JosephF. Fraumeni

RISK OF CANCER IN RENAL-TRANSPLANT RECIPIENTS

Abstract Among 6297 individuals reported to a kidney-transplant registry, the risk of developing lymphoma was about 35 times higher than normal and was derived almost entirely from a risk of reticulum-cell sarcoma, which was 350 times greater than expected. The excess lymphoma risk appeared within a year of transplantation, and remained at the same high level for the five or more years of follow-up. Skin and lip cancers occurred up to 4 times more often than expected. Other cancers were 2·5 times more common, in men only, due largely to soft-tissue sarcoma and hepatobiliary carcinoma. This excess risk of other cancers appeared later than that for the lymphomas and became more pronounced as the interval since transplantation increased.

INTRA-ABDOMINAL CARCINOMATOSIS AFTER PROPHYLACTIC OOPHORECTOMY IN OVARIAN-CANCER-PRONE FAMILIES

Prophylactic oophorectomy was performed in 28 female members of 16 families at high risk of ovarian carcinoma. 3 of these women subsequently developed disseminated intra-abdominal malignancy; there was uncertainty about the primary site despite extensive investigation. These tumours were indistinguishable histopathologically from ovarian carcinoma. It would seem that in cancer-prone families the susceptible tissue is not limited to the ovary, but includes other derivatives of the coelomic epithelium, from which primary peritoneal neoplasms may arise.

SPLENECTOMY AND SUBSEQUENT MORTALITY IN VETERANS OF THE 1939-45 WAR

A long-term follow-up of 740 American servicemen splenectomised because of trauma during the 1939-45 war showed a significant excess mortality from pneumonia and ischaemic heart-disease. Mortality from cirrhosis was also increased, but not significantly. The findings confirm that the risk of fatal infections is increased by asplenia; however, the risk of cancer was not increased, as it is in some other immunodeficiency states. Post-splenectomy thrombocytosis and hypercoagulability may account for the increased risk of fatal myocardial ischaemia in this group.

AMYL NITRITE MAY ALTER T LYMPHOCYTES IN HOMOSEXUAL MEN

To evaluate the recent outbreak of Kaposis sarcoma (KS) and opportunistic infections in homosexual men, clinical, virological, and immunological data on two homosexual men with KS and on fifteen healthy homosexual volunteers were collected. Both KS patients had regularly used amyl or butyl nitrite (AN); they had low helper/suppressor (H/S) T-lymphocyte ratios before chemotherapy and high titres of antibody against cytomegalovirus (CMV). Eight of the fifteen volunteers were regular AN users; seven of the eight had low H/S ratios due to larger than normal numbers of OKT8-positive suppressor cells and smaller numbers of OKT4-positive helper cells. In all eight AN users the fluorescence profile obtained with monoclonal antibody 9.6 (which detects the sheep E-rosette receptor) was bimodal, indicating a subpopulation of T cells with increased receptor density. A similar pattern was observed when OKT8, the antibody which detects cytotoxic suppressor cells, was used. Two of the seven men who did not use AN had abnormal fluorescence with reagent 9.6, and one of these also had a low H/S ratio. CMV-antibody titres were persistently high in fourteen of the fifteen healthy men, but the titres were not related to AN use of T-cell abnormalities. The data suggest that nitrites may be immunosuppressive in the setting of repeated viral antigenic stimulation and may contribute to the high frequency of DS and opportunistic infections in homosexual men.

Arsenical air pollution and lung cancer.

Average mortality-rates from lung cancer for White males and females in the U.S.A. 1950-69 WERE SIGNIFICANTLY INCREASED IN COUNTIES WITH COPPER, LEAD, OR ZINC SMELTING AND REFINING INDUSTRIES, BUT NOT IN COUNTIES WHERE OTHER NON-FERROUS ORES ARE PROCESSED. The excess mortality was not attributed to differences in geographic region, population density, urbanisation, socioeconomic status, or other manufacturing processes. The findings suggest the influence of community air pollution from industrial emissions containing inorganic arsenic.

CANCER OF THE UTERINE CORPUS AFTER HORMONAL TREATMENT FOR BREAST CANCER

Among 45853 women in whom breast cancer was diagnosed after age forty-nine, from the series of the End Results Program of the National Cancer Institute, cancer of the uterine corpus subsequently developed in 203. The risk was greater among those women receiving hormones than in other treatment groups, and tended to rise with increasing interval from first treatment. One method of estimating an expected value indicated that the excess risk of corpus cancer in breast-cancer patients was restricted to those treated with hormones. Given the time period under study, it may be assumed that the hormones were primarily non-steroidal oestrogens.

TRANSMISSION OF IN-VITRO RADIORESISTANCE IN A CANCER-PRONE FAMILY

Neoplasms of possible radiogenic origin developed in two members of a family prone to a diversity of cancers, including bone and soft-tissue sarcoma, brain and breast cancers, and leukaemia. Gamma-irradiation survival studies in these two patients and three other relatives, but not their spouses, over three generations demonstrated resistance to cell killing. The D10 value (radiation dose required to reduce survival to 10%) was significantly higher for the five radioresistant strains (491 +/- 30 rad) than for control cultures (405 +/- 18 rad). There was a significant correlation between individual D10 values and D0 survival-curve parameters, indicating that changes in the exponential slope of the survival curves accounted for much of the increase in D10 values. This novel radiation phenotype could be a manifestation of a basic cellular defect, predisposing to a variety of tumours in family members. Thus in-vitro radioresistance, like radiosensitivity, may be a phenotype of a mechanism that increases cancer risk in man.

FAMILIAL MALE BREAST CANCER

Infiltrating ductal carcinoma of the breast occurred in a total of six men from two families. In one family specimens from three men who had prophylactic mastectomies revealed focal intraductal hyperplasia, suggesting a familial tendency toward proliferation of mammary-duct epithelium. In the other family, benign and malignant breast lesions also developed in several women. Preliminary data suggest elevated urinary oestrogen excretion in three men from these families, implicating a defect in oestrogen production or metabolism in the pathogenesis of male breast neoplasms.

CHLORAMPHENICOL USE AND CHILDHOOD LEUKAEMIA IN SHANGHAI

A population-based case-control interview study of 309 childhood leukaemia cases and 618 age and sex matched controls showed a significant dose-response relation between chloramphenicol and risk of both acute lymphocytic leukaemia (ALL) and acute non-lymphocytic leukaemia (ANLL), treatment for more than 10 days being associated with risks of 11.0 and 12.0, respectively. A significant risk of ANLL was also observed with the use of syntomycin, a drug pharmacologically related to chloramphenicol. The risks remained high when analyses were limited to either first or latest use of these antibiotics more than 2 years before diagnosis. Although the association may have non-causal explanations, the results warrant cautious prescribing patterns and further investigations into the leukaemogenic potential of chloramphenicol.

Acute myelocytic leukaemia and leukaemia-associated antigens in sisters.

In a sibship of 5 brothers and 7 sisters, 3 sisters died from acute myelocytic leukaemia while a 4th probably had the same disease. Laboratory studies on the close relatives revealed that a 5th sister had persistently high erythrocyte sedimentation-rates and serum-IgM levels and serological evidence of acute leukaemia-associated antigens. These findings suggest a possible preleukaemic state in this patient.