Biomedical subjects
Publications and source records attributed to J J Fischer.
The collagen inhibitor D-penicillamine was evaluated as a potential radiation reaction preventive agent by studying its effect on deaths attributed to pulmonary damage in mice. Long-term administration of D-penicillamine at a rate of 100 mg/kg/day had no significant effect on the LD50/160 in mice following pulmonary irradiation.
Modern computers are powerful tools for the study of tumor and normal tissue response to various radiation treatment regimens. Computers aid in the development of mathematical models which combine well known radiobiological principles in complex ways to predict treatment results. These predictions may be useful guides to the development of hypotheses for clinical testing. Computers make possible the application of sophisticated statistical techniques to the retrospective analysis of clinical data. For both the predictive models and the analytical methods the importance of the underlying assumptions rather than the computational techniques must be emphasized.
Actinomycin D and neoarsphenamine were tested for their ability to produce therapeutically favorable radiosensitization in the WAG/Rij rat. Acute and late skin reactions and control of the BA1112 rhabdomyosarcoma were examined in drug-treated and untreated animals irradiated in single- and five-fraction schedules. Actinomycin D was found to protect skin and tumors when added 15 minutes before irradiation. Actinomycin D added 2 hours before irradiation in a five-fraction trial produced slight tumor sensitization accompanied by slight skin protection. Neoarsphenamine produced significant tumor sensitization without skin sensitization in one of the single-fraction trials, but had no effect in the five-fraction trials.
A combination of the radiosensitizer, metronidazole, and the radioprotector, dimethyl sulfoxide (DMSO), was tested for its effects on the radiation tolerance of rat skin and on the radiosensitivity of the BA1112 rhabdomyosarcoma. The simplest interpretation of the effects of the combined treatment is that: metronidazole radiosensitizes BA1112 in one-fraction but not in five-fraction treatments; metronidazole slightly increases the radiosensitivity of skin in one-fraction treatments; metronidazole radiosensitization is independent of the radioprotection produced by DMSO.
The results of treatment with radiation therapy of 65 cases of epidermoid carcinoma of the palatine tonsil have been reviewed. The major determinant of prognosis is the stage of the primary lesion. Failure usually results from the inability to control local grossly detectable tumor. Thirteen of thirteen T1 lesions but only two of sixteen T3 lesions were locally cured with external beam radiation therapy. No difference in survival was noted between patients with no clinical adenopathy vs those with clinically involved movable ipsilateral adenopathy.
Mercaptoethylamine (MEA), dimethylsulfoxide (DMSO), and S-2-(3-aminopropylamino)ethylphosphorothioate (WR-2721) were tested for their protective effects against single and fractionated doses of 250 kv X-rays. Acute and late skin reactions and control of the BA-1112 rhabdomyosarcoma were examined in protected and unprotected WAG/Rij rats. All drugs protected skin in both single and fractionated treatment regimens, with MEA giving the most protection and DMSO the least. DMSO and WR-2721 protected tumors against single doses of radiation, and all three drugs tested protected tumors against fractionated irradiation. As a result, only single-fraction treatments of MEA-protected animals showed therapeutically favorable differential protection.
Forty-three cases of cancer of the nasopharynx treated at the Yale-New Haven Hospital in the last 15 years were analyzed. The clinical aspects of the disease, the technique of therapy and results of treatment are presented. The five-year cumulative survival in all the cases treated was 27%. Patients with lymphoepitheliomas seem to do better than those with squamous cell carcinoma. Even in patients with advanced disease, a cure is still possible after radical radiation treatment. Retreatment of recurrent disease is frequently successful in these tumors. The complications after curative radiotherapy even with the use of supervoltage are still relatively frequent. The incidence of distant metastases was 29%.
Acute skin reactions resulting from orthovoltage x-irradiation were measured in the WAG/Rij rat. A wide range of combination of fraction number and overall time were used in an attempt to determine their relative importance. There appeared to be little effect of prolongation of overall treatment time until periods of over 2 weeks were reached. In treatment periods of 3 weeks and over the stimulation of extensive time-dependent recovery was seen. A model based on cell kill with provision for the stimulation of accelerated proliferation at about 17 days adequately describes the experimental results.
A new treatment program for advanced Hodgkin's disease employing five-drug combination chemotherapy and low dose radiation to the sites of bulk disease (nodal or parenchymal) was designed in 1969. Eighty patients have now been treated, 60 of whom have achieved a complete remission. More significantly, only 5 of the 60 completed responders have relapsed with follow-up from 1-6 years. The cumulative survival at 5 years of patients entering complete remission is 92%. For those patients not sustaining a complete remission, it is 19% at 2 years. This program has resulted in substantially lower relapse rates than previously reported by other investigators, probably because of the administration of radiotherapy in the manner described. Hopefully, a significant number of these patients may be cured of their disease.
Reports of the existence of a large shoulder on the radiation survival curve of cultured mouse and human malignant melanoma cells prompted a clinical trial of radiation therapy using high individual-dose-fractionation schedules. Typically, individual doses of larger than or equal to 600 rads were delivered once or twice weekly. The most clear-cut effect was against skin metastases. Twenty-nine of 33 lesions showed partial or complete regression when treated in this manner. None of 11 lesions responded that were treated with individual treatment doses of 200 to 500 rads, although in some cases the total doses were greater than 5000 rads. Some of the possible roles for an effective radiation regimen in the overall management of this complex disease are discussed.
The irradiation of locally advanced, inoperable, squamous cell caricinomas of the head and neck with conventional fractionation schedules using 200 rads/day has produced poor results. A prospectively randomized, clinical trial has been started comparing conventional with large daily fractions of 400 rads/day for 10-12 treatments. Results suggest that improved tumor control and survival rates might be obtained with the use of large daily fractions.
Beta-aminopropionitrile (BAPN), an inhibitor of collagen maturation, was tested as a radiation reaction preventive agent (RRPA) using radiation-induced lung fibrosis in rats and mice as a model. Following pulmonary irradiation, treatment with BAPN significantly prevented an increase in collagen content as measured by hydroxyproline analysis. This effect persisted during BAPN maintenance for periods of up to 10 weeks but was lost when the drug was discontinued. BAPN administration did not increase the mouse lung LD50/160 in the drug doses employed in this study. Other possible RRPAs deserving further study include D-penicillamine and beclomethasone dipropionate.
Two brothers with breast cancer are presented. One died 8 years after diagnosis and the other is presently living at 1 year with metastatic disease. The courses of 28 other previously unreported male patients with carcinoma of the breast are reviewed, and the possibility of male breast carcinoma being metastatic disease from the prostate is discussed. Useful etiologic information might be obtained from following the offspring of male breast cancer patients to see if they are at increased risk of developing the disease.
The effects of fractionated irradiation on the feet of rats were the subjects of a time-dose study. The doses required to produce various levels of early skin damage, late skin damage, and late structural damage were determined for single doses and for treatments employing three fractions per week and lasting up to 50 days. The data did not follow the relationship first proposed by strandqvist, in which dose is proportional to time-n; rather, when the normal-tissue reactions were plotted on a linear-coordinate graph, they formed parallel time-dose isoeffect curves with distinct positive curvatures.
Ninety-six patients with advanced squamous cell carcinoma of the head and neck were randomized to treatment with intravenous methotrexate followed by radical irradiation or radiotherapy alone. No significant differences were demonstrated in local disease control or actuarial survival rates at three and five years. Some patients with local treatment failure were surgically salvaged.
The random nature of cell killing by ionizing radiations sets an upper limit on the steepness of the dose-response (D-R) curve for tumor cure. This theoretical limit was approached but not reached in a carefully controlled experimental system. It would seem unlikely that this result could be achieved in clinical practice because of the potential importance of tumor heterogeneity and treatment error in decreasing the slope of the D-R curve. In attempting to achieve a high degree of precision in treatment administration, the therapist, particularly in a multitreatment course, is aided by certain statistical rules which are applicable to random errors.
Explore the source record for details and available documents.
Of 13 anterior commissure cancers treated by radiation therapy and reported in 1970, eight had residual or recurrent cancer at the primary site and required total laryngectomy. All but one of the 13 had been treated prior to 1958 by Orthovoltage radiation. A total of 19 patients with anterior commissure lesions were treated at the Yale-New Haven Hospital using a 2MEV Van de Graaf generator between mid 1958 when this supervoltage source first became available and December 1971. None was lost to follow-up and thus all are available for evaluation after more than two years. Results in this group have been compared with 20 glottic carcinomas with involvement of the anterior commissure treated surgically during the same period of time. Thirteen of the resulting 20 surgical specimens have been studied by serial section.