Now showing items 1-20 of 9964

    • An open-label, multicentre safety study of vemurafenib in patients with BRAFV600-mutant metastatic melanoma: final analysis and a validated prognostic scoring system

      Larkin, J; Brown, M; Arance, A; Hauschild, A; Queirolo, P; Vecchio, M; Ascierto, P; Krajsová, I; Schachter, J; Neyns, B; Garbe, C; Sileni, VC; Mandalà, M; Gogas, H; Espinosa, E; Hospers, G; Lorigan, Paul C; Nyakas, M; Guminski, A; Liszkay, G; Rutkowski, P; Miller, W; Donica, M; Makrutzki, M; Blank, C; Royal Marsden NHS FT, London (2019)
      BACKGROUND: The oncogenic BRAF inhibitor vemurafenib improves outcomes for patients with advanced BRAFV600 mutation-positive melanoma compared with cytotoxic chemotherapy. Vemurafenib is now approved for use in this patient population. PATIENTS AND METHODS: In this open-label, multicentre study, patients with previously treated or untreated melanoma and the BRAFV600 mutation received vemurafenib 960 mg twice daily. The primary endpoint was safety. In a post hoc analysis, overall survival (OS) was analysed according to a prognostic scoring system developed using Eastern Cooperative Oncology Group performance status, existence of brain metastases and baseline serum lactate dehydrogenase level. The index was validated using data from patients treated with vemurafenib or dacarbazine in three clinical trials and data from patients treated with vemurafenib plus cobimetinib in two studies. The study is registered with ClinicalTrials.gov (NCT01307397). RESULTS: Between March 2011 and January 2013, 3224 patients were enrolled, and 3219 patients received ?1 dose of vemurafenib (safety population); median follow-up time was 33.4 months. Vemurafenib's long-term benefits were confirmed, and no new safety signals identified. The prognostic index showed between-group differences in OS, with tight, non-overlapping confidence intervals. Validation in a pooled group of 666 vemurafenib-treated clinical trial patients revealed a similar pattern; the pattern was similar in 280 patients treated with vemurafenib plus cobimetinib. CONCLUSIONS: Final results from the vemurafenib safety study confirm vemurafenib's tolerability in BRAFV600 mutation-positive patients and resemble those seen in real-world clinical practice. This index may be useful in patients on combination therapy and as a basis for further.
    • Cancelled operations: a 7-day cohort study of planned adult inpatient surgery in 245 UK National Health Service hospitals

      Nariani, Jaya; Clark, Sam; Duniec, Larysa; Health Services Research Centre,National Institute of Academic Anaesthesia (2018)
      BACKGROUND: Cancellation of planned surgery impacts substantially on patients and health systems. This study describes the incidence and reasons for cancellation of inpatient surgery in the UK NHS. METHODS: We conducted a prospective observational cohort study over 7 consecutive days in March 2017 in 245 NHS hospitals. Occurrences and reasons for previous surgical cancellations were recorded. Using multilevel logistic regression, we identified patient- and hospital-level factors associated with cancellation due to inadequate bed capacity. RESULTS: We analysed data from 14 936 patients undergoing planned surgery. A total of 1499 patients (10.0%) reported previous cancellation for the same procedure; contemporaneous hospital census data indicated that 13.9% patients attending inpatient operations were cancelled on the day of surgery. Non-clinical reasons, predominantly inadequate bed capacity, accounted for a large proportion of previous cancellations. Independent risk factors for cancellation due to inadequate bed capacity included requirement for postoperative critical care [odds ratio (OR)=2.92; 95% confidence interval (CI), 2.12-4.02; P<0.001] and the presence of an emergency department in the treating hospital (OR=4.18; 95% CI, 2.22-7.89; P<0.001). Patients undergoing cancer surgery (OR=0.32; 95% CI, 0.22-0.46; P<0.001), obstetric procedures (OR=0.17; 95% CI, 0.08-0.32; P<0.001), and expedited surgery (OR=0.39; 95% CI, 0.27-0.56; P<0.001) were less likely to be cancelled. CONCLUSIONS: A significant proportion of patients presenting for surgery have experienced a previous cancellation for the same procedure. Cancer surgery is relatively protected, but bed capacity, including postoperative critical care requirements, are significant risk factors for previous cancellations.
    • Sun protection behavior after diagnosis of high-risk primary melanoma and risk of a subsequent primary

      von Schuckmann, L; Wilson, L; Hughes, M; Beesley, L; Janda, M; van der Pols, J; Smithers, B; Khosrotehrani, K; Green, Adèle C; Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia (2019)
      BACKGROUND: Melanoma survivors are at high risk of further primary melanomas. OBJECTIVE: To assess sun behavior after melanoma diagnosis and in relation to further primary melanomas. METHODS: We applied repeated measures latent class analysis to reported primary prevention behavior at time of diagnosis and every 6 months for 2 years after diagnosis in patients with clinical stage IB or II melanoma. Correlates of behavior trajectories and risk of subsequent primaries were determined by using multivariable logistic and Cox regression analyses, respectively. RESULTS: Among the 448 male and 341 female patients, sunscreen use fell into 3 trajectories: stable never-use (26% of males and 12% of females), stable sometimes-use (35% of males and 29% of females), and increased to often-use (39% of males and 59% of females). Most reduced their weekend sun exposure, but in 82% of males and 69% of females it remained increased. Males, smokers, the less educated, those who tanned, and those not self-checking their skin were more likely to have trajectories of inadequate protection. Patients with a history of melanoma before the study doubled their risk of another primary melanoma in the next 2 years if sunscreen use in that time was inadequate (hazard ratio, 2.45; 95% confidence interval, 1.00-6.06). LIMITATIONS: Patient-reported data are susceptible to recall bias. CONCLUSION: Our results may assist clinicians in identifying patients not using adequate sun protection and providing information for patient counseling.
    • Do airline pilots and cabin crew have raised risks of melanoma and other skin cancers? Systematic review and meta-analysis.

      Miura, K; Olsen, C; Rea, S; Marsden, J; Green, Adèle C; Population Health Department, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Queensland, 4006, Australia (2018)
      BACKGROUND: Airline pilots and cabin crew are potentially exposed to hazardous ultraviolet (UV) and cosmic radiation that may increase their risk of melanoma and other skin cancers. OBJECTIVES: To establish precise risks of melanoma and keratinocyte cancer (KC) for airline pilots and for cabin crew based on all studies published to date. METHODS: We searched Medline, ISI science citation index, EMBASE, SCOPUS, and CINAHL to June 2018. All studies of melanoma and KC risk and mortality in airline pilots and cabin crew compared with the general population were eligible. Standardised incidence ratios (SIRs) and mortality ratios (SMRs) were pooled using random effects models. RESULTS: From 5866 articles, we reviewed 44 full-text articles, of which 12 studies whose data were collected mostly between the 1970s-1990s, were eligible for inclusion. The pooled SIR (pSIR) for melanoma in pilots was 2.03 (95% confidence interval (CI) 1.71-2.40) and in cabin crew was 2.12 (95% CI 1.71-2.62). For pilots, pSMR for melanoma was 1.99 (95% CI 1.17-3.40) and for cabin crew was 1.18 (95% CI 0.73-1.89). For KC, the pSIR was 1.86 (95% CI 1.54-2.25) in pilots and 1.97 (95% CI 1.25-2.96) in cabin crew. There was no evidence of study heterogeneity. CONCLUSIONS: Available evidence shows that airline pilots and cabin crew have about twice the risk of melanoma and other skin cancers compared with the general population, with pilots more likely to die from melanoma. However, most of evidence was collected several decades ago and their relevance to contemporary levels of risk is uncertain.
    • Fluoromethylcyclopropylamine derivatives as potential in vivo toxicophores - a cautionary disclosure

      Acton, Ben; Small, Helen F; Smith, Kate M; McGonagle, Alison E; Stowell, Alexandra I; James, Dominic I; Hamilton, Nial M; Hamilton, Nicola S; Hitchin, James R; Hutton, Colin P; Waddell, Ian D; Ogilvie, Donald J; Jordan, Allan M; Drug Discovery Unit, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, Macclesfield SK10 4TG, UK (2019)
      Fluorination of metabolic hotspots in a molecule is a common medicinal chemistry strategy to improve in vivo half-life and exposure and, generally, this strategy offers significant benefits. Here, we report the application of this strategy to a series of poly-ADP ribose glycohydrolase (PARG) inhibitors, resulting in unexpected in vivo toxicity which was attributed to this single-atom modification.
    • Artificial intelligence in drug design-the storm before the calm?

      Jordan, Allan M; Drug Discovery Unit, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, Macclesfield, SK10 4TG, UK (2018)
      Artificial intelligence in drug design in experiencing a wave of excitement not seen since the emergence of computational chemistry in the late 1980s and early 1990s. Apparently failing to learn the lessons of recent history, we are promised imminent and pervasive solutions to the ills of drug design and significant increases in productivity as we seek to deliver innovative new therapeutics. However, do significant issues remain to be answered before AI enters the day-to-day toolbox of the practicing medicinal chemist?
    • Survival of patients with early invasive melanoma down-staged under the new eighth edition of the American Joint Committee on Cancer staging system.

      von Schuckmann, L; Hughes, M; Lee, R; Lorigan, Paul C; Khosrotehrani, K; Smithers, M; Green, Adèle C; Population Health Department, Queensland Institute of Medical Research Berghofer Medical Research Institute, Herston, Australia (2019)
    • Correction: cutaneous melanoma primary site is linked to nevus density

      Martin-Gorgojo, A; Llinares, M; Viros, Amaya; Requena, C; Garcia-Casado, Z; Traves, V; Kumar, R; Nagore, E; Escuela de Doctorado, Universidad Catolica de Valencia 'San Vicente Martir', Valencia, Spain (2018)
      This corrects the article DOI: 10.18632/oncotarget.22016.Erratum for Cutaneous melanoma primary site is linked to nevus density. [Oncotarget. 2017]
    • Trends in melanoma incidence rates in eight susceptible populations to 2015.

      Olsen, C; Green, Adèle C; Pandeya, N; Whiteman, D; Department of Population Health, QIMR Berghofer Medical Research Institute, Queensland, Australia (2018)
    • Changes in prostate apparent diffusion coefficient values during radiotherapy after neoadjuvant hormones

      McPartlin, Andrew J; Kershaw, L; McWilliam, Alan; Taylor, Benjamin; Hodgson, Clare; van Herk, Marcel; Choudhury, Ananya; The Christie NHS Foundation Trust, Wilmslow Road, Manchester M20 4BX, UK (2018)
      BACKGROUND: Changes in prostate cancer apparent diffusion coefficient (ADC) derived from diffusion-weighted magnetic resonance imaging (MRI) provide a noninvasive method for assessing radiotherapy response. This may be attenuated by neoadjuvant hormone therapy (NA-HT). We investigate ADC values measured before, during and after external beam radiotherapy (EBRT) following NA-HT. METHODS: Patients with ?T2c biopsy-proven prostate cancer receiving 3 months of NA-HT plus definitive radiotherapy were prospectively identified. All underwent ADC-MRI scans in the week before EBRT, in the third week of EBRT and 8 weeks after its completion. Imaging was performed at 1.5?T. The tumour, peripheral zone (PZ) and central zone (CZ) of the prostate gland were identified and median ADC calculated for each region and time point. RESULTS: Between September and December 2014, 15 patients were enrolled (median age 68.3, range 57-78) with a median Gleason score of 7 (6-9) and prostate-specific antigen (PSA) at diagnosis 14 (3-197) ng/ml. Median period of NA-HT prior to first imaging was 96 days (69-115). All patients completed treatment. Median follow up was 25 months (7-34), with one patient relapsing in this time. Thirteen patients completed all imaging as intended, one withdrew after one scan and another missed the final imaging. PZ and CZ could not be identified in one patient. Median tumour ADC before, during and post radiotherapy was 1.24?×?10-3?mm2/s (interquartile range 0.16?×?10-3?mm2/s), 1.31?×?10-3?mm2/s (0.22?×?10-3?mm2/s), then 1.32?×?10-3?mm2/s (0.13?×?10-3?mm2/s) respectively (p?>?0.05). There was no significant difference between median tumour and PZ or CZ ADC at any point. Gleason score did not correlate with ADC values. CONCLUSIONS: Differences in ADC parameters of normal and malignant tissue during EBRT appear attenuated by prior NA-HT. The use of changes in ADC as a predictive tool in this group may have limited utility.
    • EmPHasis-10 score for the assessment of quality of life in various types of pulmonary hypertension and its relation to outcome

      Favoccia, C; Kempny, A; Yorke, Janelle; Armstrong, I; Price, L; McCabe, C; Harries, C; Wort, S; Dimopoulos, K; Adult Congenital Heart Centre and National Centre for Pulmonary Hypertension, Royal Brompton Hospital, UK (2018)
    • 'Blood letting' technique with externalized microvascular anastomotic coupler: a salvage option to release intraoperative venous congestion of propeller flap

      Tsapralis, Nikolaos; Pham, Hien; Vlachogiorgos, Apostolos; Kosutic, Damir; Department of Plastic Surgery, The Christie NHS Foundation Trust, Manchester, United Kingdom (2018)
    • Brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma (ECHELON-2): a global, double-blind, randomised, phase 3 trial

      Horwitz, S; O'Connor, O; Pro, B; Illidge, Timothy M; Fanale, M; Advani, R; Bartlett, N; Christensen, J; Morschhauser, F; Domingo-Domenech, E; Rossi, G; Kim, W; Feldman, T; Lennard, A; Belada, D; Illes, A; Tobinai, K; Tsukasaki, K; Yeh, S; Shustov, A; Huttmann, A; Savage, K; Yuen, S; Iyer, S; Zinzani, P; Hua, Z; Little, M; Rao, S; Woolery, J; Manley, T; Trumper, L; Memorial Sloan Kettering Cancer Center, New York, NY, USA (2019)
      Erratum in Department of Error. [Lancet. 2019] BACKGROUND: Based on the encouraging activity and manageable safety profile observed in a phase 1 study, the ECHELON-2 trial was initiated to compare the efficacy and safety of brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone (A+CHP) versus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) for the treatment of CD30-positive peripheral T-cell lymphomas. METHODS: ECHELON-2 is a double-blind, double-dummy, randomised, placebo-controlled, active-comparator phase 3 study. Eligible adults from 132 sites in 17 countries with previously untreated CD30-positive peripheral T-cell lymphomas (targeting 75% with systemic anaplastic large cell lymphoma) were randomly assigned 1:1 to receive either A+CHP or CHOP for six or eight 21-day cycles. Randomisation was stratified by histological subtype according to local pathology assessment and by international prognostic index score. All patients received cyclophosphamide 750 mg/m2 and doxorubicin 50 mg/m2 on day 1 of each cycle intravenously and prednisone 100 mg once daily on days 1 to 5 of each cycle orally, followed by either brentuximab vedotin 1.8 mg/kg and a placebo form of vincristine intravenously (A+CHP group) or vincristine 1.4 mg/m2 and a placebo form of brentuximab vedotin intravenously (CHOP group) on day 1 of each cycle. The primary endpoint, progression-free survival according to blinded independent central review, was analysed by intent-to-treat. This trial is registered with ClinicalTrials.gov, number NCT01777152. FINDINGS: Between Jan 24, 2013, and Nov 7, 2016, 601 patients assessed for eligibility, of whom 452 patients were enrolled and 226 were randomly assigned to both the A+CHP group and the CHOP group. Median progression-free survival was 48.2 months (95% CI 35.2-not evaluable) in the A+CHP group and 20.8 months (12.7-47.6) in the CHOP group (hazard ratio 0.71 [95% CI 0.54-0.93], p=0.0110). Adverse events, including incidence and severity of febrile neutropenia (41 [18%] patients in the A+CHP group and 33 [15%] in the CHOP group) and peripheral neuropathy (117 [52%] in the A+CHP group and 124 [55%] in the CHOP group), were similar between groups. Fatal adverse events occurred in seven (3%) patients in the A+CHP group and nine (4%) in the CHOP group. INTERPRETATION: Front-line treatment with A+CHP is superior to CHOP for patients with CD30-positive peripheral T-cell lymphomas as shown by a significant improvement in progression-free survival and overall survival with a manageable safety profile. FUNDING: Seattle Genetics Inc, Millennium Pharmaceuticals Inc, a wholly owned subsidiary of Takeda Pharmacuetical Company Limited, and National Institutes of Health National Cancer Institute Cancer Center.
    • Cascaded systems analysis of a-Se/a-Si and a-InGaZnO TFT passive and active pixel sensors for tomosynthesis

      Sengupta, A; Zhao, C; Konstantinidis, Anastasios C; Kanicki, J; Electric Engineering and Computer Science, University of Michigan, 1301 Beal Avenue, Ann Arbor, Michigan, 48109-2122, USA (2018)
      Medical imaging systems like full field digital mammography (FFDM) and digital breast tomosynthesis (DBT) commonly use amorphous selenium (a-Se) based passive pixel sensor (PPS) direct conversion x-ray detectors. On one hand, direct conversion detectors inherently offer better resolution characteristics in terms of a higher modulation transfer function (MTF), in comparison to the indirect CsI:Tl PPS x-ray imager. On the other hand, especially at lower doses, this superior performance of the direct imager is seldom retained in its detective quantum efficiency (DQE) curves. It is well known that a-Se PPS x-ray imagers suffer from high additive electronic noise originating from the from the amorphous silicon (a-Si) thin film transistor (TFT) array that is being used in the current back-plane technology. This degrades the noise power spectrum (NPS) and subsequently the overall DQE. To address this deficiency, we propose to replace the PPS back-plane by active pixel sensor (APS) back-plane technology, which has the potential to reduce the back-plane electronic noise by amplifying the input signal, especially at low doses. The proposed APS is based on amorphous In-Ga-Zn-O (a-IGZO) TFT technology, which can offer high mobility (5-20?cm2 V-1 s-1), low leakage current (<10-13 A) and low flicker noise (Hooge's parameter ? H ~ 1.5 [Formula: see text] 10-3), leading to better imager noise performance. To test our hypothesis, we used linear cascaded systems analysis to model the imaging performance (MTF, NPS and DQE) of the PPS and APS a-Se direct imagers. This model was first validated using experimentally measured data obtained for a 85 µm pixel pitch a-Se/a-Si TFT PPS imager. Using this model, we analyzed the noise performance of the direct a-Se and indirect CsI:Tl x-ray a-IGZO APS imagers at different dose and electronic noise levels. Obtained results clearly showed that lowering back-plane electronic noise can significantly improve the performance of the a-Se/a-IGZO TFT APS imager. Our simulated results showed that a higher DQE at lower radiation doses (maximum DQE of 0.6 can be achieved at an exposure level of 1 µGy) can be achieved with the a-Se detector, thereby making this combination a promising candidate for low dose applications like DBT.
    • A phase II study of talazoparib after platinum or cytotoxic nonplatinum regimens in patients with advanced breast cancer and germline BRCA1/2 mutations (ABRAZO)

      Turner, N; Telli, M; Rugo, H; Mailliez, A; Ettl, J; Grischke, E; Mina, L; Balmana, J; Fasching, P; Hurvitz, S; Wardley, Andrew M; Chappey, C; Hannah, A; Robson, M; Breast Cancer Now Research Centre, Institute of Cancer Research and The Royal Marsden Hospital (2018)
      PURPOSE: To assess talazoparib activity in germline BRCA1/2 mutation carriers with advanced breast cancer (aBC). EXPERIMENTAL DESIGN: ABRAZO (NCT02034916) was a two-cohort, two-stage, phase II study of talazoparib (1 mg/day) in germline BRCA mutation carriers with a response to prior platinum with no progression on or within 8 weeks of the last platinum dose (cohort 1) or ?3 platinum-free cytotoxic regimens (cohort 2) for aBC. Primary endpoint was confirmed objective response rate (ORR) by independent radiological assessment. RESULTS: We enrolled 84 patients (cohort 1, n = 49; cohort 2, n = 35) from May 2014 to February 2016. Median age was 50 (range, 31-75) years. Triple-negative breast cancer incidence was 59% (cohort 1) and 17% (cohort 2). Median number of prior cytotoxic regimens for aBC was two and four, respectively. Confirmed ORR was 21% (95% CI, 10 to 35) (cohort 1) and 37% (95% CI, 22 to 55) (cohort 2). Median duration of response was 5.8 and 3.8 months, respectively. Confirmed ORR was 23% (BRCA1), 33% (BRCA2), 26% (TNBC) and 29% (hormone receptor positive). The most common allgrade adverse events (AEs) included anemia (52%), fatigue (45%), and nausea (42%). Talazoparib-related AEs led to drug discontinuation in three (4%) patients. In an exploratory analysis, longer platinum-free interval was associated with higher response rate in cohort 1 (0% ORR with interval <8 weeks; 47% ORR with interval >6 months). CONCLUSIONS: Talazoparib exhibited promising antitumor activity in patients with aBC and germline BRCA mutation.
    • Experimental validation of estimated spatially variant radioisotope-specific point spread functions using published positron range simulations and fluorine-18 measurements.

      Anton-Rodriguez, Jose M; Krokos, G; Kotasidis, F; Asselin, M; Morris, O; Julyan, Peter J; Archer, A; Matthews, J; Division of Informatics, Imaging and Data Sciences, MAHSC, University of Manchester, Manchester, United Kingdom (2018)
      In this work we compare spatially variant radioisotope-specific point spread functions (PSFs) derived from published positron range data with measured data using a high resolution research tomograph (HRRT). Spatially variant PSFs were measured on a HRRT for fluorine-18, carbon-11 and gallium-68 using an array of printed point sources. For gallium-68, this required modification of the original design to handle its longer positron range. Using the fluorine-18 measurements and previously published data from Monte-Carlo simulations of positron range, estimated PSFs for carbon-11 and gallium-68 were calculated and compared with experimental data. A double 3D Gaussian function was fitted to the estimated and measured data and used to model the spatially varying PSFs over the scanner field of view (FOV). Differences between the measured and estimated PSFs were quantified using the full-width-at-half-maximum (FWHM) and full-width-at-tenth-maximum (FWTM) in the tangential, radial and axial directions. While estimated PSFs were generally in agreement with the measured PSFs over the entire FOV better agreement was observed (FWHM and FWTM differences of less than 10%) when using one of the two sets of positron range simulations, especially for gallium-68 and for the FWTM. Spatially variant radioisotope specific PSFs can be accurately estimated from fluorine-18 measurements and published positron range data. We have experimentally validated this approach for carbon-11 and gallium-68, and such an approach may be applicable to other radioisotopes such as oxygen-15 for which measurements are not practical.
    • British Association of Dermatologists and U.K. Cutaneous Lymphoma Group guidelines for the management of primary cutaneous lymphomas 2018

      Gilson, D; Whittaker, S; Child, F; Scarisbrick, J; Illidge, Timothy M; Parry, E; Mohd, Mustapa M; Exton, L; Kanfer, E; Rezvani, K; Dearden, C; Morris, S; Leeds Cancer Centre, St James's University Hospital, Leeds, LS9 7TF, UK (2018)
    • The advanced prostate cancer consensus on a regional level - what can we learn?

      Omlin, A; Gillessen, Silke; Department of Medical Oncology and Haematology, Cantonal Hospital St. Gallen, University of Bern, Bern, Switzerland (2019)
    • Genomic loss of heterozygosity and survival in the REAL3 trial

      Smyth, E; Cafferkey, C; Loehr, A; Waddell, Thomas K; Begum, R; Peckitt, C; Harding, T; Nguyen, M; Okines, A; Raponi, M; Rao, S; Watkins, D; Starling, N; Middleton, G; Wadsley, J; Mansoor, W; Crosby, T; Wotherspoon, A; Chau, I; Cunningham, D; Department of Gastrointestinal Oncology and Lymphoma, Royal Marsden Hospital, London & Sutton, United Kingdom (2018)
      Homologous recombination deficiency (HRD) measured using a genomic signature for loss of heterozygosity (LOH) predicts benefit from rucaparib in ovarian cancer. We hypothesized that some oesophagogastric cancers will have high-LOH which would be prognostic in patients treated with platinum chemotherapy. Methods: Diagnostic biopsy DNA from patients treated in the REAL3 trial was sequenced using the Foundation Medicine T5 next-generation sequencing (NGS) assay. An algorithm quantified the percentage of interrogable genome with LOH. Multidimensional optimization was performed to identify a cut-off dichotomizing the population into LOH-high and low groups associated with differential survival outcomes. Results: Of 158 available samples, 117 were successfully sequenced; LOH was derived for 74 of these. A cut-off of 21% genomic LOH defined an LOH-high subgroup (n=10, 14% of population) who had median overall survival (OS) of 18.3 months (m) versus 11m for the LOH-low group (HR 0.55 95% CI 0.19-0.97, p= 0.10). Progression free survival (PFS) for LOH-high and LOH-low groups was 10.7m and 7.3m (HR 0.61 (95% CI 0.21 - 1.09, p=0.09). Sensitivity analysis censoring operated patients (n=4), demonstrated OS of 18.3m vs. 10.2m (HR 0.43, 95% CI (0.20-0.92), p=0.02; PFS was 10.5m vs. 7.2m (HR 0.55, (95% CI 0.26-1.17), p=0.09 for LOH-high and LOH-low. Conclusion: HRD assessment using an algorithmically derived LOH signature on a standard NGS panel identifies oesophagogastric cancer patients with high LOH who have prolonged survival when treated with platinum chemotherapy. Validation work will determine the signature's predictive value in patients treated with a PARP inhibitor and with platinum chemotherapy.
    • MiST3: a phase II study of oral selective AXL inhibitor bemcentinib (BGB324) incombination with pembrolizumab in pts with malignant mesothelioma

      Krebs, Matthew G; Carter, Louise; Villa, Shaun; King, A; Massey, C; Lorens, J; Darlington, Emma; Fennell, D; Experimental Cancer Medicine Team, the Christie NHS Foundation Trust, The University of Manchester and the Christie NHS Foundation Trust, Manchester, UK (2018)