Showing papers by "Rodolfo Saracci published in 1991"

Carcinogen mmetabolism and DNA adducts in human lung tissues as affected by tobacco smoking or metabolic phenotype: a case-control study on lung cancer patients

Abstract: Individual variations in activity of pulmonary enzymes that metabolize tobacco-derived carcinogens may affect an individual's cancer risk from cigarette smoking. To investigate whether some of these enzymes (e.g., cytochrome P450IA-related) can serve as markers for carcinogen-induced DNA damage accumulating in the lungs of smokers, non-tumorous lung tissue specimens were taken during surgery from middle-aged men with either lung cancer (n = 54) or non-neoplastic lung disease (n = 20). Phase I (AHH, ECDE) and phase II (EH, UDPGT, GST) enzyme activities, glutathione and malondialdehyde contents were determined in lung parenchyma and/or bronchial tissues; some samples were analyzed for DNA adducts, using 32P-postlabeling. Data analysis of subsets or the whole group of patients yielded the following results. (1) Phase I and II drug-metabolizing enzyme (AHH, EH, UDPGT, GST) activities in histologically normal surgical specimens of lung parenchyma were correlated with the respective enzyme activities in bronchial tissues of the same subject. (2) In lung parenchyma, enzyme (AHH, ECDE, EH, UDPGT) activities were significantly and positively related to each other, implying a similar regulatory control of their expression. (3) Mean activities of pulmonary enzymes (AHH, ECDE) were significantly (2- and 7-fold, respectively) higher in lung cancer patients who had smoked within 30 days before surgery (except GST, which was depressed) than in cancer-free subjects with a similar smoking history. (4) In the cancer patients, the time required for AHH, EH and UDPGT activities to return to the level found in non-smoking subjects was several weeks. (5) Bronchial tree and peripheral lung parenchyma preparations exhibited a poor efficiency in activating promutagens to bacterial mutagens in Salmonella. However, they decreased the mutagenicity of several direct-acting mutagens, an effect which was more pronounced in tissue from recent smokers. GSH concentration and GST activity were positively correlated with mutagen inactivation in the same sample. (6) In recent smokers, AHH activity in lung parenchyma was positively correlated with the level of tobacco smoke-derived DNA adducts. (7) Pulmonary AHH and EH activity had prognostic value in tobacco-related lung cancer patients. (8) An enhanced level of pro-oxidant state in the lungs was associated with recent cigarette smoking. Malondialdehyde level in lung parenchyma was associated with the degree of small airway obstruction, suggesting a common free radical-mediated pathway for both lung cancer induction and small airway obstruction.(ABSTRACT TRUNCATED AT 250 WORDS)

Is necropsy a valid monitor of clinical diagnosis performance

Abstract: OBJECTIVE--To improve the validity of comparisons between clinical and postmortem diagnoses when postmortem diagnosis is used to monitor clinical diagnosis performance. DESIGN--Analysis of elementary examples. MAIN OUTCOME MEASURES--Sensitivity and specificity of clinical and postmortem diagnoses and confirmation and agreement rates. Sensitivity and specificity permit valid comparisons of clinical and postmortem diagnoses among different procedures, sites, or times whereas agreement and confirmation rates may be misleading. Estimates of sensitivity and specificity, however, can be severely distorted by factors such as non-random selection of cases for necropsy or by unrecognised errors in postmortem diagnosis. Such distortion may be minimised by (a) estimating the likely magnitude of errors in postmortem diagnosis, (b) specifying standard conditions for performing necropsies, and (c) ensuring an unbiased sample of moderate size rather than a large biased sample. CONCLUSION--Sensitivity and specificity should be used as measures of agreement between clinical and postmortem diagnoses. IMPLICATION--Monitoring of clinical diagnosis performance by necropsy surveys requires ensuring accuracy of pathological examinations and validity of study design and analysis.

Beryllium and lung cancer: adding another piece to the puzzle of epidemiologic evidence.

Abstract: The identification of environmental carcinogens is based on the observation of an excess cancer risk in exposed human groups. This effort is indirectly guided by experimental results, among which those of long-term carcinogenicity tests in animals (mostly rodents) play a key role. All of the agents in group 1 of the International Agency for Research on Cancer evaluation scheme (7), namely those definitely carcinogenic in humans, tested positive when adequately investigated in long-term carcinogenicity tests. These results point to the high sensitivity of animal testing. However, of the agents (n = 258) for which \"sufficient evidence\" of carcinogenicity in animals was judged to exist, less than 15% can be demonstrated to be definitely carcinogenic in humans: for more than half, no human data are available; for the rest, the evidence in humans is either inadequate or positive but limited. The first reason for this state of affairs is the difficulty of obtaining informative epidemiologic data. Groups of subjects exposed to the agent of interest in numbers, levels, and durations sufficient to make an excess risk of cancer detectable often do not exist; or the exposure may be inextricably mixed with exposure to other carcinogens; or, simply, suitable study populations may not have been sought diligently enough. (As for the latter point, clear excesses of cancers may remain unnoticed unless properly searched for, as one is reminded by the recent detection of a focus of mesotheliomas in a town in northern Italy (2), most probably related to neighborhood contamination from a work site.) The case of beryllium highlights in a typical way several of the difficulties in using mortality studies to identify carcinogens in situations of past exposure in humans. Occupational exposure to beryllium, a bivalent light metal, and to its derivatives occurs in mining, extraction, refining, and alloy manufacture, as well as in a number of industries, including the nuclear industry (where the metal is used as a neutron moderator) and the aerospace industry (where it is used, for example, in the manufacture of high-performance brakes) (5). Environmental exposure of the general population occurs usually at levels several orders of magnitude lower than exposures found at workplaces. However, levels materially higher than \"permissible\" have been reported following a nuclear plant accident at Ust' Kamenogorsk, Kazakh Republic (4). In experimental animal studies, the evidence of carcinogenicity of beryllium-containing compounds is strikingly consistent and goes back almost half a century. The carcinogenic effects of beryllium have been demonstrated in a substantial number of studies using oral administration, inhalation, and intratracheal administration, as well as intravenous and intramedullary injection in the bone (5). Beryllium appears to be by far the most potent inorganic pulmonary carcinogen tested in rats (a thousand times more active per unit weight than crysotile in producing lung tumors) (5). Contrasted with this abundant evidence are the results of six epidemiologic studies (6-11), which are derived from the observation of only two U.S. occupational cohorts (totaling about 4300 workers), and of a nationwide disease registry population affected by acute or chronic berylliosis, which in part includes cases arising from the same two cohorts. The results of these studies show an excess of lung cancer, on the order of 50%, 15 years after (and, more clearly, reaching formal statistical significance 25 years after) onset of exposure. If this increase is, in toto or in part, due to the exposure to beryllium, one would expect that the greater the exposure, the higher the risk. In fact, in one of the cohorts (7), six (75%) of eight lung cancers observed at the 1967 follow-up were concentrated in the subgroup of workers (15% of the cohort) who had experienced acute berylliosis and, presumably, the high exposure often encountered in the 1940s. Consistent with this finding, a twofold to threefold lung cancer excess was observed among the subjects included in the nationwide registry as being affected by acute berylliosis (9). However, and quite inconsistently, no excess at all (actually a deficit, based on very small numbers) was observed among those affected by chronic berylliosis. This inconsistency now appears removed by the results of Steenland and Ward (72), who found an increase of about 50% of lung cancer (not statistically significant) among subjects with chronic berylliosis. The authors have updated to the end of 1988 and (unlike the previous, end of 1975, follow-up) included data on women. Furthermore, they excluded subjects (for example, those registered after the lung cancer occurrence) whose presence could contribute to spuriously increasing the association between berylliosis and lung cancer. For approximately one third of the subjects, they collected information on smoking habits as of 1965, finding that at that time there were more former and fewer current smokers among the registry members than among the corresponding U.S. population. Taking into account known relative risks for lung cancer among smokers, these differences in smoking habits would have produced a slight deficit of lung cancer among the registry members in relation to the general population, supporting the contention that the actual observed excess can hardly be attributed to smoking. The study also confirmed the more than twofold (and statistically