Silvia Spivakovsky

Endothelin receptor type B gene promoter hypermethylation in salivary rinses is independently associated with risk of oral cavity cancer and premalignancy.

Endothelin receptor type B (EDNRB) and kinesin family member 1A (KIF1A) are candidate tumor suppressor genes that are inactivated in cancers. In this study, we evaluated the promoter hypermethylation of EDNRB and KIF1A and their potential use for risk classification in prospectively collected salivary rinses from patients with premalignant/malignant oral cavity lesions. Quantitative methylation-specific PCR was performed to analyze the methylation status of EDNRB and KIF1A in salivary rinses of 191 patients. We proceeded to determine the association of methylation status with histologic diagnosis and estimate classification accuracy. On univariate analysis, diagnosis of dysplasia/cancer was associated with age and KIF1A or EDNRB methylation. Methylation of EDNRB highly correlated with that of KIF1A (P < 0.0001). On multivariable modeling, histologic diagnosis was independently associated with EDNRB (P = 0.0003) or KIF1A (P = 0.027) methylation. A subset of patients analyzed (n = 161) without prior biopsy-proven malignancy received clinical risk classification based on examination. On univariate analysis, EDNRB and risk classification were associated with diagnosis of dysplasia/cancer and remained significant on multivariate analysis (EDNRB: P = 0.047, risk classification: P = 0.008). Clinical risk classification identified dysplasia/cancer with a sensitivity of 71% and a specificity of 58%. The sensitivity of clinical risk classification combined with EDNRB methylation improved to 75%. EDNRB methylation in salivary rinses was independently associated with histologic diagnosis of premalignancy and malignancy and may have potential in classifying patients at risk for oral premalignant and malignant lesions in settings without access to a skilled dental practitioner. This may also potentially identify patients with premalignant and malignant lesions that do not meet the criteria for high clinical risk based on skilled dental examination. Cancer Prev Res; 3(9); 1093–103. ©2010 AACR.

EDNRB and DCC Salivary Rinse Hypermethylation Has a Similar Performance as Expert Clinical Examination in Discrimination of Oral Cancer/Dysplasia versus Benign Lesions

Purpose: Promoter hypermethylation has been recently proposed as a means for head and neck squamous cell carcinoma (HNSCC) detection in salivary rinses. In a prospective study of a high-risk population, we showed that endothelin receptor type B (EDNRB) promoter methylation in salivary rinses is a useful biomarker for oral cancer and premalignancy. Experimental Design: Using that cohort, we evaluated EDNRB methylation status and 8 additional genes. Clinical risk assessment by expert clinicians was conducted and compared with biomarker performance in the prediction of premalignant and malignant disease. Methylation status of 9 genes was analyzed in salivary rinses of 191 patients by quantitative methylation-specific PCR. Results: HOXA9, EDNRB, and deleted in colorectal cancer (DCC) methylation were associated (P = 0.012; P < 0.0001; P = 0.0005) with premalignant or malignant disease. On multivariable modeling, histological diagnosis was only independently associated with EDNRB (P = 0.0003) or DCC (P = 0.004) methylation. A subset of patients received clinical risk classification (CRC) by expert clinicians based on lesion examination. CRC, DCC, and EDNRB were associated with diagnosis of dysplasia/cancer on univariate (P = 0.008; P = 0.026; P = 0.046) and multivariate analysis (P = 0.012; P = 0.037; P = 0.047). CRC identified dysplasia/cancer with 56% of sensitivity and 66% of specificity with a similar area under curve [AUC; 0.61, 95% confidence interval (CI) = 0.60–0.81] when compared to EDNRB and DCC combined AUC (0.60, 95% CI = 0.51–0.69), sensitivity of 46% and specificity of 72%. A combination of EDNRB, DCC, and CRC was optimal AUC (0.67, 95% CI = 0.58–0.76). Conclusions: EDNRB and/or DCC methylation in salivary rinses compares well to examination by an expert clinician in CRC of oral lesions. These salivary biomarkers may be particularly useful in oral premalignancy and malignancy screening in clinical care settings in which expert clinicians are not available. Clin Cancer Res; 19(12); 3268–75. ©2013 AACR.

Cannabis use and oral diseases

Data sourcesMedline and the Cochrane Central register of controlled trails (CENTRAL).Study selectionRandomised Controlled Trials, Controlled Clinical Trials and Cohort Studies conducted on humans investigating cannabis usage were included. Screening was performed independently by two reviewers. Only English language studies were included. Case reports, letters and historical reviews were excluded.Data extraction and synthesisA narrative synthesis was conducted.ResultsSeven studies were included and a range of cannabis-associated oral side effects identified.ConclusionsBased on the limited data, it seems justified to conclude that with increasing prevalence of cannabis use, oral health care providers should be aware of cannabis-associated oral side effects such as xerostomia, leukoedema and an increased prevalence and density of Candida albicans.

Effect of antibiotics on implant failure and postoperative infection

Data sourcesMedline and hand search of the British Journal of Oral and Maxillofacial Surgery, Clinical Implant Dentistry and Related Research, Clinical Oral Investigations, Clinical Oral Implants Research, European Journal of Oral Implantology, Implant Dentistry, International Journal of Oral and Maxillofacial Implants, International Journal of Oral and Maxillofacial Surgery, Journal of Clinical Periodontology, Journal of Oral Implantology, Journal of Oral and Maxillofacial Surgery, Journal of Periodontology Medicina Oral, Patologa Oral y Cirugía Bucal, and Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology and Endodontology.Study selectionSearch of the literature was made to identify randomised controlled trials (RCTs) on the efficacy of antibiotics compared with a control group (not receiving antibiotics or receiving placebo.Data extraction and synthesisAll articles selected from the electronic and manual searches were independently assessed by the first and second authors of this study, in accordance with the established inclusion criteria. Two reviewers independently and in duplicate evaluated the quality of the included RCTs as part of the data extraction process.ResultsFour RCTs were included in the final review. These four RCTs grouped a total of 2063 implants and a total of 1002 patients.ConclusionsAntibiotic use significantly lowered the implant failure rate (P = 0.003), with an odds ratio of 0.331, implying that antibiotic treatment reduced the odds of failure by 66.9%. The number needed to treat (NNT) to prevent one patient from having an implant failure was 48 (95% confidence interval 31-109). In contrast, antibiotic use did not significantly reduce the incidence of postoperative infection (P = 0.754). Based on the results of this meta-analysis, and pending further research in the field, it can be concluded that there is evidence in favour of systematic antibiotic use in patients receiving dental implants, since such treatment significantly reduces implant failure. In contrast, antibiotic use does not exert a significant preventive effect against postoperative infection.

Periodontal treatment for the prevention of adverse birth outcomes

Data sourcesCochrane Oral Health and Pregnancy and Childbirths Trial Registries, Cochrane Register of Controlled Trials, Cochrane Library, Medline Ovid, Embase Ovid and LILACS BIREME, clinicaltrials.com and the WHO Clinical Trials Registry Platform were searched for published and ongoing trials until October of 2016.Study selectionRandomised controlled trials (RCTs) investigating the effects of periodontal treatment in reducing or preventing perinatal and maternal morbidity and mortality with no exclusions of language or date of publication. Primary perinatal outcomes included: gestational age at birth, birth weight, small for gestational age and perinatal mortality, while the primary maternal outcomes included mortality, pre-eclampsia and treatment adverse effects.Data extraction and synthesisTwo authors independently screened for inclusion and extracted data. Risk of bias was assessed using the Cochrane ‘risk of bias’ tool.Dichotomous results were expressed as risk ratios (RR) with a 95% confidence interval (CI), and continuous data were expressed as mean differences (MD) with 95% confidence interval. Random-effects model was used for combining results.The quality of the evidence was assessed using GRADE.ResultsFifteen studies with a total of 7,161 participants met the inclusion criteria.Eleven studies (n = 5671) compared periodontal treatment with no treatment. For the outcome preterm birth before <37 weeks a calculated RR of 0.87, 95% CI 0.70-1.10 shows no clear difference. From seven studies (n = 3470) there is evidence that periodontal treatment may reduce birth weight <2500g (RR 0.77, 95% CI 0.48-0.95).There is unclear evidence on the effect of periodontal treatment on preterm birth <35 weeks, <32 weeks, perinatal mortality and pre-eclampsia.Three studies with 3,610 participants showed no evidence of difference in the outcome small for gestational age: RR 0.97, 95% CI 0.81-1.16.ConclusionsThere is no clear evidence that periodontal treatment during pregnancy has an effect on preterm birth. There is some evidence that it may reduce incidence of low birth weight.There is insufficient evidence to define what type of periodontal treatment is superior in preventing any adverse pregnancy outcome.

Myocardial infarction and tooth extraction associated

Study designThis was a nested case control study within the Oslo study, which began in 1972/73 with the principle aim of studying prevention and epidemiology of cardiovascular diseases.InterventionWithin the Oslo study, men who attended for examination in both 1972/73 and 2000 with a self-reported history of MI (n=548) were compared to controls (n=625) selected at random from the same cohort, and matched by five-year strata for age.Outcome measureInformation on history of tooth extractions and the reasons for these extractions were obtained from a self-reported questionnaire. Reasons for tooth extractions were subgrouped into infection (marginal periodontitis and apical infection) or trauma/other causes.ResultsInvestigation of the association between the reason for extraction and MI, using prospective logistic analysis, found that extractions attributed to dental infections were significant predictors for risk factors in both 1972/73 and 2000.ConclusionsThere was an increased association between MI and tooth extraction due to dental infection compared with tooth extraction for trauma and other reasons.

Inconclusive evidence on systemic treatments for recurrent aphthous stomatitis.

Data sourcesThe trial registers of the Cochrane Oral Health and Pain, Palliative and Supportive Care Groups were searched together with The Cochrane Central database, Medline, Embase, CINHAL and AMED databases. Reference lists of relevant articles were also searched and authors of trials contacted.Study selectionRandomised controlled trials (RCTs), including those with cross-over design where the primary outcome was a reduction of pain associated with RAS, a reduction in episode duration or episode frequency were included.Data extraction and synthesisData were extracted independently by two authors and risk of bias assessment was conducted on six domains. Cochrane statistical guidelines were to be followed.ResultsTwenty-five trials were included; 22 were placebo controlled and eight made head-to-head comparisons (five trials had more than two treatment arms). Twenty-one different interventions were assessed. The interventions were grouped into two categories: immunomodulatory/anti-inflammatory and uncertain. Only one study was assessed as being at low risk of bias. There was insufficient evidence to support or refute the use of any intervention.ConclusionsNo single treatment was found to be effective and therefore the results remain inconclusive in regard to the best systemic intervention for RAS. This is likely to reflect the poor methodological rigour of trials, and lack of studies for certain drugs, rather than the true effect of the intervention. It is also recognised that in clinical practice, individual drugs appear to work for individual patients and so the interventions are likely to be complex in nature. In addition, it is acknowledged that systemic interventions are often reserved for those patients who have been unresponsive to topical treatments, and therefore may represent a select group of patients.

Botulinum toxin for facial neuralgia

Data sourcesMedline via PubMed, the Web of Science and the Cochrane Library were searched until April 2014.Study selectionRandomised controlled trials (RCTs) comparing the efficacy of botulinum toxin type A (BoTN-A) with placebo in patients with painful trigeminal (TN) and postherpetic neuralgia (PHN) reporting changes in pain intensity in patients aged 19 years and older available in English were included.Data extraction and synthesisThree authors independently assessed for inclusion, extracted standard data and assessed for risk of bias. The primary outcomes were baseline and post treatment intensity of pain and patients reporting pain relief of 50% or greater.For continuous outcomes the treatment effect was measured as mean differences with 95% confidence intervals (CIs). For dichotomous outcome of reduction of pain of 50% or more, relative risk (risk ratio) with 95% CIs was reported. Statistical heterogeneity was tested with Cochrans test for heterogeneity and quantified by the I2 statistic. Results were combined using random-effects model in the presence of statistical heterogeneity otherwise fixed effect model was used.ResultsSix studies were included. The effects of the interventions were presented in three meta-analyses. Mean difference in post treatment pain (six studies) pooled results showed a reduction of −3.009 in the VAS (95% CI −4.566 to −1.453 p<0.001) with the use of BoTN-A. Standardised difference in mean post treatment pain (six studies) was −0.918 (95% CI −1.197 to −0.639 p<0.001) in favor of BoTN-A. For the percentage of patients experiencing 50% pain reduction (three studies) absolute risk difference and relative risk were calculated (RR 2.892, 95% CI 1.726 to 4.848 p<0.001) in favour of the use of BoTN-A.ConclusionsThe authors concluded that there is moderate evidence regarding the efficacy of BoTN-A in treating patients with trigeminal neuralgia and postherpetic neuralgia.

Little evidence to support or refute interventions for the management of burning mouth syndrome

Data sourcesCochrane Oral Healths Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), Medline Ovid, Embase Ovid, US National Institutes of Health Ongoing Trials Register (ClinicalTrials.gov) and the World Health Organization International Clinical Trials Registry Platform. Handsearch of the proceedings from the British Society for Oral Medicine (BSOM), British Society for Dental Research (BSDR) and the International Association for Dental Research (IADR).Study selectionAll included studies were randomised placebo controlled trials comparing a treatment to placebo with no language or year of publication restrictions. Symptom relief and changes in quality of life were considered primary outcomes.Data extraction and synthesisTeams of two authors independently screened for inclusion, extracted data using an ad-hoc tool and assessed the risk of bias using the Cochranes tool. Outcomes were analysed for <3 months (short term) and ≥3 to ≤6 months (long term). For single studies with multiple interventions, the number of participants in the control group was adjusted to half before combining the results. For crossover studies without washout periods, the first period was analysed. RRs (risk ratios) and 85% confidence intervals were calculated for dichotomous outcomes and MDs (mean differences) and 95% confidence intervals for continuous data.ResultsA total of 23 studies encompassing 1121 patients were included. One study was considered as having overall low risk of bias, four unclear and the rest as high risk of bias. The interventions were grouped into: antidepressants and antipsychotics, anticonvulsants, benzodiazepines, cholinergics, dietary supplements, electromagnetic radiation, physical barriers, psychological therapies and topical treatments. Short-term symptom relief was demonstrated by: energy waves (one study, 58 participants) MD −30.36, 95% CI −44.22 to −16.50, physical barriers (one study, 50 participants) MD −1.1 95% CI −2.14 to 0.06, the anticonvulsant gabapentin (one study, 100 participants) RR 4.00, 95% CI 2.09 to 7.67 and topical benzodiazepine (two studies, 111 participants) MD −1.89 95% CI −2.19 to −1.59. Long term symptom relief was achieved with topical benzodiazepine (one study, 66 participants) MD −1.39 95% CI −1.96 to 0.83ConclusionsFrom studies mostly classified as high risk of bias, there is insufficient evidence to support or refute the use of any particular intervention for the management of BMS.

Reliable evidence for efficacy of single dose oral analgesics.

Data sourcesThe Cochrane library was searched for Cochrane systematic reviews.Study selectionCochrane reviews on single pain medications for the treatment of acute pain were included. Non-Cochrane reviews were included for tramadol.Data extraction and synthesisTwo reviewers independently searched, selected reviews for inclusion, assessed quality and performed data extraction. A protocol in case of disagreement was in place. Data were collected on number of included studies and participants, drug, dose and formulation and pain model. The authors concentrated on the amount of information and the potential for publication bias.Pain relief was calculated using at least 50% maximum pain relief, as a percentage, and as NNTs. Duration of analgesia was measured as mean or median and time to remedication was calculated as percentage of patients.ResultsThirty-nine reviews including 41 interventions were analysed and NNTs for at least 50% maximum pain relief were summarised in a graphic. NNTs range from almost one all the way to five. Only one intervention, codeine 60, had an NNT ≥10. Results judged to be reliable were listed in detail. Mean or median time to remedication was also presented in a graphic.The authors conclude that there is a great amount of quality information on single dose analgesics, and highlighted the potential benefit of fast acting formulations and fixed formulations to achieve good long-lasting analgesia.ConclusionsThere is a wealth of reliable evidence on the analgesic efficacy of single dose oral analgesics. Fast acting formulations and fixed dose combinations of analgesics can produce good and often long-lasting analgesia at relatively low doses. There is also important information on drugs for which there are no data, inadequate data, or where results are unreliable due to susceptibility to publication bias. This should inform choices by professionals and consumers.