Search PubMed⌕ Search

Biomedical subjects

H D Thames

Publications and source records attributed to H D Thames.

At least 37 records · Page 2Linked to original sources
PubMed1999

Fractionation sensitivities and dose-control relations of head and neck carcinomas: analysis of the randomized hyperfractionation trials.

PURPOSE: A therapeutic benefit can be achieved by hyperfractionation (HF) if tumours have small fractionation sensitivities characterized by alpha/beta values greater than those for late effects of dose limiting normal tissues. It is the purpose of the present paper to estimate alpha/beta values for head and neck carcinomas from randomized HF trials. MATERIALS AND METHODS: Maximum likelihood estimates the alpha/beta ratio were obtained from tumour control data from the randomized HF trials using the LQ model and a logit or probit type dose-response curve. A joint analysis of five randomized HF trials for head and neck carcinomas was performed to estimate overall alpha/beta and gamma50 values for tumour control. In addition, alpha/beta ratios for the individual trials were estimated using fixed gamma50 values (characteristic quantifying the steepness of dose-response curves) between 1.4 and 5 for tumours. RESULTS: An overall gamma50 of 3.1 (1.5-4.7) was estimated for the dose-tumour control relation from the HF trials, assuming a logit or probit dose-response curve. The tumours showed small fractionation sensitivities characterized by an overall alpha/beta of 10.5 (6.5-29) Gy. One trial allowed quantitative estimation of the alpha/beta values for late normal tissue damage: The alpha/beta estimate for late effects of grade 2 + was 4.0 (3.3-5.0) Gy, assuming a fixed gamma50 of 5 and was even smaller for smaller gamma50 values. CONCLUSION: Head and neck carcinomas showed small fractionation sensitivities with alpha/beta values greater than those typical for bone, soft tissues, and skin, as well as steep dose response curves. Thus, important prerequisites for improving the therapeutic benefit of radiotherapy of head and neck carcinomas by HF are fulfilled for patients who met the accession criteria of the trials.

Algorithms↗
PubMed1999

Frequency of first metastatic events in breast cancer: implications for sequencing of systemic and local-regional treatment.

PURPOSE: The sequencing of treatment for early breast cancer is controversial. The purpose of this study was to quantify the risk of delaying surgery, using estimates of the frequency of first metastases from breast primary tumors. PATIENTS AND METHODS: The probability that 560 (node-negative), 657 (with one to three positive nodes), and 505 (with more than three positive nodes) women treated without adjuvant chemotherapy would be free of distant disease at presentation was fit to a mathematical model of the seeding of distant metastases and combined with estimates of the growth rate to calculate the frequency of first distant disseminations per month. RESULTS: Frequencies of first distant metastases were approximately 1% to 2% per month, 2% to 4% per month, and 3% to 6% per month in T1 patients who were node-negative, had one to three positive nodes, or more than three positive nodes, respectively. As a result, the typical patient with T1 disease, who has a 70% to 80% chance of being free of distant disease, runs a 1% to 4% risk of distant dissemination for each month surgery is delayed. Assuming a 30% reduction in mortality caused by adjuvant chemotherapy, the model predicts that T1 patients treated with neoadjuvant chemotherapy would potentially have a higher rate of distant metastasis development than those treated with an initial surgical resection followed by adjuvant chemotherapy. CONCLUSION: We formulate the hypothesis that optimal sequencing of surgery and systemic treatment of breast cancer may be size-dependent, with a disadvantage or no benefit from neoadjuvant treatment for T1 patients but an increasing benefit with increasing size of the primary tumor.

Age Factors↗
PubMed1998

Induction of transforming growth factor alpha in irradiated mouse jejunum.

PURPOSE: To determine the involvement of the mitogenic growth factors transforming growth factor alpha (TGF alpha), epidermal growth factor (EGF), and the EGF receptor (EGF-R) in the proliferative response after irradiation of the mouse jejunum. METHODS AND MATERIALS: C3Hf/Kam mice were whole-body irradiated with 5 and 11 Gy 250 kV X rays. Mice were killed 1-10 days after irradiation, and immunohistochemistry, in situ hybridization (ISH), and RNase protection assays were performed. RESULTS: Damage to the jejunal crypts caused by irradiation resulted in a strong proliferative response 1-5 days after 5 Gy and 3-6 days after 11 Gy. Expression of TGF alpha, EGF, and EGF-R increased at 1-2 days and decreased at 4-8 days after 5- or 11-Gy irradiation. Also, TGF alpha mRNA increased during the early phase of the proliferative response (1-2 days after 5 or 11 Gy) followed by a decrease at 4 days after 5 Gy and 8 days after 11 Gy. CONCLUSION: These data indicate that, at the beginning of the proliferative response after irradiation, the transcription of TGF alpha mRNA is increased, and that it is inhibited just before compensatory proliferation decreases. Thus, active regulation of TGF alpha expression takes place at least at the transcriptional level, resulting in upregulation of TGF alpha production and increased TGF alpha levels in the crypts during the proliferative response.

Animals↗
PubMed1998

A morphometric analysis of glomerular and tubular alterations following fast-neutron irradiation of the pig and monkey kidney.

PURPOSE: The morphologic responses of the pig and monkey kidney to fractionated fast-neutron irradiation were assessed. METHODS AND MATERIALS: The right kidney of approximately 14-week-old female Large White pigs was irradiated with 6.6-12.2 Gy of fast neutrons (42 MeVd-->Be) given as 12 fractions over 18 days; the left kidney served as the contralateral unirradiated kidney. Both kidneys were removed at necropsy 2 years postirradiation. In addition, the remaining hypertrophied kidney of four unilaterally nephrectomized adult rhesus monkeys was irradiated with a total dose of 11.0 Gy fast neutrons (45 MeVp-->Be) given in an identical fractionation regimen to that used in the pig studies. These kidneys were removed when the animals exhibited renal failure, between 32-94 weeks postirradiation. Glomeruli were assessed for the presence of pathologic features, including intercapillary eosinophilic material (ICE), ectatic capillaries, thrombi, hemorrhage, and sclerosis. The relative proportion of renal cortex occupied by glomeruli, interstitium, normal, or abnormal tubules was determined using a Chalkley point grid. RESULTS: The incidence of normal glomeruli, ectatic capillaries, thrombosis, and periglomerular fibrosis were significantly different in the irradiated pig kidneys compared with the unirradiated contralateral kidneys (p < or = 0.02). Linear regression analysis demonstrated a significant dose relationship in terms of normal glomeruli, ectatic capillaries, and ICE (r > or = 0.64; p < or = 0.04). Irradiation was also associated with a significant (p < 0.0001) decrease and increase in the volume of renal cortex occupied by normal and abnormal tubules, respectively. Similar morphometric changes were noted in the irradiated monkey kidneys. CONCLUSIONS: The morphologic changes seen in the pig and monkey kidney after fractionated irradiation with fast neutrons are similar to those previously noted after single-dose or fractionated-photon irradiation. These findings support the hypothesis that the development of radiation nephropathy in these various models involves common pathophysiological mechanisms.

Animals↗
PubMed1998

Volume effects in the irradiated canine spinal cord: do they exist when the probability of injury is low?

PURPOSE: The purpose of this study was to investigate volume effects in the irradiated canine spinal cord. MATERIALS AND METHODS: Eighty-nine beagle dogs were given 44-84 Gy photons in 4 Gy fractions to 4 or 20 cm lengths of thoracic spinal cord. As controls, 36 dogs were given 60-84 Gy in 2 Gy fractions to a 20 cm length of spinal cord and six dogs were unirradiated. Dogs were evaluated for clinical signs, and after euthanasia, for occurrence of gross lesions, severe lesions of massive hemorrhage, white matter necrosis and/or parenchymal atrophy and mild lesions of focal fiber loss. White matter vacuoles, meningeal thickness and dorsal root ganglia lesions were quantified. Data were analyzed to test for an effect of volume on dose-response curves. RESULTS: Significant volume effects were found between 4 and 20 cm lengths of irradiated spinal cord for gross lesions, severe lesions and mild lesions (8.3-15.0 Gy difference at the ED50 level). The ED50 in 4 Gy fractions for severe lesions was 56.9 Gy (95% CI 53.1-60.6) for 20 cm and 68.8 Gy (95% CI 64.5-75.1) for 4 cm fields. Significant improvements in the fit of data to dose-response curves resulted when using models with either parallel or non-parallel curves, but in either case an appreciable difference existed between curves at low probabilities of injury. Volume effects were present for meningeal thickness and slopes of dose-response curves were different. Clinical signs correlated well with severe lesions for 20 cm (ED50 = 54.0 Gy), but not for 4 cm fields (ED50 = 77.6 Gy). CONCLUSIONS: Volume effects exist for the occurrence of pathologic lesions in irradiated canine spinal cord. Clinical compensation for pathologic lesions occur at small, but not large irradiated volumes. There is insufficient data to support a decreased slope of dose-response curves with decreased volume. Volume effects estimated at the 50% level of spinal cord injury could also hold at low probabilities of injury characteristic of the clinic.

Animals↗
PubMed1998

Tumor volume: a basic and specific response predictor in radiotherapy.

BACKGROUND AND PURPOSE: Predictive assays of the response of tumor and normal tissues in individual patients offer the possibility of individualized prognosis and treatment decisions. For this purpose a variety of assays are currently being explored. The impact of tumor volume on radiotherapy outcome has long been recognized and in this paper its predictive potential is investigated. METHODS: Re-evaluation of clinical data from the literature. RESULTS: Tumor volume significantly influences radiotherapy outcome and in many sites it is likely a superior prognostic indicator to tumor stage, which reflects tumor size only partially and is mainly correlated to operability. Tumors even of identical stage may vary by factors of more than 100 in volume and neglect of this heterogeneity clearly reduces the power of a study considerably. The precision requirements for the measurement of tumor volume are small; +/-50% is sufficient for reasonable results. CONCLUSION: The data evaluated here suggest that tumor volume is the most precise and most relevant predictor of radiotherapy outcome. Its determination is achievable with sufficient accuracy in most radiotherapy departments. Individual tumor volume should always be reported in clinical studies and considered in data analyses.

Animals↗
PubMed1998

Tumor response, mucosal reactions and late effects after conventional and hyperfractionated radiotherapy.

BACKGROUND: Relationships between normal tissue reactions and tumor response to radiotherapy have generally been investigated in retrospective studies, with the attendant difficulties such as different times of treatment and lack of standard scales for scoring of normal tissue reactions. This study analyses the correlation between normal tissue reactions and tumor response in a randomized trial of hyperfractionation versus conventional radiotherapy. MATERIALS AND METHODS: EORTC trial 22791, which accrued 325 T2-3, N0-1 and M0 oropharynx squamous cell carcinomas, compared conventional radiotherapy (70 Gy in 7 weeks) to a hyperfractionated regime (two daily irradiations of 1.15 Gy up to 80.5 Gy in 7 weeks). Acute and late toxicities were assessed according to the RTOG/EORTC scales. The variables were tumor regression at treatment completion, tumor control for unlimited follow-up, severity of acute mucosal reactions (grade of the peak reaction, time to onset of grade 2 mucositis, or duration of acute reactions of grade 3) and severity of late effects in normal tissues (late ulceration, cervical edema secondary to lymphatic drainage damage, late muscular fibrosis, or late mucosal necrosis as consequential damage). Kendall's rank correlation was used to assess the levels of significance of the correlation. The 95% confidence interval (95% CI) was calculated for each correlation tau-b coefficient. RESULTS: Irradiation doses and overall treatment times were consistent between the treatment arms. The time to onset of patchy mucosal reactions was inversely correlated to tumor regression at treatment completion in the hyperfractionated arm (arm 2) but not in the conventional fractionation arm (arm 1). The other significant correlations were restricted to the following pairs of end-points and patient subgroups: acute mucositis of grade 3 versus tumor regression at the end of treatment in arm 2 for T2 tumors, late ulceration versus tumor control in arm 2 and acute mucosal reactions versus late effects in normal tissues in arm 2 for T3 tumors. By and large, the 95% CIs for Kendall's tau-b included zero and did not include 0.5, an indication that the comparison had sufficient power to detect a difference, if indeed one existed. CONCLUSIONS: These results do not represent clinical evidence strong enough to demonstrate that individual differences in sensitivity influence the response of tumors to radiation.

Carcinoma, Squamous Cell↗
PubMed1998

Fractionation effect on radiation-induced growth retardation of tibia in rabbits and rats.

A study of the sensitivity to fractionation of the growing tibia of rabbits and rats was conducted by comparing the growth of the treated right bone to that of the untreated left side in each individual animal using radiographic measurements. The experimental endpoint was the percentage of normal growth 24 weeks after irradiation in rabbits and 14 weeks after treatment in rats. The results show clear dose-response relationships in all experimental arms. A clear-cut fractionation effect was demonstrated in both species. The alpha/beta-ratios determined by maximum likelihood analysis according to the LQ-model with graded responses were 3.2 Gy (95% C.I. 1.1; 5.6) in rabbits and 6.9 Gy (5.3; 8.7) in rats, when all data were included in the calculations. When single-dose data were excluded the alpha/beta-values were -0.6 Gy (-3.1; 2.3) in rabbits and 5.0 Gy (3.5; 7.0) in rats. Our data provide further evidence that low doses per fraction should be used when irradiation of the epiphysis cannot be avoided in pediatric patients.

Animals↗
PubMed1998

Diurnal variations in the expression of radiation-induced apoptosis.

Experiments were performed to determine whether diurnal variations in apoptosis in the mouse small intestine after irradiation with 2.5 Gy gamma rays depended on the time of day that the mice were irradiated, the time of day that the mice were sacrificed or the interval between irradiation and sacrifice. Experiments were performed with a 12-h light:dark regimen with the light period from 6:00 to 18:00 h. With fixed intervals of 6 h and 24 h between irradiation and sacrifice, a peak in induced apoptosis (16%) was observed in mice sacrificed at 8:00 h, two times higher than the nadir of response at 23:00 h (8%). When variable intervals were used between irradiation and measurement of apoptosis, i.e. sacrifice, at 8:00 h or 23:00 h, the induced apoptosis was dependent on the interval, with a peak for 18-h intervals. However, the level of apoptosis was always about twofold higher when measured at 8:00 h than at 23:00 h. No correlation was observed between diurnal variations in apoptosis and survival of mouse intestinal crypts. The diurnal variations in apoptosis after irradiation can be interpreted either in terms of expression of apoptosis during the G2/M phase of the cell cycle in partially synchronized cells, or in terms of a systemic mechanism such as diurnal variation in the neurohormone melatonin.

Animals↗
PubMed1998

Effects of volume irradiated on the function of the canine ureter.

This study was designed to investigate the influence of the volume irradiated on the probability of ureteral complications and to provide data for volume modeling. One hundred thirty-four purpose-bred beagle dogs received single intraoperative doses of 6 MeV electrons ranging from 12 to 54 Gy to three lengths of ureter: 2, 4 or 8 cm. The response was evaluated by excretory urography. The ED50 was 21.9 Gy (95% CI 13.3-30 Gy) for 8 cm 3 years after treatment. The estimated ED50's were greater than 43 Gy for 4 cm and 85 Gy for 2 cm. Reducing the length of ureter irradiated from 8 cm to 4 cm increased the ED50 for ureteral dilation by at least a factor of 2, while reduction from 8 cm to 2 cm increased the ED50 by at least a factor of 4. The ED50 for renal injury secondary to stenosis was 30.5 Gy (95% CI 17.2-232 Gy) when an 8-cm field was irradiated. There was a significant effect of volume irradiated on the frequency of ureteral stenosis. Reducing the length of ureter included in the treatment field should allow delivery of higher doses to tumors without increased complications.

Animals↗
PubMed1997

Hyperfractionated radiotherapy of human tumors: overview of the randomized clinical trials.

PURPOSE: Hyperfractionation (HF) is the altered fractionation schedule most frequently studied in clinical Phase III trials. In this overview, surviving fractions, rates of complete responses, and estimates of the long-term locoregional tumor control probabilities after HF and conventional fractionated irradiation (CF) available from the various reports were compared. METHODS AND MATERIALS: A metaanalysis was performed of the randomized studies on hyperfractionation vs. conventional fractionation published since 1980 on different tumor types in various locations. RESULTS: Compared with CF, HF significantly reduced the odds of death for patients with head and neck tumors (three studies, odds ratio 0.48 (0.40-0.58), p < 0.0001) and bladder cancer (two studies, odds ratio 0.53 (0.36-0.78), p = 0.001), while there was a trend in nonsmall cell lung cancer (three studies, odds ratio 0.69 (0.51-0.95), p = 0.02), and malignant gliomas (three studies, odds ratio 0.67 (0.48-0.93), p = 0.02). The probability of long-term loco-regional control of head and neck tumors was significantly enhanced after HF (four studies, odds ratio for loco-regional recurrence or related events 0.35 (0.28-0.45), p < 0.0001). In trials on head and neck tumors and bladder cancer, complete responses were seen more often after HF compared with CF (odds ratio for failure of complete response: 0.43 (0.32-0.57), p < 0.0001, and 0.43 (0.27-0.70), p = 0.0007). CONCLUSIONS: This overview demonstrates that the effectiveness of radiotherapy is consistently higher for HF than for CF. The assumption that tumors have a small effective fractionation sensitivity (alpha/beta > 5 Gy) seems to be fulfilled especially for head and neck cancers.

Brain Neoplasms↗
PubMed1997

Spatial and temporal patterns of expression of epidermal growth factor, transforming growth factor alpha and transforming growth factor beta 1-3 and their receptors in mouse jejunum after radiation treatment.

The goal of the present study was to assess changes in proliferation in the mouse jejunum after irradiation and the role of the growth factors EGF, TGF-alpha and TGF-beta 1-3 in the proliferative response. Our working hypothesis was that feedback signals from the villus to cells in the crypt regulate proliferation, and that the growth factors EGF and TGF-alpha with their common receptor EGF-R are involved in stimulation of proliferation, while the growth factors TGF-beta 1-3 with their receptors TGF-beta RI and TGF-beta RII are involved in inhibition of proliferation during this regulation. Immunohistochemical detection methods and automated image analysis were used for objective quantification of growth factor expression. The data indicate that, after 5 Gy irradiation, growth stimulation in the crypts takes place before major changes in the villi are observed. However, the combination of the reduction in the cell number, the number of cells expressing TGF-beta 1-3 and the reduction in the level of expression of TGF-beta 1-3 in the villi may cause the release of crypt cells from regulatory growth inhibition and initiate a proliferation-stimulating signal by an increase in the production of TGF-alpha and EGF. Regulation of proliferation after initiation of a proliferative response seems to be related more to the growth factors EGF, TGF-alpha and TGF-beta 3 in the crypts than to villus cellularity or growth factor expression, supporting the concept of stem cell autoregulation as a mechanism of cell regeneration in the intestinal crypt.

Animals↗
PubMed1997

The effect of proliferative status and clonogen content on the response of mouse jejunal crypts to split-dose irradiation.

The rate of cell production in hierarchical tissues is affected by the differentiation probability after each clonogen division and the frequency with which divisions take place. We have modified the latter by a high-fiber diet, which caused an increase in the BrdUrd labeling index (LI) in jejunal crypts of mice, and have tested for a change in tolerance using the in vivo colony assay. Clonogens were counted using the in vivo colony assay of crypt regeneration with Poisson correction. The LI was estimated by counting BrdUrd-labeled cells in longitudinal sections of complete crypts. Arrest in mitosis induced by injection of paclitaxel was used to test for a difference in the rate of crypt cell production in mice fed low- and high-fiber diets. Split-dose studies were used to test whether the change in proliferative status of the crypts was accompanied by changes in either the number of clonogens per crypt or their radiosensitivity, or an increased proliferative response to radiation-induced cell killing. We found an increase in the crypt LI induced by the high-fiber diet was 15-25% and was dependent on the time of day. The data on arrest in mitosis did not demonstrate a difference in cell production rates based on diet, possibly because of insufficient resolution of the assay. We conclude that the high-fiber diet had no effect on radiosensitivity, the number of clonogens per crypt (again, within the resolution of the assay) or the "repopulated dose," the dose represented by the shift in the dose-response curve for 2.5 days relative to that for 6 h. When the number of clonogens at the start of rapid proliferation was different (on account of different first doses), the repopulated dose was the same when 5 Gy X rays was given first but was higher for the animals on the high-fiber diet when 12 Gy was given first. The high-fiber diet caused an increase in the LI in the crypts that was not accompanied by any change in radiosensitivity or, within the resolution of the assay, numbers of clonogens per crypt. The increased LI also did not result in an increase in clonogen repopulation between split (and equal) doses. However, in split-dose experiments where the first dose was higher and as a consequence the number of clonogens at the start of the proliferative response was lower, there was evidence of a higher rate of clonogen production with the high-fiber diet than with the low-fiber diet.

Animals↗
PubMed1996

Tumor volume and local control probability: clinical data and radiobiological interpretations.

PURPOSE: It is well established for certain human tumor histologies that increasing tumor volume leads to a decreasing probability of tumor control. The simplest explanation for these findings is that the number of tumor clonogens that must be sterilized to control a tumor increases with tumor volume. In this investigation we consider whether clinical evidence favors a further hypothesis, namely, that clonogen number increases in direct proportion to tumor volume. METHODS AND MATERIALS: Previously published data on the volume-cure relationship for breast tumors, neck nodes, malignant melanoma, and squamous cell carcinomas of the oropharynx and the uterine cervix were analyzed. RESULTS: We found in all these data sets evidence that the effect of tumor volume on tumor control probability was less than what would be expected under the assumption of proportionality between number of clonogens and volume. We describe good reasons to believe that this is the result of patient-to-patient variability in radiocurability, and possibly other factors as well. CONCLUSIONS: Clinical data do provide evidence for a highly significant reduction of tumor control probability with increasing tumor volume. However, because of heterogeneity in patient and tumor characteristics, the volume effect is less pronounced than would be expected from a simple proportionality between number of clonogens and volume. In principle this simple proportionality does hold in individual patients, so that standard approaches for treatment plan optimization in individuals may still be valid.

Humans↗
PubMed1996

The clinical significance of ratios of radiobiological parameters.

PURPOSE: Interindividual heterogeneity of the radiobiological characteristics of malignant and normal tissues hampers the derivation of radiobiological parameters from clinical data. Focusing on the ratio Dprolif, i.e., the dose to compensate 1 day of treatment interruption, this article investigates the hypothesis that ratios of parameters might be less sensitive to interpatient heterogeneity and may constitute a more reliable description of the radiobiological properties of tissues than the parameters themselves. METHODS AND MATERIALS: Analytic calculations were performed in an idealized example in which the only source of heterogeneity was the number of clonogenic cells. Computer simulations were used to assess the effects of heterogeneity in radiosensitivity and in proliferative capacity. Treatment outcome was simulated in pseudopatients with increasing dose-time correlation. RESULTS: Interindividual heterogeneity in clonogenic cell number, radiosensitivity, or proliferative ability results in a marked underestimation of the response parameters describing these processes. In contrast, the estimates of the ratio Dprolif were more stable. The coefficients of variation increased with increasing heterogeneity. However, this only became unacceptable when heterogeneity in radiosensitivity was marked, or when total dose and treatment time were closely correlated. CONCLUSION: Parameter ratios may provide more robust radiobiological information than single parameters estimated from clinical data except when interindividual heterogeneity is very large or when the treatment modalities are too highly correlated. As usual, caution is advised in the presence of patient selection, a correlation between treatment prescription and expected outcome, or limited ranges of dose-time treatment patterns.

Cell Division↗