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Overcoming the barriers to implementing auto-contouring in external beam radiotherapy for cervical cancer
No full textThis thesis has developed methods for the clinical implementation of auto-contouring for external beam radiotherapy (EBRT) for cervical cancer. It has explored the barriers to auto-contouring, which include a lack of consensus on evaluation methods and challenges in generating high quality training data. These challenges arise due to issues such as multiple contouring protocols, reliance on clinical decision-making and inter-observer variation.
The important differences between published contouring protocols for cervical cancer EBRT have been identified. A contouring protocol based on anatomical substructures has been created, to remove the heterogeneity caused by clinical decisions. This protocol has been used to produce training data for a novel nnU-Net auto-contouring system that can contour the substructures for target volumes and organs-at-risk for cervical cancer.
This thesis has formally reviewed the auto-contouring assessment metrics in published literature. Significant variation was found, making it challenging to compare studies and recommend standardised practice. This thesis also identified the need for clinically relevant assessment methods, applicable in the context of usual inter-observer variation.
A manual inter-observer contouring study has been performed to establish a validation dataset and estimate delineation uncertainty for both manual and auto-contours. The delineation uncertainty was lower for auto-contours from a developed auto-contouring system, than for manual contours, suggesting superior performance. Delineation uncertainty may also be a novel clinically useful assessment method, as it can directly determine necessary treatment margins.
The novel auto-contouring system was found to produce contours that fall within the usual range of inter-observer variation. This range can also mostly be predicted by a pair of expert observers, which could simplify assessment processes in the future.
Finally, a novel standardised structured qualitative assessment has been developed and evaluated. This showed that inter- and intra-rater reliability is variable, an issue that must be considered when evaluating auto-contouring systems
The interplay between acute and late toxicity among patients receiving prostate radiotherapy: an individual patient data meta-analysis of six randomised trials.
No full textBACKGROUND: The association between acute and late toxicity following prostate radiotherapy has not been well studied using data from multiple randomised clinical trials and fractionation schedules. We aimed to characterise the relationship between acute and late genitourinary and gastrointestinal toxicity among patients receiving conventionally fractionated or moderately hypofractionated prostate radiotherapy. METHODS: This was an individual patient data meta-analysis that identified randomised phase 3 trials of conventionally fractionated or moderately hypofractionated prostate radiotherapy in the Meta-Analysis of Randomized trials in Cancer of the Prostate (MARCAP) Consortium that had individual-level acute and late toxicity data available and were available before Dec 1, 2023. Trials without individual patient data were excluded. Data were provided to MARCAP by study investigators. The associations between acute (≤3 months after radiotherapy) and late (>3 months after radiotherapy) grade 2 or greater genitourinary and gastrointestinal toxicities were assessed using adjusted generalised linear mixed models (adjusted for age, androgen deprivation therapy status, type of radiotherapy, radiation dose, and radiation schedule). In the subset of trials that collected Expanded Prostate Cancer Index Composite quality of life (QOL) evaluations, the association between acute genitourinary and gastrointestinal toxicity and decrements at least twice the minimal clinically important difference (MCID) for urinary and bowel QOL were also evaluated. FINDINGS: Six of 26 available trials met all the eligibility criteria. 6593 patients were included (conventionally fractionated: n=4248; moderately hypofractionated: n=2345). Median follow-up was 72 months (IQR 61-94). Acute grade 2 or greater genitourinary toxicity was associated with both late grade 2 or greater genitourinary toxicity (odds ratio 2·20 [95% CI 1·88-2·57], p<0·0001) and decrement at least twice the MCID in urinary QOL (1·41 [1·17-1·68], p=0·0002). Acute grade 2 or greater gastrointestinal toxicity was associated with both late grade 2 or greater gastrointestinal toxicity (2·53 [2·07-3·08], p<0·0001) and decrement at least twice the MCID in bowel QOL (1·52 [1·26-1·83], p<0·0001). INTERPRETATION: Acute toxicity following prostate radiotherapy was statistically significantly associated with late toxicity and with decrement in patient-reported QOL metrics. These data support efforts to evaluate whether interventions that reduce acute toxicity ultimately reduce the risk of late toxicity. FUNDING: National Institutes of Health and US Department of Defense
Low-coverage whole genome sequencing of low-grade dysplasia strongly predicts advanced neoplasia risk in ulcerative colitis.
No full textBACKGROUND: The risk of developing advanced neoplasia (AN; colorectal cancer and/or high-grade dysplasia) in ulcerative colitis (UC) patients with a low-grade dysplasia (LGD) lesion is variable and difficult to predict. This is a major challenge for effective clinical management. OBJECTIVE: We aimed to provide accurate AN risk stratification in UC patients with LGD. We hypothesised that the pattern and burden of somatic genomic copy number alterations (CNAs) in LGD lesions could predict future AN risk. DESIGN: We performed a retrospective multicentre validated case-control study using n=270 LGD samples from n=122 patients with UC. Patients were designated progressors (n=40) if they had a diagnosis of AN in the ~5 years following LGD diagnosis or non-progressors (n=82) if they remained AN-free during follow-up. DNA was extracted from the baseline LGD lesion, low-coverage whole genome sequencing performed and data processed to detect CNAs. Survival analysis was used to evaluate CNAs as predictors of future AN risk. RESULTS: CNA burden was significantly higher in progressors than non-progressors (p=2×10-6 in discovery cohort) and was a very significant predictor of AN risk in univariate analysis (OR=36; p=9×10-7), outperforming existing clinical risk factors such as lesion size, shape and focality. Optimal risk prediction was achieved with a multivariate model combining CNA burden with the known clinical risk factor of incomplete LGD resection. Within-LGD lesion genetic heterogeneity did not confound risk prediction. CONCLUSION: Measurement of CNAs in LGD is an accurate predictor of AN risk in inflammatory bowel disease and is likely to support clinical management
Novel Therapeutic Approaches for the Management of Recurrent Gynaecological Cancer
No full textManagement of recurrent gynaecological cancer is challenging and often requires a multi-modality approach. This project evaluated the potential of novel therapeutic approaches to improve treatment selection for women with recurrent gynaecological cancer.
In ovarian cancer, the feasibility of using radiotherapy with stereotactic radiotherapy (SBRT) and volumetric modulated arc therapy (VMAT) instead of secondary debulking surgery was assessed. Of 134 patients previously treated with debulking surgery, 59.7% had localised disease. To assess which radiotherapy approaches are feasible for different disease distributions, patients were allocated into three groups: Group A pelvic mass 8 cm, >5 lesions (5.2%). Results showed radiotherapy would be an option for 59.7% patients. While SBRT was deliverable for lymph nodes and small-volume disease, tumoricidal doses could also be achieved for more bulky disease with conventionally fractionated approaches.
An isotoxic dosimetric study evaluated the feasibility of using an SBRT boost when brachytherapy is not feasible for recurrent pelvic disease. Deliverable dose using five or ten fractions was compared using optimal and mandatory organ at risk (OAR) dose constraints. For central pelvic disease, median doses (EQD2) with mandatory tolerances were PTV 74.7 Gy versus 77.0 Gy; GTV 75.1 Gy versus 78.1 Gy. For pelvic sidewall disease, higher PTV doses were achieved (96.5 Gy versus 99.5 Gy) without sciatic nerve sparing, which highlighted the need for improved sciatic nerve dose constraints and localisation.
Therefore, the dosimetric impact of using different methods to contour the lumbosacral plexus (LSP) on CT and MRI scans was assessed. The median deliverable PTV dose (EQD2) was 72.2 Gy versus 81.0 Gy using regional and individual nerve localisation, respectively (p<0.005). MR-neurography improved LSP visualisation, reducing the delineated volume compared to CT and conventional MRI. Initial results suggest it may also improve the prediction of surgical resectability.
In conclusion, this thesis determines that advanced radiotherapy and imaging approaches have the potential to improve outcomes for women with recurrent gynaecological cancer
Magnetic Resonance based Metabolic Imaging of Paediatric-Type Diffuse High Grade Glioma
No full textPaediatric-type diffuse high grade glioma (PDHGG) is a leading cause of tumour-related death in children and young adults, and novel therapeutic approaches are urgently needed. Recent studies into the underlying biology of PDHGG have identified specific dysregulated signaling pathways including metabolic adaptations, that reveal therapeutic vulnerabilities that could be targeted for improved treatment.
Magnetic resonance imaging (MRI) is typically used in the clinical management of PDHGG, but their diffusely infiltrative growth means conventional scans can be limited in fully identifying and delineating disease extent in situ, and for assessing treatment response.
Chemical exchange saturation transfer (CEST) MRI, which can image proteins and macromolecules at high resolution, and deuterium (2H) MR spectroscopy (MRS), which can monitor the catabolism of deuterated substrates, were implemented and optimised on a 7T preclinical scanner.
CEST imaging was shown to successfully delineate tumours from normal-appearing brain in well-defined orthotopic PDHGG models, and demonstrated potential in detecting more diffuse tumour growth.
2H-MRS was first used to dynamically assess the metabolism of [2H]-glucose in both non-tumour bearing mouse brains and orthotopic PDHGG xenografts, enabling quantification of their glycolytic phenotype. Subsequently 2H-MRS revealed that glycolytic rate in PDHGG models, both in vitro and
in vivo, was significantly reduced by treatment with the PI3K inhibitor paxalisib. This response preceded changes in tumour cell viability or proliferation, highlighting the potential of 2H-MRS to provide an early biomarker of treatment response.
CEST and 2H-MRS, which are both clinically translatable, hold great potential for effectively imaging PDHGG metabolism, and may aid detection of diffuse disease and provide early imaging biomarkers of treatment response to metabolically targeted therapeutic intervention
Not seeing the trees for the forest. The impact of neighbours on graph-based configurations in histopathology.
No full textBACKGROUND: Deep learning (DL) has set new standards in cancer diagnosis, significantly enhancing the accuracy of automated classification of whole slide images (WSIs) derived from biopsied tissue samples. To enable DL models to process these large images, WSIs are typically divided into thousands of smaller tiles, each containing 10-50 cells. Multiple Instance Learning (MIL) is a commonly used approach, where WSIs are treated as bags comprising numerous tiles (instances) and only bag-level labels are provided during training. The model learns from these broad labels to extract more detailed, instance-level insights. However, biopsied sections often exhibit high intra- and inter-phenotypic heterogeneity, presenting a significant challenge for classification. To address this, many graph-based methods have been proposed, where each WSI is represented as a graph with tiles as nodes and edges defined by specific spatial relationships. RESULTS: In this study, we investigate how different graph configurations, varying in connectivity and neighborhood structure, affect the performance of MIL models. We developed a novel pipeline, K-MIL, to evaluate the impact of contextual information on cell classification performance. By incorporating neighboring tiles into the analysis, we examined whether contextual information improves or impairs the network's ability to identify patterns and features critical for accurate classification. Our experiments were conducted on two datasets: COLON cancer and UCSB datasets. CONCLUSIONS: Our results indicate that while incorporating more spatial context information generally improves model accuracy at both the bag and tile levels, the improvement at the tile level is not linear. In some instances, increasing spatial context leads to misclassification, suggesting that more context is not always beneficial. This finding highlights the need for careful consideration when incorporating spatial context information in digital pathology classification tasks
Short-duration preoperative endocrine therapy alters molecular profiles to predict favourable outcome in ER+/HER2+ early breast cancer: a POETIC translational study.
No full textBACKGROUND: About 15-20% of breast cancers (BC) overexpress Human Epidermal Growth Factor Receptor 2 (HER2+), and 50% of them are also oestrogen receptor positive (ER+). Patients with ER+/HER2+ BC with a limited response to systemic therapies are at an increased risk of relapse, thus understanding the mechanisms of resistance is crucial. This study investigates the changes in gene signature expression (ΔGSE) within ER+/HER2+ tumours and their intrinsic subtype (IS) in response to peri-operative aromatase inhibitors (POAI). METHODS: We analysed paired pre-treatment (baseline) and on-treatment (2wk) samples from 313 ER+/HER2+ BC from the POETIC trial using the BC360™ codeset. Early biological response to aromatase inhibitors (AI) was assessed by immunohistochemical Ki67 levels. Association of ΔGSE with biological response was evaluated using T-test and time to recurrence (TTR) with multivariable Cox regression models adjusted for clinicopathological variables. FINDINGS: The immunity-related signatures were significantly upregulated, while proliferation, TP53 surrogate mutational status and ER-signalling were downregulated (FDR <0·05) among POAI tumours with low Ki672wk. In the POAI, 79% (59/75) of Luminal B (LumB) at baseline shifted to Luminal A (LumA) at 2wk and LumA2wk was associated with better TTR compared to LumB2wk (HR 0·2; CI 95% 0·06-0·72, p = 0·01). Based on Akaike Information Criterion scores, Ki67 and IS at 2wk provided better fit of the multivariable Cox models over the variables at baseline when predicting TTR. INTERPRETATION: Assessing on-treatment IS after POAI for ER+HER2+ BC can help to identify a group of low-risk patients with LumA2wk with good outcomes on de-escalated treatment and patients that require additional treatments. FUNDING: Cancer Research UK (CRUK/07/015)
PERK-dependent reciprocal crosstalk between ER and non-centrosomal microtubules coordinates ER architecture and cell shape.
No full textThe architecture of the endoplasmic reticulum (ER) is a key determinant of its function. Its dynamics are linked to those of the cytoskeleton, but our understanding of how this coordination occurs and what its functional relevance is, limited. Here, we report that the unfolded protein response (UPRER) transducer EIF2AK3/PERK (eukaryotic translation initiation factor 2-alpha kinase 3/protein kinase R-like endoplasmic reticulum kinase) is essential for acute-stress-induced peripheral redistribution and remodeling of the ER through eukaryotic initiation factor 2 alpha (eIF2α) phosphorylation and translation initiation shutdown. PERK-mediated eIF2α phosphorylation can be bypassed by blocking polysome assembly, depleting microtubule (MT)-anchoring ER proteins such as p180/RRBP1 (ribosome-binding protein 1), or disrupting the MT cytoskeleton. Specific disruption of non-centrosomal MTs, but not centrosome depletion, rescues ER redistribution in PERK-deficient cells. Conversely, PERK deficiency stabilizes non-centrosomal MTs against proteasomal degradation, promoting polarized protrusiveness in epithelial cells and neuroblasts. Thus, PERK coordinates ER architecture and homeostasis with cell morphogenesis by coupling ER remodeling and non-centrosomal MT stability and dynamics
Differential benefit of adjuvant everolimus according to endocrine therapy backbone in the randomized UNIRAD trial.
No full textBACKGROUND: The randomized, double-blind UNIRAD trial evaluating the addition of 2 years of everolimus to endocrine therapy in patients with high-risk, early luminal breast cancer failed to demonstrate a benefit. We report the subgroup analyses. PATIENTS AND METHODS: We randomly assigned 1278 patients in a 1 : 1 ratio to receive 2 years of placebo or everolimus, added to endocrine therapy for up to 4 years after initiation. Randomization was stratified by endocrine therapy agent, prior adjuvant versus neoadjuvant therapy, progesterone receptor expression, and lymph node involvement. Subgroup analyses by each stratification factor were pre-specified. Post hoc analyses were carried out according to menopausal status and age. Treatment adherence was also analyzed. RESULTS: We observed a limited trend toward more favorable prognostic features in tamoxifen-treated patients, with more frequent estrogen receptor-positive/progesterone receptor-positive tumors (88.5% versus 84.1%, P = 0.026) and less frequent pN2-positive status (39.8% versus 46.0%, P = 0.032). In premenopausal women, we observed a numerical benefit of everolimus: 3-year disease-free survival was 86% in the placebo group and 90% in the everolimus group (hazard ratio 0.76, 95% confidence interval 0.43-1.34). In premenopausal patients treated with tamoxifen (n = 153; 12.3%), we observed an even stronger trend in favor of everolimus as 3-year DFS was 84% in the placebo group and 91% in the everolimus group (hazard ratio 0.54, 95% confidence interval 0.28-1.02). Early discontinuation of either everolimus or placebo was less frequent in the tamoxifen group than in the aromatase inhibitor group: 48.0% versus 56.9% (P = 0.028). CONCLUSIONS: The present post hoc analyses generate hypotheses regarding the interaction between menopausal status, tamoxifen, and everolimus in patients with high-risk, ER-positive, human epidermal growth factor receptor type 2-negative early breast cancer. They suggest that tamoxifen alone is an underpowered endocrine treatment in high-risk premenopausal patients
Patient- and clinician-assessed five-year normal tissue effects following one-week versus three-week axillary radiotherapy for breast cancer: Results from the phase III FAST-Forward trial randomised nodal sub-study.
No full textBACKGROUND AND PURPOSE: FAST-Forward showed that 26 Gray (Gy) in 5 fractions (Fr) over one week adjuvant radiotherapy to breast or chest wall was as safe and effective as a three-week schedule (40 Gy/15Fr) for early breast cancer. The nodal sub-study investigated whether a one-week schedule is safe for adjuvant axillary radiotherapy. MATERIALS AND METHODS: In this randomised, non-inferiority, non-blinded sub-study (ISRCTN19906132), patients with invasive breast cancer (pT1-3, pN1-3a, M0) following surgery requiring axillary radiotherapy (any or all levels 1-4) were randomised to 40 Gy/15Fr (three weeks, control), 26 Gy/5Fr or 27 Gy/5Fr (one week) atlas-based radiotherapy planning, including quality assurance. The 27 Gy/5Fr group closed early due to three-year main trial normal tissue effects suggesting 26 Gy/5Fr would be optimal; this analysis focusses on comparison between 26 Gy/5Fr and control. Primary endpoint was five-year patient-reported moderate or marked arm or hand swelling, aiming to exclude a 10 % increase (assuming 10 % incidence with control; 90 % power, one-sided α = 0.05, n = 172 per group). RESULTS: 469 patients were randomised from 50 UK centres (182 40 Gy/15Fr, 183 26 Gy/5Fr, 104 27 Gy/5Fr). Median age 61 years; 250 (54 %) and 182 (39 %) had grade 2 and 3 tumours respectively; 261 (56 %) had axillary dissection. Of those who completed a five-year questionnaire, 11/107 (10 %) 40 Gy/15Fr and 13/116 (11 %) 26 Gy/5Fr reported moderate or marked arm or hand swelling, difference 1 % (90 % confidence interval -6%, 8 %, p = 0.49). Other arm and shoulder symptoms were similar between groups with no cases of brachial plexopathy. CONCLUSION: Five-year patient-reported normal tissue effects suggest 26 Gy/5Fr/1-week hypofractionation is safe for breast cancer patients requiring adjuvant axillary radiotherapy