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H R Withers

Publications and source records attributed to H R Withers.

At least 37 records · Page 2Linked to original sources
PubMed1997

Sources of variability in the determination of micronuclei in irradiated peripheral blood lymphocytes.

Following a dose of 4 Gy 250 kVp X-rays to the blood lymphocytes from three healthy donors the frequency of micronuclei was enumerated by three scorers. Eight slides were prepared from each blood sample with 1000 cytokinesis-blocked binucleate cells being scored for micronuclei and a recount undertaken 4 weeks later. Seven possible sources of variation were investigated: differences between donors, scorers, the four stages of sample preparation and time. A complete factorial analysis indicated that the major sources of variation were differences between donors and differences between scorers. One scorer identified fewer micronuclei than did the other two scorers in all slides of the irradiated blood samples and gave wide and inconsistent results for baseline counts. These results suggest that the performance of scorers should be screened before undertaking analysis of micronuclei. The most striking result, however, was the consistent performance of the scorers on the repeat counts compared with the very large differences between the scorers.

Adult↗
PubMed1997

Non-linear effects in dose-time analyses: application of modern statistical techniques.

BACKGROUND AND PURPOSE: The non-linear effect of overall treatment time and total dose on the outcome of fractionated head and neck radiotherapy is of interest. This and other non-linear effects can be investigated using recently developed statistical techniques. This article provides an illustration of the ability of these statistical methods. MATERIALS AND METHODS: Recently developed statistical methods (Hastie, T.J. and Tibshirani, R.J. Generalised Additive Models. Chapman-Hall, London, 1990), called generalized additive models, are applied to data from the patterns of fractionation study (Withers, H.R., Peters, L.J., Taylor, J.M.G., Owen, J.B., Morrison, W.H., Schultheiss, T.E., Keane, T., O'Sullivan, B., van Dyk, J., Gupta, N., Wang, C.C., Jones, C.U., Doppke, K.P., Myint, S., Thompson, M., Parsons, J.T., Mendenhall, W.M., Dische, S., Aird, E.G.A., Henk, J.M., Bidmead, M.A.M., Svoboda, V., Chon, Y., Hanlon, A.L., Peters, T.L. and Hanks, G.E. Local control of carcinoma of the tonsil by radiation therapy: an analysis of patterns of fractionation in nine institutions. Int. J. Radiat. Oncol. Biol. Phys. 33: 549-562, 1995) of tonsil cancer. These techniques enable one to develop models which more accurately represent the relationship between multivariate predictor variables and the outcome variable in a regression analysis. These data driven methods allow the effect of each predictor variable on the outcome to be non-linear and estimated from the data. This is achieved by replacing the standard linear model combination of predictor variables, such as 'alpha0 + alpha1dose + alpha2time' by 'S1(dose) + S2(time)', where S1 and S2 are smooth non-linear functions of dose and time, respectively, which are estimated from the data. RESULTS: In the pattern of fractionation study these methods indicate that the effect of total dose on the probability of local recurrence is linear, but there is a suggestion that the effect of overall treatment time is non-linear. There is no effect of dose and time on the latency time to recurrence of those who do recur, but there is a weak suggestion of a non-linear effect of patients age, with younger patients recurring earlier. CONCLUSIONS: Generalized additive models provide a flexible and powerful means of exploring non-linear effects in experimental data.

Adult↗
PubMed1997

Induction of c-fos and junB mRNA following in vivo brain irradiation.

Although radiotherapy is a front line treatment for brain tumors, little is known about the in vivo molecular responses of brain to irradiation. In this study, expression of c-fos, c-jun and junB immediate-early genes were followed in mouse brain after irradiation. C-fos and junB, but not c-jun, mRNA was induced within 15 min in unanesthetized irradiated mice. Induction was transient and lasted < 4 h. The response was dose-dependent with increases in c-fos and junB mRNA levels after dose of > or = 2 and 7 Gy, respectively. Anesthesia of mice with pentobarbitol delayed the increases in mRNA expression and the response was attenuated. Pre-treatment of mice with dexamethasone, in a schedule which suppressed acute-phase gene expression after brain irradiation, did not significantly change c-fos and junB induction. Our results show that c-fos and junB responses occur in the brain in response to irradiation and that they can be modified by pentobarbital treatment but suggest that there is no direct correlation between the level of mRNA expression and later expression of cytokines or other acute-phase response genes.

Animals↗
PubMed1997

Effect of low-dose radiation on mouse dermal tissue using wound strength as an endpoint.

PURPOSE: To investigate the existence of enhanced sensitivity of dermal tissue to low radiation doses in the range of 0.1 Gy to 4 Gy/fraction. MATERIALS AND METHODS: Top-up technique of giving higher radiation doses to skin alone from 150 kVp X-rays followed by fractionated experimental doses to total body from 137Cs were given to C3H mice. Full-depth incisions were made and the tensile strength of skin from 14 day wounds were measured as a response of dermal tissue to radiation. RESULTS: There was no evidence of enhanced radiosensitivity to doses as low as 0.1 Gy. The data were better fitted by a nonparametric method that predicted the shape of survival curve better than an induced-repair model. CONCLUSIONS: Dermal tissue like spinal cord has a low sensitive fraction of cells, unlike jejunum, kidney or lung that showed sensitivity at these doses. Tissue kinetics play an important role in the use of low dose fractions to avoid injury to normal tissues.

Animals↗
PubMed1997

Delayed molecular responses to brain irradiation.

The chance of life-threatening complications occurring late after brain irradiation limits the efficacy of this form of cancer therapy. The molecular and cellular events that trigger radiation-induced brain damage are still unknown, but since they have the potential to serve as valuable targets for therapeutic intervention they are worth delineating. In this murine study, the effect of irradiation on the expression of molecules which are known to contribute to brain damage in other model systems was examined. Expression of genes encoding cytokines (TNF-alpha/beta, IL-1 alpha/beta, IL-2, IL-3, IL-4, IL-5, IL-6 and IFN-gamma), cytokine receptors (TNF-Rp55 and p75, IL-1R- p60 and p80, IFN-gamma R, and IL-6R), the cell adhesion molecule (ICAM-1), inducible nitric oxide synthetase (iNOS), anti-chymotrypsin (EB22/5.3), and the gliotic marker (GFAP) was evaluated over a 6-month period using a sensitive RNase protection assay (RPA). We had previously demonstrated that within 24 h of brain irradiation there is an acute transitory molecular response involving TNF-alpha, IL-1, ICAM-1, EB22/5.3 and GFAP. This study shows re-elevation of TNF-alpha, EB22/5.3 and GFAP mRNA levels at 2-3 months, but only TNF-alpha mRNA was overexpressed at 6 months. These time points are when neurological abnormalities are seen after higher doses. The data suggest that TNF-alpha may be involved in late brain responses to irradiation and could contribute to clinical symptoms.

Animals↗
PubMed1997

Incidence and kinetics of distant metastases in patients with operable breast cancer.

The purpose of this paper is to evaluate the incidence and kinetics of distant metastases in operable breast cancer and to relate these estimates to various tumor and patient characteristics. The records of 309 consecutive patients with operable breast cancer in stage T1-4N0-1M0 were reviewed, and the incidence of distant metastases (DM) and death due to DM were evaluated. 195 patients had positive axillary nodes with the following distribution of the number of nodes: 45% had 1-2 node, 16% had 3-4 nodes, 14% and 25% had 5-7 and more nodes, respectively. All patients were treated with radical mastectomy with axillary nodes dissection (the only treatment in 39% of cases). In 198 cases radical mastectomy was combined with radiotherapy and/or chemotherapy given pre- or postoperatively. Hormonal treatment was given in 27% of cases. Minimum follow-up was 10 years. Distant metastases were found in 150 cases (49%) and in 78 cases (25%) they developed early, during the first 18 months follow-up. Average rate of DM in N0 cases was 25%. Number of involved nodes and extracapsular invasion were found significant and independent prognostic factors. High risk (50%) of DM and death due to DM correlate with age < 40 y, premenopausal status, tumor stage > or = T3, more than 2 axillary nodes and/or extracapsular invasion. The linearity of the curves for freedom from DM and for freedom from death due to the DM suggest uniform distribution of progression rates with a median value for halving time for freedom from early DM of about 8 months, and of about 40 months for freedom from the DM occurring later than 18 months, being for whole group an average of 20 months. High incidence of DM is a significant cause of poor long-term survival. Early appearance (< 18 month follow-up) of about half of the DM suggests that they are already present as subclinical micrometastases at the time of initial loco-regional treatment. The time of appearance of distant metastases is consistent with a wide range of metastatic cell burdens among patients. Systemic therapy, at least for selected group of patients, might decrease the incidence of DM and improve long-term results.

Adenocarcinoma↗
PubMed1997

Sensitization of renal carcinoma to radiation using alpha interferon (IFNA) gene transfection.

The rationale for this study was that local delivery of interferon-alpha (IFN-alpha) by gene transfection may be of value during radiotherapy. To investigate the feasibility of this approach, cells of the human renal carcinoma cell line R11 were transfected with the IFNA gene and evaluated for radiation responses in vitro by clonogenic assays. R11 cells expressing IFN-alpha after gene transfection were more sensitive to radiation than R11 control cells (SF2 = 0.33 and 0.51, respectively). In addition to increasing radiosensitivity, IFNA gene transfection slowed cellular growth and reduced the plating efficiency in clonogenic assays. The addition of exogenous rhIFN-alpha to cells at different times relative to irradiation showed that its presence during the postirradiation period was critical for radiosensitization, but repair of sublethal damage did not seem to be affected. No apoptosis of R11 cells was found 1-5 days after exposure to 2-25 Gy with or without IFN-alpha. Extensive formation of multinuclear giant cells was present beginning 2 days after irradiation; however, IFN-alpha did not cause any major alterations in the yield of radiation-induced giant cells. These studies suggest that gene transfection might be an effective means of delivering IFN-alpha for clinical use in radiotherapy of cancer.

Carcinoma, Renal Cell↗
PubMed1996

What TPOT is not.

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Carcinoma, Squamous Cell↗
PubMed1996

The effect of delay in treatment on local control by radiotherapy.

PURPOSE: The objective of this study was to estimate the effect of delay in initiation of treatment on rates of local control by radiotherapy. METHODS AND MATERIALS: A model of the effects of delay was developed based on the following assumptions: (a) that tumor growth rate is exponential, (b) that a predetermined radiotherapy regimen will kill the same fraction of clonogenic cells in a given tumor whether it is administered early or late, and (c) that the absolute number of cells surviving in a tumor is determined by Poisson statistics. Monte Carlo simulation was used to estimate the expected rate of decrease in local control associated with delay in a population of tumors, which was heterogeneous with respect to doubling time and initial volume. The model was applied to carcinoma of the tonsillar region. RESULTS: It was shown that at some point in the evolution of every case, the probability of local control decreases sharply over a relatively short period of time. The maximum rate of decrease in the probability of local control occurs at the 37% local control level when it reaches 25.5% per tumor doubling time. When heterogeneity with respect to doubling time and stage was taken into account, it was estimated that the local control rate would decrease by approximately 10% per month in a typical series of patients with carcinoma of the tonsillar region. CONCLUSIONS: It was concluded that delay in initiation of radiotherapy may be associated with a clinically important deterioration in local control rates. We recommend that waiting times for radiotherapy should be As Short As Reasonably Achievable (ASARA).

Algorithms↗
PubMed1996

Influence of selection bias on dose-time analysis: a theoretical investigation.

BACKGROUND AND PURPOSE: We investigate the effect of patient selection factors on the interpretation of dose-time analyses of retrospective head and neck data treated with external beam radiation therapy. MATERIALS AND METHODS: We use a computer simulation model to ascertain the influence of individualizing the fractionation regimen on the estimated steepness of dose-response and time-response estimates, on the probability of local control and on the validity of statistical tests and confidence intervals. We assume that the total dose and overall treatment time for each patient are altered by consideration of three possible factors, the pre treatment size of the tumor, the response of the tumor to therapy or the amount of acute effects. RESULTS: We find that individualizing treatment leads to very small improvements in the local control rate, but substantial biases in the estimates of the doubling time and the effective D0 value. Patient selection also compromises the validity of confidence intervals and tests. Despite this selection bias our results suggest that if there were no real effect of treatment time then the influence of individualizing treatments would not cause treatment time to be found to be as important as it has been shown to be in many studies. CONCLUSIONS: Assuming the fundamental radiobiological assumptions in the model are appropriate, individual alterations of the fractionation schedule due to the response to therapy can compromise the interpretation of dose-time analyses of retrospective data, without giving much improvement in the control rate.

Bias↗
PubMed1996

The principles of palliative radiotherapy: a radiobiologist's perspective.

There is a dearth of knowledge on the radiobiology of palliative radiotherapy, but some of the principles relevant to radical radiation treatments can be applied to the palliative situation. Nevertheless with minimal animal or human data available, it would appear that this area can be a fertile one for future study, although many of the difficulties and problems inherent in this type of research must be acknowledged and addressed.

Animals↗
PubMed1995

Local control of carcinoma of the tonsil by radiation therapy: an analysis of patterns of fractionation in nine institutions.

PURPOSE: To investigate the importance to outcome of treatment for squamous cell carcinomas of the tonsillar fossa, of dose per fraction, overall treatment duration, and total dose. METHODS AND MATERIALS: A collaborative retrospective study was undertaken in nine centers that used widely different dose-fractionation patterns for external beam radiation therapy. RESULTS: There were 676 eligible cases treated only with photon beams during the years 1976-1985. The probability of local control (of the tonsillar fossa primary) was influenced by both T-stage and N-stage. Significant treatment parameters were total dose and overall treatment duration, but not dose per fraction. Over the range of about 40 to 90% and for a constant overall treatment duration, local tumor control probability increased by nearly 2% for each 1 Gy increase in total dose. For a constant total dose there was a decrease in the probability of local control associated with prolongation of overall treatment duration, presumed to result from accelerated regrowth of surviving tumor clonogens during the course of treatment. If it is assumed that accelerated regrowth occurred at a constant rate and began within 9 days of the start of treatment, an average of 0.53 Gy extra dose per day's extension of treatment would be required to maintain a constant probability of local control. Correspondingly, the probability of local control from a constant dose would be lowered by an average of at least 1% for each day's extension of treatment duration. However, the data are slightly more consistent with an average delay of as long as 30 days before onset of accelerated repopulation, with a consequent increase to an average of 0.73 Gy per day for the value of the compensatory dose. The alpha/beta ratio for this tumor is high enough that the effect of fraction size on the probability of local control can be ignored; a precise estimate is not possible because the best value for beta was close to zero. After accounting for the significant variables studied (treatment time, T-stage, N-stage), the dose-response curves for tumor control were still shallow, suggesting that there are additional causes for heterogeneity of responses among these tumors. CONCLUSIONS: Total dose is important to treatment outcome: After accounting for other treatment variables, there is about a 2% per Gy increase in probability of tumor control over the ranges of control commonly achieved. Overall treatment duration is important. There is at least a 1% per day decrease in tumor control probability if delivery of a constant total dose is prolonged, requiring a compensatory increase in dose by 0.5-0.7 Gy per day to achieve a constant rate of tumor control. Fraction size is not, of itself, an important factor in the response of primary carcinoma of the tonsil. If a tumor has demonstrated a capacity for metastatic spread to lymph nodes, a higher total dose should be considered to achieve control rates at the primary site equivalent to those in node negative patients. Even after accounting for variables such as tumor stage, total dose, and overall treatment duration, there is sufficient heterogeneity in other undocumented determinants of tumor control to cause the tumor control probability curve to be a shallow function of dose.

Analysis of Variance↗
PubMed1995

Late normal tissue sequelae from radiation therapy for carcinoma of the tonsil: patterns of fractionation study of radiobiology.

PURPOSE: To evaluate the influence of dose fractionation and other factors on the development of late complications in mandibular bone, muscle, and mucosa of the oral cavity after external beam radiation therapy for carcinoma of the tonsil. METHODS AND MATERIALS: A retrospective analysis was made of the results in 676 patients treated with a spectrum of fractionation regimens in nine centers during the years 1976-1985. Only severe (Grades 3-4) late complications were analyzed. RESULTS: With more than 5 years follow-up, it was found that total dose was a factor for all three types of complications, but that in other respects, the radiobiology of late-(> 3 months) developing mucosal ulcerations was different from that for mandibular necrosis and muscle injury. Dose per fraction was a significant factor for bone and muscle (estimated alpha/beta values of 0.85 Gy and 3.1 Gy, respectively). By contrast, mucosa showed no influence on response from change in fraction size over the range of approximately 1.0-3.5 Gy. Complications in bone and muscle were not related to overall treatment duration, whereas there was a significant inverse relationship for mucosa breakdown. The rate of development of complications was fastest in mucosa and slowest in bone. The appearance of complications by 4 years after treatment was about 80% of those developing by 8 years in the mucosa, 66% in muscle, and about 50% in bone. The high alpha/beta ratio, inverse relationship with overall treatment duration, and faster development of mucosal complications suggests that they may develop as a consequence of earlier mucosal injury. As anticipated, adequate retrospective analysis of acute complications could not be made even when objective criteria such as weight loss, unplanned delays in completing treatment, or hospitalization during treatment were the measures. Field size was a significant factor for mandible complications, but not for muscle or mucosa. CONCLUSION: The radiobiological characteristics of bone and muscle were those characteristic of other late-responding tissues, whereas late sequelae in mucosa had radiobiological parameters similar to those for acute responses. Field size was a significant factor for bone complications but not for others.

Carcinoma, Squamous Cell↗
PubMed1995

Induction of acute phase gene expression by brain irradiation.

PURPOSE: To investigate the in vivo acute phase molecular response of the brain to ionizing radiation. METHODS AND MATERIALS: C3Hf/Sed/Kam mice were given midbrain or whole-body irradiation. Cerebral expression of interleukins (IL-1 alpha, IL-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6), interferon (IFN-gamma), tumor necrosis factors (TNF-alpha and TNF-beta), intercellular adhesion molecule-1 (ICAM-1), inducible nitric oxide synthetase (iNOS), von Willebrand factor (vWF), alpha 1-antichymotrypsin (EB22/5.3), and glial fibrillary acidic protein (GFAP) was measured at various times after various radiation doses by ribonuclease (RNase) protection assay. The effects of dexamethasone or pentoxifylline treatment of mice on radiation-induced gene expression were also examined. RESULTS: Levels of TNF-alpha, IL-1 beta, ICAM-1, EB22/5.3 and to a lesser extent IL-1 alpha and GFAP, messenger RNA were increased in the brain after irradiation, whether the dose was delivered to the whole body or only to the midbrain. Responses were radiation dose dependent, but were not found below 7 Gy; the exception being ICAM-1, which was increased by doses as low as 2 Gy. Most responses were rapid, peaking within 4-8 h, but antichymotrypsin and GFAP responses were delayed and still elevated at 24 h, by which time the others had subsided. Pretreatment of mice with dexamethasone or pentoxifylline suppressed radiation-induced gene expression, either partially or completely. Dexamethasone was more inhibitory than pentoxifylline at the doses chosen. CONCLUSIONS: The initial response of the brain to irradiation involves expression of inflammatory gene products, which are probably responsible for clinically observed early symptoms of brain radiotherapy. This mechanism explains the beneficial effects of the clinical use of steroids in such circumstances.

Animals↗
PubMed1995

Biologically effective dose distribution based on the linear quadratic model and its clinical relevance.

PURPOSE: Radiotherapy plans based on physical dose distributions do not necessarily entirely reflect the biological effects under various fractionation schemes. Over the past decade, the linear-quadratic (LQ) model has emerged as a convenient tool to quantify biological effects for radiotherapy. In this work, we set out to construct a mechanism to display biologically oriented dose distribution based on the LQ model. METHODS AND MATERIALS: A computer program that converts a physical dose distribution calculated by a commercially available treatment planning system to a biologically effective dose (BED) distribution has been developed and verified against theoretical calculations. This software accepts a user's input of biological parameters for each structure of interest (linear and quadratic dose-response and repopulation kinetic parameters), as well as treatment scheme factors (number of fractions, fractional dose, and treatment time). It then presents a two-dimensional BED display in conjunction with anatomical structures. Furthermore, to facilitate clinicians' intuitive comparison with conventional fractionation regimen, a conversion of BED to normalized isoeffective dose (NID) is also allowed. RESULTS: Two sample cases serve to illustrate the application of our tool in clinical practice. (a) For an orthogonal wedged pair of x-ray beams treating a maxillary sinus tumor, the biological effect at the ipsilateral mandible can be quantified, thus illustrates the so-called "double-trouble" effects very well. (b) For a typical four-field, evenly weighted prostate treatment using 10 MV x-rays, physical dosimetry predicts a comparable dose at the femoral necks between an alternate two-fields/day and four-fields/day setups. However, our BED display reveals an approximate 21% higher BED for the two-fields/day scheme. This excessive dose to the femoral necks can be eliminated if the treatment is delivered with a 3:2 (anterio-posterior/posterio-anterior (AP/PA): bilaterally opposed (BLO)) dose weighting. With Co-60 beams, the increase of BED with alternate two-fields/day, 1:1 setup was even more pronounced (26%). CONCLUSION: We have demonstrated the feasibility of constructing a biologically oriented dose distribution for clinical practice of radiotherapy. The discordance between physical dose distributions and the biological counterparts based on the given treatment schemes was quantified. The computerized display of BED at nonprescription points greatly enhanced the versatility of this tool. Although the routine use of this implementation in clinical radiotherapy should be cautiously done, depending largely on the accuracy of the published biological parameters, it may, nevertheless, help the clinicians derive an optimal treatment plan with a particular fractionation scheme or use it as a quantitative tool for outcome analysis in clinical research.

Feasibility Studies↗