The Responsiveness, Content Validity, and Convergent Validity of the Measure Yourself Concerns and Wellbeing (MYCaW) Patient-Reported Outcome Measure

Objective Measure Yourself Concerns and Wellbeing (MYCaW) is a patient-centred questionnaire that allows cancer patients to identify and quantify the severity of their ‘Concerns’ and Wellbeing, as opposed to using a pre-determined list. MYCaW administration is brief and aids in prioritising treatment approaches. Our goal was to assess the convergent validity and responsiveness of MYCaW scores over time, the generalisability of the existing qualitative coding framework in different complementary and integrative healthcare settings and content validity. Methods Baseline and 6-week follow-up data (n=82) from MYCaW and FACIT-SpEx questionnaires were collected for a service evaluation of the ‘Living Well With The Impact of Cancer’ course at Penny Brohn Cancer Care. MYCaW construct validity was determined using Spearman's Rank Correlation test, and responsiveness indices assessed score changes over time. The existing qualitative coding framework was reviewed using a new dataset (n=158) and coverage of concern categories compared to items of existing outcome measures. Results Good correlation between MYCaW and FACIT-SpEx score changes were achieved (r= -0.57, p≥0.01). MYCaW Profile and Concern scores were highly responsive to change: SRM=1.02 and 1.08; effect size=1.26 and 1.22. MYCaW change scores showed the anticipated gradient of change according to clinically relevant degrees of change. Categories including ‘Spirituality’, ‘weight change’ and ‘practical concerns’ were added to the coding framework to improve generalisability. Conclusions MYCaW scores were highly responsive to change, allowing personalized patient outcomes to be quantified; the qualitative coding framework is generalisable across different oncology settings and has broader coverage of patient-identified concerns compared with existing cancer-related patient-reported outcome measures.

Petri Net Siphon Analysis and Network Centrality Measures for Identifying Combination Therapies in Signaling Pathways

Aberrant behavior of biological signaling pathways has been implicated in diseases such as cancers. Therapies have been developed to target proteins in these networks in the hope of curing the illness or bringing about remission. However, identifying targets for drug inhibition that exhibit good therapeutic index has proven to be challenging since signaling pathways have a large number of components and many interconnections such as feedback, crosstalk, and divergence. Unfortunately, some characteristics of these pathways such as redundancy, feedback, and drug resistance reduce the efficacy of single drug target therapy and necessitate the employment of more than one drug to target multiple nodes in the system. However, choosing multiple targets with high therapeutic index poses more challenges since the combinatorial search space could be huge. To cope with the complexity of these systems, computational tools such as ordinary differential equations have been used to successfully model some of these pathways. Regrettably, for building these models, experimentally-measured initial concentrations of the components and rates of reactions are needed which are difficult to obtain, and in very large networks, they may not be available at the moment. Fortunately, there exist other modeling tools, though not as powerful as ordinary differential equations, which do not need the rates and initial conditions to model signaling pathways. Petri net and graph theory are among these tools. In this thesis, we introduce a methodology based on Petri net siphon analysis and graph network centrality measures for identifying prospective targets for single and multiple drug therapies. In this methodology, first, potential targets are identified in the Petri net model of a signaling pathway using siphon analysis. Then, the graph-theoretic centrality measures are employed to prioritize the candidate targets. Also, an algorithm is developed to check whether the candidate targets are able to disable the intended outputs in the graph model of the system or not. We implement structural and dynamical models of ErbB1-Ras-MAPK pathways and use them to assess and evaluate this methodology. The identified drug-targets, single and multiple, correspond to clinically relevant drugs. Overall, the results suggest that this methodology, using siphons and centrality measures, shows promise in identifying and ranking drugs. Since this methodology only uses the structural information of the signaling pathways and does not need initial conditions and dynamical rates, it can be utilized in larger networks.

Working with people affected by cancer – Phase 1 of a mixed methods exploration of practitioner perspectives in nutritional therapy

Introduction - Nutritional therapy (NT) is a bioscience-based branch of complementary and alternative medicine (CAM) with National Occupational Standards (NOS) and accredited training courses which include compulsory clinical training. Approximately 900 practitioners are registered with the voluntary regulator, the Complementary and Natural Healthcare Council (CNHC), but the number of unregulated practitioners is unknown. Cancer is a leading cause of death worldwide; nutrition and lifestyle factors may affect recurrence and survival rates. Many cancer patients and survivors seek individualised advice on diet and use of supplements and appropriately skilled nutritional therapy practitioners (NTP) may be well-placed to safely provide this advice. Little is known of NTPs’ perspectives on working with people affected by cancer; this study seeks to explore their views on training, use of evidence and other resources, to support the development of safe evidence-based practice in this important clinical area. Methods – An on-line anonymised questionnaire collected data from participants recruited from all UK registered NTPs. Recruitment was facilitated by the British Association for Applied Nutrition and Nutritional Therapy (BANT). Quantitative data on practitioner characteristics, years in practice, other therapies practiced and work with cancer clients were collected. Qualitative data on types of evidence used, barriers to practice and perceived training and support needs when working with clients with cancer, were collected and analysed. SPSS was used to produce descriptive statistics. Preliminary Results – 274/888 (31%) of registered NTPs participated. 61% respondents had accredited NT qualifications of which 46% were at degree or post-graduate level. 73% (202) participants indicated they also had other higher education qualifications, including 153 (56%) at degree or above. When asked to describe their position on cancer work, 17% respondents (40/238) indicated no interest, and 35% (84/238) respondents already work with cancer clients (cancer practitioners - CP). A further 48% (114/238) respondents expressed interest in starting cancer work, and typically requested specialist training and practice guidelines to support this area of clinical practice. Cancer practitioners (CP) rated searches of peer-reviewed literature as most useful for information to support practice, whereas commercial product information was rated least useful. CPs requested engagement with mainstream medicine, more access to research evidence and professional recognition to facilitate and support work with cancer clients. A need for professional networking, mentorship and/or supervision was noted by CP and non-CP respondents, which is of interest since 81% all participants worked as sole practitioners exclusively or as part of their practice, <1% worked within the NHS. Discussion & Conclusions – This is the first detailed documentation of NTP perspectives on cancer work. A number of areas have been identified for further detailed evidence to be collected using focus groups and interviews, including detailed training needs, communication with mainstream cancer professionals, access to research evidence, and professional recognition. This work will inform and support the development of professional practice guidelines for NT and inform the development of specialist training and other resources.

Arteterapia en el final de la vida

El arteterapia permite una aproximación creativa biográfica particularmente valiosa en la etapa final de la vida. La persona enferma presenta múltiples necesidades – físicas, emocionales, sociales y espirituales – que solo una atención holística puede pretender abarcar, tal como lo contempla la filosofía de los cuidados paliativos. El arteterapeuta integrado en el equipo interdisciplinar contribuye a aliviar y acompañar el sufrimiento del paciente y su familia. Se presentan aquí las bases teóricas y la metodología de la intervención, así como el marco sanitario en el cual se inscribe.

Radium-223 and concomitant therapies in patients with metastatic castration-resistant prostate cancer: an international, early access, open-label, single-arm phase 3b trial

BACKGROUND: In the previously reported ALSYMPCA trial in patients with castration-resistant prostate cancer and symptomatic bone metastases, overall survival was significantly longer in patients treated with radium-223 dichloride (radium-223) than in patients treated with placebo. In this study, we investigated safety and overall survival in radium-223 treated patients in an early access programme done after the ALSYMPCA study and before regulatory approval of radium-223.

METHODS: We did an international, prospective, interventional, open-label, single-arm, phase 3b study. Enrolled patients were aged 18 years or older with histologically or cytologically confirmed progressive bone-predominant metastatic castration-resistant prostate cancer with two or more skeletal metastases on imaging (with no restriction as to whether they were symptomatic or asymptomatic; without visceral disease but lymph node metastases were allowed). Patients received intravenous injections of radium-223, 50 kBq/kg (current recommendation 55 kBq/kg after implementation of National Institute of Standards and Technology update on April 18, 2016) every 4 weeks for up to six injections. Other concomitant anticancer therapies were allowed. Primary endpoints were safety and overall survival. The safety and efficacy analyses were done on all patients who received at least one dose of the study drug. The study has been completed, and we report the final analysis here. This study is registered with ClinicalTrials.gov, number NCT01618370, and the European Union Clinical Trials Register, EudraCT number 2012-000075-16.

FINDINGS: Between July 22, 2012, and Dec 19, 2013, 839 patients were enrolled from 113 sites in 14 countries. 696 patients received one or more doses of radium-223; 403 (58%) of these patients had all six planned injections. Any-grade treatment-emergent adverse events occurred in 523 (75%) of 696 patients; any-grade treatment-emergent adverse events deemed to be related to treatment were reported in 281 (40%) patients. The most common grade 3 or worse treatment-related treatment-emergent adverse events were anaemia in 32 (5%) patients, thrombocytopenia in 15 (2%) patients, neutropenia in ten (1%) patients, and leucopenia in nine (1%) patients. Any grade of serious adverse events were reported in 243 (35%) patients. Median follow-up was 7·5 months (IQR 5-11) and 210 deaths were reported; median overall survival was 16 months (95% CI 13-not available [NA]). In an exploratory analysis of overall survival with predefined factors, median overall survival was longer for: patients with baseline alkaline phosphatase concentration less than the upper limit of normal (ULN; median NA, 95% CI 16 months-NA) than for patients with an alkaline phosphatase concentration equal to or greater than the ULN (median 12 months, 11-15); patients with baseline haemoglobin levels 10 g/dL or greater (median 17 months, 14-NA) than for patients with haemoglobin levels less than 10 g/dL (median 10 months, 8-14); patients with a baseline Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 (median NA, 17 months-NA) than for patients with an ECOG PS of 1 (median 13 months, 11-NA) or an ECOG PS of 2 or more (median 7 months, 5-11); and for patients with no reported baseline pain (median NA, 16 months-NA) than for those with mild pain (median 14 months, 13-NA) or moderate-severe pain (median 11 months, 9-13). Median overall survival was also longer in patients who received radium-223 plus abiraterone, enzalutamide, or both (median NA, 95% CI 16 months-NA) than in those who did not receive these agents (median 13 months, 12-16), and in patients who received radium-223 plus denosumab (median NA, 15 months-NA) than in patients who received radium-223 without denosumab (median 13 months, 12-NA).

INTERPRETATION: Our findings show that radium-223 can be safely combined with abiraterone or enzalutamide, which are now both part of the standard of care for patients with metastatic castration-resistant prostate cancer. Furthermore, our findings extend to patients who were asymptomatic at baseline, unlike those enrolled in the pivotal ALSYMPCA study. The findings of prolonged survival in patients treated with concomitant abiraterone, enzalutamide, or denosumab require confirmation in prospective randomised trials.

FUNDING: Pharmaceutical Division of Bayer.

Virtual Clinical Trials in PET Imaging for Improved Diagnosis of and Evaluation of Therapies for Cancer

Thesis (Ph.D.)--University of Washington, 2016-08

Evaluation of Community-led Complementary Feeding and Learning Sessions

Thesis (Master's)--University of Washington, 2016-08

Role for cell-to-cell communication in stem cell specification toward pancreatic progenitors: relevance to the design of novel therapies for diabetes.

Thesis (Ph.D.)--University of Washington, 2016-08

A signaling visualization toolkit to support rational design of combination therapies and biomarker discovery: SiViT

Targeted cancer therapy aims to disrupt aberrant cellular signalling pathways. Biomarkers are surrogates of pathway state, but there is limited success in translating candidate biomarkers to clinical practice due to the intrinsic complexity of pathway networks. Systems biology approaches afford better understanding of complex, dynamical interactions in signalling pathways targeted by anticancer drugs. However, adoption of dynamical modelling by clinicians and biologists is impeded by model inaccessibility. Drawing on computer games technology, we present a novel visualisation toolkit, SiViT, that converts systems biology models of cancer cell signalling into interactive simulations that can be used without specialist computational expertise. SiViT allows clinicians and biologists to directly introduce for example loss of function mutations and specific inhibitors. SiViT animates the effects of these introductions on pathway dynamics, suggesting further experiments and assessing candidate biomarker effectiveness. In a systems biology model of Her2 signalling we experimentally validated predictions using SiViT, revealing the dynamics of biomarkers of drug resistance and highlighting the role of pathway crosstalk. No model is ever complete: the iteration of real data and simulation facilitates continued evolution of more accurate, useful models. SiViT will make accessible libraries of models to support preclinical research, combinatorial strategy design and biomarker discovery.

A acupunctura como forma de controlo da ansiedade na performance e de resolução de patologias músculo-esqueléticas em músicos

As patologias músculo-esqueléticas apresentam um interesse particular nos tempos atuais, visto terem origem em atividades viciosas, nos movimentos repetitivos, no sedentarismo e na hipertonia muscular relacionada com o stresse no contexto profissional ou pessoal, que é tão comum nos músicos. Por outro lado, a performance musical requer alto nível de habilidade em diversos parâmetros, como coordenação motora, atenção e memória o que a torna numa atividade particularmente suscetível não só às patologias músculo-esqueléticas como também à ansiedade. É aqui que se introduz a acupunctura. É cada vez mais recorrente a procura das terapias complementares e/ou alternativas por parte dos músicos, em contraposição aos métodos utilizados pela medicina convencional. Dos diversos métodos da Medicina Tradicional Chinesa, a acupunctura, encontra-se, talvez entre o mais procurado. A acupunctura pode ser definida como um técnica terapêutica que tem como método predominante a introdução de agulhas na periferia do corpo humano. O efeito das agulhas será o de provocar alterações no sistema energético do paciente que resultarão em mudanças benéficas que ocorrem a nível físico. O que me traz à discussão do tema, para além da problemática das patologias músculo-esqueléticas nos músicos é o crescente número de músicos com problemas de ansiedade e a contribuição desta medicina como alternativa de tratamento.