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Pancreatic Neoplasms: HELP
Articles by Justin Stebbing
Based on 21 articles published since 2010
(Why 21 articles?)
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Between 2010 and 2020, J. Stebbing wrote the following 21 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Editorial Can pharmacogenomics guide effective anticancer therapy in pancreatic ductal adenocarcinoma? 2012

Krell, Jonathan / Frampton, Adam E / Jiao, Long R / Stebbing, Justin. · ·Pharmacogenomics · Pubmed #22838942.

ABSTRACT: -- No abstract --

2 Review Investigating miRNA-mRNA regulatory networks using crosslinking immunoprecipitation methods for biomarker and target discovery in cancer. 2016

Mato Prado, Mireia / Frampton, Adam E / Giovannetti, Elisa / Stebbing, Justin / Castellano, Leandro / Krell, Jonathan. ·a Division of Cancer, Dept. of Surgery & Cancer, Imperial Centre for Translational and Experimental Medicine (ICTEM) , Imperial College , London , UK. · b HPB Surgical Unit, Dept. of Surgery & Cancer , Imperial College , London , UK. · c Dept. of Medical Oncology , VU University Medical Center , Amsterdam , The Netherlands. · d Cancer Pharmacology Lab, AIRC Start-Up Unit , University of Pisa , Pisa , Italy. · e CNR-Nano , Institute of Nanoscience and Nanotechnology , Pisa , Italy. ·Expert Rev Mol Diagn · Pubmed #27784183.

ABSTRACT: INTRODUCTION: MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression at the post-transcriptional level. Recently, different experimental approaches, such as RNA Sequencing, crosslinking immunoprecipitation (CLIP) methods and its variations, together with computational approaches have been developed to elucidate the miRNA-mRNA targetome. Areas covered: This report focuses on comparing the different experimental and computational approaches, describing their advantages and disadvantages and providing several examples of preclinical (in vitro and in vivo) and clinical studies that have identified miRNA target genes in various tumour types, including breast, ovary, colorectal and pancreas. Expert commentary: The combination of CLIP methods with bioinformatic analyses is essential to better predict miRNA-mRNA interactions and associate their specific pathways within the extensive regulatory network. Nevertheless, further studies are needed to overcome the difficulties these methods have, in order to find a gold standard method that identifies, without any bias, the regulatory association between miRNAs and their target mRNAs.

3 Review Gene of the month: NANOG. 2015

Mato Prado, Mireia / Frampton, Adam E / Stebbing, Justin / Krell, Jonathan. ·Division of Cancer, Department of Surgery & Cancer, Imperial Centre for Translational and Experimental Medicine (ICTEM), Imperial College, Hammersmith Hospital Campus, London, UK. · Division of Cancer, Department of Surgery & Cancer, Imperial Centre for Translational and Experimental Medicine (ICTEM), Imperial College, Hammersmith Hospital Campus, London, UK HPB Surgical Unit, Department of Surgery & Cancer, Imperial College, Hammersmith Hospital Campus, London, UK. ·J Clin Pathol · Pubmed #26216907.

ABSTRACT: -- No abstract --

4 Review microRNAs with prognostic significance in pancreatic ductal adenocarcinoma: A meta-analysis. 2015

Frampton, Adam E / Krell, Jonathan / Jamieson, Nigel B / Gall, Tamara M H / Giovannetti, Elisa / Funel, Niccola / Mato Prado, Mireia / Krell, Daniel / Habib, Nagy A / Castellano, Leandro / Jiao, Long R / Stebbing, Justin. ·HPB Surgical Unit, Division of Surgery, Dept. of Surgery & Cancer, Imperial College, Hammersmith Hospital Campus, Du Cane Road, London W12 0HS, UK; Division of Oncology, Dept. of Surgery & Cancer, Imperial Centre for Translational and Experimental Medicine (ICTEM), Imperial College, Hammersmith Hospital campus, Du Cane Road, London W12 0NN, UK. Electronic address: a.frampton@imperial.ac.uk. · Division of Oncology, Dept. of Surgery & Cancer, Imperial Centre for Translational and Experimental Medicine (ICTEM), Imperial College, Hammersmith Hospital campus, Du Cane Road, London W12 0NN, UK. · Academic Unit of Surgery, Faculty of Medicine, Glasgow Royal Infirmary, Alexandra Parade, University of Glasgow, G31 2ER, UK. · HPB Surgical Unit, Division of Surgery, Dept. of Surgery & Cancer, Imperial College, Hammersmith Hospital Campus, Du Cane Road, London W12 0HS, UK. · Dept. of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands. · Dept. of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Italy. · Dept. of Academic Oncology, Royal Free Hospital, Pond Street, London NW3 2QG, UK. · Division of Oncology, Dept. of Surgery & Cancer, Imperial Centre for Translational and Experimental Medicine (ICTEM), Imperial College, Hammersmith Hospital campus, Du Cane Road, London W12 0NN, UK. Electronic address: j.stebbing@imperial.ac.uk. ·Eur J Cancer · Pubmed #26002251.

ABSTRACT: BACKGROUND: Reports have described the prognostic relevance of microRNAs (miRNAs) in patients treated for pancreatic ductal adenocarcinoma (PDAC). However, many of these include small numbers of patients. To increase statistical power and improve translation, we performed a systematic review and meta-analysis to determine a pooled conclusion. We examined the impact of miRNAs on overall survival (OS) and disease-free survival (DFS) in PDAC. METHODS: Eligible studies were identified and quality assessed using multiple search strategies (last search December 2014). Data were collected from studies correlating clinical outcomes with dysregulated tumoural or blood miRNAs. Studies were pooled, and combined hazard ratios (HRs) with 95% confidence intervals (CIs) were used to estimate strength of the associations. RESULTS: Twenty studies involving 1525 patients treated for PDAC were included. After correcting for publication bias, OS was significantly shortened in patients with high tumoural miR-21 (adjusted HR = 2.48; 1.96-3.14). This result persisted when only studies adjusting for adjuvant chemotherapy were combined (adjusted HR = 2.72; 1.91-3.89). High miR-21 also predicted reduced DFS (adjusted HR = 3.08; 1.78-5.33). Similarly, we found significant adjusted HRs for poor OS for high miR-155, high miR-203, and low miR-34a; and unadjusted HRs for high miR-222 and high miR-10b. The small number of studies, limited number of miRNAs and paucity of multivariate analyses are the limitations of our study. CONCLUSIONS: This is the first rigorous pooled analysis assessing miRNAs as prognostic biomarkers in PDAC. Tumoural miR-21 overexpression emerged as an important predictor of poor prognosis after PDAC resection independent of other clinicopathologic factors, including adjuvant chemotherapy use.

5 Review Epigenetic changes in gastroenteropancreatic neuroendocrine tumours. 2015

Mapelli, P / Aboagye, E O / Stebbing, J / Sharma, R. ·Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, UK. · Department of Experimental Medicine, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, UK. ·Oncogene · Pubmed #25435371.

ABSTRACT: An understanding of epigenetic drivers of tumorigenesis has developed rapidly during the last years. The identification of these changes including DNA methylation and histone modifications in gastroenteropancreatic neuroendocrine tumours (GEP-NETs) is a step forward in trying to define underlying biologic processes in this heterogeneous disease. The reversible nature of these changes represents a potential therapeutic target. We present an overview of the current knowledge of epigenetic alterations related to GEP-NETs, focusing on the influence and impact these changes have on pathogenesis and prognosis. The potential role of demethylating agents in the management of this patient population is discussed.

6 Review Cell-free DNA for the detection of pancreatic, liver and upper gastrointestinal cancers: has progress been made? 2013

Gall, Tamara M H / Frampton, Adam E / Krell, Jonathan / Habib, Nagy A / Castellano, Leandro / Stebbing, Justin / Jiao, Long R. ·HPB Surgical Unit, Department of Surgery & Cancer, Imperial College, Hammersmith Hospital Campus, Du Cane Road, London, W12 0HS, UK. ·Future Oncol · Pubmed #24295416.

ABSTRACT: Detecting alterations in blood cell-free DNA (cfDNA) is hoped to be a novel, noninvasive method for diagnosing, prognosing and monitoring cancer patients. Several studies have assessed the usefulness of measuring tumor-specific genetic and epigenetic changes of cfDNA, such as loss of heterozygosity, frequency of mutations, alterations of microsatellites and the methylation of genes in patient blood samples. However, few well-designed trials have been carried out to translate these findings effectively. In this review, we have assessed the clinical utility of cfDNA in pancreatic, liver and upper gastrointestinal malignancies.

7 Clinical Trial Randomised, open-label, phase II study of gemcitabine with and without IMM-101 for advanced pancreatic cancer. 2016

Dalgleish, Angus G / Stebbing, Justin / Adamson, Douglas Ja / Arif, Seema Safia / Bidoli, Paolo / Chang, David / Cheeseman, Sue / Diaz-Beveridge, Robert / Fernandez-Martos, Carlos / Glynne-Jones, Rob / Granetto, Cristina / Massuti, Bartomeu / McAdam, Karen / McDermott, Raymond / Martín, Andrés J Muñoz / Papamichael, Demetris / Pazo-Cid, Roberto / Vieitez, Jose M / Zaniboni, Alberto / Carroll, Kevin J / Wagle, Shama / Gaya, Andrew / Mudan, Satvinder S. ·Cancer Vaccine Institute, St George's University of London, London, UK. · Department of Oncology, Imperial College, Hammersmith Hospital, London, UK. · Department of Oncology, Ninewells Hospital, Dundee, UK. · Velindre Cancer Centre, Cardiff, UK. · Department of Oncology, Azienda Ospedaliera San Gerardo, Monza, Italy. · Department of General Surgery, Royal Blackburn Hospital, Blackburn, UK. · Department of Oncology, Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK. · Médico Adjunto de Oncología Médica, Hospital La Fe de Valencia, Valencia, Spain. · Instituto Valenciano de Oncologia, Valencia, Spain. · Mount Vernon Cancer Centre, Northwood, UK. · Medical Oncology, Azienda Ospedaliera Santa Croce e Carle, Cuneo, Italy. · Ensayos Clínicos Oncología, Hospital General Universitario de Alicante, Alicante, Spain. · Oncology Department, Peterborough and Stamford Hospitals NHS Trust, Peterborough, UK. · Medical Oncology, St Vincent's University Hospital and The Adelaide and Meath Hospital, Dublin, Republic of Ireland. · Gastrointestinal Cancer Unit, Hospital General Universitario Gregorio Marañón, Madrid, Spain. · Department of Medical Oncology, Bank of Cyprus Oncology Centre, Nicosia, Cyprus. · Servicio de Oncología Médica, Hospital Miguel Servet, Zaragoza, Spain. · Area and Neuroendocrine Tumors Gastrointestinal Medical Oncology, Hospital Central de Asturias, Asturias, Spain. · Oncology Department, Fondazione Poliambulanza, Brescia, Italy. · TranScrip Partners LLP, Reading, UK. · Clinical Oncology, Guy's & St Thomas' Hospitals NHS Trust, London, UK. · St George's University of London, Imperial College, London and The Royal Marsden Hospital, London, UK. ·Br J Cancer · Pubmed #27599039.

ABSTRACT: BACKGROUND: Immune Modulation and Gemcitabine Evaluation-1, a randomised, open-label, phase II, first-line, proof of concept study (NCT01303172), explored safety and tolerability of IMM-101 (heat-killed Mycobacterium obuense; NCTC 13365) with gemcitabine (GEM) in advanced pancreatic ductal adenocarcinoma. METHODS: Patients were randomised (2 : 1) to IMM-101 (10 mg ml(-l) intradermally)+GEM (1000 mg m(-2) intravenously; n=75), or GEM alone (n=35). Safety was assessed on frequency and incidence of adverse events (AEs). Overall survival (OS), progression-free survival (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 for exposure. Median OS in the intent-to-treat population was 6.7 months for IMM-101+GEM v 5.6 months for GEM; while not significant, the hazard ratio (HR) numerically favoured IMM-101+GEM (HR, 0.68 (95% CI, 0.44-1.04, P=0.074). In a pre-defined metastatic subgroup (84%), OS was significantly improved from 4.4 to 7.0 months in favour of IMM-101+GEM (HR, 0.54, 95% CI 0.33-0.87, P=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 on survival in patients with metastatic disease. This warrants further evaluation in an adequately powered confirmatory study.

8 Article Percutaneous irreversible electroporation with systemic treatment for locally advanced pancreatic adenocarcinoma. 2018

Leen, Edward / Picard, John / Stebbing, Justin / Abel, Mark / Dhillon, Tony / Wasan, Harpreet. ·Department of Medicine, Hammersmith Hospital, Imperial College Healthcare NHS Trust, Du Cane Road, London, UK. · Department of Anaesthetics, Hammersmith Hospital, Imperial College Healthcare NHS Trust, Du Cane Road, London, UK. · Department of Cancer Medicine, Hammersmith Hospital, Imperial College Healthcare NHS Trust, Du Cane Road, London, UK. · Department of Oncology, Royal Surrey County Hospital, Egerton Road, Guildford, Surrey, UK. ·J Gastrointest Oncol · Pubmed #29755766.

ABSTRACT: Background: The prognosis for unresectable locally advanced pancreatic adenocarcinoma (LAPC) remains poor. There is increasing interest in modern ablative techniques to improve outcomes. We report on the potential value of integrating percutaneous irreversible electroporation (IRE) in patients undergoing systemic chemotherapy. Methods: Seventy-five patients with unresectable pancreatic carcinoma underwent percutaneous IRE after chemotherapy using computerised tomography guidance under general anaesthesia. Postoperative immediate and 30-day morbidity and mortality, progression-free (PFS) and overall survival (OS) were evaluated. Results: Post-procedural immediate and 30-day mortality rates were both zero. All-grade adverse events were 25%. Median in-patient stay was 1 day (range, 1-5 days). Median OS and PFS post-IRE for LAPC were 27 and 15 months respectively. Four patients with LAPC down-staged post-IRE ablation to be surgically resectable, with R0 resections in 3 cases. Conclusions: These results suggest that percutaneous IRE ablation of unresectable LAPC is safe to integrate with standard-of-care chemotherapy and may improve survival, which provides a template for further evaluation in prospective randomized clinical trials.

9 Article TGF-β induces miR-100 and miR-125b but blocks let-7a through LIN28B controlling PDAC progression. 2018

Ottaviani, Silvia / Stebbing, Justin / Frampton, Adam E / Zagorac, Sladjana / Krell, Jonathan / de Giorgio, Alexander / Trabulo, Sara M / Nguyen, Van T M / Magnani, Luca / Feng, Hugang / Giovannetti, Elisa / Funel, Niccola / Gress, Thomas M / Jiao, Long R / Lombardo, Ylenia / Lemoine, Nicholas R / Heeschen, Christopher / Castellano, Leandro. ·Department of Surgery and Cancer, Division of Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine (ICTEM), London, W12 0NN, UK. · Department of Surgery and Cancer, HPB Surgical Unit, Imperial College, Hammersmith Hospital Campus, London, W12 0HS, UK. · Department of Surgery and Cancer, Division of Cancer, Imperial College London, Institute of Reproductive and Developmental Biology (IRDB), London, W12 0NN, UK. · Stem Cells & Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, 28028, Spain. · Stem Cells in Cancer & Ageing, Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ, UK. · Epigenetics and Genome Stability Team, The Institute of Cancer Research, 237 Fulham Road, London, SW3 6JB, UK. · Department of Medical Oncology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, 1081 HV, The Netherlands. · Cancer Pharmacology Lab, AIRC Start-Up Unit, University of Pisa, Pisa, 56126, Italy. · Clinic for Gastroenterology, Endocrinology, Metabolism and Infectiology, Philipps-University Marburg, Marburg, 35037, Germany. · Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ, UK. · Department of Surgery and Cancer, Division of Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine (ICTEM), London, W12 0NN, UK. l.castellano@sussex.ac.uk. · University of Sussex, School of life Sciences, John Maynard Smith Building, Falmer, Brighton, BN1 9QG, UK. l.castellano@sussex.ac.uk. ·Nat Commun · Pubmed #29748571.

ABSTRACT: TGF-β/Activin induces epithelial-to-mesenchymal transition and stemness in pancreatic ductal adenocarcinoma (PDAC). However, the microRNAs (miRNAs) regulated during this response have remained yet undetermined. Here, we show that TGF-β transcriptionally induces MIR100HG lncRNA, containing miR-100, miR-125b and let-7a in its intron, via SMAD2/3. Interestingly, we find that although the pro-tumourigenic miR-100 and miR-125b accordingly increase, the amount of anti-tumourigenic let-7a is unchanged, as TGF-β also induces LIN28B inhibiting its maturation. Notably, we demonstrate that inactivation of miR-125b or miR-100 affects the TGF-β-mediated response indicating that these miRNAs are important TGF-β effectors. We integrate AGO2-RIP-seq with RNA-seq to identify the global regulation exerted by these miRNAs in PDAC cells. Transcripts targeted by miR-125b and miR-100 significantly overlap and mainly inhibit p53 and cell-cell junctions' pathways. Together, we uncover that TGF-β induces an lncRNA, whose encoded miRNAs, miR-100, let-7a and miR-125b play opposing roles in controlling PDAC tumourigenesis.

10 Article Prospective validation of microRNA signatures for detecting pancreatic malignant transformation in endoscopic-ultrasound guided fine-needle aspiration biopsies. 2016

Frampton, Adam E / Krell, Jonathan / Prado, Mireia Mato / Gall, Tamara M H / Abbassi-Ghadi, Nima / Del Vecchio Blanco, Giovanna / Funel, Niccola / Giovannetti, Elisa / Castellano, Leandro / Basyouny, Mohamed / Habib, Nagy A / Kaltsidis, Harry / Vlavianos, Panagiotis / Stebbing, Justin / Jiao, Long R. ·HPB Surgical Unit, Department of Surgery and Cancer, Imperial College, Hammersmith Hospital, London, UK. · Division of Cancer, Department of Surgery and Cancer, Imperial College, Hammersmith Hospital, London, UK. · Academic Surgical Unit, Department of Surgery and Cancer, Imperial College, St. Mary's Hospital, London, UK. · Department of Systems Medicine, Gastroenterology Unit, University Tor Vergata, Rome, Italy. · Cancer Pharmacology Lab, AIRC Start-Up Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy. · CNR-Nano, Institute of Nanoscience and Nanotechnology, Pisa, Italy. · Department of Medical Oncology, VU University Medical Center, Amsterdam, Netherlands. · Department of Gastroenterology, Imperial College Healthcare NHS Trust, Hammersmith Hospital, London, UK. ·Oncotarget · Pubmed #27086919.

ABSTRACT: BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease. Novel biomarkers are required to aid treatment decisions and improve patient outcomes. MicroRNAs (miRNAs) are potentially ideal diagnostic biomarkers, as they are stable molecules, and tumour and tissue specific. RESULTS: Logistic regression analysis revealed an endoscopic-ultrasound fine-needle aspiration (EUS-FNA) 2-miRNA classifier (miR-21 + miR-155) capable of distinguishing benign from malignant pancreatic lesions with a sensitivity of 81.5% and a specificity of 85.7% (AUC 0.930). Validation FNA cohorts confirmed both miRNAs were overexpressed in malignant disease, while circulating miRNAs performed poorly. METHODS: Fifty-five patients with a suspicious pancreatic lesion on cross-sectional imaging were evaluated by EUS-FNA. At echo-endoscopy, the first part of the FNA was sent for cytological assessment and the second part was used for total RNA extraction. Candidate miRNAs were selected after careful review of the literature and expression was quantified by qRT-PCR. Validation was performed on an independent cohort of EUS-FNAs, as well as formalin-fixed paraffin embedded (FFPE) and plasma samples. CONCLUSIONS: We provide further evidence for using miRNAs as diagnostic biomarkers for pancreatic malignancy. We demonstrate the feasibility of using fresh EUS-FNAs to establish miRNA-based signatures unique to pancreatic malignant transformation and the potential to enhance risk stratification and selection for surgery.

11 Article Activating mutations of GNAS and KRAS in cystic fluid can help detect intraductal papillary mucinous neoplasms of the pancreas. 2015

Frampton, Adam E / Stebbing, Justin / Gall, Tamara M H / Silver, Benjamin / Jiao, Long R / Krell, Jonathan. ·Department of Surgery and Cancer, HPB Surgical Unit, Imperial College, Hammersmith Hospital Campus, Du Cane Road, London, W12 0HS, UK. ·Expert Rev Mol Diagn · Pubmed #25656048.

ABSTRACT: Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas have a risk of malignant transformation following an adenoma-carcinoma sequence. Surgical resection is often required, especially for main pancreatic duct IPMNs (MD-IPMNs). There is an urgent need for novel biomarkers to reliably differentiate IPMNs from more benign pancreatic cysts and therefore avoid unnecessary surgery. DNA sequencing has demonstrated that guanine nucleotide binding protein alpha stimulating (GNAS) activity polypeptide 1 mutations play a driving role in IPMN development. GNAS mutations have been shown to be highly specific for IPMNs, whereas oncogenic KRAS mutations have been associated with mucinous differentiation. The evaluated article by Singhi et al. helps to define the role of these mutations as biomarkers in preoperative endoscopic ultrasound fine-needle aspiration samples for detecting IPMNs. They found that the presence of a GNAS and/or a KRAS mutation was highly specific and sensitive for IPMNs.

12 Article Quantification of pancreatic cancer proteome and phosphorylome: indicates molecular events likely contributing to cancer and activity of drug targets. 2014

Britton, David / Zen, Yoh / Quaglia, Alberto / Selzer, Stefan / Mitra, Vikram / Löβner, Christopher / Jung, Stephan / Böhm, Gitte / Schmid, Peter / Prefot, Petra / Hoehle, Claudia / Koncarevic, Sasa / Gee, Julia / Nicholson, Robert / Ward, Malcolm / Castellano, Leandro / Stebbing, Justin / Zucht, Hans Dieter / Sarker, Debashis / Heaton, Nigel / Pike, Ian. ·Proteome Sciences plc, Cobham, United Kingdom. · Institute of Liver Studies, King's College Hospital, London, United Kingdom. · Cardiff School of Pharmacy & Pharmaceutical Sciences, Cardiff University, Cardiff, United Kingdom. · Faculty of Medicine, Department of Surgery & Cancer, Imperial College, London, United Kingdom. ·PLoS One · Pubmed #24670416.

ABSTRACT: OBJECTIVE: LC-MS/MS phospho-proteomics is an essential technology to help unravel the complex molecular events that lead to and propagate cancer. We have developed a global phospho-proteomic workflow to determine activity of signaling pathways and drug targets in pancreatic cancer tissue for clinical application. METHODS: Peptides resulting from tryptic digestion of proteins extracted from frozen tissue of pancreatic ductal adenocarcinoma and background pancreas (n = 12), were labelled with tandem mass tags (TMT 8-plex), separated by strong cation exchange chromatography, then were analysed by LC-MS/MS directly or first enriched for phosphopeptides using IMAC and TiO2, prior to analysis. In-house, commercial and freeware bioinformatic platforms were used to identify relevant biological events from the complex dataset. RESULTS: Of 2,101 proteins identified, 152 demonstrated significant difference in abundance between tumor and non-tumor tissue. They included proteins that are known to be up-regulated in pancreatic cancer (e.g. Mucin-1), but the majority were new candidate markers such as HIPK1 & MLCK. Of the 6,543 unique phosphopeptides identified (6,284 unique phosphorylation sites), 635 showed significant regulation, particularly those from proteins involved in cell migration (Rho guanine nucleotide exchange factors & MRCKα) and formation of focal adhesions. Activator phosphorylation sites on FYN, AKT1, ERK2, HDAC1 and other drug targets were found to be highly modulated (≥2 fold) in different cases highlighting their predictive power. CONCLUSION: Here we provided critical information enabling us to identify the common and unique molecular events likely contributing to cancer in each case. Such information may be used to help predict more bespoke therapy suitable for an individual case.

13 Article Reduced dissemination of circulating tumor cells with no-touch isolation surgical technique in patients with pancreatic cancer. 2014

Gall, Tamara M H / Jacob, Jimmy / Frampton, Adam E / Krell, Jonathan / Kyriakides, Charis / Castellano, Leandro / Stebbing, Justin / Jiao, Long R. · ·JAMA Surg · Pubmed #24599353.

ABSTRACT: Circulating tumor cells (CTCs) disseminate from the primary tumor and travel through the bloodstream and lymphatic system. The detection of and/or increase in the number of CTCs during a patient’s clinical course may be a harbinger of forthcoming overt metastasis. We aimed to examine the impact of 2 different surgical techniques, standard (ST) pancreaticoduodenectomy (PD) and no-touch isolation (NT) PD, on tumor behavior and outcome in patients with pancreatic cancer by using CTCs as biomarkers. In this pilot study, patients were randomized to either ST-PD (n = 6) or NT-PD (n = 6). Intraoperatively, blood samples were taken from the portal vein for measurement of CTCs before and immediately after removal of the tumor. An increase in CTCs was seen in 5 of 6 patients (83%) with ST-PD but no patients with NT-PD (P = .003). In the ST-PD and NT-PD groups, median overall survival was 13.0 and 16.7 months, respectively (P = .33); there was no difference in disease-free survival (P = .42). The use of NT-PD significantly reduced the number of CTCs in the portal vein with no benefit in survival outcomes compared with ST-PD, although more extensive studies are required.

14 Article A microRNA meta-signature for pancreatic ductal adenocarcinoma. 2014

Frampton, Adam E / Giovannetti, Elisa / Jamieson, Nigel B / Krell, Jonathan / Gall, Tamara Mh / Stebbing, Justin / Jiao, Long R / Castellano, Leandro. ·Department of Surgery and Cancer, HPB Surgical Unit, Imperial College, Hammersmith Hospital campus, Du Cane Road, London, W12 0HS, UK. ·Expert Rev Mol Diagn · Pubmed #24575833.

ABSTRACT: Due to its aggressive and late presentation, there is an urgent need for novel and reliable biomarkers for the diagnosis and prognostication of pancreatic ductal adenocarcinoma (PDAC). MiRNAs have been extensively profiled in PDAC tissues, biopsies, blood samples and other biofluids and their expression levels compared to normal and chronic pancreatitis (CP) specimens in order to identify the most relevant candidates. Consolidation of these activities has not been attempted until now. The evaluated meta-review by Ma et al. helps to define the use of miRNAs as biomarkers for detecting this tumor-type and predicting survival outcomes in PDAC. Based on frequency and consistency between microarray studies, they identified a miRNA meta-signature for recognising PDAC: upregulation of miR-21, 23a, 31, 100, 143, 155, and 221; with downregulation of miR-148a, 217 and 375. Furthermore, they validated high miR-21, high miR-31 and low miR-375 tumoural expression as independently prognostic for poor overall-survival (OS; n = 70).

15 Article MicroRNAs cooperatively inhibit a network of tumor suppressor genes to promote pancreatic tumor growth and progression. 2014

Frampton, Adam E / Castellano, Leandro / Colombo, Teresa / Giovannetti, Elisa / Krell, Jonathan / Jacob, Jimmy / Pellegrino, Loredana / Roca-Alonso, Laura / Funel, Niccola / Gall, Tamara M H / De Giorgio, Alexander / Pinho, Filipa G / Fulci, Valerio / Britton, David J / Ahmad, Raida / Habib, Nagy A / Coombes, R Charles / Harding, Victoria / Knösel, Thomas / Stebbing, Justin / Jiao, Long R. ·HPB Surgical Unit, Department of Surgery and Cancer, Imperial College, London, UK. · Division of Oncology, Department of Surgery and Cancer, Imperial Centre for Translational and Experimental Medicine, Imperial College, Hammersmith Hospital, London, UK. Electronic address: l.castellano@imperial.ac.uk. · Department of Cellular Biotechnology and Haematology, La Sapienza University, Rome, Italy. · Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands. · Division of Oncology, Department of Surgery and Cancer, Imperial Centre for Translational and Experimental Medicine, Imperial College, Hammersmith Hospital, London, UK. · Experimental and Molecular Oncology, Department of Surgery, University of Pisa, Pisa, Italy. · Proteome Sciences plc, King's College, London, UK. · Department of Pathology, Imperial College Healthcare NHS Trust, Hammersmith Hospital, London, UK. · Institute of Pathology, Ludwig-Maximilians-University, Munich, Germany. · HPB Surgical Unit, Department of Surgery and Cancer, Imperial College, London, UK. Electronic address: l.jiao@imperial.ac.uk. ·Gastroenterology · Pubmed #24120476.

ABSTRACT: BACKGROUND & AIMS: There has not been a broad analysis of the combined effects of altered activities of microRNAs (miRNAs) in pancreatic ductal adenocarcinoma (PDAC) cells, and it is unclear how these might affect tumor progression or patient outcomes. METHODS: We combined data from miRNA and messenger RNA (mRNA) expression profiles and bioinformatic analyses to identify an miRNA-mRNA regulatory network in PDAC cell lines (PANC-1 and MIA PaCa-2) and in PDAC samples from patients. We used this information to identify miRNAs that contribute most to tumorigenesis. RESULTS: We identified 3 miRNAs (MIR21, MIR23A, and MIR27A) that acted as cooperative repressors of a network of tumor suppressor genes that included PDCD4, BTG2, and NEDD4L. Inhibition of MIR21, MIR23A, and MIR27A had synergistic effects in reducing proliferation of PDAC cells in culture and growth of xenograft tumors in mice. The level of inhibition was greater than that of inhibition of MIR21 alone. In 91 PDAC samples from patients, high levels of a combination of MIR21, MIR23A, and MIR27A were associated with shorter survival times after surgical resection. CONCLUSIONS: In an integrated data analysis, we identified functional miRNA-mRNA interactions that contribute to growth of PDACs. These findings indicate that miRNAs act together to promote tumor progression; therapeutic strategies might require inhibition of several miRNAs.

16 Article Is the detection of circulating tumor cells in locally advanced pancreatic cancer a useful prognostic marker? 2013

Gall, Tamara M H / Frampton, Adam E / Krell, Jonathan / Jacob, Jimmy / Stebbing, Justin / Jiao, Long R. ·Deptartment of Surgery & Cancer, HPB Surgical Unit, Imperial College, Hammersmith Hospital campus, Du Cane Road, London, W12 0HS, UK. ·Expert Rev Mol Diagn · Pubmed #24127751.

ABSTRACT: Evaluation of: Bidard FC, Huguet F, Louvet C et al. Circulating tumor cells in locally advanced pancreatic adenocarcinoma: the ancillary CirCe 07 study to the LAP 07 trial. Ann. Oncol. 24(8), 2057-2061 (2013). Circulating tumor cells (CTCs) may be shed from the primary tumor and lead to metastatic disease. This evaluated article reports on CTCs in locally advanced pancreatic cancer (LAPC). By assessing CTCs from peripheral blood prior to any treatment and after 2 months of chemotherapy, 11% of patients had detectable CTCs. These patients had a poorer overall survival. With such low numbers of CTCs detected in LAPC patients, it is unclear whether CTCs can actually contribute toward tumor invasiveness and spread in such an aggressive cancer. Although this is a well-designed study, the small number of patients with detectable CTCs means that the statistical power is not great enough to make firm conclusions. Therefore, this expensive assay needs further investigation before being used a prognostic marker in patients with LAPC.

17 Article Circulating peripheral blood mononuclear cells exhibit altered miRNA expression patterns in pancreatic cancer. 2013

Frampton, Adam E / Fletcher, Claire E / Gall, Tamara Mh / Castellano, Leandro / Bevan, Charlotte L / Stebbing, Justin / Krell, Jonathan. ·HPB Surgical Unit, Department of Surgery & Cancer, Imperial College, Hammersmith Hospital Campus, Du Cane Road, London W12 0HS, UK. a.frampton@imperial.ac.uk ·Expert Rev Mol Diagn · Pubmed #23782250.

ABSTRACT: Evaluation of: Wang WS, Liu LX, Li GP et al. Combined serum CA19-9 and miR-27a-3p in peripheral blood mononuclear cells to diagnose pancreatic cancer. Cancer Prev. Res. (Phila.) 6(4), 331-338 (2013). Patients with pancreatic ductal adenocarcinoma (PDAC) have a bleak outlook, primarily because tumors are detected late and are often too advanced for surgical resection. In addition, these lesions are incredibly resistant to anticancer therapies. The majority of PDAC patients have impaired tumor immunity, contributing to disease development and progression, although the mechanisms remain poorly understood. miRNAs are important negative gene regulators that have critical roles in human tumorigenesis. Blood-based miRNAs have been investigated as biomarkers for various cancers, in the hope that these will outperform current serum tumor markers. The evaluated study examined the miRNA profiles in peripheral blood mononuclear cells from PDAC patients. The theory is that circulating blood cells monitor the patients' physiological state and respond by altering their transcriptome and that this can then be used to detect disease. In this article, we have examined the evidence for using circulating miRNAs to diagnose/prognose PDAC.

18 Article Defining a prognostic molecular profile for ductal adenocarcinoma of the pancreas highlights known key signaling pathways. 2012

Frampton, Adam E / Krell, Jonathan / Giovannetti, Elisa / Krell, Daniel / Stebbing, Justin / Castellano, Leandro / Jiao, Long R. ·Department of Surgery and Cancer, HPB Surgical Unit, Imperial College, Hammersmith Hospital, Du Cane Road, London, W12 0HS, UK. a.frampton@imperial.ac.uk ·Expert Rev Anticancer Ther · Pubmed #23176615.

ABSTRACT: There has been very little progress in improving outcomes for patients with pancreatic ductal adenocarcinoma (PDAC) over the past few decades. High-throughput array profiling has made it possible to discover new assays to diagnose or prognose PDAC more accurately based on the genetic profile of an individual tumor. To improve patient survival, there is a need to extract the most practical data to define tumor subgroups and personalize anticancer therapy. In the evaluated study, a multiplatform, survival-based analysis of molecular changes was performed for PDAC to discover clinically useful biomarkers. A composite score predictive for survival was calculated for individual genes, taking into account the DNA copy-number and any regulation by miRNAs. Several genes involved in the PI3K/AKT and SRC signaling pathways were identified and further investigated.

19 Article MicroRNAs targeting oncogenes are down-regulated in pancreatic malignant transformation from benign tumors. 2012

Jiao, Long R / Frampton, Adam E / Jacob, Jimmy / Pellegrino, Loredana / Krell, Jonathan / Giamas, Georgios / Tsim, Nicole / Vlavianos, Panagiotis / Cohen, Patrizia / Ahmad, Raida / Keller, Andreas / Habib, Nagy A / Stebbing, Justin / Castellano, Leandro. ·Hepato-Pancreato-Biliary Surgical Unit, Department of Surgery and Cancer, Imperial College, Hammersmith Hospital, London, UK. ·PLoS One · Pubmed #22384141.

ABSTRACT: BACKGROUND: MicroRNA (miRNA) expression profiles have been described in pancreatic ductal adenocarcinoma (PDAC), but these have not been compared with pre-malignant pancreatic tumors. We wished to compare the miRNA expression signatures in pancreatic benign cystic tumors (BCT) of low and high malignant potential with PDAC, in order to identify miRNAs deregulated during PDAC development. The mechanistic consequences of miRNA dysregulation were further evaluated. METHODS: Tissue samples were obtained at a tertiary pancreatic unit from individuals with BCT and PDAC. MiRNA profiling was performed using a custom microarray and results were validated using RT-qPCR prior to evaluation of miRNA targets. RESULTS: Widespread miRNA down-regulation was observed in PDAC compared to low malignant potential BCT. We show that amongst those miRNAs down-regulated, miR-16, miR-126 and let-7d regulate known PDAC oncogenes (targeting BCL2, CRK and KRAS respectively). Notably, miR-126 also directly targets the KRAS transcript at a "seedless" binding site within its 3'UTR. In clinical specimens, miR-126 was strongly down-regulated in PDAC tissues, with an associated elevation in KRAS and CRK proteins. Furthermore, miR-21, a known oncogenic miRNA in pancreatic and other cancers, was not elevated in PDAC compared to serous microcystic adenoma (SMCA), but in both groups it was up-regulated compared to normal pancreas, implicating early up-regulation during malignant change. CONCLUSIONS: Expression profiling revealed 21 miRNAs down-regulated in PDAC compared to SMCA, the most benign lesion that rarely progresses to invasive carcinoma. It appears that miR-21 up-regulation is an early event in the transformation from normal pancreatic tissue. MiRNA expression has the potential to distinguish PDAC from normal pancreas and BCT. Mechanistically the down-regulation of miR-16, miR-126 and let-7d promotes PDAC transformation by post-transcriptional up-regulation of crucial PDAC oncogenes. We show that miR-126 is able to directly target KRAS; re-expression has the potential as a therapeutic strategy against PDAC and other KRAS-driven cancers.

20 Minor Usefulness of Measuring microRNAs in Bile and Plasma for Pancreatic Ductal Adenocarcinoma Diagnosis. 2015

Le Large, Tessa Y S / Frampton, Adam E / Meijer, Laura L / Stebbing, Justin / Kazemier, Geert / Giovannetti, Elisa. ·1] Department of Surgery, VU University Medical Center, Amsterdam, The Netherlands [2] Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands. · Department of Surgery and Cancer, Imperial College, London, UK. · Department of Surgery, VU University Medical Center, Amsterdam, The Netherlands. · 1] Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands [2] AIRC Start-Up Unit, University of Pisa, Pisa, Italy. ·Am J Gastroenterol · Pubmed #25942302.

ABSTRACT: -- No abstract --

21 Minor The role of miR-10b in metastatic pancreatic ductal adenocarcinoma. 2012

Frampton, Adam E / Krell, Jonathan / Zhang, Yaojun / Stebbing, Justin / Castellano, Leandro / Jiao, Long R. · ·Surgery · Pubmed #22682079.

ABSTRACT: -- No abstract --