The Christie School of Oncology: Christie Research Publications Repository
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Nucleophosmin supports WNT-driven hyperproliferation and tumor initiation
No full textNucleophosmin (NPM1), a nucleolar protein frequently mutated in hematopoietic malignancies, is overexpressed in several solid tumors with poorly understood functional roles. Here, we demonstrate that Npm1 is upregulated after APC loss in WNT-responsive tissues and supports WNT-driven intestinal and liver tumorigenesis. Mechanistically, NPM1 loss induces ribosome pausing and accumulation at the 5'-end of coding sequences, triggering a protein synthesis stress response and p53 activation, which mediate this antitumorigenic effect. Collectively, our data identify NPM1 as a critical WNT effector that sustains WNT-driven hyperproliferation and tumorigenesis by attenuating the integrated stress response and p53 activation. Notably, NPM1 expression correlates with elevated WNT signaling and proliferation in human colorectal cancer (CRC), while CRCs harboring NPM1 deletions exhibit preferential TP53 inactivation, underscoring the clinical relevance of our findings. Being dispensable for adult epithelial homeostasis, NPM1 represents a promising therapeutic target in p53-proficient WNT-driven tumors, including treatment-refractory KRAS-mutant CRC, and hepatic cancers
Translating the machine; an assessment of clinician understanding of ophthalmological artificial intelligence outputs
No full textINTRODUCTION: Advances in artificial intelligence offer the promise of automated analysis of optical coherence tomography (OCT) scans to detect ocular complications from anticancer drug therapy. To explore how such AI outputs are interpreted in clinical settings, we conducted a survey-based interview study with 27 clinicians -comprising 10 ophthalmic specialists, 10 ophthalmic practitioners, and 7 oncologists. Participants were first introduced to core AI concepts and realistic clinical scenarios, then asked to assess AI-generated OCT analyses using standardized Likert-scale questions, allowing us to gauge their understanding, trust, and readiness to integrate AI into practice. METHODS: We developed a questionnaire through literature review and consultations with ophthalmologists, computer scientists, and AI researchers. A single investigator interviewed 27 clinicians across three specialties and transcribed their responses. Data were summarized as medians (ranges) and compared with Mann-Whitney U tests (α = 0.05). RESULTS: We noted important differences in the impact of various explainability methods on trust, depending on the clinical or AI scenario nature and the staff expertise. Explanations of AI outputs increased trust in the AI algorithm when outputs simply reflected ground truth expert opinion. When clinical scenarios were complex with incorrect AI outcomes, a mixed response to explainability led to correctly reduced trust in experienced clinicians but mixed feedback amongst less experienced clinicians. All clinicians had a general consensus on lack of current knowledge in interacting with AI and desire more training. CONCLUSIONS: Clinicians' trust in AI algorithms are affected by explainability methods and factors, including AI's performance, personal judgments and clinical experience. The development of clinical AI systems should consider the above and these responses ideally be factored into real-world assessments. Use of this study's findings could help improve the real world validity of medical AI systems by enhancing the human-computer interactions, with preferred explainability techniques tailored to specific situations
'If there was a quick and easy way to participate': the engagement of United Kingdom radiotherapy and diagnostic imaging departments in research strategy
No full textINTRODUCTION: Research strategies support professionals to create a shared vision and work towards common objectives which can enhance workforce satisfaction, retention and patient experience. Our research aimed to capture the current number of United Kingdom (UK) radiotherapy and diagnostic imaging departments that have a local discipline specific research strategy in place. We also sought to understand the contributing factors to their development, with the aim of generating models of support to enhance future local research strategies. METHODS: A discipline specific cross-sectional survey was co-developed by the research team, the College of Radiographers (CoR) and our patient and public involvement and engagement representative. Distribution was via the CoR to radiotherapy and imaging departments across the UK. RESULTS: Complete responses were received from 32 radiotherapy and 19 imaging departments, discipline specific strategy numbers were low with only 10 and 3 departments respectively having one in situ. Barriers and enablers to their development as well as disparate motivations and intentions to develop a strategy were evident within and across each discipline. The respondents identified a range of formats and topics to help the development of strategies. CONCLUSION: Radiographers are keen to develop and implement their own research ideas, however this work is additional to clinical service demand. Removing barriers to research participation is a strategic priority, regional cooperation and coordination may play an increasing role in research engagement, scale and support. Opportunities to increase ownership and confidence in research strategy development should be pursued including template strategies and professional facilitation. IMPLICATIONS FOR PRACTICE: A discipline specific strategy would support departments to navigate the complexities of research regulation and policy and overcome the challenges faced by competing priorities
Whole genome sequencing to identify novel germline fumarate hydratase mutation in child with bilateral renal cell carcinoma
No full textAn 11-year-old presented with bilateral renal cell carcinoma (RCC) with FH-deficient RCC confirmed by immunohistochemistry. WGS confirmed no coding variants but identified a rare intronic variant in FH (c.1391-269A>G). We illustrate how combined pathological and genomic investigations enabled a precise diagnosis of the underlying cause of an ultra-rare clinical presentation
Integration of personalised ultrasensitive ctDNA monitoring of patients with metastatic breast cancer to reduce imaging requirements
No full textCirculating tumour DNA (ctDNA) is an emerging biomarker for monitoring cancers. The personalised disease monitoring in metastatic breast cancer (PDM-MBC) study is an ongoing study instigated to evaluate ctDNA as a biomarker to individualise imaging requirements in patients with MBC. Patients receiving first-line endocrine therapy (aromatase inhibitor + cyclin-dependent kinase 4/6 inhibitor) had plasma samples collected pre-treatment, weeks 2 and 4, and concurrently with imaging until progressive disease (PD). Here, we apply an experimental analytical workflow for ultrasensitive ctDNA analysis, utilising personalised ctDNA panels designed from mutations identified in tumour tissue, and present results for 24 patients. Twenty patients (83%) had detectable ctDNA pre-treatment. The median progression-free survival was 25.6 months, and 13 patients experienced PD, with rising ctDNA detected at or prior to PD in 12 patients (92%). If imaging had been omitted until the detection of rising ctDNA for at least one mutation, 68% (n = 71) of the scans performed amongst ctDNA-positive patients would have been avoided. Our results demonstrate that integration of personalised ctDNA monitoring of patients with MBC has potential to substantially reduce the imaging needs in patients showing ctDNA response to treatment
A Study on Acute Management of Colorectal Cancer Presenting as an Emergency
No full textIntroduction Many patients in Greater Manchester underwent emergency/urgent surgery, but limited data are available about managing these patients and their outcomes. We aimed to study the clinico-demographic profile, management trends, and outcomes of the patients presenting to the ED in the real world. Methods All patients with lower GI cancer (known or newly diagnosed on the present visit) in the ED requiring admission under surgeons for treatment were identified prospectively over six months and were included in the study. Results Nineteen patients were admitted (13 (69%) colon, 5 (26%) rectum, 1 (5%) anal cancer), with a median age of 67 years, and 10 (52.6%) were female. Ten (53%) patients were on the two-week wait pathway, and 14 (73.6%) patients presented with obstruction symptoms. Only 3 (15.7%) patients had received neoadjuvant therapy. Most had moderately differentiated adenocarcinoma. All had CT of the abdomen on admission, with 9 (52.6%) having CT of the thorax. All had locally advanced or metastatic cancers. Twelve (63%) patients underwent surgery (6 (50%) definitive, 6 (50%) diversion stoma). Nine (75%) patients had early postoperative complications, and 6 (50%) required ICU admission. The median postoperative stay was 9.5 days, with a 30-day mortality rate of 25%. Conclusion This study provides a snapshot of the management and outcomes of patients presenting in emergencies. A further study at the regional/national level is needed to investigate the increasing emergency presentations of colorectal cancer (CRC) despite an established screening program
Correction to: Tivozanib Monotherapy in the Frontline Setting for Patients with Metastatic Renal Cell Carcinoma and Favorable Prognosis
No full textA cross-sectional analysis to characterise treatment decision making for advanced cancer at a tertiary treatment centre: Where can we improve the process?
No full textPURPOSE: In decisions relating to cancer treatment, the risks and benefits of treatment and the patient's preferences must be considered to ensure concordance with goals of care. Shared decision making (SDM) can facilitate these discussions and is associated with reduced decision conflict. This study aimed to characterise decision making for advanced cancer patients at a UK tertiary cancer centre and identify who may be at risk of suboptimal SDM and increased decision conflict. METHODS: Participants completed the SDM-Q-9, decision conflict and decision self-efficacy scale following a consultation where an advanced cancer treatment decision was made. Pearson's chi-square test identified patient characteristics associated with SDM-Q-9, decision self-efficacy and decision conflict score categories; odds ratios were calculated to determine which patients were at increased probability of experiencing suboptimal SDM, low decision self-efficacy or high decision conflict. RESULTS: Participant's (n = 211) scores indicated predominantly high SDM, high decision self-efficacy and low decision conflict. Patient gender and the presence of an informal caregiver in consultation were significantly associated with SDM-Q-9 score category (p > 0.05). Female patients (OR = 2.466, 95% CI: 1.223-4.974) and those attending consultations alone (OR = 0.440, 95% CI: 0.222-0.874) had greater odds of reporting lower SDM scores. CONCLUSION: High SDM scores indicate either effective SDM behaviours or satisfaction with care biasing responses. Greater support to engage with SDM is required for female patients and those who attend alone in advanced cancer treatment decision consultations
Site-selective photo-crosslinking for the characterisation of transient ubiquitin-like protein-protein interactions
No full textNon-covalent protein-protein interactions are one of the most fundamental building blocks in cellular signalling pathways. Despite this, they have been historically hard to identify using conventional methods due to their often weak and transient nature. Using genetic code expansion and incorporation of commercially available unnatural amino acids, we have developed a highly accessible method whereby interactions between biotinylated ubiquitin-like protein (UBL) probes and their binding partners can be stabilised using ultraviolet (UV) light-induced crosslinks. The stabilised protein complexes can be purified using affinity purification and identified by mass spectrometry. The resultant covalent bonds can withstand even the harshest washing conditions, allowing for the removal of indirect binders whilst retaining and capturing weak and transient interactors that are commonly lost during wash steps. This technique is widely applicable and highly effective for identifying site-selective non-covalent interactors. Members of our team have previously demonstrated the benefit of this method using the small ubiquitin-like modifier (SUMO). Here, we provide further proof-of-principle validation of the method and highlight its generality by applying an optimised workflow to a lesser studied UBL, interferon stimulated gene 15 (ISG15). We show that this method is able to capture known ISG15 interactors from a complex protein mixture in a site-selective manner, only capturing proteins that specifically interact with the region of ISG15 where the unnatural amino acid was incorporated. This exquisite degree of sensitivity and specificity greatly improves upon previous screens aimed at identifying downstream non-covalent binders, or readers, of ISG15. Taken together, the approach opens the possibility of characterising previously undetected protein-protein interactions, with the potential of elucidating molecular mechanisms behind the most complex and poorly understood processes in the cell
Large B-cell lymphoma (LBCL): EHA Clinical Practice Guidelines for diagnosis, treatment, and follow-up
No full textLarge B-cell lymphoma (LBCL) accounts for about one-third of adult lymphoma cases. Diagnosis requires specialized hematopathology laboratories, with immunophenotypic analysis essential for confirming B-cell lineage and identifying variants. MYC and BCL2 rearrangements indicate a poor prognosis. Staging and prognosis rely on positron emission tomography computed tomography (PET-CT). The International Prognostic Index (IPI) aids risk stratification. PET-CT is critical for assessing treatment response and guiding strategies. First-line management for LBCL can be informed by interim PET to assess chemosensitivity, with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or polatuzumab vedotin rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) for advanced stages depending on IPI scores. Primary mediastinal B-cell lymphoma (PMBCL) management favors R-CHOP given every 14 days (R-CHOP14) or dose-adjusted etoposide, doxorubicin, vincristine, cyclophosphamide, prednisone, and rituximab (DA-EPOCH-R) without radiotherapy in complete responders. Elderly patients, unfit or not (≥80 years or <80 with poor fitness), need geriatric assessment to guide therapy, often R-miniCHOP or non-anthracycline regimens. Frail patients should have adapted treatments. Prephase corticosteroids improve performance status, and supportive treatment should be optimized. The value of central nervous system (CNS) prophylaxis remains uncertain. CNS-IPI scores and specific anatomical sites help identify high-risk patients; magnetic resonance imaging (MRI) and colony-stimulating factor (CSF) analysis are recommended. Approximately 30%-40% of patients with LBCL experience relapsed or refractory disease after 1L treatment. Treatment strategies vary based on the timing of relapse (<1 year or ≥1 year). For those refractory or relapsing within <1 year and fit for therapy, chimeric antigen receptor T (CART) are the gold standard in 2L. CART in CART-naïve patients and bispecific antibodies appear to be the best approach in 3L. Follow-up includes clinical examination for 2 years and management for long-term side effects, such as cardiotoxicity, osteoporosis, immune dysfunction, neurocognitive impairment, endocrine dysfunction, fatigue, neuropathy, and mental distress