Increased excretion of collagen crosslinks in irradiated patients indicates destruction of collagen

PURPOSE: In a recent study we showed an instant radiogenic destruction of collagen in dental tissues. The hypothesis of this analysis was that there is a destruction of collagen directly in bone during irradiation. Our intention was to prove this assumption by the analysis of the intraindividual progression of urinary excretion of bone specific collagen crosslinks before, during and after radiotherapy (RT) of secondary malignant bone tumors. MATERIAL AND METHODS: Forty-six patients were irradiated with a mean dose of 32 Gy (range 30 - 46 Gy). Four urine probes were collected from each patient before, during, at the end and 6 - 8 weeks after RT. Measurement of the mature collagen crosslinks hydroxylysylpyridinoline (HP) and lysylpyridinoline (LP) was performed by high performance liquid chromatography (HPLC). RESULTS: In 43 patients we found increasing HP and LP concentrations by comparing the different chosen time-points. As regards to HP the urine excretion was significantly increased at the end (p = 0.02) and six weeks after RT (p = 0.01) and for LP six weeks after RT (p = 0.01). We observed significantly higher urinary HP levels in patients treated with doses of 35 - 46 Gy as compared to patients treated with 30 Gy (p = 0.05). CONCLUSIONS: The urinary excretion of HP and LP was increased directly after a course of RT. This finding may reflect either destruction of collagen or increased bone remodeling/resorption after radiotherapy. Either way these findings suggest a relation to the mechanical instability of bone directly after radiotherapy. Future investigations of irradiated patients without osseous metastases will further clarify this matter.     

The effect of supraphysiological doses of anabolic androgenic steroids on collagen metabolism

We examined the effect of supraphysiological doses of anabolic androgenic steroids (AAS) on collagen metabolism and whether the changes reflect the alterations in muscle, bone, and tendon collagen metabolism, possibly in a tissue-specific manner. Serum carboxyterminal propeptide of type I procollagen (PICP), carboxyterminal telopeptide of type I collagen (ICTP), aminoterminal propeptide of type III procollagen (PIIINP), urine hydroxylysylpyridinoline (HP), and lysylpyridinoline (LP) as well as urine creatinine were determined from 17 men abusing AAS. Measurements were made twice during the intake of AAS and twice during the subsequent withdrawal period. When the volunteers were on steroids, their serum PIIINP concentrations and urine HP/LP ratio were significantly higher and their serum ICTP concentrations were significantly lower than during the withdrawal period (p < 0.05). Serum PIIINP correlated with total cumulative doses of injectable intramuscular steroids, and serum ICTP correlated with the duration of the steroid intake period (p<0.05). The results suggest that high doses of AAS decrease the degradation and seem to increase the synthesis of type I collagen. Furthermore, high doses of AAS are suggested to enhance soft tissue collagen metabolism on the basis of increased type III collagen synthesis and elevated HP/LP ratio during the steroid administration period. Although the tissue-specific turnover of collagen of soft connective tissues remains unknown, the turnover of bone collagen seems not to change following the use of high doses of AAS, at least within the time interval of the present study.     

The determination of the RBE of neutrons based on the hydroxyproline concentration in the lung tissue of irradiated piglets

To test the radiogenic reaction of normal lung tissue experiments were done in 99 young pigs altogether. The radiation field included the total right lobe of the lung, 5 fractions of photons or neutrons (mean energy 6.2 MeV) were applied in a total treatment of 5 or 35 days. After killing the animals and taking the lungs the examination of tissue samples and others has been done for contents of hydroxyproline (HP) that has been used to register radiogenic injuries where the relation of irradiated and non-irradiated half of the same animal was estimated as measuring value. Above a limit of 1.13 for the HP-quotient (estimated in non-irradiated controls) there was a significant correlation with dose. Between the results of HP-quotients and histopathological findings a very good correlation was found. Calculation of RBE was done from relation of the dose values of photons and neutrons on base of the same level of injuries. In the tested total dose limit (photons: 14.25-38 Gy, neutrons 3.0-8.5 Gy) RBE-values of 3.8-4.5 were reached that correlates well with other tested criteria of the study in young pigs.     

Concentration of collagen cross-links in human dentin bears no relation to the individual age

Lysylpyridinoline (LP) and hydroxylysylpyridinoline (HP) are collagen cross-link residues. HP is present in most tissues, whereas LP is specific for bone and dentin. Based on the current literature there are certain indications that measurement of the concentrations of HP and LP in dentin may be a valuable tool to determine the individual age. The purpose of this investigation was to assess if the concentrations of LP and HP in dentin increase during lifetime. We have investigated 173 molars from 173 individuals (2 through 78 years of age, 31 primary and 142 secondary teeth) in the course of the present study. Levels of LP and HP were measured by HPLC and fluorescence detection. The results show that dentinal concentrations of HP and LP did not increase with age and varied between individuals of the same age and that determination of dentinal concentrations of HP and LP cannot be used to determine the individual age.     

Comparative research on cellular immunostimulation by whole-body irradiation]

The effect of the cellular immune response by total body irradiation was investigated. The transplant survival (skin grafts) was determined as immune parameter. Donors were colony-bred Wistar rats and recipients were colony-bred Sprague-Dawley rats. The investigations were carried out with irradiated rats and with rats irradiated after thymectomy and/or adrenalectomy as well as with animals without irradiation. A single total-body irradiation (1 and 2 Gy) was administered. The skin graft survival in irradiated rats was significant shorter (radiogenic immunostimulation) than in unirradiated rats; there were no significant differences between the operated (thymectomy and/or adrenalectomy) and not operated animals. Including precedent examinations this radiogenic immunostimulation is caused by a relatively selective inactivation of T-suppressor cells.     

Early retardation of 99mTc-DTPA radioaerosol transalveolar clearance in irradiated canine lung.

The alteration of 99mTc-labeled diethylenetriaminepentaacetic acid (DTPA) transalveolar clearance in an initial phase of radiation lung injury was experimentally investigated. METHODS: Fourteen dogs were irradiated to the hemithorax with a single dose of 20 Gy. A DTPA radioaerosol study was performed before irradiation and on day 12 after irradiation. On day 14, the DTPA study was repeated again, with seven animals undergoing the study after inhalation of an aerosolized synthetic surfactant. The penetration index (P.I.) and clearance half-time (T(1/2)) of DTPA were measured in each lung. To evaluate the changes in lung surfactant after irradiation, alveolar lipids were stained in the resected lungs (n = 14), and the amounts of alveolar surfactant phospholipid and protein were measured by a bronchoalveolar lavage study in another six irradiated dogs. RESULTS: In all of the 14 irradiated animals, DTPA radioaerosol distributed uniformly throughout the lungs without significant changes in P.I. The T(1/2) values in irradiated lungs were significantly prolonged compared with the matched baseline values and those in nonirradiated lungs (P < 0.05 and 0.001, respectively). The aerosolized synthetic surfactant retarded the DTPA clearance both in the irradiated and in the nonirradiated lungs (P < 0.001) without significant changes in P.I. The histologic and bronchoalveolar lavage studies revealed an increase of alveolar surfactant materials in the irradiated lungs without substantial histologic changes in the alveolar structures. CONCLUSION: DTPA transalveolar clearance was retarded soon after irradiation. Increased alveolar surfactant may be partly responsible for this retarded DTPA clearance because the aerosolized synthetic surfactant also prolonged the clearance in nonirradiated lungs. A DTPA clearance test is sensitive for the early detection of radiation lung injury and seems helpful for clarifying the association of epithelial integrity changes and lung surfactant in radiation lung injury.     

Raman spectroscopy of tissue samples irradiated by protons

PURPOSE: Since the number of cancer patients treated by proton irradiation has increased in the last few years, it seems appropriate to study dose-dependent effects of proton irradiation on mammalian tissues in more detail. MATERIALS AND METHODS: Tissue samples of normal skin of mouse and swine, of a human tumour model xenograph, and of normal skin and a skin tumour (basal cell carcinoma) of a human patient of about 1 mm thickness were irradiated by 24 MeV protons (uniform delivered doses of 1, 7 and 50 Gy: skin of mouse and a human tumour model xenograph, and 0.5, 5 and 50 Gy: swine and human skin). Raman spectra of non-irradiated and irradiated samples were recorded and analysed. RESULTS: Amide I, P=O and C-O bond vibrations and aromatics were sensitive to the proton irradiation dose. In the C-H stretching region, the irradiation-mediated change of Raman spectra was significant only in the case of the skin tumour. CONCLUSIONS: It has been shown that Raman spectroscopy is suited to assess the radiation damage done to biological samples by protons. Proteins of the human skin tumour seem to be more sensitive to proton irradiation than proteins of normal human skin.     

Raman spectroscopy of tissue samples irradiated by protons

Purpose: Since the number of cancer patients treated by proton irradiation has increased in the last few years, it seems appropriate to study dose‐dependent effects of proton irradiation on mammalian tissues in more detail.

Materials and methods: Tissue samples of normal skin of mouse and swine, of a human tumour model xenograph, and of normal skin and a skin tumour (basal cell carcinoma) of a human patient of about 1?mm thickness were irradiated by 24?MeV protons (uniform delivered doses of 1, 7 and 50?Gy: skin of mouse and a human tumour model xenograph, and 0.5, 5 and 50?Gy: swine and human skin). Raman spectra of non‐irradiated and irradiated samples were recorded and analysed.

Results: Amide I, P=O and C‐O bond vibrations and aromatics were sensitive to the proton irradiation dose. In the C‐H stretching region, the irradiation‐mediated change of Raman spectra was significant only in the case of the skin tumour.

Conclusions: It has been shown that Raman spectroscopy is suited to assess the radiation damage done to biological samples by protons. Proteins of the human skin tumour seem to be more sensitive to proton irradiation than proteins of normal human skin.     

Volume and dose-response effects for severe symptomatic pneumonitis after fractionated irradiation of canine lung

PURPOSE: To study the dose-related incidence of severe symptomatic pneumonitis following fractionated irradiation applied to three different volumes of lung in normal beagle dogs. MATERIALS AND METHODS: A three-dimensional treatment planning system was used to design mediastinal fields of increasing width to irradiate 33%, 67% or 100% of both lungs combined in 128 normal beagle dogs. Total doses, ranging from 27 to 72 Gy, were delivered in 1.5 Gy fractions over 6 weeks. RESULTS: No dogs irradiated to 33% of their total lung volume developed severe symptomatic pneumonitis. In the 67% volume group, logistic fit of the data showed a dose-response curve with a 50% probability of developing severe symptomatic pneumonitis (ED50) after a total dose of 56.0 Gy (52.2-66.0 Gy, 95% confidence interval, CI). The more clinically relevant ED5 for the first 6 months after irradiation of 67% of the lung was 48.1 Gy (18.5-52.0 Gy, 95% CI). The ED50 and ED5 values after irradiation of the whole lung (100%) were 44.1 Gy (41.2-53.5Gy, 95% CI) and 39.1 Gy (8.8-41.8 Gy, 95% CI) respectively. CONCLUSION: Severe symptomatic pneumonitis proved to be a very informative volume-effect endpoint, clearly demonstrating that irradiated lung volume is a critical parameter to be considered in assigning thoracic radiotherapy treatment parameters. Volume effects in lung are dependent on the compensatory capacity of the nonirradiated lung. Underlying pathophysiology of irradiated tissue, as well as decreased compensatory capacity of nonirradiated tissue may have a strong effect on the dose-volume response.     

Effects of spinal cord lesion level upon thermoregulation during exercise in the heat

PURPOSE: This study examined the effects of the level of spinal cord injury upon the thermoregulatory responses of wheelchair athletes during prolonged wheelchair exercise in warm conditions. METHODS: Eight tetraplegic (TP), 10 high-level paraplegic (HP), and 10 low-level paraplegic (LP) athletes exercised for 60 min at 60% [OV0312]O(2peak) in a warm environment (31.5 +/- 1.7 degrees C, 42.9 +/- 8.0% relative humidity). Skin temperature and aural temperature were monitored. RESULTS: Aural temperature increased gradually during the exercise period by 1.1 +/- 0.3 and 1.4 +/- 0.5 degrees C for the HP and LP groups, with a more marked increase observed for the TP group (2.1 +/- 0.5 degrees C; P < 0.05). Upper-arm skin temperature was higher for the TP when compared with the HP and LP between 30 and 60 min (P < 0.05). Back skin temperature was higher for the TP when compared with the HP and LP between 45 and 60 min (P < 0.05). No differences were noted between groups for the thigh or calf skin temperatures. During recovery, skin temperature remained elevated for the TP group when compared with the HP and LP groups (P < 0.05). Heat storage was greatest for the TP athletes at the end of exercise and remained elevated throughout recovery (P < 0.05). CONCLUSIONS: All athletes completed the exercise task even though the gradual increase in aural temperature observed for the HP and LP groups suggests a degree of thermal imbalance. However, this was much less than observed for TP athletes, who demonstrated a much greater imbalance in temperature regulation. Increasing the exercise or environmental strain may result in the thermoregulatory responses of athletes with a spinal cord injury being compromised.     

Collagen metabolism in the skin and bone tissue of rats after a 7-day space flight

Collagen metabolism in the skin and bone (femur) of 3-month male rats of the SPF Wistar strain was investigated. Bone of the flown rats showed an increase in pepsin-soluble collagen and a decrease in pepsin-insoluble collagen. The skin of the flown rats exhibited opposite changes. Both the skin and bone of the flown animals showed an increase of type III collagen (in the pepsin-soluble and pepsin-insoluble fractions). Similar changes were previously observed in female rats, that were launched while being pregnant, and in their offspring.     

Fatty replacement of bone marrow after radiation therapy for Hodgkin disease: Quantification with chemical shift imaging

The authors studied the long-term fatty replacement of bone marrow in 23 patients who had received radiation therapy for Hodgkin disease, with T1-weighted magnetic resonance imaging and quantitative chemical shift imaging. T1-weighted images revealed a mostly homogeneous high-signal-intensity pattern, in contrast to the hypointense pattern of nonirradiated marrow. The degree of fatty replacement was objectively assessed with chemical shift imaging, comparing patients to age-matched healthy volunteers. The authors found an increase in relative fat signal of 37% in the thoracic spine and 34% in the lumbar spine. The relative fat signal of nonirradiated pelvic and femoral marrow was decreased by 8%, indicating marrow reconversion. No radiation dose dependence was found in the range from 25 to 50 Gy. No signs of marrow regeneration were observed 15-126 months after radiation therapy. With chemical shift imaging, the degree of long-term radiogenic fatty replacement of the bone marrow can be quantified, confirming the lack of regeneration after radiation therapy for Hodgkin disease.     

Enhanced survival from radiation pneumonitis by combined irradiation to the skin

Abstract

Purpose: To develop mitigators for combined irradiation to the lung and skin.

Methods: Rats were treated with X-rays as follows: (1) 12.5 or 13 Gy whole thorax irradiation (WTI); (2) 30 Gy soft X-rays to 10% area of the skin only; (3) 12.5 or 13 Gy WTI + 30 Gy skin irradiation after 3 hours; (4) 12.5 Gy WTI + skin irradiation and treated with captopril (160 mg/m²/day) started after 7 days. Our end points were survival (primary) based on IACUC euthanization criteria and secondary measurements of breathing intervals and skin injury. Lung collagen at 210 days was measured in rats surviving 13 Gy WTI.

Results: After 12.5 Gy WTI with or without skin irradiation, one rat (12.5 Gy WTI) was euthanized. Survival was less than 10% in rats receiving 13 Gy WTI, but was enhanced when combined with skin irradiation (p < 0.0001). Collagen content was increased at 210 days after 13 Gy WTI vs. 13 Gy WTI + 30 Gy skin irradiation (p < 0.05). Captopril improved radiation-dermatitis after 12.5 Gy WTI + 30 Gy skin irradiation (p = 0.008).

Conclusions: Radiation to the skin given 3 h after WTI mitigated morbidity during pneumonitis in rats. Captopril enhanced the rate of healing of radiation-dermatitis after combined irradiations to the thorax and skin.     

High-Dose Intracoronary Irradiation after De Novo Stent Implantation

PURPOSE: This randomized study was designed to compare the efficacy of high-dose coronary beta-radiation after intravascular ultrasound-(IVUS-)guided direct stenting with sham treatment in patients with de novo lesions. PATIENTS AND METHODS: 32 patients were enrolled in the study protocol. Following angioplasty procedure, intracoronary brachytherapy was performed with the Novoste Beta-Cath System. The prescribed dose was 24 Gy referred to the lamina elastica externa. Quantitative coronary angiography and IVUS were performed to analyze the treated coronary vessel. RESULTS: Angiographic results revealed a significantly smaller minimal lumen diameter compared with the pos-tprocedural minimal lumen diameter within the stented segment (p = 0.004) in the nonirradiated group. The same significant result was observed in the injured segment of the nonirradiated patients (p = 0.011). The IVUS data revealed a significant increase of the plaque volume after 8 months in the nonirradiated group compared to the post-procedural value (irradiated 5.41 +/- 8.83 mm(3) vs. nonirradiated 21.11 +/- 16.08 mm(3); p = 0.001). Late luminal loss was significantly greater in the nonirradiated group (p = 0.004). The primary clinical endpoint (death, myocardial infarction, repeat target lesion revascularization, percutaneous revascularization, coronary artery bypass surgery) was reached by seven irradiated (33.3%) and four (18.2%) nonirradiated patients (p = 0.623). Late stent thrombosis was observed in one irradiated patient. CONCLUSION: The EVEREST trial has demonstrated the feasibility of high-dose intracoronary brachytherapy in de novo coronary lesions. There is a significant reduction of neointimal proliferation within the stented segment. Nevertheless, this benefit is vitiated by an increase of restenotic lesions outside the stent segment.     

Relation between the levels of mineral components and mechanical properties of the bones in dogs after a single acute whole-body irradiation

Mineral components and mechanical properties of different compartments of the femur and jaws of 25 dogs, 10 of which were exposed to single total-body acute irradiation at a dose of 4.0 Gy, were investigated. The mineral content and strength of spongy bone of the femur of the irradiated dogs declined. It was demonstrated that the strength limit and mineral density were closely correlated. No changes were seen in cortical bone of the femur after irradiation.     

Reduced iodide transport (stunning) and DNA synthesis in thyrocytes exposed to low absorbed doses from 131I in vitro.

Thyroid stunning refers to reduced uptake of (131)I in the thyroid tissue (or tumor) during radioiodine ((131)I) therapy compared with the uptake measured after the previous administration of (131)I for diagnostic purposes. The phenomenon is clinically important, as it can potentially lead to the undertreatment of thyroid cancer or to unnecessarily high absorbed doses in critical organs. Previous clinical and experimental studies indicated that thyroid stunning is absorbed dose dependent. The aim of this study was to investigate the effects of (131)I irradiation on (125)I(-) transport and cell proliferation at low absorbed doses in vitro. METHODS: Primary cultured porcine thyroid cells were grown to form a confluent monolayer of epithelial cells on a filter in a bicameral culture system. The cells were continuously irradiated with (131)I in the culture medium for 48 h to obtain 0.0015-1.5 Gy. At 3 d after irradiation was stopped, the transepithelial iodide transport capacity was evaluated by measuring (125)I(-) transport from the basal chamber compartment to the apical chamber compartment. The effect of (131)I irradiation on DNA synthesis was estimated by pulse labeling with (3)H-thymidine of both subconfluent and confluent cells irradiated with up to 9 Gy. Total DNA content was measured to quantify cell numbers. RESULTS: A statistically significant reduction in (125)I(-) transport was seen at absorbed doses of >or=0.15 Gy, with a 50% reduction at 1.5 Gy, compared with the results observed for nonirradiated control cells. (3)H-Thymidine incorporation was already statistically significantly reduced at absorbed doses of 0.01-0.1 Gy, but 0.15-0.3 Gy did not affect DNA synthesis. However, absorbed doses of >or=1 Gy again resulted in reduced DNA synthesis. A 50% reduction was obtained at 4 Gy. Total DNA measurements revealed a statistically significant reduction in cell numbers at 8 Gy. CONCLUSION: The lowest absorbed dose from (131)I that reduced iodide transport was 0.15 Gy. Because stunning was found at low absorbed doses, it might occur for (131)I treatment not only of thyroid cancer but also of thyrotoxicosis. On the basis of differences in dose responses, radiation-induced thyroid stunning and cell cycle arrest may be independent phenomena.     

Moist Skin Care Can Diminish Acute Radiation-Induced Skin Toxicity

BACKGROUND: Radiation treatment may induce acute skin reactions. There are several methods of managing them. Validity of these methods, however, is not sufficiently studied. We therefore investigated, whether moist skin care with 3% urea lotion will reduce acute radiation skin toxicity. PATIENTS AND METHODS: 88 patients with carcinomas of the head and neck undergoing radiotherapy with curative intent (mean total dose 60 Gy, range: 50-74 Gy) were evaluated weekly for acute skin reactions according to the RTOG-CTC score. In 63 patients, moist skin care with 3% urea lotion was performed. The control group consisted of 25 patients receiving conventional dry skin care. The incidence of grade I, II, and III reactions and the radiation dose at occurrence of a particular reaction were determined and statistically analyzed using the log-rank test. The dose-time relations of individual skin reactions are described. RESULTS: At some point of time during radiotherapy, all patients suffered from acute skin reactions grade I, > 90% from grade II reactions. 50% of patients receiving moist skin care experienced grade I reactions at 26 Gy as compared to 22 Gy in control patients (p = 0.03). Grade II reactions occurred at 51 Gy versus 34 Gy (p = 0.006). Further, 22% of the patients treated with moist skin care suffered from acute skin toxicity grade III as compared to 56% of the controls (p = 0.0007). CONCLUSION: Moist skin care with 3% urea lotion delays the occurrence and reduces the grade of acute skin reactions in percutaneously irradiated patients with head and neck tumors.     

Spectrophotometric Skin Measurements Correlate with EORTC/RTOG-Common Toxicity Criteria

Purpose: It was investigated whether the elementary EORTC/RTOG-CTC score (Common Toxicity Criteria) for radiotherapy skin reactions correlates with spectrophotometric measurements of the skin color. Patients, Material, and Methods: In 41 patients irradiated for unilateral breast cancer the regular scoring by CTC was done during radiotherapy. In parallel, a total of 4,920 spectrophotometric measurements to determine the skin color were performed at baseline, at the beginning of radiotherapy, and at 20, 40 and 60 Gy. The nonirradiated contralateral breast was used for control measurements. Results: As expected, the skin color (especially red) depended on the radiation dose applied to the skin. The objective spectrophotometric measurements were found to correlate well with the subjective CTC scores. Conclusion: For classification of acute radiation toxicity there seems to be no need to replace the common CTC scoring by technical methods.*F.M. and S.B. contributed equally as first authors.     

Effects of acute sublethal gamma radiation exposure on aggressive behavior in male mice: a dose-response study

The resident-intruder paradigm was used to assess the effects of gamma radiation (0, 3, 5, 7 Gray [Gy] cobalt-60) on aggressive offensive behavior in resident male mice over a 3-month period. The defensive behavior of nonirradiated intruder mice was also monitored. A dose of 3 Gy had no effect on either the residents' offensive behavior or the defensive behavior of the intruders paired with them. Doses of 5 and 7 Gy produced decreases in offensive behavior of irradiated residents during the second week postirradiation. The nonirradiated intruders paired with these animals displayed decreases in defensive behavior during this time period, indicating a sensitivity to changes in the residents' behavior. After the third week postirradiation, offensive and defensive behavior did not differ significantly between irradiated mice and sham-irradiated controls. This study suggests that sublethal doses of radiation can temporarily suppress aggressive behavior but have no apparent permanent effect on that behavior.     

Volume and dose–response effects for severe symptomatic pneumonitis after fractionated irradiation of canine lung

Purpose : To study the dose-related incidence of severe symptomatic pneumonitis following fractionated irradiation applied to three different volumes of lung in normal beagle dogs. Materials and methods : A three-dimensional treatment planning system was used to design mediastinal fields of increasing width to irradiate 33%, 67% or 100% of both lungs combined in 128 normal beagle dogs. Total doses, ranging from 27 to 72 Gy, were delivered in 1.5Gy fractions over 6 weeks. Results : No dogs irradiated to 33% of their total lung volume developed severe symptomatic pneumonitis. In the 67% volume group, logistic fit of the data showed a dose–response curve with a 50% probability of developing severe symptomatic pneumonitis (ED50) after a total dose of 56.0 Gy (52.2–66.0 Gy, 95% confidence interval, CI). The more clinically relevant ED 5 for the first 6 months after irradiation of 67% of the lung was 48.1 Gy (18.5–52.0 Gy, 95% CI). The ED 50 and ED 5 values after irradiation of the whole lung (100%) were 44.1 Gy (41.2–53.5 Gy, 95% CI) and 39.1 Gy (8.8–41.8 Gy, 95% CI) respectively. Conclusion : Severe symptomatic pneumonitis proved to be a very informative volume-effect endpoint, clearly demonstrating that irradiated lung volume is a critical parameter to be considered in assigning thoracic radiotherapy treatment parameters. Volume effects in lung are dependent on the compensatory capacity of the nonirradiated lung. Underlying pathophysiology of irradiated tissue, as well as decreased compensatory capacity of nonirradiated tissue may have a strong effect on the dose-volume response.