The Christie Research Publications Repository: Recent submissions
Now showing items 1-20 of 15130
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Inter-school variations in the standard of examiners' graduation-level OSCE judgementsIntroductionEnsuring equivalence in high-stakes performance exams is important for patient safety and candidate fairness. We compared inter-school examiner differences within a shared OSCE and resulting impact on students' pass/fail categorisation.MethodsThe same 6 station formative OSCE ran asynchronously in 4 medical schools, with 2 parallel circuits/school. We compared examiners' judgements using Video-based Examiner Score Comparison and Adjustment (VESCA): examiners scored station-specific comparator videos in addition to 'live' student performances, enabling 1/controlled score comparisons by a/examiner-cohorts and b/schools and 2/data linkage to adjust for the influence of examiner-cohorts. We calculated score impact and change in pass/fail categorisation by school.ResultsOn controlled video-based comparisons, inter-school variations in examiners' scoring (16.3%) were nearly double within-school variations (8.8%). Students' scores received a median adjustment of 5.26% (IQR 2.87-7.17%). The impact of adjusting for examiner differences on students' pass/fail categorisation varied by school, with adjustment reducing failure rate from 39.13% to 8.70% (school 2) whilst increasing failure from 0.00% to 21.74% (school 4).DiscussionWhilst the formative context may partly account for differences, these findings query whether variations may exist between medical schools in examiners' judgements. This may benefit from systematic appraisal to safeguard equivalence. VESCA provided a viable method for comparisons.
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A randomised phase II trial of hippocampal sparing versus conventional whole brain radiotherapy after surgical resection or radiosurgery in favourable prognosis patients with 1-10 brain metastasesAIMS: To assess in patients with 1-10 brain metastases, each of which has been treated by neurosurgery or stereotactic radiosurgery, whether hippocampal sparing whole brain radiotherapy (HS-WBRT) better spares neurocognitive function (NCF) than standard WBRT. Further, to assess whether a phase III randomised trial of HS-WBRT would be feasible in the UK. MATERIALS AND METHODS: A multicentre, randomised, open label phase II trial was undertaken, randomising patients to 30Gy in 10 fractions of WBRT or HS-WBRT. The primary endpoint was decline in Total recall using Hopkins Verbal Learning Test Revised (HVLT-R) at 4 months post treatment. To assess this, we aimed to recruit 84 patients over 3 years. Secondary endpoints included further measures of NCF, quality of life, duration of functional independence, local control of treated metastases, development of new metastases, disease control within the hippocampal regions, overall survival, steroid and antiepileptic medication requirements, and toxicity. RESULTS: The trial closed prematurely due to slower than anticipated recruitment. From April 2016 to January 2018, 23 patients were randomised. Follow up was a median of 25 months. Fifteen patients (6 WBRT, 9 HS-WBRT) were assessed for the primary endpoint; of these, 1 in each arm experienced significant decline in the 4-month HVLT-R Total recall score (p = 0.8). Patients in the HS-WBRT arm experienced less insomnia (p < 0.01) and drowsiness (p < 0.01). There were no differences in other secondary endpoints. CONCLUSION: A phase III randomised trial of HS-WBRT was shown not to be feasible at this time in the UK. As most randomised trials of HS-WBRT reported to date share common endpoints, including NCF, an individual patient data meta-analysis should be undertaken.
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Tisotumab vedotin as second- or third-line therapy for recurrent cervical cancerBackground Recurrent cervical cancer is a life-threatening disease, with limited treatment options available when disease progression occurs after first-line combination therapy. Methods We conducted a phase 3, multinational, open-label trial of tisotumab vedotin as second- or third-line therapy in patients with recurrent or metastatic cervical cancer. Patients were randomly assigned, in a 1:1 ratio, to receive tisotumab vedotin monotherapy (2.0 mg per kilogram of body weight every 3 weeks) or the investigator's choice of chemotherapy (topotecan, vinorelbine, gemcitabine, irinotecan, or pemetrexed). The primary end point was overall survival. Results A total of 502 patients underwent randomization (253 were assigned to the tisotumab vedotin group and 249 to the chemotherapy group); the groups were similar with respect to demographic and disease characteristics. The median overall survival was significantly longer in the tisotumab vedotin group than in the chemotherapy group (11.5 months [95% confidence interval {CI}, 9.8 to 14.9] vs. 9.5 months [95% CI, 7.9 to 10.7]), results that represented a 30% lower risk of death with tisotumab vedotin than with chemotherapy (hazard ratio, 0.70; 95% CI, 0.54 to 0.89; two-sided P=0.004). The median progression-free survival was 4.2 months (95% CI, 4.0 to 4.4) with tisotumab vedotin and 2.9 months (95% CI, 2.6 to 3.1) with chemotherapy (hazard ratio, 0.67; 95% CI, 0.54 to 0.82; two-sided P<0.001). The confirmed objective response rate was 17.8% in the tisotumab vedotin group and 5.2% in the chemotherapy group (odds ratio, 4.0; 95% CI, 2.1 to 7.6; two-sided P<0.001). A total of 98.4% of patients in the tisotumab vedotin group and 99.2% in the chemotherapy group had at least one adverse event that occurred during the treatment period (defined as the period from day 1 of dose 1 until 30 days after the last dose); grade 3 or greater events occurred in 52.0% and 62.3%, respectively. A total of 14.8% of patients stopped tisotumab vedotin treatment because of toxic effects. Conclusions In patients with recurrent cervical cancer, second- or third-line treatment with tisotumab vedotin resulted in significantly greater efficacy than chemotherapy. (Funded by Genmab and Seagen [acquired by Pfizer]; innovaTV 301 ClinicalTrials.gov number, NCT04697628.)
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Turning the tide in aggressive lymphoma: liquid biopsy for risk-adapted treatment strategiesDiffuse large B cell lymphoma (DLBCL) exhibits significant biological and clinical heterogeneity that presents challenges for risk stratification and disease surveillance. Existing tools for risk stratification, including the international prognostic index (IPI), tissue molecular analyses, and imaging, have limited accuracy in predicting outcomes. The therapeutic landscape for aggressive lymphoma is rapidly evolving, and there is a pressing need to identify patients at risk of refractory or relapsed (R/R) disease in the context of personalized therapy. Liquid biopsy, a minimally invasive method for cancer signal detection, has been explored to address these challenges. We review advances in liquid biopsy strategies focusing on circulating nucleic acids in DLBCL patients and highlight their clinical potential. We also provide recommendations for biomarkerguided trials to support risk-adapted treatment modalities.
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Research progress on sexual functioning and associated factors in childhood cancer survivors: a scoping reviewBackground Childhood Cancer Survivors (CCSs) are more likely to report sexual dysfunction than people without cancer history. Sexual functioning encompasses more than just sexual dysfunction. The scarcity of information regarding the status and in fl uencing factors of sexual functioning in CCSs, hampers to devise suitable screening or interventions. This review aims to summarize research progress on sexual functioning and associated factors among CCSs. Methods This review protocol is registered in PROSPERO(CRD42023427939) and performed according to PRISMA guidelines. From inception to November 15, 2023, a comprehensive search was conducted in PubMed, EMBASE, CINAHL, Web of Science, SCOPUS, PsycINFO, CNKI Database, Wanfang of Chinese Database, SinoMed Database and Cochrane Library on sexual functioning and childhood cancer survivors. Inclusion criteria were English or Chinese studies focusing on sexual functioning and related factors of cancer survivors, who diagnosed with cancer before 18 years old, and were adult and disease-free when participating in the study. Studies were excluded if the focus was on adult cancer patients or without age information. Findings 395 records were retrieved, and 22 studies were fi nally included in this review. Results suggest that CCSs experience a substantial burden of sexual issues, including delayed psychosexual development, low satisfaction, and high prevalence of dysfunction. Underlying factors related to sexual functioning of CCSs were identi fi ed, including demographic, cancer treatment-related, psychological, and physiological factors. The historical change in research on sexual functioning was summarized. Interpretation Research on sexual functioning among CCSs is limited. The extent to which cancer and related treatments affect sexual functioning remains largely unknown. The relationships between various factors and mechanisms underlying sexual functioning need to be con fi rmed by more rigorous studies to enable effective interventions to be developed. Funding None. Copyright (c) 2024 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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Empowering radiation therapists: the role of an african community of practice in developing radiation therapist education curriculumOBJECTIVES: Supported by the International Atomic Energy Agency (IAEA), the African Regional Cooperative Agreement for Research, Development and Training (AFRA) invited African Member States (MS) with a radiation therapy facility to engage in a 3-day workshop to develop a robust road map for educational standards in radiation therapist (RTT) training. The aim of the paper was to make recommendations of how the African MS could drive forward high educational standards in RTT training and education in Africa. METHODS: A pre-workshop survey was developed and sent to the participants to gather background information on each MS's national RTT training standards. An online survey was sent to all African MS with a radiation therapy facility. Two international RTT education-training experts were tasked by the IAEA to support and facilitate the workshop, which consisted of presentations and discussions around the current RTT training schemes in African MS and aspects of modern training methodology. The agenda of the workshop was structured with the aim to simulate discussions on RTT education and training standards among participants from African MS. RESULTS: Sixteen African MS completed the pre-workshop survey. The median number of radiotherapy centres within a MS was 3 (range 1--15). All MS provided two-dimensional radiation therapy services as a minimum while 75 % (12/16) MS could offer three-dimensional conformal radiation therapy service. Thirty-eight percent (6/16) reported that they had no radiation therapy machine service maintenance contracts with vendors and 56 % (9/16) MS had no biomedical engineers on site for unplanned and planned machine maintenance. The median number of RTTs at national level among MS was 23 (range 7-73). Fifty-six percent (9/16) MS had a RTT specific national training programme with 75 % (12/16) MS having clinical attachments for 6 months or more. Representatives from 12 African MS attended the AFRA workshop. An African Community of Practice (CoP) in developing Education Curriculum for RTT was established as an outcome of the workshop with the aim to facilitate knowledge exchange and drive quality initiatives among participating African MS. Four work streams were proposed to form the CoP: RTT academic qualifications, core competencies in RTT education and training, RTT education faculty composition and peer review process in RTT education curricula among African MS. CONCLUSION: By fostering collaboration, sharing knowledge, and advocating for improved policies, the African COP in developing Education Curriculum for RTT can make significant strides toward developing a RTT education curriculum that not only meets the unique challenges of the African continent but also aligns with global standards.
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Preoperative chemotherapy response and survival in patients with colorectal cancer peritoneal metastasesTreatment guidelines provided by PRODIGE-7 recommend perioperative systemic chemotherapy before cytoreductive surgery (CRS) for colorectal cancer peritoneal metastases (CRPM). Toxicity with multimodal treatment needs to be better defined. Chemotherapy response and impact on survival have not been reported. We assessed CRPM patients who received systemic oxaliplatin/irinotecan before CRS (preoperative) with Mitomycin C (35 mg/m2, 90 min) or Oxaliplatin (368 mg/m2, 30 min) heated intraperitoneal chemotherapy (HIPEC). Secondary analysis was performed from a prospective database. Overall survival (OS) in chemotherapy responders (R) and nonresponders (NR) was compared. Toxicity was assessed by rate of adverse events (AEs). From April 2005 to April 2021, 436 patients underwent CRS + HIPEC; 125 (29%) received preoperative chemotherapy. The 112 (90%) received oxaliplatin (64, 57%) or irinotecan (48, 43%). R, defined as complete (CR) or partial response on preoperative imaging and/or postoperative histology, was seen in 71, 63% (53.8-72.3); 16, 14% (8.4-22.2) had CR. Median OS in R versus NR was 43.7 months (37.9-49.4) versus 23.9 (16.3-31.4) p = 0.007, HR 0.51 (0.31-0.84). OS multivariable analysis showed HR 0.48 (0.25-0.95), p = 0.03 for chemotherapy response corrected by peritoneal cancer index, completeness of cytoreduction score. CRS led to 21% grade 3-4 AEs versus 4% for preoperative chemotherapy. HIPEC grade 3-4 AEs were 0.5%. Preoperative chemotherapy response is an independent predictor for OS in CRPM. Perioperative chemotherapy is used in the multimodal treatment of colorectal cancer peritoneal metastases (CRPM). Preoperative chemotherapy response is an independent predictor for overall survival in patients with CRPM. Grade 3-4 adverse events related to mitomycin C (35 mg/m2) and Oxaliplatin (368 mg/m2) heated intraperitoneal chemotherapy are rare (0.5%).
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CRISPR-Cas9 potential for identifying novel therapeutic targets in muscle-invasive bladder cancerGene editing technologies help identify the genetic perturbations driving tumour initiation, growth, metastasis and resistance to therapeutics. This wealth of information highlights tumour complexity and is driving cancer research towards precision medicine approaches based on an individual's tumour genetics. Bladder cancer is the 11th most common cancer in the UK, with high rates of relapse and low survival rates in patients with muscle-invasive bladder cancer (MIBC). MIBC is highly heterogeneous and encompasses multiple molecular subtypes, each with different responses to therapeutics. This evidence highlights the need to identify innovative therapeutic targets to address the challenges posed by this heterogeneity. CRISPR-Cas9 technologies have been used to advance our understanding of MIBC and determine novel drug targets through the identification of drug resistance mechanisms, targetable cell-cycle regulators, and novel tumour suppressor and oncogenes. However, the use of these technologies in the clinic remains a substantial challenge and will require careful consideration of dosage, safety and ethics. CRISPR-Cas9 offers considerable potential for revolutionizing bladder cancer therapies, but substantial research is required for validation before these technologies can be used in the clinical setting. In this Perspective, the authors provide an overview of current research using CRISPR-Cas gene editing technologies to understand biological mechanisms and identify novel therapeutic targets in muscle-invasive bladder cancer. Future perspectives about the use of CRISPR-based therapeutics in the clinic, as well as current limitations and ethical considerations, are also discussed.
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Improved outcome of COVID-19 over time in patients treated with CAR T-cell therapy: update of the european COVID-19 multicenter study on behalf of the european society for blood and marrow transplantation (EBMT) infectious diseases working party (IDWP) and the european hematology association (EHA) lymphoma groupCOVID-19 has been associated with high mortality in patients treated with Chimeric Antigen Receptor (CAR) T-cell therapy for hematologic malignancies. Here, we investigated whether the outcome has improved over time with the primary objective of assessing COVID-19-attributable mortality in the Omicron period of 2022 compared to previous years. Data for this multicenter study were collected using the MED-A and COVID-19 report forms developed by the EBMT. One-hundred-eighty patients were included in the analysis, 39 diagnosed in 2020, 35 in 2021 and 106 in 2022. The median age was 58.9 years (min-max: 5.2-78.4). There was a successive decrease in COVID-19-related mortality over time (2020: 43.6%, 2021: 22.9%, 2022: 7.5%) and in multivariate analysis year of infection was the strongest predictor of survival (p = 0.0001). Comparing 2022 with 2020-2021, significantly fewer patients had lower respiratory symptoms (21.7% vs 37.8%, p = 0.01), needed oxygen support (25.5% vs 43.2%, p = 0.01), or were admitted to ICU (5.7% vs 33.8%, p = 0.0001). Although COVID-19-related mortality has decreased over time, CAR T-cell recipients remain at higher risk for complications than the general population. Consequently, vigilant monitoring for COVID-19 in patients undergoing B-cell-targeting CAR T-cell treatment is continuously recommended ensuring optimal prevention of infection and advanced state-of-the art treatment when needed.
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An app promoting weight gain prevention via healthy behaviours amongst young women with a family history of breast cancer: acceptability and usability assessmentBackground Breast cancer is the most frequent female malignancy in the UK. Around 20% of cases are linked to weight gain, excess weight and health behaviours. We designed a weight gain prevention, health behaviour intervention for young women at increased risk. Methods The study comprised a single arm observational study over 2 months testing acceptability and usability of the intervention: online group welcome event, app and private Facebook group. Females aged 18-35 years at moderate or high risk of breast cancer (>17% lifetime risk) were recruited via invite letters and social media posts. The app included behaviour change techniques and education content. Online questionnaires were completed at baseline, as well as at 1 and 2 months. We also assessed feasibility of study procedures. Results Both recruitment methods were successful. Thirty-five women were recruited, 26% via social media posts. Median age was 33 (interquartile range = 28.2-34.5) years, the majority (94.1%) were of White ethnicity. Thirty-four participants were included in the analyses, of which 94% downloaded the app. Median self-monitoring logs per participant during the study period was 10.0 (interquartile range = 4.8-28.8). App quality mean (SD) score was 3.7 (0.6) at 1 and 2 months (scale: 1-5). Eighty-nine per cent rated the app at average or above at 1 month and 75.0% at 2 months. Nineteen women (55.9%) joined the Facebook group and there were 61 comments and 83 reactions and votes from participants during the study period. Conclusions This first iteration of the app and intervention was well received and is suitable to progress to the next stage of refining and further testing.
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Does IPSS-R downstaging before transplantation improve the prognosis of patients with myelodysplastic neoplasms?In patients with myelodysplastic syndrome (MDS), higher revised International Prognostic Scoring System (IPSS-R) scores at transplant are associated with worse transplant outcome and, thus, lowering IPSS-R scores by therapeutic intervention before transplantation may seem beneficial. fi cial. However, there is no evidence, to date, to support this approach. In a retrospective analysis, a total of 1482 patients with MDS with sufficient fi cient data to calculate IPSS-R score at diagnosis and at time of transplantation were selected from the European Society for Blood and Marrow Transplantation transplant registry and analyzed for transplant outcome in a multivariable Cox model including IPSS-R score at diagnosis, treatment intervention, change in IPSS-R score before transplant, and several patient and transplant variables. Transplant outcome was unaffected by IPSS-R score change in untreated patients and moderately superior in patients treated with chemotherapy with improved IPSS-R score at transplant. Improved IPSS-R score after hypomethylating agents (HMAs) or other therapies showed no beneficial fi cial effect. However, when IPSS-R score progressed after chemotherapy, HMAs, or other therapies, transplant outcome was worse than without any prior treatment. Similar results were found when reduction or increase in bone marrow (BM) blasts between diagnosis and transplantation was considered. The results show a limited benefit fi t of IPSS-R score downstaging or reduction of BM blasts after chemotherapy and no benefit fi t for HMAs or other treatments and thus question the role of prior therapy in patients with MDS scheduled for transplantation. The model-based survival estimates should help inform decision-making for both doctors and patients.
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Examining the effectiveness of electronic patient-reported outcomes in people with cancer: systematic review and meta-analysisBackground: Electronic patient-reported outcomes (ePROs) are commonly used in oncology clinical practice and have shownbenefits for patients and health resource use.Objective: The aim of this study was to compare the isolated effect of administering ePROs to patients with cancer versus acontrol condition.Methods: The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines were followed.Randomized controlled trials evaluating ePRO interventions that aimed to improve health-related outcomes among patients withcancer were included. The primary outcome was health-related quality of life (HRQOL), and the secondary outcomes weresymptoms, hospital admissions, unplanned visits, chemotherapy completion, survival, and satisfaction with care. The effect sizesof ePROs on health-related outcomes were analyzed as standardized mean differences (SMDs) with 95% CIs using a randomeffects model.Results: The search identified 10,965 papers, of which 19 (0.17%) from 15 studies were included. The meta-analysis showedan improvement in HRQOL at 3 months, measured by the Functional Assessment of Cancer Therapy-General (SMD 0.28, 95%CI -1.22 to 1.78), and at 6 months, assessed using various HRQOL measures (SMD 0.07, 95% CI -1.24 to 1.39). The resultsshould be interpreted with caution, given the wide 95% CIs. Of the 15 studies, 9 (60%) reported a positive signal on HRQOL,with two-thirds of the studies (n=6, 67%) including tailored patient advice and two-thirds (n=6, 67%) using clinician alert systems.Conclusions: The meta-analysis showed a potential improvement in HRQOL at 6 months and in Functional Assessment ofCancer Therapy-General scores at 3 months for studies that included tailored advice and clinician alerts, suggesting that theseelements may improve ePRO effectiveness. The findings will provide guidance for future use and help health care professionalschoose the most suitable ePRO features for their patients
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Standard or high dose chemoradiotherapy, with or without the protease inhibitor nelfinavir, in patients with locally advanced pancreatic cancer: the phase 1/randomised phase 2 SCALOP-2 trialBACKGROUND: The multi-centre two-stage SCALOP-2 trial (ISRCTN50083238) assessed whether dose escalation of consolidative chemoradiotherapy (CRT) or concurrent sensitization using the protease inhibitor nelfinavir improve outcomes in locally advanced pancreatic cancer (LAPC) following four cycles of gemcitabine/nab-paclitaxel. METHODS: In stage 1, the maximum tolerated dose (MTD) of nelfinavir concurrent with standard-dose CRT (50.4 Gy in 28 fractions) was identified from a cohort of 27 patients. In stage 2, 159 patients were enrolled in an open-label randomized controlled comparison of standard versus high dose (60 Gy in 30 fractions) CRT, with or without nelfinavir at MTD. Primary outcomes following dose escalation and nelfinavir use were respectively overall survival (OS) and progression free survival (PFS). Secondary endpoints included health-related quality of life (HRQoL). RESULTS: High dose CRT did not improve OS (16.9 (60 % confidence interval, CI 16.2-17.7) vs. 15.6 (60 %CI 14.3-18.2) months; adjusted hazard ratio, HR 1.13 (60 %CI 0.91-1.40; p = 0.68)). Similarly, median PFS was not improved by nelfinavir (10.0 (60 %CI 9.9-10.2) vs. 11.1 (60 %CI 10.3-12.8) months; adjusted HR 1.71 (60 %CI 1.38-2.12; p = 0.98)). Local progression at 12 months was numerically lower with high-dose CRT than with standard dose CRT (n = 11/46 (23.9 %) vs. n = 15/45 (33.3 %)). Neither nelfinavir nor radiotherapy dose escalation impacted on treatment compliance or grade 3/4 adverse event rate. There were no sustained differences in HRQoL scores between treatment groups over 28 weeks post-treatment. CONCLUSIONS: Dose-escalated CRT may improve local tumour control and is well tolerated when used as consolidative treatment in LAPC but does not impact OS. Nelfinavir use does not improve PFS.
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Repeated hyperarc radiosurgery for recurrent intracranial metastases and dosimetric analysis of recurrence pattern to account for diffuse dose effect on microscopical diseaseAIMS: Evaluate effectiveness and safety of multiple HyperArc courses and patterns of progression in patients affected by BMs with intracranial progression. METHODS: 56 patients were treated for 702 BMs with 197 (range 2-8) HyperArc courses in case of exclusive intracranial progression. Primary end-point was the overall survival (OS), secondary end-points were intracranial progression-free survival (iPFS), toxicity, local control (LC), neurological death (ND), and whole-brain RT (WBRT)-free survival. Site of progression was evaluated against isodoses levels (0, 1, 2, 3, 5, 7, 8, 10, 13, 15, 20, and 24 Gy.). RESULTS: The 1-year OS was 70 %, and the median was 20.8 months (17-36). At the univariate analysis (UVA) biological equivalent dose (BED) > 51.3 Gy and non-melanoma histology significantly correlated with OS. The median time to iPFS was 4.9 months, and the 1-year iPFS was 15 %. Globally, 538 new BMs occurred after the first HA cycle in patients with extracranial disease controlled. 96.4 % of them occurred within the isodoses range 0-7 Gy as follows: 26.6 % (0 Gy), 16.5 % (1 Gy), 16.5 % (2 Gy), 20.1 % (3 Gy), 13.1 % (5 Gy), 3.4 % (7 Gy) (p = 0.00). Radionecrosis occurred in 2 metastases (0.28 %). No clinical toxicity of grade 3 or higher occurred during follow-up. One- and 2-year LC was 90 % and 79 %, respectively. At the UVA BED > 70 Gy and non-melanoma histology were significant predictors of higher LC. The 2-year WBRT-free survival was 70 %. After a median follow-up of 17.4 months, 12 patients deceased by ND. CONCLUSION: Intracranical relapses can be safely and effectively treated with repeated HyperArc, with the aim to postpone or avoid WBRT. Diffuse dose by volumetric RT might reduce microscopic disease also at relatively low levels, potentially acting as a virtual CTV. Neurological death is not the most common cause of death in this population, which highlights the impact of extracranial disease on overall survival.
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State of the art modelling of the breast cancer metastatic microenvironment: where are we?Metastatic spread of tumour cells to tissues and organs around the body is the most frequent cause of death from breast cancer. This has been modelled mainly using mouse models such as syngeneic mammary cancer or human in mouse xenograft models. These have limitations for modelling human disease progression and cannot easily be used for investigation of drug resistance and novel therapy screening. To complement these approaches, advances are being made in ex vivo and 3D in vitro models, which are becoming progressively better at reliably replicating the tumour microenvironment and will in the future facilitate drug development and screening. These approaches include microfluidics, organ-on-a-chip and use of advanced biomaterials. The relevant tissues to be modelled include those that are frequent and clinically important sites of metastasis such as bone, lung, brain, liver for invasive ductal carcinomas and a distinct set of common metastatic sites for lobular breast cancer. These sites all have challenges to model due to their unique cellular compositions, structure and complexity. The models, particularly in vivo, provide key information on the intricate interactions between cancer cells and the native tissue, and will guide us in producing specific therapies that are helpful in different context of metastasis.
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Comparison between patient characteristics, aetiology and outcomes in patients with and without cirrhosis with hepatocellular carcinoma diagnosed in a regional centreIntroduction Hepatocellular carcinoma (HCC) is increasing in incidence across the UK. Most patients have underlying cirrhosis, but a significant minority do not. Progression and outcomes of HCC in patients without cirrhosis remains unclear. This study aimed to establish the proportion and characteristics of patients with HCC occurring in those with and without cirrhosis in the West of Scotland.Introduction Hepatocellular carcinoma (HCC) is increasing in incidence across the UK. Most patients have underlying cirrhosis, but a significant minority do not. Progression and outcomes of HCC in patients without cirrhosis remains unclear. This study aimed to establish the proportion and characteristics of patients with HCC occurring in those with and without cirrhosis in the West of Scotland.Methods Data were collected from our prospectively collected database on patient demographics, liver disease aetiology, stage at presentation and outcomes for patients with a diagnosis of HCC confirmed at the Regional West of Scotland multidisciplinary team from 2009 to 2015.Results 638 patients were included. 138 (21.6%) did not have cirrhosis and were older at diagnosis than those with cirrhosis (72 years vs 68 years, p=0.001). A higher proportion of those without cirrhosis presented with more advanced HCC (Barcelona clinic liver cancer (BCLC) score B or above; p=0.003). Patients with cirrhosis had median survival of 8 months, compared with those without cirrhosis (11.5 months) but survival was similar in both groups on Kaplan-Meier analysis (p=0.119). There was no difference in survival between these groups when adjusted for cancer stage. Survival was influenced by BCLC score in both cirrhotic and non-cirrhotic groups, as was survival by Child-Pugh score in patients with cirrhosis. Among the patients who underwent transarterial chemoembolisation (TACE), those with cirrhosis had worse survival (p=0.044).Results 638 patients were included. 138 (21.6%) did not have cirrhosis and were older at diagnosis than those with cirrhosis (72 years vs 68 years, p=0.001). A higher proportion of those without cirrhosis presented with more advanced HCC (Barcelona clinic liver cancer (BCLC) score B or above; p=0.003). Patients with cirrhosis had median survival of 8 months, compared with those without cirrhosis (11.5 months) but survival was similar in both groups on Kaplan-Meier analysis (p=0.119). There was no difference in survival between these groups when adjusted for cancer stage. Survival was influenced by BCLC score in both cirrhotic and non-cirrhotic groups, as was survival by Child-Pugh score in patients with cirrhosis. Among the patients who underwent transarterial chemoembolisation (TACE), those with cirrhosis had worse survival (p=0.044).Results 638 patients were included. 138 (21.6%) did not have cirrhosis and were older at diagnosis than those with cirrhosis (72 years vs 68 years, p=0.001). A higher proportion of those without cirrhosis presented with more advanced HCC (Barcelona clinic liver cancer (BCLC) score B or above; p=0.003). Patients with cirrhosis had median survival of 8 months, compared with those without cirrhosis (11.5 months) but survival was similar in both groups on Kaplan-Meier analysis (p=0.119). There was no difference in survival between these groups when adjusted for cancer stage. Survival was influenced by BCLC score in both cirrhotic and non-cirrhotic groups, as was survival by Child-Pugh score in patients with cirrhosis. Among the patients who underwent transarterial chemoembolisation (TACE), those with cirrhosis had worse survival (p=0.044).Conclusion 21.6% of patients with a new diagnosis of HCC in our region did not have underlying cirrhosis. Patients with non-cirrhotic HCC were diagnosed at an older age, with more advanced stage of HCC. There was no difference in overall survival between patients with HCC with and without cirrhosis, however, survival after TACE was higher in those without cirrhosis.
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ALDH1A3-acetaldehyde metabolism potentiates transcriptional heterogeneity in melanomaCancer cellular heterogeneity and therapy resistance arise substantially from metabolic and transcriptional adaptations, but how these are interconnected is poorly understood. Here, we show that, in melanoma, the cancer stem cell marker aldehyde dehydrogenase 1A3 (ALDH1A3) forms an enzymatic partnership with acetyl-coenzyme A (CoA) synthetase 2 (ACSS2) in the nucleus to couple high glucose metabolic flux with acetyl-histone H3 modification of neural crest (NC) lineage and glucose metabolism genes. Importantly, we show that acetaldehyde is a metabolite source for acetyl-histone H3 modification in an ALDH1A3-dependent manner, providing a physiologic function for this highly volatile and toxic metabolite. In a zebrafish melanoma residual disease model, an ALDH1-high subpopulation emerges following BRAF inhibitor treatment, and targeting these with an ALDH1 suicide inhibitor, nifuroxazide, delays or prevents BRAF inhibitor drug-resistant relapse. Our work reveals that the ALDH1A3-ACSS2 couple directly coordinates nuclear acetaldehyde-acetyl-CoA metabolism with specific chromatin-based gene regulation and represents a potential therapeutic vulnerability in melanoma.