Use of radionuclides in metastatic prostate cancer:pain relief and beyond

Bone metastases in prostate cancer are often the cause of significant morbidity in patients with castrate-resistant disease, and several studies have shown significant pain palliation with systemic radionuclide treatment. The purpose of this review is to discuss the place of radionuclides in the dynamic treatment landscape of metastatic prostate cancer in light of new evidence demonstrating benefit beyond palliation.

DNA damage responses following exposure to modulated radiation fields

During the delivery of advanced radiotherapy treatment techniques modulated beams are utilised to increase dose conformity across the target volume. Recent investigations have highlighted differential cellular responses to modulated radiation fields particularly in areas outside the primary treatment field that cannot be accounted for by scattered dose alone. In the present study, we determined the DNA damage response within the normal human fibroblast AG0-1522B and the prostate cancer cell line DU-145 utilising the DNA damage assay. Cells plated in slide flasks were exposed to 1 Gy uniform or modulated radiation fields. Modulated fields were delivered by shielding 25%, 50% or 75% of the flask during irradiation. The average number of 53BP1 or ?H2AX foci was measured in 2 mm intervals across the slide area. Following 30 minutes after modulated radiation field exposure an increase in the average number of foci out-of-field was observed when compared to non-irradiated controls. In-field, a non-uniform response was observed with a significant decrease in the average number of foci compared to uniformly irradiated cells. Following 24 hrs after exposure there is evidence for two populations of responding cells to bystander signals in-and out-of-field. There was no significant difference in DNA damage response between 25%, 50% or 75% modulated fields. The response was dependent on cellular secreted intercellular signalling as physical inhibition of intercellular communication abrogated the observed response. Elevated residual DNA damage observed within out-of-field regions decreased following addition of an inducible nitric oxide synthase inhibitor (Aminoguanidine). These data show, for the first time, differential DNA damage responses in-and out-of-field following modulated radiation field delivery. This study provides further evidence for a role of intercellular communication in mediating cellular radiobiological response to modulated radiation fields and may inform the refinement of existing radiobiological models for the optimization of advanced radiotherapy treatment plans. © 2012 Trainor et al.

Neoadjuvant hormone therapy for radical prostate radiotherapy:bicalutamide monotherapy vs. luteinizing hormone-releasing hormone agonist monotherapy: a single-institution matched-pair analysis

The purpose of this study was to compare the prostate-specific antigen (PSA) response to either neoadjuvant bicalutamide (BC) monotherapy or neoadjuvant luteinizing hormone-releasing hormone agonist (LHRHa) monotherapy and the subsequent effect on biochemical failure-free survival (BFFS) in men receiving radical radiotherapy (RT) for localized prostate cancer.

Service user involvement in teaching about conflict - an exploration of the issues

Service user involvement is now a well embedded feature of social work
education in the United Kingdom. Whilst many education institutions have
fully embraced the involvement of service users in teaching, there is still
work to be done in more fully engaging with service users who are seldom
heard. This article highlights the opportunities and challenges associated
with innovative work being piloted in Northern Ireland where victims and
survivors of political conflict are routinely involved in teaching social work
students about the impact of conflict on their lives.

Social work education and political conflict: preparing students to address the needs of victims and survivors of the Troubles in Northern Ireland

This paper reports on the evaluation of a European PEACE III sponsored teaching and learning project that was designed to enable social work students to better understand the needs of victims and survivors of the conflict in Northern Ireland. The paper begins with an introduction to policy, practice and educational contexts before reviewing the literature on social work, conflict and trauma. It also summarises key, innovative pedagogical approaches used in the teaching, including the use of ground rules, teaching teams consisting of lecturer and service user dyads, learning exercises and case studies. The paper then explains the evaluation methodology. This involved two surveys which returned 144 student and 34 practice teacher questionnaires. The findings revealed that
students were generally committed to this form of teaching and engagement with victims and survivors of the conflict, although some students reported that their attitudes towards this subject had were not changed. Some students also discussed how the conflict had affected their lives and the lives of families and friends; it is argued that such biographical details are crucial in developing new pedagogical approaches in this area.
Practice teachers who supervised some of these students on placement reported general levels of satisfaction with preparedness to work with conflict related situations but were less convinced that organisations were so committed. The paper concludes with a discussion of the study limitations and a recommendation for more robust methods of teaching and evaluation in this area of social work education and practice.

Enabling Social Work Students to Deal with the Consequences of Political Conflict: Engaging with Victim/Survivor Service Users and a ‘Pedagogy of Discomfort’

This paper describes the evaluation of an educational project, delivered in a Bachelor in Social Work degree (BSW) program in Northern Ireland. The project aimed to equip social work students to be more culturally competent in this divided society, with a central focus on including victim/survivor service users in social work training. A number of pedagogical approaches are noted, with particular consideration of Boler's ‘pedagogy of discomfort’ as a model that includes the multidimensional nature of the learning process when topics carry a high emotional tariff. The evaluation of the students' experience indicated that: there was strong support among students for the project; the unique contribution of service users was affirmed; and the project appeared to increase students' awareness and capacity to practice in a divided society. The evaluation of the trainers' experience highlighted key processes in the delivery of collaborative training. The authors argue that the lessons learned are broadly applicable to other forms of service user and carer involvement in social work training and in other societies in which health and social care professionals have to deal with the legacies of political conflict.

Older people and legal advice – the need for joined up and creative approaches

This paper reports the findings from research conducted with older people in Northern
Ireland which investigated whether their needs for legal information and advice were
being met. One of the unique aspects of the research involved investigating the
potential of the internet as a possible source for advising older people in relation to
legal problems. The findings suggest that online legal information may frequently assist
older people in identifying potential answers to their legal questions, but may not be an
adequate substitute for personal communication and advice. The research also
highlights the need for professionals to work together to meet the needs of older
persons for legal advice and to safeguard their interests. Such ‘joined up’ approaches
are particularly important, for example at the point of dementia diagnosis, where
information sharing between health and social care professionals may significantly
promote the legal and welfare interests of older people at a vulnerable point in their
lives. This paper therefore turns to work by university-based legal clinics in the United
States, such as the Elder Law Clinic at Pennsylvania State University, where social
work or healthcare professionals, lawyers and law students collaborate to support older
people in their search for resolution of legal problems.

Developing a social work curriculum on political conflict – Findings from an IASSW funded project

This paper presents the findings from an innovative project funded by the
International Association of Schools of Social Work (IASSW) and undertaken by
an international team of academics investigating the development of a global
curriculum for social work in the context of political conflict. Coupled alongside
the emerging research and literature on the subject, our small-scale survey
findings indicate support for the need for social work educators to address
political conflict more systematically within social work curricula at both
undergraduate and post-qualifying levels of social work education. The paper
illuminates the opportunities for creative pedagogy whilst also examining the
threats and challenges permeating the realisation of such initiatives. In this way,
the implementation of a proposed curriculum for political conflict is given meaning within the context of IASSW’s Global Standards for social work education. Given the exploratory nature of this project, the authors do conclude that further research is warranted in regard to potential curriculum development and suggest using a comparative case study approach with more in-depth qualitative methods as a way to address this.

A Kinetic-Based Model of Radiation-Induced Intercellular Signalling

It is now widely accepted that intercellular communication can cause significant variations in cellular responses to genotoxic stress. The radiation-induced bystander effect is a prime example of this effect, where cells shielded from radiation exposure see a significant reduction in survival when cultured with irradiated cells. However, there is a lack of robust, quantitative models of this effect which are widely applicable. In this work, we present a novel mathematical model of radiation-induced intercellular signalling which incorporates signal production and response kinetics together with the effects of direct irradiation, and test it against published data sets, including modulated field exposures. This model suggests that these so-called "bystander" effects play a significant role in determining cellular survival, even in directly irradiated populations, meaning that the inclusion of intercellular communication may be essential to produce robust models of radio-biological outcomes in clinically relevant in vivo situations.

Bone-targeting radiopharmaceuticals including radium-223

ABSTRACT: Bone-seeking radionuclides including samarium-153 ethylene diamine tetramethylene phosphonate and strontium-89 have been used for decades in the palliation of pain from bone metastases especially from prostate cancer. Emerging evidence of improved survival in metastatic castration-resistant prostate cancer (CRPC) with the first-in-class a-radionuclide, radium-223 (Ra) has rekindled interest in the role of bone-seeking radionuclide therapy.We review the literature for randomized controlled trials of bone-seeking radionuclides and explore some of the issues regarding the optimal use of these agents. In particular, we discuss dose, dose rate, radiobiology, and quality of radiation and postulate on potential future directions in particular combination schedules. ß-Emitting, bone-seeking radionuclides have proven ability to control pain in prostate cancer metastatic to bone with pain response rates in the order of 60% to 70% when used as single agents. Most of the published trials were underpowered to detect differences in survival; however, there is evidence of the potential for disease modification when these agents are used in combination with chemotherapy or in multiple cycles.Data from the recent phase III ALSYMPCA trial that compared Ra to placebo in symptomatic CRPC demonstrate a significant improvement in median overall survival of 3.6 months for patients with symptomatic CRPC metastatic to bone treated with 6 cycles of the a-emitting radionuclide Ra compared with placebo. The success of Ra in improving survival in CRPC will lead this agent to become part of the treatment paradigm for this disease, and with such an excellent safety profile, Ra has huge potential in combination strategies as well as for use earlier in the natural history of metastatic prostate cancer.

Validation of Next Generation Sequencing Technologies in Comparison to Current Diagnostic Gold Standards for BRAF, EGFR and KRAS Mutational Analysis

Next Generation Sequencing (NGS) has the potential of becoming an important tool in clinical diagnosis and therapeutic decision-making in oncology owing to its enhanced sensitivity in DNA mutation detection, fast-turnaround of samples in comparison to current gold standard methods and the potential to sequence a large number of cancer-driving genes at the one time. We aim to test the diagnostic accuracy of current NGS technology in the analysis of mutations that represent current standard-of-care, and its reliability to generate concomitant information on other key genes in human oncogenesis. Thirteen clinical samples (8 lung adenocarcinomas, 3 colon carcinomas and 2 malignant melanomas) already genotyped for EGFR, KRAS and BRAF mutations by current standard-of-care methods (Sanger Sequencing and q-PCR), were analysed for detection of mutations in the same three genes using two NGS platforms and an additional 43 genes with one of these platforms. The results were analysed using closed platform-specific proprietary bioinformatics software as well as open third party applications. Our results indicate that the existing format of the NGS technology performed well in detecting the clinically relevant mutations stated above but may not be reliable for a broader unsupervised analysis of the wider genome in its current design. Our study represents a diagnostically lead validation of the major strengths and weaknesses of this technology before consideration for diagnostic use.

Insulin-like growth factor binding protein-3 mediates vascular repair by enhancing nitric oxide generation

Insulin-like growth factor binding protein (IGFBP)-3 modulates vascular development by regulating endothelial progenitor cell (EPC) behavior, specifically stimulating EPC cell migration. This study was undertaken to investigate the mechanism of IGFBP-3 effects on EPC function and how IGFBP-3 mediates cytoprotection following vascular injury.

Effect of diabetes and aging on carboxymethyllysine levels in human urine

Carboxymethyllysine (CML) has been identified as a modified amino acid that accumulates with age in human lens proteins and collagen. CML may be formed by oxidation of fructoselysine (FL), the Amadori adduct formed on nonenzymatic glycosylation of lysine residues in protein, or by reaction of ascorbate with protein under autoxidizing conditions. We proposed that measurements of tissue and urinary CML may be useful as indices of oxidative stress or damage to proteins in vivo. To determine the extent to which oxidation of nonenzymatically glycosylated proteins contributes to urinary CML, we measured the urinary concentrations of FL and CML in diabetic (n = 26) and control (n = 28) patients. The urinary concentration of FL correlated strongly with HbA1 measurements and was significantly higher in diabetic compared with control samples (9.2 +/- 6.5 and 4.0 +/- 2.8 micrograms/mg creatinine, respectively; P less than 0.0001). There was also a strong correlation between the concentrations of CML and FL in both diabetic and control urine (r = 0.67, P less than 0.0001) but only a weakly significant increase in the CML concentration in diabetic compared with control urine (1.2 +/- 0.5 and 1.0 +/- 0.3 micrograms/mg creatinine, respectively; P = 0.05). The molar ratio of CML to FL was significantly lower in diabetic compared with control patients (0.25 +/- 0.12 and 0.43 +/- 0.16, respectively; P less than 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

What is the Role of the Bystander Response in Radionuclide Therapies?

Radionuclide therapy for cancer is undergoing a renaissance, with a wide range of radionuclide and clinical delivery systems currently under investigation. Dosimetry at the cellular and sub-cellular level is complex with inhomogeneity and incomplete targeting of all cells such that some tumor cells will receive little or no direct radiation energy. There is now sufficient preclinical evidence of a Bystander response which can modulate the biology of these un-irradiated cells with current research demonstrating both protective and inhibitory responses. Dependence upon fraction of irradiated cells has also been found and the presence of functional gap junctions appears to be import for several Bystander responses. The selection of either high or low LET radionuclides may be critical. While low LET radionuclides appear to have a Bystander response proportional to dose, the dose-response from high LET radionuclides are more complex. In media transfer experiments a "U" shaped response curve has been demonstrated for high LET treatments. However this "U" shaped response has not been seen with co-culture experiments and its relevance remains uncertain. For high LET treatments there is a suggestion that dose rate effects may also be important with inhibitory effects noted with 125I labelling study and a stimulatory seen with 123I labelling in one study.© 2013 Brady, O’Sullivan and Prise.