Impact of mandated drug monitoring on opioid use during highly conformal radiotherapy for oropharynx cancer.

BACKGROUND: Prescription drug monitoring programs (PDMPs) have proliferated due to increasing opioid-related deaths. We evaluated acute opioid use changes for 64 patients treated with highly conformal radiotherapy (RT) following a state-mandated PDMP. METHODS: Patients receiving proton therapy (PT) (n=40), intensity-modulated RT (IMRT) (n=14), or both (n=10) were divided into preintervention (n=26) and postintervention cohorts (n=38); records were reviewed retrospectively under an institutional review board (IRB)-approved tracking protocol. Dosages prescribed during acute therapy (during RT-3 months post-RT) and patient-reported pain (Defense and Veterans Pain Rating Scale) were endpoints. Dosages were treated as responses in Chi-square tests (three-level ordinal response). RESULTS: Overall, 72% (n=46) received opioids; of which 22% (n=10) of all patients and 10% (n=2) of opioid-naive patients continued analgesic management 3 months post-RT. Median total doses were 975 and 1,025 morphine milligram equivalents (MME) in pre- and postintervention groups, with no significant differences in MME prescribed (P=0.8) or uncontrolled pain (P=0.3). Statistically significant factors were tonsil primaries (P<0.01) and alcohol use (P=0.02). Uncontrolled pain episodes during and post-RT did not vary per cohort (P=0.19). CONCLUSIONS: PDMP use was not associated with management changes in patient-reported acute pain during RT (IMRT or PT). Following highly conformal RT, few patients remained on narcotics 3 months post-RT.

A preliminary study of suppression of candida infection by miconazole mucoadhesive tablets in oral or oropharyngeal cancer patients undergoing radiotherapy.

Elevated numbers of candida in the oral cavity often lead to oral candidiasis development in patients undergoing radiotherapy for oral or oropharyngeal cancer. This study aimed to verify the effect of miconazole mucoadhesive tablets on suppression of oral candida infection during radiotherapy. For this preliminary interventional study, miconazole mucoadhesive tablets were attached to the oral mucosa for 14 days from when grade 2 oral mucositis appeared in patients with oral or oropharyngeal cancer receiving radiotherapy, and the incidence of oral candidiasis was investigated. Various clinical factors were examined; univariate and multivariate Cox regression analyses were performed to investigate and compare the efficacy of this drug in preventing oral candidiasis with results of our previous study as historical control. Miconazole mucoadhesive tablets were administered to 18 patients, and oral candidiasis was observed in one patient (5.6%) after treatment completion. Among 144 historical control patients, 43 (29.9%) developed oral candidiasis. Multivariate Cox regression showed that miconazole mucoadhesive tablets significantly reduced oral candidiasis development during radiotherapy (p = 0.049, Hazard ratio 0.136, 95% confidence interval 0.019-0.994). This preliminary study suggests the efficacy of miconazole mucoadhesive tablets in preventing oral candidiasis in oral or oropharyngeal cancer patients treated with radiotherapy.Trial registration: Japan Registry of Clinical Trials (jRCT), jRCTs071190023. Registered 3 September, 2019.

Molecular mechanisms of tobacco induced oral and oropharyngeal cancer: Results of a tissue microarray and immunohistochemistry-based study from a tertiary cancer center in India.

BACKGROUND: It is well established that chronic exposure to tobacco induces head and neck cancers but the exact etiopathogenesis is not known. Though studies have shown expression of TIMP1, EPS8 and AXL in cancers, their role in tobacco-induced cancers is not known. We aimed this study to evaluate the role of these molecules in oral and oropharyngeal squamous cell cancers (SCC). MATERIALS AND METHODS: In this single institutional study, 31 patients of oral and oropharyngeal SCC with history of chewing tobacco were included. Smokers were excluded from the study. After informed consent biopsies were taken from affected and contralateral normal mucosa. Paraffin blocks were made and tissue microarray (TMA) were constructed using these blocks. Immunohistochemistry (IHC) for TIMP1, EPS8, AXL kinase was carried out on these tissue microarrays. The intensity of staining was scored from 0 to 3+, related to expression of each of the three molecules. RESULTS: The expression of TIMP1, EPS8 and AXL kinase was significantly more in the cancerous mucosa versus non-cancerous mucosa (P = 0.000 in all three) in oral and oropharyngeal SCC exposed to chewing tobacco. CONCLUSION: Immunohistochemical expression of these molecular markers in oral and oropharyngeal SCC correlated with their molecular based studies. Significant IHC expression of TIMP1, EPS8 and AXL establishes their role in the pathogenesis of oral and oropharyngeal squamous cell carcinomas. Novel targeted therapies may be researched that can detect and target these molecules at an earlier stage of pathogenesis of these tumors.

CD8 infiltration is associated with disease control and tobacco exposure in intermediate-risk oropharyngeal cancer.

Oropharyngeal squamous cell carcinoma (OPSCC) incidence is increasing at a nearly epidemic rate, largely driven by the human papillomavirus (HPV). Despite the generally favorable clinical outcomes of patients with HPV driven (HPV+) OPSCC, a significant subset of HPV tumors associated with tobacco exposure have diminished treatment response and worse survival. The tumor immune microenvironment (TIME) has been shown to be a critical driver of treatment response and oncologic outcomes in OPSCC generally and HPV+ OPSCC more specifically. However, the impact of tobacco exposure on the TIME in OPSCC patients remains unclear. We analyzed the relationship between TIME, tobacco exposure and clinical outcomes in OPSCC patients (n = 143) with extensive tobacco exposure (median pack-years = 40). P16 overexpression, a surrogate marker of HPV association, was a strong predictor of relapse-free (RFS) and overall survival (OS) (p < 0.001, p < 0.001 respectively) regardless of tobacco exposure and associated strongly with differential infiltration of the tumor by both CD3 and CD8 lymphocytes measured via immunohistochemistry (p < 001, p < 0.001 respectively). CD3 and CD8 infiltration was a strong predictor of RFS and OS and associated strongly with disease stage (AJCC 8th Edition Staging Manual). Tobacco exposure correlated significantly (p < 0.001) with decreased CD8 infiltration in p16+ OPSCC tumors. Our findings demonstrate that the HPV+ OPSCC clinical outcomes are strongly correlated with the TIME, which is potentially modulated by tobacco exposure. Immunomodulatory strategies targeting this disease in smokers must take into consideration the potential modifying effects of tobacco exposure on treatment effectiveness and clinical outcomes.

Clinical characteristics and treatment outcome of oropharyngeal squamous cell carcinoma in an endemic betel quid region.

The clinical characteristics of oropharyngeal squamous cell carcinoma (OPSCC) may be different between endemic and non-endemic regions of betel nut chewing. The impact of combined alcohol drinking/betel quid chewing/cigarette smoking (ABC) exposure on the survival of OPSCC remains unclear. We reviewed the medical records of OPSCC patients between 1999 and 2013. Immunohistochemical staining of p16 and HPV genotype detection by DNA Polymerase chain reaction were both performed for each tumor. A total of 300 eligible patients including 74 HPV+ OPSCC patients and 226 HPV- OPSCC patients were enrolled. The 5-year disease-free survival rates for the HPV-, HPV+ OPSCC with and without ABC patients were 49.8%, 58.4% and 94%, respectively. The 5-year overall survival rates for the patients with HPV-, HPV+ OPSCC with and without ABC patients were 46%, 57.4% and 86%, respectively. Advanced locoregionally disease (T3/T4, N2/N3), HPV- OPSCC, combined 2 or all ABC exposure were the independent adverse prognostic factors for disease-free and overall survival. Therefore, our data suggest that in an endemic region of betel quid chewing, HPV- OPSCC comprises the majority of OPSCC and has a worse survival. Combined 2 or all ABC exposure had a significant negative impact on disease-free and overall survival.

Occupational exposure to petroleum-based and oxygenated solvents and oral and oropharyngeal cancer risk in men: A population-based case-control study in France.

OBJECTIVE: To examine the association between occupational exposure to petroleum-based and oxygenated solvents and the risk of oral and oropharyngeal cancer. METHODS: The ICARE study is a large population-based case-control study conducted in France between 2001 and 2007. This present analysis was restricted to men and included 350 and 543 cases of squamous cell-carcinoma of the oral cavity and oropharynx, respectively, and 2780 controls. Lifetime tobacco, alcohol consumption and complete occupational history were assessed through detailed questionnaires. Job-exposure matrices allowed us to assess occupational exposure to five petroleum-based solvents (white spirits; diesel/fuel oils/kerosene; gasoline; benzene; special petroleum products) and five oxygenated solvents (diethyl ether; tetrahydrofuran; ketones and esters; alcohols; ethylene glycol). Odds-ratios (ORs), adjusted for age, smoking, alcohol consumption and socioeconomic status, and 95% confidence intervals (CI) were estimated using unconditional logistic models. RESULTS: Associations between oral cancer risk and exposure to white spirits and diesel/fuel oils/kerosene were suggested, but there was no exposure-response trend. Concerning exposure to oxygenated solvents, participants with the highest levels of cumulative exposure to diethyl ether had a significant excess risk of oropharyngeal cancer (OR = 7.78, 95%CI 1.42 to 42.59; p for trend = 0.04). Ever exposure to tetrahydrofuran was associated with a borderline significant increased risk of oral cancer (OR = 1.87, 95%CI 0.97 to 3.61), but no exposure-response trend was observed. Additional adjustments for exposure to other solvents did not substantially change the results. CONCLUSION: Our results do not provide evidence for a major role of petroleum-based and oxygenated solvents in the occurrence of oral and oropharyngeal cancers in men.

Could the endocrine disruptor bisphenol-A be implicated in the pathogenesis of oral and oropharyngeal cancer? Metabolic considerations and future directions.

Bisphenol-A (BPA), a prototype endocrine disrupting molecule, has been associated with many disease entities such as diabetes mellitus, obesity, polycystic ovarian disease, cardiovascular disease, reproductive and neurodevelopmental disorders. BPA has also been associated mainly with not only hormone sensitive cancers such as breast, prostate, endometrial, ovarian, testicular and thyroid cancers but also non-hormonal sensitive cancers such as cervical and lung cancers, osteosarcoma and meningioma. Recent research has investigated the sources of contamination which are responsible for higher BPA concentrations in the oral cavity and oropharyngeal space, representing the first site of BPA exposure after ingestion. Besides growing awareness and case registration, the incidence and prevalence of oral (OC) and oropharyngeal cancer (OPC) have increased during the last decades correlating with the increased production of BPA worldwide. So far, no study in the medical literature has explored the association of BPA with OC and OPC. BPA may be linked to the etiopathogenesis of OC and OPC through a multitude of mechanisms encompassing and interconnecting genetic, epigenetic, inflammatory, immune, metabolic, hormonal and oxidative stress alterations as well as modulation of oral microbiome. Hence, it is not possible to rule out a potential role of BPA exposure in oral and oropharyngeal tissue carcinogenesis, especially knowing its potential to participate in other non-hormonal sensitive malignancies and to deregulate signaling pathways implicated in OC and OPC. This perspective aims at outlining evidence and proposing for the first time a potential link between BPA with OC and OPC, the most frequent subtypes of head and neck malignancies.

mTOR inhibition prevents rapid-onset of carcinogen-induced malignancies in a novel inducible HPV-16 E6/E7 mouse model.

The rising incidence of human papillomavirus (HPV)-associated malignancies, especially for oropharyngeal cancers, has highlighted the urgent need to understand how the interplay between high-risk HPV oncogenes and carcinogenic exposure results in squamous cell carcinoma (SCC) development. Here, we describe an inducible mouse model expressing high risk HPV-16 E6/E7 oncoproteins in adults, bypassing the impact of these viral genes during development. HPV-16 E6/E7 genes were targeted to the basal squamous epithelia in transgenic mice using a doxycycline inducible cytokeratin 5 promoter (cK5-rtTA) system. After doxycycline induction, both E6 and E7 were highly expressed, resulting in rapid epidermal hyperplasia with a remarkable expansion of the proliferative cell compartment to the suprabasal layers. Surprisingly, in spite of the massive growth of epithelial cells and their stem cell progenitors, HPV-E6/E7 expression was not sufficient to trigger mTOR activation, a key oncogenic driver in HPV-associated malignancies, and malignant progression to SCC. However, these mice develop SCC rapidly after a single exposure to a skin carcinogen, DMBA, which was increased by the prolonged exposure to a tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA). Thus, only few oncogenic hits may be sufficient to induce cancer in E6/E7 expressing cells. All HPV-E6/E7 expressing SCC lesions exhibited increased mTOR activation. Remarkably, rapamycin, an mTOR inhibitor, abolished tumor development when administered to HPV-E6/E7 mice prior to DMBA exposure. Our findings revealed that mTOR inhibition protects HPV-E6/E7 expressing tissues form SCC development upon carcinogen exposure, thus supporting the potential clinical use of mTOR inhibitors as a molecular targeted approach for prevention of HPV-associated malignancies.

Factors affecting the outcome of related allogeneic hematopoietic cell transplantation in patients with Fanconi Anemia.

Hematopoietic cell transplantation (HCT) can cure bone marrow failure in patients with Fanconi Anemia (FA), and it is generally accepted that these patients should receive low-intensity conditioning because of the underlying DNA repair defect in their cells. Outcomes for recipients of matched related HCT have generally been favorable, but only a few studies have scrutinized the factors that may affect the eventual outcome of these patients. This retrospective analysis of 94 pediatric patients with FA who underwent related HCT at King Faisal Specialist Hospital & Research Center was carried out to attempt to identify factors that may affect outcome. Results showed overall survival (OS) probabilities of 92.5%, 89%, and 86% at 1, 5, and 10 years, respectively. In univariate analysis, use of higher dose cyclophosphamide (CY) (60 mg/kg) conditioning was associated with a better 10-year OS than lower dose CY (20 mg/kg) conditioning (91% versus 82%, respectively; P = .035), and use of radiation-containing regimens was associated with a significantly lower 10-year OS than nonradiation regimens (76% versus 91%, respectively; P = .005). Of the 4 regimens used in this study, the fludarabine-based regimen was associated with the highest survival (95.2%; P = .034). The use of the higher dose CY (60 mg/kg) was associated with a significantly increased incidence of hemorrhagic cystitis (HC) (20% versus 5.6% respectively; P = .049). Three patients (3%) developed squamous cell carcinoma (2 oropharyngeal and 1 genitourinary), at 9.4, 5.4, and 13.3 years after HCT; 2 of them had radiation-containing conditioning. In conclusion, our data suggest that although using a higher dose CY (60 mg/kg) conditioning regimen may be associated with better survival, it is also associated with a significantly increased risk of HC. The addition of fludarabine to the low-dose CY (20 mg/kg) is associated with the best survival. On the other hand, radiation-containing regimens are associated with significantly lower survival.

Oropharyngeal carcinoma arising after methotrexate and etanercept therapy for rheumatoid arthritis.

Etanercept is an anti-tumor necrosis factor α receptor agent used to treat inflammatory conditions. Previous reports described rapid development of skin squamous cell carcinoma (SCC) after etanercept use. This report describes a novel case of oropharyngeal SCC associated with the use of etanercept. A 45-year-old man with rheumatoid arthritis developed oropharyngeal pain within 2 months after the start of etanercept therapy and was diagnosed with tonsillar carcinoma. This patient had other exposures that increase the risk of oropharyngeal cancer, such as tobacco and alcohol use. However, owing to the timing of onset of his initial symptoms, etanercept should be considered as a possible factor in the etiology or progression of his tumor, especially in the context of reported skin SCC after etanercept therapy in patients at risk for SCC. Clinicians should be alert to signs of malignancy in patients on etanercept, particularly those at high risk for skin or head and neck cancers.

Mouthwash and oral cancer risk quantitative meta-analysis of epidemiologic studies.

BACKGROUND: Use of mouthwash and an increased risk of oral cancer has been a source of controversy for decades. A meta-analysis of epidemiological studies of mouthwash and oral cancer and, specifically, mouthwash containing >25% alcohol, was undertaken. METHODS: Summary estimates were obtained with maximum likelihood estimates from random effects models. Sensitivity analyses were conducted to evaluate the influence of various inclusion. RESULTS: Eighteen studies were included in the meta-analysis. There was no statistically significant associations found between regular use of mouthwash and risk of oral cancer (RR=1.13; 95% CI (0.95-1.35)). There was no significant trend in risk of oral cancer associated with increased daily usage of mouthwash (p=0.11). There was no association between reported use of mouthwash specifically containing alcohol and risk of oral cancer (RR=1.16; 95% CI (0.44, 3.08)). CONCLUSIONS: This quantitative analysis of mouthwash use and oral malignancy revealed no statistically significant associations between mouthwash use and risk of oral cancer, nor any significant trend in risk with increasing daily use; and no association between use of mouthwash containing alcohol and oral cancer risk.

Chromosomal alterations and mutagen sensitivity in human mucosal cells of the oropharynx and lymphocytes caused by BPDE.

BACKGROUND: In addition to exogenous risk factors, the development of head and neck cancer is based on genetic alterations and individual mutagen sensitivity. DNA damage caused by xenobiotics is not uniformly distributed over the DNA, as certain chromosomes and genes are more likely to be damaged than others. The DNA damaging effect of xenobiotics and the specific sites of chromosomal changes require further investigation. MATERIALS AND METHODS: In order to evaluate mutagen sensitivity in macroscopically healthy mucosal tissue of 30 patients with (15) and without cancer (15) of the oropharynx, three different chromosomes (chromosomes 3, 5 and 8) involved in carcinogenesis of the oropharynx and one control chromosome (chromosome 1) were examined. After incubation with benz[a]pyren-7,8-diol-9,10-epoxide (BPDE), a tobacco-associated carcinogen, comet fluorescence in situ hybridization (FISH) was applied to assess DNA damage of these chromosomes. Furthermore, lymphocytes and macroscopically healthy mucosal cells of the oropharynx were assessed using FISH after their incubation with BPDE in order to evaluate loss and gain of DNA in these chromosomes. RESULTS: BPDE caused significant DNA damage compared to the negative control in oropharyngeal mucosa cells of patients with and without carcinoma. No difference was observed between mutagen sensitivity of patients suffering from cancer of the oropharynx and patients without malignancy. In cells from patients suffering from squamous cell carcinoma, significantly higher DNA damage was found in chromosome 5 and 8 after incubation with BPDE and application of comet FISH. No difference was found in patients without cancer of the head and neck. After application of FISH, no difference in the amount of DNA was found in chromosomes 1, 3, 5 and 8, neither in lymphocytes nor in mucosal cells from both groups. No DNA gain or loss was detected. CONCLUSION: Our results confirm the higher sensitivity of chromosomes 5 and 8 of normal epithelial cells of oropharyngeal cancer patients to BPDE. These effects were shown in macroscopically healthy tissue of such patients for the first time. Therefore, we suggest that these are early onset effects in carcinogenesis of the head and neck. No such effect was shown for chromosome 3 and control chromosome 1.

Experimental carcinogenesis on the oropharyngeal mucosa of rats with hydrochloric acid, sodium nitrate and pepsin / Carcinogênese experimental na mucosa orofaríngea de ratos com ácido clorídrico, nitrato de sódio e pepsina

PURPOSE: To investigate the carcinogenic action of hydrochloric acid, pepsin and sodium nitrate on the oropharyngeal mucosa of rats, simulating the reflux of gastric contents. METHODS: Eighty-two Wistar rats were divided in seven groups and submitted to 2 or 3 weekly applications of hydrochloric acid, pepsin and sodium nitrate on the pharyngeal mucosa during six months. Study groups comprised 12 animals each. Rats in groups I and II were submitted to 2 (GI) or 3 (GII) weekly applications of 0.1N hydrochloric acid. Groups III and IV were submitted to 2 (GIII) or 3 (GIV) weekly applications of 0.1N hydrochloric acid solution with pepsin. Groups V and VI were submitted to 2 (GV) or 3 (GVI) weekly applications of 0.1N hydrochloric acid and treated with daily nitrate diluted in water. Group VII consisted of 10 animals submitted to 2 weekly applications of filtered water. RESULTS: No dysplasia, intra-epithelial neoplasia or invasive carcinomas were detected. Inflammatory changes were observed in varying degrees and mast cells were more common in Groups V and VI (p=0.006). CONCLUSION: The data of the current study could not corroborate the hypothesis that gastroesophageal and pharyngolaryngeal refluxes are carcinogenic factors to the laryngopharyngeal mucosa, and more studies are necessary in the future.

OBJETIVO: Investigar a ação carcinogênica do ácido clorídrico, pepsina e nitrato de sódio na mucosa orofaríngea de ratos, simulando o refluxo do conteúdo gástrico à mucosa do faringo-laringea. MÉTODOS: Oitenta e dois ratos Wistar foram divididos em 7 grupos e submetidos a 2 ou 3 aplicações semanais de ácido clorídrico, pepsina e nitrato de sódio na mucosa orofaríngea durante 6 meses. Os grupos de estudo envolveram 12 animais cada. Os ratos nos grupos I e II foram submetidos à 2 (GI) ou 3 (GII) aplicações semanais de ácido clorídrico 0,1N. Nos grupos III e IV foram 2 (GIII) ou 3 (GIV) aplicações semanais de ácido clorídrico e pepsina. Nos grupos V e VI foram 2 (GV) ou 3 (GVI) aplicações semanais de ácido clorídrico além da oferta de nitrato diluído em água diariamente. Grupo VII era composto por 10 animais submetidos a 2 aplicações semanais de água filtrada. RESULTADOS: Não se observou displasia, neoplasia intra-epitelial ou neoplasia invasora. Alterações inflamatórias em graus variados foram observadas, com infiltrado mastocitário mais intenso nos grupos V e VI. (p=0,006). CONCLUSÃO: Os dados do presente estudo não confirmam a hipótese que o refluxo gastro-esofágico e faringo-laringeo são fatores carcinogênicos para a mucosa laringo-faringea e mais estudos são necessários no futuro.

Experimental carcinogenesis on the oropharyngeal mucosa of rats with hydrochloric acid, sodium nitrate and pepsin.

PURPOSE: To investigate the carcinogenic action of hydrochloric acid, pepsin and sodium nitrate on the oropharyngeal mucosa of rats, simulating the reflux of gastric contents. METHODS: Eighty-two Wistar rats were divided in seven groups and submitted to 2 or 3 weekly applications of hydrochloric acid, pepsin and sodium nitrate on the pharyngeal mucosa during six months. Study groups comprised 12 animals each. Rats in groups I and II were submitted to 2 (GI) or 3 (GII) weekly applications of 0.1N hydrochloric acid. Groups III and IV were submitted to 2 (GIII) or 3 (GIV) weekly applications of 0.1N hydrochloric acid solution with pepsin. Groups V and VI were submitted to 2 (GV) or 3 (GVI) weekly applications of 0.1N hydrochloric acid and treated with daily nitrate diluted in water. Group VII consisted of 10 animals submitted to 2 weekly applications of filtered water. RESULTS: No dysplasia, intra-epithelial neoplasia or invasive carcinomas were detected. Inflammatory changes were observed in varying degrees and mast cells were more common in Groups V and VI (p=0.006). CONCLUSION: The data of the current study could not corroborate the hypothesis that gastroesophageal and pharyngolaryngeal refluxes are carcinogenic factors to the laryngopharyngeal mucosa, and more studies are necessary in the future.

Alcohol-containing mouthwash and oropharyngeal cancer: a review of the epidemiology.

BACKGROUND: There has been concern that the use of alcohol-containing mouthwash may increase the risk of developing oropharyngeal cancer, or OPC. The authors examine the epidemiologic literature relating to this issue. TYPES OF STUDIES REVIEWED: The authors identified all nine English-language epidemiologic studies of OPC that made reference to mouthwash. The findings and major strengths and limitations of each study are described. In addition, the authors reanalyzed data from one of the studies. RESULTS: The results of six of the studies reviewed are negative and provide no support for the hypothesis that use of alcohol-containing mouthwash increases the risk of OPC. One of the three studies with positive results was a case series and included a follow-up case-control study, the results of which were negative. The authors reanalyzed the study with the most positive results. This analysis found that the study results were just as positive for nonmucosal cancers developing in the mouth as they were for the usual type of OPC. The authors concluded that this study's positive finding resulted from recall bias. CLINICAL IMPLICATIONS: It is unlikely that the use of mouthwashes that contain alcohol increases the risk of developing OPC.

Altered genotoxicity in mucosal cells of head and neck cancer patients due to environmental pollutants.

The complexity of carcinogenesis in squamous cell cancer (SCC) of the upper aerodigestive tract requires examining environmental risk factors, including mutagen sensitivities to xenobiotics. Three environmental, occupational, and habitual pollutants - dibutylphthalate (DBP), diisobutylphthalate (DiBP), and N'nitrosodiethylamine (NDELA) - were submitted to genotoxicity testing on mucosal biopsy specimens of tumor and nontumor patients in vitro. The single-cell microgel electrophoresis (Comet) assay was applied to detect DNA strand breaks in human epithelial cells of the pharynx and larynx from nontumor patients, patients with SCC of the oropharynx and patients with SCC of the larynx. Genotoxicity was found for DBP, DiBP, and NDELA in cells derived from nontumor and tumor patients. With respect to phthalates, Olive tail moment (OTM) levels were higher in patients with SCC of the oropharynx and SCC of the larynx (P < 0.01), the latter showing even more pronounced genotoxicity for DiBP. Testing epithelial cells of the patients with either oropharyngeal or laryngeal SCC for NDELA demonstrated results similar to the nontumor patients. Present findings indicate heterogeneous mutagen sensitivities to some but not all xenobiotics.

Placental glutathione S-transferase isoenzyme expression during promotion of two-stage hamster cheek-pouch carcinogenesis.

Glutathione S-transferases (GSTs) are the products of a multigene family. A well-established function of GSTs is to metabolize carcinogens by catalysing the conjugation of electrophilic substrates to glutathione. Whether placental GST (GST-P) is expressed during the promotion of two-stage hamster buccal-pouch mucosa (HBPM) carcinogenesis was investigated here, using 7,12-dimethylbenz[a]anthracene (DMBA) as the initiator and 12-O-tetradecanoylphorbol-13-acetate (TPA) as the promoter. Cytoplasmic and nuclear staining for GST-P was seen in pouches treated with DMBA for 4 or 16 weeks, as well as in those treated with DMBA for 4 weeks and then TPA for 12 weeks. No GST-P positivity was seen in any pouches treated with only TPA or with mineral oil for either 4 or 16 weeks. The average number of GST-P-stained foci in the groups treated with DMBA for 16 weeks (246 +/- 96; mean +/- SD) or DMBA for 4 weeks followed by TPA for 12 weeks (186 +/- 67) was significantly higher than in pouches treated with only DMBA for 4 weeks (97 +/- 24). These results demonstrate that TPA alone is not sufficient for GST-P expression in hamster buccal pouch mucosa. However, after being initiated with DMBA, then promoted with TPA, GST-P activity is induced in hamster buccal pouch mucosa during squamous-cell carcinogenesis. This underpins the suggestion that GST-P may play an important part during the promotion stage of oral carcinogenesis.

A qualitative and quantitative risk assessment of snuff dipping.

The presence of highly carcinogenic tobacco-specific nitrosamines (TSNA) in snuff has been a matter of serious concern. However, the levels of TSNA in such products may differ by orders of magnitude depending on origin and manner of processing, and the mere presence of such agents at low levels does hardly constitute a meaningful prerequisite for classifying all types of snuff as human carcinogens. Reviewing available epidemiological evidence, a wide discrepancy is found for estimated cancer risk associated with snuff dipping derived from on one hand previous investigations conducted in the United States and on the other from recent extensive Swedish epidemiological studies. In spite of the fact that approximately 20% of all grown-up Swedish males use moist snuff, it has not been possible to detect any significant increase in the incidence of cancer of the oral cavity or pharynx-the prevalence of which by international standards remains low in this country. Further, there is insufficient evidence for a causal link between the use of Swedish snuff and increased risk for cardiovascular disease. Dissimilarities in the content of TSNA in oral snuff products may represent one important reason for the different outcomes of the epidemiological surveys conducted in the United States and Sweden. Bioassays using pure TSNA in rodents appear to give exaggerated risk estimates for humans, a discrepancy that could be ascribed to species-related differences in the relation between exposure and DNA target dose and/or adduct repair rates, as well as to the presence of anticarcinogens in snuff. Although a small risk cannot be excluded, the use of smokeless tobacco products low in TSNA which now are available on the market entails a risk that at any rate is more than 10 times lower than that associated with active smoking. Nevertheless, due to the decisive role of potent TSNA in determining possible cancer risks in users of smokeless tobacco, and due to the fact that large variations in the concentrations may occur, adequate control measures should be taken to keep the levels of these nitrosamines in smokeless tobacco products as low as is technically feasible.

Tobacco consumption practices and risk of oro-pharyngeal cancer: a case-control study in Central India.

A hospital based, group matched case control study was conducted with the objective to assess the association between tobacco consumption practices and risk of development of oro-pharyngeal cancer in Central India. The study included 123 cases of oro-pharyngeal cancer, diagnosed on the basis of histopathology at three tertiary care centers in Nagpur city. Each case was matched for age and sex with two hospital controls: one selected from non-cancer patients and another from patients having cancer of other sites. Tobacco chewing (OR=7.98, 95% CI 4.11-13.58) and tobacco smoking (OR=2.25, 95% CI 1.22-3.70) were found to be significantly associated with oro-pharyngeal cancer on unconditional multiple logistic regression analysis. Further analysis revealed a dose-response relationship between increasing frequency, duration and retention time of tobacco in mouth and risk of oro-pharyngeal cancer. Other risk factors which were also found to contribute significantly in the outcome of oro-pharyngeal cancer in the study population were: use of traditional/local substances (eg pan, betel nut, lime) with or without tobacco, use of tobacco containing material for teeth cleaning, type of smoking (eg bidi, chillum, cigarette) and outdoor occupations. High values of estimates of attributable risk percent (ARP) and population attributable risk percent (PARP) confirmed the positive impact of reduction or elimination of the tobacco consumption practices on reducing the risk of oro-pharyngeal cancer in the population of Central India.