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Biomedical subjects

J F Fowler

Publications and source records attributed to J F Fowler.

At least 181 records · Page 10Linked to original sources
PubMed1985

The effect of recovery from potentially lethal damage on the determination of repair and repopulation in a murine tumour.

Repair and repopulation following X irradiation of clamped-off murine anaplastic MT tumours was investigated using the established method of (Dn-D1)/(n-1). Repair was complete in 4 h, similar in extent to that reported in other tumours, and within the range of that reported for normal tissues. Subsequent repopulation commenced after 4 days and was equivalent to 1.8 Gy/day recovered dose, corresponding to a clonogenic cell number doubling time of 1.8 days. However, estimates of repair and repopulation may have been in error because the chronically hypoxic cells in this tumour alone have the ability to recover from potentially lethal damage (PLD) and so are more radioresistant than cells rendered acutely hypoxic by clamping. Because of this, even clamping off tumours at irradiation does not render all cell populations equally radioresistant, and so reoxygenation between fractions could result in an underestimate of repair and repopulation. Further, the differing sensitivity between acutely and chronically hypoxic cells renders the apparent OER a function of dose (i.e., oxygen not truly dose-modifying to chronically hypoxic cells). Consequently it is incorrect to assume a constant OER in order to compare repair in tumours irradiated under hypoxic conditions with that in normal tissues irradiated under aerobic conditions. It will be argued here that in the case of the present tumour neither reoxygenation nor the choice of OER will have qualitatively altered the conclusion reached from the conventional method.

Animals↗
PubMed1985

Repair in mouse lung for up to 20 fractions of X rays or neutrons.

Local irradiation of the mouse thorax followed by the measurement of lung damage up to 17 months after irradiation has been carried out with up to 20 fractions of 3 MeV neutrons or of 240 kV X rays. Doses per fraction down to 0.28 and 1.5 Gy respectively were used. Repair capacity and RBE values were assessed by measuring breathing rate and lethality at monthly intervals up to 17 months. Only a small sparing of neutron damage was found. Sparing with X rays continued to increase as the size of each fraction was decreased, and was the main influence on the RBE values. The single-dose RBE was approximately 1.8, increasing to approximately 5 at the lowest dose per fraction measured. Dose-response curves derived for each fraction were well fitted by the formula alpha d + beta d2 where the repair parameter alpha/beta has values of 2-4 Gy after X irradiation. A slight fall of alpha/beta with time after X irradiation was observed, from about 4 Gy for pneumonitis to about 2 Gy for late fibrosis. This was significant for lethality but not for the increase of breathing rate. With neutrons the value of alpha was much higher than with X rays and a trend of increasing value of alpha at later times after irradiation was seen. Use of the linear quadratic dose-response formula predicts a continuing increase in the sparing of X-ray damage in lung as doses per fraction are decreased below those used here, and a limiting low-dose RBE of about 7.

Animals↗
PubMed1985

Repair in mouse lung of multifraction X rays and neutrons: extension to 40 fractions.

We have extended our previous multiple irradiations of mouse lung from 20 to 40 fractions of both X-ray and neutron radiation in order to test whether the repair parameters previously derived will hold for lower doses per fraction, down to 1.1 Gy of X rays and 0.18 Gy of 3 MeV neutrons per fraction. Repair parameters were calculated from measurements of breathing rate and lethality at monthly intervals up to 17 months after irradiation with 1, 10, 20 or 40 equal fractions. Sparing of neutron damage was negligible when the neutron dose was divided into multiple fractions, but progressively greater repair of lung damage was seen after increasing numbers of X-ray fractions. A significant increase in the iso-effect dose for 40 fractions of X rays was found compared with 20 fractions, even when two fractions per day were given at intervals of about 6 hours, as was the case in the 40 fraction experiment. The data were well fitted by the linear quadratic formula for response vs. dose per fraction and the ratio alpha/beta yielded values of approximately 3 Gy after X rays and 30 to 40 Gy after neutron irradiation; these values are not different from alpha/beta ratios found for up to 20 fractions. The single dose RBE was less than 2, increasing to about 6 at the lowest dose per fraction measured, in agreement with previous results. The ratio of the alpha component for neutrons to that for X rays was about 8, which is therefore the limiting RBE predicted for infinitely small doses per fraction.

Animals↗
PubMed1985

Multiple cutaneous squamous cell carcinomas in a patient with chronic lymphocytic leukemia.

A 79-year-old white woman had stasis dermatitis and multiple cutaneous squamous cell carcinomas not only in the exposed areas of the face, neck, and arms, but also on the lower legs in the area of dermatitis. Further evaluation revealed early chronic lymphocytic leukemia. This case illustrates the need to search for an underlying abnormality in patients with multiple or unusual skin cancers and to examine biopsy specimens from suspicious skin lesions in immunocompromised patients.

Aged↗
PubMed1984

Lung radioprotection by WR-2721 at low X-ray doses per fraction.

The response of mouse lungs to single doses and ten fractionated irradiations has been tested using breathing rate and lethality as assays for damage. The radioprotective effect of 300 mg/kg WR-2721 has been determined for mice breathing air or 10% oxygen. The protection factor was assessed from dose response curves obtained at monthly intervals from 24 to 48 weeks. A low protection factor (1.2-1.4) was observed for single doses in air or 10% oxygen and also for ten fractions in air. Considerably more protection was seen with ten fractions in mice breathing the reduced oxygen concentration (protection factors of PF = 1.5-1.7). It is postulated that the low PF values normally reported for lung are due to the naturally high oxygen concentration in all cells in this tissue. A fraction of the cells becomes sufficiently hypoxic in 10% oxygen to be susceptible to WR-2721 radioprotection. This subpopulation can then be detected with small X-ray fractions (less than or equal to 5 Gy) but not with large single doses.

Amifostine↗
PubMed1984

WR-2721 protection of pneumonitis and fibrosis in mouse lung after single doses of x rays.

The radioprotective effect of WR-2721 has been studied in mouse lung after single doses of radiation. Using the breathing rate assay and lethality, radioprotection was assessed at monthly intervals between 3 and 18 months after irradiation during both pneumonitis and chronic fibrosis. The degree of radioprotection was greater for fibrosis than for pneumonitis using both assays. In replicate experiments, dose modifying factors (DMF's) ranging from 1.2 to 1.4 were obtained for pneumonitis and 1.5 and 1.6 for fibrosis. The differences in DMF's for the two phases of lung damage were significant. A difference in the time course of expression of damage was seen in both the breathing rate and lethality assays between mice irradiated with and without WR-2721: the damage ended sooner in the drug-treated mice. This difference is best explained by protection of all damage after 5 months by WR-2721. No evidence of drug toxicity was found. We conclude that WR-2721 protects against chronic lung fibrosis caused by radiation at least as well as against the earlier appearing pneumonitis after single doses of radiation. Thus, if WR-2721 is dose modifying and if late tissue complications are dose limiting in clinical radiotherapy, then a therapeutic benefit would be obtained by the use of this drug in clinical radiotherapy, provided that the radioprotection of tumors did not exceed a factor of 1.5-1.6.

Amifostine↗
PubMed1984

Dose-response relationships for human tumors: implications for clinical trials of dose modifying agents.

Clinical benefit from dose modifying agents depends upon the effectiveness of the agents and the steepness of dose response curves for the local control of human tumors by radiotherapy. We have analyzed the two prospective trials and the many retrospective analyses of clinical data from the literature to determine what dose increment is needed to increase local control from 40 to 60%. This increment ranges from 3 to greater than 35%. Thus a dose modifying factor of at least 1.03 (to greater than 1.35) will be necessary for clinical detection of the benefit of a new modality, even if 135 patients are included in each arm of a trial. Two dose levels in the new treatment arm would ensure that therapeutic advantage could be assessed, and would also generate prospective dose response information.

Animals↗
PubMed1984

Review: total doses in fractionated radiotherapy--implications of new radiobiological data.

The total dose in radiotherapy has been adjusted in the past for different fractionation schedules by the use of empirical formulae such as NSD, TDF and CRE. It is now appropriate to consider fractionation factors which include more biological insight in their formulation than was possible earlier. It has become clear, from both clinical and experimental animal data, that the total dose in multi-fraction irradiations depends more critically on size of dose-per-fraction for late than for early damage to normal tissues. This difference has been interpreted as due to different shapes of the underlying dose-response curves. The late reactions respond with more curvature in the dose-response curve, i.e. with more repair capability at very low doses per fraction, than the early tissue reactions. A linear-quadratic relationship for the dose-response curves has been found to fit experimental data well, with few exceptions. This paper reviews this interpretation and explores some of its implications for radiotherapy and for radiobiology applied to therapy. Of many repair factors that have been suggested, the ratio alpha/beta (of the linear to the quadratic coefficients) is one that should be independent of the level of damage assayed. Values of alpha/beta of about 10 Gy have been reported for a number of early tissue responses but a range of values from about 1 to 5 or 6 Gy for late responses. It is a current challenge to radiobiology to explain why this difference occurs. Once such values are known for different tissues--and the dangers of premature assumptions are emphasized--calculations are possible which might be useful in radiotherapy as an alternative to NSD, TDF, CRE etc. Some data are presented on the magnitude of differences from these previously used empirical formulae, with a discussion about how easily detected the discrepancies might be in clinical practice. Applications to hypofractionation, hyperfractionation and accelerated fractionation are illustrated.

Animals↗
PubMed1984

The eighteenth Douglas Lea lecture. 40 years of radiobiology: its impact on radiotherapy.

The contributions of radiobiology to radiotherapy in the past 40 years are reviewed, taking the work of Gray and Read on bean roots with high LET radiation as the starting point. The main impact has been strategic and didactic because methods of measuring parameters in patients so as to affect individual treatments have not yet been developed. Many patients are now being treated with radiotherapy who would have been considered unsuitable 40 years ago and the radiobiological reasons for these changes are discussed. Improvements that have occurred in radiotherapy are reviewed and some projections about future potential improvements are made.

Animals↗
PubMed1984

Fractionated radiation therapy after Strandqvist.

Models for predicting the total dose required to produce tolerable normal-tissue damage in radiation therapy are becoming less empirical, more realistic, and more specific for different tissue reactions. The progression is described from the 'cube root law', through Strandqvist's well known graph to NSD, TDF and CRE and more recently to biologically based time factors and linear-quadratic dose-response curves. New applications of the recent approach are reviewed together with their implications for non-standard fractionation in radiation therapy. It is concluded that accelerated fractionation is an important method to be investigated, as well as hyperfractionation; and that more data are required about the proliferation rates of clonogenic cells in human tumours.

Animals↗
PubMed1984

The first James Kirk memorial lecture. What next in fractionated radiotherapy?

Models for predicting the total dose required to produce tolerable normal-tissue injury are becoming less empirical, more realistic, and more specific for different tissue reactions. The trend can be seen by the progression from the "cube root law", through Strandqvist's slope of 0.22, to NSD, TDF and CRE which have separate time and fraction number exponents, to the even better approximations which are now available. The dose-response formulae that can be used, with statistical legitimacy, to define the effect of fraction size (and number) include (1) the linear quadratic(LQ) model; (2) the two-component (TC) multi-target model; and (3) repair - misrepair models. The LQ model offers considerable convenience and requires only two parameters to be determined. The use of a new model often provides fresh insights. The LQ model has emphasized the difference between late and early normal-tissue dependence on dose per fraction which was first shown by exponents greater than the NSD slope of 0.24. Exponents of overall time, e.g. T0.11, yield the wrong shape of time curve, suggesting that most proliferation occurs early, although it really occurs after a delay depending on the turnover time of the tissue. The principles of better time factors are well known but actual values for human tissues are not well determined. Fortunately the time factors are usually small, especially for late reactions. Improved clinical results are being sought by hyperfractionation, by accelerated fractionation, or by continuous low dose rate irradiation as in interstitial implants. New clinical trials are investigating these approaches, which have been suggested by the accumulation of radiobiological data.

Animals↗
PubMed1984

Cutaneous mucinosis associated with lupus erythematosus.

A 48-year-old woman with a 17-year history of systemic lupus erythematosus (SLE) presented with an exacerbation of cutaneous lupus manifested as discoid LE (DLE). In addition to the typical DLE lesions, she had multiple flesh colored nodules scattered over the trunk and extremities on both exposed and nonexposed surfaces. The association of mucinous deposits and SLE has been reported within lesions of SLE and occasionally in other cutaneous lesions. This case represents a distinct variant of cutaneous mucinosis which was associated with SLE.

Female↗
PubMed1984

Increased collagen and fluid content of mouse kidneys at 9 months after single or fractionated X irradiation.

Mouse kidneys have been analyzed at sacrifice, 9 months after single-dose and fractionated irradiation, using wet and dry weight, a biochemical determination of hydroxyproline, and quantitation of dilated renal tubules in histological preparations. Dose-response curves have been constructed to determine the sensitivity and precision of the assays and to study the influence of dose fractionation on a variety of radiation responses of the kidney. There was a marked loss of kidney weight, measured either wet or dry, with maximum changes from control values by factors of 3 and 5, respectively. The wet:dry weight ratio increased with X-ray dose, indicating that relative fluid content was increased even 9 months after irradiation. This could be partly attributed to dilated renal tubules. Total collagen content per kidney, determined by a hydroxyproline assay, showed a less marked dose dependence, with a maximum increase of a factor of 1.4. However, hydroxyproline per dry weight increased by a factor of 7, and this ratio proved to be the most sensitive and precise measure of radiation damage. The "fibrosis" that is detected in histological sections appears to be more a relative than an absolute alteration in connective tissue. The loss of parenchymal cell mass, particularly in the proximal tubules, is the predominant factor; the increase in the absolute amount of collagen per kidney contributes to a lesser degree. The influence of radiation dose fractionation was analyzed using a linear-quadratic response model. The alpha/beta ratios were between 0.9 and 2.9 Gy.

Animals↗