Late Effects of Ionizing Radiation on the Ultrastructure of Hepatocytes and Activity of Lysosomal Enzymes in Mouse Liver Irradiated In Vivo.

The study aimed to investigate late radiation-induced changes in the histology, ultrastructure, and activity of lysosomal enzymes in mouse liver exposed to ionizing radiation. The experiment was conducted on C57BL/6J male mice whose distal part of the liver was exposed occasionally to single doses of radiation (6 MV photons) during targeted heart irradiation; estimated doses delivered to analyzed tissue were 0.025 Gy, 0.25 Gy, 1 Gy, and 2 Gy. Tissues were collected 40 weeks after irradiation. We have observed that late effects of radiation have an adaptive nature and their intensity was dose-dependent. Morphological changes in hepatocytes included an increased number of primary lysosomes and autophagic vacuoles, which were visible in tissues irradiated with 0.25 Gy and higher doses. On the other hand, a significant increase in the activity of lysosomal hydrolases was observed only in tissues exposed to 2 Gy. The etiology of these changes may be multifactorial and result, among others, from unintentional irradiation of the distal part of the liver and/or functional interaction of the liver with an irradiated heart. In conclusion, we confirmed the presence of late dose-dependent ultrastructural and biochemical changes in mouse hepatocytes after liver irradiation in vivo.

Re-irradiation for intra-thoracic tumours and extra-thoracic breast cancer: dose accumulation, evaluation of efficacy and toxicity based on a literature review.

The improvement seen in the diagnostic procedures and treatment of thoracic tumours means that patients have an increased chance of longer overall survival. Nevertheless, we can still find those who have had a recurrence or developed a secondary cancer in the previously treated area. These patients require retreatment including re-irradiation. We have reviewed the published data on thoracic re-irradiation, which shows that some specific healthy tissues can tolerate a significant dose of irradiation and these patients benefit from aggressive treatment; however, there is a risk of damage to normal tissue under these circumstances. We analysed the literature data on re-irradiation in the areas of vertebral bodies, spinal cord, breast, lung and oesophagus. We evaluated the doses of primary and secondary radiotherapy, the treatment techniques, as well as the local control and median or overall survival in patients treated with re-radiation. The longest OS is reported in the case of re-irradiation after second breast-conserving therapy where the 5-year OS range is 81 to 100% and is shorter in patients with loco-reginal re-irradiation where the 5-y OS range is 18 to 60%. 2-year OS in patients re-irradiated for lung cancer and oesophagus cancer range from 13 to 74% and 18 to 42%, respectively. Majority grade ≥3 toxicity after second breast-conserving therapy was fibrosis up to 35%. For loco-regional breast cancer recurrences, early toxicity occurred in up to 33% of patients resulting in mostly desquamation, while late toxicity was recorded in up to 23% of patients and were mostly ulcerations. Early grade ≥3 lung toxicity developed in up to 39% of patients and up to 20% of Grade 5 hemoptysis. The most frequently observed early toxicity grade ≥3 in oesophageal cancer was oesophagitis recorded in up to 57% of patients, followed by hematological complications which was recorded in up to 50% of patients. The most common late complications included dysphagia, recorded in up to 16.7% of patients. We have shown that thoracic re-irradiation is feasible and effective in achieving local control in some patients. Re-irradiation should be performed with maximum accuracy and care using the best available treatment methods with a highly conformal, image-guided approach. Due to tremendous technological progress in the field of radiotherapy, we can deliver radiation precisely, shorten the overall treatment time and potentially reduce treatment-related toxicities.

Resveratrol administration prevents radiation-related changes in metabolic profiles of hearts 20 weeks after irradiation of mice with a single 2 Gy dose.

We aimed to evaluate whether resveratrol affects radiation-induced changes in metabolite profiles of the mouse heart. Hearts were irradiated in vivo with a single 2 Gy dose during the resveratrol administration and metabolite profiles of heart tissue were analyzed by the untargeted HR-MAS NMR approach twenty weeks after irradiation. The administration of resveratrol mitigated the radiation-induced decline in the content of choline-containing compounds and unsaturated lipids, which might reflect the stabilization of cell membrane structure against radiation-related damage. Results obtained with this mouse model suggest that the resveratrol supplementation may prevent metabolic changes related to radiation-induced damage in the heart.

Metabolic changes in mice cardiac tissue after low-dose irradiation revealed by 1H NMR spectroscopy.

Ionizing radiation may cause cardiotoxicity not only at high, but even at low (considered as harmless) doses, yet the molecular mechanisms of the heart's response to low doses are not clear. In this work, we used high-resolution nuclear magnetic resonance (NMR) spectroscopy to detect the early and late effects of radiation on the metabolism of murine hearts. The hearts of C57Bl/6NCrl female mice were irradiated in vivo with single 0.2 Gy or 2 Gy doses using 6 MV photons, then tissues were collected 48 h and 20 weeks after exposure. The most distinct changes in the profile of polar metabolites were detected 48 h after irradiation with 2 Gy, and included increased levels of pantothenate and glutamate as well as decreased levels of alanine, malonate, acetylcarnitine, glycine and adenosine. Significant effects of the 2 Gy dose were also observed 20 weeks after irradiation and included decreased levels of glutamine and acetylcarnitine when compared with age-matched controls. Moreover, several differences were observed between hearts irradiated with 2 Gy and analyzed either 48 h or 20 weeks after the exposure, which included changes in levels of acetylcarnitine, alanine, glycine, glutamate, glutamine, formate, myo-inositol and trimethylamine. No statistically significant effects induced by the 0.2 Gy dose were observed 20 weeks after irradiation. In general, radiation-affected compounds were associated with energy metabolism, fatty acid beta-oxidation, oxidative stress and damage to cell structures. At the same time, radiation-related effects were not detected at the level of tissue histology, which indicated a higher sensitivity of metabolomics-based tests for cardiac tissue response to radiation.

A comparison of treatment outcome between fiducial-based and bone-based image guided radiotherapy in prostate cancer patients.

BACKGROUND AND PURPOSE: To compare the clinical outcome in prostate cancer patients treated with radiotherapy using two forms of image guidance: bone-based (BB) or fiducial-based (FB). MATERIAL AND METHODS: This retrospective study consisted of 180 patients treated with kV-kV image-guided radiotherapy (IGRT) between the years 2008 and 2011. A total of 89 patients were aligned to pelvic bone (Group BB) and 91 patients to the fiducial implanted into prostate for image guidance (Group FB). Patients were treated to a total dose of 76 Gy in 38 fractions. The Cox Regression Model was used to evaluate the influence of clinical and treatment-related parameters on overall survival, biochemical progression and progression-free survival. Acute and late toxicity were evaluated based on the RTOG/EORTC criteria. Sexual function was assessed with QLQ PR-25 (EORTC QLQ forms). An assessment of the differences in patient daily set-up from the time of simulation was performed. RESULTS: The incidence of acute G2/G3 genitourinary (GU) and gastrointestinal (GI) toxicity was similar between groups. In the BB group, 34 patients had G2 and 5 had G3 GU acute toxicity - compared to 40 patients with G2 and 2 with G3 in the FB group. G2 and G3 GI acute toxicity was observed respectively in 24 patients and in 1 patient in the BB group compared to 18 patients with G2 and 1 patient with G3 toxicity in the FB group. The five-year incidence of late ≥G2 GU toxicity was 12% in both groups (p = 0.98) and ≥ G2 GI toxicity 19% (BB) vs 15% (FB, p = 0.55), respectively. The five-year progression-free survival rate was 87% in BB and 81% in the FB Group (p = 0.15). The 5-year Overall Survival rate (OS) was 80% (BB) vs 91% % (FB, p = 0.20), but the difference was most pronounced in the intermediate-risk group: 5-year OS of 93% (FB) and 75% (BB), respectively (p = 0.06). No significant changes were observed in sexual or erectile functioning as compared to that specified at the beginning of radiotherapy and between the FB and BB Groups. CONCLUSION: When comparing bone-based to fiducial-based techniques, no differences in clinical outcomes or late toxicity were seen in this population. However, intermediate risk prostate cancer patients are those who might benefit most from implementation of fiducial-based IGRT.

Changes in activity and structure of lysosomes from liver of mouse irradiated in vivo.

PURPOSE: Lysosomes may have an important role in response to ionizing radiation. Moreover, radiation could affect autophagy, which process involves the activity of lysosomal enzymes. In the present study, the effect of ionizing radiation on the lysosomal compartment of mouse liver was investigated after in vivo exposure. MATERIALS AND METHODS: Morphology and ultrastructure of hepatocytes were assessed by light and electron microscopy, and activities of selected lysosomal enzymes were assessed in 12, 36 and 120 h after exposure to the mean dose of 1 Gy. The levels of autophagy-related proteins LC3-II and p62 were compared by Western blotting between untreated and irradiated animals (120 h after exposure). RESULTS: Increased number of autophagic vacuoles in hepatocytes from exposed animals was documented in the ultrastructural study; destroyed mitochondria were the dominant component of such vacuoles. Moreover, an increased activity of lysosomal hydrolases was observed after exposure. However, levels of autophagy substrates LC3-II and p62 were barely affected in exposed animals 120 h after irradiation when the accumulation of autophagic vacuoles was observed. CONCLUSION: Effects of irradiation included an increased number of autophagic vacuoles, especially of autophagosomes, and increased activity of lysosomal enzymes. However, putative markers of autophagic flux were not observed, which suggested suppression of the completion of the radiation-mediated autophagy pathway.

Quality of life in patients with prostate cancer treated with radical image-guided radiotherapy.

AIM OF THE STUDY: The evaluation of quality of life during image-guided radiotherapy (IGRT) in patients with prostate cancer. MATERIALS AND METHODS: The study consisted of 180 prostate cancer patients treated with radical radiotherapy (IGRT). The patients were irradiated using conformal or dynamic techniques with 2 Gy fractionation doses to a total dose of 76 Gy. Patients in the high-risk group (41%) were also irradiated to the pelvic lymph nodes. Quality of life was assessed with EORTC questionnaires: general QLQ-C30 and prostate-specific module QLQ-PR25, which were filled in by patients before and upon completion of radiotherapy. A change of ≥ 10 points in a linearised scale (0-100) was considered clinically significant. RESULTS: Global quality of life decreased slightly during radiotherapy (from 61 to 57 points), but from the clinical point of view, likewise most of the other quality of life parameters remained stable. In the general module (QLQ-C30) only diarrhoea changed in a clinically relevant way, i.e. by 10 points (from 10 to 20 points), which was mainly observed in patients with elective pelvic irradiation (increase of 18 points, from 10 to 28 points). In the prostate-specific module (QLQ-PR25) only urinary symptoms changed significantly, i.e. by 13 points (from 24 to 37 points). CONCLUSIONS: The quality of life in patients with prostate cancer does not change in a clinically significant way during radiotherapy, which corroborates good treatment tolerance. Increased urinary symptoms and, in the case of pelvic irradiation, also increased diarrhoea have a negative impact on symptom-related quality of life.

Dosimetric comparison of liver tumour radiotherapy in all respiratory phases and in one phase using 4DCT.

PURPOSE: Delineation of target volume could be performed on all respiratory phases and radiation is delivered during free breathing cycle, or on the basis of one respiratory phase and deliver gated treatment choosing a specific phase for irradiation. We performed the comparison of both techniques in terms of target and normal tissue dose distributions. MATERIALS AND METHODS: We analysed 26 metastatic liver tumours using 4DCT to characterize tumour motion and to create treatment volumes: GITV4D was based on all 8 respiratory phases and GTVGAT was based on one specific phase. A 5mm automatic expansion was added to the GTVs to create PTVs. Two treatment plans were prepared to the total dose of 36 Gy in 3 fractions and dose-volume distributions were analysed for the target and organs at risk. Target motion along the superior-inferior direction was greatest with the mean of 1.1 cm ± 0.3, and in the lateral the mean was 0.7 cm ± 0.3. RESULTS: GTV and PTV volumes were larger in the 4D than in the GAT, mean 30.7 vs. 19.3 cm(3), and 66.7 vs. 45.1cm(3). We achieved similar dose coverage in PTV4D, for the 4D plan, and PTVGAT for the GAT plan, but a decrease in the average minimum dose to 17.8 Gy and the average mean dose to 35.3 Gy was found in PTV4D in the GAT plan. Radiotherapy delivered using GAT resulted in lower liver doses than using 4D with reduction of mean volume receiving 5 Gy by 6.5%±5, V(15Gy) by 4.5%±3.4, V(21Gy) by 3.4%±2.8 and reduction of mean kidney volume receiving 5 Gy by 9.1%±7.9, V(15Gy) by 4.1%±6.4, V(21Gy) by 3.2%±5.6. We also found correlations between PTV volume reduction with GAT, GTV motion and doses to normal tissues. CONCLUSIONS: Gated radiotherapy could potentially allow a reduction in PTV volumes from those delineated on all respiratory phases, maintaining acceptable target coverage. Smaller target volumes improve doses distribution in normal tissue especially in the liver and kidney, but also spinal cord and intestine. A significant correlation has been found between dose and volume reduction in the OARs and both GTV motion and PTV volume reduction.

Radiotherapy induced hip joint avascular necrosis-Two cases report.

BACKGROUND: Avascular necrosis (AVN) refers to the death of osteocytes and osteoblasts. Sites such as the femoral head, the head of the humerus and the mandibula with restricted access to local blood supply are particularly vulnerable to osteonecrosis. A COMBINATION OF SEVERAL FACTORS IS RESPONSIBLE FOR ISCHAEMIA AND IS ASSOCIATED WITH AVN: corticosteroids, alcohol abuse, Cushing's syndrome, SLE, systemic vasculitis, RA, scleroderma, haemoglobinopathies, radiotherapy. Management is based on proper diagnosis and treatment - conservative, pharmacological or surgical. Radiotherapy has become an integral part of the therapeutic programme of cancer patients. However, early and late after-effects of irradiation still constitute a significant issue in clinical practice. AIM: The aim of this report is to present two cases of acetabular protrusion and femoral head deformities after a therapeutic pelvic irradiation and draw physicians' attention to that clinical problem which continues to be underestimated. MATERIALS AND METHODS: This report documents two cases of acetabular protrusion and femoral head deformities after a therapeutic pelvic radiation. RESULTS: Avascular necrosis (AVN) constitutes a severe and challenging long-term complication in radiation oncology. CONCLUSION: It is necessary to take into account bone structures among organ at risk (OAR) involved in irradiation fields. The detailed analysis of the dose distribution and the use of collimators allow to decrease the total dose to OAR. An adequate management, early diagnosis and prompt, proper treatment may protect patients from long-term morbidities.

[Stereotactic extracranial radiosurgery of liver tumors using respiratory gating--the method presentation]. / Stereotaktyczna pozaczaszkowa radiochirurgia guzów watroby z bramkowaniem oddechowym wiazki promieniowania--prezentacja metody.

Radiotherapy has not been widely accepted in the treatment of primary and secondary liver tumors due to its limited efficacy. This is caused by insufficient radiation doses and suboptimal techniques, which were used in the past. However, a present technological progress in radiotherapy has led to the application of modern and sophisticated radiation techniques into the treatment of liver tumors. The excellent example of such progress is stereotactic body radiation therapy (SBRT) (or radiosurgery), with respiratory gating. Such treatment method enables delivery of high radiation doses precisely to the tumor with sparing of surrounding critical tissues. It is possible by application of multiple beams and a narrow margin around the tumor considering its respiratory movement. This method of treatment may be applied under the condition of very precise radiological imaging and accurate patients' immobilization. The study presents a method of stereotactic body radiation therapy with respiratory gating introduced in the MSC Cancer Center and Institute of Oncology in Gliwice. The treatment criteria are as follows: patients in good general condition with inoperable primary and secondary tumors, 1-3 lesions with a maximal diameter of 6 cm. The fractionation schedule consists of three doses of 12 Gy delivered in weekly intervals to the total dose of 36 Gy normalized to the minimum in the PTV. Pre-treatment preparation procedures included: patient immobilization in a vacuum pillow, monitoring of respiratory cycle, the choice of respiratory phase suitable for irradiation and computed tomography (CT) for treatment planning. After preparation of treatment plan, the X-ray simulation is performed with verification of the position of isocenter. A respiratory tracking is performed during simulation. At the last stage, patient is immobilized at the couch of linear accelerator, the verification of the isocenter position using MV or kV images is performed and respiratory tracking is once again conducted. Irradiation delivered intermittently in the selected respiratory phase using automatical connection between respiratory tracking system and accelerator. The SBRT with respiratory gating appears to be a promising method of local treatment in patients with inoperable liver tumors.