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Biomedical subjects

H R Withers

Publications and source records attributed to H R Withers.

At least 109 records · Page 6Linked to original sources
PubMed1987

Palliative radiotherapy of a mouse mammary carcinoma.

A mouse mammary carcinoma was exposed to one of three palliative treatment schemes: rapid, split, and extended. Tumors were treated at either 4 mm diameter or 8 mm diameter to compare the responses of small and large tumors to the three treatment schemes. In addition, acute skin reaction and late skin contracture were assessed. The results were: (1) The rapid treatment resulted in the greatest tumor response for 4 and 8 mm tumors but it also caused the most severe normal tissue reaction. (2) Lengthening the overall treatment time to 5 weeks (extended treatment) resulted in the poorest response for both large and small tumors. (3) The split course technique was almost as effective as the rapid course in treating small tumors, but its effectiveness was reduced if treatment was delayed until the tumor reached 8 mm in diameter. (4) The survival of mice with 4 mm tumors clearly depended upon the type of radiation schedule used, with the rapid treatment being superior. (5) If treatment was delayed until the tumors were large (8 mm diameter), there was no survival advantage between the three treatment schedules. (6) Palliation and survival were better when the tumor was treated when it was small, suggesting that palliation may be better if treatment is given early or electively.

Animals↗
PubMed1987

Fitting the linear-quadratic model using time of occurrence as the end-point for quantal response multifraction experiments.

A statistical technique is given for fitting the linear-quadratic model to experimental quantal response multifraction data using the time of the response as the end-point. The analysis used is based on the Cox Proportional Hazards model. The technique is useful for late effects where the time of occurrence of the response is dose dependent. The technique is compared to logistic regression analysis and the advantages and disadvantages are discussed. Both methods are applied to a lung pneumonitis experiment and a kidney experiment.

Animals↗
PubMed1987

The effect on depigmentation after multifractionated irradiation of mouse resting hair follicles.

The function of melanocytes, i.e., pigmentation, was studied after doses of radiation given in one to eight fractions ranging from 0.9 to 4.0 Gy by quantifying depigmentation of particular (zig-zag) hairs in resting phase in the mouse. Considerable variability in response was noted, perhaps related to variations in growth status of the hair follicle. The slope of the single-dose survival curve is described by a D0 value of 1.47 Gy over a dose range 5 to 10 Gy. A weighted, nonlinear regression analysis of the multifraction data gave estimates of alpha/beta of 6.5 Gy for the linear quadratic model. The same analysis suggests that there are about four clonogenic melanocytes per hair follicle. There was a fluctuating pattern of recovery in the early hours after exposure to a dose of 4.0 Gy but no evidence of melanocyte regeneration up to 4 days. However, a characteristic of the data was its variability, suggesting that the radiation response of melanocytes over the dose range 0.9 to 10 Gy may be very variable, reflecting, perhaps, variability in the kinetic status of the melanocyte.

Animals↗
PubMed1986

Predicting late normal tissue responses.

One goal of radiation research is to predict, in an individual patient, the response of the cancer and relevant normal tissues to a course of radiotherapy and to use such information in adjusting the individual's risk-benefit ratio. There are four potential types of predictors of radiation response: physical dose, biological dose, risk factors and realtime assays. Biological dose, which is derived from physical dose and tissue radiobiology, is likely to be the most useful predictor for late normal tissue injury, although risk factors are also important. For any real-time assay to be useful in predicting ultimate response to a conventional regimen, for example, of 30 fractions, it must be both accurate and precise, especially if used after only one dose fraction. No sufficiently accurate such assays exist and, in any event, they are less critical for normal tissues than for tumors, because normal tissues are less heterogeneous in their cellular composition and radiation responses than tumors. In order to apply recent concepts in biological dosimetry to late normal tissue responses, it is important to determine "tolerance" doses of human tissues more accurately; to understand and quantify the volume effect; and to determine isoeffect relationships for all tissues at doses per fraction less than 2 Gy.

Animals↗
PubMed1986

Response of previously irradiated mouse skin to a second course of irradiation: early skin reaction and skin shrinkage.

The responses of previously irradiated hind legs of mice to second courses of gamma ray irradiation were studied using early skin reaction and skin shrinkage as end points. The hind legs of mice were treated with various doses in single and multifractionated irradiation at one-day intervals, 12 months after a variety of doses in various treatment schedules and in a single exposure, respectively. The re-irradiated skin was relatively radioresistant compared to the previously non-irradiated skin, depending on the skin site used and the end point used to evaluate the skin's radiation sensitivity. Early skin reactions that occurred after test doses administered to pre-irradiated skin developed sooner, and remained longer, than skin reactions that developed in the previously non-irradiated controls, regardless of treatment regimens. The degree of early skin reaction to the test dose was greater in the pre-irradiated skin, when the test dose was relatively small, and lower, when the test dose was relatively large, regardless of treatment regimens with one exception: the ventral aspect of the mouse's hind leg responded more to multifractionated test doses in the pre-irradiated skin. The degree of skin shrinkage, assessed 50-60 days after the test dose, was less in the pre-irradiated skin than in the previously non-treated controls, for each dose in each test treatment schedule. The amount of skin shrinkage, resulting from a given test dose (25 or 40 Gy), decreased with increasing dose during the first course of each treatment schedule. The degree of skin shrinkage caused by the first and second exposure, however, increased when the total dose of the first course and the test exposure was increased.

Animals↗
PubMed1986

Alpha/beta value and the importance of size of dose per fraction for late complications in the supraglottic larynx.

In a group of 155 cases with squamous cell carcinoma of the supraglottic larynx (T3-4N0M0), with 3-year local control after radiotherapy, 21 late complications were noted. Using two different methods, an alpha/beta value of 3.8 Gy was calculated. A strong correlation between the risk of late effect in the larynx and size of dose per fraction was found; there was no influence of overall treatment time.

Carcinoma, Squamous Cell↗
PubMed1986

Age dependency of response of the mouse skin to single and multifractionated gamma irradiation.

The age dependency of the response of the mouse skin to gamma-ray irradiation was studied using early skin reaction as an end point. The isoeffect doses for almost all the given levels of early skin reaction were, even though statistically not significant, approximately 10% larger on the average for 38- and 64-week-old mice than for 12-week-old mice. No significant difference between 12-week-old mice and 64-week-old mice was observed in the proportion of dose recovered during multifractionated exposures and in the slope of the fraction number and isoeffect dose relationships plotted on a log-log scale, as well as in the effects of anatomical location on the radiosensitivity. A preliminary shaving made the mouse skin relatively sensitive to radiation, and the dose-modifying factor was smaller for 64-week-old mice than for 12-week-old mice.

Aging↗
PubMed1986

Late radiation response of kidney assayed by tubule-cell survival.

An assay for the survival of renal tubule cells was developed using mice. It is analogous to other in-situ clonogenic cell survival assays. One kidney was irradiated using a 137Cs irradiator and removed 60-68 weeks later for histological examination. In unirradiated animals there were about 370 tubules in contact with the capsule in a coronal cross section at the middle of the kidney. After irradiation, extensive tubular damage was the dominant lesion. The number of epithelialized tubules in contact with the capsule showed a dose-dependent logarithmic decline. The dose-survival relationship for the clonogenic cells responsible for the regeneration of tubule epithelium was described by a D0 value of 1.5 Gy over the dose range 11-16 Gy. This radiosensitivity resembles that of stem cells in acutely responding tissues. The lack of histological evidence of damage to the arterial vasculature at the time the tubules are initially denuded of epithelium, and the similarity of renal tubule cell radiosensitivity to that of other mammalian cells, support the hypothesis that "late" radiation injury results primarily from depletion of parenchymal cells, not indirectly from injury to blood vessels, as has been the prevailing belief.

Animals↗
PubMed1985

Metastatic melanoma in brain. Rapid treatment or large dose fractions.

A subgroup of 59 patients selected on the basis of favorable prognostic factors from a larger group of 194 patients treated for intracranial metastases of melanoma was analyzed with a view to assessing the relative efficacy of different accelerated fractionation regimens. The most effective modification of the previously standard therapy was a shortening of the overall treatment time, although this was also associated with the use of larger doses per fraction. Patients who had brain metastases only at the time of treatment showed a longer survival time than those with coexistent metastases in other organs and survived longer if treated with 10 fractions within 1 week rather than 20 fractions in 2 weeks. The same was found in patients who underwent complete resection of intracranial tumor before irradiation. A complete surgical resection also increased the probability of eliminating intracranial disease, but overall the median survival increased by less than 2 months. It is concluded that a short overall treatment time is more important than large fraction sizes in attempts to improve the treatment of metastatic intracranial melanomas with favorable prognosis.

Brain Neoplasms↗
PubMed1985

Intracranial metastases from melanoma. Clinical features and treatment by accelerated fractionation.

One hundred ninety-four patients with intracranial metastatic melanoma were treated at the M. D. Anderson Hospital between January 1972 and September 1977, using seven different accelerated irradiation regimens. The total tumor dose varied from 3000 to 4800 rad, and the overall treatment time from 1 to 2 weeks. In these patients, whose disease had progressed to brain metastases, freedom from such metastases had decreased logarithmically with time from initial presentation. This suggests a random distribution of progression rates with a mean time of 2.5 years between diagnosis and development of intracranial metastases. Overall, there was no significant improvement in the results from accelerated fractionation in the treatment of intracranial metastases. The result of treatment did not depend on the site of the primary, the number of intracranial metastases, the total dose, or the dose per fraction. There were, however, two subgroups not mutually exclusive, that benefited significantly from the accelerated fractionation: patients having had a complete resection of brain metastases, and those having no detectable extracranial metastases at the time of their treatment for intracranial metastases.

Adolescent↗
PubMed1985

Biologic basis for altered fractionation schemes.

Conventional is commonly not universally correct, and so with dose fractionation in radiotherapy. Fractionation spares slowly responding tissues more than tissues and tumors that show an early response, suggesting that therapeutic gains may be further increased by reducing fractional doses below 1.8 to 2 Gy. The overall duration of a course of radiotherapy should not be the same for all tumors in all sites because the time of onset of regeneration after the start of radiotherapy varies from tissue to tissue and among tumors. Although growth kinetics and dose-response characteristics are known to vary, inability to identify and quantify them prospectively frustrates rational selection of patients for individualized fractionation regimens. In general, curative radiotherapy should be delivered in as short an overall time as possible using the smallest practical dose per fraction. Although 2 Gy, 5 times per week may be a reasonable "average" treatment, greater individualization should be a research goal.

Animals↗
PubMed1985

Radiation-induced inhibition of thymidine incorporation in vivo as a measure of the initial slope and RBEn/gamma.

Radiation damage can be measured by decreased incorporation of 3H-TdR. The early effect of total body irradiation of mice, with doses up to 300-400 rad, of gamma rays of neutrons, on thymidine-3H incorporation into the DNA of murine proliferating normal and tumor cells are described. Total body irradiation with single doses up to 300 rad resulted in a steep dose-dependent depression of 3H-TdR incorporation into the DNA of the jejunal crypt, testis, spleen, fibrosarcoma (FSa), and FSa metastasis cells. The dose required to depress 3H-TdR incorporation values to 37% of control level (D37/thymidine) after gamma-irradiation was calculated to be 405, 443, 72, 303, and 531 rad, for jejunal crypt, testis, spleen, FSa metastasis, and FSa tumor cells, respectively. The depression progressed during the first 3 hours after irradiation. After neutron irradiation, the D37/thymidine was calculated to be 81, 140, 35, and 155 rad for jejunal crypt, testis, spleen, and FSa metastasis cells, respectively. The RBEn/gamma derived from these results were 5.00, 3.16, 2.06, and 1.95 for jejunal crypt, testis, spleen, and FSa metastasis cells, respectively. These results of D37/thymidine after gamma-irradiation and the RBEn/gamma correlate well with the 1Do for the initial slope of the survival curve and RBEn/gamma published in the literature for C3H/Kam mice using the same gamma and neutron beams. These findings show that cell survival after small doses of irradiation correlate with the effect of irradiation on the actively proliferating cells at the time of irradiation.

Animals↗
PubMed1985

MR effect on murine spermatogenesis.

The cytotoxic effects of magnetic resonance (MR) on spermatogenesis in mice were studied. Mice were exposed to a strong static magnetic field from a 0.3-T MR imaging device. The effect of this treatment on different classes of spermatogenic cells was investigated by counting sperm heads at various times after exposure. Sixty-six hours of continuous exposure did not produce any significant cytotoxicity to these cells. This period of continuous exposure is far longer than any anticipated occupational exposure to humans. Thus, acute and subacute exposure to static magnetic fields associated with diagnostic use of MR imaging devices is unlikely to have any significant adverse effect on spermatogenesis.

Animals↗
PubMed1985

Multifraction radiation response of mouse lung.

The response of mouse lung to repeated doses of 60Co gamma-rays of as low as 115 cGy per fraction was measured using death from pneumonitis between 80 and 120 days after irradiation as the endpoint. A fractionation interval of 3 h was maintained for most regimens but in the longer experiments some 12 h intervals were introduced for logistic reasons. The longest overall duration (for a 43 fraction regimen) was 8 days. The total doses required to produce 50 per cent mortality increased continuously as dose/fraction was decreased, even from 160 to 115 cGy per fraction. Of clinical relevance, the steepness of the isoeffect curve over the dose range 115-500 cGy indicates that the lung shows greater sparing from dose fractionation than is characteristic of more rapidly-responding normal tissues, resembling, in this respect, other more slowly-responding tissues such as spinal cord. The plot of the reciprocal of the LD50 values as a function of dose per fraction was non-linear, suggesting that a linear quadratic dose response model may not be appropriate or that repair of cellular injury in lung is not complete in 3 h, or both.

Animals↗
PubMed1985

Neutron radiobiology and clinical consequences.

The present day rationale for anticipating a therapeutic advantage of neutrons over X-rays is reviewed. It is based on the following characteristics of tumorous tissue: hypoxia, poor cell cycle redistribution, large repair capacity and rapid growth. It is obvious that not all of the possible reasons why X-ray therapy may fail can be circumvented by the use of neutrons. Therefore the practical consequences of the mentioned rationales must be the planning of randomized clinical trials. With patients selected for poorly reoxygenating tumors, tumors in which clonogens proliferate slowly and others where they grow rapidly and/or show an early regenerative response. Predictive assays for such a selection are, however, only scarcely available and need to be developed to supplement the indication given by conventional staging and grading. Other important consequences of radiobiological considerations are finally concerning treatment strategies. Regardless of the exact dose per fraction chosen, it seems prudent to use relatively low doses per fraction initially to maximize the chance of detecting any benefit inherent in the use of neutrons, before exploring increased doses for reasons of improved cost-effectiveness.

Cell Differentiation↗
PubMed1985

Estimating the parameters in the two-component model for cell survival from experimental quantal response data.

A statistical technique is given which can be used to estimate the parameters of the two-component model for cell survival from quantal response multifraction data. The method is a nonlinear logistic regression and relies on a mild assumption relating the probability of death to cell survival level. The method is demonstrated on mouse colon data, where more efficient estimates of the parameters are known, and the agreement is good. Also for some mouse lung LD50 data we obtain estimates of the parameters, and the fit to the data is shown to be better than that of linear-quadratic model.

Animals↗
PubMed1985

Acute effects of a perfluorochemical oxygen carrier on normal tissues of the mouse.

A single iv dose of 15 ml/kg fluosol DA (20%), a perfluorochemical oxygen carrier, caused hepatomegaly and splenomegaly which persisted for at least 3 weeks after drug injection. The peak increase in weight was at 3 days in the spleen (1.7x) and at 14 days in the liver (1.5x). Lung and kidney weights were not altered 1-21 days after administration of fluosol DA. The slopes of the single-dose radiation survival curves for intestinal epithelial cells and spermatogenic stem cells in mice breathing air or oxygen were not significantly altered by the administration of fluosol DA 10 min before irradiation, and the doses to achieve an isoeffect were altered by 1.03 or less. When mice were challenged with iv injected FSa tumor cells 24 h after treatment with fluosol DA, no increase in the number of artificial pulmonary metastases was observed.

Animals↗