Radiation-induced lung damage: a challenge for radiation biology, experimental and clinical radiotherapy.
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Animals↗
Biomedical subjects
W Dörr
Publications and source records attributed to W Dörr.
Repopulation in mouse oral mucosa: changes in the effect of dose fractionation.
PURPOSE: To define the fractionation effect, including the magnitude and kinetics of dose compensation, on days 3 and 8 after a single priming dose of 8 Gy. MATERIALS AND METHODS: Graded radiation doses were given to the snouts of C3H/Neu mice in 1 to 5 fractions within a time period of < or = 36 h, or in four fractions with intervals from 5 min to 4 h. Each protocol was terminated by a top-up dose of 2.5 Gy to a 3 x 3 mm2 test area in order to precipitate the subclinical damage induced by the snout treatment and to generate the full dose response. RESULTS: No significant increase in isoeffective dose by increasing fraction numbers or by increasing interfraction intervals could be detected at each time point after the priming treatment. This indicates that the effect of dose fractionation was entirely lost. CONCLUSIONS: The loss of fractionation effect may be interpreted as a substantial impairment of the processes underlying recovery from sublethal damage as a consequence of a repopulation-inducing priming dose given 3 days or 8 days in advance.
Animals↗
[Biological principles for multimodal therapy approaches].
Cancer development and progression has been associated with numerous genetic events in tumor cells. Germline mutations of caretaker and gatekeeper genes are responsible for hereditary cancer syndromes. Exogenous factors in conjunction with functional germline variants of a variety of genes may contribute to tumor initiation in sporadic malignant disease. Furthermore, pathways to neoplasia require somatic events in the developing tumor. Acquired or inherited genetic instability permits stepwise tumor progression. The most fearsome aspect of tumor progression is dissemination of tumor cells to draining lymph nodes of the primary or to distant organs, which limits effectiveness of surgical therapy. Cellular heterogeneity of malignant neoplasms has important implications for chemotherapy and radiotherapy. An increasing understanding of the molecular biology of tumors is the prerequisite for improved prediction, prevention and therapy of malignant disease.
Cell Transformation, Neoplastic↗
Response of pig lung to irradiation with accelerated 12C-ions.
The response of pig lungs to irradiation with 12C-ions was assessed in two experiments to validate the procedures for heavy ion therapy planning at the Gesellschaft für Schwerionenforschung (GSI) and to explore their range of applicability. In both experiments, the target volume (spread-out Bragg peak, SOBP) was planned to be a 4 cm long cylinder with a diameter of 4 cm. Doses in the SOBP were prescribed to be equivalent to 5x4 Gy, 5x5.5 Gy and 5x7 Gy of x-rays in the first experiment, and to 5 fractions of 7 Gy and 9 Gy in the second experiment. The lung response in the first experiment was less than expected on the basis of earlier experiments with photons. Pneumonitis reaction and chronic fibrotic changes were observed outside the prescribed high-dose region. In the second experiment, the effects were more pronounced than had been expected on the basis of the first experiment. Changes were most intense in the high-dose region, but were also seen throughout the lung along the beam channel. Moreover, significant skin reactions were observed at the beam entrance site in all animals and - less pronounced - at the beam exit site in 3 of the 6 animals. In conclusion, the complex irradiation geometry of the pig lung, the changes of body weight between the two experiments, and insufficient accounting for a change in the relative biological effectiveness (RBE) computation led to substantial deviations of the observed reactions from expectations, the reasons for which could be identified in a subsequent analysis. The less pronounced lung reaction in the first experiment was due to an overestimation of RBE in a preliminary version of the algorithm for its determination. The extension of the fibrotic reaction resulted from the smear-out of the high-dose region due to density variations in tissue structures, respiratory movement, and limited positioning accuracy. The skin reactions at the entrance port reflect the different treatment geometry in the two experiments. The one unexplained observation is the mild skin reaction that was observed in the second experiment at the beam exit site.
Animals↗
Late functional response of mouse urinary bladder to fractionated X-irradiation.
PURPOSE: Late functional changes in mouse urinary bladder were studied after fractionated irradiation in order to define parameters of repair of sublethal radiation damage. MATERIALS AND METHODS: In the repair capacity study, 1 to 10 fractions were applied within 5 days. To assess the kinetics of repair, 4 fractions were applied with intervals of 0, 0.5, 1, 2, 4, or 8h. The endpoint used to establish dose-effect relationships was a reduction in the cystometrically measured bladder capacity by > or = 50% of the individual pre-treatment value. Data analysis was performed with a linear-quadratic mixture model, which includes latent-time analysis in an effect-dependent manner. RESULTS: The alpha/beta values were found to be 4.4 Gy (95% confidence interval [2.0-8.4]) for the repair capacity data alone and 3.7 Gy (1.7-6.7) in combination with the repair kinetics data. The half-time of repair, assuming mono-exponential repair kinetics, was 0.39 h (95% CI [0.23-1.3]). The mean latent time decreased from around 40 weeks to 12 weeks, inversely dependent on the biologically effective dose. In animals experiencing an acute response during the first month after treatment, the incidence of severe late responses was significantly increased (p=0.0025). CONCLUSIONS: The present results confirm that the sparing effect in the mouse urinary bladder by dose fractionation is in the lower range of chronically responding tissues. The half-time of repair is in the lower range reported for mouse tissues.
Animals↗
Reirradiation after radiotherapy of primary brain tumors.
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Adolescent↗
Short-term immobilization of mice by methohexitone.
The feasibility of short-term immobilization for <5 min of female mice by methohexitone sodium was studied. In C3H/Neu mice, methohexitone at a dose <40 mg/kg did not result in chemical restraint, doses >50 mg/kg caused considerable lethality. A dose of 44 mg/kg, applied intraperitoneally at a concentration of 6.46 mg/ml, is suitable for immobilization without complications. This concentration was chosen in order to achieve an injection volume of about 0.15 ml for a mouse with an average body weight of 22 g, corresponding to about 1 mg/mouse. Complete immobilization, defined as absence of the righting reflex, was observed within 3.3 +/- 0.8 min (mean +/- SD, n = 10) after the injection and lasted for 1.5 +/- 0.7 min. Recovery of the animals was complete after a total period of 10 to 15 min post-injection. No gross pathomorphological changes were induced when intraperitoneal injections of methohexitone were repeated 10 times within 10 days. In the present study, complete immobilization of the mice was safely achieved after 87 out of 90 injections. In conclusion, immobilization by intraperitoneal injection of methohexitone is a feasible and reliable method in the experimental studies of female mice.
Anesthesia Recovery Period↗
Radiation-induced impairment of urinary bladder function in mice: fine structure of the acute response and consequences on late effects.
The time course and dose response of radiation-induced impairment of urinary bladder function in the mouse were assessed after local irradiation with graded single doses. Bladder capacity was defined by transurethral cystometry; a reduction in bladder volume at an intravesical pressure of 10 mmHg by > or =50% of the individual pretreatment control value was considered a positive radiation reaction. Reversible effects of radiation on the urinary bladder were found during the first 30 days postirradiation, followed by a symptom-free latent period and irreversible late changes. Maximum-likelihood analysis revealed that the acute response is composed of two distinct waves from days 1-15 and days 16-30, with mean latent times of 7.1 days [95% confidence interval (5.4, 9.0)] and 23.3 days (21.9, 24.5), respectively, which describe the data significantly better than a single normal distribution (P = 0.0052). The ED50 values (+/- their standard deviation sigma), i.e. the doses at which 50% of the irradiated animals show the > or = 50% reduction in bladder capacity during each of the two intervals, were 21.7 +/- 4.1 and 19.3 +/- 3.9 Gy for the first and the second acute wave, respectively. The ED50 for the late functional effects was 18.7 +/- 2.4 Gy. Multivariate analysis demonstrated (1) that a response during the first acute wave correlated significantly with a reaction in the second acute wave (P = 0.0066), and (2) that a response during the second but not the first acute wave correlated significantly with the development of a late response (P = 0.0008). In conclusion, the present analysis suggests that the radiation response of the urinary bladder of the mouse displays a significant consequential component. However, further studies are required to demonstrate if the frequency of late sequelae can be decreased by an early intervention in the sequence of pathogenic processes.
Animals↗
Documentation of radiation-induced oral mucositis. Scoring systems.
BACKGROUND: Radiation therapy of tumors in the head and neck region is frequently associated with severe side effects in the oral mucosa which often necessitate interruption of the prescribed treatment protocol. In order to compare therapeutic strategies and, more important, in order to perform multi center studies, generally accepted scoring systems have to be applied for uniform documentation of the oral mucosal response. METHODS: Different scoring protocols are found in the literature. The scoring protocols most widely accepted are the CTC classification and the RTOG/EORTC classification. These are compared with more detailed systems. RESULTS: In the CTC classification, grading of stomatitis is included in the responses of the gastrointestinal tract and emphasizes dietary effects. For effects of radiation alone or of radiochemotherapy, the RTOG/EORTC system, focusing on therapeutic interventions, has been established. However, there are only minor differences in the grading of mucositis between these 2 protocols. Based on the RTOG/EORTC classification, Maciejewski et al. introduced a classification system with inclusion of the area affected, but also changed the sensitivity of the scores. The latter may be confusing if the source of the system used is not cited in a report. An alternative system was proposed by Dische, which in addition to objective morphologic criteria also includes the symptoms induced by the mucosal response, and hence includes some subjective aspects reported by the patient. CONCLUSIONS: For routine documentation of acute radiation side effects in the oral cavity, the German version of the RTOG/EORTC classification can be recommended. In studies with particular interest in oral mucositis, a more sensitive scoring system may be applied. In any publication concerning mucositis, a table or a detailed description of the system used should be included.
Documentation↗
[The radiotherapy of histiocytosis X. A case report of an eosinophilic granuloma in adulthood and a review of the literature].
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Adult↗
The impact of acute radiation morbidity on therapeutic outcome.
BACKGROUND: The acute radiation morbidity is associated with the radiation therapy outcome. METHODS: To give a summary of the impact of acute radiation morbidity on therapeutic outcome. RESULTS: Excessive acute side effects, most often seen in accelerated or hyperfractionated protocols or in combined radiochemotherapy may lead to interruptions of the radiation cycle and consecutively decreased tumor control rates. They may also result in an increase of consequential late damages. Furtheron, the patient may feel serious discomfort by subjective or objective complaints. CONCLUSIONS: Further national and international efforts have to be performed to lower the acute radiation related morbidity and to increase the effectiveness of radiation treatment.
Humans↗
Radiobiological models of normal tissue reactions.
PURPOSE: The present review summarizes radiobiological models of normal tissue responses to radiation and their consequences for potential therapeutic interventions. MATERIAL AND METHODS: Common radiobiological principles and pathogenetic models can be established for classes of tissues. These models may support the development of general modalities, both therapeutic and supportive, for the modulation of these responses. RESULTS: The stem cell concept, based on studies in standard tissue culture, describes the clonogenic survival after radiation treatment. The factors affecting cell survival are summarized as the 4 Rs of radiotherapy. Based on the stem cell concept, the reactions of normal tissue to ionising radiation were considered a consequence exclusively of the proliferative sterilisation of cells of a given target cell population. Once stem cells are inactivated, responses develop in a passive manner. However, recent studies into the pathogenesis of radiation tissue injury have clearly shown that numerous postirradiation events occur during the symptom-free latent time in irradiated cells and tissues, which modulate the manifestation of damage. These are summarized by models of tissue radiation pathology. CONCLUSIONS: Cellular radiobiology and the tissue models based on the stem cell concept assume that exclusively the sterilisation of target cells is the radiation effect which results in both acute and late tissue responses. As a consequence, the radiation sensitivity can only be modulated by modification of radiobiological parameters at the time of irradiation, while at later time points only symptomatic treatment can be applied. Tissue radiation pathology, in contrast, allows for post-irradiation modification of the manifestation of radiation sequelae in tissues.
Animals↗
Photographic documentation of acute radiation-induced side effects of the oral mucosa.
BACKGROUND: Radiotherapy in cancer of the head and neck induces cutaneous and mucosal reactions. These must be carefully assessed and documentated to control the accuracy of individual treatment, the overall toxicity of particular treatment schedules, the efficacy of prophylaxis and treatment and to determine the adequate therapy of treatment sequelae depending on the severity of the reactions. The accurate classification of lesions according to internationally accepted schedules (WHO/RTOG/CTC) is indispensable for the comparison of radiotherapy treatment results and efficacy of supportive care. METHODS: While the treatment of cancer depends on tumor stage and medical circumstances of the patient and is more or less standardized, prophylaxis and treatment of side-effects is highly variable. Discussing an optimized prophylaxis and therapy of oral mucositis, the problem of accurate classification and documentation emerged. The verbal description of mucosal lesions is open to many subjective interpretations. Photographic documentation seems a suitable method to optimize the grading of toxicity. RESULTS: A photographic survey of typical lesions for each grade of toxicity is a tool to reach several aims in one step. Toxicity of an individual patient may be compared with representative photographic examples in daily routine to decide quickly on the grade of toxicity. Subjective differences due to intra- and interpersonal variability of the evaluating radiooncologist will be reduced. The efficacy of treatment can be proven by accurate documentation. Randomized clinical studies concerning prophylaxis and treatment of oral mucositis will provide more reliable results if evaluation of toxicity grading is standardized by photographs. CONCLUSIONS: Photographic documentation of lesions of the oral mucosa might be the best means to reduce interindividual subjectivity in grading. It is a valuable appendix to standard classification systems and only concerns the visible signs of mucosal lesions. However, the exact grading of mucositis is only possible with additional clinical information about pain and nutritional situation.
Documentation↗
Individual skin care during radiation therapy.
BACKGROUND: In many clinical settings, the irradiated patient feels additional discomfort by the inhibition of washing the treatment portals and interruption of his adapted skin care habits. MATERIAL AND METHODS: An analysis of the scientific recommendations as well as an analysis of the skin dose to the irradiated portals has been performed. An individual scheme for skin care under radiation has been developed. RESULTS: A substantial decrease of the skin dose is achieved in many modern radiation techniques. The consequent reduction of severe skin reactions allowed the use of water and mild soaps as has been approved within many radiotherapy departments. This has lead to an individualized concept for skin care under radiation treatment including the allowance of gentle washing. The skin marks may be saved by using highly tolerable adhesive plasters or small tattoo points, if they are not superfluous by using masks or single referee points instead of marks for the field borders. CONCLUSIONS: The individualized concept for skin care during radiation may offer improved life quality to the patient and may decrease the acute reactions of the skin at least in some cases.
Baths↗
Pathogenesis of acute radiation effects in the urinary bladder. Experimental results.
PURPOSE: The present review summarizes experimental studies of the pathogenesis of acute radiation-induced changes in urinary bladder function. MATERIAL AND METHODS: Transurethral cystometry was used for longitudinal assessment of bladder function in mice. With this technique, radiation-induced changes in storage capacity can be quantified. In histological studies, changes in urothelial cell density and in urothelial protein expression during the acute radiation response were determined. Acetylsalicylic acid (ASA) was used for the treatment of acute functional changes. RESULTS: The histological studies did not reveal any systematic fluctuations in urothelial cell density during the time of the acute radiation response. However, characteristic changes in the expression of proteins associated with urothelial cell function, differentiation and cell contact were observed, which correlated with the functional impairment. By local or systematical application of ASA, a significant restoration of bladder function compared to placebo treatment could be achieved. CONCLUSION: Acute functional radiation effects in the urinary bladder are not based on urothelial denudation. However, changes in protein expression indicate an impairment of the urothelial barrier function. The results of ASA treatment demonstrate that prostaglandins are involved in the response. Alterations in urothelial or endothelial prostaglandin metabolism may be primarily radiation-induced or secondary because of the impaired urothelial barrier.
Animals↗
Radiation-induced impairment of urinary bladder function. Assessment of micturition volumes.
PURPOSE: The present investigation was initiated in order to study the feasibility of repeat micturition volume measurements for the determination of acute variations in urinary bladder function in radiotherapy patients. PATIENTS AND METHODS: Thirty-seven consecutive patients with malignancies of the prostate (11), rectum (9), corpus uteri (11), or cervix uteri (6) were included in this pilot study. All patients were treated according to standard irradiation protocols. All patients were asked to present with maximum bladder filling for each radiation treatment. After irradiation, patients were weighed before and after micturition, and the weight difference was assumed to reflect the micturition volume. RESULTS: No systematical variations in bladder capacity could be assessed during treatment for uterine tumors. In rectum carcinoma patients, a decrease in micturition volume by about 20% was observed between weeks 2 and 5 which, however, was not statistically significant; subsequently, normal to supra-normal values were measured. In patients treated for prostate cancer, volumes were reduced from week 2; in weeks 5 to 6, minimum values of approximately 70% of the control volumes were seen, which represent a significant reduction (p < 0.05). CONCLUSIONS: Functional changes represent the majority of side effects of radiation therapy in the urinary bladder. The assessment of urinary bladder function by pre- and post-micturition weighing is a feasible and sensitive method to objectively determine radiation-induced changes. This method may be applied for the documentation of acute radiotherapy side effects.
Documentation↗
[New approach to conservative therapy of radiation injuries].
PURPOSE: The improvement of tumor control rates and improved survival times of radiotherapy patients result in an increasing importance of radiation side effects in normal tissues. METHODS: Possibilities for the modulation of normal tissue reaction by stimulation of tissue regeneration, or by interference with general pathogenetic pathways which are not specific for radiation damage, are illustrated by a number of examples. RESULTS AND CONCLUSIONS: Increasing knowledge about the pathogenesis of normal tissue radiation responses are expected to significantly improve the efficacy of prophylactic means and possibilities for conservative management of side effects of radiation therapy. Novel approaches may be developed if the so-called "humoral radiation pathology" is taken into consideration in addition to the cellular effects of radiation.
Erythropoietin↗
[The therapeutic management of radiogenic oral mucositis].
BACKGROUND: Acute reactions of oral mucosa are a frequent side effect of radiotherapy, which often necessitates interruption of the treatment. Marked proliferation of tumor stem cells during treatment interruptions may occur in squamous cell carcinomata, which represent the majority of tumors in the head and neck area. Hence a fatal consequence of treatment breaks may be a significant decrease in tumor cure rates. Furthermore, marked acute responses frequently result in increased late sequelae ("consequential damage"). Therefore, amelioration of the mucosal response aiming at avoiding treatment breaks and at reduction of late reactions could definitely increase the therapeutic success of radiation treatment. PATIENTS AND METHOD: Various possibilities for the therapeutic management of radiation-induced oral mucositis with a symptomatic or radio- and epithelial biological background are summarized and presented systematically. RESULTS: A variety of prophylactic and therapeutic methods have been proposed for the management of acute radiation reactions of the oral mucosa. Frequently, their efficacy has been established for chemotherapy or in combination with other immunosuppressive treatments. Hence, systematical rather than local effects have to be considered. CONCLUSIONS: In general, prophylaxis of oral mucositis is mainly based on dental restoration or edentation, in combination with frequent oral hygienic measures after the meals and with antiseptic mouthwashes. Intensive personal care is recommended. The necessity of a percutaneous endoscopic gastrostoma is dependent on the status of the patient and on size and localization of the treatment area, i.e. the impairment of food uptake which is to be expected. Therapeutic intervention is restricted to local or systemic treatment of pain and local application of antimycotics and antibiotics.
Acute Disease↗