The Christie School of Oncology: Christie Research Publications Repository
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Science, Quality and Value of Laboratory Medicine
No full textThe Meeting on Science, Quality and Value of Laboratory Medicine was held on 11 December 2025 in Padua, immediately preceding the 7th European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) Conference on the Preanalytical Phase. For organizational reasons, the meeting was structured in two parts, with the first held in December 2025 and the second scheduled for early 2026. The initiative, designed to better steer and promote the activities of all EFLM Committees and Divisions, represents a pivotal step toward overcoming fragmentation and silo-based cultures. By fostering a holistic vision that captures interactions among all EFLM Functional Units, the meeting supported the translation of value-based laboratory medicine principles into real-world practice. This collective opinion paper summarizes the lectures presented at the meeting, providing an overview of ongoing EFLM projects and future developments in value-based laboratory medicine. Importantly, the meeting also generated significant opportunities for collaboration and shared project development, underscoring the transition from isolated activities to a collaborative, value-driven approach
Exploring perceptual disparities: a study on the level of understanding of colorectal cancer care among patients and healthcare professionals
No full textBackground Emotional engagement, family support and personal beliefs can influence how patients and healthcare professionals (HCPs) perceive cancer differently. This study examined the extent to which the views of patients and HCPs on cancer care align, and identified factors that may underlie disparities. Methods Participants with colorectal cancer (CRC) were asked to describe their perception of their disease (i.e. whether they felt it was under control (DC), was progressing (PD), or was of an unknown status) and to complete psychometric assessments of anxiety, depression, PTSD and well-being. Two HCPs, who were blinded to the patients' responses, examined the case files to determine the stage of treatment at which the patients were enrolled in the study. The concordance of perceptions between patients and HCPs was examined, along with associations with clinical variables and psychometric health outcomes, using both univariate and multivariate analyses. Results A total of 205 patients with CRC were included in the study. The mean age was 65 years, with 58% of patients being male. Overall, a significant difference in perception was observed between HCPs and patients (p < 0.001), particularly for patients identified by HCPs as having PD. Significant discrepancies were observed among patients receiving palliative care (p < 0.001), whereas those in the adjuvant or neo-adjuvant pathway appeared to align more closely with HCPs' perceptions (p = 0.99). Neither demographic nor psychological factors were significant determinants of concordance between HCPs and patients' understanding of cancer status in this population. In multivariate analysis, patients perceiving PD or expressing uncertainty were found to have significantly higher levels of depression than those with DC (OR 6.42, p = 0.001 and OR 3.86, p = 0.009, respectively). Conclusions This study reveals significant differences in how cancer is perceived by HCPs and patients, particularly among those without disease control or undergoing palliative care. This highlights the importance of effective communication in addressing patients' needs and their psychological well-being
The Prognostic and Predictive Impact of ctDNA Levels in Patients with Advanced Breast Cancer Enrolled on the plasmaMATCH Trial
No full textPurpose: ctDNA dynamic levels may identify patients who will respond to therapy. We assessed ctDNA baseline levels and on-treatment dynamics in patients with advanced breast cancer on the plasmaMATCH trial with mutation-targeted therapies (cohorts A-D) and triple-negative breast cancer on olaparib and ceralasertib combination (cohort E).Experimental Design: Blood samples were collected at baseline [cycle 1 day 1 (C1D1)] and before treatment on cycle 2 day 1 (C2D1). Samples were sequenced using error-corrected targeted panels (Guardant360/GuardantOMNI). Circulating DNA ratio was calculated as the ratio of C2D1/C1D1 circulating DNA ratio, and baseline ctDNA levels were associated with progression-free survival (PFS) and confirmed objective response rates (ORR).Results: A total of 167 patients had assessable C1D1-C2D1 ctDNA results. There was a strong association between baseline ctDNA levels and response in cohort E; low baseline levels were associated with longer PFS (HR, 0.33; P = 0.001) and higher ORR (40% vs. 9.7%; P = 0.02). In cohorts A to D, there was a weaker association with PFS (HR, 0.60; P = 0.03) and ORR (15.2% vs. 5.7%; P = 0.17). Associations of baseline ctDNA level and ORR were validated in the independent PEARL study. For on-treatment dynamics, suppression of ctDNA below median was predictive in cohorts A to D (HR, 0.47; P = 0.001) but not in cohort E (HR, 1.02; P = 0.94). Undetectable ctDNA levels at C2D1 were associated with good outcomes in both cohorts: in cohort E with improved PFS (HR, 0.25; P = 0.01) and improved ORR (86% vs. 11%; P = 0.01). Six of seven patients with undetectable on-treatment ctDNA were BRCA1/BRCA2/PALB2 wild type.Conclusions: Baseline low ctDNA levels predict response to targeted therapy, potentially suggesting shared mechanisms between high ctDNA release and resistance to therapy. Both baseline ctDNA levels and on-treatment dynamics are a promising surrogate endpoint for drug development, with clearance of ctDNA being a robust cross-therapy surrogate for outcomes
Multizonal intraepithelial neoplasia of the lower genital tract and anus in women: terminology for defining the disease, an introduction by the British Society for Colposcopy and Cervical Pathology (BSCCP), International Anal Neoplasia Society (IANS), European Federation for Colposcopy (EFC) and British Society for the Study of Vulval Disease (BSSVD) scientific committees
No full textMultizonal anogenital intraepithelial neoplasia (MZIN) is an uncommon chronic pre-malignant condition. In the United Kingdom (UK) and elsewhere MZIN is managed by a variety of clinical specialities with differing strategies, resulting in a lack of standardisation in diagnosis and treatment which ultimately disadvantages those affected. Screening for anogenital precancerous conditions is sporadic rather than nationalised in the UK and elsewhere in Europe, with the exception of the cervix. To address this lack of standardisation, the BSCCP brought together a panel of stakeholders from aligned expert society committees (IANS, EFC and BSSVD) to review existing evidence and provide a framework for national UK guidelines. Here, we define terminology and scope, as a platform for subsequent guideline development and guide further research. We define MZIN as Human Papillomavirus (HPV)-related squamous intraepithelial lesions occurring in two or more anogenital regions. People with MZIN are a high-risk group for anogenital cancers and subsequently may require tailored monitoring in specialist multi-disciplinary clinics. Centralisation of care and education for primary care providers may improve management. The development of guidelines which incorporate all clinical stakeholders are now needed to provide an international framework regarding the screening, diagnosis, treatment and future prevention of MZIN
Development of a core outcome set for adolescents and young adults with cancer
No full textAdolescents and young adults aged 15-39 years diagnosed with cancer are faced with unique challenges, which affect key developmental milestones and can create complex care needs. The aim of this study was to reach international consensus on the minimum set of outcomes to measure through the development of a core outcome set (COS). The COS development followed published methodological standards. A literature review and interviews with adolescents and young adults with cancer and health-care professionals generated a comprehensive list of 129 outcomes, spanning clinical and patient-reported outcomes relevant to adolescents and young adults with cancer. A three-round online Delphi survey involving three stakeholder groups globally, was implemented to reach international consensus. Overall, 262 respondents participated in the Delphi survey and 126 (481%) completed three survey rounds. 59 outcomes met consensus in round 3 and were taken forward to the consensus meeting. The final COS consists of 20 outcomes, including two on-treatment specific domains and three off-treatment specific domains. This study developed an adolescents and young adult-specific COS that, when implemented in clinical care and research, will improve the relevance of research findings, enhance care delivery, and enable consistent data synthesis across studies. Future efforts will focus on refining measurement methods and ensuring global applicability
Distant recurrence and margin involvement in invasive breast cancer: Clinical Studies
No full textThe effect of involved margins after breast cancer surgery on distant recurrence (DR) is unknown. We determined the association between margin width or involvement, DR and cancer deaths. PATIENTS AND METHODS: Greater Manchester (GM) and the National Cancer Registry (NCRAS) cohorts were analysed. Margin status after curative surgery was measured. Cox-proportional hazards investigated factors associated with LR, DR and breast cancer deaths. RESULTS: In GM (2010-2014), 2295 (70.2%) patients had clear margins (>2 mm), 302 (9.2%) close (1-2 mm) and 673 (20.6%) involved (1 mm. After BCS, in 5246 patients who underwent chemotherapy after BCS, involved margins 1 mm were associated with lower DR and cancer deaths. Guidelines should recommend a minimum margin clearance of 1 mm
Phase I trial of ADP-A2AFP TCR T-cell therapy in patients with advanced hepatocellular or gastric hepatoid carcinoma
No full textBackground & Aims: Patients with advanced hepatocellular carcinoma (HCC) generally experience poor outcomes despite current therapies, necessitating the development of alternative treatments. ADP-A2AFP is an investigational autologous T-cell therapy with an affinity-enhanced T-cell receptor (TCR) targeting alpha-fetoprotein (AFP). Methods: We describe a phase I, open-label, first-in-human clinical trial of ADP-A2AFP (NCT03132792) in human leukocyte antigen-eligible participants with AFP-expressing HCC (or other tumor) not amenable to transplant/resection who progressed on, were intolerant to, or refused prior systemic therapy. Participants received lymphodepletion chemotherapy (cyclophosphamide 500 mg/m(2)/day for 3 days and fludarabine 20 mg/m(2)/day for 3 days, or cyclophosphamide 600 mg/m(2)/day for 3 days and fludarabine 30 mg/m(2)/day for 4 days) followed by ADP-A2AFP intravenous infusion. Safety evaluation was the primary objective; response per RECIST v1.1 was the key secondary endpoint. Results: Twenty-one participants, 20 with advanced HCC and one with gastric hepatoid carcinoma received >-1 ADP-A2AFP infusion. All participants experienced >-1 grade 3 or higher adverse event; 52.4% experienced >-1 grade 3 or higher event considered related to ADP-A2AFP treatment. Six participants experienced cytokine release syndrome (grade 1-2: n = 5; grade 4: n = 1). Best overall responses were complete response (n = 1), partial response (n = 1), and stable disease (n = 12); overall response rate was 9.5%. Eight patients had a stable disease duration of >-16 weeks. Infiltration of ADP-A2AFP TCR and CD8+ T cells was seen in AFP-positive areas of post-treatment tumor samples. A relationship was demonstrated between increased ADP-A2AFP dose and serum AFP reduction in responders. Conclusions: Lymphodepletion chemotherapy followed by ADP-A2AFP TCR T-cell therapy showed a manageable safety profile and preliminary indications of antitumor activity in these previously treated patients. Clinicaltrials.gov Number: NCT03132792; first posted 2017-04-08
Are the CTV-to-PTV margins currently used in online adaptive radiotherapy for prostate cancer too large? The impact of the distribution of microscopic disease on treatment margin requirements
No full textPurpose Planning target volume (PTV) margin recipes assume all parts of the target are equally important. For the prostate clinical target volume (CTV) this is invalid. We evaluated the impact of the spatial probability distribution of microscopic disease in the prostate on CTV-to-PTV margins. Materials and methods A prostate with a volume of 44 cm(3) was defined as CTVprostate. Homogenous dose distributions were created with margins ranging 0-5 mm. The gross tumor volume (GTV) was assumed covered with a separate margin. Microscopic satellites were sampled within the CTVprostate from a histopathology-based probability distribution for a range of numbers (1-10) and sizes (0.02-0.2 cm(3)) to define CTVsatellites. Geometric errors were sampled from a 3D Gaussian distribution, simulating online adaptive treatment of 5 fractions. Each CTV was shifted with respect to the dose according to each total error. The PTV margin ensuring 95 % of the prescribed dose to the CTVsatellites in 90 % of simulations was determined and compared with CTVprostate. Results For systematic errors with width (Sigma) 0.5 mm and random errors with width (sigma(r)) 1.5 mm, the margin for the CTVprostate was 3 mm, whereas for each definition of CTVsatellites this margin was 0-1 mm. For sigma(r) = 2.7 mm, a margin of 5 mm was adequate for the CTVprostate and 2-3 mm for all except the most favourable and unfavourable CTVsatellites definition. Conclusion The CTV-to-PTV margins used in online adaptive radiotherapy for prostate cancer can be reduced by similar to 2 mm, if the GTV is covered with an adequate margin
A phase 1, first-in-human, dose escalation study of JNJ-80038114, a PSMAxCD3 bispecific antibody, in participants with metastatic castration-resistant prostate cancer
No full textPurposeProstate-specific membrane antigen (PSMA) has been identified as a therapeutic target for metastatic castration-resistant prostate cancer (mCRPC). The recent success of radioligands targeting PSMA spurred development of new PSMA-targeting agents including immunotherapy. JNJ-80038114 is a bispecific antibody that binds PSMA on tumor cells and CD3 on T cells to induce anti-tumor activity.MethodsThis was a phase 1, open-label, multicenter study of JNJ-80038114 in participants with mCRPC and >= 1 prior systemic therapy. JNJ-80038114 was administered subcutaneously every 3 weeks (Q3W), starting at 0.1 mg. The primary endpoint was safety. Secondary endpoints included pharmacokinetics (PK), immunogenicity, and prostate-specific antigen (PSA).ResultsAt final analysis, 39 participants received 0.1-180 mg JNJ-80038114 across 11 dose-escalation cohorts for a median of 9.3 weeks (range, 0.1-31.1). The most common treatment-related adverse events (TRAEs; >= 20%) included cytokine release syndrome (CRS, 51.3%, all Grade 1-2), injection-site reactions (46.2%), and fatigue (30.8%). Related Grade >= 3 TRAEs occurred in 51.3% of participants; dose-limiting toxicities occurred in 3 (7.7%). Four participants (10.3%) developed clinically significant neuropathies. In 37 PK-evaluable participants, mean exposure (Cmax, AUC) increased with increasing doses. Anti-drug antibodies (ADA) were reported in 56.8% (21/37) participants. One participant had confirmed PSA decrease >= 50%. Three participants had radiological responses in the context of rapidly rising PSA. Following a review of data, the study was terminated.ConclusionsThis first-in-human study of JNJ-80038114 was discontinued early due to its lack of preliminary clinical activity, neurologic toxicities, high rates of CRS, and the development of ADAs impacting PK.Clinicaltrial.Gov informationNCT05441501, Registered July 1, 2022
Cell therapy in sarcoma: current landscape and future directions
No full textSarcomas are rare malignancies of mesenchymal origin, characterized by significant biological and clinical heterogeneity. Many subtypes demonstrate limited sensitivity to standard systemic treatments, including immune checkpoint inhibitors. Cell therapy has emerged as a promising strategy, with the potential of durable clinical responses seen with genetically-engineered T-cell receptor T-cell therapies (TCR-T) such as those targeting the cancer-testis antigen MAGE-A4 in synovial sarcoma, leading to the US Food and Drug Administration approval of afamitresgene autoleucel in 2024. This constituted only the second approval of a cell therapy in a solid tumor following lifileucel in melanoma and demonstrated the potential of cell therapies in sarcomas. This review provides the current landscape and growing potential of cell therapies in sarcomas, including TCR-T, chimeric antigen receptor-T cells, tumor-infiltrating lymphocytes, natural killer (NK) cells, and mesenchymal stromal cells. However, the broader application of these therapies is hindered by the lack of targetable sarcoma-restricted immunogenic epitopes, spatiotemporal intratumoral heterogeneity, and a profoundly immunosuppressive tumor microenvironment that impedes effector-cell trafficking, expansion and persistence. While cell therapies hold promise for integration into precision medicine approaches for sarcomas, their successful implementation will require careful evaluation of clinical feasibility, logistical considerations and cost-effectiveness to optimize patient outcomes