RSS 1.0Cancer and Associated Specialties
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Evaluating the efficacy and safety of single-agent etoposide intra-CSF chemotherapy in children and young people with relapsed/refractory central nervous system tumoursPurpose: The aim of the project was to evaluate intra-CSF etoposide administration in a palliative setting for children and young people with relapsed/refractory central nervous system (CNS) tumours, with the primary endpoints being overall survival and progression-free survival time. A safety endpoint was to assess the side effect profile and complications of intra-CSF etoposide. Method(s): Thirty-five patients under the age of 30 years (median age: 5.33 years) were enrolled onto the project. The cross-centre study was a service evaluation, with a data collection spreadsheet designed in Nottingham and completed by both Nottingham and Oxford centres. Data was analysed using SPSS, assessing the overall survival and progression-free survival times, as well as the 6-month and 1-year survival rates. Result(s): The median overall survival and progression-free survival times were 10.97 and 5.91 months, respectively. The 6-month and 1-year overall survival rates were 67% and 48%, and the progression-free survival rates were 50% and 22%. Age at the start of intra-CSF therapy was significantly associated with overall survival (P = 0.046), with the 6 + age group having improved overall survival. Treatment type was significantly associated with overall survival (P = 0.012), with etoposide intra-CSF treatment being associated with improved overall survival. Treatment duration was significantly associated with both overall survival (P < 0.001) and progression-free survival (P < 0.001). Conclusion(s): Intra-CSF etoposide treatment has shown to increase both overall and progression-free survival significantly, whilst having few side effects and maintaining a good quality of life for patients, reflecting it as a beneficial therapy in the palliative setting.Copyright © 2023, Crown.
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Phase II study of intravenous etoposide in patients with relapsed ependymoma (CNS 2001 04)Background: Relapsed ependymoma has a dismal prognosis, and the role of chemotherapy at relapse remains unclear. This study prospectively evaluated the efficacy of intensive intravenous (IV) etoposide in patients less than 21 years of age with relapsed intracranial ependymoma (NCT00278252). Method(s): This was a single-arm, open-label, phase II trial using Gehan's two-stage design. Patients received IV etoposide 100 mg/m2 on days 1-3, 8-10, and 15-17 of each 28-day cycle, up to maximum of 6 cycles. Primary outcome was radiological response after 3 cycles. Pharmacokinetic analysis was performed in 10 patients. Result(s): Twenty-five patients were enrolled and included in the intention-to-treat (ITT) analysis. Three patients were excluded in per-protocol (PP) analysis. After 3 cycles of etoposide, 5 patients (ITT 20%/PP 23%) had a complete response (CR), partial response (PR), or objective response (OR). Nine patients (ITT 36%/PP 41%,) had a best overall response of CR, PR, or OR. 1-year PFS was 24% in ITT and 23% in PP populations. 1-year OS was 56% and 59%, 5-year OS was 20% and 18%, respectively, in ITT and PP populations. Toxicity was predominantly hematological, with 20/25 patients experiencing a grade 3 or higher hematological adverse event. Conclusion(s): This study confirms the activity of IV etoposide against relapsed ependymoma, however, this is modest, not sustained, and similar to that with oral etoposide, albeit with increased toxicity. These results confirm the dismal prognosis of this disease, provide a rationale to include etoposide within drug combinations, and highlight the need to develop novel treatments for recurrent ependymoma.Copyright © 2022 The Author(s). Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.
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EPEN-24. SIOP ependymoma II: Central ependymoma management advisory group - The UK experiencePaediatric Ependymoma is the second most common malignant brain tumour of childhood with approximately 50% of cases recurring. It has been described as a "surgical" disease since patients who have undergone a gross total surgical resection (GTR) have a better prognosis than those who have a subtotal resection (STR). Analysis of the UKCCSG/SIOP 1992 04 clinical trial has shown that only 49% of cases had a GTR, with 5-year survival rates for STR of 22-47% and GTR of 67-80%. As part of the SIOP II Ependymoma trial the UK established a panel of experts in the treatment of Ependymoma from Neuro-oncology, Neuro-radiology and Neuro-surgery. Meeting weekly, cases are discussed to provide a consensus on radiological review, ensuring central pathological review, trial stratification and whether further surgery should be advocated on any particular case. Evaluation of the first 68 UK patients has shown a GTR in 47/68 (69%) of patients and STR in 21/68 (31%) of patients. Following discussion at EMAG it was felt that 9/21 (43%) STR patients could be offered early second look surgery. Following this 2nd look surgery the number of cases with a GTR increased to 56/68 (82%). There has been a clear increase in the number of patients for whom a GTR has been achieved following discussion at EMAG and prior to them moving forwards with their oncological treatment. This can only have beneficial effects in decreasing their risk of tumour recurrence or CSF dissemination and also in reducing the target volume for radiotherapy.
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EPEN-05. Surgery for childhood ependymoma: The ependymoma multidisciplinary advisory group (EMAG) clinical trial experienceINTRODUCTION: The National Ependymoma Multidisciplinary Advisory Group (EMAG) is the central review mechanism for the SIOP Ependymoma II clinical trial in the UK. EMAG is a multiprofessional group which meets weekly to support decision making. We report detailed surgical outcomes for children with confirmed intracranial ependymoma, discussed through EMAG between January 2020 and November 2022. METHOD(S): Data was collected on resection status, surgical outcomes, reasons for not achieving Gross Total Resection (GTR), number of surgeries and adjuvant therapies. Data was analysed descriptively. RESULT(S): After first surgery, GTR or near total resection (NTR) rate was 69/105 (66%) rising to 83/105 (79%) following repeated surgeries. 17 patients underwent second-look surgery prior to further therapy, whilst 9 underwent second-look surgery after chemotherapy but before radiotherapy. Eight (17%) posterior fossa (PF) surgeries were not completed due to factors including patient instability and tumour attachments. Most post-operative problems were seen in PF tumours with 26/60 (43%) bulbar palsy, 13/60 (22%) focal weakness and 12/60 (20%) cerebellar mutism. Incomplete PF resections were associated with increased bulbar palsy risk (p=0.02, Chi-Square test). 73% of PF patients required hydrocephalus management with external ventricular drainage, endoscopic third ventriculostomy (ETV) or shunt. Longer term hydrocephalus management with ETV or shunt was required in 29% and was more common in those with subtotal resection (R3-RX, 8/16, 50%) compared to GTR or NTR (R0-R2, 9/43, 21%, p=0.03). 27/60 (45%) received post-op NG feeding and 2/60 (3%) needed tracheostomies. Second surgery was associated with lower complication rates. DISCUSSION(S): Our National MDT approach supports collaborative surgical decision making without a need for centralisation of the surgery itself. There was no evidence of increased complication rates compared to historical trials despite a more aggressive surgical approach. We argue for continued centralisation of EPN evaluation to support optimal care for children with this devastating disease.
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Extracellular vesicles potentiate medulloblastoma metastasis in an EMMPRIN and MMP-2 dependent mannerExtracellular vesicles (EVs) have emerged as pivotal mediators of communication in the tumour microenvironment. More specifically, nanosized extracellular vesicles termed exosomes have been shown to contribute to the establishment of a premetastatic niche. Here, we sought to determine what role exosomes play in medulloblastoma (MB) progression and elucidate the underlying mechanisms. Metastatic MB cells (D458 and CHLA-01R) were found to secrete markedly more exosomes compared to their nonmetastatic, primary counterparts (D425 and CHLA-01). In addition, metastatic cell-derived exosomes significantly enhanced the migration and invasiveness of primary MB cells in transwell migration assays. Protease microarray analysis identified that matrix metalloproteinase-2 (MMP-2) was enriched in metastatic cells, and zymography and flow cytometry assays of metastatic exosomes demonstrated higher levels of functionally active MMP-2 on their external surface. Stable genetic knockdown of MMP-2 or extracellular matrix metalloproteinase inducer (EMMPRIN) in metastatic MB cells resulted in the loss of this promigratory effect. Analysis of serial patient cerebrospinal fluid (CSF) samples showed an increase in MMP-2 activity in three out of four patients as the tumour progressed. This study demonstrates the importance of EMMPRIN and MMP-2-associated exosomes in creating a favourable environment to drive medulloblastoma metastasis via extracellular matrix signalling.Copyright © 2023 by the authors.
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Impact of the SARS-CoV-2/COVID-19 pandemic on the patient journeys of those with a newly diagnosed paediatric brain tumour in the UK: A qualitative studyObjectives To explore the impact of the SARS-CoV-2/COVID-19 pandemic on the diagnosis, management and patient journey for children and young people with a newly diagnosed brain tumour in the UK. Design Exploratory qualitative study focused on patient journeys from multiple perspectives, conducted as part of a wider mixed-methods study. Setting Three paediatric oncology tertiary centres in the UK. Participants 10 children and young people with brain tumours (n=6 females, n=4 males), 20 caregivers (n=16 females, n=4 males) and 16 stakeholders (specialist nurses, consultant neurosurgeons and oncologists, and representatives from brain tumour charities) were interviewed between January 2022 and June 2023. Results The paper incorporates multiple perspectives, including those of children and young people, parents/caregivers, clinical staff and charity representatives, to explore the patient journey. Five themes describe the journey for new patients with paediatric brain tumour during the pandemic, focusing on (1) challenges getting into the healthcare system, (2) managing as a family during restrictions imposed by the pandemic, (3) complexities of building a cohesive and supportive healthcare team, (4) difficulties caregivers experienced in accessing practical and emotional support in hospital and (5) ongoing difficulties experienced by families in the community. Conclusions Findings from this study offer practical insights from children, parents/caregivers and relevant stakeholders to improve the healthcare system during future disruptions. Overall, this study not only sheds light on the challenges faced by families during the pandemic but also provides suggestions for improving healthcare services to ensure a more comprehensive and effective response in times of crisis.Copyright © Author(s) (or their employer(s)) 2025.
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EPEN-43. Targeting intra-tumour heterogeneity in paediatric ependymoma: An integrated omics study towards patient-tailored therapyEpendymoma (EPN) is the second most common malignant paediatric brain tumour, which despite extensive genomic sequencing, no novel therapeutic options have been discovered. Multi-omics are anticipated to reveal dysregulated pathways that may be predictive of patient-specific biomarkers. Given the close association between gene expression, active biochemical signaling and metabolism, there is an unmet scientific challenge to determine whether EPN gene expression correlates with aberrant metabolic pathways, thus presenting therapeutic vulnerabilities. We first compared two distinct subgroups of EPN, PF-A and ST-RELA, identifying 115 metabolites and 1580 upregulated genes between the two subgroups, therefore validating previously reported genetic clustering of these two subtypes. We next integrated transcriptomics and metabolomics, comparing 28 intra-tumour tissue regions from eight primary PF-A EPN patients. Polar metabolites and RNA were simultaneously extracted from the same population of cells. RNAseq identified dysregulated genes and liquid chromatography-mass spectrometry (LC-MS) detected 98 significantly altered metabolites between 18 multi-regions, the majority mapping onto the arginine and proline pathways. Integration of genes and metabolites using pathway-based network analysis revealed 124 aberrant gene-metabolite interactions between intra-tumour regions, with large numbers occurring in the glucogenesis and glycine metabolic pathways in 6/8 patients. These may represent ubiquitous and therapeutically relevant metabolic pathways critical for EPN survival. Additionally, patients presented at least one unique intra-tumour genomic-metabolomic interaction, applicable for patient-tailored therapy. This is the first exploration of EPN multi-omic integration and intra-tumour heterogeneity. Selected drug targets predicated on aberrant gene-metabolite networks will be validated in multi-region patient-derived cell lines and orthotopic models using repurposed therapeutics.
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EPEN-15. Transcriptomic and metabolic integration reveal intra-tumour heterogeneity and identify disulfiram and copper as a synergistic therapy in paediatric ependymomaBACKGROUND: Ependymoma (EPN) is the second most malignant paediatric brain tumour. The PF-A subgroup, associated with a hypoxic microenvironment, has a dismal survival rate of 50% with clinical trials failing to demonstrate a significant survival advantage from chemotherapy to date. As the lack of genomic alterations makes it difficult to uncover novel therapeutic targets, we present a multi-omic integration investigating whether spatially-distinct tumour microenvironments represent targetable metabolic niches in PF-A EPN. METHOD(S): Surgical sampling of spatiallydistinct regions was performed on eight PF-A EPN patients. Metabolites and RNA were simultaneously extracted from the same cellular population and analysed using liquid chromatography-mass spectrometry (LC-MS) and RNAseq. Multi-omic integration was performed using Metscape3 and functional assays evaluating proliferation, invasion and siRNA-mediated knockdown were performed in 2D and 3D models of intra-tumour region patient-derived cell lines. Selected single and drug combination therapy was performed in normoxia and hypoxia, and synergy assessed using the Chou-Talalay method. RESULT(S): Multi-omic integration revealed 124 dysregulated metabolic pathways, encompassing 156 genes and 49 metabolites with the largest number of interactions occurring in the gluconeogenesis pathway. Each anatomical region also presented at least one unique genemetabolite interaction demonstrating heterogeneity within and across PF-A EPN tumours. Four selected drug targets (Disulfiram, Vandetanib, Mildronate and FBP1 inhibitor) based on metabolically relevant genes (ALDH3A1, FMO3, BBOX1, FBP1) showed impairment of metabolic viability in vitro, with limited chemosensitivity observed in control human cerebellar astrocytes. The addition of Cu2+ significantly sensitised cells to Disulfiram, particularly under hypoxic conditions. This synergistic combination significantly impaired invasion in both normoxia and hypoxia. CONCLUSION(S): This is the first instance where multi-omic data integration and intra-tumour heterogeneity has been investigated for paediatric EPN revealing novel therapeutic targets in the context of gene-metabolite correlations. Drug tolerability will be further assessed in vivo using the previously characterised PF-A EPN orthotopic mouse xenograft MAF-928.
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Diagnostic performance of axial T2-weighted MRI sequence for exclusion of brain tumour in paediatric patients with non-localizing symptomsOBJECTIVE: To establish diagnostic performance of a single axial T2-weighted sequence for detection of brain tumours in children with non-localizing symptoms, compared to a standard MRI protocol. METHOD(S): Retrospective analysis of children undergoing MRI brain imaging for suspected brain tumours with non-localizing symptoms over a 3-year period. Axial T2-weighted images were blindly reviewed by 2 experienced paediatric neuroradiologists. Primary analysis was calculation of diagnostic performance metrics for tumour identification using axial T2-weighted image only compared to the standard MRI protocol. RESULT(S): For 312 children undergoing MRI brain during the study period, sensitivity and specificity for brain tumour detection based on axial T2-weighted images in children with non-localizing symptoms were 1.000 (95% CIs 0.598, 1.000) and 0.998 (95% CI 0.990, 0.999), respectively. Based on T2-weighted images alone, 50 patients (16%) were flagged as needing recall for further imaging compared to 14 (4.5%) recalled after the standard protocol. CONCLUSION(S): Axial T2-weighted images have high sensitivity and specificity for detection of brain tumours in children with non-localizing symptoms but are associated with increased imaging recall rates. Prospective evaluation of this approach to identify patients requiring more comprehensive imaging is warranted. ADVANCES IN KNOWLEDGE: A truncated MRI protocol with single axial T2-weighted sequence has high diagnostic performance for brain tumour detection in children with non-localizing features. Radiologists can be reassured that a child with this presentation who is unable to complete the full MRI scan protocol is very unlikely to have a brain tumour missed provided an axial T2-weighted sequence is obtained.Copyright © The Author(s) 2024. Published by Oxford University Press on behalf of the British Institute of Radiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.
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LAsting Symptoms after Oesophageal Resectional Surgery (LASORS): Multicentre validation cohort studyBackground: Long-term symptom burden and health-related quality-of-life outcomes after curative oesophageal cancer treatment are poorly understood. Existing tools are cumbersome and do not address the post-treatment population specifically. The aim of this study was to validate the six-symptom LASORS tool for identifying patients after curative oesophageal cancer treatment with poor health-related quality of life and to assess its clinical utility. Method(s): Between 2015 and 2019, patients from 15 UK centres who underwent curative-intent oesophageal cancer treatment, and were disease-free at least 1 year after surgery, were invited to participate in the study and complete LASORS and European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-OG25 questionnaires. Receiver operating characteristic curve analysis was used to examine the accuracy of the LASORS tool for identifying patients with poor health-related quality of life. Result(s): A total of 263 patients completed the questionnaire. Four of the six LASORS symptoms were associated with poor health-related quality of life: reduced energy (OR 2.13 (95% c.i. 1.45 to 3.13)); low mood (OR 1.86 (95% c.i. 1.20 to 2.88)); diarrhoea more than three times a day unrelated to eating (OR 1.48 (95% c.i. 1.06 to 2.07)); and bloating or cramping after eating (OR 1.35 (95% c.i. 1.03 to 1.77)). The LASORS tool showed good diagnostic accuracy with an area under the receiver operating characteristic curve of 0.858 for identifying patients with poor health-related quality of life. Conclusion(s): The six-symptom LASORS tool generated a reliable model for identification of patients with poor health-related quality of life after curative treatment for oesophageal cancer. This is the first tool of its kind to be prospectively validated in the post-esophagectomy population. Clinical utility lies in identification of patients at risk of poor health-related quality of life, ease of use of the tool, and in planning survivorship services.Copyright © 2025 The Author(s).
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Post-cancer treatment reflections by patients concerning the provisions and support required for a prehabilitation programmeBACKGROUND: Evidence suggests that physical fitness interventions, mental health support and nutritional advice before surgery (prehabilitation) could reduce hospital stay and improve quality of life of patients with cancer. In this study we captured the opinions of a group of patients with cancer undergoing these interventions after treatment to discover what a prehabilitation programme should encompass. METHOD(S): Patients from the Cancer and Rehabilitation Exercise (CARE) programme based in Nottingham took part in a 26-point online questionnaire about the design of prehabilitation programmes. RESULT(S): The questionnaire was completed over a 2-week period in December 2021 by 54 patients from the CARE programme. Their responses were as follows: 44 (81.5%) participants would have participated in prehabilitation had it been available to them and 28 (51.9%) ranked physical exercise as the most important component. Forty (74.1%) participants believed the counselling aspect of prehabilitation would have contributed to a successful outcome and 35 (64.8%) thought dietary advice would have benefitted them before surgery. Thirty-one (57.4%) participants preferred the programme to take place in a fitness centre, rather than at home or hospital and 43 (79.6%) would have liked to have known about prehabilitation from their doctor at the time of diagnosis. CONCLUSION(S): Patients are interested in prehabilitation to become more physically fit and mentally prepared for surgery. They expressed the need for a focus on physical exercise, counselling to improve mental health and personalised nutritional advice. Tailoring a prehabilitation programme, with input from patients, could contribute to improving patient outcomes following cancer treatments.Copyright © 2023. The Author(s).
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COLOFIT: Development and internal-external validation of models using age, sex, faecal immunochemical and blood tests to optimise diagnosis of colorectal cancer in symptomatic patientsBackground: Colorectal cancer (CRC) is the third most common cancer in the United Kingdom and the second largest cause of cancer death. Aim(s): To develop and validate a model using available information at the time of faecal immunochemical testing (FIT) in primary care to improve selection of symptomatic patients for CRC investigations. Method(s): We included all adults (>= 18 years) referred to Nottingham University Hospitals NHS Trust between 2018 and 2022 with symptoms of suspected CRC who had a FIT. Predicted 1-year CRC diagnosis were calculated, and externally validated, using Cox proportional hazards modelling with selected multiple fractional polynomial transformations for age, faecal haemoglobin concentration (f-Hb) value, mean corpuscular volume (MCV), platelet count and sex. Result(s): At a CRC risk threshold of 0.6% (equivalent to f-Hb = 10 mug Hb/g (mug/g)) overall performance of the validated model across age strata using Harrell's C index was >= 0.91% (overall C-statistic 93%, 95% CI 92%-95%) with acceptable calibration. Using this model yields similar numbers of detected and missed cancers, but requires ~20% fewer investigations than a f-Hb >= 10 mug/g strategy. For approximately 100,000 people per year with symptoms of suspected CRC, we predict it might save > 4500 colonoscopies with no evidence that more cancers would be missed if we used our model compared to using FIT f-Hb >= 10 mug/g. Conclusion(s): Including age, sex, MCV, platelets and f-Hb in a survival analysis model to predict the risk of CRC yields greater diagnostic utility than a simple binary cut off f-Hb >= 10 mug/g.Copyright © 2025 The Author(s). Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.
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Systematic review: Mortality associated with raised faecal immunochemical test and positive faecal occult blood resultsBackground: Faecal haemoglobin (f-Hb) testing is used in colorectal cancer (CRC) screening and increasingly to guide the investigation in patients with symptoms suggestive of CRC. Studies have demonstrated increased mortality with raised f-Hb. Aim(s): To assess the association of raised f-Hb with all-cause, non-CRC (any cause excluding CRC) and cause-specific mortality. Method(s): We searched Medline and Embase on 9 February 2024 to identify papers reporting mortality after faecal immunochemical (FIT) or guaiac faecal occult blood tests (gFOBT). The primary outcome was all-cause mortality following a positive compared to a negative test. Result(s): The search identified 3155 papers. Ten met the inclusion criteria: three reported gFOBT and seven reported FIT results, as screening tests. These reported a total of 14,687,625 f-Hb results. Elevated f-Hb was associated with an increased risk of all-cause, non-CRC and cause-specific mortality including death from cardiovascular, digestive and respiratory diseases. Crude risk ratios for all-cause mortality with a positive versus negative test were derived from six papers (three reporting gFOBT, three FIT). An increased risk was demonstrated in five, with RRs ranging from 1.11 (95% CI: 1.06-1.16) to 2.95 (95% CI: 2.85-3.05). For non-CRC mortality risk, RRs ranged from 1.09 (95% CI: 1.04-1.15) to 2.79 (95% CI: 2.70-2.89). We did not perform meta-analysis due to a limited number of papers reporting suitable results for each type of f-Hb test. Conclusion(s): All-cause, non-CRC and cause-specific mortality appear higher in those with raised f-Hb. Population-based studies are warranted to elicit whether this association occurs in symptomatic patients.Copyright © 2024 The Author(s). Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.
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'Low' faecal immunochemical test (FIT) colorectal cancer: A 4-year comparison of the Nottingham '4F' protocol with FIT10 in symptomatic patientsAim: The aim of this work was to evaluate colorectal cancer (CRC) outcomes after 'low' (sub-threshold) faecal immunochemical test (FIT) results in symptomatic patients tested in primary care. Method(s): This work comprised a retrospective audit of 35 289 patients with FIT results who had consulted their general practitioner with lower gastrointestinal symptoms and had subsequent CRC diagnoses. The Rapid Colorectal Cancer Diagnosis pathway was introduced in November 2017 to allow incorporation of FIT into clinical practice. The local '4F' protocol combined FIT results with blood tests and digital rectal examination (DRE): FIT, full blood count, ferritin and finger DRE]. The outcome used was detection rates of CRC, missed CRC and time to diagnosis in local 4F protocols for patients with a subthreshold faecal haemoglobin (fHb) result compared with thresholds of 10 and 20 mug Hb/g faeces. Result(s): A single threshold of 10 mug Hb/g faeces identifies a population in whom the risk of CRC is 0.2%, but this would have missed 63 (10.5%) of 599 CRCs in this population. The Nottingham 4F protocol would have missed fewer CRCs 42 of 599 (7%)] despite using a threshold of 20 mug Hb/g faeces for patients with normal blood tests. Subthreshold FIT results in patients subsequently diagnosed with a palpable rectal tumour yielded the longest delays in diagnosis. Conclusion(s): A combination of FIT with blood results and DRE (the 4F protocol) reduced the risk of missed or delayed diagnosis. Further studies on the impact of such protocols on the diagnostic accuracy of FIT are expected. The value of adding blood tests to FIT may be restricted to specific parts of the fHb results spectrum.Copyright © 2024 The Authors. Colorectal Disease published by John Wiley & Sons Ltd on behalf of Association of Coloproctology of Great Britain and Ireland.
