Single nucleotide polymorphisms conferring susceptibility to leukemia and oral mucositis: a multi-center pilot study of patients prior to conditioning therapy for hematopoietic cell transplant.

PURPOSE: Leukemias have been associated with oral manifestations, reflecting susceptibility to cancer therapy-induced oral mucositis. We sought to identify SNPs associated with both leukemia and oral mucositis (OM). METHODS: Whole exome sequencing was performed on leukemia and non-cancer blood disorder (ncBD) patients' saliva samples (N = 50) prior to conditioning therapy. WHO OM grading scores were determined: moderate to severe (OM2-4) vs. none to mild (OM0-1). Reads were processed using Trim Galorev0.6.7, Bowtie2v2.4.1, Samtoolsv1.10, Genome Analysis Toolkit (GATK)v4.2.6.1, and DeepVariantv1.4.0. We utilized the following pipelines: P1 analysis with PLINK2v3.7, SNP2GENEv1.4.1 and MAGMAv1.07b, and P2 [leukemia (N = 42) vs. ncBDs (N = 8)] and P3 [leukemia + OM2-4 (N = 18) vs. leukemia + OM0-1 (N = 24)] with Z-tests of genotypes and protein-protein interaction determination. GeneCardsSuitev5.14 was used to identify phenotypes (P1 and P2, leukemia; P3, oral mucositis) and average disease-causing likelihood and DGIdb for drug interactions. P1 and P2 genes were analyzed with CytoScape plugin BiNGOv3.0.3 to retrieve overrepresented Gene Ontology (GO) terms and Ensembl's VEP for SNP outcomes. RESULTS: In P1, 457 candidate SNPs (28 genes) were identified and 21,604 SNPs (1016 genes) by MAGMAv1.07b. Eighteen genes were associated with "leukemia" per VarElectv5.14 analysis and predicted to be deleterious. In P2 and P3, 353 and 174 SNPs were significant, respectively. STRINGv12.0 returned 77 and 32 genes (C.L. = 0.7) for P2 and P3, respectively. VarElectv5.14 determined 60 genes from P2 associated with "leukemia" and 11 with "oral mucositis" from P3. Overrepresented GO terms included "cellular process," "signaling," "hemopoiesis," and "regulation of immune response." CONCLUSIONS: We identified candidate SNPs possibly conferring susceptibility to develop leukemia and oral mucositis.

Subjective Oral Dryness following Hematopoietic Cell Transplantation: A Report from the Orastem Study.

Xerostomia, or subjective oral dryness, is a serious complaint after hematopoietic cell transplantation (HCT). Xerostomia is rated as one of the most bothersome symptoms by HCT recipients, negatively affecting quality of life. This substudy of the Orastem study, a prospective longitudinal, international, observational, multicenter study, aimed to describe the prevalence and severity of xerostomia following HCT. Furthermore, the effect of the conditioning regimen, type of transplantation, and oral mucosal changes related to chronic graft-versus-host disease (cGVHD) in the development of xerostomia were studied. All HCT recipients rated xerostomia on a scale of 0 to 10 before the conditioning regimen, several times early post-HCT, and at 3 months post-HCT, and only allogeneic HCT recipients also rated xerostomia at 6 and 12 months post-HCT. In addition, stimulated whole mouth saliva was collected several times. Linear regression models and longitudinal mixed-effects models were created to investigate the influence of risk indicators on xerostomia. A total of 99 autologous and 163 allogeneic HCT recipients were included from 6 study sites in Sweden, Canada, the Netherlands, and the United States. The prevalence of xerostomia was 40% before the conditioning regimen, 87% early post-HCT, and 64% at 3 months post-HCT. Complaints after autologous HCT were transient in nature, while the severity of xerostomia in allogeneic HCT recipients remained elevated at 12 months post-HCT. Compared to autologous HCT recipients, allogeneic HCT recipients experienced 1.0 point more xerostomia (95% confidence interval [CI], .1 to 2.0) early post-HCT and 1.7 points more (95% CI, .4 to 3.0) at 3 months post-HCT. Allogeneic HCT recipients receiving a high-intensity conditioning regimen experienced more xerostomia compared to those receiving a nonmyeloablative or reduced-intensity conditioning regimen. The difference was 2.0 points (95% CI, 1.1 to 2.9) early post-HCT, 1.8 points (95% CI, .3 to 3.3) after 3 months, and 1.7 points (95% CI, .0 to 3.3) after 12 months. Total body irradiation as part of the conditioning regimen and oral mucosal changes related to cGVHD did not significantly influence the severity of xerostomia. Conditioning regimen intensity was a significant risk indicator in the development of xerostomia, whereas total body irradiation was not. Allogeneic HCT recipients experienced more xerostomia than autologous HCT recipients, a difference that cannot be explained by a reduction in stimulated salivary flow rate or the development of oral mucosal changes related to cGVHD.

Incidence, severity, and temporal development of oral complications in pediatric allogeneic hematopoietic stem cell transplant patients - a multicenter study.

PURPOSE: Oral mucositis is a common complication for patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) and causes pain and difficulties in functions like eating and swallowing, resulting in lower quality of life and greater need of treatment with opioids and parenteral nutrition. This prospective multicenter study focused on pediatric recipients of HSCT in the neutropenic phase concerning oral complications, timing, severity, and patient experience. METHODS: The cohort comprised 68 patients, median age 11.1 years (IQR 6.3) receiving allogeneic HSCT at three clinical sites. Medical records were retrieved for therapy regimens, concomitant medications, oral and dental history, and subjective oral complaints. Calibrated dentists conducted an oral and dental investigation before HSCT. After HSCT graft infusion, study personnel made bedside assessments and patients filled out a questionnaire once or twice a week until neutrophil engraftment. RESULTS: We followed 63 patients through the neutropenic phase until engraftment. 50% developed oral mucositis of grades 2-4. Peak severity occurred at 8-11 days after stem cell infusion. Altogether, 87% had subjective oral complaints. The temporal distribution of adverse events is similar to the development of oral mucositis. The most bothersome symptoms were blisters and oral ulcerations, including mucositis; 40% reported severe pain and major impact on activities of daily living despite continuous use of opioids. CONCLUSION: This study highlights the burden of oral complications and their negative effect on the health and quality of life of HSCT recipients.

The effect of conditioning regimen and prescribed medications on hyposalivation in haematopoietic cell transplantation (HCT) patients: an 18-month prospective longitudinal study.

OBJECTIVES: Haematopoietic cell transplantation (HCT) preceded by a conditioning regimen is an established treatment option for (non)malignant haematologic disorders. We aim to describe the development of hyposalivation over time in HCT recipients, and determine risk indicators. MATERIALS AND METHODS: A multi-centre prospective longitudinal observational study was conducted. Unstimulated (UWS) and stimulated (SWS) whole saliva was collected before HCT, early post-HCT, and after 3, 6, 12, and 18 months. The effect of type of transplantation (allogeneic vs autologous) and intensity (full vs reduced) of the conditioning regimen on hyposalivation (UWS < 0.2 mL/min; SWS < 0.7 mL/min) was explored. RESULTS: A total of 125 HCT recipients were included. More than half of the patients had hyposalivation early post-HCT; a quarter still had hyposalivation after 12 months. The conditioning intensity was a risk indicator in the development of hyposalivation of both UWS (OR: 3.9, 95% CI: 1.6-10.6) and SWS (OR: 8.2, 95% CI: 2.9-24.6). After 3 and 12 months, this effect was not statistically significant anymore. CONCLUSIONS: Hyposalivation affects the majority of patients early post-HCT. The conditioning intensity and the type of transplantation were significant risk indicators in the development of hyposalivation. The number of prescribed medications, total body irradiation as part of the conditioning regimen and oral mucosal graft-versus-host disease did not influence hyposalivation significantly. CLINICAL RELEVANCE: Because of the high prevalence of hyposalivation, HCT recipients will have an increased risk of oral complications. It might be reasonable to plan additional check-ups in the dental practice and consider additional preventive strategies.

Identification of single nucleotide polymorphisms (SNPs) associated with chronic graft-versus-host disease in patients undergoing allogeneic hematopoietic cell transplantation.

INTRODUCTION: Chronic graft-versus-host disease (cGVHD) is a debilitating side effect of allogeneic hematopoietic cell transplantation (HCT), affecting the quality of life of patients. We used whole exome sequencing to identify candidate SNPs and complete a multi-marker gene-level analysis using a cohort of cGVHD( +) (N = 16) and cGVHD( -) (N = 66) HCT patients. METHODS: Saliva samples were collected from HCT patients (N = 82) pre-conditioning in a multi-center study from March 2011 to May 2018. Exome sequencing was performed and FASTQ files were processed for sequence alignments. Significant SNPs were identified by logistic regression using PLINK2v3.7 and Fisher's exact test. One cGVHD( -) patient sample was excluded from further analysis since no SNP was present in at least 10% of the sample population. The FUMA platform's SNP2GENE was utilized to annotate SNPs and generate a MAGMA output. Chromatin state visualization of lead SNPs was completed using Epilogos tool. FUMA's GENE2FUNC was used to obtain gene function and tissue expression from lead genomic loci. RESULTS: Logistic regression classified 986 SNPs associated with cGVHD( +). SNP2GENE returned three genomic risk loci, four lead SNPs, 48 candidate SNPs, seven candidate GWAS tagged SNPs, and four mapped genes. Fisher's exact test identified significant homozygous genotypes of four lead SNPs (p < 0.05). GENE2FUNC analysis of multi-marker SNP sets identified one positional gene set including lead SNPs for KANK1 and KDM4C and two curated gene sets including lead SNPs for PTPRD, KDM4C, and/or KANK1. CONCLUSIONS: Our data suggest that SNPs in three genes located on chromosome 9 confer genetic susceptibility to cGVHD in HCT patients. These genes modulate STAT3 expression and phosphorylation in cancer pathogenesis. The findings may have implications in the modulation of pathways currently targeted by JAK inhibitors in cGVHD clinical trials.

Oral health in patients scheduled for hematopoietic stem cell transplantation in the Orastem study.

Despite advances in transplant medicine, prevalence of complications after hematopoietic stem cell transplantation (HSCT) remains high. The impact of pre-HSCT oral health factors on the incidence and severity of complications post-HSCT is poorly understood. The aim of this prospective, observational study was to analyze oral health in patients planned for HSCT. Patients ≥18 years requiring HSCT were included from five sites between 2011-2018. General health, oral findings and patient-reported symptoms were registered in 272 patients. Oral symptoms around disease onset were reported by 43 patients (15.9%) and 153 patients (58.8%) reported oral complications during previous chemotherapy. One third of patients experienced oral symptoms at the oral examination before conditioning regimen and HSCT. In total, 124 (46.1%) patients had dental caries, 63 (29.0%) had ≥one tooth with deep periodontal pockets, 147 (75.0%) had ≥one tooth with bleeding on probing. Apical periodontitis was observed in almost 1/4 and partially impacted teeth in 17 (6.3%) patients. Oral mucosal lesions were observed in 84 patients (30.9%). A total of 45 (17.4%) of 259 patients had at least one acute issue to be managed prior to HSCT. In conclusion, oral symptoms and manifestations of oral disease were prevalent in patients planned for HSCT. The extent of oral and acute dental diseases calls for general oral screening of patients pre-HSCT.

Caries Progression after Haematopoietic Stem Cell Transplantation and the Role of Hyposalivation.

Haematopoietic stem cell transplantation (HSCT) preceded by a conditioning regimen is an established treatment option for many haematological diseases. Decreased salivary flow rates after HSCT may increase caries risk. We aim to estimate the extent to which caries lesions develop or progress in adult HSCT recipients and assess its association with salivary flow rates. A multi-centre prospective observational study was conducted in which patients receiving HSCT were followed up for 18 months. We included 116 patients (median age 56 years, 43% female) from two medical centres in the Netherlands. Unstimulated whole saliva (UWS) and stimulated whole saliva (SWS) were collected, and full caries charts were made before HSCT and 3, 6, 12, and 18 months post-HSCT. Caries was scored according to the ICDAS criteria by trained dentist-examiners. New dentine lesions or lesion progression into dentine (ICDAS ≥4 or cavitated root lesions) occurred in 32% of patients over 18 months. The median number of affected surfaces was 2 (range: 1-12) per patient with caries progression. The influence of hyposalivation of unstimulated saliva (<0.2 mL/min) and stimulated saliva (<0.7 mL/min) at baseline and after 3 months on caries progression was determined with a negative binomial regression model. Hyposalivation of SWS 3 months after HSCT was a significant risk indicator for caries progression (incidence rate ratio: 5.30, 95% CI: 2.09-13.4, p < 0.001), while hyposalivation of SWS at baseline and hyposalivation of UWS were not. We conclude that caries progression is a common oral complication in patients after HSCT, and stimulated hyposalivation shortly after treatment is a significant risk indicator for caries progression.

Long-Term Analysis of Resilience of the Oral Microbiome in Allogeneic Stem Cell Transplant Recipients.

Stem cell transplantation (SCT) is associated with oral microbial dysbiosis. However, long-term longitudinal data are lacking. Therefore, this study aimed to longitudinally assess the oral microbiome in SCT patients and to determine if changes are associated with oral mucositis and oral chronic graft-versus-host disease. Fifty allogeneic SCT recipients treated in two Dutch university hospitals were prospectively followed, starting at pre-SCT, weekly during hospitalization, and at 3, 6, 12, and 18 months after SCT. Oral rinsing samples were taken, and oral mucositis (WHO score) and oral chronic graft-versus-host disease (NIH score) were assessed. The oral microbiome diversity (Shannon index) and composition significantly changed after SCT and returned to pre-treatment levels from 3 months after SCT. Oral mucositis was associated with a more pronounced decrease in microbial diversity and with several disease-associated genera, such as Mycobacterium, Staphylococcus, and Enterococcus. On the other hand, microbiome diversity and composition were not associated with oral chronic graft-versus-host disease. To conclude, dysbiosis of the oral microbiome occurred directly after SCT but recovered after 3 months. Diversity and composition were related to oral mucositis but not to oral chronic graft-versus-host disease.

Lasting Gammaproteobacteria profile changes characterized hematological cancer patients who developed oral mucositis following conditioning therapy.

Background: Oral mucositis (OM) is a common side effect of conditioning therapy implemented before hematopoietic stem cell transplantation (HSCT). The role of oral microbiome in OM is not fully elucidated. Objective: To determine oral microbiome profile changes post-conditioning in HSCT patients who developed moderate OM, or mild to no OM. Design: Patient groups were: Muc0-1 with OM-score = 0-1 (43 paired samples) and Muc2 with WHO OM-score = 2 (36 paired samples). Bacterial DNA was isolated from oral samples (saliva, swabs of buccal mucosa, tongue, and supragingival plaque) at pre-conditioning (T 0 ), post-conditioning mucositis onset (T Muc ), and one-year post-conditioning (T Year ). 16S-rRNA gene next-generation sequencing was used to determine the relative abundance (RA) of >700 oral species. Alpha-diversity, beta-diversity and linear discriminant analyses (LDA) were performed Muc2 versus Muc0-1. Results: Muc2 oral microbiome alpha- and beta-diversity differed between T 0 and T Muc . Muc2 alpha-diversity and Muc0-1 beta-diversity did not differ between T 0 and T Year . T 0 to T Muc LDA scores were significant in Muc2 for Gammaproteobacteria. For Muc2 patients, the average RA decreased for Haemophilus parainfluenza, a species known as mucosal surfaces protector, but increased for Escherichia-Shigella genera. Conclusions: Post-conditioning OM might contribute to long-term oral microbiome changes affecting Gammaproteobacteria, in HSCT patients.

Microbial changes in relation to oral mucositis in autologous hematopoietic stem cell transplantation recipients.

The aim of this prospective, two center study was to investigate the dynamics of the microbial changes in relation to the development of ulcerative oral mucositis in autologous SCT (autoSCT) recipients. Fifty-one patients were diagnosed with multiple myeloma and treated with high-dose melphalan followed by autoSCT. They were evaluated before, three times weekly during hospitalization, and three months after autoSCT. At each time point an oral rinse was collected and the presence or absence of ulcerative oral mucositis (UOM) was scored (WHO scale). Oral microbiome was determined by using 16S rRNA amplicon sequencing and fungal load by qPCR. Twenty patients (39%) developed UOM. The oral microbiome changed significantly after autoSCT and returned to pre-autoSCT composition after three months. However, changes in microbial diversity and similarity were more pronounced and rapid in patients who developed UOM compared to patients who did not. Already before autoSCT, different taxa discriminated between the 2 groups, suggesting microbially-driven risk factors. Samples with high fungal load (>0.1%) had a significantly different microbial profile from samples without fungi. In conclusion, autoSCT induced significant and reversible changes in the oral microbiome, while patients who did not develop ulcerative oral mucositis had a more resilient microbial ecosystem.

Swedish Quality Registry for Caries and Periodontal Diseases - a framework for quality development in dentistry.

OBJECTIVES: There is a need for monitoring dental health and healthcare, as support for quality development, allocation of resources and long-term planning of dental care. The aim of this paper is to describe the concept and implementation of the Swedish Quality Registry for Caries and Periodontal Diseases (SKaPa). MATERIALS AND METHODS: The SKaPa receives information by automatic transfer of data daily from electronic patient dental records via secure connections from affiliated dental care organisations (DCOs). The registry stores information about DCOs, dental professionals and patients. Information on a patient level includes personal identifier, gender, age, living area, dental status, risk assessments for caries and periodontitis, and dental care provided. In addition, data generated from a global question on patient-perceived oral health are uploaded. In total, more than 400 variables are transferred to the registry and updated daily. RESULTS: In 2018, all of the 21 public DCOs and the largest private DCO in Sweden were affiliated to SKaPa, representing a total of 1,089 public and 234 private dental clinics. The accumulated amount of information on dental healthcare covers 6.9 million individuals out of the total Swedish population of 10 million. SKaPa produces reports on de-identified data, both cross-sectional and longitudinal. CONCLUSION: As a nationwide registry based on automatic retrieval of data directly from patient records, SKaPa offers the basis for a new era of systematic evaluation of oral health and quality of dental care. The registry supports clinical and epidemiological research, data mining and external validation of results from randomised controlled trials.

Impact of Oral Side Effects from Conditioning Therapy Before Hematopoietic Stem Cell Transplantation: Protocol for a Multicenter Study.

BACKGROUND: The oral cavity is a common site of complications related to the cytotoxic effect of high-dose chemotherapy and radiation therapy. Considering our limited understanding of the burden of illness in the oral cavity from various cytotoxic therapies, it is difficult to produce evidence-based, preventive and management protocols. A prospective multicenter study is necessary to collect data on the burden of illness from various cytotoxic regimens. OBJECTIVE: The objectives of this prospective international observational multicenter study in hematopoietic stem cell transplant (HSCT) patients are to establish the nature, incidence and temporal relationship of oral complications related to conditioning regimens (chemotherapy with or without total body irradiation), stem cell transplantation and the immunologic reactions (mainly graft-vs-host-disease) that may follow, and to determine what subjective and objective oral complications related to treatment can predict negative clinical and economic outcomes and reduced quality of life. METHODS: Adult patients at six study sites receiving full intensity conditioning, reduced intensity conditioning or nonmyeloablative conditioning, followed by autologous or allogeneic hematopoietic stem cell infusion, are included. A pre-treatment assessment includes medical conditions, planned chemo- and radiation therapy regimen, medications, allergies, social history, patient report of oral problems, dental history, subjective oral complaints, objective measures of oral conditions, current laboratory values, dental treatment recommended and untreated dental disease. Starting 1-3 days after hematopoietic stem cell infusion, a bedside assessment is completed 3 days per week until resolution of neutropenia. A patient questionnaire is also completed during hospitalization. Beyond this time, patients with continued oral mucositis or other oral problems are followed 1 day per week in an inpatient or outpatient setting. Additional visits for urgent care for acute oral problems after hospitalization are documented. Autologous transplant patients are being followed up at 100 days (SD 30 days) and at 1 year (SD 30 days) post-transplantation to identify any long-term side effects. Patients treated with allogeneic transplantation are being followed at 100 days (SD 30 days), 6 months (SD 30 days), and 12 months (SD 30 days). The follow-up assessments include cancer response to therapy, current medical conditions, medications, subjective and objective oral findings, quality of life measures and laboratory values. The targeted enrollment is 254 patients who have received HSCT. RESULTS: A total of 260 participants have been enrolled, with 233 (91%) who have received HSCT. We anticipate enrollment of 20-30 additional participants to obtain the sample size of 254 enrolled participants who have received HSCT. CONCLUSIONS: The results of the ongoing prospective study will provide a unique dataset to understand the impact of oral complications on patients undergoing HSCT and provide needed evidence for guidelines regarding the management of this patient cohort.

Incidence and causes of dental trauma in children living in the county of Värmland, Sweden.

AIM: The aims of this study were to determine the incidence of injuries to permanent incisors in 2011-2013 in children aged 8-10 years living in the county of Värmland, Sweden, and to compare it with the incidence rates in 1989/1990 in the county of Västmanland, as well as to determine the cause of dental trauma in relation to time and place. METHOD: The study analysed the patient records from dental visits (2011-2013) of trauma to the permanent incisors in children aged 8-10 years. The incidence rates were the incidence per 1000 children at risk. Standardized incidence rates were calculated for the comparison between different years. Information about month, location where the trauma occurred as well as cause of trauma was recorded. RESULTS: A total of 2.2% of 21 721 children aged 8-10 years had experienced at least one trauma. The incidence rate in Värmland increased from 18.9 in 2011 to 21.3 in 2012 to 28.5 in 2013. The standardized incidence rate in Värmland in 2011 and 2012 was not significantly different than in Västmanland in 1989/1990 (P > 0.05), but the standardized rates in 2013 were significantly higher than in 1989/90 (P < 0.001). Dental trauma occurred most often outdoors, followed by sports arenas/sports fields, and more often at school than at home. Falling and slipping was the most common cause of trauma, followed by accidents during leisure activities, playing and sports. CONCLUSION: The incidence rate for dental trauma has not decreased in the past 20 years, and there is an indication that parents and teachers should be more aware of the risks of dental trauma at leisure times and at school as well as during sports and exercise.

Systematic review of cytokines and growth factors for the management of oral mucositis in cancer patients.

PURPOSE: The aim of this project was to review the literature and define clinical practice guidelines for the use of cytokines and growth factor agents for the prevention or treatment of oral mucositis induced by cancer chemotherapy or radiotherapy. METHODS: A systematic review was conducted by the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society for Oral Oncology (MASCC/ISOO). The body of evidence for each intervention, in each cancer treatment setting, was assigned an evidence level. Based on the evidence level, one of the following three guideline determinations was possible: Recommendation, Suggestion, No guideline possible. RESULTS: Sixty-four clinical studies across 11 interventions were evaluated. A recommendation was made for the use of recombinant human KGF-1 (palifermin) at a dose of 60 µg/kg per day for 3 days prior to conditioning treatment and for 3 days post-transplant for prevention of oral mucositis in patients receiving high-dose chemotherapy and total body irradiation followed by autologous stem cell transplantation for hematological malignancies. A suggestion was made against using granulocyte macrophage colony-stimulating factor mouthwash for the prevention of oral mucositis in the setting of high-dose chemotherapy followed by autologous or allogeneic stem cell transplantation. No guideline was possible for any other cytokine or growth factor agents due to inconclusive evidence. CONCLUSIONS: Of the cytokine and growth factor agents studied for oral mucositis, the evidence only supports use of palifermin in the specific population listed above. Additional well-designed research is needed on other cytokine and growth factor interventions and in other cancer treatment settings.

Topical immunomodulators for management of oral mucosal conditions, a systematic review; Part II: miscellaneous agents.

INTRODUCTION: Topical immunomodulating preparations have utility in inflammatory/immune-mediated oral mucosal disease resistant to topical steroids, in immunologically mediated systemic disease with primary oral involvement or more severe lesions primarily involving the oral mucosa. AREAS COVERED: This paper is the second part of a systematic review of a variety of topical immunomodulators for management of immune/inflammatory oral mucosal conditions. The literature search revealed studies of azathioprine, benzydamine, GM-CSF and G-CSF, tetracyclines, retinoids, imiquimod, amlexanox, sirolimus and bacillus Calmette-Guerin polysaccharide nucleic acid. Weighted conclusions are provided for the topical use of each of the immunomodulators reviewed in the management of these oral diseases. EXPERT OPINION: Topical immunomodulators may be useful as second line treatment in several oral diseases, particularly oral lichen planus and recurrent aphthous stomatitis. Benzydamine was found to be preventive in radiotherapy-induced mucositis; however, it is unclear if this outcome is related to its immunomodulating effects or other mechanisms of action. Topical application of tetracyclines and retinoic acid also shows potential anti-inflammatory actions.

Topical immunomodulators for management of oral mucosal conditions, a systematic review; part I: calcineurin inhibitors.

IMPORTANCE OF THE FIELD: Topical immunomodulators have been used for the management of oral mucosal diseases. Topical immunomodulating preparations may have utility in local management of oral disease which is resistant to topical steroids and oral findings of an immunologic-mediated systemic disease with primary or persisting, oral mucosal involvement. AREAS COVERED IN THIS REVIEW: This paper is the first part of a systematic review of topical immunomodulators for the management of various oral indications focused on calcineurin inhibitors. The literature search revealed that data are available for cyclosporine, tacrolimus and pimecrolimus. In addition to the review of scientific evidence, this paper presents the potential market, the mechanism of action, the competitive environment and future development options. WHAT THE READER WILL GAIN: The reader will find weighted conclusions for the topical use of the calcineurin inhibitors in the management of oral diseases. TAKE HOME MESSAGE: Topical calcineurin inhibitors may be useful as a second-line treatment in several oral diseases, particularly oral lichen planus.

Salivary dysfunction associated with systemic diseases: systematic review and clinical management recommendations.

OBJECTIVES: The objective of this study was to identify systemic diseases associated with hyposalivation and xerostomia and develop evidence-based management recommendations for hyposalivation/xerostomia. STUDY DESIGN: Literature searches covered the English language medical literature from 1966 to 2005. An evidence-based review process was applied to management studies published from 2002 to 2005. RESULTS: Several systemic diseases were identified. From studies published 2002 to 2005, 15 were identified as high-quality studies and were used to support management recommendations: pilocarpine and cevimeline are recommended for treating hyposalivation and xerostomia in primary and secondary Sjögren's syndrome (SS). IFN-alpha lozenges may enhance saliva flow in primary SS patients. Anti-TNF-alpha agents, such as infliximab or etanercept, are not recommended to treat hyposalivation in SS. Dehydroepiandrosterone is not recommended to relieve hyposalivation or xerostomia in primary SS. There was not enough evidence to support any recommendations for the use of local stimulants, lubricants, and protectants for hyposalivation/xerostomia. However, professional judgment and patient preferences may support the use of a specific product for an individual patient. CONCLUSIONS: These evidence-based management recommendations should guide the clinician's management decisions for patients with salivary dysfunction related to systemic disease. Future treatment strategies may include new formulations of existing drugs, e.g., local application of pilocarpine. Recent discoveries on gene expression and a better understanding of the etiopathogenesis of SS may open new treatment options in the future.

Combining paracetamol with a selective cyclooxygenase-2 inhibitor for acute pain relief after third molar surgery: a randomized, double-blind, placebo-controlled study.

Severe pain after third molar surgery is often encountered and more effective treatment regimes are warranted. The objective of this study was to evaluate if the combination of paracetamol and rofecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, improves analgesic effects following third molar surgery compared with rofecoxib alone. Paracetamol alone was also evaluated. Altogether 120 patients with moderate to severe pain after third molar surgery were given a single postoperative dose of one of the following treatments: rofecoxib + paracetamol; rofecoxib alone; paracetamol alone; or placebo. Patients assessed level of pain and pain relief every 30 min for 8 h after surgery, and made a global evaluation of the medication 4 and 8 h after surgery. Paracetamol and rofecoxib combined improved the analgesic effect compared with rofecoxib alone for the first 1.5 h. Rofecoxib alone and the combination of paracetamol and rofecoxib had a significantly better analgesic effect than paracetamol alone from 3 h onwards. The early onset of pain relief for the combination of paracetamol and rofecoxib, compared with rofecoxib alone, could be of great importance when treating acute pain after third molar surgery. After data collection for this study, rofecoxib was withdrawn from the market as a result of reported fatal cardiovascular events. Whether this is relevant for short-term use is unknown, but it has to be considered before rofecoxib may be used for pain relief following third molar surgery.

Growth factors and cytokines in the prevention and treatment of oral and gastrointestinal mucositis.

GOALS OF WORK: Growth factors and cytokines may be useful in preventing chemotherapy (CT)- and radiotherapy (RT)-induced oral and gastrointestinal mucositis. Two systematic reviews of the medical literature on growth factors and cytokines for the amelioration of CT- and RT-induced mucositis throughout the alimentary tract were performed by the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society for Oral Oncology. The aim of these evidence-based scientific reviews was to critically evaluate the literature and create evidence-based guidelines for the use of growth factors and cytokines in the prevention or treatment of CT- and RT-induced mucositis. METHOD: The two reviews covered articles on clinical trials from January 1966 through May 2002 and preclinical studies from June 2002 through May 2005, respectively. The systematic review process was based on a well-established method for evaluating scientific literature. MAIN RESULTS: The number of articles in the first review was 29. In the second review, 23 articles were evaluated, 14 preclinical and 9 clinical studies. It was concluded from the first review that there was no sufficient evidence to provide any recommendations for clinical practice guidelines regarding growth factors and cytokines. From the second review, a guideline could be presented recommending the use of recombinant human keratinocyte growth factor-1 (palifermin) to prevent oral mucositis in patients receiving high-dose CT and total body irradiation followed by stem cell transplantation for haematological malignancies. A guideline could also be provided suggesting that granulocyte macrophage colony-stimulating factor mouthwash not be used for the prevention of oral mucositis in the transplant setting with high-dose CT and autologous or allogeneic stem cell transplantation. CONCLUSIONS: These systematic reviews have provided clarity and shown exciting new results. Further studies will provide new options for this debilitating side-effect of cancer therapy.

Alimentary mucositis: putting the guidelines into practice.

BACKGROUND: The Mucositis Study Group of the Multinational Association of Supportive Care in Cancer and International Society of Oral Oncology completed an evidence-based review of the literature for the management of alimentary mucositis. DISCUSSION: The present manuscript puts these guidelines into clinical practice by presenting two cases of alimentary mucositis from cancer therapy. These cases illustrate the impact of oral and gastrointestinal mucositis on patient care.