Practising social justice: Community organisations, what matters and what counts

This thesis investigates the situated knowing-in-practice of locally-based community organisations, and studies how this practice knowledge is translated and contested in inter-organisational relations in the community services field of practices. Despite participation in government-led consultation processes, community organisations express frustration that the resulting policies and plans inadequately take account of the contributions from their practice knowledge. The funding of locally-based community organisations is gradually diminishing in real terms and in the competitive tendering environment, large nationally-based organisations often attract the new funding sources. The concern of locally-based community organisations is that the apparent lack of understanding of their distinctive practice knowing is threatening their capacity to improve the well-being of local people and their communities. In this study, I work with practitioners, service participants and management committee members to present an account of their knowing-in-practice, its character and conditions of efficacy; and then investigate what happens when this local practice knowledge is translated into results-based accountability (RBA) planning with diverse organisations and institutions. This thesis analyses three points of observation: knowing in a community of practitioners; knowing in a community organisation and knowing in the community services field of practices. In choosing these points of observation, the inquiry explores some of the relations and intra-actions from the single organisation to the institutional at a time when state government bureaucracy has mandated that community organisations implement RBA to articulate outcomes that can be measured by performance indicators. A feminist, performative, relational practice-based approach employs participatory action research to achieve an enabling research experience for the participants. It aims to intervene strategically to enhance recognition of the distinctive contributions of community organisations’ practice knowledge. This thesis reconfigures understandings of the roles, contributions and accountabilities of locally-based community organisations. Observations of situated practices together with the accounts of workers and service participants demonstrate how community organisations facilitate service participants’ struggles over social justice. A new topology for rethinking social justice as processual and practice-based is developed. It demonstrates how these struggles are a dynamic complex of iteratively-enfolded practices of respect and recognition, redistribution and distributive justice, representation and participation, belonging and inclusion. The focus on the practising of social justice in this thesis offers an alternative to the neo-liberal discourse that positions community organisations as sub-contractors accountable to government for delivering measurable outputs, outcomes and efficiencies in specified service provision contracts. The study shows how knowing-in-practice in locally-based community organisations contests the representational conception of knowledge inextricably entangled with accountability and performance measurement apparatus such as RBA. Further, it suggests that practitioner and service participant contributions are marginalised and diminished in RBA through the privileging of knowledge that takes an ‘expert’, quantifiable and calculative form. Thus crucially, harnessing local practice knowing requires re-imagining and enacting knowledge spaces that assemble and take seriously all relevant stakeholder perspectives, diverse knowledges and methods

Basal cytokines profile in metastatic renal cell carcinoma patients treated with subcutaneous IL-2-based therapy compared with that of healthy donors

<p>Abstract</p> <p>Background and purpose</p> <p>Metastatic renal cell carcinoma (MRCC) has a poor prognosis with a median overall survival of about one year. Since only a minority of patients experienced therapeutic benefit to current treatments, several studies have attempted to identify factors that may have an impact on response and survival. Cytokines play a crucial role in the host's immune response by regulating the development and function of a lot of biological compartments. Nevertheless, available data on basal cytokine levels in MRCC are very few and no clear profile of serum cytokines has been identified yet in these patients population. Thus, determining the levels of cytokines in MRCC could not only help in understanding the biological mechanisms of the tumor growth, but also in evaluating if different cytokine profiles are correlated with particular clinical behaviors.</p> <p>Materials and methods</p> <p>In 144 healthy donors and 55 MRCC treated with subcutaneous IL-2-based regimens, we analysed a panel of basal cytokines particularly involved in the neoplastic progression (IL-1beta, IL-6, IL-8, IL-10, IL-12, alpha-TNF) and C-reactive protein (CRP) in order to compare their levels in the two groups, and to verify their impact on patient response and survival.</p> <p>We first compared cytokines levels in patients population and healthy donors. Than, in definite patients group, univariate and multivariate analyses were performed to evaluate the correlation existing between each factor considered and clinical outcomes. For these analyses, baseline values were included as dichotomous variables using the median values (above and below) of control group.</p> <p>Results</p> <p>In general, higher levels of cytokines were found in patients with respect to those of healthy donors, both in term of percentage of undetectable levels or median values. The impact on response was insignificant, except for higher levels of CRP that were strongly correlated with a worse response (p < 0.001). Within the patients groups, a worse survival was associated with higher values of CRP (8 vs 31 months, p = 0.0000), IL-6 (9 vs 25 months, p = 0.0295), and IL-8 (9 vs 17 months, p = 0.0371). Conversely, higher levels of IL-12 were associated with a better survival (25 vs 15 months, months p = 0.0882). A correlation was found between CRP and IL-6 (p = 0.009) and between CRP and IL-10 (p = 0.038). After multivariate analysis only CRP (p = 0.0035) and IL-12 (p = 0.0371) maintained an independent impact on survival, while IL-6 showed a borderline value (p = 0.0792).</p> <p>Conclusion</p> <p>Higher cytokines levels characterize patients population with respect to healthy donors. Moreover, higher basal level of some immunosuppressive cytokines (CRP, IL-6, IL-8) result correlated with a poorer survival, whereas higher levels of IL-12, a cytokine with a potent antineoplastic activity, was associated with a better survival. A wider sample of patients is needed to better clarify if our findings are intrinsically related to patients population or if they are simply an epiphenomenon of disease progression.</p

Chemokine-mediated distribution of dendritic cell subsets in renal cell carcinoma

<p>Abstract</p> <p>Background</p> <p>Renal cell carcinoma (RCC) represents one of the most immunoresponsive cancers. Antigen-specific vaccination with dendritic cells (DCs) in patients with metastatic RCC has been shown to induce cytotoxic T-cell responses associated with objective clinical responses. Thus, clinical trials utilizing DCs for immunotherapy of advanced RCCs appear to be promising; however, detailed analyses concerning the distribution and function of DC subsets in RCCs are lacking.</p> <p>Methods</p> <p>We characterized the distribution of the different immature and mature myeloid DC subsets in RCC tumour tissue and the corresponding normal kidney tissues. In further analyses, the expression of various chemokines and chemokine receptors controlling the migration of DC subsets was investigated.</p> <p>Results</p> <p>The highest numbers of immature CD1a+ DCs were found within RCC tumour tissue. In contrast, the accumulation of mature CD83+/DC-LAMP+ DCs were restricted to the invasive margin of the RCCs. The mature DCs formed clusters with proliferating T-cells. Furthermore, a close association was observed between MIP-3α-producing tumour cells and immature CCR6+ DC recruitment to the tumour bed. Conversely, MIP-3β and SLC expression was only detected at the tumour border, where CCR7-expressing T-cells and mature DCs formed clusters.</p> <p>Conclusion</p> <p>Increased numbers of immature DCs were observed within the tumour tissue of RCCs, whereas mature DCs were found in increased numbers at the tumour margin. Our results strongly implicate that the distribution of DC subsets is controlled by local lymphoid chemokine expression. Thus, increased expression of MIP-3α favours recruitment of immature DCs to the tumour bed, whereas <it>de novo </it>local expression of SLC and MIP-3β induces accumulation of mature DCs at the tumour margin forming clusters with proliferating T-cells reflecting a local anti-tumour immune response.</p

Expression of the 5T4 oncofoetal antigen in renal cell carcinoma: a potential target for T-cell-based immunotherapy

The 5T4 oncofoetal antigen is a heavily glycosylated cell surface protein found on human placental trophoblast and on diverse types of human cancer but is not expressed at significant levels on adult human tissues in health. It therefore satisfies the criteria for a tumour-associated antigen and is an ideal target for the immunotherapy of cancer. We report here that 5T4 is strongly expressed on the majority of renal cell carcinomas and therefore this population of patients is suitable for trials of 5T4-targeted therapies. In particular, we have shown that T cells from renal cell carcinoma patients can be genetically modified to kill 5T4 expressing renal cancer cell lines by introduction of a chimeric-signalling protein. This protein consists of a single chain antibody fragment capable of binding antigen directly at the cell surface and then activating the T cell by virtue of a CD3ζ-signalling domain. This is a powerful tool that bypasses a number of mechanisms that allow tumours to escape T-cell killing and can be readily scaled up for clinical use

Novel therapies in genitourinary cancer: an update

In recent years, new treatment for renal cell carcinoma (RCC) has been a spotlight in the field of cancer therapeutics. With several emerging agents branded as 'targeted therapy' now available, both medical oncologists and urologists are progressively more hopeful for better outcomes. The new remedies may provide patients with improved survival and at the same time less toxicity when compared to traditional cytotoxic agents. This article will center on current and emerging treatment strategies for advanced RCC and other GU malignancies with updates from 2008 annual ASCO meeting

Dendritic Cell Based Tumor Vaccination in Prostate and Renal Cell Cancer: A Systematic Review and Meta-Analysis

BACKGROUND: More than 200 clinical trials have been performed using dendritic cells (DC) as cellular adjuvants in cancer. Yet the key question whether there is a link between immune and clinical response remains unanswered. Prostate and renal cell cancer (RCC) have been extensively studied for DC-based immunotherapeutic interventions and were therefore chosen to address the above question by means of a systematic review and meta-analysis. METHODOLOGY/PRINCIPAL FINDINGS: Data was obtained after a systematic literature search from clinical trials that enrolled at least 6 patients. Individual patient data meta-analysis was performed by means of conditional logistic regression grouped by study. Twenty nine trials involving a total of 906 patients were identified in prostate cancer (17) and RCC (12). Objective response rates were 7.7% in prostate cancer and 12.7% in RCC. The combined percentages of objective responses and stable diseases (SD) amounted to a clinical benefit rate (CBR) of 54% in prostate cancer and 48% in RCC. Meta-analysis of individual patient data (n = 403) revealed the cellular immune response to have a significant influence on CBR, both in prostate cancer (OR 10.6, 95% CI 2.5-44.1) and in RCC (OR 8.4, 95% CI 1.3-53.0). Furthermore, DC dose was found to have a significant influence on CBR in both entities. Finally, for the larger cohort of prostate cancer patients, an influence of DC maturity and DC subtype (density enriched versus monocyte derived DC) as well as access to draining lymph nodes on clinical outcome could be demonstrated. CONCLUSIONS/SIGNIFICANCE: As a 'proof of principle' a statistically significant effect of DC-mediated cellular immune response and of DC dose on CBR could be demonstrated. Further findings concerning vaccine composition, quality control, and the effect of DC maturation status are relevant for the immunological development of DC-based vaccines

Specific immunotherapy for renal cell carcinoma.

Despite the fact that evaluation of cytokine-based therapies for mRCC shows that a subset of patients react favourable to immunotherapy, significant side effects do occur. With the increased knowledge of tumor-immunology, the recognition of immunogenic tumor proteins and antibodies, new treatment options with increased specificity and subsequently less side-effects are of interest. In this thesis several studies have been performed to evaluate these new treatment options. Chapter 2 discusses the need for a staging sytem that adequately discriminates patients with RCC into prognostic groups in order to provide improved counseling, follow-up evaluation and identification of high risk patients potentially suitable for adjuvant therapies and clinical trials. This chapter presents a clinical algorithm using 3 well-known prognostic factors that can be used to predict survival and stratify patients undergoing nephrectomy for localized disease into 3 risk groups. External data from 2 outside institutions suggest the validity of this algorithm with a high concordance index. These risk categories can be used in clinical trial design and interpretation as well as in clinical management areas such as surveillance. Chapters 3 & 4 discuss dendritic cell-based immunotherapy. Dendritic cells (DC) are the most potent antigen presenting cells (APC's) of the immune system with the ability to stimulate naive resting T cells to proliferate and differentiate into activated cytotoxic T cells specific against the presented antigen. Two clinical trials were performed evaluating safety and clinical or immunological responses of DC-based vaccines. Chapters 5 & 6 deal with monoclonal antibody-based immunotherapy. Currently, several monoclonal antibodies (mAb) are used in cancer treatment. In RCC the chimeric mAb G250 (WX-G250) has been identified and developed for both therapeutical and diagnostical purposes. Antibody dependent cellular cytotoxicity (ADCC) has been suggested to be the main effector mechanism of WX-G250 and in-vitro data showed that interleukin-2 (IL-2) has the capacity to up-regulate WX-G250 mediated ADCC. This led to the initiation of two successive clinical trials evaluating infusions of WX-G250 as monotherapy and the combination of WX-G250 with a low-dose IL-2 pulsing regime

Specific immunotherapy for renal cell carcinoma.

Contains fulltext : 50137.pdf (publisher's version ) (Open Access)Despite the fact that evaluation of cytokine-based therapies for mRCC shows that a subset of patients react favourable to immunotherapy, significant side effects do occur. With the increased knowledge of tumor-immunology, the recognition of immunogenic tumor proteins and antibodies, new treatment options with increased specificity and subsequently less side-effects are of interest. In this thesis several studies have been performed to evaluate these new treatment options. Chapter 2 discusses the need for a staging sytem that adequately discriminates patients with RCC into prognostic groups in order to provide improved counseling, follow-up evaluation and identification of high risk patients potentially suitable for adjuvant therapies and clinical trials. This chapter presents a clinical algorithm using 3 well-known prognostic factors that can be used to predict survival and stratify patients undergoing nephrectomy for localized disease into 3 risk groups. External data from 2 outside institutions suggest the validity of this algorithm with a high concordance index. These risk categories can be used in clinical trial design and interpretation as well as in clinical management areas such as surveillance. Chapters 3 & 4 discuss dendritic cell-based immunotherapy. Dendritic cells (DC) are the most potent antigen presenting cells (APC's) of the immune system with the ability to stimulate naive resting T cells to proliferate and differentiate into activated cytotoxic T cells specific against the presented antigen. Two clinical trials were performed evaluating safety and clinical or immunological responses of DC-based vaccines. Chapters 5 & 6 deal with monoclonal antibody-based immunotherapy. Currently, several monoclonal antibodies (mAb) are used in cancer treatment. In RCC the chimeric mAb G250 (WX-G250) has been identified and developed for both therapeutical and diagnostical purposes. Antibody dependent cellular cytotoxicity (ADCC) has been suggested to be the main effector mechanism of WX-G250 and in-vitro data showed that interleukin-2 (IL-2) has the capacity to up-regulate WX-G250 mediated ADCC. This led to the initiation of two successive clinical trials evaluating infusions of WX-G250 as monotherapy and the combination of WX-G250 with a low-dose IL-2 pulsing regimenRU Radboud Universiteit Nijmegen, 27 juni 2006Promotor : Debruyne, F.M.J. Co-promotores : Mulders, P.F.A., Oosterwijk, E.144 p

Antibody therapy in renal cell carcinoma.

Contains fulltext : 69826.pdf (publisher's version ) (Open Access)The treatment of metastasized renal cell carcinoma (RCC) still represents a formidable challenge, despite the development of small molecule, tyrosine kinase inhibitors (TKI) that have made a major impact on the disease. Although the percentage of patients achieving a partial response or stabilization of disease has been impressive, these effects are mostly non-durable. Additionally, drug-related side effects can be quite severe. Alternative treatment modalities might be monoclonal antibodies (mAbs). mAbs against RCC-associated antigens have been developed and have shown promise. Additionally, current efforts focus on Bevacizumab that recognizes vascular endothelial growth factor (VEGF). VEGF overexpression in RCC provides the opportunity to inhibit this proangiogenic pathway. Also with Bevacizumab, promising results have been obtained, particularly in combination with other treatment modalities. It is likely that mAbs, either as single agents or in combination with other agents, may become useful additions to the armamentarium to diagnose and treat RCC

Microcystic stromal tumour of testis

Within the group of gonadal sex cord-stromal tumours, microcystic stromal tumour (MCST) is a rare entity. In the literature, most case series and reviews discussed MCST arising in the ovary, only one case-report concerned a testicular MCST. We present a Caucasian man in his late 30s, who presented with an MCST in his right testis. The tumour was encapsulated and composed of vaguely lobulated cellular nodules and cystic spaces with bland spindle cells and hyalinised fibrous stroma. By immunohistochemistry, the tumour cells expressed cluster designation 10, androgen receptor, steroidogenic factor-1 and nuclear beta-catenine, and there was focal nuclear expression of cyclin D1. Molecular diagnostics confirmed the presence of an exon 3 mutation (c.98C>T) in the CTNNB1 gene. These features are similar to MSCT described in the ovary. Clinical follow-up (more than 1 year) was uneventful.Although the clinical and radiological presentation was that of a possible malignant testicular lesion, this entity is benign