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Pancreatic Neoplasms: HELP
Articles by William Gillies McKenna
Based on 10 articles published since 2010
(Why 10 articles?)
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Between 2010 and 2020, W. Gillies McKenna wrote the following 10 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 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.

3 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.

4 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

5 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.

6 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.

7 Article The radiosensitizing effects of Nelfinavir on pancreatic cancer with and without pancreatic stellate cells. 2016

Al-Assar, Osama / Bittner, Martin-Immanuel / Lunardi, Serena / Stratford, Michael R / McKenna, W Gillies / Brunner, Thomas B. ·CRUK/MRC Oxford Institute for Radiation Oncology, Heidelberg, Partner Site Freiburg, Germany. · CRUK/MRC Oxford Institute for Radiation Oncology, Heidelberg, Partner Site Freiburg, Germany; Dept. of Radiation Oncology Freiburg, Heidelberg, Partner Site Freiburg, Germany. · CRUK/MRC Oxford Institute for Radiation Oncology, Heidelberg, Partner Site Freiburg, Germany; Dept. of Radiation Oncology Freiburg, Heidelberg, Partner Site Freiburg, Germany; German Cancer Consortium (DKTK), Heidelberg, Partner Site Freiburg, Germany. Electronic address: thomas.brunner@uniklinik-freiburg.de. ·Radiother Oncol · Pubmed #27247056.

ABSTRACT: AIMS: We have previously shown in a phase I trial that nelfinavir (NFV) is safe with chemoradiation in PDAC with good signs for efficacy. Reverse translationally, we aimed to test the influence of PSCs on nelfinavir mediated radiosensitization to PDAC preclinically, because PDAC is very rich in desmoplasia and PSCs are known to mediate radioresistance. METHODS: In a direct co-culture model of several PDAC cell lines with PSC we performed clonogenic assays +/- nelfinavir. This was repeated exposing cells to hypoxic conditions. In xenograft PDAC tumors we tested radiation +/- nelfinavir +/- PSC. RESULTS: NFV sensitized both, PDAC only and PDAC cocultured with PSC (PDAC: Panc-1, MiaPaCa-2, PSN-1). In Panc-1 and PSN-1 this effect was larger +PSC compared to -PSC. Human pancreatic stellate cells (hPSC) were also sensitized by NFV which reduced p-FAK levels in hPSC, an effect that we previously found to sensitize specifically PDAC/PSC coculture. Contrarily, LY294002 reduced p-Akt in PSC (hPSC and LTC-14) but had no impact on PSC radiation survival. In vitro, nelfinavir sensitized Panc-1 and PSN-1 under normoxic and hypoxic conditions. In PSN-1 xenografts, +PSC led to faster tumor regrowth after radiation vs -PSC. The regrowth delay effect of nelfinavir after radiation was dramatically larger +PSC vs -PSC (time to reach 250mm(3) 183% vs 22%). CONCLUSION: NFV mediated radiosensitization in PDAC with stroma is partly mediated by p-FAK inhibition (Chen et al., 2013). In vitro, NFV sensitizes both normoxic and hypoxic PDAC +/- PSC to a roughly similar extent. The dramatic increased effect of xenograft regrowth inhibition by nelfinavir in tumors with PSC is attributed to vascular normalization (Brunner et al., 2014) rather than direct modification of hypoxia as shown by the tumor regrowth after gemcitabine with NFV.

8 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.

9 Article Contextual regulation of pancreatic cancer stem cell phenotype and radioresistance by pancreatic stellate cells. 2014

Al-Assar, Osama / Demiciorglu, Fevzi / Lunardi, Serena / Gaspar-Carvalho, Maria Manuela / McKenna, William Gillies / Muschel, Ruth M / Brunner, Thomas B. ·The Radiobiology Research Institute, MRC/CR-UK Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Churchill Hospital, UK. · The Radiobiology Research Institute, MRC/CR-UK Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Churchill Hospital, UK. Electronic address: thomas.brunner@uniklinik-freiburg.de. ·Radiother Oncol · Pubmed #24780634.

ABSTRACT: BACKGROUND AND PURPOSE: Progression of pancreatic ductal adenocarcinoma (PDAC) is promoted by desmoplasia induced by pancreatic stellate cells (PSC). Contributory to this progression is epithelial mesenchymal transition (EMT), which shares many characteristics with the cancer stem cell (CSC) hypothesis. We investigated the role of these processes on the radioresponse and tumorigenicity of pancreatic cancer cells. MATERIALS AND METHODS: We used an in vitro sphere model and in vivo xenograft model to examine the role of PSC in EMT and CSC processes. RESULTS: We demonstrated that PSC enhanced the CSC phenotype and radioresistance of pancreatic cancer cells. Furthermore, the expression of several EMT and CSC markers supported enhanced processes in our models and that translated into remarkable in vivo tumorigenicity. Multi-dose TGFβ neutralizing antibody inhibited the EMT and CSC processes, sensitized cells to radiation and reduced in vivo tumorigenicity. A proteomic screen identified multiple novel factors that were regulated by PSC in pancreatic cells. CONCLUSION: These results are critical in highlighting the role of PSC in tumor progression and radioresistance by manipulating the EMT and CSC processes. TGFβ and the novel factors identified are important targets for better therapeutic outcome in response to PSC mediated mechanisms.

10 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.