Now showing items 1-20 of 10378

    • Assessment of the environmental impact of clinical trials

      Darlington, Emma; Frost, Hannah; Patel, Alkesh; Descamps, Tine; Loong, Herbert; Alt, Marie; Bedard, Phillipe :; Graham, Donna M; The Christie NHS Foundation Trust, Manchester, UK
    • An evaluation of radiographers' extended practice in the detection of brain metastases on magnetic resonance images

      McDaid, Lisa; Eccles, Cynthia L; Yorke, Janelle; Department of Radiotherapy, The Christie NHS Foundation Trust, Manchester, UK. Department of Quality and Standards, The Christie NHS Foundation Trust, Manchester, UK Division of Cancer Sciences, Faculty of Medicine, Biology and Health University of Manchester, UK. (2024)
      INTRODUCTION: Patients who undergo magnetic resonance (MR) imaging to confirm or rule out metastatic brain disease are required to wait for image review by a radiologist before leaving the department at the institute where this study was carried out. The aim was to evaluate whether radiographers can review images and reduce waiting times in those patients without metastases. METHODS: Prospective observational study of MR radiographers (n = 11) was undertaken. Radiographers commented on images to confirm whether the images showed evidence of metastatic disease, pathology but no metastases, or no pathology. Responses were compared to the radiological report (reference standard). Online questionnaires determined the views and opinions of radiographers (n = 8) and consultant radiologists (n = 6) towards radiographers expanding their scope of practice to include the confirmation or exclusion of brain metastases. RESULTS: Despite a lack of formal training for image reviewing, overall level of agreement between the radiographer reviews and reference standard was 77.9 % (κ = 0.45). Pooled sensitivity and specificity were 88.6 % & 71.3 % respectively. Kendall's τ = -0.03 (bootstrap 95 % CI -0.73 to 0.61, p = 0.925). Positive predictive value (PPV) was 65.5 % (CI 59.2%-71.4 %) and negative predictive value (NPV) 91.1 % (CI 84.9%-94.9 %). Radiographers and radiologists surveyed demonstrated a willingness to engage with role expansion. CONCLUSION: Based on our small study and interdisciplinary survey, local radiographers and radiologists agree, following a program of radiographer training, screening for brain metastases by radiographers could be implemented. IMPLICATIONS FOR PRACTICE: With appropriate governance and training support, the introduction of formal radiographer screening for patients referred to exclude brain metastases could provide more efficient working practice.
    • Exploring the advantages and challenges of MR-guided radiotherapy in non-small-cell lung cancer: who are the optimal candidates?

      Wu, T. C.; Smith, L. M.; Woolf, David; Faivre-Finn, Corinne; Lee, P.; Radiotherapy Related Research, The Christie NHS Foundation Trust, Manchester, United Kingdom.; Division of Cancer Sciences, The University of Manchester, Manchester, United Kingdom. (2024)
      The landscape of lung radiotherapy (RT) has rapidly evolved over the past decade with modern RT and surgical techniques, systemic therapies, and expanding indications for RT. To date, 2 MRI-guided RT (MRgRT) units, 1 using a 0.35T magnet and 1 using a 1.5T magnet, are available for commercial use with more systems in the pipeline. MRgRT offers distinct advantages such as real-time target tracking, margin reduction, and on-table treatment adaptation, which may help overcome many of the common challenges associated with thoracic RT. Nonetheless, the use of MRI for image guidance and the current MRgRT units also have intrinsic limitations. In this review article, we will discuss clinical experiences to date, advantages, challenges, and future directions of MRgRT to the lung.
    • Comparison of fludarabine/melphalan (FluMel) with fludarabine/melphalan/BCNU or thiotepa (FBM/FTM) in patients with AML in first complete remission undergoing allogeneic hematopoietic stem cell transplantation - a registry study on behalf of the EBMT acute leukemia working party

      Duque-Afonso, J.; Finke, J.; Ngoya, M.; Galimard, J. E.; Craddock, C.; Raj, K.; Bloor, Adrian; Nicholson, E.; Eder, M.; Kim, O.; et al. (2023)
      Conditioning protocols for patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) are being developed continuously to improve their anti-leukemic efficacy and reduce their toxicity. In this study, we compared the conditioning protocol of fludarabine with melphalan 140 mg/m(2) (FluMel) with conditioning protocols based on this same backbone but with an additional alkylating agent i.e., either fludarabine/BCNU (also known as carmustine)/melphalan (FBM), or fludarabine/thiotepa/melphalan (FTM) 110 mg/m(2). We included 1272 adult patients (FluMel, n = 1002; FBM/FTM, n = 270) with acute myeloid leukemia (AML) with intermediate/poor cytogenetic risk in first complete remission (CR) from the registry of the EBMT Acute Leukemia Working Party. Despite patients in the FBM/FTM group were older (64.1 years vs. 59.8 years, p < 0.001) and had a worse Karnofsky performance score (KPS < 90, 33% vs. 24%, p = 0.003), they showed a better overall survival (OS) (2 y OS: 68.3% vs. 58.1%, p = 0.02) and less non-relapse mortality (NRM) (2 y NRM: 15.8% vs. 22.2%, p = 0.009) compared to patients treated with FluMel. No significant differences were observed in relapse incidence (RI) (2 y RI: 24.9% vs. 23.7%, p = 0.62). In conclusion, the addition of a second alkylating agent (BCNU/carmustine or thiotepa) to FluMel as FBM/FTM conditioning, improves OS in AML patients in first CR with intermediate/poor risk cytogenetics after allo-HCT.
    • European society of cardiology core curriculum for cardio-oncology

      López-Fernández, T.; Farmakis, D.; Ameri, P.; Asteggiano, R.; de Azambuja, E.; Aznar, Marianne; Barac, A.; Bayes-Genis, A.; Bax, J. J.; Bergler-Klein, J.; et al. (2023)
      Cardio-oncology is a rapidly growing field of cardiovascular (CV) medicine that has resulted from the continuously increasing clinical demand for specialized CV evaluation, prevention and management of patients suffering or surviving from malignant diseases. Dealing with CV disease in patients with cancer requires special knowledge beyond that included in the general core curriculum for cardiology. Therefore, the European Society of Cardiology (ESC) has developed a special core curriculum for cardio-oncology, a consensus document that defines the level of experience and knowledge required for cardiologists in this particular field. It is structured into 8 chapters, including (i) principles of cancer biology and therapy; (ii) forms and definitions of cancer therapy-related cardiovascular toxicity (CTR-CVT); (iii) risk stratification, prevention and monitoring protocols for CTR-CVT; (iv) diagnosis and management of CV disease in patients with cancer; (v) long-term survivorship programmes and cardio-oncology rehabilitation; (vi) multidisciplinary team management of special populations; (vii) organization of cardio-oncology services; (viii) research in cardio-oncology. The core curriculum aims at promoting standardization and harmonization of training and evaluation in cardio-oncology, while it further provides the ground for an ESC certification programme designed to recognize the competencies of certified specialists.
    • Artificial Intelligence for image-based breast cancer risk prediction using attention

      Romanov, S.; Howell, Sacha; Harkness, E.; Bydder, M.; Evans, D. G.; Squires, S.; Fergie, M.; Astley, S.; Division of Cancer Sciences, University of Manchester, Manchester M20 4GJ, UK. Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK. (2023)
      Accurate prediction of individual breast cancer risk paves the way for personalised prevention and early detection. The incorporation of genetic information and breast density has been shown to improve predictions for existing models, but detailed image-based features are yet to be included despite correlating with risk. Complex information can be extracted from mammograms using deep-learning algorithms, however, this is a challenging area of research, partly due to the lack of data within the field, and partly due to the computational burden. We propose an attention-based Multiple Instance Learning (MIL) model that can make accurate, short-term risk predictions from mammograms taken prior to the detection of cancer at full resolution. Current screen-detected cancers are mixed in with priors during model development to promote the detection of features associated with risk specifically and features associated with cancer formation, in addition to alleviating data scarcity issues. MAI-risk achieves an AUC of 0.747 [0.711, 0.783] in cancer-free screening mammograms of women who went on to develop a screen-detected or interval cancer between 5 and 55 months, outperforming both IBIS (AUC 0.594 [0.557, 0.633]) and VAS (AUC 0.649 [0.614, 0.683]) alone when accounting for established clinical risk factors.
    • Systematic review and meta-analysis of minimally invasive procedures for surgical inguinal nodal staging in penile carcinoma

      Greco, I.; Fernandez-Pello, S.; Sakalis, V. I.; Barreto, L.; Albersen, M.; Ayres, B.; Antunes Lopes, T.; Campi, R.; Crook, J.; García Perdomo, H. A.; et al. (2023)
      CONTEXT: There are several procedures for surgical nodal staging in clinically node-negative (cN0) penile carcinoma. OBJECTIVE: To evaluate the diagnostic accuracy, perioperative outcomes, and complications of minimally invasive surgical procedures for nodal staging in penile carcinoma. EVIDENCE ACQUISITION: A systematic review of the Medline, Embase, and Cochrane controlled trials databases and was conducted. Published and ongoing studies reporting on the management of cN0 penile cancer were included without any design restriction. Outcomes included the false negative (FN) rate, the number of nodes removed, surgical time, and postoperative complications. EVIDENCE SYNTHESIS: Forty-one studies were eligible for inclusion. Four studies comparing robot-assisted (RA-VEIL) and video-endoscopic inguinal lymphadenectomy (VEIL) to open inguinal lymph node dissection (ILND) were suitable for meta-analysis. A descriptive synthesis was performed for single-arm studies on modified open ILND, dynamic sentinel node biopsy (DSNB) with and without preoperative inguinal ultrasound (US), and fine-needle aspiration cytology (FNAC). DSNB with US + FNAC had lower FN rates (3.5-22% vs 0-42.9%) and complication rates (Clavien Dindo grade I-II: 1.1-20% vs 2.9-11.9%; grade III-V: 0-6.8% vs 0-9.4%) in comparison to DSNB alone. Favourable results were observed for VEIL/RA-VEIL over open ILND in terms of major complications (2-10.6% vs 6.9-40.6%; odds ratio [OR] 0.18; p < 0.01). Overall, VEIL/RA-VEIL had lower wound-related complication rates (OR 0.14; p < 0.01), including wound infections (OR 0.229; p < 0.01) and skin necrosis (OR 0.16; p < 0.01). The incidence of lymphatic complications varied between 20.6% and 49%. CONCLUSIONS: Of all the surgical staging options, DSNB with inguinal US + FNAC had the lowest complication rates and high diagnostic accuracy, especially when performed in high-volume centres. If DSNB is not available, favourable results were also found for VEIL/RA-VEIL over open ILND. Lymphatic-related complications were comparable across open and video-endoscopic ILND. PATIENT SUMMARY: We reviewed studies on different surgical approaches for assessing lymph node involvement in cases with penile cancer. The results show that a technique called dynamic sentinel node biopsy with ultrasound guidance and fine-needle sampling has high diagnostic accuracy and low complication rates. For lymph node dissection in penile cancer cases, a minimally invasive approach may offer favourable postoperative outcomes.
    • Variation in outcome measurement and reporting in studies of pelvic exenteration for locally advanced and recurrent rectal cancer: a systematic review

      Brown, K. G. M.; Pisaniello, J.; Ng, K. S.; Solomon, M. J.; Sutton, Paul A; Hatcher, S.; Steffens, D.; Colorectal and Peritoneal Oncology Centre, The Christie NHS Foundation Trust, Manchester, UK. Division of Cancer Sciences, The University of Manchester, Manchester, UK. (2023)
      AIM: There is increasing research interest in pelvic exenteration for locally advanced and recurrent rectal cancer. Heterogeneity in outcome reporting can prevent meaningful interpretation and valid synthesis of pooled data and meta-analyses. The aim of this study was to assess homogeneity in outcome measures in the current pelvic exenteration literature. METHOD: MEDLINE, Embase, CENTRAL, CINAHL and Scopus databases were searched from 1990 to 25 April 2023 to identify studies reporting outcomes of pelvic exenteration for locally advanced or recurrent rectal cancer. All reported outcomes were extracted, merged with those of similar meaning and assigned a domain. RESULTS: Of 4137 abstracts screened, 156 studies met the inclusion criteria. A total of 2765 outcomes were reported, of which 17% were accompanied by a definition. There were 1157 unique outcomes, merged into 84 standardized outcomes and assigned one of seven domains. The most reported domains were complications (147 studies, 94%), survival (127, 81%) and surgical outcomes (123, 79%). Resection margins were reported in 122 studies (78%): the definition of a clear resection margin was not provided in 45 studies (37%), it was unclear in 11 studies (9%) and not specified beyond microscopically 'clear' or 'negative' in 31 (28%). Measurements of 2, 1, 0.5 mm and any healthy tissue were all used to define R0 margins. CONCLUSION: There is significant heterogeneity in outcome measurement and reporting in the current pelvic exenteration literature, raising concerns about the validity of comparative or collaborative studies between centres and meta-analyses. Coordinated international collaboration is required to define core outcome sets and benchmarks.
    • Experiences and unmet Nneeds of adolescent and young adult survivors of a brain tumor (aged 15-39 years): a systematic review and meta-ethnography

      Law, Kate; Salam, Iram.; McCabe, Martin G; van der Veer, S. N.; Gibson, F.; Yorke, Janelle; Author Affiliations: Division of Nursing, Midwifery and Social Work, The University of Manchester (Ms Law and Dr Yorke); The Christie Hospital NHS Foundation Trust (Mss Law and Salam, and Drs McCabe and Yorke), Manchester; and Division of Cancer Sciences (Dr McCabe) and Centre for Health Informatics, Division of Informatics, Imaging and Data Sciences, Manchester Academic Health Science Centre (Dr van der Veer), The University of Manchester; Centre for Outcomes and Experience Research in Children's Health, Illness and Disability, Great Ormond Street Hospital for Children NHS Foundation Trust, London; and School of Health Sciences, University of Surrey (Dr Gibson), Guildford, United Kingdom. (2023)
      BACKGROUND: Brain tumors account for 15% of all adolescent and young adult cancers, and survivors are at risk of ongoing late effects that can severely impact their ability to reach independence. Despite follow-up initiatives advocating a personalized approach, survivors continue to experience ongoing sequelae. A better understanding of the survivorship experience is required to ensure services are able to deliver personalized support. OBJECTIVE: The aim of this systematic search and meta-ethnography was to identify and synthesize qualitative studies to better understand the experiences, perspectives, and needs of adolescent and young adult brain tumor survivors. METHODS: Five databases were searched using predefined criteria, studies were independently screened by two researchers, and those meeting inclusion criteria were synthesized. RESULTS: Twenty-seven studies were synthesized, generating 2 main themes, each with subthemes: (1) individual factors impacting resilience, namely, positive coping styles, managing emotions, and family functioning, and (2) cancer-related factors that challenge the individual, namely, living with societal expectations and barriers to coping. CONCLUSION: The conceptual framework illustrates the challenges and resilience of survivors along the continuum from adolescence to adulthood, reflecting the needs of this age group in 1 model, despite it being a time of rapid growth. The lack of awareness of potential physical and emotional late effects challenges individual resilience, which is further challenged when significant milestones cannot be reached. IMPLICATIONS FOR PRACTICE: There is a role for follow-up services to identify and address unmet needs, provide better information to equip survivors to manage late effects, and support families, particularly those who underwent more intensive treatment.
    • Controversies in upper GI: liquid biopsies

      Pietrantonio, F.; Rothwell, Dominic; Valpione, Sara; Department of Clinical and Experimental Pharmacology, Cancer Research UK Manchester Institute, Manchester. Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK. . (2023)
    • Therapeutic targeting of EP300/CBP by bromodomain inhibition in hematologic malignancies

      Nicosia, Luciano; Spencer, Gary J.; Brooks, N.; Amaral, Fabio M R; Basma, Nasar J; Chadwick, John A; Revell, Bradley; Wingelhofer, Bettina; Maiques-Diaz, Alba; Sinclair, Oliver; et al. (2023)
      CCS1477 (inobrodib) is a potent, selective EP300/CBP bromodomain inhibitor which induces cell-cycle arrest and differentiation in hematologic malignancy model systems. In myeloid leukemia cells, it promotes rapid eviction of EP300/CBP from an enhancer subset marked by strong MYB occupancy and high H3K27 acetylation, with downregulation of the subordinate oncogenic network and redistribution to sites close to differentiation genes. In myeloma cells, CCS1477 induces eviction of EP300/CBP from FGFR3, the target of the common (4; 14) translocation, with redistribution away from IRF4-occupied sites to TCF3/E2A-occupied sites. In a subset of patients with relapsed or refractory disease, CCS1477 monotherapy induces differentiation responses in AML and objective responses in heavily pre-treated multiple myeloma. In vivo preclinical combination studies reveal synergistic responses to treatment with standard-of-care agents. Thus, CCS1477 exhibits encouraging preclinical and early-phase clinical activity by disrupting recruitment of EP300/CBP to enhancer networks occupied by critical transcription factors.
    • On the use of solid (133)Ba sources as surrogate for liquid (131)I in SPECT/CT calibration: a European multi-centre evaluation

      Tran-Gia, J; Denis-Bacelar, AM; Ferreira, KM; Robinson, AP; Bobin, C; Bonney, LM; Calvert, Nicolas; Collins, SM; Fenwick, AJ; Finocchiaro, D; et al. (2023)
      INTRODUCTION: Commissioning, calibration, and quality control procedures for nuclear medicine imaging systems are typically performed using hollow containers filled with radionuclide solutions. This leads to multiple sources of uncertainty, many of which can be overcome by using traceable, sealed, long-lived surrogate sources containing a radionuclide of comparable energies and emission probabilities. This study presents the results of a quantitative SPECT/CT imaging comparison exercise performed within the MRTDosimetry consortium to assess the feasibility of using (133)Ba as a surrogate for (131)I imaging. MATERIALS AND METHODS: Two sets of four traceable (133)Ba sources were produced at two National Metrology Institutes and encapsulated in 3D-printed cylinders (volume range 1.68-107.4 mL). Corresponding hollow cylinders to be filled with liquid (131)I and a mounting baseplate for repeatable positioning within a Jaszczak phantom were also produced. A quantitative SPECT/CT imaging comparison exercise was conducted between seven members of the consortium (eight SPECT/CT systems from two major vendors) based on a standardised protocol. Each site had to perform three measurements with the two sets of (133)Ba sources and liquid (131)I. RESULTS: As anticipated, the (131)I pseudo-image calibration factors (cps/MBq) were higher than those for (133)Ba for all reconstructions and systems. A site-specific cross-calibration reduced the performance differences between both radionuclides with respect to a cross-calibration based on the ratio of emission probabilities from a median of 12-1.5%. The site-specific cross-calibration method also showed agreement between (133)Ba and (131)I for all cylinder volumes, which highlights the potential use of (133)Ba sources to calculate recovery coefficients for partial volume correction. CONCLUSION: This comparison exercise demonstrated that traceable solid (133)Ba sources can be used as surrogate for liquid (131)I imaging. The use of solid surrogate sources could solve the radiation protection problem inherent in the preparation of phantoms with (131)I liquid activity solutions as well as reduce the measurement uncertainties in the activity. This is particularly relevant for stability measurements, which have to be carried out at regular intervals.
    • Germline testing of BRCA1, BRCA2, PALB2 and CHEK2 c.1100delC in 1514 triple negative familial and isolated breast cancers from a single centre, with extended testing of ATM, RAD51C and RAD51D in over 400

      Woodward, Emma R; Lalloo, F; Forde, C; Pugh, S; Burghel, G J; Schlecht, H; Harkness, E F; Howell, Anthony; Howell, Sacha J; Gandhi, A; et al. (2023)
      BACKGROUND: The identification of germline pathogenic gene variants (PGVs) in triple negative breast cancer (TNBC) is important to inform further primary cancer risk reduction and TNBC treatment strategies. We therefore investigated the contribution of breast cancer associated PGVs to familial and isolated invasive TNBC. METHODS: Outcomes of germline BRCA1, BRCA2 and CHEK2_c.1100delC testing were recorded in 1514 women (743-isolated, 771-familial), and for PALB2 in 846 women (541-isolated, 305-familial), with TNBC and smaller numbers for additional genes. Breast cancer free controls were identified from Predicting Risk Of Cancer At Screening and BRIDGES (Breast cancer RIsk after Diagnostic GEne Sequencing) studies. RESULTS: BRCA1_PGVs were detected in 52 isolated (7.0%) and 195 (25.3%) familial cases (isolated-OR=58.9, 95% CI: 16.6 to 247.0), BRCA2_PGVs in 21 (2.8%) isolated and 67 (8.7%) familial cases (isolated-OR=5.0, 95% CI: 2.3 to 11.2), PALB2_PGVs in 9 (1.7%) isolated and 12 (3.9%) familial cases (isolated-OR=8.8, 95% CI: 2.5 to 30.4) and CHEK2_c.1100delC in 0 isolated and 3 (0.45%) familial cases (isolated-OR=0.0, 95% CI: 0.00 to 2.11). BRCA1_PGV detection rate was >10% for all familial TNBC age groups and significantly higher for younger diagnoses (familial: <50 years, n=165/538 (30.7%); ≥50 years, n=30/233 (12.9%); p<0.0001). Women with a G3_TNBC were more likely to have a BRCA1_PGV as compared with a BRCA2 or PALB2_PGV (p<0.0001). 0/743 isolated TNBC had the CHEK2_c.1100delC PGV and 0/305 any ATM_PGV, but 2/240 (0.83%) had a RAD51D_PGV. CONCLUSION: PGVs in BRCA1 are associated with G3_TNBCs. Familial TNBCs and isolated TNBCs <30 years have a >10% likelihood of a PGV in BRCA1. BRCA1_PGVs are associated with younger age of familial TNBC. There was no evidence for any increased risk of TNBC with CHEK2 or ATM PGVs.
    • Validation of metastasis-free survival as a surrogate endpoint for overall survival in localized prostate cancer in the era of docetaxel for castration resistant prostate cancer

      Xie, W.; Ravi, P.; Buyse, M.; Halabi, S.; Kantoff, P.; Sartor, O.; Soule, H.; Clarke, Noel; Dignam, J.; James, N.; et al. (2023)
      BACKGROUND: Prior work from the Intermediate Clinical Endpoints in Cancer of the Prostate (ICECaP) consortium (ICECaP-1) demonstrated that metastasis-free survival (MFS) is a valid surrogate for overall survival (OS) in localized prostate cancer (PCa). This was based on data from patients treated predominantly before 2004, prior to docetaxel being available for the treatment of metastatic castrate-resistant prostate cancer (mCRPC). We sought to validate surrogacy in a more contemporary era (ICECaP-2) with greater availability of docetaxel and other systemic therapies for mCRPC. PATIENTS & METHODS: Eligible trials for ICECaP-2 were those providing individual patient data (IPD) after publication of ICECaP-1 and evaluating adjuvant/salvage therapy for localized PCa, and which collected MFS and OS data. MFS was defined as distant metastases or death from any cause, and OS defined as death from any cause. Surrogacy was evaluated using a meta-analytic two-stage validation model, with an R(2) ≥0.7 defined a priori as clinically relevant. RESULTS: 15,164 IPD from 14 trials were included in ICECaP-2, with 70% of patients treated after 2004. Median follow-up was 8.3 years and median post-metastasis survival was 3.1 years in ICECaP-2, compared to 1.9 years in ICECaP-1. For surrogacy condition 1, Kendall's tau was 0.92 for MFS with OS at the patient-level, and R(2) from weighted linear regression (WLR) of 8-yr OS on 5-yr MFS was 0.73 (95% CI 0.53-0.82) at the trial level. For condition 2, R(2) was 0.83 (0.64-0.89) from WLR of log(HR)-OS on log(HR)-MFS. The surrogate threshold effect on OS was an HR(MFS) of 0.81. CONCLUSION: MFS remained a valid surrogate for OS in a more contemporary era, where patients had greater access to docetaxel and other systemic therapies for mCRPC. This supports the use of MFS as the primary outcome measure for ongoing adjuvant trials in localized PCa.
    • Exploring the promise of second-line chemotherapy in biliary tract tumours: a glimpse into novel treatment approaches

      Villalba Cuesta, P; Avedillo Ruidiaz, M; Ruiz Hispán, E; Fuentes Mateos, R; Lamarca, Angela; Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK. (2023)
      Biliary tract tumours, including bile duct, gallbladder, and ampulla of Vater malignancies, pose a rare but formidable oncologic challenge. Typically diagnosed at advanced stages, these tumours offer limited treatment options and dismal prognoses, with a five-year survival rate below 20%. First-line chemotherapy with gemcitabine-cisplatin has demonstrated only modest efficacy, leaving a pressing need for improved therapeutic strategies. This comprehensive review provides a detailed examination of the current landscape of second-line chemotherapy for biliary tract tumours. The pivotal ABC-06 trial established FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) as the standard second-line therapy, demonstrating improved overall survival compared to active symptom control alone. Conversely, the NIFTY trial introduced nal-IRI (nanoliposomal irinotecan) plus 5-FU/LV (5-fluorouracil and leucovorin) as an alternative option, demonstrating substantial gains in progression-free and overall survival. However, the posterior NALIRICC trial presented conflicting results, raising questions about the added benefit of nal-IRI. Challenges in delivering second-line chemotherapy include rapid patient performance deterioration post-first-line treatment and limited access to second-line therapy. Only a fraction of eligible patients receive second-line therapy, emphasising the need for more effective first-line therapies to maintain patient fitness. The role of monotherapy in the second-line setting remains uncertain, particularly in unfit patients, and the absence of biomarkers for tailored treatment underscores the need for ongoing research. While challenges persist, ongoing investigations offer hope for optimising second-line therapy for biliary tract tumours, promising improved outcomes for patients facing this disease. This review provides an overview of current facts and challenges when delivering second-line chemotherapy for advanced biliary tract tumours.
    • Ibrutinib as first line therapy for mantle cell lymphoma: A multicentre, real-world UK study

      Tivey, A; Shotton, R; Eyre, TA; Lewis, D; Stanton, L; Allchin, R; Walter, H S; Miall, F; Zhao, R; Santarsieri, A; et al. (2023)
      During the Covid-19 pandemic, ibrutinib +/- rituximab was approved in England for initial treatment of mantle cell lymphoma (MCL) instead of immunochemotherapy. As limited data are available in this setting, we conducted an observational cohort study evaluating safety and efficacy. Adults receiving ibrutinib +/- rituximab for untreated MCL were evaluated for treatment toxicity, response and survival, including outcomes in high-risk MCL (TP53 mutation/deletion/p53 overexpression, blastoid/pleomorphic, or Ki67 >/=30%). 149 patients from 43 participating centres were enrolled: 74.1% male, median age 75, 75.2% ECOG 0-1, 36.2% high-risk, 8.9% autologous transplant candidates. All patients received >/= 1 cycle ibrutinib (median 8 cycles), 39.0% with rituximab. Grade >/= 3 toxicity occurred in 20.3%, 33.8% required dose reductions/delays. At 15.6 months (mo) median follow-up, 41.6% discontinued ibrutinib; 8.1% due to toxicity. Of 104 response-assessed patients, overall (ORR) and complete response (CR) rates were 71.2% and 20.2% respectively. ORR was 77.3% (low-risk) vs. 59.0% (high-risk), p=0.05, and 78.7% (ibrutinib-rituximab) vs. 64.9% (ibrutinib), p=0.13. Median progression-free survival was 26.0mo (all patients); 13.7mo (high-risk) vs. not reached (NR) (low-risk), p=0.004. Median overall survival was NR (all); 14.8mo (high-risk) vs. NR (low-risk), p=0.005. Median post-ibrutinib survival was 1.4mo, longer in 41.9% patients receiving subsequent treatment (median 8.6 vs 0.6mo, p=0.002). Ibrutinib +/- rituximab was effective and well tolerated as first-line treatment of MCL, including older and transplant-ineligible patients. PFS and OS were significantly inferior in one-third of patients with high-risk disease and those unsuitable for post-ibrutinib treatment, highlighting the need for novel approaches in these groups.
    • Randomised phase III trial of the hypoxia modifier nimorazole added to radiotherapy with benefit assessed in hypoxic head and neck cancers determined using a gene signature (NIMRAD)

      Thomson, David J; Slevin, Nick; Baines, H; Betts, G; Bolton, Steve; Evans, M; Garcez, Kate; Irlam, J; Lee, Lip; Melillo, N; et al. (2023)
      BACKGROUND: Tumour hypoxia is an adverse prognostic factor in head and neck squamous cell carcinoma (HNSCC). We assessed whether patients with hypoxic HNSCC benefited from the addition of nimorazole to definitive intensity-modulated radiotherapy (IMRT). METHODS: NIMRAD was a phase III, multi-centre, placebo controlled, double-anonymized trial in patients with HNSCC unsuitable for concurrent platinum chemotherapy or cetuximab with definitive IMRT (NCT01950689). Patients were randomized 1:1 to receive IMRT (65 Gy in 30 fractions over 6 weeks) plus nimorazole (1.2 g/m2 daily, prior to IMRT) or placebo. The primary endpoint was freedom from loco-regional progression (FFLRP) in patients with hypoxic tumours, defined as greater than or equal to the median tumour hypoxia score of the first 50 patients analysed (≥0.079), using a validated 26-gene signature. The planned sample size was 340 patients allowing for signature generation in 85%, assumed HR 0.50 for nimorazole effectiveness in the hypoxic group, and requiring 66 loco-regional failures to have 80% power in a two-tail log-rank test at the 5% significance level. RESULTS: 338 patients were randomised by 19 UK centres from May 2014 to May 2019, with a median follow-up of 3.1 years (95%CI 2.9-3.4). Hypoxia scores were available for 286 (85%). The median patient age was 73 years (range: 44-88, IQR: 70-76). There were 36 (25.9%) loco-regional failures in the hypoxic group, where nimorazole + IMRT did not improve FFLRP (adjusted HR 0.72; 95% CI 0.36-1.44; p=0.35), or overall survival (adjusted HR 0.96; 0.53-1.72; p=0.88) compared with placebo + IMRT. Similarly, nimorazole + IMRT did not improve FFLRP or OS in the whole population. In total (n=338), 73% of patients allocated nimorazole adhered to the drug for ≥50% of IMRT fractions. Nimorazole + IMRT caused more acute nausea compared with placebo + IMRT (CTCAE v4.0 G1+2: 56.6% vs 42.4%, G3: 10.1% vs 5.3%, respectively; p<0.05). CONCLUSIONS: Addition of the hypoxia modifier nimorazole to IMRT for locally advanced HNSCC in older and less fit patients did not improve loco-regional control or survival.
    • Structural characterization and origin of surface vesicles in monocytes: another membranous pathway from cytoplasm to cell surface

      Ru, Y; Dong, S; Liu, J; Liu, J; Eyden, Brian; Department of Histopathology, Christie NHS Foundation Trust, Manchester, UK. (2024)
      The monocytes in acute monocytic leukemia (AML-M5b) were analyzed by scanning and transmission electron microscopy (SEM and TEM) to understand more fully their structure and origin. By SEM, monocytes exhibited localized expansions of the surface, some of which appeared to bud off as surface vesicles (SVs). Filopodial processes and pseudopodia were also present. TEM demonstrated that the SVs were composed of a double-membrane at the pole away from the cell body, and a single membrane nearer to the cell body. In the peripheral cytoplasm, intracellular vesicles (IVs) had the appearance of vacuoles and were enclosed by single membranes. Most SVs were characterized by a notch as a rER edge and an expanded head. Filopodial processes had the same thickness of 40 nm as the SV walls, which suggested a close developmental relationship between the two. Pseudopodia between SVs were irregular in size. Rod-like rER cisternae were prominent in the peripheral cytoplasm and some showed a close physical juxtaposition as to suggest a transition from rER to IVs to SVs. Ultrastructural cytochemistry demonstrated activity of 5'-nucleotidase over rER, SVs, filopodial processes and pseudopodia, and a patchy reaction over other areas of plasma membrane. Overall, the results indicated that rER transforms into SVs, filopodial processes and pseudopodia, as a way of integrating cytoplasmic membranes into the plasma membrane.
    • Pentafluoropropane with tetrafluoroethane: a hidden greenhouse gas in regional anaesthesia

      Sparke, RE; Song, A; Shelton, CL; Patey, Suzannah J; Department of Anaesthesia, The Christie NHS Foundation Trust, Manchester, UK (2023)