Long-term radiation-related health effects in a unique human population: lessons learned from the atomic bomb survivors of Hiroshima and Nagasaki.

For 63 years scientists in the Atomic Bomb Casualty Commission and its successor, the Radiation Effects Research Foundation, have been assessing the long-term health effects in the survivors of the atomic bombings of Hiroshima and Nagasaki and in their children. The identification and follow-up of a large population (approximately a total of 200,000, of whom more than 40% are alive today) that includes a broad range of ages and radiation exposure doses, and healthy representatives of both sexes; establishment of well-defined cohorts whose members have been studied longitudinally, including some with biennial health examinations and a high survivor-participation rate; and careful reconstructions of individual radiation doses have resulted in reliable excess relative risk estimates for radiation-related health effects, including cancer and noncancer effects in humans, for the benefit of the survivors and for all humankind. This article reviews those risk estimates and summarizes what has been learned from this historic and unique study.

T-cell immunosenescence and inflammatory response in atomic bomb survivors.

In this paper we summarize the long-term effects of A-bomb radiation on the T-cell system and discuss the possible involvement of attenuated T-cell immunity in the disease development observed in A-bomb survivors. Our previous observations on such effects include impaired mitogen-dependent proliferation and IL-2 production, decreases in naive T-cell populations, and increased proportions of anergic and functionally weak memory CD4 T-cell subsets. In addition, we recently found a radiation dose-dependent increase in the percentages of CD25(+)/CD127(-) regulatory T cells in the CD4 T-cell population of the survivors.

Biodegradable cisplatin polymer in limb-sparing surgery for canine osteosarcoma.

Background: The rate of local recurrence of osteosarcoma after limb-sparing surgery in dogs and humans has been reported up to 28%. The primary purpose of this study was to determine whether a biodegradable cisplatin-containing implant (OPLA-Pt), inserted into the limb-sparing surgery site at the time of surgery, would decrease the rate of local recurrence. Secondary aims included evaluation of systemic toxicity associated with the release of cisplatin from the implant and identification of prognostic factors associated with limb-sparing surgery for osteosarcoma in dogs.

The status of the seventh report in the series Biological Effects of Ionizing Radiations and a revised dosimetry for the Radiation Effects Research Foundation's A-bomb studies.

Results of a National Academies workshop and feasibility study led US Governmental agencies to request the Board on Radiation Effects Research of the National Research Council to commence a risk assessment study in 1998 as the seventh report in the series Biological Effects of Ionizing Radiations (BEIR VII). Originally targeted for completion in the autumn of 2001, the study Potential Health Effects of Exposure to Low Dose, Low-LET Ionizing Radiation was extended until the autumn of 2003 at the request of the sponsors. Two factors contributing to this decision are discussed: a revised dosimetry to update DS86 for the Radiation Effects Research Foundation's A-bomb-survivor studies and the potential for new information to become available from low-dose studies that are under way.

Effects of a controlled-release cisplatin delivery system used after resection of mammary carcinoma in mice.

Objective: To evaluate efficacy of a controlled-release cisplatin delivery system, used after marginal resection of mammary carcinoma (ie, resection of grossly evident tumor) in mice, to prevent tumor regrowth and metastasis.

Animals: 42 female C3H-HeJ mice.

Procedure: Mice were inoculated with mammary carcinoma cells.

Slow release cisplatin combined with radiation for the treatment of canine nasal tumors.

Thirteen dogs with malignant tumors of the nasal cavity were treated with a combination of slow release cisplatin and megavoltage radiation. Radiation was delivered on a Monday through Friday schedule using a 6 MV linear accelerator. The median total dose was 49.

Irradiation-enhanced binding of carboplatin to DNA.

Carboplatin (3.6 mM) and salmon sperm DNA (3 micrograms), either double-stranded (dsDNA) or denatured single-stranded) (ssDNA), were irradiated (100 Gy) under hypoxic or oxic conditions. The drug and DNA were mixed either before, during, or after irradiation, and platinum binding to DNA was measured using atomic absorption spectrometry.

Enhanced radiation-induced cell killing by carboplatin in cells of repair-proficient and repair-deficient cell lines.

The objective of this study was to determine whether a deficiency for either one of two repair processes influences the phenomenon of enhancement of radiation-induced cell killing by carboplatin which has been reported previously in one cell line (V79) and which is presumably a result of an interaction between these two therapeutic modalities. Cell killing was enhanced in cells of four cell lines when the cells were exposed to carboplatin before and during irradiation in either air or hypoxia. In cell lines proficient in both excision repair and DNA double-strand break repair (K1 and AA8), and in a cell line deficient in nucleotide excision repair (UV41), the enhancement was characterized as both a reduction in the shoulder region of the survival curves indicated by a reduced Dq and a reduction in D0 in the terminal region of the survival curves determined for cells exposed in air and under hypoxic conditions.

Irradiation enhances cellular uptake of carboplatin.

Purpose: Because radiation is known to damage cellular membranes, the purpose of this study was to determine whether irradiation of cultured cells might modify the cellular uptake of the chemotherapy agent carboplatin.

Methods And Materials: Total intracellular platinum was measured using atomic absorption spectrometry in cultured V79 cells and in four Chinese hamster ovary (CHO) cell lines.

Results: Intracellular carboplatin concentrations increased linearly with radiation dose (10-50 Gy) under both hypoxic and oxic irradiation conditions.

Production of DNA double-strand breaks by interactions between carboplatin and radiation: a potential mechanism for radiopotentiation.

The production of DNA double-strand breaks (DSBs) was studied in cells of four CHO cell lines under conditions where combining radiation with carboplatin enhanced cell killing (radiosensitization and radiopotentiation). The cell lines included repair-proficient (AA8 and K1), excision repair-deficient (UV41) and DSB repair-deficient (xrs-5) cells. Double-strand breaks were analyzed by neutral elution either immediately after or 4 h after a single 55-Gy radiation dose delivered under hypoxic conditions.

Carboplatin enhances the production and persistence of radiation-induced DNA single-strand breaks.

Fluorometric analysis of DNA unwinding and alkaline elution were used to investigate the production and persistence of DNA single-strand breaks (SSBs) in Chinese hamster V79 and xrs-5 cells treated with the chemotherapeutic agent carboplatin in combination with radiation. Carboplatin was administered to cells before irradiation in hypoxic conditions, or the drug was added immediately after irradiation during the postirradiation recovery period in air. The results of DNA unwinding studies suggest that carboplatin enhances the production of radiation-induced SSBs in hypoxic V79 cells and xrs-5 cells by a factor of 1.

Effects of cis-diamminedichloroplatinum II released from D,L-polylactic acid implanted adjacent to cortical allografts in dogs.

This study was performed to determine the pharmacokinetics and local and systemic effects of cis-diamminedichloroplatinum II (cisplatin) released from an open-cell polylactic acid polymer when the drug delivery device was placed adjacent to a cortical allograft. Bilateral intercalary femoral allografts were implanted in six normal beagles. The polymer containing cisplatin was implanted adjacent to the allograft in one femur, and the polymer without cisplatin was implanted adjacent to the allograft in the contralateral femur.

Theoretical and experimental analysis of air cooling for intracavitary microwave hyperthermia applicators.

An intracavitary microwave antenna array system has been developed and tested for the hyperthermia treatment of prostate cancer at Thayer School of Engineering and Dartmouth-Hitchcock Medical Center. The antenna array consists of a choked dipole antenna inserted into the urethra and a choked dipole antenna eccentrically embedded in a Teflon obturator inserted into the rectum. To prevent unnecessary heating of the healthy tissue that surrounds each applicator, an air cooling system has been incorporated into the rectal applicator.

Effect of phase modulation on the temperature distribution of a microwave hyperthermia antenna array in vivo.

Perfused, canine skeletal muscle and the brain tumour of a cancer patient were heated with an array of four parallel, interstitial antennas placed on the corners of a 2-cm square and driven at 915 MHz. The temperature distributions along the axial and diagonal catheters were measured with equal-phase driving of the antennas and with several time-varying schemes of driving phase differences among the antennas. When equal-phase driving was replaced by a rotating scheme of 90 degrees driving phase differences, the tissue area in the junction plane heated above a normalized index temperature of 0.

A coaxial microwave applicator for transurethral hyperthermia of the prostate.

Benign prostatic hyperplasia (BPH) is a common disease of elderly men. The current definitive treatment for urinary obstruction caused by this disease is surgery (transurethral resection of the prostate, or TURP). Recent evidence suggests that hyperthermia may be a useful nonsurgical alternative for treatment of symptomatic BPH.

Potentiation of hyperthermia in a murine tumour by metabolic inhibitors rhodamine 123 and 2-deoxy-D-glucose or 5-thio-D-glucose.

Rhodamine 123 injected into mice on 3 days consecutively before a single hyperthermia treatment (45 degrees C for 15 min) potentiated hyperthermia as evidenced by an increased mean tumour growth delay of a transplantable murine mammary adenocarcinoma (MTG-B). Addition of three daily injections of either 2-deoxy-D-glucose, or 5-thio-D-glucose, coordinated with the rhodamine 123, and administered before hyperthermia, resulted in an additional tumour growth delay, but not large enough to suggest an additional significant interaction between the two drugs and heat. This effect was obtained using doses of the glucose analogues which did not potentiate therapeutically when combined with heat without rhodamine 123.

Techniques for intraoperative hyperthermia with ultrasound: the Dartmouth experience with 19 patients.

Over the course of 3 years, tumours of 19 patients were heated with ultrasound in the operating room during surgical resection. Immediately following intraoperative radiation therapy, thermocouples were inserted into tumour and adjacent normal structures. Patients were then given a 60-min heat treatment with ultrasound after a 10-15-min heatup period.

Combined modality treatment with ternary Cu(II) complexes and X rays.

Ternary Cu(II) complexes with bidentate malonato- and heterocyclic amine ligands were tested with regard to cytotoxicity and potentiation of x-ray induced cell killing in V79 cells. Two lead complexes were also tested in a tumor assay using the MTG-B murine adenocarcinoma model growing in the flanks of female C3H/HeJ mice. One complex, [2,2'-bipyridyl malonatoCu(II)] (RL-5077), produced sensitizer enhancement ratios (SER's) of 1.

Experimental brain hyperthermia: techniques for heat delivery and thermometry.

An experimental canine brain model was developed to assess the effects of hyperthermia for a range of time and temperature endpoints, delivered within a specified distance of an interstitial microwave antenna in normal brain. The target temperature location was defined radially at 5.0 or 7.

The effect of air cooling on the radial temperature distribution of a single microwave hyperthermia antenna in vivo.

Canine skeletal muscle was heated with a single microwave antenna within a brachytherapy catheter driven at 2000 MHz. The radial, steady-state temperature distribution was measured with and without air cooling of the antenna, as produced by room temperature air flowing in the catheter at 7.5 l/min.

Effect of step-down heating on brachytherapy in a murine tumor system.

The effects of step-down heating combined with low-dose-rate irradiation (brachytherapy) were studied using a murine mammary adenocarcinoma (MTG-B) grown in the flanks of C3H mice. Treatment was initiated when tumors reached 0.9 to 1.

The effect of in vivo GSH depletion on thermosensitivity, radiosensitivity and thermal radiosensitization.

The effect of glutathione (GSH) depletion on the interaction of hyperthermia (HT) and single-dose external-beam radiation delivered at conventional dose rates (RT) and low-dose-rate brachytherapy (BT) was examined in a murine mammary adenocarcinoma (MTG-B). Tumour volume growth delay from the day of treatment to double the treatment volume (GDDV) was used as the experimental end-point. The growth delay for radiation alone was greater when combined with GSH depletion, while this level of GSH depletion produced no effect on the BT alone or HT alone response.

Intraoperative radiation therapy and hyperthermia. Morbidity and mortality from this combined treatment modality for unresectable intra-abdominal carcinomas.

This is a report of a phase I trial of intraoperative radiation therapy in combination with intraoperative hyperthermia for the treatment of locally advanced, unresectable intra-abdominal carcinomas. Using an ultrasound transducer system specifically designed for intraoperative applications, 19 patients have been successfully treated, demonstrating the feasibility of this combination modality. The morbidity (58%) and mortality (11%) rates reported in this series are comparable to rates reported in series of similar patients receiving intraoperative radiation therapy alone.

Thermal enhancement of low dose rate irradiation in a murine tumour system.

The effects of localized hyperthermia (HT) in combination with low dose rate irradiation (brachytherapy) have been investigated in vivo using a murine mammary adenocarcinoma. Flank tumours were grown to 0.45-0.

The independent action of radiation and cisplatin on the survival or recovery of human normal or tumour cells in vitro or in vivo.

Recovery from radiation- or cisplatin-induced lethal damage has been studied in euoxic normal human foetal lung fibroblasts (HFL cells) that remain viable for at least 20 days in plateau-phase culture. After a 1 hour treatment with cisplatin the half-time of recovery was about 2 days. By contrast recovery after radiation was more rapid with half-times of approximately 10 h.