Hydrochlorothiazide treatment and risk of non-melanoma skin cancer: Review of the literature. / Terapêutica com hidroclorotiazida e risco de cancro cutâneo não melanoma: revisão da literatura.

Non-melanoma skin cancer is the most prevalent malignancy in fair-skinned people and its incidence is increasing. Recently, studies have suggested that antihypertensive drugs may increase the risk of these tumors, particularly hydrochlorothiazide, due to its photosensitizing properties. The Portuguese National Authority for Medicines and Health Products, INFARMED, has issued an alert to healthcare professionals concerning the increased risk of non-melanoma skin cancer in patients exposed to cumulative doses of this drug. However, study results have been heterogeneous and sometimes conflicting. The high incidence of non-melanoma skin cancer and the large number of patients under chronic hydrochlorothiazide therapy may thus have important public health consequences. In this article, the authors review the published evidence and conclude that there may be an association between hydrochlorothiazide use and the risk of non-melanoma skin cancer, but also point out some limitations of the studies in the literature. It is important to promote preventive strategies against sun exposure, regular skin examinations, and individual assessment of the benefits of hydrochlorothiazide use, particularly in patients with previous skin cancer.

Multidimensional analysis of the effect of occupational exposure to organic solvents on lung cancer risk: the ICARE study.

BACKGROUND: The association between lung cancer and occupational exposure to organic solvents is discussed. Since different solvents are often used simultaneously, it is difficult to assess the role of individual substances. OBJECTIVES: The present study is focused on an in-depth investigation of the potential association between lung cancer risk and occupational exposure to a large group of organic solvents, taking into account the well-known risk factors for lung cancer, tobacco smoking and occupational exposure to asbestos. METHODS: We analysed data from the Investigation of occupational and environmental causes of respiratory cancers (ICARE) study, a large French population-based case-control study, set up between 2001 and 2007. A total of 2276 male cases and 2780 male controls were interviewed, and long-life occupational history was collected. In order to overcome the analytical difficulties created by multiple correlated exposures, we carried out a novel type of analysis based on Bayesian profile regression. RESULTS: After analysis with conventional logistic regression methods, none of the 11 solvents examined were associated with lung cancer risk. Through a profile regression approach, we did not observe any significant association between solvent exposure and lung cancer. However, we identified clusters at high risk that are related to occupations known to be at risk of developing lung cancer, such as painters. CONCLUSIONS: Organic solvents do not appear to be substantial contributors to the occupational risk of lung cancer for the occupations known to be at risk.

Does topical voriconazole trigger dysplastic changes on the ocular surface?

PURPOSE: Systemic voriconazole treatment was reported to cause photosensitivity and related cutaneous malignancies. The aim of this report is to demonstrate a graft-related Candida endophthalmitis case that developed ocular surface dysplastic changes after receiving topical 1% voriconazole treatment. METHODS: Full ocular examination, photography, and in vivo confocal microscopy examination (Rostock Cornea Module/HRT II, Heidelberg, Germany) were performed. RESULTS: A 73-year-old male with graft-related Candida endophthalmitis that was on topical 1% voriconazole for 4 months developed a whitish gelatinous lesion on the cornea originating from the nasal limbus. In vivo confocal microscopy examination revealed mild dysplastic changes in the cornea epithelium. CONCLUSION: Topical voriconazole might trigger neoplastic changes on the ocular surface as reported with systemic use in other sun-exposed parts of the body. Further studies are needed to relate topical use of voriconazole with ocular surface dysplasia.

FANCD2 activates transcription of TAp63 and suppresses tumorigenesis.

Fanconi anemia (FA) is a rare genetic disorder characterized by an increased susceptibility to squamous cell cancers. Fifteen FA genes are known, and the encoded proteins cooperate in a common DNA repair pathway. A critical step is the monoubiquitination of the FANCD2 protein, and cells from most FA patients are deficient in this step. How monoubiquitinated FANCD2 suppresses squamous cell cancers is unknown. Here we show that Fancd2-deficient mice are prone to Ras-oncogene-driven skin carcinogenesis, while Usp1-deficient mice, expressing elevated cellular levels of Fancd2-Ub, are resistant to skin tumors. Moreover, Fancd2-Ub activates the transcription of the tumor suppressor TAp63, thereby promoting cellular senescence and blocking skin tumorigenesis. For FA patients, the reduction of FANCD2-Ub and TAp63 protein levels may account for their susceptibility to squamous cell neoplasia. Taken together, Usp1 inhibition may be a useful strategy for upregulating TAp63 and preventing or treating squamous cell cancers in the general non-FA population.

Development of ferret as a human lung cancer model by injecting 4-(Nmethyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK).

OBJECTIVE: Development of new animal lung cancer models that are relevant to human lung carcino-genesis is important for lung cancer research. Previously we have shown the induction of lung tumor in ferrets (Mustela putorius furo) exposed to both tobacco smoke and a tobacco carcinogen (4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone, NNK). In the present study, we investigated whether NNK treatment alone induces both preneoplastic and neoplastic lesions in the lungs of ferrets. METHODS: We exposed ferrets to NNK by i.p. injection of NNK (50 mg/kg BW) once a month for four consecutive months and then followed up for 24, 26 and 32 weeks. The incidences of pulmonary pre-neoplastic and neoplastic lesions were assessed by histopathological examination. The expressions of 7 nicotinic acetylcholine receptor ( 7 nAChR, which has been shown to promote lung carcinogenesis)and its related molecular biomarkers in lungs were examined by immunohistochemistry and/or Western blotting analysis. RESULTS: Ferrets exposed to NNK alone developed both preneoplastic lesions (squamous metaplasia, dysplasia and atypical adenomatous hyperplasia) and tumors (squamous cell carcinoma, adenocarcinoma and adenosquamous carcinoma), which are commonly seen in humans. The incidence of tumor induced by NNK was time-dependent in the ferrets (16.7%, 40.0% and 66.7% for 24, 26 and 32 weeks, respectively). 7 nAChR is highly expressed in the ferret bronchial/bronchiolar epithelial cells, and alveolar macrophages in ferrets exposed to NNK, and in both squamous cell carcinoma and adenocarcinoma of the ferrets. In addition, we observed the tendency for an increase in phospho-ERK and cyclin D1 protein levels (p = 0.081 and 0.080, respectively) in the lungs of ferrets exposed to NNK. CONCLUSION: The development of both preneoplastic and neoplastic lesions in ferret lungs by injecting NNK alone provides a simple and highly relevant non-rodent model for studying biomarkers/molecular targets for the prevention, detection and treatment of lung carcinogenesis in humans.

Oral carcinogenesis is not achieved in different carcinogen-treated PAI-1 transgenic and wild-type mouse models.

AIM: In an effort to assess the role of plasminogen activator inhibitor-1 (PAI-1) in oral squamous cancer development and progression, two different carcinogen treatment protocols were conducted. MATERIALS AND METHODS: Protocol I included mice from a PAI-1 transgenic (Tg) breed (n=56) and their wild-type (WT) counterparts (n=56), divided into one control group and two main experimental groups, treated with 7,12-dimethylbenz[a]anthracene (DMBA) for 8 and 16 weeks, respectively. Protocol II included the same number and types of animals and groups, which were similarly treated with 4-Nitroquinoline 1-oxide (4-NQO) in drinking water. Two drugs that affect plasma PAI-1 levels, enalapril and pravastatin, were administered to certain subgroups of animals in both protocols. RESULTS: None of the animals developed macroscopically-visible oral cancer lesions. Eleven animals under Protocol I and 52 animals under Protocol II died. Skin lesions were noted only in DMBA-treated animals (n=9). Almost all animals administered with 4-NQO developed alopecia and lost weight, while two of them developed stomach tumours, and one female mouse developed a large ovarian cyst. CONCLUSION: Transgenic mice may respond differently when used in well-established carcinogen models and oral carcinogenesis is hard to achieve in these rodents.

Cell type specificity of female lung cancer associated with sulfur dioxide from air pollutants in Taiwan: an ecological study.

BACKGROUND: Many studies have examined the association between air pollutants (including sulfur dioxide [SO2], carbon monoxide [CO], nitrogen dioxide [NO2], nitric oxide [NO], ozone [O3], and particulate matter < 10 µm [PM10]) and lung cancer. However, data from previous studies on pathological cell types were limited, especially for SO2 exposure. We aimed to explore the association between SO2 exposure from outdoor air pollutants and female lung cancer incidence by cell type specificity. METHODS: We conducted an ecological study and calculated annual average concentration of 6 air pollutants (SO2, CO, NO2, NO, O3, and PM10) using data from Taiwan Environmental Protection Administration air quality monitoring stations. The Poisson regression models were used to evaluate the association between SO2 and age-standardized incidence rate of female lung cancer by two major pathological types (adenocarcinoma [AC] and squamous cell carcinoma [SCC]). In order to understand whether there is a dose-response relationship between SO2 and two major pathological types, we analyzed 4 levels of exposure based on quartiles of concentration of SO2. RESULTS: The Poisson regression results showed that with the first quartile of SO2 concentration as the baseline, the relative risks for AC/SCC type cancer among females were 1.20 (95% confidence interval [CI], 1.04-1.37)/1.39 (95% CI, 0.96-2.01) for the second, 1.22 (95% CI, 1.04-1.43)/1.58 (95% CI, 1.06-2.37) for the third, and 1.27 (95% CI, 1.06-1.52)/1.80 (95% CI, 1.15-2.84) for the fourth quartile of SO2 concentration. The tests for trend were statistically significant for both AC and SCC at P = 0.0272 and 0.0145, respectively. CONCLUSION: The current study suggests that SO2 exposure as an air pollutant may increase female lung cancer incidence and the associations with female lung cancer is much stronger for SCC than for AC. The findings of this study warrant further investigation on the role of SO2 in the etiology of SCC.

Asphalt fume dermal carcinogenicity potential: I. dermal carcinogenicity evaluation of asphalt (bitumen) fume condensates.

Asphalt (bitumen) fume condensates collected from the headspace above paving and Type III built up roofing asphalt (BURA) tanks were evaluated in two-year dermal carcinogenicity assays in male C3H/HeNCrl mice. A third sample was generated from the BURA using a NIOSH laboratory generation method. Similar to earlier NIOSH studies, the BURA fume condensates were applied dermally in mineral oil twice per week; the paving sample was applied 7 days/week for a total weekly dose of 50 mg/wk in both studies. A single benign papilloma was observed in a group of 80 mice exposed to paving fume condensate at the end of the two-year study and only mild skin irritation was observed. The lab generated BURA fume condensate resulted in statistically significant (P<0.0001) increases in squamous cell carcinomas (35 animals or 55% of animals at risk). The field-matched BURA condensate showed a weaker but significant (P=0.0063) increase (8 carcinomas or 13% of animals) and a longer average latency (90 weeks vs. 76 for the lab fume). Significant irritation was observed in both BURA condensates. It is concluded that the paving fume condensate was not carcinogenic under the test conditions and that the field-matched BURA fume condensate produced a weak tumor response compared to the lab generated sample.

p53 in head and neck cancer: functional consequences and environmental implications of TP53 mutations.

BACKGROUND: Although TP53 mutations in human tumours generally have been extensively studied, the significance of p53 in the aetiology of head and neck cancers is still incompletely characterized. In recent years, considerable interest has been focused on mutant forms of p53, the abnormal protein product of TP53 alleles with missense mutation that often accumulate in cancer cells. METHODS: We compared the nature of TP53 mutations in primary 46 head and neck squamous cell carcinomas (HNSCC) analyzed by PCR-SSCP and sequencing, immunohistochemistry, and using structural information available at IARC p53 database. RESULTS: Sequencing confirmed 36 TP53 mutations in 23 tumours of the 39 mutations in 26 tumours found by PCR-SSCP. Only half (17) putatively affect the function of p53 protein. Of these 8 were in the L2 domain, three affected the LSH motif and three the L3 domain. Three were in other domains. Codon 259 (GAC > GAA) which is a very rare mutation was found in 4 samples in our study. There were indications of p53 aberrations being associated with the combined effect of smoking, alcohol and work history. Patients with a negative family history of cancer had more often TP53 mutations than patients with a positive family history (71% vs. 46%). CONCLUSIONS: Our study contributes to the knowledge of cumulative chemical exposure and p53 aberrations in head and neck cancer, an area where literature is scarce.

Menopause, hormone replacement and gynaecological cancers.

Approximately 18,000 women are diagnosed with a gynaecological cancer in the UK each year. Predisposing risk factors for some of these gynaecological cancers include an early menarche/late menopause and hormone replacement therapy (HRT). Furthermore, treatment of gynaecological malignancies often induces an iatrogenic menopause, which may be more severe than a natural onset. HRT is an extremely effective treatment that may dramatically improve physical and psychological symptoms and ultimately quality of life in patients with cancer. However, the safety of using HRT in patients with gynaecological cancer is a controversial issue and not entirely clear. The main concern is the theoretical risk of the stimulation of residual cancer cells by estrogen replacement. The review of the evidence in this article found that for most gynaecological cancers this hypothesis was not proven. No study to date has found HRT to have a detrimental effect on survival in patients with early stage endometrial cancer, epithelial ovarian cancer, cervical cancer and vulval tumours. HRT is only an absolute contraindication in low-grade endometrial stromal sarcomas and is best avoided in granulosa cell ovarian tumours. Therefore, HRT should not be withheld in the majority of patients with gynaecological cancer. If quality of life is being adversely affected by symptoms of the menopause, then patients with cancer should be counselled regarding the known risks and benefits of HRT to enable them to make an informed decision on their treatment.

LKB1 deficiency sensitizes mice to carcinogen-induced tumorigenesis.

Lkb1 is a central regulator of cell polarity and energy metabolism through its capacity to activate the AMP-activated protein kinase (AMPK)-related family of protein kinases. Germ line-inactivating mutation of Lkb1 leads to Peutz-Jeghers syndrome, which is characterized by benign hamartomas and a susceptibility to malignant epithelial tumors. Mutations in Lkb1 are also found in sporadic carcinomas, most frequently in lung cancers associated with tobacco carcinogen exposure. The basis for Lkb1-dependent tumor suppression is not defined. Here, we uncover a marked sensitivity of Lkb1 mutant mice to the chemical carcinogen 7,12-dimethylbenz(a)anthracene (DMBA). Lkb1(+/-) mice are highly prone to DMBA-induced squamous cell carcinoma (SCC) of the skin and lung. Confirming a cell autonomous tumor suppressor role of Lkb1, mice with epidermal-specific Lkb1 deletion are also susceptible to DMBA-induced SCC and develop spontaneous SCC with long latency. Restoration of wild-type Lkb1 causes senescence in tumor-derived cell lines, a process that can be partially bypassed by inactivation of the Rb pathway, but not by inactivation of p53 or AMPK. Our data indicate that Lkb1 is a potent suppressor of carcinogen-induced skin and lung cancers and that downstream targets beyond the AMPK-mTOR pathway are likely mediators of Lkb1-dependent tumor suppression.

Exposure to iron and welding fumes and the risk of lung cancer.

OBJECTIVES: Exposure to iron fumes and dust and welding fumes is widespread and may increase the risk of lung cancer. The aim of this study was to identify associations between exposure to iron and welding fumes and the incidence of lung cancer among Finnish men. METHODS: The cohort of all economically active Finnish men, born in 1906-1945, who participated in the national census in 1970 was followed through the Finnish Cancer Registry for lung cancer cases (N=30,137) during 1971-1995. Their census occupations in 1970 were converted to estimates of cumulative exposure to iron and welding fumes with the Finnish job-exposure matrix on the basis of likelihood, average level, and estimated duration of exposure. Relative risk estimates for categorized cumulative exposure were defined by a Poisson regression, adjusted for smoking, socioeconomic status, and exposure to asbestos and silica dust. RESULTS: The relative risks for lung cancer increased as the cumulative exposure to iron and welding fumes increased. Relative risks in the highest exposure category was 1.35 [95% confidence interval (95% CI) 1.05-1.73] for iron and 1.15 (95% CI 0.90-1.46) for welding fumes. The respective relative risks estimated for squamous-cell carcinoma of the lungs were 1.94 (95% CI 1.35-2.78) and 1.55 (95% CI 1.08-2.24). There was no excess risk of small-cell carcinoma in any exposure category. CONCLUSIONS: Occupational exposure to iron and welding fumes was associated with an increase in lung cancer risk, mainly that of squamous-cell carcinoma. The simultaneous exposure to both of these agents and other potential work-related carcinogens complicates the interpretation of the independent roles of the risk factors.

Squamous dysplasia of the rectum in a patient with ulcerative colitis treated with 6-mercaptopurine.

Human papilloma virus (HPV) has been found to be a precursor and risk factor for both cervical and anal dysplasia. Cervical dysplasia, which is the precursor to carcinoma, is associated with immunosuppression from a variety of causes; reports of anal dysplasia associated with immune suppression exist as well. A recent study published in abstract form only demonstrated that women with inflammatory bowel disease (IBD) had high rates of cervical dysplasia and that those on immune suppressants had even higher rates of dysplasia. We report a case of a 50-year-old woman with refractory ulcerative colitis chronically treated with 6-mercaptopurine that developed severe squamous dysplasia of the rectum. The dysplastic mucosa was found to be positive for p16 (associated with high-risk HPV) after immunostaining. A total colectomy was performed. This case highlights the importance of immune suppression in the development of dysplasia of the anus/cervix secondary to HPV infection.

Inactivation of the Wwox gene accelerates forestomach tumor progression in vivo.

The WWOX gene encodes a tumor suppressor spanning the second most common human fragile site, FRA16D. Targeted deletion of the Wwox gene in mice led to an increased incidence of spontaneous and ethyl nitrosourea-induced tumors. In humans, loss of heterozygosity and reduced or loss of WWOX expression has been reported in esophageal squamous cell cancers (SCC). In the present study, we examined whether inactivation of the Wwox gene might lead to enhanced esophageal/forestomach tumorigenesis induced by N-nitrosomethylbenzylamine. Wwox+/- and Wwox+/+ mice were treated with six intragastric doses of N-nitrosomethylbenzylamine and observed for 15 subsequent weeks. Ninety-six percent (25 of 26) of Wwox+/- mice versus 29% (10 of 34) of Wwox+/+ mice developed forestomach tumors (P = 1.3 x 10(-7)). The number of tumors per forestomach was significantly greater in Wwox+/- than in Wwox+/+ mice (3.2 +/- 0.34 versus 0.47 +/- 0.17; P < 0.0001). In addition, 27% of Wwox+/- mice had invasive SCC in the forestomach, as compared with 0% of wild-type controls (P = 0.002). Intriguingly, forestomachs from Wwox+/- mice displayed moderately strong Wwox protein staining in the near-normal epithelium, but weak and diffuse staining in SCC in the same tissue section, a result suggesting that Wwox was haploinsufficient for the initiation of tumor development. Our findings provide the first in vivo evidence of the tumor suppressor function of WWOX in forestomach/esophageal carcinogenesis and suggest that inactivation of one allele of WWOX accelerates the predisposition of normal cells to malignant transformation.

Characterization and reclassification of titanium dioxide-related pulmonary lesions.

OBJECTIVE: Using current diagnostic criteria, this work summarizes the microscopic review of 16 proliferative squamous lesions, previously diagnosed as cystic keratinizing squamous cell carcinoma, in the lungs of rats from a 2-year inhalation study with pigment-grade titanium dioxide particles. METHODS: In the aftermath of two international pathology workshops designed, in part, to establish histological criteria for classifying pulmonary keratin lesions, these lesions were evaluated by four pathologists using current diagnostic criteria. RESULTS: Unanimous agreement was reached as to the diagnosis of each of the lesions. Two of the lesions were diagnosed as squamous metaplasia and one as a poorly keratinizing squamous cell carcinoma. The remaining 13 lesions were diagnosed as non-neoplastic pulmonary keratin cysts. CONCLUSIONS: These keratin cysts are a species-specific lesion that is unique to the rat lung under conditions of particle overload exposure.

Rapid induction of skin tumors in human but not mouse c-Ha-ras proto-oncogene transgenic mice by chemical carcinogenesis.

The rasH2 transgenic mice carry human c-Ha-ras proto-oncogene, and are highly susceptible to chemical carcinogenesis. Previous studies showed that the mutation of c-Ha-ras induced by DMBA in the tumors of rasH2 were detected only in transgenes. To examine if the difference between the codons of the c-Ha-ras gene in human and mouse contributed to the tissue-specific sensitivity to DMBA, we generated a line of transgenic mice, mras, carrying mouse c-Ha-ras genome with its own promoter. Western blot analysis showed that the protein expression of H-RAS in the skin was increased in both rasH2 and mras compared with wild-type. Chemical skin carcinogenesis was induced by DMBA and TPA. In rasH2 mice, the latency of tumor formation was shorter than wild-type littermates. Both the number and the volume of skin tumors were increased in rasH2 than those of wild-type. However, in mras mice, enhancement of tumor formation was not observed as compared with wild-type. The mean number of tumors and the latency of tumor development was almost the same between mras and wild-type littermates. Mutational analysis showed only A to T transversion in human c-Ha-ras transgenes at codon 61 but not in murine endogenous c-Ha-ras gene in the tumors of rasH2. In the tumors of wild-type littermates and mras, A to T transversion in murine c-Ha-ras at codon 61 were detected. These results indicate that the differences in the codon of the c-Ha-ras gene between mouse and human might contribute to the tissue-specific sensitivity of DMBA.

Chronic lymphocytic leukaemia, synchronous small cell carcinoma and squamous neoplasia of the urinary bladder in a paraplegic man following long-term phenoxybenzamine therapy.

STUDY DESIGN: A case report. OBJECTIVE: To raise awareness among spinal cord clinicians of the possible carcinogenic effect of phenoxybenzamine and of the rare occurrence of small cell carcinoma in the neuropathic bladder. SETTING: Regional Spinal Injuries Centre and District General Hospital, Southport, Merseyside, United Kingdom. CASE REPORT: A 28-year-old man sustained a fracture dislocation of L-1 with consequent paraplegia (ASIA impairment scale A). Phenoxybenzamine treatment enabled his indwelling catheter to be discarded in favour of a penile sheath, but it caused unacceptable dizziness and was stopped after 7 years. After 20 years, he developed chronic lymphocytic leukaemia, which was treated with chlorambucil and fludarabine. After 2 years, investigation of bilateral hydronephrosis revealed a primary small cell carcinoma of the bladder with coexistent squamous dysplasia. Uraemia supervened and, declining active treatment, the patient died 3 weeks after diagnosis. CONCLUSION: Phenoxybenzamine, a known carcinogen in rodents, is likely also to be carcinogenic in humans, and patients with spinal cord injury who have received the drug for any significant period of time, need close follow-up to allow early detection of cancer. Phenoxybenzamine should not be prescribed on a long-term basis, and should instead be replaced with a selective alpha-blocker.

Photodynamic therapy using a novel photosensitizer, ATX-S10(Na): comparative effect with 5-aminolevulinic acid on squamous cell carcinoma cell line, SCC15, ultraviolet B-induced skin tumor, and phorbol ester-induced hyperproliferative skin.

Photodynamic therapy (PDT) using 5-aminolevulinic acid (ALA) is available for the treatment of actinic keratosis (AK). Recently, we developed a new PDT photosensitizer, ATX-S10(Na), and have shown that ATX-S10(Na) PDT is effective for the treatment of various human skin diseases, such as squamous cell carcinoma, Bowen's disease, basal cell carcinoma, and psoriasis. In the present study, we compared the effects of ATX-S10(Na) PDT and ALA PDT on hyperproliferative skin induced by 12-O-tetradecanoylphorbol-13-acetate (TPA), on the squamous cell carcinoma cell line, SCC15, in vitro, and on UVB-induced skin tumors in vivo. TPA treatment induced epidermal acanthosis, which was more markedly suppressed by ATX-S10(Na) PDT than by ALA PDT. ATX-S10(Na) PDT more effectively eliminated UVB-induced AK and squamous cell carcinoma (SCC) than ALA PDT. Furthermore, both ATX-S10(Na) PDT and ALA PDT induced the death of SCC15 cells, and the effect of ATX-S10(Na) PDT was greater than that of ALA PDT. Our results indicate that ATX-S10(Na) PDT might be more effective than ALA PDT for the treatment of various skin diseases.

Reliability and validity of opiate use self-report in a population at high risk for esophageal cancer in Golestan, Iran.

OBJECTIVE: To assess the reliability and validity of self-reported opium use in a rural Iranian population at high risk for esophageal cancer in preparation for a large cohort study. METHOD: 1,057 subjects ages 33 to 84 years were recruited from Gonbad city and three surrounding villages in Golestan province of Iran and completed a questionnaire and provided biological samples. The history and duration of using opium, smoking tobacco, chewing nass, and drinking alcohol were measured by questionnaire in the entire cohort. A subgroup of 130 people was reinterviewed after 2 months to assess reliability. Validity of the opium question was assessed by comparing the questionnaire responses with the presence of codeine and morphine in the urine of 150 selected subjects. RESULTS: Self-reported opiate use is reliable and valid in this population. The reliability of ever opium use and duration of opium use had kappa's of 0.96 and 0.74, respectively. The validity of self-reported opium use was also high. Using urine codeine or morphine as the gold standard for use of opium, self-report had a sensitivity of 0.93 and a specificity of 0.89. CONCLUSIONS: The self-reported use of opium can provide a reliable and valid measurement in this population and will be useful for studying associations between opium use and occurrence of esophageal cancer and other diseases.