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The international diffuse intrinsic pontine glioma registry: an infrastructure to accelerate collaborative research for an orphan disease.
No full textDiffuse intrinsic pontine glioma (DIPG), a rare, often fatal childhood brain tumor, remains a major therapeutic challenge. In 2012, investigators, funded by the DIPG Collaborative (a philanthropic partnership among 29 private foundations), launched the International DIPG Registry (IDIPGR) to advance understanding of DIPG. Comprised of comprehensive deidentified but linked clinical, imaging, histopathological, and genomic repositories, the IDIPGR uses standardized case report forms for uniform data collection; serial imaging and histopathology are centrally reviewed by IDIPGR neuro-radiologists and neuro-pathologists, respectively. Tissue and genomic data, and cell cultures derived from autopsies coordinated by the IDIPGR are available to investigators for studies approved by the Scientific Advisory Committee. From April 2012 to December 2016, 670 patients diagnosed with DIPG have been enrolled from 55 participating institutions in the US, Canada, Australia and New Zealand. The radiology repository contains 3558 studies from 448 patients. The pathology repository contains tissue on 81 patients with another 98 samples available for submission. Fresh DIPG tissue from seven autopsies has been sent to investigators to develop primary cell cultures. The bioinformatics repository contains next-generation sequencing data on 66 tumors. Nine projects using data/tissue from the IDIPGR by 13 principle investigators from around the world are now underway. The IDIPGR, a successful alliance among philanthropic agencies and investigators, has developed and maintained a highly collaborative, hypothesis-driven research infrastructure for interdisciplinary and translational projects in DIPG to improve diagnosis, response assessment, treatment and outcome for patients
Prevalence of Cardiovascular Disease in Patients With Potentially Curable Malignancies: A National Registry Dataset Analysis.
No full textBACKGROUND: Although a common challenge for patients and clinicians, there is little population-level evidence on the prevalence of cardiovascular disease (CVD) in individuals diagnosed with potentially curable cancer. OBJECTIVES: We investigated CVD rates in patients with common potentially curable malignancies and evaluated the associations between patient and disease characteristics and CVD prevalence. METHODS: The study included cancer registry patients diagnosed in England with stage I to III breast cancer, stage I to III colon or rectal cancer, stage I to III prostate cancer, stage I to IIIA non-small-cell lung cancer, stage I to IV diffuse large B-cell lymphoma, and stage I to IV Hodgkin lymphoma from 2013 to 2018. Linked hospital records and national CVD databases were used to identify CVD. The rates of CVD were investigated according to tumor type, and associations between patient and disease characteristics and CVD prevalence were determined. RESULTS: Among the 634,240 patients included, 102,834 (16.2%) had prior CVD. Men, older patients, and those living in deprived areas had higher CVD rates. Prevalence was highest for non-small-cell lung cancer (36.1%) and lowest for breast cancer (7.7%). After adjustment for age, sex, the income domain of the Index of Multiple Deprivation, and Charlson comorbidity index, CVD remained higher in other tumor types compared to breast cancer patients. CONCLUSIONS: There is a significant overlap between cancer and CVD burden. It is essential to consider CVD when evaluating national and international treatment patterns and cancer outcomes
Nilotinib in KIT-driven advanced melanoma: Results from the phase II single-arm NICAM trial
No full textThe need for consensus on delineation and dose constraints of dentofacial structures in paediatric radiotherapy: Outcomes of a SIOP Europe survey.
No full textBACKGROUND AND PURPOSE: Children receiving radiotherapy for head-and-neck tumours often experience severe dentofacial side effects. Despite this, recommendations for contouring and dose constraints to dentofacial structures are lacking in clinical practice. We report on a survey aiming to understand current practice in contouring and dose assessment to dentofacial structures. METHODS: A digital survey was distributed to European Society for Paediatric Oncology members of the Radiation Oncology Working Group, and member-affiliated centres in Europe, Australia, and New Zealand. The questions focused on clinical practice and aimed to establish areas for future development. RESULTS: Results from 52 paediatric radiotherapy centres across 27 countries are reported. Only 29/52 centres routinely delineated some dentofacial structures, with the most common being the mandible (25 centres), temporo-mandibular joint (22), dentition (13), orbit (10) and maxillary bone (eight). For most bones contoured, an 'As Low As Reasonably Achievable' dose objective was implemented. Only four centres reported age-adapted dose constraints.The largest barrier to clinical implementation of dose constraints was firstly, the lack of contouring guidance (49/52, 94%) and secondly, that delineation is time-consuming (33/52, 63%). Most respondents who routinely contour dentofacial structures (25/27, 90%) agreed a contouring atlas would aid delineation. CONCLUSION: Routine delineation of dentofacial structures is infrequent in paediatric radiotherapy. Based on survey findings, we aim to 1) define a consensus-contouring atlas for dentofacial structures, 2) develop auto-contouring solutions for dentofacial structures to aid clinical implementation, and 3) carry out treatment planning studies to investigate the importance of delineation of these structures for planning optimisation
Cancer Evolution: A Multifaceted Affair.
No full textUNLABELLED: Cancer cells adapt and survive through the acquisition and selection of molecular modifications. This process defines cancer evolution. Building on a theoretical framework based on heritable genetic changes has provided insights into the mechanisms supporting cancer evolution. However, cancer hallmarks also emerge via heritable nongenetic mechanisms, including epigenetic and chromatin topological changes, and interactions between tumor cells and the tumor microenvironment. Recent findings on tumor evolutionary mechanisms draw a multifaceted picture where heterogeneous forces interact and influence each other while shaping tumor progression. A comprehensive characterization of the cancer evolutionary toolkit is required to improve personalized medicine and biomarker discovery. SIGNIFICANCE: Tumor evolution is fueled by multiple enabling mechanisms. Importantly, genetic instability, epigenetic reprogramming, and interactions with the tumor microenvironment are neither alternative nor independent evolutionary mechanisms. As demonstrated by findings highlighted in this perspective, experimental and theoretical approaches must account for multiple evolutionary mechanisms and their interactions to ultimately understand, predict, and steer tumor evolution
Clinical validation of circulating GDF15/MIC-1 as a marker of response to docetaxel and survival in men with metastatic castration-resistant prostate cancer.
No full textBACKGROUND: Elevated circulating growth differentiation factor (GDF15/MIC-1), interleukin 4 (IL4), and IL6 levels were associated with resistance to docetaxel in an exploratory cohort of men with metastatic castration-resistant prostate cancer (mCRPC). This study aimed to establish level 2 evidence of cytokine biomarker utility in mCRPC. METHODS: IntVal: Plasma samples at baseline (BL) and Day 21 docetaxel (n = 120). ExtVal: Serum samples at BL and Day 42 of docetaxel (n = 430). IL4, IL6, and GDF15 levels were measured by ELISA. Monocytes and dendritic cells were treated with 10% plasma from men with high or low GDF15 or recombinant GDF15. RESULTS: IntVal: Higher GDF15 levels at BL and Day 21 were associated with shorter overall survival (OS) (BL; p = 0.03 and Day 21; p = 0.004). IL4 and IL6 were not associated with outcomes. ExtVal: Higher GDF15 levels at BL and Day 42 predicted shorter OS (BL; p < 0.0001 and Day 42; p < 0.0001). Plasma from men with high GDF15 caused an increase in CD86 expression on monocytes (p = 0.03), but was not replicated by recombinant GDF15. CONCLUSIONS: Elevated circulating GDF15 is associated with poor prognosis in men with mCRPC receiving docetaxel and may be a marker of changes in the innate immune system in response to docetaxel resistance. These findings provide a strong rationale to consider GDF15 as a biomarker to guide a therapeutic trial of drugs targeting the innate immune system in combination with docetaxel in mCRPC
Exploration of the autophagy degradome and MAP1LC3B interactome using novel tools in combination with quantitative proteomics
No full textThis thesis describes our efforts to study autophagy’s role in cancer by developing new assays that allow extensive profiling of the autophagy degradome and MAP1LC3B interactome. Autophagy plays a central role in many cellular processes but has also been extensively implicated in the pathology of many diseases, including in cancer. However, the role of autophagy in cancer appears both complex, paradoxical and cancer specific. The exact nature of its role appears to be context dependent and is yet to be elucidated. This project aimed to study autophagy’s role in cancer by developing new assays that have enabled elucidation of the autophagy degradome and MAP1LC3B interactome. We have utilised novel cell permeating peptides, derived from Phytophthora infestans virulence factors, which allow temporal and selective inhibition of autophagy, in combination with quantitative mass spectrometry based proteomics to optimise multiple whole-cell proteomics, proximity dependent and IP-MS workflows. Using these optimised workflows, we have profiled the MAP1LC3B interactome and autophagy degradome, whilst also delineating LIR dependent interactors of MAP1LC3B. These optimised protocols have been expanded in a pan-cancer fashion to establish high confidence, cancer-specific autophagy cargo and interactors, which have the potential to explain the differential role of autophagy between cancers and identify cancer-specific therapeutic vulnerabilities
Deep cell phenotyping and spatial analysis of multiplexed imaging with TRACERx-PHLEX.
No full textThe growing scale and dimensionality of multiplexed imaging require reproducible and comprehensive yet user-friendly computational pipelines. TRACERx-PHLEX performs deep learning-based cell segmentation (deep-imcyto), automated cell-type annotation (TYPEx) and interpretable spatial analysis (Spatial-PHLEX) as three independent but interoperable modules. PHLEX generates single-cell identities, cell densities within tissue compartments, marker positivity calls and spatial metrics such as cellular barrier scores, along with summary graphs and spatial visualisations. PHLEX was developed using imaging mass cytometry (IMC) in the TRACERx study, validated using published Co-detection by indexing (CODEX), IMC and orthogonal data and benchmarked against state-of-the-art approaches. We evaluated its use on different tissue types, tissue fixation conditions, image sizes and antibody panels. As PHLEX is an automated and containerised Nextflow pipeline, manual assessment, programming skills or pathology expertise are not essential. PHLEX offers an end-to-end solution in a growing field of highly multiplexed data and provides clinically relevant insights
Utilising Quantitative Imaging And Radiomics To Unravel Intra-tumoural Heterogeneity In Soft Tissue Sarcoma
No full textSoft tissue sarcomas (STS) are rare mesenchymal tumours that exhibit extensive biological and clinical heterogeneity. Our understanding of this heterogeneity is incomplete and has continued to be a barrier to clinical advancements, and as such, outcomes for STS patients remain poor. Across oncology, radiology has transformed into a data-driven specialty, where advanced imaging techniques and computational science such as quantitative imaging and radiomics have the potential to provide in-depth information about tumour biology. If clinically translated, these tools could provide tumour characterisation by probing biology in a non-invasive and global manner revolutionising STS diagnostics and prognostics. However, progression of these tools has been slow as we continue to lack an understanding of the biology underlying imaging outputs. Herein, my project aimed to utilise imaging to approach biological heterogeneity in retroperitoneal sarcoma (RPS) in two ways: direct radiological-pathological correlation and large-scale CT-based radiomics. Using a retrospective cohort of 21 patients with RPS, immunohistochemistry of multi-regional tissue matched to regions of interest on quantitative MRI (qMRI) were analysed. Specifically key immune cells were characterised and correlation analysis with qMRI and histopathological data was carried out. Expansion to patient level data was conducted to include clinical data for correlation. Key findings were intra-tumoural heterogeneity of immune cells, the correlation of MRI enhancing fraction with T cells and the correlation of Ki67 proliferation index with T cells and CD68+ cells at both block and patient levels. To interrogate further the capability of unravelling heterogeneity using imaging, radiomic and deep learning (DL-) radiomic data available for the same cohort was analysed. Correlation analysis revealed 32 correlations between immune and histopathological data with DL-radiomics whilst 5 correlations were found between histopathological and radiomic data, with absence of any correlations between immune and radiomic data. In addition, clustering of DL-radiomics data revealed a persistent cluster inclusive of all recurrence cases alluding to a possible DL-radiomic signature for RPS disease recurrence. Using large-scale CT-based radiomics, we developed and tested a classification model for the two most common RPS subtypes, leiomyosarcoma (LMS) and liposarcoma (LPS) and for histological grade. Our model utilised a novel feature selection pipeline, sub-segmentation to provide sub-region volumes, repeatability analysis and intense cross-validation to increase the explainability and stability of our final models. Selecting the best performing models for prediction of subtype and for grade, we successfully independently validated our models using international, multi-centre trial data. Final area under the receiver operator curves were 0.928 for subtype and 0.882 for low versus intermediate/high grade RPS. Compared with standard of care radiological and histopathological assessment of subtype and grade, our models outperformed with regards to accuracy: 0.843 (radiomics) versus 0.65 (clinical) for subtype and 0.823 (radiomics) versus 0.44 (clinical) for low versus intermediate/high grade. These powerful and validated radiomics models, if prospectively validated could revolutionise the upfront characterisation of RPS tumours, offering a complimentary tool for diagnosis and risk stratification. Overall, my project has provided an exciting foundation of using qMRI and radiomics to provide a virtual biopsy of underlying biology of RPS tumours. It qualifies as a rich resource to guide future work to ultimately encourage the clinical translation of cutting-edge tools that may be utilised in diagnosis, risk stratification, treatment planning and monitoring and prognosis of STS
Weekly ultra-hypofractionated radiotherapy in localised prostate cancer.
No full textBACKGROUND: Moderately hypofractionated radiotherapy regimens or stereotactic body radiotherapy (SBRT) are standard of care for localised prostate cancer. However, some patients are unable or unwilling to travel daily to the radiotherapy department and do not have access to, or are not candidates for, SBRT. For many years, The Royal Marsden Hospital NHS Foundation Trust has offered a weekly ultra-hypofractionated radiotherapy regimen to the prostate (36 Gy in 6 weekly fractions) to patients unable/unwilling to travel daily. METHODS: The current study is a retrospective analysis of all patients with non-metastatic localised prostate cancer receiving this treatment schedule from 2010 to 2015. RESULTS: A total of 140 patients were included in the analysis, of whom 86 % presented with high risk disease, with 31 % having Gleason Grade Group 4 or 5 disease and 48 % T3 disease or higher. All patients received hormone treatment, and there was often a long interval between start of hormone treatment and start of radiotherapy (median of 11 months), with 34 % of all patients having progressed to non-metastatic castrate-resistant disease prior to start of radiotherapy. Median follow-up was 52 months. Median progression-free survival (PFS) and overall survival (OS) for the whole group was 70 months and 72 months, respectively. PFS and OS in patients with hormone-sensitive disease at time of radiotherapy was not reached and 75 months, respectively; and in patients with castrate-resistant disease at time of radiotherapy it was 20 months and 61 months, respectively. CONCLUSION: Our data shows that a weekly ultra-hypofractionated radiotherapy regimen for prostate cancer could be an option in those patients for whom daily treatment or SBRT is not an option