2
424 Abstracts/Lung Cancer 11 (1994) 423-444 Retinoid chemoprevention stud& in upper aerodiieative tract and Chemoprevention of respiratory tract neoplasia in the hamster by lung carcinogeneais oltipraz, alone and in combination Lippman SM, Benner SE. Waun Ki Hong lhoracic/Head/Neck Med. Oncol. Dept., Texas Univ. M. D. Anderson Can. Ctr., Box 80, 1515 Holcombe Boulevard, Hourron, TX 77030. Cancer Rea 1994;54:Suppl 2025s~8s. Moon RC, Rao KVN, Detrisac CJ, Kelloff GJ, Steele VE, Doody LA. Specialized Cancer Center, College of Medicine, University of Illinois, Chicago, a 60612. Int J Gncol 1994;4:661-7. Chemoprevention is a clinical strategy to block or reverse carcinogeneais before the development of invasive cancer. Studies of chemoprevention in the lungs and upper aemdigeative tract have relied on the field carcinogenesis hypothesis, which predicts that diffuse epithelial injury will result from exposure of that epithelium to carcinogens. This hypothesis is supported by the frequent occurrence of multiple primary tumors within the exposed field. In addition, the understanding of carcinogenesis as a multistep process supports the use of interventions in damaged epithelium before the development of clinically invasive cancer. Current efforts are focused on applying to chemoprevention studies the increasing knowledge of the molecular events in carcinogeneais. In our program, clinical trials in lung and head and neck chemoprevention have focused on individuals with evidence of field carcinogeneais, i.e., ahistory ofprevious epithelial cancer or the presence of premalignant lesions. These trials include studies to develop clinically applicable intermediate markers of carcinogeneais and large Phase III trials to evaluate the efficacy of the retinoid isotretinoin in preventing second primary tumors following head and neck or lung cancers. TWO doses of oltipraz (300, 600 mg/kg diet) and 6- difluoromethylomithine (DFMO; 1600,320O mg/kg diet), alone and in combinations with N-(Chydroxyphenyl) retinamide (4-HPR; 98, 196 mg/kgdiet)and/or8-carotene(3,1.5 mg; sc. 2x/week), wereinvestigated for prevention of hamster respiratory carcinogeneais. After 25 weeks, onlyhighdoseoltiprax(-100%) inhibitedtheincidenceofDEN-induced (17.8 mglkg BW, SC,Zx/weak, 20 weeks) bronchial carcinomas when given alone. Low dose oltiprax (-34%, n.s.) synergistically decreased carcinoma incidence in combinationswith 4-HPR (-80%), &carotene (- 90%) or both (-100%). Other effective combinations were low dose DFMO + B-carotene (-64%) and high dose DFMO with 4-HPR (- 56 %), O-carotene (-63 W) or both (-67 W). Risk factors of primary lung cancer and spirometry Rhee YK, Hwang KM, Lee YC. Depamnent of Internal Medicine, School of Medicine, Chonbuk National University, Chonju. Tuberc Reapir Dis 1993;40:646-52. Campnlgrrs against smoking: Compliance and results Arciti C, Pistone M, Persici P, Gallo M, Barbieri A, Santi L. Lega ItalianaLotta Contm i Tumori. ViaBertani, 9, Genova. Anticancer Res 1994;14:B 283-8. Smoking has become a true epidemic that intereats a lot of people in the world. The sntismolcmg progrsmmes are at these moments the most important strategy to prevent lung cancer and cardiovascular diseases. This article analyses the compliance and the results of the antismoking campaigns in the world. Data show the long term efficacy of school based smoking prevention programmes and underline their importance even ifthemethodologiescanbediffemnt in thevariouscountriea. Other data show that the Percentage of young smokers is increasing during the last three years; for this-n it is necessary to implement everywhere new programmes against smoking. The Alpha-Tocopherol, Beta-Carotene Lung Cancer Prevention Study: Jhxsign, methods, participant characteristics, andcompliance Heinonen OP, Huthmen JK, Albanes D, Haapakoski J, Palmgren J, Pietinen P et al. National Public Health Itwtitute, Mannerheimintie 166. FINaoJoo Helsinki. Ann Epidemiol 1994;4: I-IO. Background: Lung cancer and chronic obstructive lung disease often coexist in the same person who are elderly and cigarette smoking. There are several reports that the presence of chronic obstructive pulmonary disease constitutes an independent risk factor for the development of lung cancer. Moreover, the association between mucus hypersecretion and lung cancer has been reported. Method: In 72 cases with primary lung cancer which were confirmed histopathologically at Chonbuk University Hospital from August 1986 to July 1991, We evaluated the relationship between spirometry and lung cancer characteristics. Results: Six cases (8.3%) showed normal lung function, 16(22.2%) cases showedpurerestrictivelungdisease, 46(63.9%)casesshowedmoderated obstructive lung disease and 4(5.6%) cases showed severe obstructive lung disease. FEV, (96) was lower in central type than in peripheral type, lower in advanced non-small cell cancer and lower in subjects with phlegm. FEV,/FVC (96) was higher in small cell cancer than in squamous cell cancer and higher in patients without previous pulmonary disease than with previous pulmonary disease. But there was no statistically significant difference in lung function according to histologic types and smoking history. Lung cancers with FEV,/FVC leas than 75 A consisted of 35 cases of squamous cell cancer, 7 of small cell cancer (14%). 5 of adenocarcinoma (10%). 2 of large-cell carcinoma and 1 of unclassified carcinoma. Squamous cell carcinoma occurred more in patientswithFEV,/FVC <75% thanwithFEV,/FVC75% (p < 0.05). Conclusion: It was suggested that low FEV,/FVC, as reflection of obstructive lung disease, may be at greater risk for squamous cell carcinoma in cigarette smokers. The Alpha-Tocopherol, Beta-Carotene (ATBC) Lung Cancer Prevention Study was a randomized, double-blind, placeboumtmlled, 2 x 2 factorial design, primary prevention trial testing the hypothesis that alpha-tocopheml (50 n&lay) and beta-camtene (20 mg/day) supplements reduce the incidence of lung cancer and possibly other cancers. Total and disease-specificmortalityandincidenceofvariousdi-andsymptoms were monitored for safety. Between 1985 and 1993, 29,133 eligible male smokers aged 50 to 69 years at entry were randomized to receive daily activesupplements or placebocapsules for 5 to 8 years (median 6.1 years), accumulating 169,751 follow-up years. This report describes the study design, methods, and protocol as well as the baseline characteristics and capsule compliance of the participants. The ATBC Study is the largest lung cancer chemoprevention trial conducted to date. Epidemiology and etiology Lung cancer among newspaper printers exposed to ink mist: A study of trade union ~mmbers in Mnncheater, England Leon DA, Thomas P, Hutchings S. Epidemiology/Population Sri. Dept., London Sch. of Hygiene/%pical Med., Keppel Street, London WClE 7HT. Gccup Environ Med 1994;51:87-94. A nested case-control study of lung cancer among men exposed to ink mist in newspaper production with rotary letterpress technology is presented. It isbasedwithinahistorical cohortof9232printing workers inManchester(l94963). Menwhooperatednewspapermtaryletterpreas

Lung cancer among newspaper printers exposed to ink mist: A study of trade union members in Manchester, England

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Page 1: Lung cancer among newspaper printers exposed to ink mist: A study of trade union members in Manchester, England

424 Abstracts/Lung Cancer 11 (1994) 423-444

Retinoid chemoprevention stud& in upper aerodiieative tract and Chemoprevention of respiratory tract neoplasia in the hamster by lung carcinogeneais oltipraz, alone and in combination Lippman SM, Benner SE. Waun Ki Hong lhoracic/Head/Neck Med. Oncol. Dept., Texas Univ. M. D. Anderson Can. Ctr., Box 80, 1515 Holcombe Boulevard, Hourron, TX 77030. Cancer Rea 1994;54:Suppl 2025s~8s.

Moon RC, Rao KVN, Detrisac CJ, Kelloff GJ, Steele VE, Doody LA. Specialized Cancer Center, College of Medicine, University of Illinois, Chicago, a 60612. Int J Gncol 1994;4:661-7.

Chemoprevention is a clinical strategy to block or reverse carcinogeneais before the development of invasive cancer. Studies of chemoprevention in the lungs and upper aemdigeative tract have relied on the field carcinogenesis hypothesis, which predicts that diffuse epithelial injury will result from exposure of that epithelium to carcinogens. This hypothesis is supported by the frequent occurrence of multiple primary tumors within the exposed field. In addition, the understanding of carcinogenesis as a multistep process supports the use of interventions in damaged epithelium before the development of clinically invasive cancer. Current efforts are focused on applying to chemoprevention studies the increasing knowledge of the molecular events in carcinogeneais. In our program, clinical trials in lung and head and neck chemoprevention have focused on individuals with evidence of field carcinogeneais, i.e., ahistory ofprevious epithelial cancer or the presence of premalignant lesions. These trials include studies to develop clinically applicable intermediate markers of carcinogeneais and large Phase III trials to evaluate the efficacy of the retinoid isotretinoin in preventing second primary tumors following head and neck or lung cancers.

TWO doses of oltipraz (300, 600 mg/kg diet) and 6- difluoromethylomithine (DFMO; 1600,320O mg/kg diet), alone and in combinations with N-(Chydroxyphenyl) retinamide (4-HPR; 98, 196 mg/kgdiet)and/or8-carotene(3,1.5 mg; sc. 2x/week), wereinvestigated for prevention of hamster respiratory carcinogeneais. After 25 weeks, onlyhighdoseoltiprax(-100%) inhibitedtheincidenceofDEN-induced (17.8 mglkg BW, SC, Zx/weak, 20 weeks) bronchial carcinomas when given alone. Low dose oltiprax (-34%, n.s.) synergistically decreased carcinoma incidence in combinationswith 4-HPR (-80%), &carotene (- 90%) or both (-100%). Other effective combinations were low dose DFMO + B-carotene (-64%) and high dose DFMO with 4-HPR (- 56 %), O-carotene (-63 W) or both (-67 W).

Risk factors of primary lung cancer and spirometry Rhee YK, Hwang KM, Lee YC. Depamnent of Internal Medicine, School of Medicine, Chonbuk National University, Chonju. Tuberc Reapir Dis 1993;40:646-52.

Campnlgrrs against smoking: Compliance and results Arciti C, Pistone M, Persici P, Gallo M, Barbieri A, Santi L. Lega ItalianaLotta Contm i Tumori. ViaBertani, 9, Genova. Anticancer Res 1994;14:B 283-8.

Smoking has become a true epidemic that intereats a lot of people in the world. The sntismolcmg progrsmmes are at these moments the most important strategy to prevent lung cancer and cardiovascular diseases. This article analyses the compliance and the results of the antismoking campaigns in the world. Data show the long term efficacy of school based smoking prevention programmes and underline their importance even ifthemethodologiescanbediffemnt in thevariouscountriea. Other data show that the Percentage of young smokers is increasing during the last three years; for this-n it is necessary to implement everywhere new programmes against smoking.

The Alpha-Tocopherol, Beta-Carotene Lung Cancer Prevention Study: Jhxsign, methods, participant characteristics, andcompliance Heinonen OP, Huthmen JK, Albanes D, Haapakoski J, Palmgren J, Pietinen P et al. National Public Health Itwtitute, Mannerheimintie 166. FINaoJoo Helsinki. Ann Epidemiol 1994;4: I-IO.

Background: Lung cancer and chronic obstructive lung disease often coexist in the same person who are elderly and cigarette smoking. There are several reports that the presence of chronic obstructive pulmonary disease constitutes an independent risk factor for the development of lung cancer. Moreover, the association between mucus hypersecretion and lung cancer has been reported. Method: In 72 cases with primary lung cancer which were confirmed histopathologically at Chonbuk University Hospital from August 1986 to July 1991, We evaluated the relationship between spirometry and lung cancer characteristics. Results: Six cases (8.3%) showed normal lung function, 16(22.2%) cases showedpurerestrictivelungdisease, 46(63.9%)casesshowedmoderated obstructive lung disease and 4(5.6%) cases showed severe obstructive lung disease. FEV, (96) was lower in central type than in peripheral type, lower in advanced non-small cell cancer and lower in subjects with phlegm. FEV,/FVC (96) was higher in small cell cancer than in squamous cell cancer and higher in patients without previous pulmonary disease than with previous pulmonary disease. But there was no statistically significant difference in lung function according to histologic types and smoking history. Lung cancers with FEV,/FVC leas than 75 A consisted of 35 cases of squamous cell cancer, 7 of small cell cancer (14%). 5 of adenocarcinoma (10%). 2 of large-cell carcinoma and 1 of unclassified carcinoma. Squamous cell carcinoma occurred more in patientswithFEV,/FVC <75% thanwithFEV,/FVC75% (p < 0.05). Conclusion: It was suggested that low FEV,/FVC, as reflection of obstructive lung disease, may be at greater risk for squamous cell carcinoma in cigarette smokers.

The Alpha-Tocopherol, Beta-Carotene (ATBC) Lung Cancer Prevention Study was a randomized, double-blind, placeboumtmlled, 2 x 2 factorial design, primary prevention trial testing the hypothesis that alpha-tocopheml (50 n&lay) and beta-camtene (20 mg/day) supplements reduce the incidence of lung cancer and possibly other cancers. Total and disease-specificmortalityandincidenceofvariousdi-andsymptoms were monitored for safety. Between 1985 and 1993, 29,133 eligible male smokers aged 50 to 69 years at entry were randomized to receive daily activesupplements or placebocapsules for 5 to 8 years (median 6.1 years), accumulating 169,751 follow-up years. This report describes the study design, methods, and protocol as well as the baseline characteristics and capsule compliance of the participants. The ATBC Study is the largest lung cancer chemoprevention trial conducted to date.

Epidemiology and etiology

Lung cancer among newspaper printers exposed to ink mist: A study of trade union ~mmbers in Mnncheater, England Leon DA, Thomas P, Hutchings S. Epidemiology/Population Sri. Dept., London Sch. of Hygiene/%pical Med., Keppel Street, London WClE 7HT. Gccup Environ Med 1994;51:87-94.

A nested case-control study of lung cancer among men exposed to ink mist in newspaper production with rotary letterpress technology is presented. It isbasedwithinahistorical cohortof9232printing workers inManchester(l94963). Menwhooperatednewspapermtaryletterpreas

Page 2: Lung cancer among newspaper printers exposed to ink mist: A study of trade union members in Manchester, England

Abstracts/Lung Cancer 11 (1994) 423-444 425

machinea had a lung cancer standardised mortality ratio (SMR) of 179 (95 $6 confidence interval (95 96 CI) 144-218) when compared with rates for England and Wales for the follow up period 1950-83. When adjustment was made for thehigher rates in the local area, the SMR was reduced to 122 (95% CI 98-148). The nested case control study was based on 110 lung cancer cases (1949-86) and 316 matched controls. Duration of work in a rotary letterpress machine room was positively associated with risk of lung cancer (CM* linear trend = 3’30, p = 0.07); menwith 30ormoreyearsdurationofexposurehadariskof l-73 (95% CI O-94-3-17). relative to those with less than 20 years of exposure. Adjustment for period of first exposure in a machine room reduced the strength of the positive duration effect. the magnitude of the SMRs found in the cohort study could be explained by confounding with smoking. The duration effect seen in the case-control study, however, suggests that there may be a real effect of exposure to letterpress ink mists. This isbiologically plausible, as benxo[a]pyrene, a known human carcinogen, hasbeen foundinappreciableconcentratioosinthea~here of rotary letterpress machine rooms.

Repmdueibility of mqior diagnoses in a binational study of lung cancer in uranium miners and atomic bomb survivors Keehn R, Auerbach 0, Nambu S, Carter D, Shimosato Y, Greenberg SD et al. Rodiotion Epidemiology Branch, 6130 Executive Boulevard, Bethesda, MD 2fM52. Am J Clin Path01 1994;101:478-82.

A binational panel of four Japanese and four American pathologists examined 208 pulmonary neoplasms, according to the World Health Grganixation (WHO) recommendations, second edition, for thehistologic typingoflungtumors.ThesaYlydesipincludedindependentevPluatioas by pathologists working alone, followed by group reviews. The individual evaluations, and their implications for reproducibility of the WHorecommendations, arereported. Consensus (agreement by six or more pathologists) with respect to major (ie, first digit) diagnosis was obtainedfor76.496ofthecases. Consensuswasobtainedfor72.596of the cases with any major diagnosis of small cell cancer; the comparable figures for adenocarcinoma and squamous cell caminoma were 56 % and 4896, respectively. American pathologists were twice as liiely as Japanese pathologists to diagnose large-cell cancer, theonly significant national difference. Consensus was far less frequent with the minor (ie, second digit) diagnosis categories. This study shows that lung cancers continue to be difficult to classify reproducibly.

Aryl hydrocarbon hydroxylase adivity in human lung tissw: In relation to cIgnrette snokhtg and lung cancer Yoshikawa M, Arashidani K, Kawamoto T, Kodama Y. Division of Occupational Hygiene, School of Nursing/Medical Technology, Univ. of OccupationallEnvtl. Health, l-l Iseigaoka, Yabatanishi-ku, Kitakyushu 807. Environ Res 1994;65: l-l 1.

In order to investigate the relationship between aryl hydrocarbon hydroxylase (AHH) activity and smoking or lung cancer, AHH activities in fresh lungs (normal tissue, tumorous tissue, and surrounding tissue of tumor) obtained from lung cancer patients and non-lung cancer patients were measured. There were no differences in lung AHH activity inthelunglobea. Inthenon-lungcancerpatients, AHHactivitiearanged fmmO.13 to 2.37 (pm013 hydmxybenxo[a]py~e/2OminImgpmtein), and whereas in the normal tissues of the lung cancer patients they ranged from 0.19 to 5.05. Lung AHH activities showed normal distribution, and a large variation (26 times) was observed in normal tissues in the lung cancer patients. In most casea, AHH activities in the tumorous tissues and the surrounding tissue of the tumor were lower than those in

the normal tissues of the lung cancer patients. In the non-lung cancer group, the means of AHH activity of the nonsmoker subgroup (NN) and the smoker subgtoup (SN) were 0.62 and 0.96, respectively. On the other hand, in the lung cancer group the means of AHH activity of the nonsmoker subgroup (NC) and smoker subgroup (SC) were 0.85 and 1.05, respectively. Statistically significant differences were observed betweenNNandSN, NNandNC, andNNandSC.Theseresultssuggest that human lung AHH activity was increased by cigarette smoke as in rodent lungs, and the distribution of basal AHH activity in lung tissue of the nonsmokers group in the lung cancer patients shifted toward high levels compared to the nonsmokers group in the non-lung cancer group. The effect of the histological cell types of the lung cancer on the AHH activity was not observed in this study.

Oncopmteins as biomarkera of a preclinical form of cancer of the respiratory tract induced by envimnmental carcinogens Lutz W, Sulkowski W, Krajewska B. Deparhnent of Laboratory Diagnostics, Nofm Institute of Occupational Med., P. 0. Box 199,90- 95OLudz. Pol J Gccup Med Environ Health 1993;6:347-55.

Experimen~datoandclinicnlo~ationsindicotethot~increesed expression of oncogenes or their point mutations play an essential role in the process of carcinogenesis. It was important to find out that environment and occupational carcinogens activate cellular oncogenes andcontributetoi amountsoroccu-ofmutatedoncoptoteins. The latter are responsible for activating mechanisms which further the ncoplastilc transformation ofcells. The researcheaaremainIyconcerned about two oncoproteins: oncoprotein coded by the ras oncogene - called p2 1 protein and oncoprotein coded by the e&B-2 oncogen -called ~185 protein. Investigations performed on neoplastic cells show that the neoplastic transformation process involves not only the afore-said oncogenea and their oncoproteins but also other oncogenes. and that the process itself required activating of more than one oncogen. At present, it is possible to use measurements of oncoproteins in the biological material which is easily available. Due to this fact, a number of works in which measurements of oncoproteins in blood serum were used to assess cancer risk in persons exposed to carcinogens present at the work place, have been published.

Malignant transformation of human bronchial epithelial cells by radon-simulated a-particks Hei TK, Piao CQ, Willey JC, Thomas S, HaB BJ. i’he Cenrer for Rodiologiml Rcscarch. Vanderbilt Clinic 1 I-218. Columbia Vnivemity. 630 West 168th Street, New York, NY 10032. Carcinogenesis 1994;15:431-7.

Epidemiological studies have shown that mhalation of radon is associated with an increased risk for bronchogeoic carcinoma in uranium miners. These a+mitting radon daughters also rep-t the largeat component of background radiion to the general public. In the p-t study, the oncogwtic transforming effects of single versus multiple doses of radon-simulated a-particlea were examined using human papillomavints-immortalixed human bronchial epithelial cells. Endpoints such as gmwth kinetics, resistance to serum and 12-0- tetradecanoylphorbol-13-acetate-induced terminal differentiation, anchorage-indepmde& growth and hnnorigenicity in nude mice were used to assess the various stages of transformation in the bronchial epithelial cells. We show here, for the first time, that immortalized human cells in culhne can be malignantly transformed by a single 30 CGy dose of a-particles. Transformed cells produced progressively growing subcutaneous tumors upon inoculation intoathymic nude mice.