The etiology of renal-cell carcinoma

Experimental renal-cell carcinoma can be induced by many different chemical carcinogens; dimethyl nitrosoamine has been most studied. The disease so induced in experimental animals closely resembles the spontaneous disease in man in histopathology, course, and other characteristics. Two agents that are probably etiological of renal-cell cancer in man are tobacco and the analgesic, phenacetin; however, these materials can account for only a minority of the cases. The predominance of males in adult renal carcinoma might be explained by the more efficient metabolic activation of carcinogens by renal enzymes that are induced by male hormones. Mouse experiments support this hypothesis. Studies utilizing human kidney tissues that would test the hypothesis in man can and should be done. No obvious clues have emerged to explain the wide geographic differences in incidence of renal carcinoma. No group of industrial workers, or of others with a unique environment, has yet been described that has an especially high incidence of renal-cell carcinoma. A minority of renal carcinomas are familial. They represent a number of different diseases, one of which is associated with the von Hippel-Lindau disease. The hereditary renal-cell carcinoma of the Ecker rat, which is transmitted as an autosomal dominant, provides a useful laboratory model for hereditary carcinoma of man. Recently, two human families with renal-cell carcinoma were described in which there were unique chromosomal abnormalities associated with the disease. Such changes have been linked with oncogene activation in the instance of other tumors. Further studies of chromosomal abnormalities in renal-cell carcinoma will probably define a common pattern of chromosomal rearrangements. While estrogen readily induces renal-cell carcinoma in hamsters other species, including man, appear resistant. An excess of renal-cell carcinoma has not been reported in men on chronic estrogen therapy for prostatic carcinoma, nor has it been associated with the DES syndrome. A virus etiology for renal-cell carcinoma in man comparable to that of the Lucke tumor in frogs is unlikely on epidemiologic, ultrastructural morphologic, and other grounds. There is nothing suggesting horizontal transmission in the human disease, and a unique excess of renal-cell carcinomas in immunosuppressed patients or patients with the acquired immunodeficiency syndrome (AIDS) is not apparent. There is overwhelming evidence that renal adenomas represent early adenocarcinomas, or at least precursor lesions; certainly they are closely related to renal-cell carcinomas.(ABSTRACT TRUNCATED AT 400 WORDS)     

Prolactin and mammary gland carcinogenesis. The problem of human prolactin

The ultimate objective of experimental cancer research must be to apply the findings obtained to the prevention or treatment of the disease in humans. In this review it is shown that prolactin is suspected of being one of the hormones mainly responsible for the development of mammary carcinoma in mice. Investigations into the question of whether this might also be true in man are hampered by the fact that the existence of prolactin in this species is still a matter of debate. Because of the intrinsic prolactin-like activity of purified human growth hormone, the need for the presence of prolactin as a separate hormone might be questioned. It is shown, however, on the basis of a number of biological arguments and clinical observations, that it is extremely unlikely that all prolactin-like effects in man are due to one of the manifold activities of growth hormone alone; consequently the urgent need to analyse the role of prolactin as a separate hormone in man becomes evident, especially in the field of breast cancer. Tentatively, ways are indicated by which this objective might be reached.     

A dose-response study on urethane carcinogenesis in rats and mice

Sprague-Dawley rats and NMRI mice were treated with urethane in the drinking water for 2 years. In both species the daily doses were: 100, 500, 2,500, and 12,500 μg/kg. The frequency of animals with malignancies increased steadily with increasing doses, beginning from 500 μg/kg/day for rats, and from 100 μg/kg/day for mice. To evaluate the possible cancer risk for man due to urethane in beverages, the observed response rates were used to extrapolate responses at lower doses. At a daily dose of 0.14 μg/kg/day (corresponding to daily consumption of a beverage with 10 ppb urethane by a 70-kg man) the upper risk limits were estimated to be 3.2 in 100,000 for rats, and 470 in 100,000 for mice (modified Mantel-Bryan procedure). Problems in calculating a possible cancer risk for man on the basis of animal observations are discussed. Since treatment of beverages with diethyldicarbonate leads to the formation of urethane, and since a cancer risk to man from urethane cannot be excluded, replacement of diethyldicarbonate by a toxicologically unobjectionable compound is called for.     

Environmental nickel pathways to man

From representative values of nickel concentrations in the background environment, a pathways analysis and exposure assessment for man is performed. Estimated daily intakes of nickel are of the order of 170 micrograms via ingestion and 0.4 microgram via inhalation. The ingestion pathway is thus quite predominant in normal circumstances. From the estimated body burden of nickel of 500 micrograms, the effective mean retention time of nickel in the body is inferred to be 200 days. The exposure evaluation is performed for total nickel in the environment and in man. Assessments for specific nickel compounds can be made as data become available.     

Non-asbestos-related malignant mesothelioma. A review

Malignant mesothelioma is an uncommon, but increasingly important, neoplasm. The existing English-language medical literature concerning non-asbestos-related malignant mesotheliomas was reviewed for evidence of other agents associated with the induction of malignant mesothelioma. Both animal and human data were reviewed. In most reviews of malignant mesothelioma, there are a significant proportion of cases without documented asbestos exposure (range, 0% to 87%). Furthermore, there are several fairly well-documented agents other than asbestos that induce malignant mesothelioma in animals, and strong evidence exists that such is the case in man. In reviews of malignant mesothelioma, the percentage of cases with asbestos exposure varies, but a significant number are apparently not asbestos related. It is believed that sufficient evidence exists to suggest that non-asbestos agents can induce malignant mesotheliomas in man, and additional epidemiologic studies in this area are needed.     

Giant polypoid basal cell carcinoma

A giant polypoid basal cell carcinoma occurring in the back of a 64-year-old man is reported. Three other such cases from the English literature are reviewed.     

Phase I trials--clinical studies of antineoplastic agents]

The establishment of the starting dose and the dose escalation are the principal issues of the Phase I trials of anticancer agents. We report the procedures and results of the Phase I studies we participated in Japan in the 1980's concerning 17 intravenous anticancer agents. The drugs indicated a correlation between the mouse LD10 and the man MTD (maximum tolerated dose) in mg/m2. Median mouse LD10 (135 mg/m2) approximated to median man MTD (137 mg/m2) in mg/m2. One fifth of the mouse LD10 was lower than the man MTD. Therefore, as recognized at the 23rd Annual Congress, Japan Society for Cancer Therapy, the lower one of either 1/5 the mouse LD10 or 1/3 the dog TDL (toxic dose low) in mg/m2 has to be determined as safe starting dose. The modified Fibonacci search scheme has been generally adopted for the dose escalation. 14 applicable drugs were examined including 7 drugs in the early 1980's and 7 drugs in the late 1980's. The real number of steps that reached the man MTD was compared to the number of the steps taken in the dose escalation by the Fibonacci's method. The real steps were more than the Fibonacci's ones in the late 1980's. It showed the tendency of a more careful and safer dose escalation, however, to put it critically, the dose escalation was not efficient enough. It is expected that the contradictory problem between safety and efficacy in the Phase I studies will be solved by developing methods like pharmacokinetic study in animals and man.     

Malignant Mediastinal Tumor with Bone Formation - Mesothelioma or Sarcoma?

Mesothelioma can occur in different variants, some of which are difficult or impossible to differentiate from sarcomas. There are scattered reports of sarcomatous mesotheliomas that have osteogenic properties. Here, we report a 57-year old man who presented with a mediastinal tumor containing scattered irregular calcifications with some scattered pleural thickening of the right pleura. Biopsy showed a sarcoma with bone formation. The man was born in the Turkish village of Karain, where the incidence of mesothelioma is extremely high, and a sarcomatous mesothelioma was therefore diagnosed. Since the tumor was pressing against the large vessels and heart, a debulking was performed, followed by Pemetrexed and Carboplatin treatment. However, the tumor grew rapidly and spread to the pleura, involved the heart, and the patient succumbed. This is to our knowledge the first report of a sarcomatous mesothelioma with bone formation from environmental exposure to mineral fibers.     

La tache aveugle de la transparence

The informed patient has become a kind of “informational” man who has been given a totally transparent “cognitive card” about his illness and the various treatment options possible, thereby enabling him to decide what to do independently. But confusing revelation with information in this way is confusing cognitive man with tragic man. The concepts of consent and transparency turn out in fact to be ideological ways of denying the continual and increasing commodification of the body, sexuality and death, in a utilitarian political and economic context.     

Case report of a Burkitt-like lymphoma in a bisexual HIV-positive man

The clinical and pathologic features of a Burkitt-like lymphoma in a bisexual HIV-sero-positive man are reported. Emphasis is placed on some histologic characteristics present in a hyperplastic lymph node removed 2 years before the development of the B-cell lymphoma.     

The occurrence of soft tissue sarcomas in three siblings with Werner's syndrome

Werner's syndrome, a relatively rare and autosomal recessive disorder, is well known to be characterized by a high frequency of malignant neoplasm. The occurrence of familial neoplasm in patients with this condition, however, has been recorded only once before in the literature. Reported are the findings with regard to the occurrence of sarcomas in three siblings with Werner's syndrome. Two of the current three cases were of malignant fibrous histiocytomas, one in a 36-year-old man and one in a 32-year-old woman. The other case was of a leiomyosarcoma in a 26-year-old man. Two of the patients died of the tumors, although the third is still alive. The exact cause of the high incidence of malignant tumor in this family remains unknown, as is still so in other cases of Werner's syndrome.     

Anthracyclines - a review of general and special toxicity studies

Preclinical safety assessment data on doxorubicin (DOXO), epirubicin (EPI), idarubicin (IDA) and methoxymorpholinodoxorubicin (MORPHO), from mouse, rat and dog studies are reviewed. These data are put into perspective allowing for extrapolations across species, doses and dose regimens with recommendations for proper human use. The compounds were administered intravenously or intraperitoneally in studies ranging from single dose to multiple dose studies of different durations. The compounds were given once, daily, weekly or cyclically. In the cyclic administration studies, DOXO, EPI, and IDA were given for 3 consecutive days a week for 6 or 13 weeks; MORPHO was given for 3 consecutive days a week every three weeks for a total of 9 cycles. The duration of the cyclic studies was from 6-26 weeks. Daily dose studies lasted from 4-26 weeks. In the single dose studies the recovery ranged from 4 weeks to one year; in the multiple dose studies from 4 to 8 weeks. A few special studies were also considered. In all studies reviewed, 2 different types of toxicity were observed. These toxicities occur also in man. The first is the acute toxicity, which is the consequence of cytotoxicity and expresses the exaggerated pharmacological activity of the compounds. The target sites in all 3 species and in man include the hemolymphopoietic system (HLPS), the gastrointestinal (GI) tract, skin and testes; all renewing cell types. The second type of toxicity is the chronic progressive toxicity. This toxicity is the expression and result of sustained disruption of cytoplasmic homeostasis and occurs in non-renewing cell types. The target sites include the heart (both animals and man), kidneys (rodents) and peripheral nervous system (PNS) (rodents). From single administration animal data, chronicity, site and magnitude of toxicities can be predicted in man. Despite strong mitogenic stimuli in the rat, there is no evidence that there is a potential for hemolympho- or hepatocarcinogenicity with these compounds.     

Adenocarcinoma of the rete testis

Adenocarcinoma of the rete testis is very rare. It is highly malignant with potential of early metastasis. We are reporting such a case occurring in a 34-year-old man who remains tumor-free 7 years after orchiectomy. Another 20 reported cases of such a tumor from the English literature are reviewed.     

Thoracic chordoma mimicking a neurogenic tumour

A case of chordoma arising in the thoracic spine of a 20-year-old man is presented. Plain film and magnetic resonance imaging findings are included. The case is unusual in that the neoplasm presented as dumb-bell-shaped extradural mass, traversing and expanding a thoracic neural foramen and thereby mimicking a neurogenic tumour.     

Antibody targeted therapy in cancer: comparison of murine and clinical studies

Antibody targeted therapy can be effective in animal models of cancer. Treatment has been less successful in man, though some responses are reported. Understanding the distribution of antibody in man and animals shows how toxicity may be minimized and patients selected for therapy on the basis of efficient antibody localization in the tumour.     

Aminothiadiazoles

Summary 2-Amino-1,3,4-thiadiazole (ATDA) and some of its analogs have antitumor, uricogenic, and teratogenic activity. In general, these effects are reversed by nicotinamide. Although ATDA is not extensively metabolized in animals, a portion is apparently converted to an NAD⁺ or nucleotide analog that is a potent inhibitor of IMP dehydrogenase. Inhibition of this enzyme is probably related to the increased de novo synthesis of uric acid that has been observed in man and in chick embryos. The moderate activity of ATDA against experimental tumors has led to clinical trials in man.Work performed at Southern Research Institute and reported here was supported by Contracts NO1-CM-86152 and NO1-CM-43784, Division of Cancer Treatment, National Cancer Institute, NIH     

Glioblastoma multiforme of the cerebellum in an elderly man. A case report

Glioblastoma multiforme of the cerebellum is rare and comprises a small fraction of all glioblastomas. Eight-five cases have been reported in the literature to date. A 75 year old man is reported with a left cerebellar glioblastoma multiforme. The pathogenesis, course, treatment and prognosis are reviewed.     

Aetiology of oesophageal cancer: some operative factors.

Of the thousands of chemicals tested, the only compounds found to be potent carcinogens for the oesophagus are the N-nitrosamines. Many of these compounds are readily formed from common precursors in the environment (eg example in food during its storage or preparation) and also in vivo in the human stomach. Exposure is therefore likely to be ubiquitous. Although man may be exposed to other oesophageal carcinogens these have yet to be chemically identified, and at present nitrosamines are the sole contenders for the role of initiators of oesophageal cancer in man. Evidence suggests strongly that oesophageal cancer is initiated world-wide by nitrosamines, and promoted by secondary factors, the nature of which varies with the population concerned, notably alcohol in Europe and the USA, dietary deficiencies in China and Iran, mycotoxins in South Africa. When several risk factors coincide in one locality, the result can be a very high incidence of oesophageal cancer, with no one major cause.     

Endpoints for damage to normal tissues.

The response of normal tissues is vital in assessing any cancer treatment. Reasons are discussed why the response of normal structures in small animals is thought to be relevant to that in man. Endpoints for damage to a variety of normal tissues are considered and examples of dose response curves for many of these systems, taken from the published literature, are used as illustrations.