[The use of photodynamic therapy in patients with severe forms of leukoplakia]. / Primenenie fotodinamicheskoi terapii u patsientov s tyazhelymi formami leikoplakii.

OBJECTIVE: The aim the study is to increase the effectiveness of the treatment of severe forms of leukoplakia with the use of photodynamic therapy. MATERIAL AND METHODS: 120 patients with severe forms of leukoplakia were examined. 30 patients were diagnosed with Cr and carcinoma in situ, and therefore they were excluded from the study. In 90 patients, the diagnosis was confirmed by histological and IHC studies. Before the use of photodynamic therapy, the degree of saturation of pathological foci with a photosensitizer was determined by the method of fluorescent diagnostics using the LED device «RFS-400¼. RESULTS: As a result of treatment with photodynamic therapy using a 2nd generation photosensitizer («Photoditazine¼ 0.5% gel penetrator), a significant improvement in the epithelization of lesion elements was observed: in 92% of patients with verrucous leukoplakia and in 83% of patients with erosive leukoplakia. CONCLUSION: The use of photodynamic therapy for the treatment of patients with complicated forms of leukoplakia is an effective method of treatment for this pathology.

Adverse Drug Events in the Oral Cavity.

Adverse reactions to medications are common and may have a variety of clinical presentations in the oral cavity. Targeted therapies and new biologic agents have revolutionized the treatment of cancers, autoimmune diseases, and inflammatory and rheumatologic diseases but have also been associated with adverse events in the oral cavity. This review describes the most common clinical presentations of oral mucosal reactions to medications, namely hyposalivation, lichenoid reactions, ulcers, bullous disorders, pigmentation, fibrovascular hyperplasia, reactive keratosis, dysesthesia, osteonecrosis, infection, angioedema, and malignancy.

Oral mucosal health in liver transplant recipients and controls.

Immunosuppressive drugs and other medications may predispose patients to oral diseases. Data on oral mucosal health in recipients of liver transplantation (LT) are limited. We, therefore, recruited 84 LT recipients (64 with chronic liver disease and 20 with acute liver failure) for clinical oral examinations in a cross-sectional, case-control study. Their oral health had been clinically examined before transplantation. The prevalence of oral mucosal lesions (OMLs) was assessed in groups with different etiologies of liver disease and in groups with different immunosuppressive medications, and these groups were compared to controls selected from a nationwide survey in Finland (n = 252). Risk factors for OMLs were evaluated with logistic regression. OMLs were more frequent in LT recipients versus controls (43% versus 15%, P < 0.001), and the use of steroids raised the prevalence to 53%. Drug-induced gingival overgrowth was the single most common type of lesion, and its prevalence was significantly higher for patients using cyclosporine A (CSA; 29%) versus patients using tacrolimus (TAC; 5%, P = 0.007); the prevalence was even higher with the simultaneous use of calcium channel blockers and CSA (47%) or TAC (8%, P = 0.002). Lesions with malignant potential such as drug-induced lichenoid reactions, oral lichen planus-like lesions, leukoplakias, and ulcers occurred in 13% of the patients with chronic liver disease and in 6% of the controls. Every third patient with chronic liver disease had reduced salivary flow, and more than half of all patients were positive for Candida; this risk was higher with steroids. In conclusion, the high frequency of OMLs among LT recipients can be explained not only by immunosuppressive drugs but also by other medications. Because dry mouth affects oral health and OMLs may have the potential for malignant transformation, annual oral examinations are indicated.

Rise and fall of oral health products with Canadian bloodroot extract.

The rhizome of Sanguinaria canadensis (SC, bloodroot) contains an active principle with antimicrobial, antiinflammatory, antioxidative and immunomodulatory effects. For this reason SC extract has been added to toothpastes and mouthwashes in various concentrations. When tested separately, neither the toothpastes nor the mouthwashes with SC extract had any demonstrable clinical effectiveness against dental plaque and gingivitis. Although using them together twice a day seemed more effective than using placebo, more recent studies have shown conflicting results. Preclinical safety studies up to 2000, which did not include studies longer than 6 months, were thought not to indicate any appreciable potential for harm - to the oral mucosa in particular. In 2003, the FDA Subcommittee on Oral Health Care Drug Products for Over-the-Counter Human Use concluded from a review that using SC-containing products is safe. However, for reasons unknown, the review failed to consider publications between 1999 and 2001 that suggested a possible link between the use of SC-containing products and the pre-neoplastic lesion, leukoplakia. As it happened, bloodroot had already been removed (in 2001) from the formula of one of the most widely used products in question and the brand has since then disappeared altogether from the worldwide market.

Reference moist smokeless tobacco-induced apoptosis in human monocytes/macrophages cell line MM6.

Moist smokeless tobacco use is associated with various types of oral injury, including leukoplakia and dipper's pouch, although the mechanism by which the injury is caused still remains unclear. One possible mechanism is that moist smokeless tobacco affects the inflammatory response. For example, a study by Johnson et al. demonstrated a reduction in the volume density of macrophages and increased inflammation and redness at the smokeless tobacco placement site when compared to non-placement site. The current study investigated the direct effect of reference moist smokeless tobacco extract (STE) exposure on the viability of MM6 monocyte/macrophage cell line. The exposure of MM6 cells to various concentrations of STE, led to a significant and dose-related decrease in cell viability. Furthermore, STE exposure resulted in an increase in Annexin V/PI positive cells, an increase in TUNEL-positive cells, and cleaved PARP staining all of which were inhibited by pre-incubation with a pan-caspase inhibitor, suggesting that the observed STE toxicity was due to the induction of apoptosis. Next, the role of various moist smokeless tobacco-derived components in STE-induced apoptosis of MM6 cells was investigated. Our findings suggest that STE-induced osmotic stress, but not exposure to nicotine, plays an important role in STE-induced apoptosis of MM6 cells. Together, these data show for the first time that STE exposure leads to the induction of apoptosis in human monocyte/macrophage cells, which appears to be induced in part, by reference STE-mediated osmotic stress.

Oral manifestations of habitual khat chewing: a case-control study.

BACKGROUND AND OBJECTIVES: Khat, or qat (Catha edulis), is a shrub indigenous to Yemen and certain parts of eastern Africa. Chewing the leaves, which have sympathomimetic and euphoric effects, is a popular habit in numerous countries including the Yemenite population in Israel. Khat has potentially significant toxic effects; however, its oral effects have been only sporadically examined and some changes suggested. The aim of this study was to assess the association between habitual Khat use and oral/dental pigmentation, gingival health, and reports of oral dryness. STUDY DESIGN: Forty-seven Yemenite Israeli individuals >30 years old, who chewed Khat at least twice a week for over 3 years, and 55 control subjects were studied. All individuals underwent standard clinical oral examinations for color changes and gingival health. RESULTS: White changes were significantly more prevalent in the khat chewers, identified primarily at the chewing site (83% vs. 16%). The difference in the prevalence of oral mucosal pigmentation between nonchewing nonsmoking (66.7%) and the khat-chewing (100%) groups was highly significant. The mean gingival index and the depth of periodontal pockets of the khat-chewing subjects were significantly reduced at the chewing side compared with the nonchewing side. Increased gingival recession was recorded on the khat-chewing side. Discoloration of the teeth adjacent to the site of chewing was recorded. Oral dryness occurring 30 minutes after initiating the khat-chewing session was reported by khat users. CONCLUSION: Khat chewing may result in a number of changes in the oral mucosa and the dentition. The mechanical and chemical irritation may result in the development of mucosal white lesions and dark pigmentation. Khat chewing may reduce aspects related to risk of gingival and periodontal inflammation, but it appears to be associated with attachment loss at the site of chewing.

Exposure to alcohol or tobacco affects the pattern of maturation in oral mucosal cells: a cytohistological study.

OBJECTIVE: To assess the maturation pattern of oral mucosal cells of patients exposed to tobacco and alcohol. METHODS: (i) Group without lesions. Smears obtained from the lower lip, border of the tongue and floor of the mouth of 31 control individuals (group I), 49 tobacco users (group II) and 27 tobacco/alcohol users (group III) were stained using the Papanicolaou method. The first 100 cells counted on each smear determined the maturation pattern and the keratinization index (KI). Analysis of variance (ANOVA) and the Tukey multiple comparison test were used for statistical analysis, at a 5% significance level. (ii) Group with lesions. Cytopathological and histopathological studies were conducted for 15 patients: eight with leucoplakia without epithelial dysplasia, two with epithelial dysplasia and five with squamous cell carcinoma. RESULTS: (i) Group without lesions. Statistical analysis revealed a smaller number of superficial cells with nuclei in all sites of the group of tobacco/alcohol users (group III) when compared to the control group (group I), and this difference was statistically significant (P<0.005). (ii) Group with lesions. The severity of histopathological findings increased with the increase in the number of cells of the deeper epithelial layers, with a statistically significant difference in the number of intermediate (P=0.013) and parabasal cells (P=0.049), which increased with the severity of the epithelial maturation disorder: leucoplakias with dysplasia had a greater number of intermediate and parabasal cells than leucoplakias without dysplasia; and the number in squamous cell carcinomas was greater than in leucoplakias with dysplasia. CONCLUSION: The maturation pattern of cells in the three anatomic sites showed changes that may be associated with the synergistic effect of tobacco and alcohol. Also, the severity of histopathological findings was associated with the increase in the number of cells in the deeper epithelial layers.

Exacerbation of oral erosive lichen planus by combination of interferon and ribavirin therapy for chronic hepatitis C.

Hepatitis C virus (HCV) induces extrahepatic manifestations such as oral lichen planus (OLP) as well as chronic liver diseases. The treatment of HCV-related chronic liver disease has evolved from the use of a single agent, mainly interferon (IFN), to the combination of IFN and ribavirin. We present a case of erosive OLP, cutaneous lichen planus (CLP), and leukoplakia of the vocal cord in a man with chronic hepatitis C infection treated with IFN and ribavirin. A 65-year-old man suffered from OLP before undergoing combination of IFN and ribavirin therapy for chronic hepatitis C. He was initially treated with IFNbeta (6 million units (MU) /day for 2 weeks), then a combination of IFNalpha-2b (6 MU/day for 2 weeks and 3 times a week for 14 weeks) and ribavirin (400-600 mg/day). The OLP lesion was not aggravated by application of steroids during the 7 weeks after the treatment, but after 18 weeks, the combination of IFN and ribavirin was stopped because of aggravation of the OLP. Elevated aminotransferase levels returned to normal during the therapy. But 7 weeks after discontinuation, aminotransferase levels rose to 10 times the normal range. Five months after discontinuation, the papules of CLP appeared. Eight months after discontinuation, the OLP erosion had gradually reduced, but some erosion remained. Aminotransferase levels were decreased, but serum HCV RNA had not disappeared. Caution should be exercised when IFN or ribavirin therapy is given to chronic hepatitis C patients with prior erosive OLP.

Laryngeal findings in users of combination corticosteroid and bronchodilator therapy.

EDUCATIONAL OBJECTIVE: At the conclusion of this article, the readers should be able to 1) describe the laryngeal findings in patients who use combination therapy for asthma, 2) discuss the mechanism of laryngeal irritation from the use of inhalers, and 3) describe possible mechanisms for reducing laryngeal irritation and secondary dysphonia from the use of inhalers. OBJECTIVES: To describe voice changes and laryngeal findings in patients who are started on combination corticosteroid and bronchodilator therapy in the form of a dry powder inhaler (DPI). STUDY DESIGN: Retrospective, single-subject design. METHODS: Retrospective review of 10 consecutive patients meeting inclusion criteria, who presented at the voice center with more than 4 weeks of dysphonia after being started on a combination form of asthma medication for control and maintenance therapy. All patients were nonsmokers and without history of previous identification or excision of vocal pathology. All patients were treated previously with a proton pump inhibitor for gastroesophageal reflux. Laryngeal videostroboscopic evaluations were performed on all patients. Patients were asked to complete a questionnaire regarding their perceived voice change and history of medical maintenance therapy for asthma. RESULTS: Dysphonia was present in the patients selected for greater than 4 weeks. Patients had been switched to combination therapy after previously using traditional two-drug asthma regimens. In eight of nine patients, the vocal folds demonstrated areas of hyperemia, with plaque-like changes on the surface mucosa. Reduced amplitude of vibration and a reduction in mucosal wave propagation were present on videostroboscopy. Questionnaires revealed that all patients were initiated on combination DPI treatment within the last 6 months. CONCLUSIONS: Dysphonia caused by a change in the surface mucosa is a side effect from the use of DPI therapy for asthma. The high-impact force during inhalation of the medication and carrier leads to deposition of particles in the upper airway. We believe the extent of mucosal irritation can be minimized by patient education in the proper delivery of DPI. In some cases, however, return of the two medications delivered separately was necessary. The irritation of the laryngeal mucosa and return of normal vibratory parameters occurred in all patients.

Specific induction of the high-molecular-weight microtubule-associated protein 2 (hmw-MAP2) by betel quid extract in cultured oral keratinocytes: clinical implications in betel quid-associated oral squamous cell carcinoma (OSCC).

Betel quid (BQ) chewing, a popular habit in numerous Asian countries including India and Taiwan, has a strong correlation with an increased risk of oral squamous cell carcinoma (OSCC). While substantial efforts have been made to test the cytotoxic, genotoxic and mutagenic effects of BQ extract and its components, the disease mechanisms underlying BQ-induced oral carcinogenesis remain obscure. Here, we show that a neuronal protein, microtubule-associated protein 2 (MAP2), was induced by BQ extract in cultured normal human oral keratinocytes (NHOKs). Subsequent analyses demonstrated that such induction was more eminent and consistent in the high-molecular-weight isoform of MAP2 (hmw-MAP2) than that in its low-molecular-weight counterpart (lmw-MAP2). Furthermore, we analyzed expression of hmw-MAP2 protein in 88 oral specimens consisting of clinicopathologically pre-malignant (leukoplakia) and malignant (OSCC) lesions, along with their adjacent normal mucosa. Immunohistochemistry revealed that, with the exposure to BQ, the hmw-MAP2 was over-expressed in 41.2% (7/17) of OSCC, 11.2% (1/9) of leukoplakia and none (0/19) of normal mucosa. In contrast, expression of the hmw-MAP2 was barely detected in BQ-free OSCC. These results suggest a significant correlation between expression of the hmw-MAP2 and BQ-associated progression of oral carcinogenesis (P=0.0046). Interestingly, the hmw-MAP2 was found to preferentially express in histopathologically less differentiated OSCC (P=0.014); the percentages of positive staining in poorly, moderately and well differentiated OSCC were 62.5, 21.4 and 7.1%, respectively. However, BQ chewing appeared to have marginal correlation with such propensity. Finally, we show that the majority of hmw-MAP2-positive poorly differentiated lesions were also histopathologically invasive. Taken together, these findings suggest the possibility that the hmw-MAP2 may be a diagnostic marker for BQ-chewing lesions and a potential therapeutic target. To our knowledge, this study has provided the first clinical implication that closely links a cytoskeletal protein to BQ-associated oral cancer.

The association between Viadent use and oral leukoplakia.

Recently, leukoplakia of the maxillary vestibule was described in patients with no traditional risk factors but who had used Viadent products. We designed a case-control study to evaluate the hypothesis that Viadent users were more likely to have lesions. One hundred and forty-eight cases and controls were identified through the Section of Oral and Maxillofacial Pathology. Cases and controls were administered a questionnaire about Viadent use and other known risks. Results of crude, stratified, and logistic regression analyses showed that use of Viadent products was a risk indicator for leukoplakia (adjusted OR = 9.7, 95% CI = 4.7-21.6), with a strong dose-response relation.

Smokeless tobacco potentiates VIP-induced DNA synthesis and inactivates NEP 24.11 in oral keratinocytes.

The purpose of this study was to determine whether exposure of cultured chemically transformed hamster oral keratinocytes (HCPC-1) to an aqueous extract of smokeless tobacco (STE) potentiates DNA synthesis elicited by vasoactive intestinal peptide (VIP), an autocrine neuropeptide, and, if so, whether this response is associated with inactivation of neutral endopeptidase 24.11 (NEP 24. 11), an ectoenzyme that cleaves and inactivates VIP very effectively, in these cells. I found that STE and VIP each elicited a modest, albeit significant, increase in DNA synthesis in cultured HCPC-1 cells (P < 0.05). However, incubation of HCPC-1 cells with STE together with VIP evoked a significant, concentration- dependent increase in DNA synthesis that was mediated by VIP receptors. The effects of STE and VIP were synergistic. Maximal response was observed after a 48-h incubation. STE significantly attenuated NEP 24.11 activity in HCPC-1 cells at a time when VIP-induced DNA synthesis was maximal. Collectively, these data indicate that STE potentiates VIP-induced DNA synthesis in cultured oral keratinocytes, and that this response is temporally related to STE-induced inactivation of NEP 24.11 in these cells. I suggest that NEP 24.11 modulates the mitogenic effects of smokeless tobacco in the oral epithelium, in part, by inactivating VIP.

Expression of keratin 13, 14 and 19 in oral hyperplastic and dysplastic lesions from Sudanese and Swedish snuff-dippers: association with human papillomavirus infection.

Changes in the expression of keratins (Ks), indicating disturbed tissue differentiation, is one possible marker of malignant potential in stratified squamous epithelia. The presence of human papillomaviruses (HPVs) in the epithelium of the uterine cervix is increasingly regarded as a marker of risk for cervical cancer: However, a similar role in oral cancer and precancer remains controversial. To address these questions, potentially malignant oral mucosal lesions from Sudanese (9 hyperplasias/40 dysplasias) and Swedish (15 hyperplasias) snuff-dippers were examined by immunohistochemistry for expression of K types 13, 14 and 19 using monoclonal antibodies directed against each. HPV infection was searched for by in situ hybridization (ISH) using the cocktail HPV OmniProbe and the ViraType probe. For the Sudanese lesions, moderate to intense expression of both K13 (basal, basal/intermediate, basal/intermediate/superficial and intermediate/superficial cell layers) and K14 (basal, basal/intermediate cell layers) was found in 49/49 (100%). For the Swedish lesions, weak to moderate expression of K13 (basal, basal/intermediate cell layers) was found in 12/15 (80%) and 10/15 (67%), respectively. In the Sudanese lesions, expression of K13 showed a distinct pattern through the oral mucosa and its verrucous projections, with an increase towards the superficial cell layers of dysplastic, but not hyperplastic epithelium. K19 was expressed in the basal cell layer in 16/49 (33%) of the Sudanese lesions, while all the Swedish lesions were negative. HPV was found in only 2 Sudanese cases, both of which harboured both type 6 and type 11: both these cases demonstrated mild epithelial dysplasia, The present study shows that a) there is a high prevalence of expression of both K13 and K14 in oral lesions from Sudanese toombak dippers indicating dysregulation of keratinocyte maturation b) one-third of the Sudanese oral lesions expressed K19, regarded as a basal keratin representing epithelial dedifferentiation, which may prove to be a valuable risk marker in follow-up studies c) HPV genome is found infrequently in oral lesions from Sudanese toombak-dippers, suggesting that these viruses may not play a prominent role in the early stages of carcinogenesis in these subjects. These markers were less often expressed in the Swedish lesions, consistent with their much lower rate of malignant transformation.

The involvement of reactive oxygen species in oral cancers of betel quid/tobacco chewers.

Most biological reactions, including carcinogenesis, are complex processes involving thousands of compounds, their metabolites and intermediates. The separation of events which form part of a direct chain leading to neoplastic transformation from those which are mere by-products is a herculean task. In this study, we focused on the pros and cons of reactive oxygen species (ROS) being involved in the development of oral cancer among chewers of tobacco and areca nuts. The results revealed that bursts of ROS generation occur at different stages of carcinogenesis, and are caused by different mechanisms. This observation may have considerable practical implications. Different strategies will be required in the administration of chemopreventive agents in order to trap ROS formed in the alkaline (due to the addition of slaked lime) chewing mixture within the saliva of a chewer, to scavenge ROS within mucosal cells exposed to an array of tobacco- or areca nut-related carcinogens or tumour promoters, and to inhibit the action of ROS released from ROS-generating white cells during lymphocytic infiltration of the oral mucosa at a precancerous stage. The remission of oral leukoplakias following the administration of vitamin A (200,000 IU/week) or vitamin A (100,000 IU/week) plus beta-carotene (180 mg/week) for 6 months, the inhibition of new leukoplakias during this trial period, and the reduction of micronucleated oral mucosal cells in chewers treated with beta-carotene or vitamin A are indeed promising results. However, a better understanding of the role of ROS in various stages of carcinogenesis will provide the basis for selection of the proper chemopreventive agents and the design of a treatment regime which may either prevent the formation of precancerous lesions, induce their remission, or inhibit the progression of precancerous lesions into malignant cancers.

DNA adducts, micronuclei and leukoplakias as intermediate endpoints in intervention trials.

Internal dosimeters that can provide information about responses to chemopreventive agents in a short time would be invaluable for planning treatment protocols for large-scale intervention trials. Micronuclei meet many of the prerequisites of a good intermediate endpoint. They can be quantified in cultured cells, animal tissues and human exfoliated cells and biopsies. With image scanning, up to 10(5) cells can be screened for micronuclei within a few minutes. The predictive value of micronuclei has been demonstrated using cultured cells exposed to carcinogens and chemopreventive agents and using oral mucosa of betel-quid chewers. DNA adducts, as detected by 32P-postlabelling techniques, could conceivably be another potentially useful marker. However, prior to their use in intervention trials, interindividual variations in their levels in primary, secondary and nontarget tissues and the relationship with doses of carcinogens must be established. The wide scatter of DNA adduct levels in the bronchial mucosa of smokers and of nonsmokers reveals one difficulty that can be encountered using this marker in intervention trials.

Inhibition of hamster tongue carcinogenesis by selenium and retinoic acid.

The inhibitory effect of selenium, 13-cis-retinoic acid, and their combination was studied in an animal model in which squamous cell carcinoma of the tongue was induced by 0.5% 9,10 dimethyl-1,2 benzanthracene (DMBA). A controlled, blinded experiment was carried out using 60 Syrian hamsters divided into four groups of 15 each. When compared to controls, the mean day of carcinoma onset was delayed 3 weeks for animals given selenium, 6 weeks for animals given retinoic acid, and 5.5 weeks for animals given selenium plus retinoic acid. The differences between each experimental group and the control group are statistically significant. We conclude that both selenium and retinoic acid inhibit the development of DMBA-induced squamous cell carcinoma of the tongue in hamsters. The dose of retinoic acid used produces a stronger inhibitory effect, but is associated with significant toxicity. At the doses used, combined inhibitory effect is no greater than that for retinoic acid alone.

[Precancerous and cancerous lesions of the esophagus and forestomach in mice with skin exposure to a heavy catalytic gas oil]. / Predrakovye i rakovoe porazheniia pishchevoda i predzheludka u myshei pri nakozhnom vozdeistvii tiazhelym kataliticheskim gazoilem.

Painting with heavy catalytic gas oil was followed by skin tumor development in 97 (84.3%) mice: benign lesions--21 and carcinoma--76 cases. Pathologic changes in the upper part of the digestive tract were found in 55 out of 106 mice (51.9%): precancerous lesions (leukoplakia, dysplasia and papilloma) in 54 cases and cancer in one animal. Frequency of development of papilloma in the cardia was 27 times that in the esophagus. Multicentric growth was typical of precancerous lesions. Papilloma of the cardia was found in one control animal. Resorptive as well as direct action of gas oil seem to have been the causative factors of the development of precancerous and neoplastic lesions of the upper part of the gastrointestinal tract. The agent found its way into the digestive tract as animals licked each other in the course of the experiments.