Publications
817 results found
Bidard F-C, Michiels S, Mueller V, et al., 2017, IMENEO: International MEta-analysis of circulating tumor cell detection in early breast cancer patients treated by NEOadjuvant chemotherapy, San Antonio Breast Cancer Symposium, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
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- Citations: 6
Pinato DJ, Sharma R, Yen C, et al., 2017, The ALBI grade provides objective hepatic reserve phenotyping across each BCLC stage of hepatocellular carcinoma, Journal of Hepatology, Vol: 66, Pages: 338-346, ISSN: 1600-0641
BACKGROUND & AIMS: Overall survival (OS) is a composite clinical endpoint in hepatocellular carcinoma (HCC) due to the mutual influence of cirrhosis and active malignancy in dictating patient's mortality. The ALBI grade is a recently described index of liver dysfunction in hepatocellular carcinoma, based solely on albumin and bilirubin levels. Whilst accurate, this score lacks cross-validation, especially in intermediate stage HCC, where OS is highly heterogeneous. METHODS: We evaluated the prognostic accuracy of the ALBI grade in estimating OS in a large, multi-centre study of 2426 patients, including a large proportion of intermediate stage patients treated with chemoembolization (n=1461) accrued from Europe, the United States and Asia. RESULTS: Analysis of survival by primary treatment modality confirmed the ALBI grade as a significant predictor of patient OS after surgical resection (p<0.001), transarterial chemoembolization (p<0.001) and sorafenib (p<0.001). Stratification by Barcelona Clinic Liver Cancer stage confirmed the independent prognostic value of the ALBI across the diverse stages of the disease, geographical regions of origin and time of recruitment to the study (p<0.001). CONCLUSIONS: In this large, multi-centre retrospective study, the ALBI grade satisfied the criteria for accuracy and reproducibility following statistical validation in Eastern and Western HCC patients, including those treated with chemoembolization. Consideration should be given to the ALBI grade as a stratifying biomarker of liver reserve in routine clinical practice. LAY SUMMARY: Liver failure is a key determinant influencing the natural history of hepatocellular carcinoma (HCC). In this large multi-centre study we externally validate a novel biomarker of liver functional reserve, the ALBI grade, across all the stages of HCC.
Giamas G, Grothey T, Grothey A, et al., 2017, Stromal kinome screening identifies a novel regulatory kinase implicated in fibroblast-mediated progression of invasion in triple negative breast cancer tumours, San Antonio Breast Cancer Symposium, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Page K, Guttery DS, Fernandez-Garcia D, et al., 2017, Next Generation Sequencing of Circulating Cell-Free DNA for Evaluating Mutations and Gene Amplification in Metastatic Breast Cancer, CLINICAL CHEMISTRY, Vol: 63, Pages: 532-541, ISSN: 0009-9147
Castellano L, Dabrowska A, Pellegrino L, et al., 2017, Sustained expression of miR-26a promotes chromosomal instability and tumorigenesis through regulation of CHFR, Nucleic Acids Research, Vol: 45, Pages: 4401-4412, ISSN: 1362-4962
MicroRNA 26a (miR-26a) reduces cell viability in several cancers, indicating that miR-26a could be used as a therapeutic option in patients. We demonstrate that miR-26a not only inhibits G1-S cell cycle transition and promotes apoptosis, as previously described, but also regulates multiple cell cycle checkpoints. We show that sustained miR-26a over-expression in both breast cancer (BC) cell lines and mouse embryonic fibroblasts (MEFs) induces oversized cells containing either a single-large nucleus or two nuclei, indicating defects in mitosis and cytokinesis. Additionally, we demonstrate that miR-26a induces aneuploidy and centrosome defects and enhances tumorigenesis. Mechanistically, it acts by targeting G1-S transition genes as well as genes involved in mitosis and cytokinesis such as CHFR, LARP1 and YWHAE. Importantly, we show that only the re-expression of CHFR in miR-26a over-expressing cells partially rescues normal mitosis and impairs the tumorigenesis exerted by miR-26a, indicating that CHFR represents an important miR-26a target in the regulation of such phenotypes. We propose that miR-26a delivery might not be a viable therapeutic strategy due to the potential deleterious oncogenic activity of this miRNA.
Shaw JA, Guttery DS, Hills A, et al., 2017, Mutation analysis of cell-free DNA and single circulating tumor cells in metastatic breast cancer patients with high CTC counts, Clinical Cancer Research, Vol: 22, ISSN: 1557-3265
Purpose: The purpose of this study was to directly compare mutation profiles in multiple single CTCs and cfDNA isolated from the same blood samples taken from patients with metastaic breast cancer (MBC). We aimed to determine whether cell-free DNA would reflect the heterogeneity observed in 40 single CTCs. Experimental design: CTCs were enumerated by Cellsearch. CTC count was compared with the quantity of matched cfDNA and serum CA15-3 and alkaline phosphatase (ALP) in 112 patients with metastatic breast cancer. In 5 patients with {greater than or equal to}100 CTCs, multiple individual EpCAM-positive CTCs were isolated by DEPArray and compared with matched cfDNA and primary tumour tissue by targeted next generation sequencing (NGS) of ~2200 mutations in 50 cancer genes. Results: In the whole cohort, total cfDNA levels and cell counts ({greater than or equal to}5 CTCs) were both significantly associated with overall survival, unlike CA15-3 and ALP. NGS analysis of 40 individual EpCAM-positive CTCs from 5 patients with MBC revealed mutational heterogeneity in PIK3CA, TP53, ESR1 and KRAS genes between individual CTCs. In all 5 patients cfDNA profiles provided an accurate reflection of mutations seen in individual CTCs. ESR1 and KRAS gene mutations were absent from primary tumour tissue and therefore likely reflect either a minor sub-clonal mutation or were acquired with disease progression. Conclusion: Our results demonstrate that cfDNA reflects persisting EpCAM-positive CTCs in patients with high CTC counts and therefore may enable monitoring of the metastatic burden for clinical decision-making.Experimental Design: DNA methylation was investigated in independent tumor cohorts using Illumina HumanMethylation arrays and gene expression by Affymetrix arrays and qRT-PCR. The role of Msh homeobox 1 (MSX1) in drug sensitivity was investigated by gene reintroduction and siRNA knockdown of ovarian cancer cell lines.Results: CpG sites at contiguous genomic locations within th
Balachandran K, Stebbing J, 2016, Quackery Turmeric: a spice for life?, LANCET ONCOLOGY, Vol: 17, Pages: 1639-1639, ISSN: 1470-2045
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- Citations: 2
Balachandran K, Stebbing J, 2016, Turmeric: a spice for life?, Lancet Oncol, Vol: 17, Pages: 1639-1639
Tree AC, Harding V, Bhangu A, et al., 2016, The need for multidisciplinarity in specialist training to optimize future patient care, NATURE REVIEWS CLINICAL ONCOLOGY, Vol: 14, Pages: 508-517, ISSN: 1759-4774
Nachiappan S, Askari A, Mamidanna R, et al., 2016, Initiation of adjuvant chemotherapy within 8weeks of elective colorectal resection improves overall survival regardless of reoperation, COLORECTAL DISEASE, Vol: 18, Pages: 1041-1049, ISSN: 1462-8910
Prado MM, Frampton AE, Giovannetti E, et al., 2016, Investigating miRNA-mRNA regulatory networks using crosslinking immunoprecipitation methods for biomarker and target discovery in cancer, EXPERT REVIEW OF MOLECULAR DIAGNOSTICS, Vol: 16, Pages: 1155-1162, ISSN: 1473-7159
Harrod A, Fulton J, Nguyen VTM, et al., 2016, Genomic modelling of the ESR1 Y537S mutation for evaluating function and new therapeutic approaches for metastatic breast cancer, Oncogene, Vol: 36, Pages: 2286-2296, ISSN: 1476-5594
Drugs that inhibit estrogen receptor-α (ER) activity have been highlysuccessful in treating and reducing breast cancer progression in ER-positivedisease. However, resistance to these therapies presents a major clinicalproblem. Recent genetic studies have shown that mutations in the ER geneare found in >20% of tumours that progress on endocrine therapies.Remarkably, the great majority of these mutations localise to just a few aminoacids within or near the critical helix 12 region of the ER hormone bindingdomain, where they are likely to be single allele mutations. Understandinghow these mutations impact on ER function is a prerequiste for identifyingmethods to treat breast cancer patients featuring such mutations. Towardsthis end, we used CRISPR-Cas9 genome editing to make a single alleleknockin of the most commonly mutated amino acid residue, tyrosine 537, inthe estrogen-responsive MCF7 breast cancer cell line. Genomic analysesusing RNA-seq and ER ChIP-seq demonstrated that the Y537S mutationpromotes constitutive ER activity globally, resulting in estrogen-independentgrowth. MCF7-Y537S cells were resistant to the anti-estrogen tamoxifen andfulvestrant. Further, we show that the basal transcription factor TFIIH isconstitutively recruited by ER-Y537S, resulting in ligand-independentphosphorylation of Serine 118 (Ser118) by the TFIIH kinase, CDK7. TheCDK7 inhibitor, THZ1 prevented Ser118 phosphorylation and inhibited growthof MCF7-Y537S cells. These studies confirm the functional importance of ERmutations in endocrine resistance, demonstrate the utility of knockinmutational models for investigating alternative therapeutic approaches andhighlight CDK7 inhibition as a potential therapy for endocrine resistant breastcancer mediated by ER mutations.
Dalgleish AG, Stebbing J, Adamson DJ, et al., 2016, Corrigendum: Randomised, open-label, phase II study of gemcitabine with and without IMM-101 for advanced pancreatic cancer, British Journal of Cancer, Vol: 115, Pages: e16-e16, ISSN: 0007-0920
Davies A, Hidalgo M, Stebbing J, et al., 2016, Mouse clinical trials of pancreatic cancer: Integration of PDX models with genomics to improve patient outcomes to chemotherapeutics, ANNALS OF ONCOLOGY, Vol: 27, ISSN: 0923-7534
Chandrasinghe P, Stebbing J, Warusavitarne J, 2016, The MACC1-SPON2 axis: a new biomarker and therapeutic target in colorectal cancer, ONCOGENE, Vol: 36, Pages: 1474-1475, ISSN: 0950-9232
Pinato DJ, Shiner RJ, White SDT, et al., 2016, Intra-tumoral heterogeneity in the expression of programmed-death (PD) ligands in isogeneic primary and metastatic lung cancer: Implications for immunotherapy, OncoImmunology, Vol: 5, ISSN: 2162-4011
Purpose: There is inconclusive evidence to suggest the expression of programmed cell death (PD) ligand 1 (PD-L1) is a putative predictor of response to PD-1/PD-L1-targeted therapies in lung cancer. We evaluated the heterogeneity in the expression of PD-1 ligands in isogeneic primary and metastatic LC specimens. Experimental Design: From 12,580 post mortem cases, we identified 214 patients with untreated metastatic LC, of which 98 had adequately preserved tissues to construct a syngeneic primary LC/metastasis tissue microarray. Immunostaining for PD-L1 and 2 was evaluated in paired primary and metastatic lesions and correlated with clinicopathologic features. Results: We included 98 patients with non-small cell (NSCLC, n = 65, 66%), small cell histology (SCLC, n = 29, 30%) and four (4%) atypical carcinoids (AC). In total 8/65 (12%) primary PD-L1 positive NSCLC, had discordant matched metastases (14/17, 82%). PD-L1 negative primaries had universally concordant distant metastases. SCLCs were universally PD-L1 negative across primary and metastatic disease. PD-L2 positive NSCLC (n = 11/65, 17%) had high rate of discordant metastases (n = 24/27, 88%) and four cases (6%) had PD-L2 positive metastases with negative primaries. 2/29 SCLC (7%) and 1/4 AC (25%) were PD-L2 positive with discordance in all the sampled metastatic sites (n = 5). We found no correlation between the expression of PD ligands and clinicopathologic features of LC. Conclusions: Intra-tumoral heterogeneity in the expression of PD ligands is common in NSCLC, while PD-L1 is homogeneously undetectable in primary and metastatic SCLC. This holds implications in the clinical development of immune response biomarkers in LC.
Dalgleish AG, Stebbing J, Adamson DJA, et al., 2016, Randomised, open-label, phase II study of gemcitabine with and without IMM-101 for advanced pancreatic cancer, British Journal of Cancer, Vol: 115, Pages: 789-796, ISSN: 0007-0920
Background: Immune Modulation and Gemcitabine Evaluation-1, a randomised, open-label, phase II, first-line, proof of conceptstudy (NCT01303172), explored safety and tolerability of IMM-101 (heat-killed Mycobacterium obuense; NCTC 13365) withgemcitabine (GEM) in advanced pancreatic ductal adenocarcinoma.Methods: Patients were randomised (2 : 1) to IMM-101 (10 mg ml l intradermally) þ GEM (1000 mg m 2 intravenously; n ¼ 75), orGEM alone (n ¼ 35). Safety was assessed on frequency and incidence of adverse events (AEs). Overall survival (OS), progressionfreesurvival (PFS) and overall response rate (ORR) were collected.Results: IMM-101 was well tolerated with a similar rate of AE and serious adverse event reporting in both groups after allowance forexposure. Median OS in the intent-to-treat population was 6.7 months for IMM-101þ GEM v 5.6 months for GEM; while not significant,the hazard ratio (HR) numerically favoured IMM-101þ GEM (HR, 0.68 (95% CI, 0.44–1.04, P¼ 0.074). In a pre-defined metastatic subgroup(84%), OS was significantly improved from 4.4 to 7.0 months in favour of IMM-101þ GEM (HR, 0.54, 95% CI 0.33–0.87, P¼ 0.01).Conclusions: IMM-101 with GEM was as safe and well tolerated as GEM alone, and there was a suggestion of a beneficial effect onsurvival in patients with metastatic disease. This warrants further evaluation in an adequately powered confirmatory study.
Zamorano JL, Lancellotti P, Rodriguez Muñoz D, et al., 2016, 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC), European Journal of Heart Failure, Vol: 19, Pages: 9-42, ISSN: 1879-0844
Zamorano JL, Lancellotti P, Rodriguez Muñoz D, et al., 2016, 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC), European Heart Journal, Vol: 37, Pages: 2768-2801, ISSN: 1522-9645
Miller HC, Frampton AE, Malczewska A, et al., 2016, MicroRNAs associated with small bowel neuroendocrine tumours and their metastases, Endocrine-Related Cancer, Vol: 23, Pages: 711-726, ISSN: 1479-6821
Novel molecular analytes are needed in small bowel neuroendocrine tumours (SBNETs) to better determine disease aggressiveness and predict treatment response. In this study, we aimed to profile the global miRNome of SBNETs, and identify microRNAs (miRNAs) involved in tumour progression for use as potential biomarkers. Two independent miRNA profiling experiments were performed (n=90), including primary SBNETs (n=28), adjacent normal small bowel (NSB; n=14), matched lymph node (LN) metastases (n=24), normal LNs (n=7), normal liver (n=2) and liver metastases (n=15). We then evaluated potentially targeted genes by performing integrated computational analyses. We discovered 39 miRNAs significantly deregulated in SBNETs compared with adjacent NSB. The most upregulated (miR-204-5p, miR-7-5p and miR-375) were confirmed by qRT-PCR. Two miRNAs (miR-1 and miR-143-3p) were significantly downregulated in LN and liver metastases compared with primary tumours. Furthermore, we identified upregulated gene targets for miR-1 and miR-143-3p in an existing SBNET dataset, which could contribute to disease progression, and show that these miRNAs directly regulate FOSB and NUAK2 oncogenes. Our study represents the largest global miRNA profiling of SBNETs using matched primary tumour and metastatic samples. We revealed novel miRNAs deregulated during SBNET disease progression, and important miRNA–mRNA interactions. These miRNAs have the potential to act as biomarkers for patient stratification and may also be able to guide treatment decisions. Further experiments to define molecular mechanisms and validate these miRNAs in larger tissue cohorts and in biofluids are now warranted.
Lucchiari G, Zhang H, Nunes J, et al., 2016, Role of phosphorylation in Lmtk3 activation and its contribution in breast cancer progression, AACR 107th Annual Meeting on Bioinformatics and Systems Biology, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Guttery DS, Shaw JA, Hills A, et al., 2016, Mutation analysis of cell-free DNA captures heterogeneity of individual circulating tumor cells in metastatic breast cancer, AACR 107th Annual Meeting on Bioinformatics and Systems Biology, Publisher: American Association for Cancer Research, Pages: LB-339-LB-339, ISSN: 1538-7445
Davies A, Stebbing J, Zacharoulis S, et al., 2016, Patient-derived xenografts effectively capture patient clinical responses to oncology therapy, Publisher: ELSEVIER SCI LTD, Pages: S203-S203, ISSN: 0959-8049
de Giorgio A, Stebbing J, 2016, Garlic: a stake through the heart of cancer?, Lancet Oncology, Vol: 17, Pages: 879-880, ISSN: 1474-5488
Pinato DJ, Stebbing J, Ishizuka M, et al., 2016, Corrigendum to “A novel and validated prognostic index in hepatocellular carcinoma: The Inflammation Based Index (IBI)”, Journal of Hepatology, Vol: 65, Pages: 453-453, ISSN: 1600-0641
Stebbing J, Frampton AE, Miller HC, et al., 2016, MicroRNAs associated with small bowel neuroendocrine tumors and their metastases., Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO), Publisher: AMER SOC CLINICAL ONCOLOGY, ISSN: 0732-183X
Pinato DJ, Brown M, White SDT, et al., 2016, Programmed cell death (PD-1) ligands expression in gastro-entero-pancreatic neuroendocrine tumours (GEP-NETs): relationship with angiogenesis and clinical outcome., Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO), Publisher: AMER SOC CLINICAL ONCOLOGY, ISSN: 0732-183X
Mirnezami R, Veselkov K, Strittmatter N, et al., 2016, Spatially resolved profiling of colorectal cancer lipid biochemistry via DESI imaging mass spectrometry to reveal morphology-dependent alterations in fatty acid metabolism, Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO), Publisher: American Society of Clinical Oncology, ISSN: 0732-183X
Background: Lipid metabolic alterations are recognised as potential oncogenic triggers that promote malignant transformation. Here we performed spatially-resolved profiling of lipid signatures in colorectal cancer (CRC) tissue and matched healthy mucosa using desorption electrospray ionisation imaging mass spectrometry (DESI-MSI). The objectives of this study were to comprehensively define the CRC ‘lipidome’ and to assess lipid signatures in discrete histological regions-of-interest, specifically morphologically bland peri-tumoural epithelium (PT-e) and tumour stroma (T-s). Methods: Fresh frozen tissue sections from 42 patients with confirmed CRC were subjected to negative-ion mode DESI-MSI analysis. Mass spectra in the 200-1000 m/zrange were collated from CRC epithelium (CRC-e), PT-e, T-s and healthy tumour-remote epithelium (TR-e). Spectral signatures were subjected to multivariate analysis using a recursive maximum margin criterion (RMMC) algorithm operating in MATLAB. Results: Increased levels of long/very-long chain fatty acids (LCFA/VLCFA) were seen in CRC-e compared with TR-e(AUC = 0.99). Correspondingly, increased expression of lipogenic and elongase enzymes was found on IHC. Transmission electron microscopy was performed to evaluate peroxisomal distribution and morphology in CRC-e, as these organelles metabolise LCFA/VLCFA through β-oxidation, to negligibly low levels, in healthy cells. No discernible difference in peroxisomal distribution, abundance or structure was found between CRC-e and TR-e. PT-e demonstrated a lipid expression pattern almost identical to that of CRC-e, and markedly different from TR-e (AUC = 0.89). Conclusions: A shift towards increased LCFA/VLCFA production may be an important metabolic trait in CRC facilitated through upregulation of de novo lipogenesis and fatty acid elongation and concurrent impairment of peroxisomal β-oxidation. This phenotype was also observed in morphologically bland PT-e, suggesting that
Pinato DJ, Shiner RJ, White SDT, et al., 2016, Intra-tumoral heterogeneity in the expression of programmed-death (PD) ligands in isogeneic primary and metastatic lung cancer (LC): Implications for immunotherapy., Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO), Publisher: AMER SOC CLINICAL ONCOLOGY, ISSN: 0732-183X
Coombes RC, Kilburn LS, Tubiana-Mathieu N, et al., 2016, Epirubicin dose and sequential hormonal therapy-Mature results of the HMFEC randomised phase III trial in premenopausal patients with node positive early breast cancer, European Journal of Cancer, Vol: 60, Pages: 146-153, ISSN: 1879-0852
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