[Hyperfractionated radiotherapy: the status of research].
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Dose Fractionation, Radiation↗
Biomedical subjects
T Herrmann
Publications and source records attributed to T Herrmann.
Crosslinking of progesterone receptor to DNA using tuneable nanosecond, picosecond and femtosecond UV laser pulses.
UV laser crosslinking is a potentially powerful tool to investigate transient DNA-protein interactions and binding kinetics in intact cells. As the processes underlying UV laser crosslinking are not fully understood, we have performed a study of the influence of laser pulses with different physical parameters on crosslinking of the progesterone receptor to an oligonucleotide containing a hormone-responsive element. We also studied the influence of the various parameters on the amount of laser-irradiated DNA that can be correctly primer extended as an operational measurement of DNA integrity. A strong influence of pulse intensity and pulse length on the crosslink yield was found, likely due to a change in the 'two photon' processes responsible for crosslinking. The highest efficiency of protein crosslinking to DNA was achieved with femtosecond pulses and should be sufficient to enable use of this technique for in vivo studies.
Animals↗
[CHARTWEL-Bronchus (ARO 97-1): a randomized multicenter trial to compare conventional fractionated radiotherapy with CHARTWEL radiotherapy in inoperable non-small-call bronchial carcinoma].
BACKGROUND: The CHART-bronchus trial sponsored by the Medical Research Council showed an improvement in survival of 10% compared to conventional fractionation to 60 Gy when patients with inoperable non-small-cell lung cancer (NSCLC) were treated with CHART to 54 Gy. At present it is not known whether this survival advantage holds when the dose of conventional treatment is increased and whether CHART can be replaced by the more practicable CHARTWEEL (CHART-weekend less). PROTOCOL OF THE TRIAL: A randomized multicenter trial of definite radiotherapy in locally advanced inoperable NSCLC was designed (ARO 97-1, Arbeitsgemeinschaft Radioonkologie der Deutschen Krebsgesellschaft). Conventional fractionation to 66 Gy (5 weekly fractions of 2 Gy) is compared with CHARTWEEL to 60 Gy (15 weekly fractions of 1.5 Gy, Monday to Friday, interval between fractions > or = 6 hours, overall treatment time 2.5 weeks). The main endpoint of the trial is overall survival. It was calculated that an entry of 665 patients is needed to detect an improvement in 2-year survival of 10%, the actual time is estimated to be 5 years or less. The trial was activated on 1.9.1997.
Adult↗
[Radiation reactions in the gonads: importance in patient counseling].
PURPOSE: The intention of this article is to summarize the effects of radiation therapy on the female and male gonadal function. RESULTS: In woman a decreasing tolerance to radiation is observed with increasing age, due to the decreasing number of follicles. The mean tolerance dose for sterilization is between 5 and 10 Gy. If both ovaries receive only scattered doses-radiation effects on the ovaries are dependent on the age of the women at the time of treatment. However, if both ovaries are included in the treatment volume of a tumor radiation therapy, sterilisation is unavoidable. In man even scattered doses are able to decrease the sperm cell counts in the range of 2 to 3 Gy in conventional fractionation regimes. Complete restoration of spermatogenesis is possible during the first 2 years after treatment, but is unlikely after 3 years. In contrast to the situation in female, impairment of male endocrine gonadal functions are observed only after testicular doses higher than 20 to 30 Gy. In female children the tolerance dose of the ovaries is higher than in the adult woman, while the gonadal endocrine function in boys is more sensitive than in adult men. In contrast, spermatogenesis is not initiated in young boys, and hence less radiation effects are induced. CONCLUSIONS: In all treatment situations-in adults as well as in children-an additive effect of the combination of chemotherapy with radiation on gonadal function has been shown. However, the severity of damage by radio-chemotherapy is highly dependent on the drugs used.
Adolescent↗
[Outcome of CHART radiotherapy in squamous cell carcinoma of the head and neck and in non-small cell bronchial carcinoma].
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Carcinoma, Bronchogenic↗
[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↗
Effect of irradiated volume on lung damage in pigs.
BACKGROUND AND PURPOSE: The volume dependence of radiation induced lung damage is of important clinical concern. The aim of the present study was to investigate the effect of irradiated volume on radiation pneumonitis and lung fibrosis in pigs after fractionated irradiation. MATERIALS AND METHODS: Twenty-five animals were irradiated with 10 x 14 cm2 fields to the whole right lung (about 530 cm3), while 19 animals received irradiation only to the lower part of the right lung (10 x 8 cm2 fields, about 260 cm3). The irradiations were given in five fractions over 5 days with total doses ranging from 14.3-38.0 Gy (whole lung) or 21.3-31.2 Gy (half lung) using a 60cobalt unit and an isocentric technique. Early lung damage was assessed during the first 8 weeks after the start of treatment by weekly chest radiographs and by twice weekly determinations of the breathing rate in resting animals. Fibrosis was quantified at autopsy (after 8 weeks or after 5-8 months) by histological evaluation and by determination of the hydroxyproline content of the lung tissue. Based on reference values obtained in 17 untreated control animals the experimental data were converted to quantals for probit analysis. RESULTS: The data did not indicate any significant differences for the incidence of lung damage after half lung and whole lung irradiation when injury was assessed by radiography, histology, or hydroxyproline content. However, using an increase in breathing rate as experimental endpoint, significant differences of radiation induced morbidity were observed. While none of the animals after half lung irradiation showed pathological breathing rates even after doses of 29 Gy and 31 Gy, a clear if shallow dose-response relationship with an ED50-value of 27 +/- 11 Gy (SD) was obtained after whole lung irradiation (P < 0.01). CONCLUSIONS: A volume effect can only be demonstrated for functional lung morbidity whereas induction of structural lung damage is independent of the volume irradiated.
Animals↗
Control of TCR V alpha-mediated positive repertoire selection and alloreactivity by differential J alpha usage and CDR3 alpha composition.
In rats expressing the f allele of the rat MHC (RT1f), CD8 T cells utilizing the V alpha 8.2 segment are 10-fold overselected during thymic development, resulting in V alpha 8.2 expression by 14% of mature CD8 T cells as compared to 1-2% in MHC congenic strains. In the alloreactive responses of CD8 T cells from RT1f-negative rats against RT1f, V alpha 8.2+ CD8 T cells are also preferentially expanded. Neither overselection nor alloreactivity of V alpha 8.2+ TCR require selective V beta pairing. However, RT1f alloreactive V alpha 8.2+ TCR preferentially use a related set of J alpha segments which contribute short homogeneous CDR3 alpha loops, with features suggesting peptide promiscuity, and little N additions. In contrast, only few overselected V alpha 8.2+ CD8 T cells showed an imprint of positive selection on J usage or CDR3 composition. The results demonstrate that a single V alpha segment can promote both MHC allele-specific positive selection and alloreactivity, and that the latter is more dependent on an additional contribution of CDR3 alpha, possibly by promoting reactivity with a diverse set of MHC-bound peptides or by providing additional MHC contacts.
Alleles↗
Acute response of pig skin to irradiation with 12C-ions or 200 kV X-rays.
The acute response of pig skin to treatment with high energy carbon ions (plateau region) at the Gesellschaft für Schwerionenforschung (GSI, Darmstadt, Germany) was compared with changes after 200 kV x-irradiation. Carbon doses isoeffective to the x-ray doses were computed with a recently established model for calculation of the biological effect of heavy ions. Clinical changes and physiological symptoms (blood flow, erythema, trans-epidermal water loss, skin hydration) were scored. The parameters analyzed were maximum and mean values of each symptom during days 24 to 70 after irradiation, and the quantal endpoints for the establishment of dose effect curves were the median values of these. With exception of the maximum change in the red blood cell concentration (p < 0.02) no significant differences could be found in the response to x-rays and RBE-corrected heavy ions. These results indicate that the model is valid for the calculation of biological effects of 12C-ions (plateau region) and may at least for epidermis be applied to treatment planning.
Animals↗
Alleles of highly homologous rat T cell receptor beta-chain variable segments 8.2 and 8.4: strain-specific expression, reactivity to superantigens, and binding of the mAb R78.
This study addresses the molecular basis of a Tcrb-V polymorphism in the reactivity to the superantigens staphylococcus enterotoxin B (SEB) and the mtv-7 sag (MIs1a) of T cells recognized by the mAb R78, which reacts with the T cell receptor beta-chain variable segment 8.2 (Tcrb-V8.2) of Lewis (LEW) rats. Tcrb-V8.2-like sequences were isolated from liver DNA of the responder strain LEW (I) and the nonresponder strain DA (a) and alleles of the Tcrb-V8.2 and the highly homologous Tcrb-V8.4 were identified. Their expression was analyzed by RNase protection studies and cDNA clones were characterized. A comparison of thymocytes, activated R78+ cells, Con A-stimulated and SEB-stimulated cells allows the following conclusions: the newly identified Lewis allele of Tcrb-V8.4 (Trcb-V8.4I) is nonfunctional due to a frame shift induced by deletion of one nucleotide. The R78 epitope is expressed by Tcrb-V8.2I and Tcrb-V8.4a but not by Tcrb-V8.2a. The implication of this finding for mapping of the R78 epitope and the study of V region usage in experimental autoimmune encephalitis are discussed. Finally, the expression of both Tcrb-V8.2 alleles but not of Tcrb-V8.4a in SEB-stimulated cells defines a polymorphism of the CDR2 and/or CDR4 as the molecular basis of the differential superantigen reactivity.
Alleles↗
The canonical T cell receptor of dendritic epidermal gamma delta T cells is highly conserved between rats and mice.
Two monoclonal antibodies with specificity for rat gammadelta T cell receptor (TCR) were generated. One, called V65, reacts with all CD3+ alphabeta TCR- rat Tcells and thus recognizes a constant determinant of the rat gammadelta TCR (Kühnlein et al., Journal of Immunology 1994, 153: 979). The other, called V45, reacts with approximately 80% of gammadelta T cells in peripheral lymphoid organs. In rat epidermis, V65 but not V45 detects a dense network of the dendritic epidermal Tcells (DETC). Analysis of epidermal RNA by polymerase chain reaction (PCR) indicated that Vgamma3 and Vdelta1 are the predominant, if not exclusive TCR V transcripts present at this site. Sequence analysis of cDNA clones obtained by reverse transcription-PCR with Vgamma3- and Vdelta1-specific primers revealed that the variable domains of rat DETC gamma and delta chains are very homologous to those described in mice (92% and 95% identity at the protein level). The complete conservation between the two species of the amino acid sequences at the V-(D)-J transitions of this monomorphic receptor indicates that the interaction of the DETC TCR with its as yet unknown ligand must be of central importance for DETC function.
Amino Acid Sequence↗
[Nomenclature of modified fractionation protocols in radiotherapy].
BACKGROUND/AIM: During the last few years a number of new, unconventional fractionation protocols have been established for various biological reasons. Recently specific terms, established for these schedules, have frequently been applied inappropriately in oral presentations as well as in publications. Hence, the present work was initiated in order to clarify definitions and, in addition, to illustrate the respective biological basis for the various fractionation designs.
Humans↗
[The efficacy of radiotherapy in vertebral hemangiomas].
AIM: Assessment of the efficacy of radiation therapy for symptomatic vertebral hemangiomas. PATIENTS AND METHODS: Records of 19 patients who were treated from 1969 to 1988 were retrospectively analyzed. Radiation treatment was given at 2 Gy per fraction to 20 Gy (n = 2), 30 Gy (n = 11), or 40 Gy (n = 6). Improvement of symptoms was chosen to determine the efficacy of the treatment. In addition the lesions were controlled radiographically. RESULTS: Symptomatic improvement was achieved in 17 of 19 patients, remission was complete in 7 patients. No dose-response relationship was observed. The median time to improvement of symptoms was 3 months. The radiographic controls did not correlate with the clinical course. CONCLUSIONS: Radiation therapy is an effective treatment for symptomatic vertebral hemangiomas. The aim of the treatment is to ameliorate clinical symptoms, radiographic improvement is of minor importance.
Adult↗
18:1 n7 fatty acids inhibit growth and decrease inositol phosphate release in HT-29 cells compared to n9 fatty acids.
Studies have shown that trans fatty acids may play a role in the development of chronic diseases such as heart disease and cancer. The objective of the present project was to examine the effect of supplementation with 18:1 isomers, both positional and geometrical, as compared to 18:0 on the growth, membrane fatty acid composition and the phosphoinositide cycle of HT-29 human colon cancer cells. Cells were supplemented with 30 microM stearic acid (18:0), elaidic acid (18:1, n9, trans), oleic acid (18:1, n9, cis), vaccenic acid (18:1, n7, cis) or trans-vaccenic acid (18:1, n7, trans) as sodium salts complexed to fatty acid-free bovine serum. Cells were grown in these media for 9 days. Cell growth was examined by counting the number of cells and expressed as percentage of control (18:0 supplemented cells). The phosphoinositide (PI) cycle was examined by measuring the inositol phosphate (IP) released from phosphoinositides in the absence (basal) or presence of stimuli (0.1 mM carbachol, 0.1 mM A23187 or 20 mM NaF). The results obtained indicated that cis and trans n7 fatty acids inhibited the growth of HT-29 cells by 11% and 23%, respectively, as compared to 18:0 supplementation. 18:1, n9 had no effect on tumor growth. Supplementation with all forms of 18:1 resulted in an increase in IP and IP2 production as compared to 18:0 supplemented cells without influencing IP3. The presence of the double bond at the 9 position in the supplemented fatty acid increases total IP production by 59% and in the cis form by 37% above the control. The breakdown of phosphoinositides in the absence and presence of several stimuli supports the observed finding on IP. Trans fatty acid supplementation resulted in lower hydrolysis of PI as compared to cis fatty acids. It is concluded that the observed inhibition of tumor growth by the vaccenic acids may be mediated by their effect(s) on the PI cycle which may be associated with their incorporation into membrane lipids.
Cell Division↗
Normal clonal expansion but impaired Fas-mediated cell death and anergy induction in interleukin-2-deficient mice.
Despite a normal development of all major lymphoid subsets, with time, interleukin-2 (IL-2)-deficient mice develop a fatal immunopathology. The disease phenotype is characterized by lymphoadenopathy, splenomegaly, T cell infiltration of various organs, overproduction of a number of cytokines and autoantibody formation. Phenotypically, CD4+ and CD8+ T cells exhibit features characteristic of antigenically experienced cells. The accumulation of cells with a memory phenotype together with the previous suggestion of an involvement of IL-2 in the termination phase of immune responses prompted us to study the fate of superantigen-reactive T cells in IL-2-deficient mice in comparison to their IL-2-producing littermates. We show that expansion in vivo of CD4+ and, to a lesser extent, CD8+ T cells reactive to the superantigens staphylococcal enterotoxin A and B (SEA and SEB) proceeds normally in the absence of IL-2, but that fewer CD4+ cells are subsequently deleted. The residual superantigen-reactive cells fail to become anergic as measured by proliferation in vitro in response to the same superantigen. T cell blasts generated in vitro from lymph node cells of IL-2-deficient mice by superantigen stimulation in the absence of exogenous IL-2 also fail to become anergic. In contrast to cells from IL-2-producing littermates, they do not exhibit Fas-induced apoptosis when cultured on anti-Fas antibody-coated plates, although Fas expression by IL-2-deficient cells is normal or even elevated compared to the IL-2-producing control cells. The data suggest that activation of T cells in the absence of IL-2 fails to generate a signal which is necessary to activate the apoptotic pathway and thus leads to an accumulation of antigen-experienced cells and the chronic inflammatory responses observed in IL-2-deficient mice.
Animals↗
Effects of stimulated repopulation on oral mucositis during conventional radiotherapy.
The effect of local conditioning of human oral mucosa by silver nitrate solution (3%) on epithelial proliferation rates was tested in 11 healthy volunteers by in vitro labelling of biopsies with tritiated thymidine. Compared to control biopsies from 13 volunteers, stimulation over 3 days, 3 times per day, yielded a significant (p = 0.006) increase in the epithelial labelling index (LI) from 4.75 +/- 0.32% to 6.85 +/- 0.65%, i.e., by 44%. The increase in the absolute number of labelled cells per mm epithelial length was dependent on the overall cell density at the various intraoral sites and varied between 45% in the maxillary vestibule and 91% at the floor of the mouth. In an analysis of variance, stimulation turned out to be the most important source causing the effect (p = 0.011 for LI and 0.015 for labelled cells per mm). In a radiotherapy trial with conventional postoperative treatment with 5 x 2 Gy/week to a total dose of 60 Gy in 6 weeks, the left buccal mucosa in 10 patients with squamous cell carcinomas of the head and neck was conditioned (3% silver nitrate, 3 times per day, 5 days before and the first 2 days of radiotherapy) while the contralateral mucosa, receiving an identical dose, served as individual control. Mucositis scores according to the EORTC/RTOG or the Dische system showed that the time course and severity of the mucosal response was almost identical in both cheeks, which is in clear contrast to a previous clinical study (Maciejewski et al. Radiother. Oncol. 22, 7-11, 1991). Differences in radiation dose intensity, i.e., weekly dose, in these studies are discussed as a tentative explanation for the different clinical findings.
Adult↗
[The documentation and publishing of radiotherapy side effects. A workshop report].
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Documentation↗
[Radiogenic lung reactions. Pathogenesis--prevention--therapy].
PURPOSE: The lung is the dose-limiting structure within the thorax. Radiation-induced lung damage resulting in either pneumonitis or pulmonary fibrosis limits the total dose of radiotherapy in the thoracic region. The paper reviewed and discussed the current knowledge of radiogenic pneumopathy. PATIENTS AND METHODS: Analysis was done of experimental results and published data concerning lung reaction after radiotherapy. RESULTS: From a clinical point of view the radiation-induced lung damage can be described by 2 distinct phases: pneumonitis (4 to 6 weeks post radiationem) and pulmonary fibrosis (1 to 2 years post radiationem). Although there is increasing additional information on the etiology of radiation-induced lung damage up to now effective treatment based on these knowledges is available. The frequency of radiogenic pneumopathy detected by X-ray investigation after a radiation treatment demonstrates great difference between several investigators which is mainly caused by differences in the sequence of X-ray investigation. The ED50-value of pneumonitis after a conventional fractionated radiotherapy is about 35 Gy. CONCLUSION: Minimizing the frequency of radiation-induced lung injury it ist necessary to check prior to radiotherapy the treatment ability of a patient concerning its lung function conditions, to remain a great untreated lung volume in treatment planning, to use smaller doses per fraction in the irradiated parts of the lung and to calculate the dose-distribution with the individual values of lung density of the patient. In cases of occurring pneumopathy with clinical signs only symptomatic treatment is possible.
Dose-Response Relationship, Radiation↗