communication with oral medicine and stomatological societies across the world, the web page http://en.wikipedia.org/wiki/List_of_dental_organizations, and discussions with a wide range of key senior persons in the specialty.

Factors associated with geographic tongue and fissured tongue.

OBJECTIVES: The primary objective of this study was to investigate the association of systemic diseases, use of medications, allergies and tobacco habits with geographic tongue (GT) and fissured tongue (FT) lesions. The secondary objectives were to evaluate the clinical characteristics of tongue lesions and to compare the overall results for referred and non-referred patients. METHODOLOGY: Non-referred patients with GT (GTgp; n = 130) and FT (FTgp; n = 62) were examined by general practitioners (gp) and compared to a control group without oral mucosal lesions (C; n = 1029). Referred patients with GT (GTs; n = 166) and FT (FTs; n = 15) were examined by oral medicine specialists (s) and compared to GTgp and FTgp. Statistical analyses were performed using unpaired t-test or Fisher's exact test. A multiple logistic regression model was developed to control for age and gender as confounders. RESULTS: Compared to the C group, GTgp patients used more anti-hypertensive medications and Swedish snus (p < 0.01). The GTgp group consisted of older males (p < 0.001) compared to C. Compared to the GTgp group, the GTs group was younger, more likely to have symptomatic lesions (p < 0.0001) and comprised of more females. Among the groups examined, FT patients had the highest mean age. CONCLUSION: This study identified an association between GT and anti-hypertensive medications, as well as the use of Swedish snus. It also found differences in the activities and symptoms of the lesions between referred patients and their counterparts who were seen in general dental practice; these parameters influenced the results when these conditions were taken into account.

Clinical characteristics of patients with concomitant oral lichen planus and thyroid disease.

OBJECTIVE: To study the prevalence and profile of thyroid disease in a cohort of referred patients with oral lichen planus (OLP) in comparison with a random population sample and to examine the clinical characteristics of OLP patients with and without thyroid disease. STUDY DESIGN: Data from 1611 patients with OLP and 1615 patients from the general population were collected by using a standardized registration method. Patients with OLP using levothyroxine (OLP/levothyroxine+) were re-examined to collect information about existing OLP lesions and to confirm the thyroid disease diagnosis. The clinical characteristics of OLP lesions in this group were compared with those in an age- and gender-matched population of patients with OLP without a history of thyroid disease or levothyroxine medication (OLP/levothyroxine-). RESULTS: Nearly 11% (n=170) of the patients with OLP were taking levothyroxine compared with 2.5% (n=40) of the controls (multivariate odds ratio 2.99, 95% confidence interval 2.03-4.44; P<.0001). No difference was found in the thyroid disease profile between the groups. At the time of re-examination, patients with OLP/levothyroxine- displayed more erythematous OLP lesions and complained of more severe symptoms compared with the OLP/levothyroxine+ group (P<.001). CONCLUSIONS: The prevalence of thyroid disease in patients with OLP was significantly higher than in the general population. The OLP lesions of patients with concomitant thyroid disease have a different presentation over time, which indicates a specific subgroup of OLP.

Salivary mucin MUC7 oligosaccharides in patients with recurrent aphthous stomatitis.

OBJECTIVES: The aetiology of recurrent aphthous stomatitis remains unknown. In this study, we investigate the composition of oligosaccharides from mucin MUC7 in recurrent aphthous stomatitis as these heavily O-glycosylated mucins confer many of saliva's protective properties such as defence against mucosal pathogens. MATERIALS AND METHODS: Unstimulated whole saliva samples were collected from six individuals, three with recurrent aphthous stomatitis and three corresponding sibling, without this condition. Oligosaccharides from salivary MUC7 were isolated and analysed by liquid chromatography-tandem mass spectrometry. RESULTS: The types of oligosaccharides identified in the patients and control subjects were similar; however, statistical evaluation indicated semi-quantitative differences between specific oligosaccharide classes. These changes focused on a reduction in terminal glycan residues including fucosylation, sialylation and sulfation on galactose. CONCLUSIONS: This study was able to show differential MUC7 glycosylation in the patients suggesting functional changes to salivary mucins in this condition. The terminal glycans altered in disease have been shown to be important for a range of immunological and bacterial binding roles. Further investigation of these epitopes in a larger study may provide critical insights into the pathology of recurrent aphthous stomatitis. CLINICAL RELEVANCE: MUC7 glycosylation is altered in recurrent aphthous stomatitis. This may change the protective properties of this mucin against mucosal pathogens, which may effect this condition.

World Workshop on Oral Medicine VI: Utilization of Oral Medicine-specific software for support of clinical care, research, and education: current status and strategy for broader implementation.

OBJECTIVES: To assess the current scope and status of Oral Medicine-specific software (OMSS) utilized to support clinical care, research, and education in Oral Medicine and to propose a strategy for broader implementation of OMSS within the global Oral Medicine community. STUDY DESIGN: An invitation letter explaining the objectives was sent to the global Oral Medicine community. Respondents were interviewed to obtain information about different aspects of OMSS functionality. RESULTS: Ten OMSS tools were identified. Four were being used for clinical care, one was being used for research, two were being used for education, and three were multipurpose. Clinical software was being utilized as databases developed to integrate of different type of clinical information. Research software was designed to facilitate multicenter research. Educational software represented interactive, case-orientated technology designed for clinical training in Oral Medicine. Easy access to patient data was the most commonly reported advantage. Difficulty of use and poor integration with other software was the most commonly reported disadvantage. CONCLUSIONS: The OMSS presented in this paper demonstrate how information technology (IT) can have an impact on the quality of patient care, research, and education in the field of Oral Medicine. A strategy for broader implementation of OMSS is proposed.