James A. Belli

Clinical and Immunologic Effects of Fractionated Total Lymphoid Irradiation in Refractory Rheumatoid Arthritis

Ten patients with refractory rheumatoid arthritis were given 3000 rad of fractionated total lymphoid irradiation in an uncontrolled therapeutic trial. Total lymphoid irradiation was associated with objective evidence of considerable clinical improvement in eight patients and with reduced blood lymphocyte counts in all 10. On completion of irradiation, there was an abrogation of lymphocyte reactivity in vitro in the patients with clinical responses, but abnormal antibody activities characteristic of rheumatoid arthritis and normal components of humoral immunity were not suppressed. Partial recrudescence of arthritis occurred shortly after a year after the completion of irradiation and was paralleled by a restitution of lymphocyte concentrations and responsiveness to mitogens to levels similar to those observed before irradiation. These data provide further evidence of T-cell involvement in the pathogenesis of rheumatoid arthritis and demonstrate that total lymphoid irradiation can induce temporary relief, but they do not ascertain whether the natural history of this disease was altered.

An evaluation of long-term survival and treatment complications in children with Hodgkin's disease

Between April 1969 and July 1977, 83 patients, 16 years or younger, with pathologically staged IAIIIB Hodgkins disease were seen and treated at the Joint Center for Radiation Therapy. The five‐year actuarial relapse‐free and overall survivals were 82 and 95%, respectively, with a median follow‐up from diagnosis of 65 months. Relapse occurred in 6/50 Stage IA–IIA, 2/9 Stage IIB, 4/9 Stage IIIA, and 3/15 Stage IIIB patients. Of patients who relapsed, 11/15 are currently disease‐free following retreatment with chemotherapy. Nine patients with Stage IV disease were also evaluated. Four of seven patients initially treated with chemotherapy remain free of disease. Forty‐two patients in this study were treated with mantle and para‐aortic irradiation alone, thus avoiding the risk of sterility associated with pelvic irradiation or MOPP chemotherapy while retaining a high probability for long‐term diseasefree survival. Complications of radiation therapy included growth retardation and thyroid function abnormalities in some patients. Standing height measurements were normal regardless of age at initial treatment, however, 16 of 23 patients 3–12 years old at initial treatment had sitting heights measuring more than one standard deviation below the mean. Intraclavicular distances were shortened in some patients and examples are shown. Thyroid stimulating hormone levels were elevated in 21 of 37 patients evaluated. Radiation therapy, without adjuvant chemotherapy remains an important treatment approach for children with early stage Hodgkins disease.

Radiation therapy of tumors of the brainstem and midbrain in children: Experience of the joint center for radiation therapy and children's hospital medical center (1971–1981)

Between 1971 and 1981, 79 previously untreated children with proven or presumed gliomas of the brainstem or midbrain were seen and treated at the Joint Center for Radiation Therapy and Childrens Hospital Medical Center in Boston. Twenty-seven patients had tumors of the thalamus and midbrain (Group I) and 52 had lesions of the pons or medulla (Group II). Overall 5- and 10-year survivals were 50% and 41% respectively. Eighty percent of deaths occurred within 2 years of treatment. Eighty-six percent of the children (69/79) had clinical improvement or stabilization of disease after treatment. Group I patients had a 5-year survival of 73% which was significantly greater than that of Group II patients (38%) (p = 0.007). Children who presented with hypothalamic tumors in association with a diencephalic syndrome or other growth abnormality appeared to have had a better prognosis with 6/6 (100%) surviving without evidence of disease. Age at presentation was not correlated with prognosis. Of 10 children less than 3 years of age at presentation and treatment, 6 are alive (60%) at 2, 3, 7, 9, 10, and 12 years after treatment. The functional results in this group have been good--all six are leading apparently normal lives in regular schools with minor or no apparent neurologic deficits. Although these children will require long term follow-up to determine whether cures have actually been achieved, it appears that the majority achieve some benefit, that a significant proportion enjoy long term survival, and that very young children may be treated successfully with minimal radiation-induced neurologic sequela.

The effect of dose rate and adriamycin on the tolerance of thoracic radiation in mice

Radiation damage to the lung may be a predisposing factor in the development of interstitial pneumonitis in patients undergoing total body radiation and subsequent bone marrow transplantation in the treatment of leukemia. Adriamycin has been used in conjunction with bone marrow transplantation, and has also been shown to interact with radiation. This experiment was designed to study the effects of pre-administration of adriamycin on the radiation tolerance of the lung and esophagus. Since total body radiation is usually administered at low dose rates in order to spare the gastrointestinal tract preferentially as compared to the bone marrow, we investigated whether such a dose rate effect was present for the lung and if so, whether this pulmonary and esophageal dose rate effect would be ameliorated by pre-treatment with adriamycin. Mice were irradiated at 5 rad; 15 rad or 70 rad per minute to the upper body, 24 hours or 7 days after adriamycin. Oral esophageal death occurred within one month; thus deaths within 30 days were ascribed to this mechanism. In comparison, deaths because of pulmonary toxicity occurred later. Those between 30 and 160 days were ascribed to this mechanism. In the absence of adriamycin, a dose rate effect was found for the lung and confirmed for the upper gastrointestinal tract. The dose of radiation necessary to give pulmonary and gastrointestinal toxicity was markedly reduced when adriamycin was administered 24 hours before radiation. If seven days were allowed between adriamycin and radiation there was still an effect seen only at the high dose rate for the esophagus while for the lung at the high dose rate and for both systems at low dose rate no significant drug effects were noted. The dose rate effect is still seen after the drug, but it is reduced. These studies indicate that adriamycin given shortly before can significantly increase the oral esophageal and pulmonary toxicity of radiation and can practically abrogate the sparing effect of dose rate. This must be considered when clinically using total body radiation and adriamycin in preparation for bone marrow transplantation.

Hyperthermia and radiation response of plateau phase cells. Potentiation and radiation damage repair.

Hyperthermia (41/sup 0/C for 1 hr) before or after irradiation of plateau phase V79 Chinese hamster cells potentiated radiation effect. This effect was characterized primarily by a decreased width of the survival curve. However, the repair of potentially lethal or sublethal damage was not suppressed by preirradiation hyperthermia. It is suggested that hyperthermic potentiation of radiation effect in plateau phase cells may not depend upon inhibition of damage repair.

Interaction between Radiation and Drug Damage in Mammalian Cells: I. Delayed Expression of Actinomycin D/X-Ray Effects in Exponential and Plateau Phase Cells

The survival characteristics of V79 Chinese hamster cells exposed to either X-radiation or actinomycin-D and subsequently treated with the other modality were studied. Exponentially growing cells were exposed to either 820 R, 50 kVp X rays or 3.0 μg/ml AMD for 30 min and the survivors were exposed to graded doses of the other agent 2, 3, and 7 days afterward. The previously irradiated cells did not differ in their response to subsequent AMD, whereas the cells which had survived AMD demonstrated a decrease in extrapolation number and

Adriamycin resistance and radiation response

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Interaction between radiation and drug damage in mammalian cells. II. The effect of actinomycin‐D on the repair of sublethal radiation damage in plateau phase cells

when exposed to X rays as compared to cells not previously treated with AMD. The X-ray two-dose response was studied in cells exposed to 3.0 μg/ml 3 days before. The AMD treated cells had a lower maximum recovery ratio than controls and subsequent survival with time between doses was lower than in controls. Similar experiments were done with stationary (plateau phase) V79 cells. The response of stationary cells to AMD after either similar d...

Interaction between Radiation and Drug Damage in Mammalian Cells IV. Radiation Response of Adriamycin-Resistant V79 Cells

Abstract Mammalian cells (V79) in culture developed resistance to Adriamycin during continuous exposure to low levels of drug. This resistance was accompanied by change in X-ray survival properties which, in turn depended upon the isolation of subpopulations from resistant sub lines. These changes in X-ray survival properties were characterized by reduced D Q values and a decrease in the D 0 . However, these changes were not observed together in the same cell sub line. Adriamycin-resistant cells did not appear to be radiation damage repair deficient. Other phenotypic changes (cell morphology, DNA content and chromosome number) suggested mutational events coincident with the development of Adriamycin resistance.

Adriamycin uptake in V79 and adriamycin resistant CHINESE hamster cells

The effect of actinomycin‐D (AMD) on radiation damage repair was studied in plateau phase V79 Chinese hamster cells. Sublethal radiation damage repair, as demonstrated by survival fluctuations following two x‐ray exposures separated by time, was observed in our plateau phase cells. Plateau phase cells exposed to 0.01–0.04 μg/ml AMD (a nontoxic regimen to 8 hours) between x‐ray exposures were less able to repair sublethal damage. If plateau phase cells were plated at low dilutions into fresh medium (conditions for resuming exponential growth) immediately after the first x‐ray dose, and exposed to 0.01–0.04 μg/ml AMD until the second dose, inhibition of sublethal damage repair and additional cell killing were observed particularly at 0.04 μg/ml AMD. It is suggested that radiation‐drug damage interactions should be studied in plateau phase cells and in cells resuming exponential growth after plateau phase (possibly analogous to “recruitment”), as well as in exponential phase cultures.