Publications
817 results found
Magbanua MJM, Li W, Wolf DM, et al., 2020, Circulating tumor DNA (ctDNA) and magnetic resonance imaging (MRI) for monitoring and predicting response to neoadjuvant therapy (NAT) in high-risk early breast cancer patients in the I-SPY 2 TRIAL, AACR Special Conference on Advances in Liquid Biopsies, Publisher: AMER ASSOC CANCER RESEARCH, Pages: 59-60, ISSN: 1078-0432
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- Citations: 2
Peng L, Zagorac S, Stebbing J, 2020, Managing patients with cancer in the COVID-19 era, EUROPEAN JOURNAL OF CANCER, Vol: 132, Pages: 5-7, ISSN: 0959-8049
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- Citations: 15
Pallett S, Denny S, Patel A, et al., 2020, Point-of-care serological assays for SARS-CoV-2 in a UK hospital population: potential for enhanced case finding
Abstract Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic. Case identification is currently made by real-time polymerase chain reaction (PCR) during the acute phase and largely restricted to healthcare laboratories. Serological assays are emerging but independent validation is urgently required to assess their utility.We evaluated five different point-of-care (POC) SARS-CoV-2 antibody test kits against PCR, finding concordance across the assays ( n= 15). We subsequently tested 200 patients using the OrientGene COVID-19 IgG/IgM Rapid Test Cassette and find a sensitivity of 74% in the early infection period (day 5-9 post symptom onset), with 100% sensitivity not seen until day 13. Specificity was 96%, but in validating the serological tests uncovered potential false-negatives from PCR testing late-presenting cases. A positive predictive value (PPV) of 37% in the general population precludes any use for general screening. Where a case definition is applied however, the PPV is substantially improved (95·4%), supporting use of serology testing in carefully targeted populations. Larger studies in specific patient cohorts, including those with mild infection are urgently required to inform on the applicability of POC serological assays to help control the spread of SARS-CoV-2 and improve case finding of patients that may experience late complications.
Richardson PJ, Ottaviani S, Prelle A, et al., 2020, CNS penetration of potential anti-COVID-19 drugs., Journal of Neurology, Vol: 267, Pages: 1880-1882, ISSN: 0340-5354
Stebbing J, Krishnan V, Bono SD, et al., 2020, Mechanism of baricitinib supports artificial intelligence-predicted testing in COVID-19 patients, Publisher: Research Square
<jats:title>Abstract</jats:title> <jats:p>Baricitinib, is an oral Janus kinase (JAK)1/JAK2 inhibitor approved for the treatment of rheumatoid arthritis (RA) that was independently hypothesized, using artificial intelligence (AI)-algorithms, to be useful for the treatment of COVID-19 infection via a proposed anti-cytokine effects and as an inhibitor of host cell viral propagation<jats:sup>1,2</jats:sup>. We validated the AI-predicted biochemical inhibitory effects of baricitinib on human numb-associated kinase (hNAK) members measuring nanomolar affinities for AAK1, BIKE, and GAK. Inhibition of NAKs led to reduced viral infectivity with baricitinib using human primary liver spheroids, which express hAAK1 and hGAK. We evaluated the in vitro pharmacology of baricitinib across relevant leukocyte subpopulations coupled to its in vivo pharmacokinetics and showed it inhibited signaling of cytokines implicated in COVID-19 infection. In a case series of patients with bilateral COVID-19 pneumonia, baricitinib treatment was associated with clinical and radiologic recovery, a rapid decline in SARS-CoV-2 viral load, inflammatory markers, and IL-6 levels. This represents an important example of an AI-predicted treatment showing scientific and clinical promise during a global health crisis. Collectively, these data support further evaluation of the AI-derived hypothesis on anti-cytokine and anti-viral activity and supports its assessment in randomized trials in hospitalized COVID-19 patients.</jats:p>
Stebbing J, Mainwaring PN, Curigliano G, et al., 2020, Understanding the Role of Comparative Clinical Studies in the Development of Oncology Biosimilars, JOURNAL OF CLINICAL ONCOLOGY, Vol: 38, Pages: 1070-+, ISSN: 0732-183X
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- Citations: 15
Stebbing J, Phelan A, Griffin I, et al., 2020, COVID-19: combining antiviral and anti-inflammatory treatments, LANCET INFECTIOUS DISEASES, Vol: 20, Pages: 400-402, ISSN: 1473-3099
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- Citations: 431
Maclean W, Singh R, Mackenzie P, et al., 2020, The two-week rule colorectal cancer pathway: an update on recent practice, the unsustainable burden on ditienostics and the role of faecal immunochemical testing, ANNALS OF THE ROYAL COLLEGE OF SURGEONS OF ENGLAND, Vol: 102, Pages: 308-311, ISSN: 0035-8843
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- Citations: 14
Bhimani J, Ball K, Stebbing J, 2020, Patient-derived xenograft models-the future of personalised cancer treatment, BRITISH JOURNAL OF CANCER, Vol: 122, Pages: 601-602, ISSN: 0007-0920
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- Citations: 35
Malczewska A, Frampton A, Prado MM, et al., 2020, Diagnosis and Assessment of Effectiveness of Surgical Resection of Small Bowel Neuroendocrine Tumours: The Roles of Circulating MicroRNAs, 17th Annual European-Neuroendocrine-Tumor-Society (ENETS) Conference for the Diagnosis and Treatment of Neuroendocrine Tumor Disease, Publisher: KARGER, Pages: 145-145, ISSN: 0028-3835
Richardson P, Griffin I, Tucker C, et al., 2020, Baricitinib as potential treatment for 2019-nCoV acute respiratory disease, LANCET, Vol: 395, Pages: E30-E31, ISSN: 0140-6736
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- Citations: 619
Jin Y, Bao H, Le X, et al., 2020, Distinct co-acquired alterations and genomic evolution during TKI treatment in non-small-cell lung cancer patients with or without acquired T790M mutation, ONCOGENE, Vol: 39, Pages: 1846-1859, ISSN: 0950-9232
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- Citations: 22
Jin Y, Bao H, Le X, et al., 2020, Distinct co-acquired alterations and genomic evolution during TKI treatment in non-small-cell lung cancer patients with or without acquired T790M mutation (vol 39, pg 1846, 2020), ONCOGENE, Vol: 39, Pages: 2027-2027, ISSN: 0950-9232
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- Citations: 1
Peng L, Qin B-D, Xiao K, et al., 2020, A meta-analysis comparing responses of Asian versus non-Asian cancer patients to PD-1 and PD-L1 inhibitor-based therapy, ONCOIMMUNOLOGY, Vol: 9, ISSN: 2162-402X
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- Citations: 30
Huang Y, Gu B, Liu C, et al., 2019, Thermosensitive liposome-mediated drug delivery in chemotherapy: mathematical modelling for spatio-temporal drug distribution and model-based optimisation, Pharmaceutics, Vol: 11, ISSN: 1999-4923
Thermosensitive liposome-mediated drug delivery has shown promising results in terms of improved therapeutic efficacy and reduced side effects compared to conventional chemotherapeutics. In order to facilitate our understanding of the transport mechanisms and their complex interplays in the drug delivery process, computational models have been developed to simulate the multiple steps involved in liposomal drug delivery to solid tumours. In this study we employ a multicompartmental model for drug-loaded thermosensitive liposomes, with an aim to identify the key transport parameters in determining therapeutic dosing and outcomes. The computational model allows us to not only examine the temporal and spatial variations of drug concentrations in the different compartments by utilising the tumour cord concept, but also assess the therapeutic efficacy and toxicity. In addition, the influences of key factors on systemic plasma concentration and intracellular concentration of the active drug are investigated; these include different chemotherapy drugs, release rate constants and heating duration. Our results show complex relationships between these factors and the predicted therapeutic outcome, making it difficult to identify the “best” parameter set. To overcome this challenge, a model-based optimisation method is proposed in an attempt to find a set of release rate constants and heating duration that can maximise intracellular drug concentration while minimising systemic drug concentration. Optimisation results reveal that under the operating conditions and ranges examined, the best outcome would be achieved with a low drug release rate at physiological temperature, combined with a moderate to high release rate at mild hyperthermia and 1 h heating after injection.
Gagliano T, Shah K, Gargani S, et al., 2019, Global kinome silencing combined with 3D invasion screening of the tumor microenvironment identifies fibroblast-expressed PIK3Cδ involvement in triple-negative breast cancer progression
<jats:title>Abstract</jats:title><jats:p>As there is growing evidence for the tumor microenvironment’s (TME) role in tumorigenesis, we sought to investigate the role of fibroblast-expressed kinases in triple negative breast cancer (TNBC). Using a high-throughput kinome screen combined with 3D invasion assays, we identified fibroblast-expressed PIK3Cδ (f-PIK3Cδ) as a key regulator of progression. Although PIK3Cδ has been mainly described in leucocytes, we detected high expression in primary fibroblasts derived from TNBC patients, while PIK3Cδ was undetectable in cancer epithelial cell lines. Genetic and pharmacologic gain- and loss-of functions experiments verified the contribution of f-PIK3Cδ in TNBC cell invasion. By employing an integrated secretomics and transcriptomics analysis, we revealed a paracrine mechanism via which f-PIK3Cδ confers its pro-tumorigenic effects. Inhibition of f-PIK3Cδ promoted the secretion of factors, including PLGF and BDNF, which subsequently led to upregulation of NR4A1 in TNBC cells where it acts as a tumor suppressor. Inhibition of PIK3Cδ in an orthotopic BC mouse model reduced tumor growth only after inoculation with fibroblasts, indicating a role of f-PIK3Cδ in cancer progression. Similar results were observed in the MMTV-PyMT transgenic BC mouse model, in addition to a decrease on tumor metastasis emphasizing the potential immune-independent effects of PIK3Cδ inhibition. Finally, analysis of BC patient cohorts and TCGA datasets identified f-PIK3Cδ (protein and mRNA levels) as an independent prognostic factor for overall and disease free survival, highlighting it as a therapeutic target for TNBC.</jats:p>
Fu C, Stebbing J, Esteva FJ, 2019, Clinical development of CT-P6 in HER2 positive breast cancer, EXPERT OPINION ON BIOLOGICAL THERAPY, Vol: 19, Pages: 987-992, ISSN: 1471-2598
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- Citations: 5
Stebbing J, Baranau Y, Baryash V, et al., 2019, 3-year follow-up of a phase III trial comparing the efficacy and safety of neoadjuvant and adjuvant trastuzumab and its biosimilar CT-P6 in HER2 positive early breast cancer (EBC), 44th Congress of the European-Society-for-Medical-Oncology (ESMO), Publisher: OXFORD UNIV PRESS, Pages: 63-+, ISSN: 0923-7534
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- Citations: 2
Esteva FJ, Baranau YV, Baryash V, et al., 2019, Efficacy and safety of CT-P6 versus reference trastuzumab in HER2-positive early breast cancer: updated results of a randomised phase 3 trial, Cancer Chemotherapy and Pharmacology, Vol: 84, Pages: 839-847, ISSN: 0344-5704
PurposeNeoadjuvant CT-P6, a trastuzumab biosimilar, demonstrated equivalent efficacy to reference trastuzumab in a phase 3 trial of HER2-positive early-stage breast cancer (EBC) (NCT02162667). We report post hoc analyses evaluating pathological complete response (pCR) and breast pCR alongside additional efficacy and safety measures.MethodsFollowing neoadjuvant treatment and surgery, patients received adjuvant CT-P6 or trastuzumab (6 mg/kg) every 3 weeks for ≤ 1 year.ResultsIn total, 271 and 278 patients received CT-P6 and trastuzumab, respectively. pCR and breast pCR rates were comparable between treatment groups regardless of age, region, or clinical stage. Overall, 47.6% (CT-P6) and 52.2% (trastuzumab) of patients experienced study drug-related treatment-emergent adverse events (TEAEs), including 17 patients reporting heart failure (CT-P6: 10; trastuzumab: 7). Two CT-P6 and three trastuzumab patients discontinued adjuvant treatment due to TEAEs.ConclusionAdjuvant CT-P6 demonstrated comparable efficacy and safety to trastuzumab at 1 year in patients with HER2-positive EBC, supporting CT-P6 and trastuzumab comparability.
Lane R, Simon T, Vintu M, et al., 2019, Cell-derived extracellular vesicles can be used as a biomarker reservoir for glioblastoma tumor subtyping, COMMUNICATIONS BIOLOGY, Vol: 2
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- Citations: 60
Lane R, Simon T, Vintu M, et al., 2019, Cell-derived extracellular vesicles can be used as a biomarker reservoir for glioblastoma tumor subtyping., Commun Biol, Vol: 2
Glioblastoma (GBM) is one of the most aggressive solid tumors for which treatment options and biomarkers are limited. Small extracellular vesicles (sEVs) produced by both GBM and stromal cells are central in the inter-cellular communication that is taking place in the tumor bulk. As tumor sEVs are accessible in biofluids, recent reports have suggested that sEVs contain valuable biomarkers for GBM patient diagnosis and follow-up. The aim of the current study was to describe the protein content of sEVs produced by different GBM cell lines and patient-derived stem cells. Our results reveal that the content of the sEVs mirrors the phenotypic signature of the respective GBM cells, leading to the description of potential informative sEV-associated biomarkers for GBM subtyping, such as CD44. Overall, these data could assist future GBM in vitro studies and provide insights for the development of new diagnostic and therapeutic methods as well as personalized treatment strategies.
Ottaviani S, Stebbing J, Frampton AE, et al., 2019, Author Correction: TGF-beta induces miR-100 and miR-125b but blocks let-7a through LIN28B controlling PDAC progression, Nature Communications, Vol: 10, ISSN: 2041-1723
Stebbing J, Singh Wasan H, 2019, Decoding Metastatic Colorectal Cancer to Improve Clinical Decision Making., J Clin Oncol, Vol: 37, Pages: 1847-1850
Coombes RC, Page K, Salari R, et al., 2019, Personalized detection of circulating tumor DNA antedates breast cancer metastatic recurrence, Clinical Cancer Research, Vol: 25, Pages: 4255-4263, ISSN: 1078-0432
Purpose: Up to 30% of patients with breast cancer relapse after primary treatment. There are no sensitive and reliable tests to monitor these patients and detect distant metastases before overt recurrence. Here, we demonstrate the use of personalized circulating tumor DNA (ctDNA) profiling for detection of recurrence in breast cancer.Experimental Design: Forty-nine primary patients with breast cancer were recruited following surgery and adjuvant therapy. Plasma samples (n = 208) were collected every 6 months for up to 4 years. Personalized assays targeting 16 variants selected from primary tumor whole-exome data were tested in serial plasma for the presence of ctDNA by ultradeep sequencing (average >100,000X).Results: Plasma ctDNA was detected ahead of clinical or radiologic relapse in 16 of the 18 relapsed patients (sensitivity of 89%); metastatic relapse was predicted with a lead time of up to 2 years (median, 8.9 months; range, 0.5–24.0 months). None of the 31 nonrelapsing patients were ctDNA-positive at any time point across 156 plasma samples (specificity of 100%). Of the two relapsed patients who were not detected in the study, the first had only a local recurrence, whereas the second patient had bone recurrence and had completed chemotherapy just 13 days prior to blood sampling.Conclusions: This study demonstrates that patient-specific ctDNA analysis can be a sensitive and specific approach for disease surveillance for patients with breast cancer. More importantly, earlier detection of up to 2 years provides a possible window for therapeutic intervention.
Murphy R, Adams L, Brown A, et al., 2019, Impact of Routine Use of CDK4/6 Inhibitor Therapy on Breast Cancer Outpatient Clinic Workload and Patient Experience, Publisher: ELSEVIER SCIENCE LONDON, Pages: E112-E112, ISSN: 0936-6555
Pfeifer M, Brem R, Lippert T, et al., 2019, SSB1/SSB2 proteins safeguard B-cell development by protecting the genomes of B-cell precursors, Journal of Immunology, Vol: 202, Pages: 3423-3433, ISSN: 1550-6606
Induction of programmed DNA damage and its recognition and repair are fundamental for B cell development. The ssDNA-binding protein SSB1 has been described in human cells as essential for the recognition and repair of DNA damage. To study its relevance for B cells, we recently developed Ssb1−/− and conditional Ssb1−/− mice. Although SSB1 loss did not affect B cell development, Ssb1−/− cells exhibited compensatory expression of its homolog SSB2. We have now generated Ssb2−/− mice and show in this study that SSB2 is also dispensable for B cell development and DNA damage response activation. In contrast to the single loss of Ssb1 or Ssb2, however, combined SSB1/2 deficiency caused a defect in early B cell development. We relate this to the sensitivity of B cell precursors as mature B cells largely tolerated their loss. Toxicity of combined genetic SSB1/2 loss can be rescued by ectopic expression of either SSB1 or SSB2, mimicked by expression of SSB1 ssDNA-binding mutants, and attenuated by BCL2-mediated suppression of apoptosis. SSB1/2 loss in B cell precursors further caused increased exposure of ssDNA associated with disruption of genome fragile sites, inefficient cell cycle progression, and increased DNA damage if apoptosis is suppressed. As such, our results establish SSB1/2 as safeguards of B cell development and unveil their differential requirement in immature and mature B lymphocytes.
Rani A, Stebbing J, Giamas G, et al., 2019, Endocrine Resistance in Hormone Receptor Positive Breast Cancer-From Mechanism to Therapy, FRONTIERS IN ENDOCRINOLOGY, Vol: 10, ISSN: 1664-2392
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- Citations: 114
Renziehausen A, Wang H, Rao B, et al., 2019, The renin angiotensin system (RAS) mediates bifunctional growth regulation in melanoma and is a novel target for therapeutic intervention, Publisher: NATURE PUBLISHING GROUP, Pages: 2320-2336, ISSN: 0950-9232
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- Citations: 30
Chandrasinghe P, Cereser B, Moorghen M, et al., 2019, SMAD7 shows a biphasic expression pattern during progression of ulcerative colitis-associated colorectal cancer, Publisher: OXFORD UNIV PRESS, Pages: S124-S124, ISSN: 1873-9946
Esteva FJ, Lee S, Yu S, et al., 2019, 24 months results from a double-blind, randomized phase III trial comparing the efficacy and safety of neoadjuvant then adjuvant trastuzumab and its biosimilar candidate CT-P6 in HER2 positive early breast cancer (EBC), San Antonio Breast Cancer Symposium, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
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- Citations: 4
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