The intent of this pooled analysis as part of the German society for radiation oncology (DEGRO) stereotactic body radiotherapy (SBRT) initiative was to analyze the patterns of care of SBRT for liver ...oligometastases and to derive factors influencing treated metastases control and overall survival in a large patient cohort.
From 17 German and Swiss centers, data on all patients treated for liver oligometastases with SBRT since its introduction in 1997 has been collected and entered into a centralized database. In addition to patient and tumor characteristics, data on immobilization, image guidance and motion management as well as dose prescription and fractionation has been gathered. Besides dose response and survival statistics, time trends of the aforementioned variables have been investigated.
In total, 474 patients with 623 liver oligometastases (median 1 lesion/patient; range 1–4) have been collected from 1997 until 2015. Predominant histologies were colorectal cancer (n = 213 pts.; 300 lesions) and breast cancer (n = 57; 81 lesions). All centers employed an SBRT specific setup. Initially, stereotactic coordinates and CT simulation were used for treatment set-up (55%), but eventually were replaced by CBCT guidance (28%) or more recently robotic tracking (17%). High variance in fraction (fx) number (median 1 fx; range 1–13) and dose per fraction (median: 18.5 Gy; range 3–37.5 Gy) was observed, although median BED remained consistently high after an initial learning curve. Median follow-up time was 15 months; median overall survival after SBRT was 24 months. One- and 2-year treated metastases control rate of treated lesions was 77% and 64%; if maximum isocenter biological equivalent dose (BED) was greater than 150 Gy EQD2Gy, it increased to 83% and 70%, respectively. Besides radiation dose colorectal and breast histology and motion management methods were associated with improved treated metastases control.
After an initial learning curve with regards to total cumulative doses, consistently high biologically effective doses have been employed translating into high local tumor control at 1 and 2 years. The true impact of histology and motion management method on treated metastases control deserve deeper analysis. Overall survival is mainly influenced by histology and metastatic tumor burden.
Intestinal epithelial cells (IECs) not only have a critical function in the absorption of nutrients, but also act as a physical barrier between our body and the outside world. Damage and death of the ...epithelial cells lead to the breakdown of this barrier function and inflammation due to access of the immune system to compounds of the intestinal flora. Intestinal epithelial damage is frequently associated with various inflammatory disorders, chemo- and radiotherapy as well as drug-mediated toxicity. Until recently, intestinal epithelial-damaging activities of drugs and treatments could be tested only in vivo in animal models because of the poor survival rate of primary IECs ex vivo. The three-dimensional culture and outgrowth of intestinal crypt stem cells into organoids have offered new possibilities to culture and study IECs ex vivo. Here we demonstrate that intestinal organoids are a useful and physiologically relevant model system to study cell death and survival in IECs. We further describe a number of microscopy-based as well as colorimetric methods to monitor and score survival and death of intestinal organoids. Finally, the comparison of organoids isolated from gene-deficient mice and wild-type mice allows investigating the role of specific genes in the regulation of IEC death. Owing to their comparable structure and behavior, intestinal organoids may serve as an interesting and physiologically relevant surrogate system for large- and mid-scale in vitro testing of intestinal epithelium-damaging drugs and toxins, and for the investigation of cell death pathways.
The chemical composition of solid biofuels (as defined in Directive 2000/76/EC of the European Parliament and of the Council on the Incineration of Waste. In: European Commission, editor. Official ...Journal of the European Communities, vol. L 332; 2000. p. 91–111 and CEN/TC 335—WG2 N94. Final draft. European Committee for standardization, editor. Solid biofuels—fuel specifications and classes. Brussels, Belgium; 2003. has manifold effects on their thermal utilisation. C, H and O are the main components of solid biofuels and are of special relevance for the gross calorific value, H in addition also for the net calorific value. The fuel N content is responsible for NO
x
formation. NO
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emissions belong to the main environmental impact factors of solid biofuel combustion. Cl and S are responsible for deposit formation and corrosion and are therefore relevant for a high plant availability. Furthermore, Cl causes HCl as well as PCDD/F and S SO
x
emissions and both elements are involved in the formation of aerosols (submicron particle emissions). The ash content influences the choice of the appropriate combustion technology and influences deposit formation, fly ash emissions and the logistics concerning ash storage and ash utilisation/disposal. Major ash forming elements (Al, Ca, Fe, K, Mg, Na, P, Si, Ti) are of relevance for the ash melting behaviour, deposit formation and corrosion. In addition, volatile elements such as Na and K are main constituents of aerosols. Volatile minor elements (As, Cd, Hg, Pb, Zn) play a major role in gaseous and especially aerosol emissions as well as in deposit formation, corrosion and ash utilisation/disposal. Either partly or non-volatile minor elements (Ba, Co, Cr, Cu, Mo, Mn, V) are of special relevance for ash utilisation. The present paper discusses the influence of chemical fuel properties on biomass combustion plants as well as possibilities and recommendations for controlling them.
The anti-inflammatory action of adrenal-derived glucocorticoids has been recognized since several decades. This knowledge has found broad application in the clinics and today synthetic ...glucocorticoids are widely used in the treatment of various inflammatory diseases. However, the use of synthetic glucocorticoids in the treatment of diseases associated with viral infections of epithelial surfaces, like the lung or the intestine, is still under debate and seems not as efficient as desired. Basic research on the anti-viral immune responses and on regulatory mechanisms in the prevention of immunopathological disorders, however, has led us back again to focus on endogenous glucocorticoid synthesis. It has become established that this synthesis is not restricted to the adrenal glands alone, but that numerous tissues also produce glucocorticoids in situ. Extra-adrenal derived glucocorticoids have the capacity to locally control and maintain immune homeostasis under steady-state and inflammatory conditions. Here, we discuss the current knowledge of extra-adrenal glucocorticoid synthesis in the lung and the intestine, and its role in the regulation of anti-viral immune responses.
Abstract Introduction Stereotactic body radiation therapy (SBRT) is applied in the oligometastatic setting to treat liver metastases. However, factors influencing tumor control probability (TCP) ...other than radiation dose have not been thoroughly investigated. Here we set out to investigate such factors with a focus on the influence of histology and chemotherapy prior to SBRT using a large multi-center database from the German Society of Radiation Oncology. Methods 452 SBRT treatments in 363 patients were analyzed after collection of patient, tumor and treatment data in a multi-center database. Histology was considered through random effects in semi-parametric and parametric frailty models. Dose prescriptions were parametrized by conversion to the maximum biologically effective dose using alpha/beta of 10 Gy (BEDmax ). Results After adjusting for histology, BEDmax was the strongest predictor of TCP. Larger PTV volumes, chemotherapy prior to SBRT and simple motion management techniques predicted significantly lower TCP. The model predicted a BED of 209 ± 67 Gy10 necessary for 90% TCP at 2 years with no prior chemotherapy, but 286 ± 78 Gy10 when chemotherapy had been given. Breast cancer metastases were significantly more responsive to SBRT compared to other histologies with 90% TCP at 2 years achievable with BEDmax of 157 ± 80 Gy10 or 80 ± 62 Gy10 with and without prior chemotherapy, respectively. Conclusions Besides dose, histology and pretreatment chemotherapy were important factors influencing local TCP in this large cohort of liver metastases. After adjusting for prior chemotherapy, our data add to the emerging evidence that breast cancer metastases do respond better to hypofractionated SBRT compared to other histologies.
Combined radiochemotherapy is the currently used therapy for locally advanced pancreatic ductal adenocarcinoma (PDAC), but normal tissue toxicity limits its application. Here we test the hypothesis ...that inhibition of ATR (ATM-Rad3-related) could increase the sensitivity of the cancer cells to radiation or chemotherapy without affecting normal cells. We tested VE-822, an ATR inhibitor, for in vitro and in vivo radiosensitization. Chk1 phosphorylation was used to indicate ATR activity, γH2AX and 53BP1 foci as evidence of DNA damage and Rad51 foci for homologous recombination activity. Sensitivity to radiation (XRT) and gemcitabine was measured with clonogenic assays in vitro and tumor growth delay in vivo. Murine intestinal damage was evaluated after abdominal XRT. VE-822 inhibited ATR in vitro and in vivo. VE-822 decreased maintenance of cell-cycle checkpoints, increased persistent DNA damage and decreased homologous recombination in irradiated cancer cells. VE-822 decreased survival of pancreatic cancer cells but not normal cells in response to XRT or gemcitabine. VE-822 markedly prolonged growth delay of pancreatic cancer xenografts after XRT and gemcitabine-based chemoradiation without augmenting normal cell or tissue toxicity. These findings support ATR inhibition as a promising new approach to improve the therapeutic ration of radiochemotherapy for patients with PDAC.
The aim of this analysis was to model the effect of local control (LC) on overall survival (OS) in patients treated with stereotactic body radiotherapy (SBRT) for liver or lung metastases from ...colorectal cancer.
The analysis is based on pooled data from two retrospective SBRT databases for pulmonary and hepatic metastases from 27 centers from Germany and Switzerland. Only patients with metastases from colorectal cancer were considered to avoid histology as a confounding factor. An illness-death model was employed to model the relationship between LC and OS.
Three hundred eighty-eight patients with 500 metastatic lesions (lung n = 209, liver n = 291) were included and analyzed. Median follow-up time for local recurrence assessment was 12.1 months. Ninety-nine patients with 112 lesions experienced local failure. Seventy-one of these patients died after local failure. Median survival time was 27.9 months in all patients and 25.4 months versus 30.6 months in patients with and without local failure after SBRT. The baseline risk of death after local failure exceeds the baseline risk of death without local failure at 10 months indicating better survival with LC.
In CRC patients with lung or liver metastases, our findings suggest improved long-term OS by achieving metastatic disease control using SBRT in patients with a projected OS estimate of > 12 months.
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