Metastatic breast cancer 42 years after bilateral subcutaneous mastectomies.

Subcutaneous mastectomy has a possible role as prophylaxis in patients at high risk of developing breast cancer. A case history is presented of a woman who developed metastatic breast carcinoma 42 years after bilateral subcutaneous mastectomies for non-malignant disease. This case is presented to draw attention to the persistent risk of developing breast cancer even decades after subcutaneous mastectomy and to point out that the role of such surgery in preventing breast cancer has still not been clarified. The appropriateness of prophylactic mastectomy for an individual is better assessed on the absolute risk of breast cancer developing over a defined period rather than the relative risk.

New Zealand: one small country's history of radiation oncology.

New Zealand, with its short history, has a proud record in the development of radiation oncology. The first independent department of radiotherapy was formed in Dunedin in 1931, and the first clinical physicist was appointed in Wellington in 1933. Prominent research workers include the radiobiologist Dr. John Read and the physicist Sir Ernest Rutherford.

Is phenytoin contraindicated in patients receiving cranial irradiation?

Three recent publications have reported the development of erythema multiforme and Stevens-Johnson syndrome in patients receiving cranial irradiation and sodium phenytoin. Some authors have recommended that patients receiving whole brain radiation therapy and who have had seizures should not be prescribed phenytoin but an alternative anti-convulsant. This article reviews the current literature pertaining to the development of this potentially lethal complication in patients receiving whole brain radiation and phenytoin, with reference to the single recorded case of Stevens-Johnson syndrome in a patient receiving cranial irradiation and phenytoin in Auckland, New Zealand. While the clinical picture in the 16 patients reported in the literature and the current case report differed from the classical form of erythema multiforme, a similar pattern of presentation and outcome appeared in all patients reviewed, suggesting that the combination of phenytoin, cranial irradiation and the gradual reduction of concomitant steroids seem to lead to the development of erythema multiforme and/or Stevens-Johnson syndrome. The data presented, although sparse, suggest that phenytoin should not be prescribed in patients receiving cranial irradiation.

Radiation therapy for the management of localized prostate carcinoma.

Radiation therapy has been reported as an effective modality for the curative management of localized prostate carcinoma. In a 6 year period (1982-87), 141 patients with localized prostate carcinoma were treated at Auckland Hospital. Most patients were given radiation to the prostate alone. The overall local failure rate was 14%, with 57 patients developing distant metastases at the time of analysis. Toxicity was generally acceptable but was clearly related to the size of the treatment volume. The 5 year actuarial survival for all patients was 69.5%. Relapse-free survival rate was 39% at 5 years. Clinical stage and histological differentiation were significant factors affecting survival. Histology was a significant factor in local control. Radiation therapy for localized prostate carcinoma is effective, with a high rate of local control and low morbidity.

Half body irradiation for the palliation of bone metastases.

Half body irradiation using single large doses of photons has been reported as an effective modality for the palliation of symptoms due to widespread metastatic bone malignancy. Over a 7 year period (1982-1988) sixteen patients with disseminated malignancy were given half body irradiation at Auckland Hospital. Treatment consisted of a single dose of radiation of between 5 and 8 Gray. Either 6 or 8 MV photon beams were used. Twelve patients received treatment to the lower half body, three patients to the upper half body and one patient to both upper and lower half body. Significant pain relief occurred in fifteen patients and two patients experienced improvement with hypercalcaemia. All patients tolerated the treatment well and toxicity was minimal.

Reductive metabolism and hypoxia-selective toxicity of nitracrine.

The 1-nitroacridine nitracrine [NC,1-nitro-9-(dimethylaminopropyl-amino)acridine] is a potent hypoxia-selective cytotoxic agent in culture, but lacks activity against hypoxic tumor cells in vivo at therapeutically accessible doses. To clarify reasons for this failure in vivo the metabolism of NC was investigated in stirred suspension cultures of Chinese hamster ovary cells, in EMT-6 spheroids, and in mice. One major low molecular weight metabolite (identical to that generated by NaBH4/Pd/C reduction) was observed in hypoxic (less than 10 ppm O2) single cell suspensions, while [G-3H-acridinyl]NC formed trichloroacetic acid- and acetonitrile-insoluble macromolecular adducts (MA) at a rate seven-fold higher than in aerobic (20% O2) cultures. Formation of these adducts correlated with cytotoxicity under air or nitrogen, and hence may provide a dosimeter for NC-induced damage. Autoradiographic investigation of the distribution of MA in spheroids equilibrated with 5% O2 showed that the label was restricted to the outer cell layers rather than being localized in the hypoxic central region. Thus metabolic activation is probably too rapid, even in well-oxygenated cells, to allow adequate distribution to hypoxic microenvironments in tumors. In mice, levels of MA were higher in liver, kidney, spleen and lung than in Lewis lung tumors, indicating that oxygen concentration does not exert a dominant influence on relative rates of metabolic activation in vivo. The development of nitroacridines with useful hypoxic selectivity in vivo will require identification of analogs for which reductive metabolism is more completely inhibited at oxygen concentrations found in normal tissues.

Maternal transmission of hepatocellular carcinoma.

A family in which four members have died of hepatocellular carcinoma is presented. Hepatitis B surface antigen was present in both cases in which it was sought and also present in nine of ten surviving siblings in the second generation. Maternal transmission of hepatitis B surface antigen and susceptibility to hepatocellular carcinoma is postulated.

Selective toxicity of nitracrine to hypoxic mammalian cells.

Hypoxic cells in solid tumours are resistant to ionizing radiation and may be refractory to treatment by many chemotherapeutic agents. For these reasons the identification of drugs with selective toxicity towards hypoxic cells is an important objective in cancer chemotherapy. Nitroimidazoles such as misonidazole demonstrate such hypoxia-selective toxicity but have very low dose potency. The 1-nitroacridine derivative 1-nitro-9-(dimethylaminopropylamino)acridine (nitracrine) binds reversibly to DNA but also forms covalent adducts with DNA in vivo. We have found nitracrine to be selectively toxic to the Chinese hamster ovary cell line AA8 under hypoxic conditions in culture, with a potency approximately 100,000 times higher than that of misonidazole. The effect of oxygen is not a simple dose-modifying one in this system, probably in part because of rapid metabolic inactivation of nitracrine under hypoxic conditions. Viscometric studies with the mini col E1 plasmid PML-21 confirmed that nitracrine binds to DNA by intercalation, and provided an unwinding angle of 16 degrees (relative to 26 degrees for ethidium). It is proposed that the cytotoxicity of nitracrine under hypoxia is due to reductive metabolism to form an alkylating species, but that intercalation of the chromophore may enhance reactivity towards DNA and hence contribute to the marked enhancement of potency with respect to simple nitroheteroaromatic drugs.

Phase II study of m-AMSA in advances malignant melanoma.

A phase II study of methanesulfonamide, N-(4-(9 acridinylamino)-3-methoxyphenyl)-(m-AMSA) was undertaken by the Eastern Cooperative Oncology Group. Thirty-five evaluable patients were studied, 18 of whom had had no prior therapy and eight of whom had been treated only one cytotoxic drug. Thirty-one of these patients were ECOG performance status 2 or better. The dose of m-AMSA employed in this study was 40 mg/M2 as an I.V. infusion over 20 minutes daily for 3 days, repeated every 3 weeks. Leukopenia was found to be dose-limiting; thrombocytopenia and anemia were also observed. Other prominent toxicities included anorexia, nausea, and vomiting. No cardiovascular toxicity was observed in this study, but none of the patients had received prior anthracycline therapy. Only one partial response of measurable disease was observed, all other patients had progressive disease on m-AMSA therapy. No significant clinical activity of m-AMSA against malignant melanoma was demonstrated in this very favorable group of patients.

Early and late radiation changes following a second course of irradiation.

The effect of two 10-fraction courses of irradiation separated by intervals varying from 1 to 10 months on both the early skin reaction and late deformity of the leg was studied in mice. It was found that the "memory" of the first course was much greater for the late end point (deformity) than for early skin reactions at all intervals between the two courses. The extent of the late deformity reaction following a second course was predicted fairly well from the Ellis formula for decay of partial tolerance, but it also appeared to be more complex than is evident from the formula. Evaluation of early vs. late reactions showed that the extent of the deformity is not governed entirely by the level of the early skin reaction; rather, it depends critically on the previous radiation history of the tissue.

The effects of radiation therapy on bone growth.

Results of a study of the effects of external irradiation on growing bone conducted at Stanford University School of Medicine are presented together with a review of the literature. Standing and sitting heights of 29 children receiving more than 3,500 rads of megavoltage radiation to the spine and 15 children receiving less than 2,500 rads were compared with those of 15,000 normal children. Retardation of spinal growth was seen in children irradiated during the periods of most active bone growth, i.e., under 6 years of age and during puberty. Correlative radiographic findings similar to those seen with orthovoltage therapy were seen in the high-dose group but not in the low-dose group.