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Metastatic Hormone-sensitive Prostate Cancer: Patient Selection for Prostate Radiotherapy.
No full textAdaptive-Radiation Therapy Using Functional Magnetic-Resonance Imaging In Head and Neck Cancers
No full textTreatment strategies for locally-advanced head and neck cancers have evolved with a strong emphasis on treatment adaptation based on disease risk or intra-treatment response. Magnetic resonance imaging offers an ideal platform to perform adaptive radiotherapy as it is non-invasive, adds no additional radiation risk and allows superior soft-tissue definition to conventional CT-based methods. This thesis explored the role of functional-MRI for delivering adaptive radiotherapy for head and neck cancers.
This thesis analysed the treatment-related changes of two diffusion-weighted image sequences (ssEPI and RESOLVE) and demonstrated good concordance between the two sequences when assessing for disease response in the second week of radiotherapy. As part of the INSIGHT II trial, ssEPI was used to help dose-escalate for non-responding patients (change in ADC <15% in week 2 of chemo-radiotherapy) without compromising the dose to organs at risk such as parotid glands. There was a modest dose-sparing effect for low-risk and responding tumours.
However, there were no patients with residual disease in this study to validate the findings from the original INSIGHT study, as to whether an Apparent Diffusion Coefficient threshold of 15% (for ssEPI and RESOLVE) is able to stratify between responders and non-responders. Exploratory imaging biomarkers such as intra-voxel incoherent motion and T2* did not show any significant trends to stratify patients into risk groups or determination of treatment response.
The final chapter explores laryngeal motion and shows that laryngeal motion is most prominent in the cranio-caudal directions. However this motion is not deemed significant as the duration and frequency of swallow are limited. Individualised treatment target volumes, based on respiratory-related laryngeal motion, were created for radiotherapy-planning studies using intensity-modulated based methods. This approach significantly spared organs at risk such as carotid arteries. Analysis of intra-fraction swallow-related motions demonstrated no compromise in dose to the treatment target when treating smaller targets
Neoadjuvant and Adjuvant Immune-based Approach for Renal Cell Carcinoma: Pros, Cons, and Future Directions.
No full textCONTEXT: Immune-oncology strategies are revolutionising the perioperative treatment in several tumour types. The perioperative setting of renal cell carcinoma (RCC) is an evolving field, and the advent of immunotherapy is producing significant advances. OBJECTIVE: To critically review the potential pros and cons of adjuvant and neoadjuvant immune-based therapeutic strategies in RCC, and to provide insights for future research in this field. EVIDENCE ACQUISITION: We performed a collaborative narrative review of the existing literature. EVIDENCE SYNTHESIS: Adjuvant immunotherapy with pembrolizumab is a new standard of care for patients at a higher risk of recurrence after nephrectomy, demonstrating a disease-free survival and overall survival benefit in the phase 3 KEYNOTE-564 trial. Current data do not support neoadjuvant therapy use outside clinical trials. While both adjuvant and neoadjuvant immune-based approaches are driven by robust biological rationale, neoadjuvant immunotherapy may enable a stronger and more durable antitumour immune response. If neoadjuvant single-agent immune checkpoint inhibitors demonstrated limited activity on the primary tumour, immune-based combinations may show increased activity. Overtreatment and a risk of relevant toxicity for patients who are cured by surgery alone are common concerns for both neoadjuvant and adjuvant strategies. Biomarkers helping patient selection and treatment deintensification are lacking in RCC. No results from randomised trials comparing neoadjuvant or perioperative immune-based therapy with adjuvant immunotherapy are available. CONCLUSIONS: Adjuvant immunotherapy is a new standard of care in RCC. Both neoadjuvant and adjuvant immunotherapy strategies have potential advantages and disadvantages. Optimising perioperative treatment strategies is nuanced, with the role of neoadjuvant immune-based therapies yet to be defined. Given strong biological rationale for a pre/perioperative approach, there is a need for prospective clinical trials to determine clinical efficacy. Research investigating biomarkers aiding patient selection and treatment deintensification strategies is needed. PATIENT SUMMARY: Immunotherapy is transforming the treatment of kidney cancer. In this review, we looked at the studies investigating immunotherapy strategies before and/or after surgery for patients with kidney cancer to assess potential pros and cons. We concluded that both neoadjuvant and adjuvant immunotherapy strategies may have potential advantages and disadvantages. While immunotherapy administered after surgery is already a standard of care, immunotherapy before surgery should be better investigated in future studies. Future trials should also focus on the selection of patients in order to spare toxicity for patients who will be cured by surgery alone
Genotes - a 'just-in-time' genomics education resource co-designed with clinicians.
No full textBACKGROUND: Powerful new genomic technologies are transforming the way healthcare is delivered, shaping medical practice across all specialties. In this rapidly changing landscape, there is an urgent need to equip the clinical workforce with knowledge and skills to navigate the new healthcare terrain. Co-design of healthcare resources with end users is increasingly gaining traction as a method of ensuring that educational content and delivery are tailored to users' needs, increasing likelihood of use and resulting in better outcomes for patients. Here we describe the co-design and ongoing co-creation of GeNotes - an NHS England National Genomics Education flagship online resource providing genomics education at the point of patient care. METHODS: To understand the barriers to implementation of genomic medicine and the training needs of the diverse NHS workforce, we adopted a co-design approach with clinicians from both primary and secondary care who are uniquely placed to understand the context in which they are working and identify their own training needs. Concept design, initial user research and subsequent 'alpha' and 'private beta' phase user research was conducted in a series of co-design iterations employing a mixed methodology integrating quantitative and qualitative data collection and analysis. RESULTS: User evaluation data demonstrated excellent feedback across the tested domains (content, navigation, likelihood of use and recommendation to colleagues). We identified several key themes from user testing that shaped the resource's development. CONCLUSIONS: The co-design approach to the development of this point-of-care genomics education resource for clinicians has allowed insight into the education needs, challenges and learning styles of end-users. The utility of this approach was supported by excellent user feedback across the tested domains, and we recommend it to others involved in developing healthcare resources in a fast-paced environment
AR coactivators, CBP/p300, are critical mediators of DNA repair in prostate cancer.
No full textCastration resistant prostate cancer (CRPC) remains an incurable disease stage with ineffective treatments options. Here, the androgen receptor (AR) coactivators CBP/p300, which are histone acetyltransferases, were identified as critical mediators of DNA damage repair (DDR) to potentially enhance therapeutic targeting of CRPC. Key findings demonstrate that CBP/p300 expression increases with disease progression and selects for poor prognosis in metastatic disease. CBP/p300 bromodomain inhibition enhances response to standard of care therapeutics. Functional studies, CBP/p300 cistrome mapping, and transcriptome in CRPC revealed that CBP/p300 regulates DDR. Further mechanistic investigation showed that CBP/p300 attenuation via therapeutic targeting and genomic knockdown decreases homologous recombination (HR) factors in vitro, in vivo, and in human prostate cancer (PCa) tumors ex vivo. Similarly, CBP/p300 expression in human prostate tissue correlates with HR factors. Lastly, targeting CBP/p300 impacts HR-mediate repair and patient outcome. Collectively, these studies identify CBP/p300 as drivers of PCa tumorigenesis and lay the groundwork to optimize therapeutic strategies for advanced PCa via CBP/p300 inhibition, potentially in combination with AR-directed and DDR therapies
Association between circulating inflammatory markers and adult cancer risk: a Mendelian randomization analysis.
No full textBACKGROUND: Tumour-promoting inflammation is a "hallmark" of cancer and conventional epidemiological studies have reported links between various inflammatory markers and cancer risk. The causal nature of these relationships and, thus, the suitability of these markers as intervention targets for cancer prevention is unclear. METHODS: We meta-analysed 6 genome-wide association studies of circulating inflammatory markers comprising 59,969 participants of European ancestry. We then used combined cis-Mendelian randomization and colocalisation analysis to evaluate the causal role of 66 circulating inflammatory markers in risk of 30 adult cancers in 338,294 cancer cases and up to 1,238,345 controls. Genetic instruments for inflammatory markers were constructed using genome-wide significant (P 70% was employed to indicate support for shared causal variants across inflammatory markers and cancer outcomes. Findings were replicated in the FinnGen study and then pooled using meta-analysis. FINDINGS: We found strong evidence to support an association of genetically-proxied circulating pro-adrenomedullin concentrations with increased breast cancer risk (OR: 1.19, 95% CI: 1.10-1.29, q-value = 0.033, PPH4 = 84.3%) and suggestive evidence to support associations of interleukin-23 receptor concentrations with increased pancreatic cancer risk (OR: 1.42, 95% CI: 1.20-1.69, q-value = 0.055, PPH4 = 73.9%), prothrombin concentrations with decreased basal cell carcinoma risk (OR: 0.66, 95% CI: 0.53-0.81, q-value = 0.067, PPH4 = 81.8%), and interleukin-1 receptor-like 1 concentrations with decreased triple-negative breast cancer risk (OR: 0.92, 95% CI: 0.88-0.97, q-value = 0.15, PPH4 = 85.6%). These findings were replicated in pooled analyses with the FinnGen study. Though suggestive evidence was found to support an association of macrophage migration inhibitory factor concentrations with increased bladder cancer risk (OR: 2.46, 95% CI: 1.48-4.10, q-value = 0.072, PPH4 = 76.1%), this finding was not replicated when pooled with the FinnGen study. For 22 of 30 cancer outcomes examined, there was little evidence (q-value ≥0.20) that any of the 66 circulating inflammatory markers examined were associated with cancer risk. INTERPRETATION: Our comprehensive joint Mendelian randomization and colocalisation analysis of the role of circulating inflammatory markers in cancer risk identified potential roles for 4 circulating inflammatory markers in risk of 4 site-specific cancers. Contrary to reports from some prior conventional epidemiological studies, we found little evidence of association of circulating inflammatory markers with the majority of site-specific cancers evaluated. FUNDING: Cancer Research UK (C68933/A28534, C18281/A29019, PPRCPJT∖100005), World Cancer Research Fund (IIG_FULL_2020_022), National Institute for Health Research (NIHR202411, BRC-1215-20011), Medical Research Council (MC_UU_00011/1, MC_UU_00011/3, MC_UU_00011/6, and MC_UU_00011/4), Academy of Finland Project 326291, European Union's Horizon 2020 grant agreement no. 848158 (EarlyCause), French National Cancer Institute (INCa SHSESP20, 2020-076), Versus Arthritis (21173, 21754, 21755), National Institutes of Health (U19 CA203654), National Cancer Institute (U19CA203654)
Elucidating the Clinical Significance and Therapeutic Implications of the Anti-apoptotic BCL2 Family Proteins in Advanced Prostate Cancer
No full textMetastatic, or advanced, castration-resistant prostate cancer (mCRPC) is invariably fatal
and novel therapeutic strategies are urgently required. Eradicating cancer cells through
apoptosis should reduce the chance of treatment resistance. BH3 mimetics target the antiapoptotic BCL2 family proteins, including BCL2, MCL1 and BCLXL. There is an unmet
clinical need to identify mCRPC with a vulnerability in the apoptotic machinery that respond
to these therapies. To investigate the clinical significance, biology importance, and
therapeutic implications of the anti-apoptotic BCL2 family proteins in advanced prostate
cancer (PC), I studied a variety of biopsy cohorts, as well as interrogating and manipulating
a range of PC models, including cell lines and patient-derived xenografts in vitro and in
vivo. BCL2 expression was enriched in AR-negative mCRPC with features of lineage
plasticity and associated with worse clinical outcomes. BCL2 expression was regulated by
DNA methylation and driven by Snail and ASCL1. BCL2 inhibition had anti-tumour activity
in some, but not all, BCL2-positive PC models. MCL1 copy number gains were common
in mCRPC and occurred early in PC evolution. These associated with worse clinic outcome
and may predict sensitivity to MCL1 targeting. Irrespective of copy number alterations,
some PC cells were exquisitely sensitive to MCL1 inhibition, warranting further
investigation. A deubiquitinating enzyme siRNA screen identified UCHL3 as a potential
regulator of MCL1 stability, but studies revealed this was driven through a seed-mediated
off-target effect, highlighting the critical importance of robust ‘hit’ validation. These studies
confirmed that targeting BCLXL and MCL1 in combination is a lethal to PC cells and may
be an attractive strategy, if expected toxicity can be mitigated. Nevertheless, UCHL3 was
found to be commonly lost in mCRPC and identified as a novel regulator of RESF1 at
protein level. RESF1 is associated with immune pathways in mCRPC, providing rationale
for future studies in this space
Contrast Clearance Analysis (CCA) to Assess Viable Tumour following Stereotactic Radiosurgery (SRS) to Brain Metastasis in Non-Small Cell Lung Cancer (NSCLC).
No full textBACKGROUND AND OBJECTIVE: Brain metastases are common in lung cancer and increasingly treated using targeted radiotherapy techniques such as stereotactic radiosurgery (SRS). Using MRI, post-SRS changes may be difficult to distinguish from progressive brain metastasis. Contrast clearance analysis (CCA) uses T1-weighted MRI images to assess the clearance of gadolinium and can be thus used to assess vascularity and active tumours. DESIGN AND METHODS: We retrospectively assessed CCAs in 62 patients with non-small cell lung cancer (NSCLC) undergoing 104 CCA scans in a single centre. RESULTS: The initial CCA suggested the aetiology of equivocal changes on standard MRI in 80.6% of patients. In all patients whose initial CCA showed post-SRS changes and who underwent serial CCAs, the initial diagnosis was upheld with the serial imaging. In only two cases of a presumed progressive tumour on the initial CCA, subsequent treatment for radionecrosis was instigated; a retrospective review and re-evaluation of the CCAs show that progression was reported where a thin rim of rapid contrast clearance was seen, and this finding has been subsequently recognised as a feature of post-treatment change on CCAs. The lack of concordance with CCA findings in those who underwent surgical resection was also found to be due to the over-reporting of the thin blue rim as disease in the early cases of CCA use and, in three cases, potentially related to timelines longer than 7 days prior to surgery, both factors being unknown during the early implementation phase of CCA at our centre but subsequently learned. CONCLUSIONS: Our single-centre experience shows CCA to be feasible and useful in patients with NSCLC in cases of diagnostic uncertainty in MRI. It has helped guide treatment in the majority of patients, with subsequent outcomes following the implementation of the treatment based on the results, suggesting correct classification. Recommendations from our experience of the implementation include the careful consideration of the thin rim of the rapid contrast clearance and the timing of the CCA prior to surgery for suspected brain metastasis progression
Magnetic Resonance Fingerprinting for glioma characterisation in the human brain
No full textChapter 1 introduces the physics of MRI, and the formation of T1 and T2-weighted images which are conventionally used for clinical assessment. Clinical imaging of glioma is then introduced, followed by quantitative relaxometry with a focus on Magnetic Resonance Fingerprinting (MRF), and in glioma.
Chapter 2 assesses the repeatability of MRF T1 and T2 in the brains of 10 healthy volunteers. T1 and T2 relaxation times estimated by a WIP Siemens MRF sequence are compared to T1 estimates via Variable Flip Angle (VFA) and T2 estimates via Multi-Echo Spin Echo (MESE). It was found that MRF underestimated relaxation times in comparison to these reference methods, especially in regions of white matter. The difference in measurement method may be linked to microstructure, which was not present in a previous similar study on the NIST phantom, and may be influenced by Magnetisation Transfer (MT).
Chapter 3 extends the study to 20 glioma patients (grades 2-4). MRF in tumour regions was less repeatable than in normal appearing contralateral tissue, since tumour regions and subregions are smaller than normal appearing contralateral tissue regions. The MRF dictionary is also coarser at longer relaxation times found in glioma. When compared with VFA T1 mapping and MESE T2 mapping, MRF is found to underestimate relaxation times in all tumour regions except for cysts present in grade 3 tumours.
In Chapter 4, an in-house MRF FISP sequence with cartesian readout is implemented and tested in the NIST phantom. In Chapter 5, off-resonance pulses are incorporated at every repetition time to investigate MT effects. Relaxation time estimates in the NIST phantom were unaffected, but in the white matter of a single healthy volunteer estimated T1 decreased, and T2 increased.
Chapter 6 summarises conclusions and outlines further work towards the clinical translation of MRF for glioma characterisation
