Radiobiological model comparison of 3D conformal radiotherapy and IMRT plans for the treatment of prostate cancer

The main aim of radiotherapy is to deliver a dose of radiation that is high enough to destroy the tumour cells while at the same time minimising the damage to normal healthy tissues. Clinically, this has been achieved by assigning a prescription dose to the tumour volume and a set of dose constraints on critical structures. Once an optimal treatment plan has been achieved the dosimetry is assessed using the physical parameters of dose and volume. There has been an interest in using radiobiological parameters to evaluate and predict the outcome of a treatment plan in terms of both a tumour control probability (TCP) and a normal tissue complication probability (NTCP). In this study, simple radiobiological models that are available in a commercial treatment planning system were used to compare three dimensional conformal radiotherapy treatments (3D-CRT) and intensity modulated radiotherapy (IMRT) treatments of the prostate. Initially both 3D-CRT and IMRT were planned for 2 Gy/fraction to a total dose of 60 Gy to the prostate. The sensitivity of the TCP and the NTCP to both conventional dose escalation and hypo-fractionation was investigated. The biological responses were calculated using the Källman S-model. The complication free tumour control probability (P+) is generated from the combined NTCP and TCP response values. It has been suggested that the alpha/beta ratio for prostate carcinoma cells may be lower than for most other tumour cell types. The effect of this on the modelled biological response for the different fractionation schedules was also investigated.

Exploring non-cancer pain conditions in a community sample : critiquing a current conceptual model of the acute to chronic pain transition and examining predictors of chronicity

This program of research examines the experience of chronic pain in a community sample. While, it is clear that like patient samples, chronic pain in non-patient samples is also associated with psychological distress and physical disability, the experience of pain across the total spectrum of pain conditions (including acute and episodic pain conditions) and during the early course of chronic pain is less clear. Information about these aspects of the pain experience is important because effective early intervention for chronic pain relies on identification of people who are likely to progress to chronicity post-injury. A conceptual model of the transition from acute to chronic pain was proposed by Gatchel (1991a). In brief, Gatchel’s model describes three stages that individuals who have a serious pain experience move through, each with worsening psychological dysfunction and physical disability. The aims of this program of research were to describe the experience of pain in a community sample in order to obtain pain-specific data on the problem of pain in Queensland, and to explore the usefulness of Gatchel’s Model in a non-clinical sample. Additionally, five risk factors and six protective factors were proposed as possible extensions to Gatchel’s Model. To address these aims, a prospective longitudinal mixed-method research design was used. Quantitative data was collected in Phase 1 via a comprehensive postal questionnaire. Phase 2 consisted of a follow-up questionnaire 3 months post-baseline. Phase 3 consisted of semi-structured interviews with a subset of the original sample 12 months post follow-up, which used qualitative data to provide a further in-depth examination of the experience and process of chronic pain from respondents’ point of view. The results indicate chronic pain is associated with high levels of anxiety and depressive symptoms. However, the levels of disability reported by this Queensland sample were generally lower than those reported by clinical samples and consistent with disability data reported in a New South Wales population-based study. With regard to the second aim of this program of research, while some elements of the pain experience of this sample were consistent with that described by Gatchel’s Model, overall the model was not a good fit with the experience of this non-clinical sample. The findings indicate that passive coping strategies (minimising activity), catastrophising, self efficacy, optimism, social support, active strategies (use of distraction) and the belief that emotions affect pain may be important to consider in understanding the processes that underlie the transition to and continuation of chronic pain.

Implication of 3D culture system for study of prostate cancer (CaP) mediated bone metastasis

Introduction : For the past decade, three dimensional (3D) culture has served as a foundation for regenerative medicine study. With an increasing awareness of the importance of cell-cell and cell-extracellular matrix interactions which are lacking in 2D culture system, 3D culture system has been employed for many other applications namely cancer research. Through development of various biomaterials and utilization of tissue engineering technology, many in vivo physiological responses are now better understood. The cellular and molecular communication of cancer cells and their microenvironment, for instance can be studied in vitro in 3D culture system without relying on animal models alone. Predilection of prostate cancer (CaP) to bone remains obscure due to the complexity of the mechanisms and lack of proper model for the studies. In this study, we aim to investigate the interaction between CaP cells and osteoblasts simulating the natural bone metastasis. We also further investigate the invasiveness of CaP cells and response of androgen sensitve CaP cells, LNCaP to synthetic androgen.----- Method : Human osteoblast (hOB) scaffolds were prepared by seeding hOB on medical grade polycaprolactone-tricalcium phosphate (mPLC-TCP) scaffolds and induced to produce bone matrix. CaP cell lines namely wild type PC3 (PC3-N), overexpressed prostate specific antigen PC3 (PC3k3s5) and LNCaP were seeded on hOB scaffolds as co-cultures. Morphology of cells was examined by Phalloidin-DAPI and SEM imaging. Gelatin zymography was performed on the 48 hours conditioned media (CM) from co-cultures to determine matrix metalloproteinase (MMP) activity. Gene expression of hOB/LNCaP co-cultures which were treated for 48 hours with 1nM synthetic androgen R1881 were analysed by quantitative real time PCR (qRT-PCR).----- Results : Co-culture of PCC/hOB revealed that the morphology of PCCs on the tissue engineered bone matrix varied from homogenous to heterogenous clusters. Enzymatically inactive pro-MMP2 was detected in CM from hOBs and PCCs cultured on scaffolds. Elevation in MMP9 activity was found only in hOB/PC3N co-culture. hOB/LNCaP co-culture showed increase in expression of key enzymes associated with steroid production which also corresponded to an increase in prostate specific antigen (PSA) and MMP9.----- Conclusions : Upregulation of MMP9 indicates involvement of ECM degradation during cancer invasion and bone metastases. Expression of enzymes involved in CaP progression, PSA, which is not expressed in osteoblasts, demonstrates that crosstalk between PCCs and osteoblasts may play a part in the aggressiveness of CaP. The presence of steroidogenic enzymes, particularly, RDH5, in osteoblasts and stimulated expression in co-culture, may indicate osteoblast production of potent androgens, fuelling cancer cell proliferation. Based on these results, this practical 3D culture system may provide greater understanding into CaP mediated bone metastasis. This allows the role of the CaP/hOB interaction with regards to invasive property and steroidogenesis to be further explored.