Radiotherapy for tumors of the stomach and gastroesophageal junction - a review of its role in multimodal therapy

There is broad consensus on surgical resection being the backbone of curative therapy of gastric- and gastroesophageal junction carcinoma. Nevertheless, details on therapeutic approaches in addition to surgery, such as chemotherapy, radiotherapy or radiochemotherapy are discussed controversially; especially whether external beam radiotherapy should be applied in addition to chemotherapy and surgery is debated in both entities and differs widely between regions and centers. Early landmark trials such as the Intergroup-0116 and the MAGIC trial must be interpreted in the context of potentially insufficient lymph node resection. Despite shortcomings of both trials, benefits on overall survival by radiochemotherapy and adjuvant chemotherapy were confirmed in populations of D2-resected gastric cancer patients by Asian trials. Recent results on junctional carcinoma patients strongly suggest a survival benefit of neoadjuvant radiochemotherapy in curatively resectable patients. An effect of chemotherapy in the perioperative setting as given in the MAGIC study has been confirmed by the ACCORD07 trial for junctional carcinomas; however both the studies by Stahl et al. and the excellent outcome in the CROSS trial as compared to all other therapeutic approaches indicate a superiority of neoadjuvant radiochemotherapy as compared to perioperative chemotherapy in junctional carcinoma patients. Surgery alone without neoadjuvant or perioperative therapy is considered suboptimal in patients with locally advanced disease. In gastric carcinoma patients, perioperative chemotherapy has not been compared to adjuvant radiochemotherapy in a randomized setting. Nevertheless, the results of the recently published ARTIST trial and the Chinese data by Zhu and coworkers, indicate a superiority of adjuvant radiochemotherapy as compared to adjuvant chemotherapy in terms of disease free survival in Asian patients with advanced gastric carcinoma. The ongoing CRITICS trial is supposed to provide reliable conclusions about which therapy should be preferred in Western patients with gastric carcinoma. If radiotherapy is performed, modern approaches such as intensity-modulated radiotherapy and image guidance should be applied, as these methods reduce dose to organs at risk and provide a more homogenous coverage of planning target volumes

PPARγ Loss Leads to Reduced Fertility

The peroxisome proliferation-activated receptor gamma (PPARγ) is expressed in many cell types including mammary epithelium, ovary, macrophages, and B- and T-cells. PPARγ has an anti-proliferative effect in pre-adipocytes and mammary epithelial cells, and treatment with its ligands reduced the progression of carcinogen-induced mammary tumors in mice. Because PPARγ-null mice die in utero it has not been possible to study its role in development and tumorigenesis in vivo. To investigate whether PPARγ is required for the establishment and physiology of different cell types, a cell-specific deletion of the gene was carried out in mice using the Cre-loxP recombination system. We deleted the PPARγ gene in mammary epithelium using WAP-Cre transgenic mice and in epithelial cells, B- and T-cells, and ovary cells using MMTV-Cre mice. The presence of PPARγ was not required for functional development of the mammary gland during pregnancy and for the establishment of B- and T-cells. In addition, no increase in mammary tumors was observed. However, loss of the PPARγ gene in oocytes and granulosa cells resulted in impaired fertility. These mice have normal populations of follicles, they ovulate and develop corpora lutea. Although progesterone levels are decreased and implantation rates are reduced, the exact cause of the impaired fertility remains to be determined

Monocytes Do Not Transdifferentiate into Proper Osteoblasts

Recent publications suggested that monocytes might be an attractive cell type to transdifferentiate into various cellular phenotypes. Aim was, therefore, to evaluate the potential of blood monocytes to transdifferentiate into osteoblasts. Monocytes isolated from peripheral blood were subjected to two previously published treatments to obtain unique, multipotent cell fractions, named programmable cells of monocytic origin (PCMOs) and monocyte-derived mesenchymal progenitor cells (MOMPs). Subsequently, MOMPs and PCMOs were treated with osteogenic differentiation medium (including either vitamin D or dexamethasone) for 14 days. Regarding a variety of surface markers, no differences between MOMPs, PCMOs, and primary monocytes could be detected. The treatment with osteogenic medium neither resulted in loss of hematopoietic markers nor in adoption of mesenchymal phenotype in all cell types. No significant effect was observed regarding the expression of osteogenic transcription factors, bone-related genes, or production of mineralized matrix. Osteogenic medium resulted in activation of monocytes and appearance of osteoclasts. In conclusion, none of the investigated monocyte cell types showed any transdifferentiation characteristics under the tested circumstances. Based on our data, we rather see an activation and maturation of monocytes towards macrophages and osteoclasts

Hypofractionated image-guided breath-hold SABR (Stereotactic Ablative Body Radiotherapy) of liver metastases - clinical results

Purpose: Stereotactic Ablative Body Radiotherapy (SABR) is a non-invasive therapy option for inoperable liver oligometastases. Outcome and toxicity were retrospectively evaluated in a single-institution patient cohort who had undergone ultrasound-guided breath-hold SABR. Patients and methods: 19 patients with liver metastases of various primary tumors consecutively treated with SABR (image-guidance with stereotactic ultrasound in combination with computer-controlled breath-hold) were analysed regarding overall-survival (OS), progression-free-survival (PFS), progression pattern, local control (LC), acute and late toxicity. Results: PTV (planning target volume)-size was 108 +/- 109cm(3) (median 67.4 cm(3)). BED2 (Biologically effective dose in 2 Gy fraction) was 83.3 +/- 26.2 Gy (median 78 Gy). Median follow-up and median OS were 12 months. Actuarial 2-year-OS-rate was 31%. Median PFS was 4 months, actuarial 1-year-PFS-rate was 20%. Site of first progression was predominantly distant. Regression of irradiated lesions was observed in 84% (median time to detection of regression was 2 months). Actuarial 6-month-LC-rate was 92%, 1- and 2-years-LC-rate 57%, respectively. BED2 influenced LC. When a cut-off of BED2 = 78 Gy was used, the higher BED2 values resulted in improved local control with a statistical trend to significance (p = 0.0999). Larger PTV-sizes, inversely correlated with applied dose, resulted in lower local control, also with a trend to significance (p-value = 0.08) when a volume cut-off of 67 cm(3) was used. No local relapse was observed at PTV-sizes < 67 cm(3) and BED2 > 78 Gy. No acute clinical toxicity > degrees 2 was observed. Late toxicity was also <= degrees 2 with the exception of one gastrointestinal bleeding-episode 1 year post-SABR. A statistically significant elevation in the acute phase was observed for alkaline-phosphatase; in the chronic phase for alkaline-phosphatase, bilirubine, cholinesterase and C-reactive protein. Conclusions: A trend to statistically significant correlation of local progression was observed for BED2 and PTV-size. Dose-levels BED2 > 78 Gy cannot be reached in large lesions constituting a significant fraction of this series. Image-guided SABR (igSABR) is therefore an effective non-invasive treatment modality with low toxicity in patients with small inoperable liver metastases

Quercetin Protects Primary Human Osteoblasts Exposed to Cigarette Smoke through Activation of the Antioxidative Enzymes HO-1 and SOD-1

Smokers frequently suffer from impaired fracture healing often due to poor bone quality and stability. Cigarette smoking harms bone cells and their homeostasis by increased formation of reactive oxygen species (ROS). The aim of this study was to investigate whether Quercetin, a naturally occurring antioxidant, can protect osteoblasts from the toxic effects of smoking. Human osteoblasts exposed to cigarette smoke medium (CSM) rapidly produced ROS and their viability decreased concentration- and time-dependently. Co-, pre- and postincubation with Quercetin dose-dependently improved their viability. Quercetin increased the expression of the anti-oxidative enzymes heme-oxygenase- (HO-) 1 and superoxide-dismutase- (SOD-) 1. Inhibiting HO-1 activity abolished the protective effect of Quercetin. Our results demonstrate that CSM damages human osteoblasts by accumulation of ROS. Quercetin can diminish this damage by scavenging the radicals and by upregulating the expression of HO-1 and SOD-1. Thus, a dietary supplementation with Quercetin could improve bone matter, stability and even fracture healing in smokers

Determinants of a transcriptionally competent environment at the GM-CSF promoter

Granulocyte macrophage-colony stimulating factor (GM-CSF) is produced by T cells, but not B cells, in response to immune signals. GM-CSF gene activation in response to T-cell stimulation requires remodelling of chromatin associated with the gene promoter, and these changes do not occur in B cells. While the CpG methylation status of the murine GM-CSF promoter shows no correlation with the ability of the gene to respond to activation, we find that the basal chromatin environment of the gene promoter influences its ability to respond to immune signals. In unstimulated T cells but not B cells, the GM-CSF promoter is selectively marked by enrichment of histone acetylation, and association of the chromatin-remodelling protein BRG1. BRG1 is removed from the promoter upon activation concomitant with histone depletion and BRG1 is required for efficient chromatin remodelling and transcription. Increasing histone acetylation at the promoter in T cells is paralleled by increased BRG1 recruitment, resulting in more rapid chromatin remodelling, and an associated increase in GM-CSF mRNA levels. Furthermore, increasing histone acetylation in B cells removes the block in chromatin remodelling and transcriptional activation of the GM-CSF gene. These data are consistent with a model in which histone hyperacetylation and BRG1 enrichment at the GM-CSF promoter, generate a chromatin environment competent to respond to immune signals resulting in gene activation

Statistical Techniques Complement UML When Developing Domain Models of Complex Dynamical Biosystems

Computational modelling and simulation is increasingly being used to complement traditional wet-lab techniques when investigating the mechanistic behaviours of complex biological systems. In order to ensure computational models are fit for purpose, it is essential that the abstracted view of biology captured in the computational model, is clearly and unambiguously defined within a conceptual model of the biological domain (a domain model), that acts to accurately represent the biological system and to document the functional requirements for the resultant computational model. We present a domain model of the IL-1 stimulated NF-κB signalling pathway, which unambiguously defines the spatial, temporal and stochastic requirements for our future computational model. Through the development of this model, we observe that, in isolation, UML is not sufficient for the purpose of creating a domain model, and that a number of descriptive and multivariate statistical techniques provide complementary perspectives, in particular when modelling the heterogeneity of dynamics at the single-cell level. We believe this approach of using UML to define the structure and interactions within a complex system, along with statistics to define the stochastic and dynamic nature of complex systems, is crucial for ensuring that conceptual models of complex dynamical biosystems, which are developed using UML, are fit for purpose, and unambiguously define the functional requirements for the resultant computational model