Athanasios I. Zavras

Factors Associated with Delay in the Diagnosis of Oral Cancer

Early detection and treatment improve the prognosis for oral cancer. Delays from the onset of symptoms to clinical diagnosis are common. Our aim is to identify factors associated with this delay. Between 1995 and 1998, we interviewed 105 consecutive patients with histologically confirmed oral cancer in Greece. If 21 or more days elapsed from the time the patient noticed major symptoms to a definitive diagnosis, we called it a delay (52% of cases). We used logistic and linear regression to estimate odds ratios of delayed diagnosis and to identify correlates of length of delay, respectively. Former smokers had a 4.3 times greater risk of delayed diagnosis compared with current smokers (95% confidence interval: 1.1-17.1). The length of delay was greater among single patients, non-smokers, or those with stage IV tumors. Clinicians should be advised that delay in the diagnosis of oral cancer occurs frequently, even in individuals who do not smoke heavily.

Smoking and alcohol in the etiology of oral cancer: gender-specific risk profiles in the south of Greece

Oral and pharyngeal cancer (OC) mortality is very low in Greece, especially among men, compared to other European countries. We conducted a case-control study of OC in Athens, and obtained information on tobacco, alcohol use and other potential risk factors and confounding variables for 110 incident cases and 115 hospital-based controls. We used multivariate logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Tobacco smoking (pack years, P(trend)=0.01) and alcohol use (drinks/week, P(trend)=0.07) were independent risk factors, with a multiplicative effect for combined exposures (OR, 8.3; 95% CI, 2.4-29.1, for >28 alcohol drinks/week and >50 pack years of cigarette smoking). The type of alcoholic beverage also seemed important: drinking ouzo and tsipouro (liquors of high ethanol concentration) was associated with greater increased OC risk than drinking comparable amounts of wine, beer or dark spirits. While alcohol drinking is more common for male cases versus controls, few men reported regularly consuming large quantities of ethanol associated with highest risk of OC in other studies. This may partially explain the low rates of male OC mortality in Greece. Among the 38% of our cases who were women, however, neither smoking nor alcohol drinking frequencies were significantly elevated compared to controls, and so the etiology of OC risk in females requires further investigation.

Bisphosphonates and Time to Osteonecrosis Development

Bisphosphonate-associated osteonecrosis of the jaw (BONJ) is a complication of long-term bisphosphonate (BP) use. Given the beneficial effects of BP on bone quality in patients with cancer or osteoporosis, it is of great importance to understand the risk as it relates to time to event or cumulative dose until the onset of disease. Because there is no information on the lowest toxic dose from clinical trials, here we report on a review of 71 case series published since 2003. We calculated the weighted mean time to event, as well as the minimum reported time and dose for zoledronate, pamidronate, and oral bisphosphonates. The mean time to BONJ after zoledronate treatment was calculated at 1.8 years and the minimum was 10 months; after pamidronate, the mean time was 2.8 years and the minimum was 1.5 years; and after oral BP therapy, the mean time was 4.6 years and the minimum was 3 years. Zoledronic acid seems to be the most potent among the nitrogen-containing BPs. Factors that seem to affect BONJ and time to event were invasive dental procedures and other comorbid factors such as advanced age, rheumatoid arthritis, diabetes, use of corticosteroids, vitamin D deficiency, and more. Understanding the pathophysiology of the disease requires further research.

Using DEA to Evaluate Efficiency and Formulate Policy Within a Greek National Primary Health Care Network

The purpose of this paper is to critically evaluate the relative efficiency of primary health care centers of the principal Greek public insurance provider, the Social Security Institute (IKA). The source of the efficiency data was the Statistical Unit of IKA. Using Data Envelopment Analysis, we analyzed data from 133 centers nationwide. Input variables included the number of personnel, stratified in different categories, and the number of people covered by each health center. The number of pensioners enlisted to each health care facility was used as an index of aging and vulnerability of the covered population. According to the results of the study, centers with the technological infrastructure to perform laboratory and/or radiographic examinations exhibited higher efficiency scores. In addition, centers with eligible covered populations from 10,000 to 50,000 were found as the most efficient. Health sector reforms should be planned on the basis of such analyses. If the model is supplemented with valid demographic, socioeconomic, and epidemiological data, it may become the basis for the creation of a national health care chart, matching available resources to the population and its health care needs.

Prospective Study of Alcohol Consumption and Risk of Oral Premalignant Lesions in Men

Recent case-control studies indicate that alcohol increases the risk of oral premalignant lesions (OPL) among tobacco users, but the independent association between alcohol and OPL remains unclear. We prospectively evaluated the association between alcohol consumption and the incidence of OPL. Participants were 41,458 men in the Health Professionals Follow-up Study. Alcohol consumption was assessed every 4 years using validated food frequency questionnaires. We confirmed clinically or histopathologically diagnosed OPL events occurring between 1986 and 2002 by medical record review (193 cases). Multivariate-adjusted relative risks of OPL were calculated from Cox proportional hazards models. With detailed control for tobacco and other variables, multivariate relative risks (95% confidence intervals) were 1.7 (0.9-3.2) for drinkers of 0.1 to 14.9 g/d, 2.9 (1.5-5.6) for 15 to 29.9 g/d, and 2.5 (1.3-5.1) for ≥30 g/d, compared with nondrinkers. Approximately one additional drink per day (12.5 g) was associated with a 22% increase in risk (P < 0.001). The associations did not vary by beverage type, frequency, or consumption with meals. Results were similar when restricted to cases of oral epithelial dysplasia. Alcohol increased OPL risk in never-users of tobacco as well as in past or current users. An interaction between alcohol and tobacco was apparent by their more-than-additive joint effects. Alcohol is an independent risk factor for OPL, regardless of beverage type or drinking pattern. Recommendations to reduce alcohol intake have the potential to reduce incidence of OPL in nonsmokers and smokers alike. (Cancer Epidemiol Biomarkers Prev 2006;15(4):774–81)

Interaction between a single nucleotide polymorphism in the alcohol dehydrogenase 3 gene, alcohol consumption and oral cancer risk†

We investigated effects on oral cancer (OC) risk of an interaction between a single nucleotide polymorphism (SNP) in the alcohol dehydrogenase 3 (ADH3) gene and alcohol consumption levels using a hospital‐based study of 93 cases and 99 controls conducted in Athens, Greece. This SNP affects ethanol metabolism in vitro and appeared to interact with alcohol consumption in a previous OC study. We also evaluated a SNP in CYP2E1, another gene involved in ethanol metabolism, reported to be associated with OC risk in a European population. Data on genotypes and risk factors obtained from interviews were analyzed using multivariate logistic regression, accounting for potential confounders. No overall (marginal) association was found between OC risk and ADH3 genotypes. An interaction between ADH3 genotypes and alcohol consumption levels, however, was suggested. In non‐drinkers, the ADH31‐1 genotype has higher risk than ADH31‐2 or ADH32‐2 genotypes, but for subjects consuming alcohol, lower risk was observed for ADH3 We fit a logistic regression model to estimate the increase in OC risk associated with each alcohol drink consumed per week. We estimated that OC risk increased by 31.5% per drink/week for the ADH32‐2 genotype, 4.1% for the ADH31‐2 genotype and 1.6% for the ADH31‐1 genotype. Evidence of genotype‐environment interaction was suggestive (p = 0.048, Wald χ p = 0.145, likelihood ratio). This finding is opposite to that reported for a population in Puerto Rico, where the ADH31‐1 genotype seemed more sensitive to ethanol exposure. In Greece, genetic variation at the CYP2E1 SNP is almost entirely absent, with only 1 case and 1 control heterozygous for the variant. By contrast, in a population in France where an OC association was reported, the frequency of CYP2E1 heterozygotes was 5% in controls and 9% in OC cases. These findings illustrate the importance of replicating SNP associations both within and between different racial and ethnic groups and geographic regions. Published 2001 Wiley‐Liss, Inc.

Challenges in global improvement of oral cancer outcomes: findings from rural Northern India

BackgroundIn India, 72% of the population resides in rural areas and 30-40% of cancers are found in the oral cavity. The majority of Haryana residents live in villages where inadequate medical facilities, no proper primary care infrastructure or cancer screening tools and high levels of illiteracy all contribute to poor oral cancer (OC) outcomes. In this challenging environment, the objective of this study was to assess the association between various risk factors for OC among referrals for suscipious lesions and to design and pilot test a collaborative community-based effort to identify suspicious lesions for OC.MethodsSetting: Community-based cross sectional OC screening.Participants: With help from the Department of Health (DOH), Haryana and the local communities, we visited three villages and recruited 761 participants of ages 45-95 years. Participants received a visual oral cancer examination and were interviewed about their dental/medical history and personal habits. Pregnant women, children and males/females below 45 years old with history of OC were excluded.Main outcome: Presence of a suspicious oral lesion.ResultsOut of 761 participants, 42 (5.5%) were referred to a local dentist for follow-up of suspicious lesions. Males were referred more than females. The referral group had more bidi and hookah smokers than non smokers as compared to non referral group. The logistic regression analysis revealed that smoking bidi and hookah (OR = 3.06 and 4.42) were statistically significant predictors for suspicious lesions.ConclusionsTobacco use of various forms in rural, northern India was found to be quite high and a main risk factor for suspicious lesions. The influence of both the DOH and community participation was crucial in motivating people to seek care for OC.

The impact of bisphosphonates on oral health: lessons from the past and opportunities for the future

Osteonecrosis of the jaw (ONJ), a challenging medical condition seen primarily among intravenous bisphosphonate (BP) users, is characterized by exposed necrotic bone that persists for more than eight weeks. While rare among people with osteoporosis treated with oral BPs, ONJ has captured the publics attention and caused significant distress. For many, the risk‐benefit scale has conceptually changed, tipping steeply toward risk, while for others the benefit of increased bone mass still outweighs the possibility of ONJ. While more than seven years have passed since the first cases were published, the scientific and medical communities are not yet ready to address with certainty the issue of causal inference, nor do they have any concrete recommendations for risk assessment or management of ONJ. Equally important, the dental literature has been skewed by the perceived risk associated with prolonged use of BPs and has neglected to explore how the antiosteoclastic activity of BPs may be utilized to improve dental outcomes. This article reviews critically the current state of knowledge about the impact of bisphosphonates on oral health. Using the principles of epidemiology, the article identifies scientific gains, research challenges, and future research opportunities on the topic.

Oral and Pharyngeal Cancer in Women

Although in the United States the incidence of oral and pharyngeal cancer (OPC) has been significantly higher in men than in women, the identification of human papilloma virus as a risk factor for OPC has focused new scrutiny on who may develop OPC. One surprising element is that non-Hispanic white women have a higher incidence of OPC than of cervical cancer. OPC is thus a womans disease, and diligence is needed to ensure that the occurrence of OPC in women does not go undetected by their oral health care providers.

Zoledronate and other risk factors associated with osteonecrosis of the jaw in cancer patients: a case-control study

PURPOSE Bisphosphonates (BPs) effectively treat metastatic bone disease, hypercalcemia, and osteoporosis. BP exposure, however, may be associated with osteonecrosis of the jaw (ONJ). The aim of the present study was to estimate the magnitude of the association between intravenous (IV) BP exposure and ONJ, and to identify potential confounders. MATERIALS AND METHODS Using a case-control study design, the investigators identified and adjudicated a sample of cases with ONJ and matched them randomly with 5 controls per case. The controls were matched to cases on age, gender, cancer type, and date of cancer diagnosis. The medical records were abstracted and data on BP exposure, cancer therapy, and comorbidities were recorded. Statistical analyses were carried out using conditional logistic regression in Stata 9.0 (Stata Corp, College Station, TX). RESULTS Thirty cases of ONJ were identified at Massachusetts General Hospital from February 2003 through February 2007. Zoledronate was found to confer significant risk toward development of ONJ (adjusted odds ratio = 31.8, P < .05). Although a trend toward increased risk was noted for pamidronate, this association was not significant after controlling for zoledronate. Obesity and smoking were associated significantly with ONJ development, whereas oral BPs had no effect. CONCLUSION In this study, cancer patients who had received zoledronate exhibited a significant 30-fold increase in their risk to develop ONJ. More studies are needed to elucidate the exact role of obesity and smoking in the development of ONJ, and the complex interactions of IV BPs with other chemotherapies during cancer treatment.