Combined radiotherapy (RT) and hyperthermia (HT) treatments may improve treatment outcome by heat induced radio-sensitisation. We propose an empirical cell survival model (AlphaR model) to describe this multimodality therapy. The model is motivated by the observation that heat induced radio-sensitisation may be explained by a reduction in the DNA damage repair capacity of heated cells. We assume that this repair is only possible up to a threshold level above which survival will decrease exponentially with dose. Experimental cell survival data from two cell lines (HCT116, Cal27) were considered along with that taken from the literature (baby hamster kidney [BHK] and Chinese hamster ovary cells [CHO]) for HT and combined RT-HT. The AlphaR model was used to study the dependence of clonogenic survival on treatment temperature, and thermal dose R2 ≥ 0.95 for all fits). For HT survival curves (0–80 CEM43 at 43.5–57 °C), the number of free fit AlphaR model parameters could be reduced to two. Both parameters increased exponentially with temperature. We derived the relative biological effectiveness (RBE) or HT treatments at different temperatures, to provide an alternative description of thermal dose, based on our AlphaR model. For combined RT-HT, our analysis is restricted to the linear quadratic arm of the model. We show that, for the range used (20–80 CEM43, 0–12 Gy), thermal dose is a valid indicator of heat induced radio-sensitisation, and that the model parameters can be described as a function thereof. Overall, the proposed model provides a flexible framework for describing cell survival curves, and may contribute to better quantification of heat induced radio-sensitisation, and thermal dose in general.

Combined radiotherapy and hyperthermia offer great potential for the successful treatment of radio-resistant tumours through thermo-radiosensitization. Tumour response heterogeneity, due to intrinsic, or micro-environmentally induced factors, may greatly influence treatment outcome, but is difficult to account for using traditional treatment planning approaches. Systems oncology simulation, using mathematical models designed to predict tumour growth and treatment response, provides a powerful tool for analysis and optimization of combined treatments. We present a framework that simulates such combination treatments on a cellular level. This multiscale hybrid cellular automaton simulates large cell populations (up to 107 cells) in vitro, while allowing individual cell-cycle progression, and treatment response by modelling radiation-induced mitotic cell death, and immediate cell kill in response to heating. Based on a calibration using a number of experimental growth, cell cycle and survival datasets for HCT116 cells, model predictions agreed well (R2 > 0.95) with experimental data within the range of (thermal and radiation) doses tested (0–40 CEM43, 0–5 Gy). The proposed framework offers flexibility for modelling multimodality treatment combinations in different scenarios. It may therefore provide an important step towards the modelling of personalized therapies using a virtual patient tumour.

The rare benign giant cell tumour of bone (GCTB) is defined by an almost unique mutation in the H3.3 family of histone genes H3-3A or H3-3B; however, the same mutation is occasionally found in primary malignant bone tumours which share many features with the benign variant. Moreover, lung metastases can occur despite the absence of malignant histological features in either the primary or metastatic lesions. Herein we investigated the genetic events of 17 GCTBs including benign and malignant variants and the methylation profiles of 122 bone tumour samples including GCTBs. Benign GCTBs possessed few somatic alterations and no other known drivers besides the H3.3 mutation, whereas all malignant tumours harboured at least one additional driver mutation and exhibited genomic features resembling osteosarcomas, including high mutational burden, additional driver event(s), and a high degree of aneuploidy. The H3.3 mutation was found to predate the development of aneuploidy. In contrast to osteosarcomas, malignant H3.3-mutated tumours were enriched for a variety of alterations involving TERT, other than amplification, suggesting telomere dysfunction in the transformation of benign to malignant GCTB. DNA sequencing of the benign metastasising GCTB revealed no additional driver alterations; polyclonal seeding in the lung was identified, implying that the metastatic lesions represent an embolic event. Unsupervised clustering of DNA methylation profiles revealed that malignant H3.3-mutated tumours are distinct from their benign counterpart, and other bone tumours. Differential methylation analysis identified CCND1, encoding cyclin D1, as a plausible cancer driver gene in these tumours because hypermethylation of the CCND1 promoter was specific for GCTBs. We report here the genomic and methylation patterns underlying the rare clinical phenomena of benign metastasising and malignant transformation of GCTB and show how the combination of genomic and epigenomic findings could potentially distinguish benign from malignant GCTBs, thereby predicting aggressive behaviour in challenging diagnostic cases.

Syndrome (CAPS) Registry Project Group (European Forum on Antiphospholipid Antibodies). Relapsing catastrophic antiphospholipid syndrome potential role of microangiopathic hemolytic anemia in disease relapses.