Reduction of cardiac and coronary artery doses in irradiation of left-sided breast cancer during inspiration breath hold : A planning study.

BACKGROUND AND PURPOSE: The radiation dose received by the heart during adjuvant left-sided breast irradiation plays a crucial role in development of late toxicity. Although the absolute risk of cardiotoxicity can be reduced with modern irradiation techniques, cardiotoxic chemotherapy increases the risk of late damage. Thus, the radiation dose to the heart should be minimized. This study evaluated the influence of different amplitudes of inspiration breath hold (IBH) during simulated left-sided breast irradiation on cardiac doses compared to free breathing (FB). PATIENTS AND METHODS: CT data of 11 lung cancer patients were retrospectively used as left-sided pseudo-breast cancer cases. Two CT scans were used, one during IBH and one during FB, and two treatment plans were generated. Relevant heart, lung, and left anterior descending artery (LAD) parameters were derived from dose-volume histograms. The normal tissue complication probabilities (NTCPs) for the heart were calculated based on the relative seriality model. Inspiration depth was quantified using chest volume and diameter, and correlated thereafter to a possible sparing of heart tissue. RESULTS: Mean reduction of heart dose for IBH compared to FB was 40 % (1.65 vs. 0.99 Gy; p = 0.007). Maximum dose to the heart and LAD could be decreased by 33 % (p = 0.011) and 43 % (p = 0.024), respectively. The mean anteroposterior shift was 5 mm (range 0.9-9.5 mm). Significant negative correlations between the relative change in LAD mean dose and the mean thoracic diameter and volume change, as well as with the absolute change in thoracic diameter were seen. The NTCP for cardiac mortality could be decreased by about 78 % (p = 0.017). CONCLUSION: For left-sided breast cancer patients, cardiac doses can be significantly decreased with tangential irradiation and IBH.

Early time course of neointima formation and vascular remodelling following percutaneous coronary intervention and vascular brachytherapy of in-stent restenotic lesions as assessed by intravascular ultrasound analysis.

In-stent restenosis (ISR) represents the major limitation of stent implantation. Treatment, although of relative technical ease, is unsatisfactory due to a high incidence of recurrent restenosis. Vascular brachytherapy (VBT) has emerged as a powerful adjunct therapeutic modality to treat ISR. Inhibition of neointima formation has been regarded as the relevant mechanism of action. Yet, positive remodelling has been suspected as another contributing factor. Since only very few precise analyses of the extent, distribution and time course of the respective mechanims exist, the goal of the present study was to describe the changes of the vessel geometry at the target lesion and at the reference site following angioplasty and VBT of ISR in 42 patients by means of quantitative coronary angiography (QCA) and intravascular ultrasound (IVUS) before and after the index procedure and at the 3 and 6 month follow-up. By QCA the acute lumen gain measured 2.2+/-0.8 mm, the late lumen loss at 3 months was 0.1+/-0.5 mm and at 6 months 0.4+/-0.7 mm. By IVUS luminal cross-sectional area increased from 1.5+/-1.2 mm(2) to 7.9+/-1.9 mm(2) (p<0.001). The intima hyperplasia cross-sectional area at 3 months was only 0.2+/-1.0 mm(2) (p=0.191), but increased to 0.7+/-0.6 mm(2) (p<0.001) at 6 months resulting in a lumen cross-sectional area of 7.1+/-1.7 mm(2). Stent dimensions did not show any significant changes over time. The external elastic membrane cross-sectional area at 3 months increased by 1.3+/-1.9 mm(2) (p<0.001), and showed a further increase by 0.7+/-2.9 mm(2) at 6 months. Positive remodelling could be demonstrated also at the reference segment. In conclusion the absolute amount of intima hyperplasia during a 6-month follow-up period after VBT of ISR is low and most pronounced between the third and sixth month. Besides this, predominantly within the first 3 months of follow-up, significant positive remodelling could be demonstrated at the target lesion and at the reference site. Both observed effects may contribute to the preservation of the vessel lumen.

Effects of single-dose irradiation on bronchial epithelium: a comparison of BEAS 2B cell monolayers, human organ cultures, and Goettinger minipigs.

To assess the effects of radiation on bronchial epithelium, BEAS 2B cells cultured as monolayers and human bronchial epithelium cultured as organ cultures were exposed to single doses of 0, 10 and 30 Gy. The lactate dehydrogenase in the supernatant of the BEAS 2B cells increased markedly 24 h after irradiation, whereas in the organ cultures only a minor increase was found after 48 h. The nucleosomes in the supernatant of the BEAS 2B cells showed a massive increase in response to irradiation, whereas in the organ cultures no change could be seen. The number of BEAS 2B cells was dramatically diminished after 96 h, whereas in the organ cultures a smaller decrease was observed no earlier than 21 days after irradiation. To assess the effects of brachytherapy in bronchial epithelium in vivo, brachytherapy with 30 Gy was performed in Goettinger minipigs, and histological sections of the bronchi were analyzed for morphological alterations and cell numbers. After 2 weeks, only slight cell damage was observable, and after 3 weeks, moderate morphological changes and decreased cell numbers were found. However, after 8 weeks, the epithelium had nearly regained its normal structure. We conclude that the bronchial epithelium has a remarkably high radioresistance and that organ cultures, but not monolayers of BEAS 2B cells, reflect the effects of radiation in vivo.

Enhanced dendritic cell maturation by TNF-alpha or cytidine-phosphate-guanosine DNA drives T cell activation in vitro and therapeutic anti-tumor immune responses in vivo.

Dendritic cells (DC) manipulated ex vivo can induce tumor immunity in experimental murine tumor models. To improve DC-based tumor vaccination, we studied whether DC maturation affects the T cell-activating potential in vitro and the induction of tumor immunity in vivo. Maturation of murine bone marrow-derived DC was induced by GM-CSF plus IL-4 alone or by further addition of TNF-alpha or a cytidine-phosphate-guanosine (CpG)-containing oligonucleotide (ODN-1826), which mimics the immunostimulatory effect of bacterial DNA. Flow cytometric analysis of costimulatory molecules and MHC class II showed that DC maturation was stimulated most by ODN-1826, whereas TNF-alpha had an intermediate effect. The extent of maturation correlated with the secretion of IL-12 and the induction of alloreactive T cell proliferation. In BALB/c mice, s.c. injection of colon carcinoma cells resulted in rapidly growing tumors. In this model, CpG-ODN-stimulated DC cocultured with irradiated tumor cells also induced prophylactic protection most effectively and were therapeutically effective when administered 3 days after tumor challenge. Thus, CpG-ODN-enhanced DC maturation may represent an efficient means to improve clinical tumor vaccination.

High-dose-rate brachytherapy: dose escalation in three-dimensional miniorgans of the human bronchial wall.

PURPOSE: High-dose-rate (HDR) brachytherapy of human lung cancer is well established, however fractionation schemes and dosages are based mainly on experience. The aim of this investigation was to study the effects of different doses of HDR iridium-192 on normal human bronchial epithelium in three-dimensional miniorgans of the human bronchial wall. METHODS AND MATERIALS: Forty-eight biopsies from normal bronchi were cultivated for 14 days and exposed at random to different doses of HDR iridium 192 (0 Gy, 30 Gy, 45 Gy, 60 Gy, or 75 Gy). Cell viability was assessed immediately after irradiation, after 4 or 18 days by fluorescent staining, and cell damage of the culture was analyzed by light microscopy. Lactate dehydrogenase (LDH) was measured in the supernatant for 4 days. RESULTS: There was no histologically apparent tissue damage regardless of the irradiation dose. The number of nonvital cells increased in irradiated miniorgans depending on the dose used (p < 0. 05 at 75 Gy). This effect occurred early and was less pronounced with time. LDH measurements showed an increase only in the first 24 hours. CONCLUSIONS: Our results confirm that normal bronchial epithelium has a high tolerance to early epithelial damage by irradiation. This model of human bronchial miniorgans is useful for further studies of the effects of irradiation on human bronchi.