[Role of anatomopathological studies in the evaluation of the risk of lung cancer caused by passive smoking ]. / Rôle des études anatomopathologiques dans l'évaluation des risques de cancers pulmonaires entraînés par le tabagisme passif.

The current practice as regards the treatment of lung cancers consists of establishing a diagnosis of possible cancer and treating the patient as quickly as possible. However, the distinction between a primary neoplasm and metastases coming from an extrapulmonary primary cancer unfortunately can only be made with certainty in those cases which have a necropsy. However, epidemiological studies which are intended to evaluate the possible correlation between passive smoking and primary lung cancers are based on the available diagnoses, which themselves are often established uniquely on cytological examination or on biopsies of bronchi or pleura. The formal proof that the patients are suffering from primary pulmonary cancer thus does not exist in numerous cases cited and the confirmation of the existence of the risk between passive smoking and primary pulmonary cancer remains speculative.

The role of histopathology in the evaluation of risk of lung cancer from environmental tobacco smoke.

Current clinical practice for treating lung cancer does not provide adequate histopathological evaluation for the clear distinction between primary and metastatic neoplasia. Reliance on such clinical diagnosis jeopardises the scientific validity of many epidemiological studies designed to assess the risk of inhalation of environmental tobacco smoke (ETS).

Dazoxiben, a prototype inhibitor of thromboxane synthesis, has little toxicity in laboratory animals.

Dazoxiben, an orally active specific inhibitor of thromboxane synthetase, was administered by mouth daily to dogs and rats for 6 months. Dogs showed no evidence of toxicity up to 300 mg day-1 kg-1, the highest dose level used. Rats showed no evidence of toxicity after 100 mg day-1 kg-1, but at 300 mg day-1 kg-1 there were slight increases in plasma calcium and urea concentrations and a moderate incidence of focal nephrosis; males showed a slightly increased platelet count. Studies in rats and rabbits at dose levels up to 400 mg day-1 kg-1, by mouth, revealed no adverse effects on male or female fertility, embryogenesis, parturition or postnatal development. As dazoxiben is well absorbed after oral administration, the generally negative outcome to these toxicity studies suggests that selective inhibitors of thromboxane synthesis may be largely free of adverse effects which might impede their therapeutic or prophylactic use in clinical medicine.

Coronary hyperemia and cardiac hypertrophy following inhibition of fatty acid oxidation. Evidence of a regulatory role for cytosolic phosphorylation potential.

Oxfenicine (S-4-hydroxyphenylglycine) is a cardioselective inhibitor of long-chain fatty acid oxidation. In anesthetized dogs, oxfenicine (3.3 mg/kg, i.v.) increased myocardial blood flow by 33% under normal conditions and by 71% during isoprenaline infusion, but produced no other hemodynamic changes. Similar results were obtained with two other inhibitors of fatty acid oxidation, 2-bromopalmitate and 2-tetradecylglycidate. Chronic administration of oxfenicine to dogs for 1 year produced dose-related, nonpathological increases in relative heart weight (up to 85% at 750 mg/kg per day). Smaller effects (up to 30% at 900 mg/kg per day) were observed in a similar study in rats. Cardiac hypertrophy has previously been reported in rodents treated with 2-tetradecylglycidate. Moreover, cardiomegaly is frequently observed in cases of carnitine deficiency. We therefore suggest that coronary hyperemia and cardiac hypertrophy following either inhibition of fatty acid oxidation or an increase in cardiac work load may be adaptive changes triggered by a common mechanism-namely, a fall in cytosolic phosphorylation potential. In support of this, oxfenicine decreased the phosphocreatine/creatine ratio in rat hearts perfused in the presence of oleate. These findings suggest the possibility that metabolic abnormalities may provide the key to many idiopathic cardiomyopathies of uncertain origin.

European Ethical Review Committee: the experience of an international ethics committee reviewing protocols for drug trials.

An international ethics review committee, founded seven years ago, has several unusual features: it selects its own members, who are independent of the drug industry; it includes members with no medical or paramedical background, such as lay people and lawyers; and it reviews protocols together with the study's sponsor. Membership of 31 from nine European countries enables frequent meetings and there is a full meeting of the committee every year to review progress and consider policy. Of the first 294 protocols for phase I, II, or III trials reviewed, 37 were admitted outright, 243 were amended (usually during the discussion of the protocol), and 14 were rejected. It is suggested that, to overcome the problem of ethics review in smaller institutions, regional health authorities in Britain might consider establishing similar committees.

Comparative study of methods chosen by the Association Française de Normalisation (AFNOR) for evaluating sensitizing potential in the albino guinea-pig.

An evaluation was made of the different protocols recommended by the Association Française de Normalisation (AFNOR) for assessing the sensitizing potential of chemicals in the guinea-pig. The methods studied were those of Magnusson & Kligman (J. invest. Derm. 1969, 52, 268), Maguire (J. Soc. cosmet. Chem. 1973, 24, 151), Maurer et al. (Agents & Actions 1975, 5, 174), Klecak et al. (J. Soc. cosmet. Chem. 1977, 28, 53), Dossou & Sicard (1984, to be published) and a hitherto unpublished method of Guillot, Gonnet, Clément & Brulos. Results obtained by each method were compared in tests on the allergenic reference substances dihydrocoumarin, p-phenylenediamine, formalin, penicillin G and benzocaine (ethoform) and on propylene glycol (negative control). The results showed that the number of animals sensitized often varies with the choice of experimental protocol, that inclusion of tests on a control substance is essential, and that while quantitative differences were found, the methods were qualitatively similar in their capacity to identify allergens in the guinea-pig.

Spontaneous fibrous histiocytic neoplasms in rats.

A total of 85 spontaneous rat fibrohistiocytic tumours were evaluated histologically and assessed for the presence or absence of metastases. The overall incidence in controls from 2-year carcinogenicity studies was 2.7%. The tumours occurred principally in the subcutaneous and deep soft tissues, and generally appeared after 18 months of age. Four histological types were recognized: histiocytic (17%), pleomorphic (33%), cellular (17%) and very fibrous (33%). Histiocytic tumours were highly malignant, and most produced metastases. Pleomorphic and cellular neoplasms occasionally produced metastases and must be regarded as potentially malignant. Very fibrous lesions were essentially benign. The close resemblance, both histologically and biologically, between rat and human fibrohistiocytic neoplasms supports the use of the fibrohistiocytic concept in laboratory-animal pathology. Study of these rat tumours may provide insight into the development of human fibrohistiocytic neoplasms.

Negative results of carcinogenicity bioassay of methyl carbazate in rats: significance for the toxicological evaluation of carbadox.

Methyl carbazate, a metabolite of carbadox in the rat, was administered orally to rats for 2 years. The compound was mixed in the diet at concentrations corresponding to dose levels of 0, 2.5, 5 and 10 mg/kg body wt/day. There was no evidence of any treatment-related toxicity or, in particular, of carcinogenicity.

A carcinogenicity study in mice of a beta-adrenergic antagonist, primidolol; increased total tumour incidence without tissue specificity.

The beta-adrenergic blocking agent, primidolol hydrochloride, was administered, mixed in the diet, to mice (CD-1, Charles River, France) for 18 months. Experimental groups comprised untreated controls (100/sex) and those receiving 12.5, 25 and 50 mg drug/kg body weight (50/sex). There were no non-neoplastic lesions which could be attributed to the treatment. The pattern of tumour incidence was sex-related; in females the proportion of tumour-carrying animals was significantly higher in the top dose group (48%) than in the controls (24%), whereas in males the converse was found (30% in the top dose group vs. 48% in the controls). In the top dose female group there was no one tissue in which the tumour incidence was significantly higher than in the controls. We debate whether the analysis of total tumours in the absence of a target organ is an appropriate assay for carcinogenicity. Against a background of regulatory action towards beta-blocking agents, we discuss the possibility that the results of the present study could represent either a co-carcinogenic effect of beta-blocking agents or, alternatively, a statistical contingency.

Effects on mice of numbers of animals per cage: an 18-month study (preliminary results).

Mice were housed 1, 2, 4, or 8 per cage for 18 months. The more densely housed groups showed markedly reduced food consumption, slightly decreased mean body weights, and a smaller variance of body weights. Tumour incidence was not affected, but gastritis was more prevalent in the more densely housed groups.

Female adnexal tumour of probable Wolffian origin.

Two further cases of 'female adnexal tumour of probable Wolffian origin' are described Both were retroperitoneal and presented a unique histology of uniformly close-packed bland spaces. solid islands, cords, and diffuse areas. A small hamartoma in a female fetus, part of which resembled the tumours, was traced to an area of near apposition with some paroophoron canals, providing further evidence of a Wolffian origin. The literature of this and some other putative Wolffian tumours is briefly reviewed, and the relation to rete adenomas is discussed.

Computer analysis and integration of animal pathology data.

Computer storage of data from toxicology, biochemistry, haematology and pathology has been found necessary in our Laboratory in order to handle the vast amount of information generated by animal toxicology studies. The value of the system to pathology is enormous and its potential has not been exhausted. All finding, from organ weights and macroscopic observations made at autopsy, to the final histopathological diagnosis made by the pathologist are computerized. A modified version of the American College of Pathologists' systematized nomenclature of pathology is used. The pathologist recordtor whose role in the system is indispensable. The designation of a pathologist with special responsibility for supervising the computerisation and its scientific validity ensures its smooth running. The integration of data from haematology and clinical chemistry as a profile for each animal is available to the pathologist when making the final diagnosis. The system has resulted in a standardisation of pathological terminology, greater speed and improved accuracy in report formulation, the establishment of a readily retrievable in-house data bank and an enormous saving in the time of pathologists and secretaries.

Histologic changes following the grafting of connective tissue into human gingiva.

Grafting connective tissue from the palate to partial-thickness sites prepared in patients with an inadequate width of attached gingiva resulted in an increased width of keratinized mucosa. Biopsies of these grafts at the newly created mucogingival junction at 24 weeks showed the epithelium to be keratinized with a normal architecture, except over scar tissue at the edges of the grafts, where rete-peg formation was absent. The results support the concept that morphodifferentiation of gingival epithelium is influenced by the underlying connective tissue.

Disorders of bone and fracture of the femoral neck. Evaluation of computer image analysis in diagnosis.

The quantity of bone and osteoid has been measured in undecalcified sections of iliac-crest biopsy specimens taken from patients with fracture of the femoral neck. A control group of bone samples was obtained from post-mortem material. The 'Quantimet 720' image-analysing computer system was used to measure the area of bone and osteoid. An eye-piece graticule was used to measure the proportion of bone-surfaces covered with osteoid, and there was good correlation between the results obtained by these two methods. Little difference was found between the proportion of bone in the fracture and control groups, but the fracture group contained many more individuals with an increased proportion of trabecular osteoid measured with the quantimet and of osteoid-covered surfaces measured with an eyepiece graticule.