C. M. van Leeuwen

Sketching and creative discovery

Abstract In the search for helpful computer tools for sketching in the early phases of design, the approach was taken to experimentally study sketching behaviour. In two series of experiments two mental processes revealed themselves as essential in the creative process: Restructuring and Combining. These two processes are in turn influenced by expertise in sketching and individual creativity. In this article each of the factors: Combining, Restructuring, Expertise and Creativity, will be separately highlighted with respect to their impact on sketching behavior. Finally, on the basis of these results conclusions are drawn for computerized sketching aids.

Creative discovery in imagery and perception: Combining is relatively easy, restructuring takes a sketch

A figure combination task, in which three components are combined into an object, was administered under imagery-alone and externalization conditions to subjects with different levels of sketching expertise. In externalization conditions the imaged combinations were sketched. In accordance with earlier studies, the combinations were rated equally creative across conditions. The combinations were scored with regard to the novelty of their spatial configurations of the components (combining score), and with regard to the novelty of the structure of the components (restructuring score). For expert sketchers the latter score was found to be increased by sketching. Creativity ratings correlated with both combining and restructuring scores in the sketching condition, but only with combining scores in the imagery condition. The results are interpreted in terms of a model in which creative processes use combining and restructuring strategies in a flexible way. Whereas restructuring draws heavily on both externalization and expertise in externalization, combining can be used independently of externalization and expertise.

3D radiobiological evaluation of combined radiotherapy and hyperthermia treatments

Abstract Purpose: Currently, clinical decisions regarding thermoradiotherapy treatments are based on clinical experience. Quantification of the radiosensitising effect of hyperthermia allows comparison of different treatment strategies, and can support clinical decision-making regarding the optimal treatment. The software presented here enables biological evaluation of thermoradiotherapy plans through calculation of equivalent 3D dose distributions. Methods: Our in-house developed software (X-Term) uses an extended version of the linear-quadratic model to calculate equivalent radiation dose, i.e. the radiation dose yielding the same effect as the thermoradiotherapy treatment. Separate sets of model parameters can be assigned to each delineated structure, allowing tissue specific modelling of hyperthermic radiosensitisation. After calculation, the equivalent radiation dose can be evaluated according to conventional radiotherapy planning criteria. The procedure is illustrated using two realistic examples. First, for a previously irradiated patient, normal tissue dose for a radiotherapy and thermoradiotherapy plan (with equal predicted tumour control) is compared. Second, tumour control probability (TCP) is assessed for two (otherwise identical) thermoradiotherapy schedules with different time intervals between radiotherapy and hyperthermia. Results: The examples demonstrate that our software can be used for individualised treatment decisions (first example) and treatment optimisation (second example) in thermoradiotherapy. In the first example, clinically acceptable doses to the bowel were exceeded for the conventional plan, and a substantial reduction of this excess was predicted for the thermoradiotherapy plan. In the second example, the thermoradiotherapy schedule with long time interval was shown to result in a substantially lower TCP. Conclusions: Using biological modelling, our software can facilitate the evaluation of thermoradiotherapy plans and support individualised treatment decisions.

Enhancing radiosensitisation of BRCA2-proficient and BRCA2-deficient cell lines with hyperthermia and PARP1-i

Abstract Poly(ADP-ribose)polymerase1 (PARP1) is an important enzyme in regulating DNA replication. Inhibition of PARP1 can lead to collapsed DNA forks which subsequently causes genomic instability, making DNA more susceptible in developing fatal DNA double strand breaks. PARP1-induced DNA damage is generally repaired by homologous recombination (HR), in which BRCA2 proteins are essential. Therefore, BRCA2-deficient tumour cells are susceptible to treatment with PARP1-inhibitors (PARP1-i). Recently, BRCA2 was shown to be down-regulated by hyperthermia (HT) temporarily, and this consequently inactivated HR for several hours. In this study, we investigated whether HT exclusively interferes with HR by analysing thermal radiosensitisation of BRCA2-proficient and deficient cells. After elucidating the equitoxicity of PARP1-i on BRCA2-proficient and deficient cells, we studied the cell survival, apoptosis, DNA damage (γ-H2AX foci and comet assay) and cell cycle distribution after different treatments. PARP1-i sensitivity strongly depends on the BRCA2 status. BRCA2-proficient and deficient cells are radiosensitised by HT, indicating that HT does not exclusively act by inhibition of HR. In all cell lines, the addition of HT to radiotherapy and PARP1-i resulted in the lowest cell survival, the highest levels of DNA damage and apoptotic levels compared to duo-modality treatments. Concluding, HT not only inhibits HR, but also has the capability of radiosensitising BRCA2-deficient cells. Thus, in case of BRCA2-mutation carriers, combining HT with PARP1-i may boost the treatment efficacy. This combination therapy would be effective for all patients with PARP1-i regardless of their BRCA status.

Measurement and analysis of the impact of time-interval, temperature and radiation dose on tumour cell survival and its application in thermoradiotherapy plan evaluation

Abstract Purpose: Biological modelling of thermoradiotherapy may further improve patient selection and treatment plan optimisation, but requires a model that describes the biological effect as a function of variables that affect treatment outcome (e.g. temperature, radiation dose). This study aimed to establish such a model and its parameters. Additionally, a clinical example was presented to illustrate the application. Methods: Cell survival assays were performed at various combinations of radiation dose (0–8 Gy), temperature (37–42 °C), time interval (0–4 h) and treatment sequence (radiotherapy before/after hyperthermia) for two cervical cancer cell lines (SiHa and HeLa). An extended linear-quadratic model was fitted to the data using maximum likelihood estimation. As an example application, a thermoradiotherapy plan (23 × 2 Gy + weekly hyperthermia) was compared with a radiotherapy-only plan (23 × 2 Gy) for a cervical cancer patient. The equivalent uniform radiation dose (EUD) in the tumour, including confidence intervals, was estimated using the SiHa parameters. Additionally, the difference in tumour control probability (TCP) was estimated. Results: Our model described the dependency of cell survival on dose, temperature and time interval well for both SiHa and HeLa data (R2=0.90 and R2=0.91, respectively), making it suitable for biological modelling. In the patient example, the thermoradiotherapy plan showed an increase in EUD of 9.8 Gy that was robust (95% CI: 7.7–14.3 Gy) against propagation of the uncertainty in radiobiological parameters. This corresponded to a 20% (95% CI: 15–29%) increase in TCP. Conclusions: This study presents a model that describes the cell survival as a function of radiation dose, temperature and time interval, which is essential for biological modelling of thermoradiotherapy treatments.

The effect of time interval between radiotherapy and hyperthermia on planned equivalent radiation dose

Abstract Purpose: Thermoradiotherapy is an effective treatment for locally advanced cervical cancer. However, the optimal time interval between radiotherapy and hyperthermia, resulting in the highest therapeutic gain, remains unclear. This study aims to evaluate the effect of time interval on the therapeutic gain using biological treatment planning. Methods: Radiotherapy and hyperthermia treatment plans were created for 15 cervical cancer patients. Biological modeling was used to calculate the equivalent radiation dose, that is, the radiation dose that results in the same biological effect as the thermoradiotherapy treatment, for different time intervals ranging from 0–4 h. Subsequently, the thermal enhancement ratio (TER, i.e. the ratio of the dose for the thermoradiotherapy and the radiotherapy-only plan) was calculated for the gross tumor volume (GTV) and the organs at risk (OARs: bladder, rectum, bowel), for each time interval. Finally, the therapeutic gain factor (TGF, i.e. TERGTV/TEROAR) was calculated for each OAR. Results: The median TERGTV ranged from 1.05 to 1.16 for 4 h and 0 h time interval, respectively. Similarly, for bladder, rectum and bowel, TEROARs ranged from 1–1.03, 1–1.04 and 1–1.03, respectively. Radiosensitization in the OARs was much less than in the GTV, because temperatures were lower, fractionation sensitivity was higher (lower α/β) and direct cytotoxicity was assumed negligible in normal tissue. TGFs for the three OARs were similar, and were highest (around 1.12) at 0 h time interval. Conclusion: This planning study indicates that the largest therapeutic gain for thermoradiotherapy in cervical cancer patients can be obtained when hyperthermia is delivered immediately before or after radiotherapy.

EP-2024: Optimising hyperthermia induced radiosensitisaion for treating HPV+ cervical tumours

S955 ________________________________________________________________________________ Conclusion: HDR-BT seems to be a good alternative for treatment of epitheliomas in special locations, above all in elderly patients with comorbidities that preclude surgery. Its ability to treat a wide area with minimal alteration of normal tissues allows a high probability of cure with excellent cosmetic results and without affecting functionality. We can conclude that HDR-BT could be a valid alternative to surgery with acceptable acute toxicity, good early local control and exceptional cosmetic outcomes in skin lesions.