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Pancreatic Neoplasms: HELP
Articles by Emmanouil Fokas
Based on 18 articles published since 2010
(Why 18 articles?)
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Between 2010 and 2020, E. Fokas wrote the following 18 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Review Pancreatic ductal adenocarcinoma: From genetics to biology to radiobiology to oncoimmunology and all the way back to the clinic. 2015

Fokas, Emmanouil / O'Neill, Eric / Gordon-Weeks, Alex / Mukherjee, Somnath / McKenna, W Gillies / Muschel, Ruth J. ·Department of Oncology, Oxford Institute for Radiation Oncology, Oxford University, Oxford, UK. Electronic address: emmanouil.fokas@oncology.ox.ac.uk. · Department of Oncology, Oxford Institute for Radiation Oncology, Oxford University, Oxford, UK. · Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK. ·Biochim Biophys Acta · Pubmed #25489989.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death. Despite improvements in the clinical management, the prognosis of PDAC remains dismal. In the present comprehensive review, we will examine the knowledge of PDAC genetics and the new insights into human genome sequencing and clonal evolution. Additionally, the biology and the role of the stroma in tumour progression and response to treatment will be presented. Furthermore, we will describe the evidence on tumour chemoresistance and radioresistance and will provide an overview on the recent advances in PDAC metabolism and circulating tumour cells. Next, we will explore the characteristics and merits of the different mouse models of PDAC. The inflammatory milieu and the immunosuppressive microenvironment mediate tumour initiation and treatment failure. Hence, we will also review the inflammatory and immune escaping mechanisms and the new immunotherapies tested in PDAC. A better understanding of the different mechanisms of tumour formation and progression will help us to identify the best targets for testing in future clinical studies of PDAC.

2 Clinical Trial [The results of the LAP07 trial should not be misunderstood as the end of chemoradiotherapy in pancreatic cancer]. 2016

Brunner, Thomas / Fokas, Emmanouil. ·Klinik für Strahlenheilkunde, Universitätsklinikum Freiburg, Albert-Ludwigs-Universität Freiburg, Robert‑Koch‑Str. 3, 79106, Freiburg, Deutschland. thomas.brunner@uniklinik-freiburg.de. · , Frankfurt/Main, Deutschland. ·Strahlenther Onkol · Pubmed #27757498.

ABSTRACT: -- No abstract --

3 Clinical Trial A phase-I trial of pre-operative, margin intensive, stereotactic body radiation therapy for pancreatic cancer: the 'SPARC' trial protocol. 2016

Holyoake, Daniel L P / Ward, Elizabeth / Grose, Derek / McIntosh, David / Sebag-Montefiore, David / Radhakrishna, Ganesh / Patel, Neel / Silva, Michael / Mukherjee, Somnath / Strauss, Victoria Y / Odondi, Lang'o / Fokas, Emmanouil / Melcher, Alan / Hawkins, Maria A. ·CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford, OX3 7DQ, UK. · Oncology Clinical Trials Office, Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford, OX3 7DQ, UK. · The Beatson West of Scotland Cancer Centre, 1053 Great Western Rd, Glasgow, G12 0YN, UK. · The University of Leeds, Cancer Research UK Leeds Centre,14 Leeds Institute of Cancer and Pathology, Cancer Genetics Building, St James's University Hospital, 15 Beckett Street, Leeds, West Yorkshire, LS9 7TF, UK. · Leeds Cancer Centre, Leeds Teaching Hospitals NHS Trust, Bexley Wing, Beckett Street, Leeds, LS9 7TF, UK. · Oxford University Hospitals NHS Foundation Trust, Old Road, Headington, Oxford, OX3 7LE, UK. · Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Botnar Research Centre, Windmill Road, Oxford, OX3 7LD, UK. · The Institute of Cancer Research, Chester Beatty Laboratories, 237, Fulham Rd, London, SW3 6JB, UK. · CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford, OX3 7DQ, UK. maria.hawkins@oncology.ox.ac.uk. ·BMC Cancer · Pubmed #27619800.

ABSTRACT: BACKGROUND: Standard therapy for borderline-resectable pancreatic cancer in the UK is surgery with adjuvant chemotherapy, but rates of resection with clear margins are unsatisfactory and overall survival remains poor. Meta-analysis of single-arm studies shows the potential of neo-adjuvant chemo-radiotherapy but the relative radio-resistance of pancreatic cancer means the efficacy of conventional dose schedules is limited. Stereotactic radiotherapy achieves sufficient accuracy and precision to enable pre-operative margin-intensive dose escalation with the goal of increasing rates of clear resection margins and local disease control. METHODS/DESIGN: SPARC is a "rolling-six" design single-arm study to establish the maximum tolerated dose for margin-intensive stereotactic radiotherapy before resection of pancreatic cancer at high risk of positive resection margins. Eligible patients will have histologically or cytologically proven pancreatic cancer defined as borderline-resectable per National Comprehensive Cancer Network criteria or operable tumour in contact with vessels increasing the risk of positive margin. Up to 24 patients will be recruited from up to 5 treating centres and a 'rolling-six' design is utilised to minimise delays and facilitate ongoing recruitment during dose-escalation. Radiotherapy will be delivered in 5 daily fractions and surgery, if appropriate, will take place 5-6 weeks after radiotherapy. The margin-intense radiotherapy concept includes a systematic method to define the target volume for a simultaneous integrated boost in the region of tumour-vessel infiltration, and up to 4 radiotherapy dose levels will be investigated. Maximum tolerated dose is defined as the highest dose at which no more than 1 of 6 patients or 0 of 3 patients experience a dose limiting toxicity. Secondary endpoints include resection rate, resection margin status, response rate, overall survival and progression free survival at 12 and 24 months. Translational work will involve exploratory analyses of the cytological and humoral immunological responses to stereotactic radiotherapy in pancreatic cancer. Radiotherapy quality assurance of target definition and radiotherapy planning is enforced with pre-trial test cases and on-trial review. Recruitment began in April 2015. DISCUSSION: This prospective multi-centre study aims to establish the maximum tolerated dose of pre-operative margin-intensified stereotactic radiotherapy in pancreatic cancer at high risk of positive resection margins with a view to subsequent definitive comparison with other neoadjuvant treatment options. TRIAL REGISTRATION: ISRCTN14138956 . Funded by CRUK.

4 Clinical Trial Comparison of investigator-delineated gross tumour volumes and quality assurance in pancreatic cancer: Analysis of the on-trial cases for the SCALOP trial. 2016

Fokas, Emmanouil / Spezi, Emiliano / Patel, Neel / Hurt, Chris / Nixon, Lisette / Chu, Kwun-Ye / Staffurth, John / Abrams, Ross / Mukherjee, Somnath. ·Department of Oncology, CRUK/MRC Institute for Radiation Oncology, University of Oxford, UK. · School of Engineering, Cardiff University, UK. · Oxford University Hospital NHS Foundation Trust, UK. · Wales Cancer Trials Unit, Centre for Trials Research, Cardiff University, UK. · Department of Oncology, CRUK/MRC Institute for Radiation Oncology, University of Oxford, UK; Oxford University Hospital NHS Foundation Trust, UK. · Institute of Cancer and Genetics, Cardiff University, UK; Cardiff NCRI RTTQA Centre, Velindre NHS Trust, UK. · Department of Radiation Oncology, Rush University Medical Center, Chicago, USA. · Department of Oncology, CRUK/MRC Institute for Radiation Oncology, University of Oxford, UK; Oxford University Hospital NHS Foundation Trust, UK. Electronic address: somnath.mukherjee@oncology.ox.ac.uk. ·Radiother Oncol · Pubmed #27497804.

ABSTRACT: BACKGROUND AND PURPOSE: We performed a retrospective central review of tumour outlines in patients undergoing radiotherapy in the SCALOP trial. MATERIALS AND METHODS: The planning CT scans were reviewed retrospectively by a central review team, and the accuracy of investigators' GTV (iGTV) and PTV (iPTV) was compared to the trials team-defined gold standard (gsGTV and gsPTV) using the Jaccard Conformity Index (JCI) and Geographical Miss Index (GMI). The prognostic value of JCI and GMI was also assessed. The RT plans were also reviewed against protocol-defined constraints. RESULTS: 60 patients with diagnostic-quality planning scans were included. The median whole volume JCI for GTV was 0.64 (IQR: 0.43-0.82), and the median GMI was 0.11 (IQR: 0.05-0.22). For PTVs, the median JCI and GMI were 0.80 (IQR: 0.71-0.88) and 0.04 (IQR: 0.02-0.12) respectively. Tumour was completely missed in 1 patient, and⩾50% of the tumour was missed in 3. Patients with JCI for GTV⩾0.7 had 7.12 (95% CIs: 1.83-27.67, p=0.005) higher odds of progressing by 9months in multivariate analysis. Major deviations in RT planning were noted in 4.5% of cases. CONCLUSIONS: Radiotherapy workshops and real-time central review of contours are required in RT trials of pancreatic cancer.

5 Clinical Trial ARCII: A phase II trial of the HIV protease inhibitor Nelfinavir in combination with chemoradiation for locally advanced inoperable pancreatic cancer. 2016

Wilson, James M / Fokas, Emmanouil / Dutton, Susan J / Patel, Neel / Hawkins, Maria A / Eccles, Cynthia / Chu, Kwun-Ye / Durrant, Lisa / Abraham, Aswin G / Partridge, Mike / Woodward, Martha / O'Neill, Eric / Maughan, Tim / McKenna, W Gillies / Mukherjee, Somnath / Brunner, Thomas B. ·Department of Oncology, CRUK/MRC Institute for Radiation Oncology, University of Oxford, UK. · Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, UK. · Department of Radiology, Oxford University Hospitals NHS Foundation Trust, UK. · Department of Radiotherapy, Oxford University Hospitals NHS Foundation Trust, UK. · Department of Oncology, CRUK/MRC Institute for Radiation Oncology, University of Oxford, UK; Department of Radiotherapy, Oxford University Hospitals NHS Foundation Trust, UK. · Early Phase Research Hub, Department of Oncology, Oxford Cancer and Haematology Centre, Oxford University Hospitals NHS Foundation Trust, UK. · Department of Oncology, CRUK/MRC Institute for Radiation Oncology, University of Oxford, UK. Electronic address: somnath.mukherjee@oncology.ox.ac.uk. · Department of Radiation Oncology, University of Freiburg, Germany; German Cancer Consortium (DKTK), Heidelberg, Partner Site Freiburg, Germany. ·Radiother Oncol · Pubmed #27117177.

ABSTRACT: BACKGROUND AND PURPOSE: Nelfinavir can enhance intrinsic radiosensitivity, reduce hypoxia and improve vascularity. We conducted a phase II trial combining nelfinavir with chemoradiotherapy (CRT) for locally advanced inoperable pancreatic cancer (LAPC). MATERIALS AND METHODS: Radiotherapy (50.4Gy/28 fractions; boost to 59.4Gy/33 fractions) was administered with weekly gemcitabine and cisplatin. Nelfinavir started 3-10days before and was continued during CRT. The primary end-point was 1-year overall survival (OS). Secondary end-points included histological downstaging, radiological response, 1-year progression free survival (PFS), overall survival (OS) and treatment toxicity. An imaging sub-study (n=6) evaluated hypoxia ((18)F-Fluoromisonidazole-PET) and perfusion (perfusion CT) during induction nelfinavir. RESULTS: The study closed after recruiting 23 patients, due to non-availability of Nelfinavir in Europe. The 1-year OS was 73.4% (90% CI: 54.5-85.5%) and median OS was 17.4months (90% CI: 12.8-18.8). The 1-year PFS was 21.8% (90% CI: 8.9-38.3%) and median PFS was 5.5months (90% CI: 4.1-8.3). All patients experienced Grade 3/4 toxicity, but many were asymptomatic laboratory abnormalities. Four of 6 patients on the imaging sub-study demonstrated reduced hypoxia and increased perfusion post-nelfinavir. CONCLUSIONS: CRT combined with nelfinavir showed acceptable toxicity and promising survival in pancreatic cancer.

6 Clinical Trial Comparison of investigator-delineated gross tumor volumes and quality assurance in pancreatic cancer: Analysis of the pretrial benchmark case for the SCALOP trial. 2015

Fokas, Emmanouil / Clifford, Charlotte / Spezi, Emiliano / Joseph, George / Branagan, Jennifer / Hurt, Chris / Nixon, Lisette / Abrams, Ross / Staffurth, John / Mukherjee, Somnath. ·Radiotherapy Physics Department, University Hospitals Birmingham NHS Foundation Trust, UK. Electronic address: emmanouil.fokas@oncology.ox.ac.uk. · Department of Oncology, University of Oxford, UK. · Department of Medical Physics, Velindre Hospital, Cardiff, UK. · Velindre Cancer Centre, Velindre Hospital, Cardiff, UK. · Oncology Department, Northampton General Hospital, UK. · Wales Cancer Trials Unit, Cardiff University, UK. · Department of Radiation Oncology, Rush University Medical Center, Chicago, USA. · Institute of Cancer and Genetics, Cardiff University, UK; Cardiff NCRI RTTQA Centre, Velindre NHS Trust, UK. · Radiotherapy Physics Department, University Hospitals Birmingham NHS Foundation Trust, UK. ·Radiother Oncol · Pubmed #26328939.

ABSTRACT: BACKGROUND AND PURPOSE: To evaluate the variation in investigator-delineated volumes and assess plans from the radiotherapy trial quality assurance (RTTQA) program of SCALOP, a phase II trial in locally advanced pancreatic cancer. MATERIALS AND METHODS: Participating investigators (n=25) outlined a pre-trial benchmark case as per RT protocol, and the accuracy of investigators' GTV (iGTV) and PTV (iPTV) was evaluated, against the trials team-defined gold standard GTV (gsGTV) and PTV (gsPTV), using both qualitative and geometric analyses. The median Jaccard Conformity Index (JCI) and Geographical Miss Index (GMI) were calculated. Participating RT centers also submitted a radiotherapy plan for this benchmark case, which was centrally reviewed against protocol-defined constraints. RESULTS: Twenty-five investigator-defined contours were evaluated. The median JCI and GMI of iGTVs were 0.57 (IQR: 0.51-0.65) and 0.26 (IQR: 0.15-0.40). For iPTVs, these were 0.75 (IQR: 0.71-0.79) and 0.14 (IQR: 0.11-0.22) respectively. Qualitative analysis showed largest variation at the tumor edges and failure to recognize a peri-pancreatic lymph node. There were no major protocol deviations in RT planning, but three minor PTV coverage deviations were identified. . CONCLUSIONS: SCALOP demonstrated considerable variation in iGTV delineation. RTTQA workshops and real-time central review of delineations are needed in future trials.

7 Clinical Trial A treatment planning comparison of four target volume contouring guidelines for locally advanced pancreatic cancer radiotherapy. 2013

Fokas, Emmanouil / Eccles, Cynthia / Patel, Neel / Chu, Kwun-Ye / Warren, Samantha / McKenna, W Gillies / Brunner, Thomas B. ·Gray Institute for Radiation Oncology and Biology, Department of Oncology, Oxford University, United Kingdom. emmanouil.fokas@kgu.de ·Radiother Oncol · Pubmed #23647755.

ABSTRACT: BACKGROUND AND PURPOSE: Contouring of target volumes varies significantly in radiotherapy of pancreatic ductal adenocarcinoma (PDAC). There is a lack of consensus as to whether elective lymph nodes (eLN's) should be included or not in the planning target volume (PTV). In the present study we analyzed the dosimetric coverage of the eLN's and organs at risk (OAR) by comparing four different contouring guidelines. METHODS AND MATERIALS: PTVs were delineated with (Oxford and RTOG guidelines) or without (Michigan and SCALOP guidelines) including the eLNs in eleven patients with PDAC. eLNs included the peripancreatic, paraaortic, paracaval, celiac trunk, superior mesenteric and portal vein clinical target volumes (CTVs). A 3D-CRT plan (50.40 Gy in 28 fractions) was performed to analyze and compare the dosimetric coverage of all eLNs and OAR between the 4 contouring guidelines. RESULTS: The size of Oxford and RTOG PTVs was comparable and significantly larger than the SCALOP and Michigan PTVs. Interestingly the eLNs received a significant amount of incidental dose irradiation by PTV-based plans that only aimed to treat the tumor without the eLNs. The dosimetric coverage of eLN presented a large variability according to the respective contouring methods. The difference in the size of the 4 PTVs was reflected to the dose distribution at the OAR. CONCLUSIONS: Our study provides important information regarding the impact of different contouring guidelines on the dose distribution to the eLNs and the OAR in patients with locally advanced PDAC treated with radiotherapy.

8 Article Gemcitabine-Induced TIMP1 Attenuates Therapy Response and Promotes Tumor Growth and Liver Metastasis in Pancreatic Cancer. 2017

D'Costa, Zenobia / Jones, Keaton / Azad, Abul / van Stiphout, Ruud / Lim, Su Y / Gomes, Ana L / Kinchesh, Paul / Smart, Sean C / Gillies McKenna, W / Buffa, Francesca M / Sansom, Owen J / Muschel, Ruth J / O'Neill, Eric / Fokas, Emmanouil. ·Department of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, United Kingdom. · CRUK Beatson Institute of Oncology, University of Glasgow, Glasgow, United Kingdom. · Department of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, United Kingdom. emmanouil.fokas@oncology.ox.ac.uk eric.oneill@oncology.ox.ac.uk. ·Cancer Res · Pubmed #28765154.

ABSTRACT: Gemcitabine constitutes one of the backbones for chemotherapy treatment in pancreatic ductal adenocarcinoma (PDAC), but patients often respond poorly to this agent. Molecular markers downstream of gemcitabine treatment in preclinical models may provide an insight into resistance mechanisms. Using cytokine arrays, we identified potential secretory biomarkers of gemcitabine resistance (response) in the transgenic KRasG12D; Trp53R172H; Pdx-1 Cre (KPC) mouse model of PDAC. We verified the oncogenic role of the cytokine tissue inhibitor of matrix metalloproteinases 1 (TIMP1) in primary pancreatic tumors and metastases using both

9 Article Neutrophils promote hepatic metastasis growth through fibroblast growth factor 2-dependent angiogenesis in mice. 2017

Gordon-Weeks, Alex N / Lim, Su Y / Yuzhalin, Arseniy E / Jones, Keaton / Markelc, Bostjan / Kim, K Jin / Buzzelli, Jon N / Fokas, Emmanouil / Cao, Yunhong / Smart, Sean / Muschel, Ruth. ·Nuffield Department of Surgical Sciences, John Radcliffe Hospital, Oxford, United Kingdom. · CRUK/MRC Oxford Institute for Radiation Oncology, Oxford, United Kingdom. · Galaxy Biotech, LLC, Sunnyvale, CA. ·Hepatology · Pubmed #28133764.

ABSTRACT: Hepatic metastases are amenable to ablation; however, many patients are not suitable candidates for such therapy and recurrence is common. The tumor microenvironment is known to be essential for metastatic growth, yet identification of plausible targets for cancer therapy in the microenvironment has proven elusive. We found that human colorectal cancer liver metastases and murine gastrointestinal experimental liver metastases are infiltrated by neutrophils. Plasticity in neutrophils has recently been shown to lead to both protumor and antitumor effects. Here, neutrophils promoted the growth of hepatic metastases, given that depletion of neutrophils in already established, experimental, murine liver metastases led to diminished metastatic growth. Decreased growth was associated with reductions in vascular density and branching suggestive of vessel normalization. Metastasis-associated neutrophils expressed substantially more fibroblast growth factor 2 (FGF2) than naïve neutrophils, indicating neutrophil polarization by the tumor microenvironment. Administration of FGF2 neutralizing antibody to mice bearing experimental liver metastases phenocopied neutrophil depletion by reducing liver metastatic colony growth, vascular density, and branching. CONCLUSION: Here, we show, using FGF2 as an example, that identification of factors responsible for the protumoral effects of infiltrating myeloid cells can be used to target established liver metastases. Such therapies could be utilized to limit disease progression and potentiate the effects of standard ablative therapies. (Hepatology 2017;65:1920-1935).

10 Article PD-L1 blockade enhances response of pancreatic ductal adenocarcinoma to radiotherapy. 2017

Azad, Abul / Yin Lim, Su / D'Costa, Zenobia / Jones, Keaton / Diana, Angela / Sansom, Owen J / Kruger, Philipp / Liu, Stanley / McKenna, W Gillies / Dushek, Omer / Muschel, Ruth J / Fokas, Emmanouil. ·Department of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UK. · CRUK Beatson Cancer Institute, University of Glasgow, Glasgow, UK. · Sir William Dunn School of Pathology, University of Oxford, Oxford, UK. · Department of Radiation Oncology, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada. · Department of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UK emmanouil.fokas@oncology.ox.ac.uk. ·EMBO Mol Med · Pubmed #27932443.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is considered a non-immunogenic tumor, and immune checkpoint inhibitor monotherapy lacks efficacy in this disease. Radiotherapy (RT) can stimulate the immune system. Here, we show that treatment of KPC and Pan02 murine PDAC cells with RT and gemcitabine upregulated PD-L1 expression in a JAK/Stat1-dependent manner. In vitro, PD-L1 inhibition did not alter radio- and chemosensitivity. In vivo, addition of anti-PD-L1 to high (12, 5 × 3, 20 Gy) but not low (6, 5 × 2 Gy) RT doses significantly improved tumor response in KPC and Pan02 allografts. Radiosensitization after PD-L1 blockade was associated with reduced CD11b

11 Article Prognostic role and correlation of CA9, CD31, CD68 and CD20 with the desmoplastic stroma in pancreatic ductal adenocarcinoma. 2016

Diana, Angela / Wang, Lai Mun / D'Costa, Zenobia / Azad, Abul / Silva, Michael A / Soonawalla, Zahir / Allen, Paul / Liu, Stanley / McKenna, W Gillies / Muschel, Ruth J / Fokas, Emmanouil. ·Department of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UK. · Department of Pathology, Oxford University Hospital NHS Foundation Trust, Oxford, UK. · Department of Surgery, Oxford University Hospital NHS Foundation Trust, Oxford, UK. · Department of Radiation Oncology, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Canada. · Current address: Department of Radiotherapy and Oncology, Goethe University of Frankfurt, Frankfurt, Germany. ·Oncotarget · Pubmed #27637082.

ABSTRACT: We assessed the prognostic value of hypoxia (carbonic anhydrase 9; CA9), vessel density (CD31), with macrophages (CD68) and B cells (CD20) that can interact and lead to immune suppression and disease progression using scanning and histological mapping of whole-mount FFPE pancreatectomy tissue sections from 141 primarily resectable pancreatic ductal adenocarcinoma (PDAC) samples treated with surgery and adjuvant chemotherapy. Their expression was correlated with clinicopathological characteristics, and overall survival (OS), progression-free survival (PFS), local progression-free survival (LPFS) and distant metastases free-survival (DMFS), also in the context of stroma density (haematoxylin-eosin) and activity (alpha-smooth muscle actin). The median OS was 21 months after a mean follow-up of 20 months (range, 2-69 months). The median tumor surface area positive for CA9 and CD31 was 7.8% and 8.1%, respectively. Although total expression of these markers lacked prognostic value in the entire cohort, nevertheless, high tumor compartment CD68 expression correlated with worse PFS (p = 0.033) and DMFS (p = 0.047). Also, high CD31 expression predicted for worse OS (p = 0.004), PFS (p = 0.008), LPFS (p = 0.014) and DMFS (p = 0.004) in patients with moderate density stroma. High stromal and peripheral compartment CD68 expression predicted for significantly worse outcome in patients with loose and moderate stroma density, respectively. Altogether, in contrast to the current notion, hypoxia levels in PDAC appear to be comparable to other malignancies. CD31 and CD68 constitute prognostic markers in patient subgroups that vary according to tumor compartment and stromal density. Our study provides important insight on the pathophysiology of PDAC and should be exploited for future treatments.

12 Article Prognostic value, localization and correlation of PD-1/PD-L1, CD8 and FOXP3 with the desmoplastic stroma in pancreatic ductal adenocarcinoma. 2016

Diana, Angela / Wang, Lai Mun / D'Costa, Zenobia / Allen, Paul / Azad, Abul / Silva, Michael A / Soonawalla, Zahir / Liu, Stanley / McKenna, W Gillies / Muschel, Ruth J / Fokas, Emmanouil. ·Department of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UK. · Department of Pathology, Oxford University Hospital NHS Foundation Trust, Oxford, UK. · Department of Surgery, Oxford University Hospital NHS Foundation Trust, Oxford, UK. · Department of Radiation Oncology, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Canada. ·Oncotarget · Pubmed #27329602.

ABSTRACT: We examined the prognostic value of programmed cell death-1 (PD-1) and its ligand (PD-L1) together with CD8+ tumor-infiltrating lymphocytes (TILs) and FOXP3+ Tregs in resectable pancreatic ductal adenocarcinoma (PDAC) samples treated with adjuvant chemotherapy. Whole-mount FFPE tissue sections from 145 pancreatectomies were immunohistochemically stained for PD-1, PD-L1, CD8 and FOXP3. Their expression was correlated with clinicopathological characteristics, and overall survival (OS), progression-free survival (PFS), local progression-free survival (LPFS) and distant metastases free-survival (DMFS), in the context of stroma density (haematoxylin-eosin) and activity (alpha-smooth muscle actin) and in regard to intratumoral lymphoid aggregates. The median OS was 21 months after a mean follow-up of 20 months (range, 2-69 months). In multivariate analysis, high PD-1+ TILs expression was associated with better OS (p = 0.049), LPFS (p = 0.017) and DMFS (p = 0.021). Similar findings were observed for CD8+ TILs, whereas FOXP3 and PD-L1 lacked prognostic significance. Although TIL distribution was heterogeneous, tumors of high stroma density had higher infiltration of CD8+ TILs than loose density stroma and vice versa (p < 0.001), whereas no correlation was found with stromal activity. Sixty (41.4%) tumors contained lymphoid aggregates and the presence of PD-1+ TILs was associated with better OS (p = 0.030), LPFS (p = 0.025) and DMFS (p = 0.033), whereas CD8+ TILs only correlated with superior LPFS (p = 0.039). PD-1+ and CD8+ TILs constitute independent prognostic markers in patients with PDAC treated with adjuvant chemotherapy. Our study provides important insight on the role of PD-1/PD-L1 in the context of desmoplastic stroma and could help guide future immunotherapies in PDAC.

13 Article The prognostic role of desmoplastic stroma in pancreatic ductal adenocarcinoma. 2016

Wang, Lai Mun / Silva, Michael A / D'Costa, Zenobia / Bockelmann, Robin / Soonawalla, Zahir / Liu, Stanley / O'Neill, Eric / Mukherjee, Somnath / McKenna, W Gillies / Muschel, Ruth / Fokas, Emmanouil. ·Department of Pathology, Oxford University Hospital NHS Trust, University of Oxford, Oxford, UK. · Department of Surgery, Oxford University Hospital NHS Trust, Oxford, UK. · Department of Oncology, CRUK/MRC Institute for Radiation Oncology, University of Oxford, Oxford, UK. · Department of Radiation Oncology, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Canada. ·Oncotarget · Pubmed #26716653.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is characterized by an abundant desmoplastic stroma. We examined the prognostic value of stroma density and activity in patients with resectable PDAC treated with surgery and adjuvant gemcitabine-based chemotherapy. FFPE-tissue from the pancreatectomy of 145 patients was immunohistochemically stained for haematoxylin-eosin and Masson's trichrome to assess stroma density, and alpha-smooth muscle actin (αSMA) expression for activated pancreatic stellate cells. Their expression was correlated with clinicopathological characteristics as well as overall survival (OS), progression-free survival (PFS), local progression-free survival (LPFS) and distant metastases free-survival (DMFS). After a mean follow-up of 20 months (range, 2-69 months), the median OS was 21 months and the 3-year OS was 35.7%. In multivariate analysis, highly-dense stroma was an independent prognostic parameter for OS (p = 0.001), PFS (p = 0.007), LPFS (p = 0.001) and DMFS (p = 0.002), while αSMA expression lacked significance. Interestingly, highly-dense stroma retained significance for the four clinical endpoints only in early (pT1-2) but not late (pT3-4) stage tumors. Additionally, late pT-stage (pT3-4), the presence of lymph node metastases (pN+ vs pN0), perineural/neural invasion and administration of adjuvant chemotherapy also correlated with prognosis in multivariate analysis. Altogether, stroma density constitutes an independent prognostic marker in PDAC patients treated with adjuvant chemotherapy. Our findings highlight the dynamic complexity of desmoplasia and indicate that highly-dense stroma is correlated with better outcome. Further validation of the prognostic value of stroma as a biomarker and its role in PDAC patients after adjuvant chemotherapy is warranted and will be performed in a prospective study.

14 Article miR-620 promotes tumor radioresistance by targeting 15-hydroxyprostaglandin dehydrogenase (HPGD). 2015

Huang, Xiaoyong / Taeb, Samira / Jahangiri, Sahar / Korpela, Elina / Cadonic, Ivan / Yu, Nancy / Krylov, Sergey N / Fokas, Emmanouil / Boutros, Paul C / Liu, Stanley K. ·Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Canada. · Department of Medical Biophysics, University of Toronto, Toronto, Canada. · Department of Chemistry, York University, Toronto, Canada. · CRUK/MRC Oxford Institute for Radiation Oncology, Gray Laboratories, Department of Oncology, University of Oxford, Oxford, UK. · Ontario Institute for Cancer Research, University of Toronto, Toronto, Canada. · Department of Radiation Oncology, University of Toronto, Toronto, Canada. ·Oncotarget · Pubmed #26068950.

ABSTRACT: MicroRNA contribute to tumor radiation resistance, which is an important clinical problem, and thus we are interested in identifying and characterizing their function. We demonstrate that miR-620 contributes to radiation resistance in cancer cells by increasing proliferation, and decreasing the G2/M block. We identify the hydroxyprostaglandin dehydrogenase 15-(nicotinamide adenine dinucleotide) (HPGD/15-PGDH) tumor suppressor gene as a direct miR-620 target, which results in increased prostaglandin E2 (PGE2) levels. Furthermore, we show that siRNA targeting of HPGD or administration of exogenous PGE2 recapitulates radioresistance. Targeting of the EP2 receptor that responds to PGE2 using pharmacological or genetic approaches, abrogates radioresistance. Tumor xenograft experiments confirm that miR-620 increases proliferation and tumor radioresistance in vivo. Regulation of PGE2 levels via targeting of HPGD by miR-620 is an innovative manner by which a microRNA can induce radiation resistance.

15 Article Comparing dose-volume histogram and radiobiological endpoints for ranking intensity-modulated arc therapy and 3D-radiotherapy treatment plans for locally-advanced pancreatic cancer. 2013

Warren, Samantha / Partridge, Mike / Fokas, Emmanouil / Eccles, Cynthia L / Brunner, Thomas B. ·The Gray Institute of Radiation Oncology and Biology, Department of Oncology, University of Oxford , Old Road Campus Research Building, Oxford , UK. ·Acta Oncol · Pubmed #23957620.

ABSTRACT: -- No abstract --

16 Article Comparison of four target volume definitions for pancreatic cancer. Guidelines for treatment of the lymphatics and the primary tumor. 2013

Fokas, E / Eccles, C / Patel, N / Chu, K-Y / Warren, S / Gillies McKenna, W / Brunner, T B. ·Gray Institute for Radiation Oncology and Biology, Department of Oncology, Oxford Cancer Centre, University of Oxford. ·Strahlenther Onkol · Pubmed #23553047.

ABSTRACT: BACKGROUND AND PURPOSE: Target volume definitions for radiotherapy in pancreatic ductal adenocarcinoma (PDAC) vary substantially. Some groups aim to treat the primary tumor only, whereas others include elective lymph nodes (eLNs). eLNs close to the primary tumor are often included unintentionally within the treatment volume, depending on the respective treatment philosophies. We aimed to measure the percentages of anatomical coverage of eLNs by comparing four different contouring guidelines. PATIENTS AND METHODS: Planning target volumes (PTVs) were contoured using planning computed tomography (CT) scans of 11 patients with PDAC based on the Oxford, RTOG (Radiation Therapy Oncology Group), Michigan, and SCALOP (Selective Chemoradiation in Advanced Localised Pancreatic Cancer trial) guidelines. Clinical target volumes (CTVs) included the peripancreatic, para-aortic, paracaval, celiac trunk, superior mesenteric, and portal vein lymph node areas. Volumetric comparisons of the coverage of all eLN regions were conducted to illustrate the differences between the four contouring strategies. RESULTS: The PTV sizes of the RTOG and Oxford guidelines were comparable. The SCALOP and Michigan PTV sizes were similar to each other and significantly smaller than the RTOG and Oxford PTVs. A large variability of eLN coverage was found for the various subregions according to the respective contouring strategies. CONCLUSION: This is the first study to directly compare the percentage of anatomical coverage of eLNs according to four PTVs in the same patient cohort. Potential practical consequences are discussed in detail.

17 Article Targeting ATR in vivo using the novel inhibitor VE-822 results in selective sensitization of pancreatic tumors to radiation. 2012

Fokas, E / Prevo, R / Pollard, J R / Reaper, P M / Charlton, P A / Cornelissen, B / Vallis, K A / Hammond, E M / Olcina, M M / Gillies McKenna, W / Muschel, R J / Brunner, T B. ·Gray Institute for Radiation Oncology and Biology, Oxford University, Oxford, UK. ·Cell Death Dis · Pubmed #23222511.

ABSTRACT: Combined radiochemotherapy is the currently used therapy for locally advanced pancreatic ductal adenocarcinoma (PDAC), but normal tissue toxicity limits its application. Here we test the hypothesis that inhibition of ATR (ATM-Rad3-related) could increase the sensitivity of the cancer cells to radiation or chemotherapy without affecting normal cells. We tested VE-822, an ATR inhibitor, for in vitro and in vivo radiosensitization. Chk1 phosphorylation was used to indicate ATR activity, γH2AX and 53BP1 foci as evidence of DNA damage and Rad51 foci for homologous recombination activity. Sensitivity to radiation (XRT) and gemcitabine was measured with clonogenic assays in vitro and tumor growth delay in vivo. Murine intestinal damage was evaluated after abdominal XRT. VE-822 inhibited ATR in vitro and in vivo. VE-822 decreased maintenance of cell-cycle checkpoints, increased persistent DNA damage and decreased homologous recombination in irradiated cancer cells. VE-822 decreased survival of pancreatic cancer cells but not normal cells in response to XRT or gemcitabine. VE-822 markedly prolonged growth delay of pancreatic cancer xenografts after XRT and gemcitabine-based chemoradiation without augmenting normal cell or tissue toxicity. These findings support ATR inhibition as a promising new approach to improve the therapeutic ration of radiochemotherapy for patients with PDAC.

18 Article The novel ATR inhibitor VE-821 increases sensitivity of pancreatic cancer cells to radiation and chemotherapy. 2012

Prevo, Remko / Fokas, Emmanouil / Reaper, Philip M / Charlton, Peter A / Pollard, John R / McKenna, W Gillies / Muschel, Ruth J / Brunner, Thomas B. ·Gray Institute for Radiation Oncology and Biology, Oxford University, Oxford, UK. ·Cancer Biol Ther · Pubmed #22825331.

ABSTRACT: DNA damaging agents such as radiotherapy and gemcitabine are frequently used for the treatment of pancreatic cancer. However, these treatments typically provide only modest benefit. Improving the low survival rate for pancreatic cancer patients therefore remains a major challenge in oncology. Inhibition of the key DNA damage response kinase ATR has been suggested as an attractive approach for sensitization of tumor cells to DNA damaging agents, but specific ATR inhibitors have remained elusive. Here we investigated the sensitization potential of the first highly selective and potent ATR inhibitor, VE-821, in vitro. VE-821 inhibited radiation- and gemcitabine-induced phosphorylation of Chk1, confirming inhibition of ATR signaling. Consistently, VE-821 significantly enhanced the sensitivity of PSN-1, MiaPaCa-2 and primary PancM pancreatic cancer cells to radiation and gemcitabine under both normoxic and hypoxic conditions. ATR inhibition by VE-821 led to inhibition of radiation-induced G 2/M arrest in cancer cells. Reduced cancer cell radiosurvival following treatment with VE-821 was also accompanied by increased DNA damage and inhibition of homologous recombination repair, as evidenced by persistence of γH2AX and 53BP1 foci and inhibition of Rad51 foci, respectively. These findings support ATR inhibition as a novel approach to improve the efficacy and therapeutic index of standard cancer treatments across a large proportion of pancreatic cancer patients.