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Pancreatic Neoplasms: HELP
Articles by Thomas B. Brunner
Based on 30 articles published since 2010
(Why 30 articles?)
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Between 2010 and 2020, T. Brunner wrote the following 30 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Review Pancreatic stellate cells in pancreatic cancer: In focus. 2017

Allam, A / Thomsen, A R / Gothwal, M / Saha, D / Maurer, J / Brunner, T B. ·Department of Radiation Oncology, Medical Center, Faculty of Medicine, University of Freiburg, Germany; Clinical Oncology and Nuclear Medicine Department, Assiut University Hospitals, Egypt. · Department of Radiation Oncology, Medical Center, Faculty of Medicine, University of Freiburg, Germany; German Cancer Consortium (DKTK), Partner Site Freiburg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany. · Department of Visceral Surgery, Medical Center, Faculty of Medicine, University of Freiburg, Germany. · Department of Visceral Surgery, Medical Center, Faculty of Medicine, University of Freiburg, Germany; German Cancer Consortium (DKTK), Partner Site Freiburg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany. · Department of Radiation Oncology, Medical Center, Faculty of Medicine, University of Freiburg, Germany; German Cancer Consortium (DKTK), Partner Site Freiburg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany. Electronic address: thomas.brunner@uniklinik-freiburg.de. ·Pancreatology · Pubmed #28601475.

ABSTRACT: Pancreatic stellate cells are stromal cells that have multiple physiological functions such as the production of extracellular matrix, stimulation of amylase secretion, phagocytosis and immunity. In pancreatic cancer, stellate cells exhibit a different myofibroblastic-like morphology with the expression of alpha-smooth muscle actin, the activated form is engaged in several mechanisms that support tumorigenesis and cancer invasion and progression. In contrast to the aforementioned observations, eliminating the stromal cells that are positive for alpha-smooth muscle actin resulted in immune-evasion of the cancer cells and resulted in worse prognosis in animal models. Understanding the cancer-stromal signaling in pancreatic adenocarcinoma will provide novel strategies for therapy. Here we provide an updated review of studies that handle the topic "pancreatic stellate cells in cancer" and recent experimental approaches that can be the base for future directions in therapy.

2 Review Stereotactic body radiotherapy for renal cell cancer and pancreatic cancer : Literature review and practice recommendations of the DEGRO Working Group on Stereotactic Radiotherapy. 2016

Panje, Cédric / Andratschke, Nikolaus / Brunner, Thomas B / Niyazi, Maximilian / Guckenberger, Matthias. ·Department of Radiation Oncology, Zurich University Hospital, Rämistrasse 100, 8091, Zurich, Switzerland. · Department of Radiation Oncology, Freiburg University Hospital, Freiburg, Germany. · Department of Radiation Oncology, University of Munich, Munich, Germany. · Department of Radiation Oncology, Zurich University Hospital, Rämistrasse 100, 8091, Zurich, Switzerland. matthias.guckenberger@usz.ch. ·Strahlenther Onkol · Pubmed #27778052.

ABSTRACT: PURPOSE: This report of the Working Group on Stereotactic Radiotherapy of the German Society of Radiation Oncology (DEGRO) aims to provide a literature review and practice recommendations for stereotactic body radiotherapy (SBRT) of primary renal cell cancer and primary pancreatic cancer. METHODS: A literature search on SBRT for both renal cancer and pancreatic cancer was performed with focus on prospective trials and technical aspects for clinical implementation. RESULTS: Data on renal and pancreatic SBRT are limited, but show promising rates of local control for both treatment sites. For pancreatic cancer, fractionated SBRT should be preferred to single-dose treatment to reduce the risk of gastrointestinal toxicity. Motion-compensation strategies and image guidance are paramount for safe SBRT delivery in both tumor entities. CONCLUSION: SBRT for renal cancer and pancreatic cancer have been successfully evaluated in phase I and phase II trials. Pancreatic SBRT should be practiced carefully and only within prospective protocols due to the risk of severe gastrointestinal toxicity. SBRT for primary renal cell cancer appears a viable option for medically inoperable patients but future research needs to better define patient selection criteria and the detailed practice of SBRT.

3 Review Pancreatic cancer chemoradiotherapy. 2016

Brunner, Thomas B / Seufferlein, Thomas. ·Department of Radiation Oncology, University Medical Center Freiburg, Robert-Koch-Str. 3, Freiburg, Germany; German Cancer Consortium (DKTK), Freiburg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany. Electronic address: thomas.brunner@uniklinik-freiburg.de. · Department of Internal Medicine I, Ulm University, Albert-Einstein-Allee 23, D-89081, Ulm, Germany. Electronic address: thomas.seufferlein@uniklinik-ulm.de. ·Best Pract Res Clin Gastroenterol · Pubmed #27644909.

ABSTRACT: Pancreatic cancer is the most lethal gastrointestinal tumour. Chemotherapy is the mainstay of therapy in the majority of the patients whereas resection is the only chance of cure but only possible in 15-20% of all patients. The integration of radiotherapy into multimodal treatment concepts is heavily investigated. It is now commonly accepted that induction chemotherapy should precede radiotherapy. When fractionated conventionally it should be given as chemoradiotherapy. Recently, stereotactic body radiotherapy emerged as an alternative, but will have to be carefully investigated in clinical trials. This review aims to give an overview of radiotherapeutic strategies with a focus on the latest developments in the field in the context of chemotherapy and surgery.

4 Review International Association of Pancreatology (IAP)/European Pancreatic Club (EPC) consensus review of guidelines for the treatment of pancreatic cancer. 2016

Takaori, Kyoichi / Bassi, Claudio / Biankin, Andrew / Brunner, Thomas B / Cataldo, Ivana / Campbell, Fiona / Cunningham, David / Falconi, Massimo / Frampton, Adam E / Furuse, Junji / Giovannini, Marc / Jackson, Richard / Nakamura, Akira / Nealon, William / Neoptolemos, John P / Real, Francisco X / Scarpa, Aldo / Sclafani, Francesco / Windsor, John A / Yamaguchi, Koji / Wolfgang, Christopher / Johnson, Colin D / Anonymous8350852. ·Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan. Electronic address: takaori@kuhp.kyoto-u.ac.jp. · Department of Surgery and Oncology, Pancreas Institute, University of Verona, Verona, Italy. · Academic Unit of Surgery, University of Glasgow, Glasgow, United Kingdom. · Department of Radiation Oncology, University Hospitals Freiburg, Germany. · Department of Pathology and Diagnostics, University of Verona, Verona, Italy. · Department of Pathology, Royal Liverpool University Hospital, Liverpool, United Kingdom. · Department of Medicine, The Royal Marsden NHS Foundation Trust, London and Surrey, United Kingdom. · Pancreatic Surgery Unit, Università Vita e Salute, Milano, Italy. · HPB Surgical Unit, Department of Surgery and Cancer, Imperial College, Hammersmith Hospital, London, United Kingdom. · Department of Medical Oncology, Kyorin University School of Medicine, Tokyo, Japan. · Endoscopic Unit, Paoli-Calmettes Institute, Marseille, France. · NIHR Pancreas Biomedical Research Unit, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom. · Department of Radiation Oncology and Image-applied Therapy, Kyoto University Hospital, Kyoto, Japan. · Division of General Surgery, Yale University, New Haven, CT, United States of America. · Epithelial Carcinogenesis Group, CNIO-Spanish National Cancer Research Centre, Madrid, Spain. · Department of Surgery, University of Auckland, HBP/Upper GI Unit, Auckland City Hospital, Auckland, New Zealand. · Department of Advanced Treatment of Pancreatic Disease, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan. · Department of Surgery, The Johns Hopkins University, Baltimore, MD, United States of America. · University Surgical Unit, Southampton General Hospital, Southampton, United Kingdom. ·Pancreatology · Pubmed #26699808.

ABSTRACT: BACKGROUND: Pancreatic cancer is one of the most devastating diseases with an extremely high mortality. Medical organizations and scientific societies have published a number of guidelines to address active treatment of pancreatic cancer. The aim of this consensus review was to identify where there is agreement or disagreement among the existing guidelines and to help define the gaps for future studies. METHODS: A panel of expert pancreatologists gathered at the 46th European Pancreatic Club Meeting combined with the 18th International Association of Pancreatology Meeting and collaborated on critical reviews of eight English language guidelines for the clinical management of pancreatic cancer. Clinical questions (CQs) of interest were proposed by specialists in each of nine areas. The recommendations for the CQs in existing guidelines, as well as the evidence on which these were based, were reviewed and compared. The evidence was graded as sufficient, mediocre or poor/absent. RESULTS: Only 4 of the 36 CQs, had sufficient evidence for agreement. There was also agreement in five additional CQs despite the lack of sufficient evidence. In 22 CQs, there was disagreement regardless of the presence or absence of evidence. There were five CQs that were not addressed adequately by existing guidelines. CONCLUSION: The existing guidelines provide both evidence- and consensus-based recommendations. There is also considerable disagreement about the recommendations in part due to the lack of high level evidence. Improving the clinical management of patients with pancreatic cancer, will require continuing efforts to undertake research that will provide sufficient evidence to allow agreement.

5 Review Comparison of toxicity after IMRT and 3D-conformal radiotherapy for patients with pancreatic cancer - a systematic review. 2015

Bittner, Martin-Immanuel / Grosu, Anca-Ligia / Brunner, Thomas B. ·Department of Radiation Oncology, University Medical Centre Freiburg, Germany; CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, UK(1). · Department of Radiation Oncology, University Medical Centre Freiburg, Germany. · Department of Radiation Oncology, University Medical Centre Freiburg, Germany. Electronic address: thomas.brunner@uniklinik-freiburg.de. ·Radiother Oncol · Pubmed #25497876.

ABSTRACT: IMRT has been suggested to reduce treatment-related toxicity in pancreatic cancer. We attempted to identify all IMRT-studies indexed in PubMed/Medline, comparing them with recent 3D-CRT trials. The predominant treatment-related toxicities, namely nausea/vomiting, diarrhoea and late GI toxicity, are significantly reduced with IMRT while there was no apparent difference for outcome measures.

6 Review SBRT in pancreatic cancer: what is the therapeutic window? 2015

Brunner, Thomas B / Nestle, Ursula / Grosu, Anca-Ligia / Partridge, Mike. ·Department of Radiation Oncology, University Hospitals Freiburg, Germany. Electronic address: Thomas.brunner@uniklinik-freiburg.de. · Department of Radiation Oncology, University Hospitals Freiburg, Germany. · CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, UK. ·Radiother Oncol · Pubmed #25466369.

ABSTRACT: PURPOSE/OBJECTIVE: To analyse outcome and toxicity of stereotactic body radiotherapy (SBRT) in pancreatic cancer (PDAC). MATERIAL/METHODS: We systematically reviewed full reports on outcome and toxicity transforming prescription doses to equivalent doses of 2 Gy (EQD2) and biological equivalent doses (BED). Pearson product-moment correlation coefficient, regression analysis and Lyman-Kutcher-Burman modelling were used. RESULTS: Sixteen trials (572 patients) were identified. Local control correlated with dose. Additionally 4 upper gastrointestinal-SBRT trials (149 patients) were included for toxicity analysis. Acute toxicity was mild but late toxicity ⩾G2 was substantial and predominantly gastrointestinal. Late toxicity ⩾G2 and ⩾G3 correlated highly with EQD2/BED after linear (R(2)=0.85 and 0.77, respectively) and Lyman-Kutcher-Burman modelling. Linear regression lines indicated ⩾G2 and ⩾G3 toxicity frequencies of 5% at 65 Gy and 80 Gy EQD2-α/β=3, respectively. A comparison of toxicity with dose constraints for duodenum revealed partly inadequate dose constraints. CONCLUSION: RESULTS from multiple fraction regimens could be successfully interpreted to estimate toxicity according to EQD2/BED prescription doses, and dose constraints for the duodenum were derived, whereas local control appeared to be less dose-dependent. This analysis may be useful to plan clinical trials for SBRT and hypofractionated radiotherapy in pancreatic cancer.

7 Review Radiotherapy for SMAD4-negative musculoskeletal lesions from pancreatic cancer: case report and review. 2015

Zamboglou, Constantinos / Bronsert, Peter / Küsters, Simon / Salm, Natalie / Azèmar, Marc / Brunner, Thomas. ·Klinik für Strahlenheilkunde, Universitätsklinikum Freiburg i. Br., Robert-Koch-Straße 3, 79106, Freiburg, Deutschland, constantinos.zamboglou@uniklinik-freiburg.de. ·Strahlenther Onkol · Pubmed #25300625.

ABSTRACT: BACKGROUND: Pancreatic cancer (PC) predominantly metastasizes to liver, lung, and peritoneum. Metastatic disease correlates with SMAD4 status. Musculoskeletal metastases (MSM) are rare in pancreatic cancer. The role of radiation therapy (RT) in patients with musculoskeletal metastases is not clear. METHODS: We present a case of a woman with musculoskeletal metastases of PC evolving 4 years after Whipple's procedure and adjuvant therapy. She was treated with RT for 7 MSM. Radiation dose was 15-45 Gy, delivered in doses of 2.5-5 Gy per fraction. SMAD4 status was examined by immunohistochemistry. Furthermore we undertook a review of the literature to examine the value of RT in musculoskeletal metastasis of PC. RESULTS: In the presented patient we treated 7 MSM of SMAD4-mutant PC with RT. RT achieved local control in 4 of the 7 MSM. At the resection margin of one MSM recurrent tumor was observed after RT. The status of one MSM was unknown and one MSM showed local progression. Follow-up revealed progression of pain in 1 of the 7 MSM. Except of hyperpigmentation no side effects occurred. There was no dose-correlation effect on tumor control observed. A review of the literature showed that a musculoskeletotrophic phenotype of metastases is rare in PC. MSM of PC are rapidly increasing soft tissue masses causing pain and loss of anatomical function. RT as a treatment option for musculoskeletal metastasis is described in the current literature in only 2 cases. Radiotherapy aims to achieve local control, pain relief, and to maintain anatomical function. CONCLUSION: Radiotherapy is an effective and well-tolerated approach for multiple musculoskeletal metastases of PC.

8 Review The stromal compartments in pancreatic cancer: are there any therapeutic targets? 2014

Lunardi, Serena / Muschel, Ruth J / Brunner, Thomas B. ·Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Churchill Hospital, RRI, Oxford OX3 7LJ, UK. · Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Churchill Hospital, RRI, Oxford OX3 7LJ, UK; Department of Radiation Oncology, University Hospitals Freiburg, Robert-Koch-Straße 3, 79106 Freiburg, Germany. Electronic address: tbbrunner@gmail.com. ·Cancer Lett · Pubmed #24141189.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is characterised by an abundant stromal response also known as a desmoplastic reaction. Pancreatic Stellate Cells have been identified as playing a key role in pancreatic cancer desmoplasia. There is accumulating evidence that the stroma contributes to tumour progression and to the low therapeutic response of PDAC patients. In this review we described the main actors of the desmoplastic reaction within PDAC and novel therapeutic approaches that are being tested to block the detrimental function of the stroma.

9 Review Neoadjuvant therapy for potentially resectable pancreatic cancer: an emerging paradigm? 2013

Brunner, Thomas B. ·Department of Radiation Oncology, Freiburg University, Freiburg, Germany. thomas.brunner@uniklinik-freiburg.de ·Curr Oncol Rep · Pubmed #23325567.

ABSTRACT: Although neoadjuvant chemoradiotherapy has been tested for more than two decades and can be safely delivered to patients with non-metastatic pancreatic cancer, no randomised trials have been reported until now. Here we provide an overview of the first randomised trial in patients with potentially resectable cancer and of the latest developments in neoadjuvant therapy for this group of patients. It is necessary to continue to perform clinical trials in this field to accurately identify the effect on survival and quality of life in patients with potentially resectable, borderline resectable and unresectable pancreatic cancer. Aspects of imaging for restaging and clinical prognostic factors are also discussed given they will be useful instruments for future trials.

10 Review The role of radiotherapy in multimodal treatment of pancreatic carcinoma. 2010

Brunner, Thomas B / Scott-Brown, Martin. ·Gray Institute for Radiation Oncology & Biology, University of Oxford, Oxford, UK. thomas.brunner@rob.ox.ac.uk ·Radiat Oncol · Pubmed #20615227.

ABSTRACT: Pancreatic ductal carcinoma is one of the most lethal malignancies, but in recent years a number of positive developments have occurred in the management of pancreatic carcinoma. This article aims to give an overview of the current knowledge regarding the role of radiotherapy in the treatment of pancreatic ductal adenocarcinoma (PDAC). The results of meta-analyses, phase III-studies, and phase II-studies using chemoradiotherapy and chemotherapy for resectable and non-resectable PDAC were reviewed. The use of radiotherapy is discussed in the neoadjuvant and adjuvant settings as well as in the locally advanced situation. Whenever possible, radiotherapy should be performed as simultaneous chemoradiotherapy. Patients with PDAC should be offered entry into clinical trials to identify optimal treatment results.

11 Clinical Trial Correlation of 2017

Wilson, J M / Mukherjee, S / Brunner, T B / Partridge, M / Hawkins, M A. ·CRUK/MRC Oxford Institute for Radiation Oncology, Gray Laboratories, Oxford, UK. Electronic address: james.wilson@icr.ac.uk. · CRUK/MRC Oxford Institute for Radiation Oncology, Gray Laboratories, Oxford, UK. · Department of Radiation Oncology, University Hospitals Freiburg, Freiburg im Breisgau, Germany. ·Clin Oncol (R Coll Radiol) · Pubmed #28190636.

ABSTRACT: AIMS: A proportion of patients with pancreatic cancer never develop metastatic disease. We evaluated a role for MATERIAL AND METHODS: Patients with histologically confirmed LAPC entered a single-centre phase II study of definitive upfront chemoradiotherapy (CRT). All patients underwent FDG-PET/CT before and 6 weeks after CRT. Tumour volume, standardised uptake values (SUV RESULTS: Twenty-three patients with LAPC were recruited; 17/23 completed treatment and had interpretable sequential imaging. Twenty-four per cent of patients only ever experienced local disease. Median pre-CRT FDG-PET parameters were significantly lower in patients with local disease only during follow-up compared with those who developed metastatic disease: SUV CONCLUSIONS: Our findings suggest that patients with less FDG-avid tumours are less likely to metastasise and may therefore benefit from upfront local treatment intensification.

12 Clinical Trial Stereotactic body radiotherapy (SBRT) in recurrent or oligometastatic pancreatic cancer : A toxicity review of simultaneous integrated protection (SIP) versus conventional SBRT. 2017

Gkika, E / Adebahr, S / Kirste, S / Schimek-Jasch, T / Wiehle, R / Claus, R / Wittel, U / Nestle, U / Baltas, D / Grosu, A L / Brunner, T B. ·Department of Radiation Oncology, University Medical Center Freiburg, Robert-Koch-Str. 3, 79106, Freiburg im Breisgau, Germany. eleni.gkika@uniklinik-freiburg.de. · Department of Radiation Oncology, University Medical Center Freiburg, Robert-Koch-Str. 3, 79106, Freiburg im Breisgau, Germany. · German Cancer Consortium (DKTK), Heidelberg (partner site Freiburg), Germany. · Division of Medical Physics, Department of Radiation Oncology, University Medical Center Freiburg, Freiburg, Germany. · Department of Hematology, Oncology and Stem-Cell Transplantation, University Medical Center Freiburg, Freiburg, Germany. · Department of General and Visceral Surgery, University Medical Center Freiburg, Freiburg, Germany. · Faculty of Medicine, University of Freiburg, Freiburg, Germany. ·Strahlenther Onkol · Pubmed #28138949.

ABSTRACT: BACKGROUND: Stereotactic body radiotherapy (SBRT) in pancreatic cancer can be limited by its proximity to organs at risk (OAR). In this analysis, we evaluated the toxicity and efficacy of two different treatment approaches in patients with locally recurrent or oligometastatic pancreatic cancer. MATERIALS AND METHODS: According to the prescription method, patients were divided in two cohorts (C1 and C2). The planning target volume (PTV) was created through a 4 mm expansion of the internal target volume. In C2, a subvolume was additionally created, a simultaneous integrated protection (SIP), which is the overlap of the PTV with the planning risk volume of an OAR to which we prescribed a reduced dose. RESULTS: In all, 18 patients were treated (7 with local recurrences, 9 for oligometastases, 2 for both). Twelve of 23 lesions were treated without SIP (C1) and 11 with SIP (C2). The median follow-up was 12.8 months. Median overall survival (OS) was 13.2 (95% confidence interval [CI] 9.8-14.6) months. The OS rates at 6 and 12 months were 87 and 58%, respectively. Freedom from local progression for combined cohorts at 6 and 12 months was 93 and 67% (95% CI 15-36), respectively. Local control was not statistically different between the two groups. One patient in C2 experienced grade ≥3 acute toxicities and 1 patient in C1 experienced a grade ≥3 late toxicity. CONCLUSION: The SIP approach is a useful prescription method for abdominal SBRT with a favorable toxicity profile which does not compromise local control and overall survival despite dose sacrifices in small subvolumes.

13 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 --

14 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.

15 Clinical Trial Neoadjuvant chemoradiation therapy with gemcitabine/cisplatin and surgery versus immediate surgery in resectable pancreatic cancer: results of the first prospective randomized phase II trial. 2015

Golcher, Henriette / Brunner, Thomas B / Witzigmann, Helmut / Marti, Lukas / Bechstein, Wolf-Otto / Bruns, Christiane / Jungnickel, Henry / Schreiber, Stefan / Grabenbauer, Gerhard G / Meyer, Thomas / Merkel, Susanne / Fietkau, Rainer / Hohenberger, Werner. ·Department of Surgery, University Hospital Erlangen, Krankenhausstr. 12, 91054, Erlangen, Germany, henriette.golcher@uk-erlangen.de. ·Strahlenther Onkol · Pubmed #25252602.

ABSTRACT: BACKGROUND: In nonrandomized trials, neoadjuvant treatment was reported to prolong survival in patients with pancreatic cancer. As neoadjuvant chemoradiation is established for the treatment of rectal cancer we examined the value of neoadjuvant chemoradiotherapy in pancreatic cancer in a randomized phase II trial. Radiological staging defining resectability was basic information prior to randomization in contrast to adjuvant therapy trials resting on pathological staging. PATIENTS AND METHODS: Patients with resectable adenocarcinoma of the pancreatic head were randomized to primary surgery (Arm A) or neoadjuvant chemoradiotherapy followed by surgery (Arm B), which was followed by adjuvant chemotherapy in both arms. A total of 254 patients were required to detect a 4.33-month improvement in median overall survival (mOS). RESULTS: The trial was stopped after 73 patients; 66 patients were eligible for analysis. Twenty nine of 33 allocated patients received chemoradiotherapy. Radiotherapy was completed in all patients. Chemotherapy was changed in 3 patients due to toxicity. Tumor resection was performed in 23 vs. 19 patients (A vs. B). The R0 resection rate was 48% (A) and 52% (B, P = 0.81) and (y)pN0 was 30% (A) vs. 39% (B, P = 0.44), respectively. Postoperative complications were comparable in both groups. mOS was 14.4 vs. 17.4 months (A vs. B; intention-to-treat analysis; P = 0.96). After tumor resection, mOS was 18.9 vs. 25.0 months (A vs. B; P = 0.79). CONCLUSION: This worldwide first randomized trial for neoadjuvant chemoradiotherapy in pancreatic cancer showed that neoadjuvant chemoradiation is safe with respect to toxicity, perioperative morbidity, and mortality. Nevertheless, the trial was terminated early due to slow recruiting and the results were not significant. ISRCTN78805636; NCT00335543.

16 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.

17 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.

18 Article IP-10/CXCL10 attracts regulatory T cells: Implication for pancreatic cancer. 2015

Lunardi, Serena / Lim, Su Yin / Muschel, Ruth J / Brunner, Thomas B. ·Gray Institute for Radiation Oncology and Biology; Department of Oncology; University of Oxford ; Oxford, UK. · Gray Institute for Radiation Oncology and Biology; Department of Oncology; University of Oxford ; Oxford, UK ; These authors contributed equally to this work. · Gray Institute for Radiation Oncology and Biology; Department of Oncology; University of Oxford ; Oxford, UK ; Department of Radiation Oncology; University Hospitals Freiburg ; Freiburg, Germany ; These authors contributed equally to this work. ·Oncoimmunology · Pubmed #26405599.

ABSTRACT: Pancreatic stellate cells (PSCs) are key components of pancreatic ductal adenocarcinoma (PDAC). We recently demonstrated that IP-10/CXCL10 is highly expressed by PSCs in the presence of pancreatic cancer cells (PCCs) and its expression correlates with infiltration by regulatory T cells (Tregs) and poor survival. Thus, stromal cells in pancreatic cancer can promote immunosuppression and tumor progression, through the expression of IP-10.

19 Article Endobiliary Stent Position Changes during External-beam Radiotherapy. 2015

Chu, Kwun-Ye / Eccles, Cynthia L / Brunner, Thomas B. ·CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, United Kingdom ; Radiotherapy Department, Churchill Hospital, Oxford University Hospitals NHS Trust, Oxford, United Kingdom. · CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, United Kingdom ; Department of Radiation Oncology, University of Freiburg, Freiburg im Breisgau, Germany. ·J Med Imaging Radiat Sci · Pubmed #26090069.

ABSTRACT: PURPOSE: Endobiliary stents can be used as surrogates for pancreatic localization when using cone-beam computed tomography (CBCT) during external-beam radiotherapy (EBRT). This work reports on interfraction stent position changes during EBRT for locally advanced pancreatic cancer (LAPC). MATERIALS AND METHODS: Six patients with endobiliary stents who underwent EBRT for LAPC were assessed. Measurements from the most superior aspect of the stent (sup stent) and the most inferior aspect of the stent (inf stent) to the most inferior, posterior aspect of the L1 vertebra central spinous process were determined from daily treatment CBCTs and compared with those determined from the planning computed tomography (CT) scan. Changes in stent-L1 measurements were interpreted as changes in relative stent position. RESULTS: Three patients showed mean interfraction stent position changes of ≥1 cm when treatment measurements were compared with planning measurements. The sup stent for patient A moved to the right (2.66 ± 2.77 cm) and inferiorly (3.0 ± 3.12 cm), and the inf stent moved to the right (1.92 ± 2.02 cm) inferiorly (3.23 ± 3.34 cm) and posteriorly (1.41 ± 1.43 cm). The inf stent for patient B moved superiorly (2.23 ± 0.49 cm) and posteriorly (1.72 ± 0.59 cm). The sup and inf stent for patient F moved inferiorly (0.98 ± 0.35 cm and 1.21 ± 0.38 cm, respectively). The remaining three patients C, D, and E showed interfraction position changes of <1 cm. CONCLUSION: Endobiliary stent migration and deformation were observed in a small subset of patients. Further investigation is required before confirming their use as surrogates for LAPC target localization during image-guided EBRT.

20 Article IP-10/CXCL10 induction in human pancreatic cancer stroma influences lymphocytes recruitment and correlates with poor survival. 2014

Lunardi, Serena / Jamieson, Nigel B / Lim, Su Yin / Griffiths, Kristin L / Carvalho-Gaspar, Manuela / Al-Assar, Osama / Yameen, Sabira / Carter, Ross C / McKay, Colin J / Spoletini, Gabriele / D'Ugo, Stefano / Silva, Michael A / Sansom, Owen J / Janssen, Klaus-Peter / Muschel, Ruth J / Brunner, Thomas B. ·Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Oxford, OX3 7DQ, United Kingdom. · West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, G31 2ER, United Kingdom. · Jenner Institute, University of Oxford, Old Road Campus, OX2 7BN, Oxford, United Kingdom. · Hepatobiliary and Pancreatic Surgery, Churchill Hospital, Oxford, United Kingdom. · Beatson Institute of Cancer Research, Garscube Estate, Glasgow, G61 1BD, United Kingdom. · Department of Surgery, Technische Universitaet Muenchen, 81675 Muenchen, Germany. · Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Oxford, OX3 7DQ, United Kingdom. Department of Radiation Oncology, University Hospitals Freiburg, 79106 Freiburg, Germany. ·Oncotarget · Pubmed #25415223.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is characterized by an abundant desmoplastic reaction driven by pancreatic stellate cells (PSCs) that contributes to tumor progression. Here we sought to characterize the interactions between pancreatic cancer cells (PCCs) and PSCs that affect the inflammatory and immune response in pancreatic tumors. Conditioned media from mono- and cocultures of PSCs and PCCs were assayed for expression of cytokines and growth factors. IP-10/CXCL10 was the most highly induced chemokine in coculture of PSCs and PCCs. Its expression was induced in the PSCs by PCCs. IP-10 was elevated in human PDAC specimens, and positively correlated with high stroma content. Furthermore, gene expression of IP-10 and its receptor CXCR3 were significantly associated with the intratumoral presence of regulatory T cells (Tregs). In an independent cohort of 48 patients with resectable pancreatic ductal adenocarcinoma, high IP-10 expression levels correlated with decreased median overall survival. Finally, IP-10 stimulated the ex vivo recruitment of CXCR3+ effector T cells as well as CXCR3+ Tregs derived from patients with PDAC. Our findings suggest that, in pancreatic cancer, CXCR3+ Tregs can be recruited by IP-10 expressed by PSCs in the tumor stroma, leading to immunosuppressive and tumor-promoting effects.

21 Article Challenges in using ¹⁸F-fluorodeoxyglucose-PET-CT to define a biological radiotherapy boost volume in locally advanced pancreatic cancer. 2014

Wilson, James M / Mukherjee, Somnath / Chu, Kwun-Ye / Brunner, Thomas B / Partridge, Mike / Hawkins, Maria. ·CRUK/MRC Oxford Institute for Radiation Oncology, Gray Laboratories, University of Oxford, Old Road Campus Research Building, Off Roosevelt Drive, Oxford OX3 7DQ, UK. james.wilson@oncology.ox.ac.uk. ·Radiat Oncol · Pubmed #24962658.

ABSTRACT: BACKGROUND: The best method of identifying regions within pancreatic tumours that might benefit from an increased radiotherapy dose is not known. We investigated the utility of pre-treatment FDG-PET in predicting the spatial distribution of residual metabolic activity following chemoradiotherapy (CRT) in locally advanced pancreatic cancer (LAPC). METHODS: 17 patients had FDG-PET/CT scans at baseline and six weeks post-CRT. Tumour segmentation was performed at 40% and 50% of SUVmax at baseline and 60%, 70%, 80% and 90% post-CRT. FDG-PET scans were non-rigidly registered to the radiotherapy planning CT using the CT component of the FDG-PET/CT. Percentage overlap of the post-CRT volumes with the pre-CRT volumes with one another and the gross tumour volume (GTV) was calculated. RESULTS: SUVmax decreased during CRT (median pre- 8.0 and post- 3.6, p < 0.0001). For spatial correlation analysis, 9 pairs of scans were included (Four were excluded following complete metabolic response, one patient had a non-FDG avid tumour, one had no post-CRT imaging, one had diffuse FDG uptake that could not be separated from normal tissues and one had an elevated blood glucose). The Pre40% and 50% of SUVmax volumes covered a mean of 50.8% and 30.3% of the GTV respectively. The mean% overlap of the 90%, 80%, 70%, 60% of SUVmax post-CRT with the Pre40% and Pre50% volumes were 83.3%, 84.0%, 83.7%, 77.9% and 77.8%, 69.9%, 74.5%, 64.8% respectively. CONCLUSIONS: Regions of residual metabolic activity following CRT can be predicted from the baseline FDG-PET and could aid definition of a biological target volume for non-uniform dose prescriptions.

22 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.

23 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 --

24 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.

25 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.

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