A collection of research papers published by the staff of The Christie NHS Foundation Trust between 1999 to present day. The collection is intended to back date all publications published since 1999. Older papers may be submitted by request to the Kostoris Library.

 

Recent Submissions

  • Encouraging inclusivity in technology clinical trials: guidance co-developed by patients, members of the public, clinical staff and researchers

    Goodwin, Leanna; Graham, Donna M; Starling, B; Harrigan, K; Keane, A; Frost, Hannah; Mustafa, S; Saeed, Shahfaz; Laverty, L; Experimental Cancer Medicine Team, Christie NHS Foundation Trust and Vocal (The University of Manchester, 2024-02)
    Clinical research is vital to develop and provide safe and effective treatment for patients with illness, with changes to healthcare having global impact. Fortunately, in the UK, many patients are willing to participate in clinical studies with recruitment numbers continuing to increase.
  • The effectiveness and safety of proton beam radiation therapy in children and young adults with central nervous system (CNS) tumours: a systematic review

    Wilson, J. S.; Main, C.; Thorp, Nicky; Taylor, R. E.; Majothi, S.; Kearns, P. R.; English, M.; Dandapani, M.; Phillips, R.; Wheatley, K.; et al. (2024)
    BACKGROUND: Central nervous system (CNS) tumours account for around 25% of childhood neoplasms. With multi-modal therapy, 5-year survival is at around 75% in the UK. Conventional photon radiotherapy has made significant contributions to survival, but can be associated with long-term side effects. Proton beam radiotherapy (PBT) reduces the volume of irradiated tissue outside the tumour target volume which may potentially reduce toxicity. Our aim was to assess the effectiveness and safety of PBT and make recommendations for future research for this evolving treatment. METHODS: A systematic review assessing the effects of PBT for treating CNS tumours in children/young adults was undertaken using methods recommended by Cochrane and reported using PRISMA guidelines. Any study design was included where clinical and toxicity outcomes were reported. Searches were to May 2021, with a narrative synthesis employed. RESULTS: Thirty-one case series studies involving 1731 patients from 10 PBT centres were included. Eleven studies involved children with medulloblastoma / primitive neuroectodermal tumours (n = 712), five ependymoma (n = 398), four atypical teratoid/rhabdoid tumour (n = 72), six craniopharyngioma (n = 272), three low-grade gliomas (n = 233), one germ cell tumours (n = 22) and one pineoblastoma (n = 22). Clinical outcomes were the most frequently reported with overall survival values ranging from 100 to 28% depending on the tumour type. Endocrine outcomes were the most frequently reported toxicity outcomes with quality of life the least reported. CONCLUSIONS: This review highlights areas of uncertainty in this research area. A well-defined, well-funded research agenda is needed to best maximise the potential of PBT. SYSTEMATIC REVIEW REGISTRATION: PROSPERO-CRD42016036802.
  • New EAU/ASCO guideline recommendations on sentinel node biopsy for penile cancer and remaining challenges from a nuclear medicine perspective

    Vreeburg, M. T. A.; Donswijk, M. L.; Albersen, M.; Parnham, Arie; Ayres, B.; Protzel, C.; Pettaway, C.; Spiess, P. E.; Brouwer, O. R.; Department of Urology, The Christie NHS Foundation Trust, Manchester, UK. (2024)
    INTRODUCTION: The European Association of Urology (EAU) and the American Society of Clinical Oncology (ASCO) recently issued updated guidelines on penile cancer, emphasising dynamic sentinel node biopsy (DSNB) as the preferred method for surgical staging among patients with invasive penile tumours and no palpable inguinal lymphadenopathy. This paper outlines the rationale behind this new recommendation and describes remaining challenges, as well as strategies for promoting DSNB worldwide. MAIN TEXT: DSNB offers high diagnostic accuracy with the lowest postoperative complications compared to open or minimally invasive inguinal lymph node dissection (ILND), prompting its preference in the new guidelines. Nevertheless, despite its advantages, there are challenges hampering the widespread adoption of DSNB. This includes the false-negative rate associated with DSNB and the potential negative impact on patient outcome. To address this issue, improvements should be made in several areas, including refining the timing and interpretation of the lymphoscintigraphy and the single photon emission computed tomography/computed tomography images. In addition, the quantity of tracer employed and choice of the injection site for the radiopharmaceutical should be optimised. Finally, limiting the removal of nodes without tracer activity during surgery may help minimise complication rates. CONCLUSION: Over the years, DSNB has evolved significantly, related to the dedicated efforts and innovations in nuclear medicine and subsequent clinical studies validating its efficacy. It is now strongly recommended for surgical staging among selected penile cancer patients. To optimise DSNB further, multidisciplinary collaborative research is required to improve SN identification for better diagnostic accuracy and fewer complications.
  • Fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin with gemtuzumab ozogamicin improves event-free survival in younger patients with newly diagnosed AML and overall survival in patients with NPM1 and FLT3 mutations

    Russell, N. H.; Wilhelm-Benartzi, C.; Othman, J.; Dillon, R.; Knapper, S.; Batten, L. M.; Canham, J.; Hinson, E. L.; Betteridge, S.; Overgaard, U. M.; et al. (2024)
    PURPOSE: To determine the optimal induction chemotherapy regimen for younger adults with newly diagnosed AML without known adverse risk cytogenetics. PATIENTS AND METHODS: One thousand thirty-three patients were randomly assigned to intensified (fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin [FLAG-Ida]) or standard (daunorubicin and Ara-C [DA]) induction chemotherapy, with one or two doses of gemtuzumab ozogamicin (GO). The primary end point was overall survival (OS). RESULTS: There was no difference in remission rate after two courses between FLAG-Ida + GO and DA + GO (complete remission [CR] + CR with incomplete hematologic recovery 93% v 91%) or in day 60 mortality (4.3% v 4.6%). There was no difference in OS (66% v 63%; P = .41); however, the risk of relapse was lower with FLAG-Ida + GO (24% v 41%; P < .001) and 3-year event-free survival was higher (57% v 45%; P < .001). In patients with an NPM1 mutation (30%), 3-year OS was significantly higher with FLAG-Ida + GO (82% v 64%; P = .005). NPM1 measurable residual disease (MRD) clearance was also greater, with 88% versus 77% becoming MRD-negative in peripheral blood after cycle 2 (P = .02). Three-year OS was also higher in patients with a FLT3 mutation (64% v 54%; P = .047). Fewer transplants were performed in patients receiving FLAG-Ida + GO (238 v 278; P = .02). There was no difference in outcome according to the number of GO doses, although NPM1 MRD clearance was higher with two doses in the DA arm. Patients with core binding factor AML treated with DA and one dose of GO had a 3-year OS of 96% with no survival benefit from FLAG-Ida + GO. CONCLUSION: Overall, FLAG-Ida + GO significantly reduced relapse without improving OS. However, exploratory analyses show that patients with NPM1 and FLT3 mutations had substantial improvements in OS. By contrast, in patients with core binding factor AML, outcomes were excellent with DA + GO with no FLAG-Ida benefit.
  • Sorting lung tumor volumes from 4D-MRI data using an automatic tumor-based signal reduces stitching artifacts

    Warren, M.; Barrett, A.; Bhalla, N.; Brada, M.; Chuter, Robert; Cobben, D.; Eccles, Cynthia L; Hart, C.; Ibrahim, E.; McClelland, J.; et al. (2024)
    PURPOSE: To investigate whether a novel signal derived from tumor motion allows more precise sorting of 4D-magnetic resonance (4D-MR) image data than do signals based on normal anatomy, reducing levels of stitching artifacts within sorted lung tumor volumes. METHODS: (4D-MRI) scans were collected for 10 lung cancer patients using a 2D T2-weighted single-shot turbo spin echo sequence, obtaining 25 repeat frames per image slice. For each slice, a tumor-motion signal was generated using the first principal component of movement in the tumor neighborhood (TumorPC1). Signals were also generated from displacements of the diaphragm (DIA) and upper and lower chest wall (UCW/LCW) and from slice body area changes (BA). Pearson r coefficients of correlations between observed tumor movement and respiratory signals were determined. TumorPC1, DIA, and UCW signals were used to compile image stacks showing each patient's tumor volume in a respiratory phase. Unsorted image stacks were also built for comparison. For each image stack, the presence of stitching artifacts was assessed by measuring the roughness of the compiled tumor surface according to a roughness metric (Rg). Statistical differences in weighted means of Rg between any two signals were determined using an exact permutation test. RESULTS: The TumorPC1 signal was most strongly correlated with superior-inferior tumor motion, and had significantly higher Pearson r values (median 0.86) than those determined for correlations of UCW, LCW, and BA with superior-inferior tumor motion (p < 0.05). Weighted means of ratios of Rg values in TumorPC1 image stacks to those in unsorted, UCW, and DIA stacks were 0.67, 0.69, and 0.71, all significantly favoring TumorPC1 (p = 0.02-0.05). For other pairs of signals, weighted mean ratios did not differ significantly from one. CONCLUSION: Tumor volumes were smoother in 3D image stacks compiled using the first principal component of tumor motion than in stacks compiled with signals based on normal anatomy.
  • Outcomes and characteristics of nonmelanoma skin cancers in patients with myeloproliferative neoplasms on ruxolitinib

    Rampotas, A.; Carter-Brzezinski, Luke; Somervaille, Tim C P; Forryan, J.; Panitsas, F.; Harrison, C.; Witherall, R.; Innes, A. J.; Wallis, L.; Butt, N. M.; et al. (2024)
    Nonmelanoma skin cancers (NMSCs) in ruxolitinib-treated patients with myeloproliferative neoplasms behave aggressively, with adverse features and high recurrence. In our cohort, mortality from metastatic NMSC exceeded that from myelofibrosis. Vigilant skin assessment, counseling on NMSC risks, and prospective ruxolitinib-NMSC studies are crucial.
  • Geographic and sociodemographic access to systemic anticancer therapies for secondary breast cancer: a systematic review

    Pearson, Sally A; Taylor, Sally; Marsden, A.; O'Reilly, J. D.; Krishan, A.; Howell, Sacha; Yorke, J.; Division of Nursing, Midwifery and Social Work, The Christie NHS Foundation Trust, University of Manchester, Oxford Rd, Manchester, M13 9PL, UK Christie Patient Centred Research, The Christie NHS Foundation Trust, 550 Wilmslow Road, Manchester, M20 4BX, UK. Division of Cancer Sciences, University of Manchester, Oxford Rd, Manchester, M13 9PL, UK. (2024)
    BACKGROUND: The review aimed to investigate geographic and sociodemographic factors associated with receipt of systemic anticancer therapies (SACT) for women with secondary (metastatic) breast cancer (SBC). METHODS: Included studies reported geographic and sociodemographic factors associated with receipt of treatment with SACT for women > 18 years with an SBC diagnosis. Information sources searched were Ovid CINAHL, Ovid MEDLINE, Ovid Embase and Ovid PsychINFO. Assessment of methodological quality was undertaken using the Joanna Briggs Institute method. Findings were synthesised using a narrative synthesis approach. RESULTS: Nineteen studies published between 2009 and 2023 were included in the review. Overall methodological quality was assessed as low to moderate. Outcomes were reported for treatment receipt and time to treatment. Overall treatment receipt ranged from 4% for immunotherapy treatment in one study to 83% for systemic anticancer therapies (unspecified). Time to treatment ranged from median 54 days to 95 days with 81% of patients who received treatment < 60 days. Younger women, women of White origin, and those women with a higher socioeconomic status had an increased likelihood of timely treatment receipt. Treatment receipt varied by geographical region, and place of care was associated with variation in timely receipt of treatment with women treated at teaching, research and private institutions being more likely to receive treatment in a timely manner. CONCLUSIONS: Treatment receipt varied depending upon type of SACT. A number of factors were associated with treatment receipt. Barriers included older age, non-White race, lower socioeconomic status, significant comorbidities, hospital setting and geographical location. Findings should however be interpreted with caution given the limitations in overall methodological quality of included studies and significant heterogeneity in measures of exposure and outcome. Generalisability was limited due to included study populations. Findings have practical implications for the development and piloting of targeted interventions to address specific barriers in a socioculturally sensitive manner. Addressing geographical variation and place of care may require intervention at a commissioning policy level. Further qualitative research is required to understand the experience and of women and clinicians. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020196490.
  • Results of a randomised phase II trial of olaparib, chemotherapy or olaparib and cediranib in patients with platinum-resistant ovarian cancer

    Nicum, S.; McGregor, N.; Austin, R.; Collins, L.; Dutton, S.; McNeish, I.; Glasspool, R.; Hall, M.; Roux, R.; Michael, A.; et al. (2024)
    BACKGROUND: OCTOVA compared the efficacy of olaparib (O) versus weekly paclitaxel (wP) or olaparib + cediranib (O + C) in recurrent ovarian cancer (OC). AIMS: The main aim of the OCTOVA trial was to determine the progression-free survival (PFS) of olaparib (O) versus the oral combination of olaparib plus cediranib (O + C) and weekly paclitaxel (wP) in recurrent ovarian cancer (OC). METHODS: In total, 139 participants who had relapsed within 12 months of platinum therapy were randomised to O (300 mg twice daily), wP (80 mg/m(2) d1,8,15, q28) or O + C (300 mg twice daily/20 mg daily, respectively). The primary endpoint was progression-free survival (PFS) of olaparib (O) versus olaparib plus cediranib (O + C) or weekly paclitaxel (wP). The sample size was calculated to observe a PFS hazard ratio (HR) 0.64 in favour of O + C compared to O (20% one-sided type I error, 80% power). RESULTS: The majority had platinum-resistant disease (90%), 22% prior PARPi, 34% prior anti-angiogenic therapy, 30% germline BRCA1/2 mutations. The PFS was increased for O + C vs O (O + C 5.4 mo (2.3, 9.6): O 3.7 mo (1.8, 7.6) HR = 0.73; 60% CI: 0.59, 0.89; P = 0.1) and no different between wP and O (wP 3.9 m (1.9, 9.1); O 3.7 mo (1.8, 7.6) HR = 0.89, 60% CI: 0.72, 1.09; P = 0.69). The main treatment-related adverse events included manageable diarrhoea (4% Grade 3) and hypertension (4% Grade 3) in the O + C arm. DISCUSSION: OCTOVA demonstrated the activity of O + C in women with recurrent disease, offering a potential non-chemotherapy option. TRIAL REGISTRATION: ISRCTN14784018, registered on 19th January 2018 http://www.isrctn.com/ISRCTN14784018 .
  • Real-world concordance between germline and tumour BRCA1/2 status in epithelial ovarian cancer

    Morgan, Robert D; Burghel, G. J.; Schlecht, H.; Clamp, A. R.; Hasan, J.; Mitchell, C. L.; Salih, Z.; Shaw, J.; Desai, S.; Jayson, G. C.; et al. (2023)
    Patients diagnosed with epithelial ovarian cancer may undergo reflex tumour BRCA1/2 testing followed by germline BRCA1/2 testing in patients with a positive tumour test result. This testing model relies on tumour BRCA1/2 tests being able to detect all types of pathogenic variant. We analysed germline and tumour BRCA1/2 test results from patients treated for epithelial ovarian cancer at our specialist oncological referral centre. Tumour BRCA1/2 testing was performed using the next-generation sequencing (NGS)-based myChoice((R)) companion diagnostic (CDx; Myriad Genetics, Inc.). Germline BRCA1/2 testing was performed in the North West Genomic Laboratory Hub using NGS and multiplex ligation-dependent probe amplification. Between 11 April 2021 and 11 October 2023, 382 patients were successfully tested for tumour BRCA1 and BRCA2 variants. Of these, 367 (96.1%) patients were tested for germline BRCA1/2 variants. In those patients who underwent tumour and germline testing, 15.3% (56/367) had a BRCA1/2 pathogenic variant (36 germline and 20 somatic). All germline BRCA1/2 pathogenic small sequencing variants were detected in tumour DNA. By contrast, 3 out of 8 germline BRCA1/2 pathogenic large rearrangements were not reported in tumour DNA. The overall concordance of germline BRCA1/2 pathogenic variants detected in germline and tumour DNA was clinically acceptable at 91.7% (33/36). The myChoice((R)) CDx was able to detect most germline BRCA1/2 pathogenic variants in tumour DNA, although a proportion of pathogenic large rearrangements were not reported. If Myriad's myChoice((R)) CDx is used for tumour BRCA1/2 testing, our data supports a testing strategy of germline and tumour BRCA1/2 testing in all patients diagnosed with epithelial ovarian cancer aged < 79 years old, with germline BRCA1/2 testing only necessary for patients aged >/= 80 years old with a tumour BRCA1/2 pathogenic variant.
  • A young male presenting with chest pain, elevated troponin levels, and a clinical dilemma: a case report

    Omodara, A. B.; Areo, O.; Kintu, Joanita; Ziada, A. A.; Thornton, M.; Hematology, The Christie NHS Foundation Trust, Manchester, GBR. (2023)
    Chest pain is a common presentation that may represent a wide variety of underlying etiologies ranging from mild self-limiting conditions to immediately life-threatening emergencies. The combination of 'cardiac-sounding chest pain' and elevated troponin levels would raise suspicion of an acute ischemic event. An acute coronary syndrome is a diagnosis that may be straightforward; however, oftentimes, patients with elevated troponin levels and chest pain may bring about a state of diagnostic uncertainty. Alternative diagnoses to consider would be inflammatory or infectious conditions of the myocardium and pericardium. We present the case of a young gentleman in his twenties who presents with cardiac chest pain, elevated troponin, and non-specific changes on his electrocardiogram who was treated for an alternative cause of elevated troponin and chest pain, myopericarditis. We present the case of a 24-year-old male who presented with a six-hour history of debilitating retrosternal chest pain. Initial workup showed a Troponin I level greater than 15,000 ng/L, D-Dimer greater than 1,000 mcg/L with no overt ischemic features on electrocardiogram. The patient had no high-risk features in his medical history & denied the use of recreational drugs. A formal same-day echocardiogram revealed normal biventricular systolic function and no evidence of regional wall motion abnormality (RWMA). He was eventually treated clinically for myopericarditis. A Cardiac MRI (CMR) imaging was done to confirm the diagnosis and rule out, most importantly, ischemic heart disease or any other underlying pathology. The main dilemma in this case was working out whether there was indeed peri-myocardial inflammation, or an acute coronary event (such as spontaneous coronary artery dissection) given his age and clinical history. Patients presenting with a very high troponin level, particularly in young patient cohorts, should raise suspicion of a myocardial or pericardial inflammatory process. In addition to a thorough history and in the absence of ischemic changes on the electrocardiogram, subtle findings such as PR segment depression may point to a diagnosis of pericardial inflammation. While urgent echocardiography is useful to quickly assess ventricular function and for RWMA, CMR imaging is the Gold Standard modality of investigation to provide detailed structural information of the heart.
  • Sudden onset of broad complex tachycardia in a fit young man: a case report

    Omodara, A. B.; Areo, O.; Kintu, Joanita; Thornton, M.; Haematology, The Christie Hospital, Manchester, GBR. (2023)
    Wolff-Parkinson-White (WPW) syndrome is a clinical pre-excitation syndrome often strongly associated with tachyarrhythmias that are predominantly atrioventricular re-entrant tachycardia (AVRT). It is generally considered to be a relatively benign arrhythmogenic condition associated with a slightly higher risk of sudden cardiac death (SCD) in comparison to the general population. Epidemiological data suggests that 0.1%-0.3% of the general population have electrocardiographic (ECG) findings suggesting that during sinus rhythm, in addition to atrioventricular (AV) conduction over the AV node-His bundle pathway, there is an additional atrioventricular conduction across an accessory pathway. Whilst in most cases, such phenomenon is associated with WPW syndrome, other similar conditions, including Lown-Ganong-Levine (LGL) syndrome and Mahaim-type pre-excitation, have also been documented. Our patient is a young man in his late twenties admitted with broad complex tachycardia at 252 beats per minute associated with diaphoresis and pre-syncope. In our case report, we describe how we managed this emergency, eventually unveiling the underlying aetiology as well as a stepwise approach to dealing with adult broad-complex tachycardia.
  • Improving international medical graduates' understanding of the UK appraisal system: an interventional study

    Nageswaran, P.; Nageswaran, P.; Gajanan, Kantappa; The Christie NHS Foundation Trust, Manchester, UK. (2023)
    International medical graduates (IMGs) face countless challenges when migrating to a new healthcare system, of which understanding the UK appraisal and revalidation system is one. We investigated whether provision of educational material on appraisals would improve IMGs' confidence in their understanding of the UK appraisal system. A prospective pre-post interventional study aimed at IMGs was carried out between 25 February 2022 and 9 March 2022. A mixed-methods survey was undertaken pre (n=519) and post (n=63) intervention. The pre-interventional survey highlighted IMGs' lack of experience and knowledge of the General Medical Council (GMC) appraisal and revalidation process. Postinterventional responses showed a significantly higher confidence rating in IMGs' understanding of the UK appraisal process (p<0.001). Utilising simple educational tools can be beneficial for IMGs to gain confidence in navigating appraisals and help bridge the attainment gap when entering a new healthcare system. Barriers, such as lack of knowledge, can be easily rectified without the need for significant investment.
  • The development and validation of a needs assessment tool for use with young adult survivors of a central nervous system tumor (YOU-CAN)

    Law, Kate; McCabe, Martin G; van der Veer, S. N.; Yorke, Janelle; Division of Cancer Sciences, Manchester, Lancashire, England Christie Hosp NHS Foundation Trust, Manchester, England (2024)
    Background Adolescent and young adult (AYA) survivors of a central nervous system (CNS) tumor represent a vulnerable group who can experience: social isolation, low rates of employment, and achieving independence can be compromised, leading to poorer quality of life compared with survivors of other cancer types. The aim of this study is to develop and evaluate the validity of a needs assessment tool (NAT) for AYA survivors of a CNS tumor.Methods Items generated using data from 29 qualitative studies and cognitive interviews (n = 8) produced NAT V1.1 (49 items). 128 of 316 eligible participants attending neuro-oncology clinics at 4 NHS sites between June 2022 and March 2023 completed the NAT V1.1 to allow for item reduction and refinement and to evaluate reliability and validity. A pilot study (n = 6) using YOU-CAN in routine follow-up concluded the study.Results Hierarchical analysis and Rasch analysis identified 18- and 15-items for removal, respectively. YOU-CAN, comprised of the remaining 16 items, demonstrates excellent test-retest reliability (intra-class correlation coefficient, 0.901, n = 40) and sufficient correlation with the European Quality of Life questionnaire and Supportive Care Needs Survey (Pearson r = 0.433 and 0.590, respectively). Pilot testing showed YOU-CAN triggered discussions of unmet needs in consultations and highlighted the importance of multidisciplinary support.Conclusions YOU-CAN is a valid and reliable instrument containing items related to concerns about physical and emotional health; family and relationships; self-acceptance; and independence. Future efforts should examine YOU-CAN's feasibility, and develop guidance for managing unmet needs. Routine use of YOU-CAN may improve the identification of otherwise undiscussed unmet needs and opportunities to deliver personalized support.
  • Developing and validating a multivariable prognostic-predictive classifier for treatment escalation of oropharyngeal squamous cell carcinoma: the PREDICTR-OPC study

    Mehanna, H.; Rapozo, D.; von Zeidler, S. V.; Harrington, K. J.; Winter, S. C.; Hartley, A.; Nankivell, P.; Schache, A. G.; Sloan, P.; Odell, E. W.; et al. (2024)
    PURPOSE: While there are several prognostic classifiers, to date, there are no validated predictive models that inform treatment selection for oropharyngeal squamous cell carcinoma (OPSCC).Our aim was to develop clinical and/or biomarker predictive models for patient outcome and treatment escalation for OPSCC. EXPERIMENTAL DESIGN: We retrospectively collated clinical data and samples from a consecutive cohort of OPSCC cases treated with curative intent at ten secondary care centers in United Kingdom and Poland between 1999 and 2012. We constructed tissue microarrays, which were stained and scored for 10 biomarkers. We then undertook multivariable regression of eight clinical parameters and 10 biomarkers on a development cohort of 600 patients. Models were validated on an independent, retrospectively collected, 385-patient cohort. RESULTS: A total of 985 subjects (median follow-up 5.03 years, range: 4.73-5.21 years) were included. The final biomarker classifier, comprising p16 and survivin immunohistochemistry, high-risk human papillomavirus (HPV) DNA in situ hybridization, and tumor-infiltrating lymphocytes, predicted benefit from combined surgery + adjuvant chemo/radiotherapy over primary chemoradiotherapy in the high-risk group [3-year overall survival (OS) 63.1% vs. 41.1%, respectively, HR = 0.32; 95% confidence interval (CI), 0.16-0.65; P = 0.002], but not in the low-risk group (HR = 0.4; 95% CI, 0.14-1.24; P = 0.114). On further adjustment by propensity scores, the adjusted HR in the high-risk group was 0.34, 95% CI = 0.17-0.67, P = 0.002, and in the low-risk group HR was 0.5, 95% CI = 0.1-2.38, P = 0.384. The concordance index was 0.73. CONCLUSIONS: We have developed a prognostic classifier, which also appears to demonstrate moderate predictive ability. External validation in a prospective setting is now underway to confirm this and prepare for clinical adoption.
  • The impact of frailty and geriatric syndromes on metrics of acute care performance: results of a national day of care survey

    Knight, T.; Atkin, C.; Kamwa, V.; Cooksley, Tim; Subbe, C.; Holland, M.; Sapey, E.; Lasserson, D.; The Christie NHS Foundation Trust, Manchester, UK. (2023)
    BACKGROUND: Frailty is associated with a range of adverse clinical outcomes in the acute hospital setting. We sought to determine whether frailty and related factors affected clinical processes such as time to assessment during emergency hospital admission within the National Health Service (NHS) in the UK. METHODS: The Society for Acute Medicine Benchmarking Audit (SAMBA) is an annual cross-sectional day of care survey. SAMBA 2022 was conducted on Thursday 23rd June 2022. We assessed whether the Clinical Frailty Scale (CFS) and presence of a geriatric syndrome affected performance against nationally recognised clinical quality indicators based on time to initial assessment and time to consultant review. CFS was graded into robust (CFS1-3), mild (CFS 4-5), moderate (CFS 6), severe (CFS7-8) and terminal illness (CFS 9). Plausible values were created for missing variables using multi-level multiple imputation. The association was described using mixed effect generalised linear models adjusting for initial National Early Warning Score 2 (NEWS2) and time of arrival. FINDINGS: A total of 152 hospitals provided patient level data relating to 7248 emergency medical admissions. Patients with mild, moderate and severe frailty were less likely to be assessed within 4 h of arrival (adjusted OR, mild 0.79, 95% CI 0.68-0.96, moderate 0.67 95% CI 0.53-0.84, severe, 0.75 95% CI 0.58-0.96, terminally ill 0.59 95% CI 0.23-1.43) and less likely to be achieve the clinical quality indicator for consultant review (adjusted OR, mild 0.69 95% CI 0.58-0.83, moderate 0.55 95% CI 0.44-0.70, severe 0.54 95% CI 0.41-0.69, terminally ill 0.76 95% CI 0.42-1.5). Patients with geriatric syndromes were also less likely to be assessed within 4 h of arrival (adjusted OR 0.66 95% CI 0.56-0.76) or by a consultant within the recommended time frame (adjusted OR 0.45 95% CI 0.39-0.51). The difference was partially explained by differential use of SDEC pathways. Sub-group analysis of 5148 patients assessed outside of SDEC areas demonstrated patients with geriatric syndromes (adjusted OR 0.71, 95% CI 0.60-0.83), but not frailty defined by CFS were less likely to be assessed within 4 h of arrival. Moderate and severe frailty and the presence of a geriatric syndrome were associated with a decreased likelihood of achieving the consultant review standard (moderate, adjusted OR 0.75, 95% CI 0.59-0.94, severe adjusted OR 0.75 95% CI 0.58-0.96, geriatric syndrome adjusted OR 0.59, 95% CI 0.50-0.69). INTERPRETATION: Frailty is associated with delayed clinical assessment. This association may suggest a systemic issue with clinical prioritisation, with important implications for acute care policy. FUNDING: The database for SAMBA is funded by the Society for Acute Medicine.
  • Protocol for the development of a core outcome set (COS) for adolescents and young adults (AYAs) with cancer

    Husson, O.; Janssen, S. H. M.; Reeve, B. B.; Sodergren, S. C.; Cheung, C. K.; McCabe, Martin G; Salsman, J. M.; van der Graaf, W. T. A.; Darlington, A. S.; Division of Cancer Sciences, University of Manchester, Manchester, UK. The Christie NHS Foundation Trust, Manchester, UK. (2024)
    BACKGROUND: Adolescents and young adults (AYAs) with cancer, defined as individuals aged 15-39 years at initial cancer diagnosis, form a unique population; they face age-specific issues as they transition to adulthood. This paper presents the protocol for the development of a core outcome set (COS) for AYAs with cancer. METHODS: The methodological standards from the Core Outcome Measures in Effectiveness Trials (COMET) and the International Consortium for Health Outcomes Measurement (ICHOM) for COS development will guide the development of the COS for AYAs with cancer. The project will consist of the following phases: (1) define the scope of the COS; (2) establish the need for a COS in this field (3) assemble an international, multi-stakeholder working group; (4) develop a detailed protocol; (5) determine 'what to measure' (i.e., outcomes); (6) determine 'how to measure' (i.e., measures); and (7) determine 'case-mix' variables. CONCLUSIONS: The development of a COS for AYAs with cancer will facilitate the implementation of efficient and relevant standards for data collection, both for clinical trials and in routine healthcare, thereby increasing the usefulness of these data to improve the value of the care given to these underserved young cancer patients.
  • Revolutionizing anti-HER2 therapies for extrahepatic cholangiocarcinoma and gallbladder cancer: current advancements and future perspectives

    Haaft, B. H. T.; Pedregal, M.; Prato, J.; Klümpen, H. J.; Moreno, V.; Lamarca, Angela; Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom. (2024)
    Biliary tract cancers (BTCs) encompass a heterogeneous group of rare tumors, including intrahepatic cholangiocarcinoma (iCCA), extrahepatic cholangiocarcinoma (eCCA), gallbladder cancer (GBC) and ampullary cancer (AC). The present first-line palliative treatment regimen comprises gemcitabine and cisplatin in combination with immunotherapy based on two randomized controlled studies. Despite the thorough investigation of these palliative treatments, long-term survival remains low. Moving beyond conventional chemotherapies and immunotherapies, the realm of precision medicine has demonstrated remarkable efficacy in malignancies such as breast and gastric cancers, characterized by notable HER2 overexpression rates. In the context of biliary tract cancer, significant HER2 alterations are observed, particularly within eCCA and GBC, heightening the interest in precision medicine. Various anti-HER2 therapies, including trastuzumab, pertuzumab, trastuzumab-deruxtecan, zanidatamab and neratinib, have undergone investigation. The objective of this review is to summarize the current evidence and outline future directions of targeted HER2 treatment therapy in patients with biliary tract tumors, specially extrahepatic cholangiocarcinoma and gallbladder cancer.
  • The impact of transportation mode, socioeconomic deprivation and rurality on travel times to radiotherapy and surgical services for patients with prostate cancer: a national population-based evaluation

    Han, L.; Sullivan, R.; Tree, A.; Lewis, D.; Price, P.; Sangar, Vijay; van der Meulen, J.; Aggarwal, A.; The Christie NHS Trust, Manchester, UK (2024)
    BACKGROUND: The distances that patients have to travel can influence their access to cancer treatment. We investigated the determinants of travel time, separately for journeys by car and public transport, to centres providing radical surgery or radiotherapy for prostate cancer. METHODS: Using national cancer registry records linked to administrative hospital data, we identified patients who had radical surgery or radiotherapy for prostate cancer between January 2017 and December 2018 in the English National Health Service. Estimated travel times from the patients' residential area to the nearest specialist surgical or radiotherapy centre were estimated for journeys by car and by public transport. RESULTS: We included 13,186 men who had surgery and 26,581 who had radiotherapy. Estimated travel times by public transport (74.4 mins for surgery and 69.4 mins for radiotherapy) were more than twice as long as by car (33.4 mins and 29.1mins, respectively). Patients living in more socially deprived neighbourhoods in rural areas had the longest travel times to the nearest cancer treatment centres by car (62.0 mins for surgery and 52.1 mins for radiotherapy). Conversely patients living in more affluent neighbourhoods in urban conurbations had the shortest (18.7 mins for surgery and 17.9 mins for radiotherapy). CONCLUSION: Travel times to cancer centres vary widely according to mode of transport, socioeconomic deprivation, and rurality. Policies changing the geographical configuration of cancer services should consider the impact on the expected travel times both by car and by public transport to avoid enhancing existing inequalities in access to treatment and patient outcomes.
  • Repotrectinib in ROS1 fusion-positive non-small-cell lung cancer

    Drilon, A.; Camidge, D. R.; Lin, J. J.; Kim, S. W.; Solomon, B. J.; Dziadziuszko, R.; Besse, B.; Goto, K.; de Langen, A. J.; Wolf, J.; et al. (2024)
    BACKGROUND: The early-generation ROS1 tyrosine kinase inhibitors (TKIs) that are approved for the treatment of ROS1 fusion-positive non-small-cell lung cancer (NSCLC) have antitumor activity, but resistance develops in tumors, and intracranial activity is suboptimal. Repotrectinib is a next-generation ROS1 TKI with preclinical activity against ROS1 fusion-positive cancers, including those with resistance mutations such as ROS1 G2032R. METHODS: In this registrational phase 1-2 trial, we assessed the efficacy and safety of repotrectinib in patients with advanced solid tumors, including ROS1 fusion-positive NSCLC. The primary efficacy end point in the phase 2 trial was confirmed objective response; efficacy analyses included patients from phase 1 and phase 2. Duration of response, progression-free survival, and safety were secondary end points in phase 2. RESULTS: On the basis of results from the phase 1 trial, the recommended phase 2 dose of repotrectinib was 160 mg daily for 14 days, followed by 160 mg twice daily. Response occurred in 56 of the 71 patients (79%; 95% confidence interval [CI], 68 to 88) with ROS1 fusion-positive NSCLC who had not previously received a ROS1 TKI; the median duration of response was 34.1 months (95% CI, 25.6 to could not be estimated), and median progression-free survival was 35.7 months (95% CI, 27.4 to could not be estimated). Response occurred in 21 of the 56 patients (38%; 95% CI, 25 to 52) with ROS1 fusion-positive NSCLC who had previously received one ROS1 TKI and had never received chemotherapy; the median duration of response was 14.8 months (95% CI, 7.6 to could not be estimated), and median progression-free survival was 9.0 months (95% CI, 6.8 to 19.6). Ten of the 17 patients (59%; 95% CI, 33 to 82) with the ROS1 G2032R mutation had a response. A total of 426 patients received the phase 2 dose; the most common treatment-related adverse events were dizziness (in 58% of the patients), dysgeusia (in 50%), and paresthesia (in 30%), and 3% discontinued repotrectinib owing to treatment-related adverse events. CONCLUSIONS: Repotrectinib had durable clinical activity in patients with ROS1 fusion-positive NSCLC, regardless of whether they had previously received a ROS1 TKI. Adverse events were mainly of low grade and compatible with long-term administration. (Funded by Turning Point Therapeutics, a wholly owned subsidiary of Bristol Myers Squibb; TRIDENT-1 ClinicalTrials.gov number, NCT03093116.).

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