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L J Peters

Publications and source records attributed to L J Peters.

At least 199 records · Page 11Linked to original sources
PubMed1985

Effect of dose-rate on total body irradiation: lethality and pathologic findings.

The effect of low dose-rate total body irradation (TBI) on hemopoietic and nonhemopoietic lethality has been studied in BALB/c mice using dose-rates ranging from 25 to 1 cGy/min. Deaths were scored at 10 days, 30 days, and one year after irradiation, and dose-response curves were constructed to determine the dose-rate dependence of deaths from the gastrointestinal syndrome, hemopoietic syndrome, and late lethal syndrome(s), respectively. A plot of the LD50S for each of these lethal syndromes versus dose-rate showed the dose-rate dependence for late lethality to be somewhat greater than that for gut death, but both of these endpoints were markedly more dose-rate dependent than was hemopoietic lethality, particularly at dose rates less than 5 cGy/min. To determine which late responding normal tissues might be critical for low dose-rate TBI, complete necropsies were performed on all mice dying later than 60 days after irradiation and on all mice surviving at one year; all tissues were examined histologically. Morphologic evidence of radiation injury was present in only three tissues, lung (fibrosis and scarring) kidney (tubule depletion), and liver (presence of mitoses). Subjectively, the lung changes were most severe up to 9 months while kidney changes became more prominent after this time, suggesting that late death after low dose-rate TBI may not be entirely attributable to lung injury. However, regardless of which late responding normal tissue is dose-limiting, it is clear that low dose-rate TBI preferentially spares these tissues compared with hemopoietic stem cells.

Animals↗
PubMed1985

Predictors of tumor response to radiotherapy.

The present method for predicting the radiocurability of individual human tumors is based upon considerations of tumor size, site, histological type and grade, and host factors such as sex and age. Small tumors located such that normal tissues do not seriously limit total dose and those with "favorable" histology are more radiocurable than large tumors located over a critical normal tissue. However, the precision of prognosis based upon those features is relatively low. The need for other parameters for more accurate predictability is greater than ever because of the existence of different radiation modalities, including neutrons, and the development of a broad range of chemotherapeutic drugs that can be used alone or in combination with radiation and surgery. In this laboratory we are testing the micronucleus (MN) assay for measuring the relative biological effectiveness of high- and low-LET irradiations in mouse tumors and a new primary human tumor cell culture system for making direct measurements of tumor cell radiosensitivity. The potential usefulness of these two systems in predicting human tumor response to radiotherapy is discussed.

Animals↗
PubMed1985

Review of clinical results of fast neutron therapy in the USA.

Fast neutron radiotherapy in the United States is entering a new era in which dedicated hospital-based generators with isocentric beam capability are replacing treatment facilities based on fixed beams extracted from physics accelerators. All available clinical data, however, come from the older facilities. The majority of randomized trials conducted in the U.S. have used neutrons in a mixed schedule with photons, in which the aim was to deliver two-fifths of the total dose with neutrons; the neutron dose per fraction was set as the estimated equivalent of 2 Gy photons in terms of late normal tissue injury. Overall treatment time was held constant compared with the control photon therapy regimens (usually six to eight weeks). Random studies of this type showed no evidence of a therapeutic gain in the treatment of advanced primary carcinomas of the head and neck, lung, uterine cervix, or pancreas. A statistically significant benefit in favor of the mixed schedule is presently apparent for local control and survival in patients with advanced prostate cancer, and for clearance of neck nodes in patients with advanced squamous carcinoma of the head and neck. Based on encouraging results in a pilot study of mixed scheduled irradiation preoperatively for bladder cancer, a random study was begun in 1981, but too few cases have been accrued for analysis. Other randomized trials comparing protracted neutron only regimens with photon therapy have been conducted. These were negative for lung and pancreatic cancer, but a suggestion of a therapeutic gain (with small patient numbers) has been observed for treatment of inoperable salivary gland tumors and advanced squamous carcinomas of the head and neck. Two large randomized studies of various neutron doses delivered as a boost to high grade astrocytomas after or concurrently with photon irradiation have failed to define any therapeutic window between tumor destruction and brain necrosis. Based on a reassessment of all the available clinical and radiobiological data, and taking advantage of the greater technical flexibility offered by hospital-based facilities, the strategy of fast neutron therapy for future trials has been changed. In these trials neutrons are being used in a twelve fraction, four week regimen to treat gross disease, with elective therapy being given wherever possible using low LET irradiation. Concomitantly, research is proceeding to define predictors of tumor response to high LET radiations in order to better select patients for fast neutron radiotherapy.

Fast Neutrons↗
PubMed1985

Evaluation of cardiac output, total peripheral vascular resistance, and plasma concentrations of vasopressin in the conscious, unrestrained rat during endotoxemia.

To eliminate the influence of anesthesia while investigating the role of vasoactive hormones during shock, we have developed an unanesthetized rat model that provides information on key cardiovascular parameters pertinent to shock. Enfluane anesthesia was used while the animals were being catheterized. After recovery from anesthesia, endotoxin (40 mg/kg) was given, and after 4 hr of measurements, animals (11) were killed. Cardiac index (CI) fell significantly 5 min after endotoxin and remained depressed for 4 hr. Mean blood pressure (MBP) decreased from 121 +/- 5.7 mmHg to 79 +/- 5.6 at 5 and 15 min, and increased to 113 +/- 3.0 at 180 min. Central venous pressure (CVP) was decreased from 30 min to the end of the study. Heart rate (HR) increased from 357 +/- 13 to a high of 448 +/- 14 at 5 min and remained at well over 400 for the 4-hr monitoring period. Total peripheral vascular resistance (TPVR) was twice that of the control at 30 min and remained elevated. Stroke volume decreased to 37% of that of the control at 15 and 30 min and remained at 50% of that of the control until sacrifice. Plasma concentrations of vasopressin measured by radioimmunoassay increased from 14 pg/ml (+/- 2.2, SEM) to 144 (+/- 56) and 144 (+/- 66) at 15 and 240 min after endotoxin. Pathological examination at the end of the study revealed extensive hemorrhage in all areas of the small intestine. We conclude that in the conscious endotoxic rat decreases in CI, MBP, and CVP are accompanied by compensatory increases in HR and TPVR; plasma vasopressin concentrations are greatly elevated; and severe small intestinal hemorrhage occurs. The control animals (12) were stable throughout the entire study period, establishing the conscious, instrumented, unrestrained rat presented here as an attractive model for the study of shock without the bias of anesthesia.

Animals↗
PubMed1984

Modification by dexamethasone of radiation response of in vitro cultured cells.

Because of the potential clinical significance of the report that dexamethasone is a radioprotector of Chinese hamster V-79 cells, the effect of dexamethasone treatment on the radiosensitivity of five other cultured mammalian cell lines (including two human cell lines) was tested and preliminary investigations into the mechanism of protection of V-79 cells were undertaken. In agreement with the published results of others, we found that treatment of V-79 cells with dexamethasone results in a 1.3-fold increase in D0. Conversely, dexamethasone had no effect on the radiosensitivity of Chinese hamster ovary cells, murine fibrosarcoma, rat glioma cells, human diploid fibroblasts, or human mammary carcinoma cells. To study the mechanism of the radioprotective effect of dexamethasone on V-79 cells, the cell cycle was examined. Dexamethasone treatment causes a change in cell cycle distribution in V-79 cells, resulting in a dose-dependent reduced fraction of S-phase and an increased fraction of G1- and G2 + M-phase cells. However, these kinetic changes cannot explain the observed radioprotection of asynchronous populations, since purified G1 cells are more radiosensitive. Furthermore, cells synchronized in G1 by centrifugal elutriation were shown to be protected by dexamethasone to the same extent as was the unsorted population, thereby ruling out the mechanism of protection being a redistribution in the cell cycle.

Animals↗
PubMed1984

In vivo radioprotective activities of diethyldithiocarbamate (DDC).

Studies were performed to determine whether diethyldithiocarbamate (DDC) protects against radiation damage to bone marrow, jejunal crypts, testicular tubules, hair follicles, tissues in the leg responsible for leg contractures, and a fibrosarcoma (FSA) of C3Hf/Kam mice. In most experiments, DDC at a dose of 400 mg/kg or 1000 mg/kg body weight was given i.p. 30 minutes before single doses of gamma radiation. DDC (1000 mg/kg) given 30 minutes before whole-body irradiation protected hematopoietic stem cells by a factor (PF) of 1.59, as assessed by the LD50/30 assay, and by PFs of 1.32-1.55, as assessed by the endogenous spleen colony assay. A dose of 400 mg/kg DDC was less effective. Protection was also significant against hair loss and leg contractures; PFs produced by 1000 mg/kg DDC were 1.44 and 1.38-1.51, respectively. Jejunum was protected by 400 mg/kg DDC (PF = 1.2), but not by 1000 mg/kg. The opposite was observed with testis: 1000 mg/kg was protective (PF = 1.2), but not 400 mg/kg. DDC also protected the FSa tumor, either as lung micrometastases or as a solitary tumor in the leg. Both 400 mg/kg and 1000 mg/kg DDC protected 4 day-old micrometastases by a PF of approximately 1.1. DDC at a dose of 1000 mg/kg protected 8 mm leg tumors by a PF of 1.24 at the TCD50 level. Therefore, DDC protected both normal tissues and FSA, but the degree of protection varied greatly. A therapeutic gain was achieved in some instances.

Animals↗
PubMed1984

Twice-daily fractionation schemes for advanced head and neck cancer.

Eighty-five patients with advanced squamous cell carcinoma of the head and neck were treated with twice-a-day fractionation schedules between April 1972 and December 1980. Two types of treatment were distinguished: hyperfractionation, by which 65 patients (Group I) were treated at a weekly dose rate of 1100 to 1200 rad (10 fractions of 110 to 120 rad) in 5 to 6 1/2 weeks for either advanced primary disease (Group 1A) and/or advanced neck metastases (Group IB); and accelerated treatment, used to treat 20 patients (Group 2) who had fast-growing and usually massive neck nodes, at a weekly dose rate of 1300 to 1500 rad in 7 to 10 fractions, to a total dose of 6100 to 8000 rad in 4 to 6 weeks. The radiation portals for patients in Group 2 excluded the mucosa of mouth and throat for part of the treatment. The local control rate at 1 year in Groups 1A and 1B was 41 and 54%, respectively; the incidence of complications was 17%, 5% of them fatal. The local control rate in Group 2 was 80%. Seven patients in this group underwent a neck dissection 6 to 8 weeks following irradiation. Four specimens were negative for tumor. In two, only necrotic tumor cells were identified, and in one specimen morphologically intact tumor cells were seen. There were no fatal complications.

Carcinoma, Squamous Cell↗
PubMed1984

Effect of tumor type, size, and endpoint on tumor radioprotection by WR-2721.

Experiments are reported showing that the degree of tumor radioprotection afforded by WR-2721 varies with the type of tumor and assay endpoint, and that for a given tumor system, microaggregates are protected better than larger cell masses. The tumors used were a methylcholanthrene-induced fibrosarcoma (FSa), and two tumors of spontaneous origin, another fibrosarcoma (NFSa), and a mammary carcinoma (MCa-4), all syngeneic to C3Hf/Kam mice. WR-2721 was given in a dose of 400 mg/kg 30 minutes before irradiation in all experiments. In TCD50 assays, WR-2721 protected 5 mm diameter and impalpable 3 day-old transplants of 5 X 10(5) FSa cells growing in the leg by factors of 1.11 and 1.13, respectively. Using the tumor latency endpoint, 3 day-old s.c. transplants of 10(3) FSa in the abdominal wall were protected by a factor of 1.27, a degree of protection similar to that reported earlier for sterilization of lung micrometastases of the same tumor. MCa-4 tumors growing in the leg were protected better than FSa in TCD50 assays with protection factors of 1.3 for 4 day-old transplants, 1.24 for 5 mm tumors, and 1.23 for 8 mm tumors. MCa-4 tumors recurrent after irradiation as 4 day-old transplants grew more rapidly in mice that had received WR-2721, and this was shown to be most likely due to protection by the drug against expression of the tumor bed effect. Using the lung micrometastases assay, NFSa was protected by a factor of 1.22. This variability in protection with different tumor types, sizes, and assay endpoints is discussed in terms of drug delivery and uptake, and also in relation to the influence of tumor hypoxia on the radioprotective ability of WR-2721.

Amifostine↗
PubMed1984

Inhibition of radiation carcinogenesis in mice by S-2-(3-aminopropylamino)-ethylphosphorothioic acid.

We have demonstrated that S-2-(3-aminopropylamino)ethylphosphorothioic acid (WR-2721) given to mice prior to ionizing radiation inhibits development of radiation-induced sarcomas. The right hind legs of C3Hf/Kam mice were exposed to single doses of gamma-rays ranging from 3400 to 5700 rads. Thirty min before irradiation, approximately one-half of the mice were given i.p. injections of WR-2721 (400 mg/kg). Mice were checked for development of radiation-induced tumors within the irradiated tissue of legs from 250 up to 786 days after irradiation. Tumors first appeared in both groups of mice at approximately 300 days after irradiation. Thereafter, the rate of tumor development was slower in mice that received both WR-2721 and leg irradiation. At the end of the observation period, the overall actuarial tumor incidence in these mice was 26%, compared to 87% in mice exposed to radiation only. Since WR-2721 has the ability to protect against radiation carcinogenesis, it may also afford protection against the carcinogenic effect of alkylating agents.

Amifostine↗
PubMed1984

Tissue repair capacity and repair kinetics deduced from multifractionated or continuous irradiation regimens with incomplete repair.

A model is proposed to account for cell survival after multiple doses, when the interfraction interval is insufficient for complete Elkind repair. In the limit of ever-increasing numbers of ever-smaller fractional doses, the model transforms into the accumulation model (Roesch, 1978) of survival after continuous irradiation. When it is adapted to describe tissue responses to isoeffective multifractionated regimens, wherein repair is incomplete, a generalization of the usually linear plot of reciprocal total dose versus dose per fraction is obtained, in which downward curvature is evident. There is some advantage in studying tissue responses to multifractionated regimens with incomplete repair in the interfraction intervals, or continuous exposures at various dose rates since in addition to determination of repair capacity (defined by beta/alpha) there is an estimate of repair kinetics (defined by the halftime T1/2 for repair of sublethal injury). There is a saving in overall treatment time with either method, thereby reducing the influence of regeneration on the interpretation of the results. The results of analyses of previously published data are presented to illustrate the use of the models. Estimated from the response of three acutely responding normal tissues in the mouse (jejunum, colon and bone marrow), repair halftimes ranged from 0.3-0.9 h and values of beta/alpha were approximately 0.1 Gy-1. From the response of mouse lung (LD50 for pneumonitis) to multifractionated regimens with incomplete repair, the repair halftime was estimated at 1.5 h and beta/alpha was 0.27 Gy-1. In the rat spinal cord beta/alpha was 0.7 Gy-1 and T 1/2 was 1.5 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

Accelerated fractionation vs hyperfractionation: rationales for several treatments per day.

Treatment with several doses per day offers the prospect of a significant therapeutic gain using readily available low LET beams. These regimens can be classified as either accelerated fractionation or hyperfractionation according to their rationales. With accelerated fractionation a conventional number of dose fractions is delivered in a significantly shortened overall treatment time in order to reduce the opportunity for tumor cell regeneration during treatment. With hyperfractionation, on the other hand, a large number of significantly reduced dose fractions is used to give a greater total dose in a conventional overall treatment time. The rationale for this strategy is threefold: 1) increased opportunity for tumor cell redistribution and reoxygenation between dose fractions: 2) a possibly lower oxygen enhancement ratio with small incremental doses; and 3) different sparing of late reacting normal tissues with small dose fractions. A review of the published clinical experience with multiple fractions per day treatment reveals few studies of either pure accelerated fractionation or hyperfractionation since both are limited by acute normal tissue reactions. This has led to a variety of hybrid regimens, some of which have no clear rationale. The choice between accelerated fractionation and hyperfractionation is determined by the regenerative capability of tumor clonogens during treatment. A method of selection based on potential doubling times is presented.

Clone Cells↗
PubMed1983

Neutron therapy for head and neck cancer: I. A final report of the MDAH-TAMVEC pilot studies.

Between October 1972 and December 1979, 142 patients with advanced head and neck cancer were treated in neutron-therapy pilot studies. Forty-nine patients were treated with neutron irradiation twice weekly, 17 with neutron irradiation four times per week, 31 with mixed-schedule irradiation (two neutron and three photon fractions per week), and 45 with conventional treatment (surgery, photon irradiation, or combined surgery and photon irradiation). The tumor was locally controlled in 47% of patients treated with irradiation twice weekly, in 29% of those treated with neutron irradiation four times per week, in 45% of those treated with mixed-schedule irradiation, and in 44% of those treated with conventional modalities. The complication rates were 18%, 6%, 0%, and 20%, respectively. On the basis of this experience, a prospective randomized trial comparing mixed-schedule and photon irradiation for advanced head and neck cancer was initiated in January, 1977.

Adenocarcinoma↗
PubMed1983

Neutron therapy for head and neck cancer: II. Further follow-up on the M. D. Anderson TAMVEC randomized clinical trial.

Between January 1977 and February 1980, 95 patients with inoperable squamous carcinomas of the head and neck were treated in a two-armed randomized clinical trial comparing 1) mixed schedule irradiation using two neutron and three photon fractions per week and 2) standard photon irradiation. Complete tumor regression was achieved in 80% of patients treated with mixed-schedule irradiation, and in 68% of patients treated with photons. The local control rate was 44% in patients treated with mixed-schedule irradiation and 41% in patients treated with photons. There were four complications of treatment in each treatment arm. Absolute survival was 20% with mixed-schedule treatment and 17% in photons. Actuarial analysis shows superior local control and survival rates with mixed-schedule irradiation over photons only in the first two years.

Carcinoma, Squamous Cell↗
PubMed1983

Causes of failure of radiotherapy in head and neck cancer.

Causes of failure of radiation therapy are reviewed and illustrated with clinical examples from cancers of the head and neck region. Radiobiological factors relating to volume of cancer, hypoxia, tumor cell kinetics, intrinsic cellular radiosensitivity and repair capability are considered, along with physical factors relating to fraction size and inadvertent underdosage. In addition, reference is made to failures attributable to a sigmoid dose response curve for tumor control and to the development of second primary cancers. The distinction is made between those causes of failure that can be minimized by optimal application of concepts and techniques readily available to all radiotherapists, those that are not amenable to any modification of radiotherapeutic technique, and those that are potentially remediable by new treatment strategies based on the radiobiological attributes of individual tumors.

Dose-Response Relationship, Radiation↗
PubMed1983

A new isoeffect curve for change in dose per fraction.

A method is proposed for using survival curve parameters for calculating the change in total dose necessary to achieve an equal response in a tissue when the dose per fraction is varied. The method uses the ratio alpha/beta of the coefficients of the linear quadratic survival formula and accounts only for the effect of repair of cellular injury. Absolute values for alpha and beta are not required. The isoeffect curves vary for different tissues. A dose adjustment to account for differences in the regeneration of surviving cells that might result from changing a treatment regimen must be made separately and will also vary from tissue to tissue. Examples of the use of the curves are given. At present, the curves, particularly those for late effects, are uncertain and caution should be observed in using them until they are defined more accurately with additional data.

Cell Survival↗