• N-(phosphonacetyl)-L-aspartate (PALA) in advanced soft tissue sarcoma: a phase II trial of the EORTC soft tissue sarcoma group.

      Bramwell, Vivien H C; Van Oosterom, A; Mouridsen, H T; Cheix, F; Somers, R; Thomas, D; Rozencweig, M; University of Manchester, Department of Medical Oncology, Christie Hospital, Wilmslow Road, Manchester, U.K. (1982-01)
      Thirty-six patients with measurable or evaluable advanced soft tissue sarcoma were entered in a phase II trial with PALA. Among the 27 evaluable patients, 15 were men, the median age was 55 yr (16-69) and the median performance status (Karnofsky) was 80 (50-100). Most patients had leiomyosarcoma (8), liposarcoma (3), neurofibrosarcoma (3), synovial cell sarcoma (3), or undifferentiated sarcoma (3). Indicator lesions consisted essentially of lung metastases (21) and/or soft tissue lesions (14). All patients had received prior chemotherapy with 1-5 regimens and 6 had achieved objective response with these previous treatments. PALA was given as a 60-min i.v. infusion at a daily dose of 2.5 g/m2 for two consecutive days. Courses were repeated every two weeks. A median number of 3 courses (2-17) were administered. Partial remission (greater than 50%) was obtained in one patient with a liposarcoma who had also responded to prior combination chemotherapy. This single response to PALA lasted 6 weeks from initiation of therapy. Four patients had unchanged disease after 6+ courses of PALA and 22 had progressive disease. Toxic effects were generally mild to moderate and included cutaneous toxicity (17), diarrhea (14), stomatitis (13), ocular manifestations, consisting of conjunctivitis, corneal ulceration and/or photophobia (11), nausea and vomiting (6) and, possibly, seizures (2). There was no evidence of drug-related myelosuppression. It is concluded that PALA given at the dose schedule selected for this trial has no significant antitumor activity in advanced soft tissue sarcoma previously treated with chemotherapy.
    • N-cadherin/FGFR promotes metastasis through epithelial-to-mesenchymal transition and stem/progenitor cell-like properties.

      Qian, X; Anzovino, A; Kim, S; Suyama, K; Yao, J; Hulit, James; Agiostratidou, G; Chandiramani, N; McDaid, H; Nagi, C; et al. (2014-06-26)
      N-cadherin and HER2/neu were found to be co-expressed in invasive breast carcinomas. To test the contribution of N-cadherin and HER2 in mammary tumor metastasis, we targeted N-cadherin expression in the mammary epithelium of the MMTV-Neu mouse. In the context of ErbB2/Neu, N-cadherin stimulated carcinoma cell invasion, proliferation and metastasis. N-cadherin caused fibroblast growth factor receptor (FGFR) upmodulation, resulting in epithelial-to-mesenchymal transition (EMT) and stem/progenitor like properties, involving Snail and Slug upregulation, mammosphere formation and aldehyde dehydrogenase activity. N-cadherin potentiation of the FGFR stimulated extracellular signal regulated kinase (ERK) and protein kinase B (AKT) phosphorylation resulting in differential effects on metastasis. Although ERK inhibition suppressed cyclin D1 expression, cell proliferation and stem/progenitor cell properties, it did not affect invasion or EMT. Conversely, AKT inhibition suppressed invasion through Akt 2 attenuation, and EMT through Snail inhibition, but had no effect on cyclin D1 expression, cell proliferation or mammosphere formation. These findings suggest N-cadherin/FGFR has a pivotal role in promoting metastasis through differential regulation of ERK and AKT, and underscore the potential for targeting the FGFR in advanced ErbB2-amplified breast tumors.
    • N-myc gene is amplified in alveolar rhabdomyosarcomas (RMS) but not in embryonal RMS.

      Dias, P; Kumar, Patricia; Marsden, Henry B; Gattamaneni, Rao; Heighway, Jim; Kumar, Shant; Christie Hospital and Holt Radium Institute, Withington, Manchester, UK. (1990-04-15)
      DNA from 13 (6 alveolar and 7 embryonal) childhood rhabdomyosarcomas (RMS) was examined to determine the incidence and prognostic relevance of N- and c-myc genes. Southern analysis showed 5- to 20-fold amplification of N-myc gene in 4 of 6 alveolar but in none of 7 embryonal RMS (p less than 0.04; Fisher's exact test). The number of children who died with multiple- and single-copy N-myc gene was 4/4 and 5/9 respectively (p greater than 0.05; Chi-squared test). There was no statistically significant correlation between N-myc amplification and age, gender, site, stage or survival time. There was no amplification or gross rearrangement of c-myc in any of the 13 RMS.
    • Naming disease states for clinical utility in prostate cancer: a rose by any other name might not smell as sweet.

      Armstrong, A; Antonarakis, E; Taplin, M; Kelly, W; Beltran, H; Fizazi, K; Dahut, W; Shore, N; Slovin, S; George, D; et al. (2017-10-23)
    • Nano-scavengers for blood biomarker discovery in ovarian carcinoma

      Hadjidemetriou, M.; Papafilippou, L.; Unwin, R. D.; Rogan, Jane; Clamp, Andrew R; Kostarelosa, K.; Nanomedicine Lab, Faculty of Biology, Medicine & Health, AV Hill Building, The University of Manchester, Manchester, (2020)
      The development and implementation of biomarker-based screening tools for ovarian cancer require novel analytical platforms to enable the discovery of biomarker panels that will overcome the limitations associated with the clinically used CA-125.The systematic discovery of protein biomarkers directly from human plasma using proteomics remains extremely challenging, due to the wide concentration range of plasma proteins. Here, we describe the use of lipid-based nanoparticles (NPs) as an ‘omics’ enrichment tool to amplify cancer signals in the blood and to uncover disease specific signatures. We aimed to exploit the spontaneous interaction of clinically-used liposomes (Caelyx®) with plasma proteins, also known as’ protein corona’ formation, in order to facilitate the discovery of previously unreported differentially abundant molecules. Caelyx® liposomes were incubated with plasma samples obtained from advanced ovarian carcinoma patients and healthy donors and corona-coated liposomes were subsequently recovered. Comprehensive comparison between ‘healthy’ and ‘diseased’ corona samples by label-free proteomics resulted in the identification of multiple differentially abundant proteins. Moreover, immunoassay-based validation of selected proteins demonstrated the potential of nanoparticle-platform proposed to discover novel molecules with great diagnostic potential. This study proposes a nanoparticle-enabled workflow for plasma proteomic analysis in healthy and diseased states and paves the way for further work needed to discover and validate panels of novel biomarkers for disease diagnosis and monitoring.
    • Nanodosimetric Simulation of Direct Ion-Induced DNANanodosimetric simulation of direct ion-induced DNA damage using different chromatin geometry models.

      Henthorn, N; Warmenhoven, J; Sotiropoulos, M; Mackay, Ranald I; Kirkby, Karen J; Merchant, Michael J; Division of Molecular and Clinical Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, United Kingdom (2017-08-09)
      Monte Carlo based simulation has proven useful in investigating the effect of proton-induced DNA damage and the processes through which this damage occurs. Clustering of ionizations within a small volume can be related to DNA damage through the principles of nanodosimetry. For simulation, it is standard to construct a small volume of water and determine spatial clusters. More recently, realistic DNA geometries have been used, tracking energy depositions within DNA backbone volumes. Traditionally a chromatin fiber is built within the simulation and identically replicated throughout a cell nucleus, representing the cell in interphase. However, the in vivo geometry of the chromatin fiber is still unknown within the literature, with many proposed models. In this work, the Geant4-DNA toolkit was used to build three chromatin models: the solenoid, zig-zag and cross-linked geometries. All fibers were built to the same chromatin density of 4.2 nucleosomes/11 nm. The fibers were then LET proton irradiated (5-80 keV/μm) or LET alpha-particle irradiated (63-226 keV/μm). Nanodosimetric parameters were scored for each fiber after each LET and used as a comparator among the models. Statistically significant differences were observed in the double-strand break backbone size distributions among the models, although nonsignificant differences were noted among the nanodosimetric parameters. From the data presented in this article, we conclude that selection of the solenoid, zig-zag or cross-linked chromatin model does not significantly affect the calculated nanodosimetric parameters. This allows for a simulation-based cell model to make use of any of these chromatin models for the scoring of direct ion-induced DNA damage.
    • Nanoliposomal irinotecan in the clinical practice guideline for metastatic pancreatic cancer: applicability to clinical situations.

      Wang-Gillam, A; Von Hoff, D; Siveke, J; Hubner, Richard A; Belanger, B; Pipas, J; Chen, L; Washington University School of Medicine, St. Louis, MO (2016-12-05)
    • Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial.

      Wang-Gillam, A; Li, C; Bodoky, G; Dean, A; Shan, Y; Jameson, G; Macarulla, T; Lee, K; Cunningham, D; Blanc, J; et al. (2015-11-29)
      Nanoliposomal irinotecan showed activity in a phase 2 study in patients with metastatic pancreatic ductal adenocarcinoma previously treated with gemcitabine-based therapies. We assessed the effect of nanoliposomal irinotecan alone or combined with fluorouracil and folinic acid in a phase 3 trial in this population.
    • NAPOLI-1 phase 3 study of liposomal irinotecan in metastatic pancreatic cancer: final overall survival analysis and characteristics of long-term survivors.

      Wang-Gillam, A; Hubner, Richard A; Siveke, J; Von Hoff, D; Belanger, B; de Jong, F; Mirakhur, B; Chen, L; Washington University School of Medicine, 660 S Euclid Avenue, St. Louis, MO 63110, USA (2019)
      BACKGROUND: Liposomal irinotecan (nal-IRI) plus 5-fluorouracil and leucovorin (5-FU/LV) is approved for patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) previously treated with gemcitabine-based therapy. This approval was based on significantly improved median overall survival compared with 5-FU/LV alone (6.1 vs 4.2 months; hazard ratio [HR], 0.67) in the global phase 3 NAPOLI-1 trial. Here, we report the final survival analysis and baseline characteristics associated with long-term survivors (survival of ?1 year) in the NAPOLI-1 trial. PATIENTS AND METHODS: Patients with mPDAC were randomised to receive nal-IRI + 5-FU/LV (n = 117), nal-IRI (n = 151), or 5-FU/LV (n = 149) for the first 4 weeks of 6-week cycles. Baseline characteristics and efficacy in the overall population were compared with those in patients who survived ?1 year. Through 16th November 2015, 382 overall survival events had occurred. RESULTS: The overall survival advantage for nal-IRI+5-FU/LV vs 5-FU/LV was maintained from the original nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1) analysis (6.2 vs 4.2 months, respectively; HR, 0.75; 95% confidence interval: 0.57-0.99). Median progression-free survival, objective response rate and disease control rate also favoured nal-IRI+5-FU/LV therapy. Estimated one-year overall survival rates were 26% with nal-IRI+5-FU/LV and 16% with 5-FU/LV. Baseline characteristics associated with long-term survival in the nal-IRI+5-FU/LV arm were Karnofsky performance status ?90, age ?65 years, lower CA19-9 levels, neutrophil-to-lymphocyte ratio ?5 and no liver metastases. No new safety concerns were detected. CONCLUSIONS: The survival benefits of nal-IRI+5-FU/LV versus 5-FU/LV were maintained over an extended follow-up, and prognostic markers of survival ?1 year were identified.
    • NAPOLI-3: An open-label, randomized, phase III study of first-line liposomal irinotecan+5-fluorouracil/leucovorin plus oxaliplatin versus nab-paclitaxel plus gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma

      Wainberg, Z. A.; Bekaii-Saab, T. S.; Hubner, Richard A; Macarulla, T.; Paulson, A. S.; Van Cutsem, E.; Maxwell, F.; Moore, Y.; Wang, H. T.; Zhang, B.; et al. (2020)
      Background: Liposomal irinotecan administered with 5-fluorouracil/leucovorin (5-FU/LV) is approved in the USA for metastatic pancreatic ductal adenocarcinoma (mPDAC) following progression with gemcitabine-based therapy. A phase 1/2 study in previously untreated locally advanced/metastatic PDAC showed promising anti-tumor activity with liposomal irinotecan 50 mg/m2 free base + 5-FU 2400 mg/m2 + LV 400 mg/m2 + oxaliplatin (OX) 60 mg/m2 on days 1 and 15 of a 28-day cycle (Wainberg et al. Ann Oncol 2019;30 Suppl 4: SO-005). Herein, we present the design of the phase 3 NAPOLI-3 study investigating the efficacy and safety of this regimen as first-line therapy in patients with mPDAC. Methods: NAPOLI-3 (NCT04083235) is a phase 3, open-label, randomized, global study in adults with histologically/cytologically confirmed pancreatic adenocarcinoma not previously treated in the metastatic setting. Patients are required to have one or more metastatic tumors measurable with computed tomography/magnetic resonance imaging and an Eastern Cooperative Oncology Group performance status score of 0–1. Site activation began in Dec 2019 and enrollment is ongoing. Random allocation (1:1) of 750 patients is planned to liposomal irinotecan + 5-FU/LV + OX (regimen as per phase 1/2 study) or nab-paclitaxel 125 mg/m2 + gemcitabine 1000 mg/m2 on days 1, 8 and 15 in a 28-day cycle. The primary endpoint is overall survival (OS). Secondary endpoints (progression-free survival [PFS] and overall response rate assessed with Response Evaluation Criteria in Solid Tumors v1.1 criteria) will be compared only if the primary endpoint shows superiority for liposomal irinotecan + 5-FU/ LV + OX over nab-paclitaxel + gemcitabine. Safety assessments include adverse-event monitoring. Patients will continue treatment until disease progression, unacceptable toxicity or study withdrawal, and will then be followed for survival every 2 months until death or study end (when all patients have died, withdrawn consent or are lost to follow-up).
    • A narrative review of primary research endpoints of neoadjuvant therapy for lung cancer: past, present and future

      Ren, S.; Xu, A.; Lin, Y.; Camidge, D. R.; Di Maio, M.; Califano, Raffaele; Hida, T.; Rossi, A.; Guibert, N.; Zhu, C; et al. (2021)
      Objective: This review summarizes the current status of neoadjuvant therapy and discusses the choice of new clinical research endpoints for non-small cell lung cancer. Background: Neoadjuvant chemotherapy is a recognized practice in patients with resectable and locally advanced lung cancer. With the introduction of molecular targeted drugs and immune checkpoint inhibitors (ICIs), the overall survival (OS) of patients with lung cancer has been significantly improved, and the original traditional clinical research endpoints are no longer suitable for existing clinical research. In order to accelerate the process of clinical trials and the development and approval of drugs, it is necessary to find suitable alternative indicators as the main indicators of clinical research. Methods: Therefore, this article focuses on clinical trials using disease-free survival (DFS), progression free survival, and pathological evaluation indicators, pathologic complete response and major pathologic response, as surrogate endpoints. We search related literature through PubMed database and clinical trials through clinicaltrials.gov. Conclusions: Pathologic complete response and major pathologic response are recommended as surrogate endpoints in the era of neoadjuvant immunotherapy, and secondary endpoints are listed for the prediction of pathological results. In addition, the definitions of major pathological response (MPR) and PCR should be standardized, and a new pathological evaluation standard should be developed, which is applicable to all current treatment methods.
    • Nasoethmoidal adenocarcinoma in woodworking twins.

      Logue, John P; Slevin, Nicholas J; Department of Radiotherapy and Oncology, Christie Hospital, Withington, Manchester, UK. (1990-09)
      The occurrence of nasoethmoidal adenocarcinoma in twins has not previously been reported. This paper describes the concurrent presentation in twins over 50 years after their first occupational exposure to hardwoods. There was a remarkable similarity in presentation.
    • Nasopharyngeal carcinoma - a retrospective review of demographics, treatment and patient outcome in a single centre.

      Colaco, Rovel J; Betts, Guy N J; Donne, A; Swindell, Ric; Yap, Beng K; Sykes, Andrew J; Slevin, Nicholas J; Homer, Jarrod J; Lee, Lip W; Department of Clinical Oncology, The Christie NHS Foundation Trust, Manchester, UK. (2013-03)
      Nasopharyngeal cancer (NPC) is relatively uncommon, especially in the Western world. We report our single institution experience of 20 years of data in 128 patients with NPC, including responses to different treatment modalities and outcomes by histological subtype.
    • Nasopharyngeal carcinoma in children.

      Roper, Henry P; Essex-Cater, A; Marsden, Henry B; Dixon, P F; Campbell, Richard H A; Department of Child Health, St. Mary's Hospital, Manchester, U.K. (1986)
      The results of treatment are reviewed in 18 cases of childhood nasopharyngeal carcinoma. Since 1976 adjuvant chemotherapy with cyclophosphamide, methotrexate, and adriamycin has been used in Manchester and Leeds. The outcome is compared in 9 patients treated with radiotherapy alone and 9 patients treated later with both radiotherapy and adjuvant chemotherapy. Relapse-free survival rates were 0% for those treated with radiotherapy alone and 78% at 13-80 months after diagnosis for those treated with both radiotherapy and chemotherapy. It is concluded that adjuvant chemotherapy improves relapse-free survival in childhood nasopharyngeal carcinoma.
    • Nasopharyngeal carcinoma mimicking large-cell anaplastic lymphoma.

      Menasce, Lia P; Eyden, Brian P; Department of Histopathology, Christie Hospital NHS Trust, Manchester, UK. (2005-03)
    • National Cancer Intelligence Network data for NET in England-accuracy by comparison to a large clinical database.

      Ramage, J; Rous, B; Sissons, M; Talbot, D; Reed, N; Khan, M; Valle, Juan W; Elshafie, M; Luong, T; Munir, A; et al. (2017)
    • National cohort study comparing severe medium-term urinary complications after robot-assisted vs laparoscopic vs retropubic open radical prostatectomy.

      Sujenthiran, A; Nossiter, J; Parry, M; Charman, S; Aggarwal, A; Payne, H; Dasgupta, P; Clarke, Noel W; van der Meulen, J; Cathcart, P; et al. (2017-10-15)
      To evaluate the occurrence of severe urinary complications within 2 years of surgery in men undergoing either robot-assisted radical prostatectomy (RARP), laparoscopic radical prostatectomy (LRP) or retropubic open radical prostatectomy (ORP).
    • A national dosimetric audit of IMRT.

      Budgell, Geoff J; Berresford, Joe; Trainer, Michael; Bradshaw, Ellie; Sharpe, Peter; Williams, Peter C; North Western Medical Physics, The Christie NHS Foundation Trust, Manchester, UK. (2011-05)
      A dosimetric audit of IMRT has been carried out within the UK between June 2009 and March 2010 in order to provide an independent check of safe implementation and to identify problems in the modelling and delivery of IMRT.
    • National implementation of the use of tisagenlecleucel in paediatric and young adult patients with acute lymphoblastic leukaemia (ALL) in National Health Service England (NHSE)

      Furness, C. L.; Hough, R.; Cummins, M.; Murphy, G.; Ghorashian, S.; Amrolia, P.; Roddie, C.; O'Reilly, M.; Wynn, R.; Bonney, D.; et al. (2020)
      Background: Following European Medicines Agency (EMA) approval of Tisagenlecleucel (KYMRIAH®) for the treatment of relapsed/refractory acute lymphoblastic leukaemia (ALL) in children and young adults in 2018, England established a structured funding programme via the National Health Service England (NHSE) Cancer Drugs Fund. Methods: NHSE established a national CAR-T clinical panel for ALL (NCCP ALL). The aim of the NCCP ALL was to review cases to confirm eligibility against published criteria in line with the ELIANA study inclusion criteria and ensure prompt national access to Tisagenlecleucel. All CAR-T centres (3 open at NCCP set up and 9 open at 1 year review) were accredited for the Immune Effector Cell Standards in the 7th edition of the JACIE Standards in line with EBMT/JACIE recommendations (Yakoub-Agha et al 2019). The NCCP ALL consisted of representatives from NHSE, CAR-T centres, patient representation and independent ALL clinical experts. We describe panel experience over a one year period. Results: The NCCP met by weekly teleconference to review cases referred by individual CAR-T centre lead clinicians who endorsed eligibility. Approval for access to Tisagenlecleucel was granted through unanimous panel consensus agreement following review of eligibility criteria (according to disease and CD19+ status, absence of CNS disease, performance status and organ function). Allocation to centre was achieved by review of geography, slot availability and patient preference. From 19.11.2018-18.11.2019 34 patients were approved (age range 9 months - 21 years, median age 10.5 years). 5 did not proceed to leukapheresis (2 incorrect diagnosis of relapse, 1 received alternative CAR-T clinical trial product, 2 unable to proceed due to disease progression/complications). At time of abstract submission 23/29 (79.3%) patients had undergone CAR-T infusion. 3 patients who underwent leukapheresis were unable to proceed to infusion (1 patient due to emergence of CD19 negative disease, 1 patient due to CNS disease progression, 1 patient received cranial radiotherapy to control CNS disease and suffered frank bone marrow relapse treated with Inotuzumab followed by a failed manufacture). 3 patients await infusion. Mean time from panel approval to leukapheresis was 15 days (range 0-47 days) and mean time from leukapheresis to CAR-T infusion for patients infused was 64 days (range 35 - 92 days) Of 15 patients evaluable beyond 100 days (8 patients yet to reach this time point), 11 have a documented status of ‘alive in MRD negative remission’. This represents 73% patients infused (11/15). Brief toxicity and follow up data will be reported at EBMT 2020 with future planned efficacy analysis. Conclusions: The establishment of a national panel in England for Tisagenlecleucel approval has allowed prompt, equitable and trackable access to this CAR-T product for ALL. From a worldwide perspective, NHSE is one of the first health services to introduce a national co-ordinated access programme of care and will utilise programme data to assess real world outcomes for patients treated with Tisagenlecleucel.
    • The National Institute for Health and Care Excellence (NICE) guidance on bladder cancer; a step in the right direction?

      Trainor, S; Choudhury, Ananya; Huddart, R; Kiltie, A; Kockelbergh, R; Turner, W; Birtle, A; Crabb, S; Department of Medical Oncology, St James's Institute of Oncology, Leeds (2017-02-09)