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Pancreatic Neoplasms: HELP
Articles from Cambridgeshire
Based on 135 articles published since 2009
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These are the 135 published articles about Pancreatic Neoplasms that originated from Cambridgeshire during 2009-2019.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4 · 5 · 6
1 Review Diagnosis and management of pancreatic cancer in adults: A summary of guidelines from the UK National Institute for Health and Care Excellence. 2018

O'Reilly, Derek / Fou, Linyun / Hasler, Elise / Hawkins, James / O'Connell, Susan / Pelone, Ferruccio / Callaway, Mark / Campbell, Fiona / Capel, Margred / Charnley, Richard / Corrie, Pippa / Elliot, Dawn / Goodburn, Lesley / Jewell, Anna / Joharchi, Suzanne / McGeeney, Laura / Mukherjee, Somnath / Oppong, Kofi / Whelan, Phil / Primrose, John / Neoptolemos, John. ·Manchester Royal Infirmary, Central Manchester NHS Foundation Trust and University of Manchester, United Kingdom. Electronic address: doreilly@doctors.org.uk. · National Institute for Health and Care Excellence, United Kingdom. · Bristol Royal Infirmary, University Hospitals Bristol NHS Foundation Trust, United Kingdom. · University of Liverpool, The Royal Liverpool & Broadgreen University Hospital NHS Trust, United Kingdom. · George Thomas Hospice, United Kingdom. · Freeman Hospital, Newcastle upon Tyne, United Kingdom. · Cambridge University Hospitals NHS Foundation Trust and University of Cambridge, United Kingdom. · Northumbria Healthcare Foundation Trust, United Kingdom. · Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Germany. · CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford & Churchill Hospital, United Kingdom. · University of Southampton, Southampton General Hospital, United Kingdom. · University of Heidelberg, Germany. ·Pancreatology · Pubmed #30292643.

ABSTRACT: To enable standardisation of care of pancreatic cancer patients and facilitate improvement in outcome, the United Kingdom's National Institute for Health and Care Excellence (NICE) developed a clinical guideline for the diagnosis and management of pancreatic cancer in adults. Systematic literature searches, systematic review and meta-analyses were undertaken. Recommendations were drafted on the basis of the group's interpretation of the best available evidence of clinical and cost effectiveness. There was patient involvement and public consultation. Recommendations were made on: diagnosis; staging; monitoring of inherited high risk; psychological support; pain; nutrition management; and the specific management of people with resectable-, borderline-resectable- and unresectable-pancreatic cancer. The guideline committee also made recommendations for future research into neoadjuvant therapy, cachexia interventions, minimally invasive pancreatectomy, pain management and psychological support needs. These NICE guidelines aim to promote best current practice and support and stimulate research and innovation in pancreatic cancer.

2 Review Drug development and clinical trial design in pancreatico-biliary malignancies. 2018

Harrington, Jennifer / Carter, Louise / Basu, Bristi / Cook, Natalie. ·Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital, Cambridge, UK. · Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK; Division of Cancer Sciences, University of Manchester, Manchester, UK. · Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital, Cambridge, UK; Department of Oncology, University of Cambridge, Cambridge, UK. · Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK; Division of Cancer Sciences, University of Manchester, Manchester, UK. Electronic address: Natalie.cook@christie.nhs.uk. ·Curr Probl Cancer · Pubmed #29402439.

ABSTRACT: Pancreatico-biliary (P-B) tumors arise from the pancreas, bile duct, and ampulla of Vater. Despite their close anatomical location, they have different etiology and biology. However, they uniformly share a poor prognosis, with no major improvements observed in overall survival over decades, even in the face of progress in diagnostic imaging and surgical techniques, and advances in systemic and loco-regional radiation therapies. To date, cytotoxic treatment has been associated with modest benefits in the advanced disease setting, and survival for patients with stage IV disease has not exceeded a year. Therefore, there is a pressing need to identify better treatments which may impact more significantly. Frequently, encouraging signals of potential efficacy for novel agents in early phase clinical trials have been followed by disappointing failures in larger phase III trials, raising the valid question of how drug development can be optimized for patients with pancreatic adenocarcinoma and biliary tract malignancies. In this article we summarize the current therapeutic options for these patients and their limitations. The biological context of these cancers is reviewed, highlighting features that may make them resistant to standard chemotherapeutics and could be potential therapeutic targets. We discuss the role of early phase clinical trials, defined as phase I and non-randomised phase II trials, within the clinical context and current therapeutic landscape of P-B tumors and postulate how translational studies and trial design may enable better realization of emerging targets together with a proposed model for future patient management. A detailed summary of current phase I clinical trials in P-B tumors is provided.

3 Review Symptom Signatures and Diagnostic Timeliness in Cancer Patients: A Review of Current Evidence. 2018

Koo, Minjoung M / Hamilton, William / Walter, Fiona M / Rubin, Greg P / Lyratzopoulos, Georgios. ·University College London, 1-19 Torrington Place, London WC1E 6BT, UK. Electronic address: Monica.koo.14@ucl.ac.uk. · University of Exeter Medical School, St Luke's Campus, Heavitree Road, Exeter, EX1 2LU, UK. · University of Cambridge, Primary Care Unit, Strangeways Research Laboratory, Cambridge, CB2 0SR, UK. · Institute of Health and Society, Newcastle University, Sir James Spence Institute, Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4LP, UK. · University College London, 1-19 Torrington Place, London WC1E 6BT, UK; University of Cambridge, Primary Care Unit, Strangeways Research Laboratory, Cambridge, CB2 0SR, UK. ·Neoplasia · Pubmed #29253839.

ABSTRACT: Early diagnosis is an important aspect of contemporary cancer prevention and control strategies, as the majority of patients are diagnosed following symptomatic presentation. The nature of presenting symptoms can critically influence the length of the diagnostic intervals from symptom onset to presentation (the patient interval), and from first presentation to specialist referral (the primary care interval). Understanding which symptoms are associated with longer diagnostic intervals to help the targeting of early diagnosis initiatives is an area of emerging research. In this Review, we consider the methodological challenges in studying the presenting symptoms and intervals to diagnosis of cancer patients, and summarize current evidence on presenting symptoms associated with a range of common and rarer cancer sites. We propose a taxonomy of cancer sites considering their symptom signature and the predictive value of common presenting symptoms. Finally, we consider evidence on associations between symptomatic presentations and intervals to diagnosis before discussing implications for the design, implementation, and evaluation of public health or health system interventions to achieve the earlier detection of cancer.

4 Review Re-engineering the Pancreas Tumor Microenvironment: A "Regenerative Program" Hacked. 2017

Evan, Gerard I / Hah, Nasun / Littlewood, Trevor D / Sodir, Nicole M / Campos, Tania / Downes, Michael / Evans, Ronald M. ·Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom. evans@salk.edu gie20@cam.ac.uk. · Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, California. · Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom. · Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, California. evans@salk.edu gie20@cam.ac.uk. · Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, California. ·Clin Cancer Res · Pubmed #28373363.

ABSTRACT: The "hallmarks" of pancreatic ductal adenocarcinoma (PDAC) include proliferative, invasive, and metastatic tumor cells and an associated dense desmoplasia comprised of fibroblasts, pancreatic stellate cells, extracellular matrix, and immune cells. The oncogenically activated pancreatic epithelium and its associated stroma are obligatorily interdependent, with the resulting inflammatory and immunosuppressive microenvironment contributing greatly to the evolution and maintenance of PDAC. The peculiar pancreas-specific tumor phenotype is a consequence of oncogenes hacking the resident pancreas regenerative program, a tissue-specific repair mechanism regulated by discrete super enhancer networks. Defined as genomic regions containing clusters of multiple enhancers, super enhancers play pivotal roles in cell/tissue specification, identity, and maintenance. Hence, interfering with such super enhancer-driven repair networks should exert a disproportionately disruptive effect on tumor versus normal pancreatic tissue. Novel drugs that directly or indirectly inhibit processes regulating epigenetic status and integrity, including those driven by histone deacetylases, histone methyltransferase and hydroxylases, DNA methyltransferases, various metabolic enzymes, and bromodomain and extraterminal motif proteins, have shown the feasibility of disrupting super enhancer-dependent transcription in treating multiple tumor types, including PDAC. The idea that pancreatic adenocarcinomas rely on embedded super enhancer transcriptional mechanisms suggests a vulnerability that can be potentially targeted as novel therapies for this intractable disease.

5 Review GEMMs as preclinical models for testing pancreatic cancer therapies. 2015

Gopinathan, Aarthi / Morton, Jennifer P / Jodrell, Duncan I / Sansom, Owen J. ·Cancer Research UK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge, CB2 0RE, UK Aarthi.Gopinathan@cruk.cam.ac.uk o.sansom@beatson.gla.ac.uk. · Cancer Research UK Beatson Institute, Glasgow, G61 1BD, UK. · Cancer Research UK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge, CB2 0RE, UK. · Cancer Research UK Beatson Institute, Glasgow, G61 1BD, UK Aarthi.Gopinathan@cruk.cam.ac.uk o.sansom@beatson.gla.ac.uk. ·Dis Model Mech · Pubmed #26438692.

ABSTRACT: Pancreatic ductal adenocarcinoma is the most common form of pancreatic tumour, with a very limited survival rate and currently no available disease-modifying treatments. Despite recent advances in the production of genetically engineered mouse models (GEMMs), the development of new therapies for pancreatic cancer is still hampered by a lack of reliable and predictive preclinical animal models for this disease. Preclinical models are vitally important for assessing therapies in the first stages of the drug development pipeline, prior to their transition to the clinical arena. GEMMs carry mutations in genes that are associated with specific human diseases and they can thus accurately mimic the genetic, phenotypic and physiological aspects of human pathologies. Here, we discuss different GEMMs of human pancreatic cancer, with a focus on the Lox-Stop-Lox (LSL)-Kras(G12D); LSL-Trp53(R172H); Pdx1-cre (KPC) model, one of the most widely used preclinical models for this disease. We describe its application in preclinical research, highlighting its advantages and disadvantages, its potential for predicting clinical outcomes in humans and the factors that can affect such outcomes, and, finally, future developments that could advance the discovery of new therapies for pancreatic cancer.

6 Review Microbiota, oral microbiome, and pancreatic cancer. 2014

Michaud, Dominique S / Izard, Jacques. ·From the *Department of Epidemiology, School of Public Health, Brown University, Providence, RI; †Department of Epidemiology and Public Health, Imperial College, London, United Kingdom; ‡The Forsyth Institute, Cambridge MA; and §Harvard School of Dental Medicine, Boston MA. ·Cancer J · Pubmed #24855008.

ABSTRACT: Only 30% of patients with a diagnosis of pancreatic cancer survive 1 year after the diagnosis. Progress in understanding the causes of pancreatic cancer has been made, including solidifying the associations with obesity and diabetes, and a proportion of cases should be preventable through lifestyle modifications. Unfortunately, identifying reliable biomarkers of early pancreatic cancer has been extremely challenging, and no effective screening modality is currently available for this devastating form of cancer. Recent data suggest that the microbiota may play a role in the disease process, but many questions remain. Future studies focusing on the human microbiome, both etiologically and as a marker of disease susceptibility, should shed light on how to better tackle prevention, early detection, and treatment of this highly fatal disease.

7 Review Chromosome instability and carcinogenesis: insights from murine models of human pancreatic cancer associated with BRCA2 inactivation. 2014

Cassidy, Liam D / Liau, Siong-Seng / Venkitaraman, Ashok R. ·University of Cambridge, Medical Research Council Cancer Cell Unit, Hutchison/MRC Research Centre, Hills Road, Cambridge CB2 0XZ, United Kingdom. · University of Cambridge, Medical Research Council Cancer Cell Unit, Hutchison/MRC Research Centre, Hills Road, Cambridge CB2 0XZ, United Kingdom. Electronic address: arv22@hutchison-mrc.cam.ac.uk. ·Mol Oncol · Pubmed #24268522.

ABSTRACT: Chromosomal instability is a hallmark of human cancer cells, but its role in carcinogenesis remains poorly resolved. Insights into this role have emerged from studies on the tumour suppressor BRCA2, whose inactivation in human cancers causes chromosomal instability through the loss of essential functions of the BRCA2 protein in the normal mechanisms responsible for the replication, repair and segregation of DNA during cell division. Humans who carry heterozygous germline mutations in the BRCA2 gene are highly predisposed to cancers of the breast, ovary, pancreas, prostate and other tissues. Here, we review recent studies that describe genetically engineered mouse models (GEMMs) for pancreatic cancer associated with BRCA2 mutations. These studies not only surprisingly show that BRCA2 does not follow the classical Knudson "two hit" paradigm for tumour suppression, but also highlight features of the interplay between TP53 inactivation and carcinogenesis in the context of BRCA2 deficiency. Thus, the models reveal novel aspects of cancer evolution in carriers of germline BRCA2 mutations, provide new insights into the tumour suppressive role of BRCA2, and establish valuable new preclinical settings for testing approaches to pancreatic cancer therapy; together, these features emphasize the value of GEMMs in cancer research.

8 Review The pancreas cancer microenvironment. 2012

Feig, Christine / Gopinathan, Aarthi / Neesse, Albrecht / Chan, Derek S / Cook, Natalie / Tuveson, David A. ·Cambridge Research Institute, Cancer Research UK. ·Clin Cancer Res · Pubmed #22896693.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) is a common and lethal malignancy resulting in more than 250,000 deaths per year worldwide. Despite extensive efforts, cytotoxic and targeted therapies have provided only limited efficacy for patients with PDA to date. One contributing factor to the failure of systemic therapies may be the abundant tumor stromal content that is the characteristic of PDA. The PDA stroma, aptly termed the tumor microenvironment, occupies the majority of the tumor mass, and consists of a dynamic assortment of extracellular matrix components and nonneoplastic cells including fibroblastic, vascular, and immune cells. Recent work has revealed that the PDA stroma supports tumor growth and promotes metastasis and simultaneously serves as a physical barrier to drug delivery. Accordingly, methods that alter stromal composition or function, for instance interference with the vasculature via Notch/Hedgehog pathway inhibition or relief of vascular compression by hyaluronidase, are under active investigation. Here, we will review our current understanding of the PDA tumor microenvironment, and highlight opportunities for further exploration that may benefit patients.

9 Review What we have learned about pancreatic cancer from mouse models. 2012

Pérez-Mancera, Pedro A / Guerra, Carmen / Barbacid, Mariano / Tuveson, David A. ·Li Ka Shing Centre, Cambridge Research Institute, and Department of Oncology, Cancer Research UK, Cambridge, England. ·Gastroenterology · Pubmed #22406637.

ABSTRACT: -- No abstract --

10 Review Stromal biology and therapy in pancreatic cancer. 2011

Neesse, Albrecht / Michl, Patrick / Frese, Kristopher K / Feig, Christine / Cook, Natalie / Jacobetz, Mike A / Lolkema, Martijn P / Buchholz, Malte / Olive, Kenneth P / Gress, Thomas M / Tuveson, David A. ·Li Ka Shing Centre, Cambridge Research Institute, Cancer Research UK, Cambridge, UK. ·Gut · Pubmed #20966025.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) is an almost uniformly lethal disease. One explanation for the devastating prognosis is the failure of many chemotherapies, including the current standard of care therapy gemcitabine. Although our knowledge of the molecular events underlying multistep carcinogenesis in PDA has steadily increased, translation into more effective therapeutic approaches has been inefficient over the last several decades. Evidence for this innate resistance to systemic therapies was recently provided in an accurate mouse model of PDA by the demonstration that chemotherapies are poorly delivered to PDA tissues because of a deficient vasculature. This vascular deficiency correlated with the presence of a dense stromal matrix that is a prominent histological hallmark of PDA tumours. Therapeutic targeting of stromal cells decreased the stroma from pancreatic tumours, resulting in increased intratumoral perfusion and therapeutic delivery of gemcitabine. Stromal cells contained within the PDA tumour microenvironment therefore represent an additional constituent to neoplastic cells that should be critically evaluated for optimal therapeutic development in preclinical models and early clinical trials.

11 Review Options for the treatment of gemcitabine-resistant advanced pancreatic cancer. 2010

Gounaris, Ioannis / Zaki, Kamarul / Corrie, Pippa. ·Oncology Centre, Cambridge University Hospitals NHS Trust, Cambridge, United Kingdom. ioannis.gounaris@addenbrookes.nhs.uk ·JOP · Pubmed #20208317.

ABSTRACT: CONTEXT: Pancreatic cancer is noteworthy in that the number of patients dying from the disease is roughly equal to the number diagnosed. For more than a decade, gemcitabine has constituted the standard of care for the palliative treatment of the majority of patients who present with metastatic or relapsed disease, although the survival gains are limited. Despite a median survival of less than 6 months, there is a significant proportion of advanced pancreatic cancer patients who progress on gemcitabine that remains fit and these patients are candidates for second-line treatment. METHODS: The OVID MEDLINE database was searched from 1950 to present using the MeSH terms "pancreatic neoplasms", "drug treatment" and "gemcitabine". After excluding non-relevant results, 31 published studies were identified. These results were supplemented by searching the last three (2007-2009) American Society of Clinical Oncology (ASCO) Proceedings of Annual Meetings for studies published only in abstract form and reviewing reference lists of published articles. RESULTS AND DISCUSSION: The evidence for second line treatments of metastatic pancreatic cancer consists mostly of single arm, small phase II studies. Oxaliplatin-fluoropyrimidine combinations appear promising and have shown increased survival compared to best supportive care. As the molecular pathways governing pancreatic cancer are unravelled, novel targeted therapies may offer the greatest promise for this disease either given alone, combined with one another, or with cytotoxic agents. The need for further, collaborative research is emphasised.

12 Review High mobility group A: a novel biomarker and therapeutic target in pancreatic adenocarcinoma. 2009

Liau, S S / Whang, E. ·Department of Surgery, Addenbrooke's Hospital, Cambridge. liauss@doctors.org.uk ·Surgeon · Pubmed #19848064.

ABSTRACT: High mobility group A1 (HMGA1) proteins are architectural transcriptional factors that are over-expressed in a wide range of human malignancies. Recently published evidence suggests HMGA1 is a promising candidate biomarker and therapeutic target in pancreatic cancer. This review summarises data implicating HMGA1 as an important mediator of progression in human cancer and in pancreatic cancer.

13 Clinical Trial Maintenance Olaparib for Germline 2019

Golan, Talia / Hammel, Pascal / Reni, Michele / Van Cutsem, Eric / Macarulla, Teresa / Hall, Michael J / Park, Joon-Oh / Hochhauser, Daniel / Arnold, Dirk / Oh, Do-Youn / Reinacher-Schick, Anke / Tortora, Giampaolo / Algül, Hana / O'Reilly, Eileen M / McGuinness, David / Cui, Karen Y / Schlienger, Katia / Locker, Gershon Y / Kindler, Hedy L. ·From the Oncology Institute, Sheba Medical Center, Tel Aviv University, Tel Aviv, Israel (T.G.) · Hôpital Beaujon (Assistance Publique-Hôpitaux de Paris), Clichy, and University Paris VII, Paris (P.H.) · IRCCS Ospedale San Raffaele Scientific Institute, Milan (M.R.), Azienda Ospedaliera Universitaria Integrata Verona, Verona (G.T.), and Fondazione Policlinico Universitario Gemelli IRCCS, Rome (G.T.) - all in Italy · University Hospitals Gasthuisberg and KU Leuven, Leuven, Belgium (E.V.C.) · Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology, Barcelona (T.M.) · Fox Chase Cancer Center, Philadelphia (M.J.H.) · Samsung Medical Center, Sungkyunkwan University School of Medicine (J.-O.P.), and Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine (D.-Y.O.) - both in Seoul, South Korea · University College London Cancer Institute, London (D.H.), and AstraZeneca, Cambridge (D.M.) - both in the United Kingdom · Asklepios Tumorzentrum Hamburg Asklepios Klinik Altona, Hamburg (D.A.), St. Josef-Hospital, Ruhr University Bochum, Bochum (A.R.-S.), and Klinikum rechts der Isar, Department of Internal Medicine II, Technische Universität München, Munich (H.A.) - all in Germany · Memorial Sloan Kettering Cancer Center, New York (E.M.O.) · AstraZeneca, Gaithersburg, MD (K.Y.C., G.Y.L.) · Merck, Kenilworth, NJ (K.S.) · and the University of Chicago, Chicago (H.L.K.). ·N Engl J Med · Pubmed #31157963.

ABSTRACT: BACKGROUND: Patients with a germline METHODS: We conducted a randomized, double-blind, placebo-controlled, phase 3 trial to evaluate the efficacy of olaparib as maintenance therapy in patients who had a germline RESULTS: Of the 3315 patients who underwent screening, 154 underwent randomization and were assigned to a trial intervention (92 to receive olaparib and 62 to receive placebo). The median progression-free survival was significantly longer in the olaparib group than in the placebo group (7.4 months vs. 3.8 months; hazard ratio for disease progression or death, 0.53; 95% confidence interval [CI], 0.35 to 0.82; P = 0.004). An interim analysis of overall survival, at a data maturity of 46%, showed no difference between the olaparib and placebo groups (median, 18.9 months vs. 18.1 months; hazard ratio for death, 0.91; 95% CI, 0.56 to 1.46; P = 0.68). There was no significant between-group difference in health-related quality of life, as indicated by the overall change from baseline in the global quality-of-life score (on a 100-point scale, with higher scores indicating better quality of life) based on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (between-group difference, -2.47 points; 95% CI, -7.27 to 2.33). The incidence of grade 3 or higher adverse events was 40% in the olaparib group and 23% in the placebo group (between-group difference, 16 percentage points; 95% CI, -0.02 to 31); 5% and 2% of the patients, respectively, discontinued the trial intervention because of an adverse event. CONCLUSIONS: Among patients with a germline

14 Clinical Trial Study protocol: a multi-centre randomised study of induction chemotherapy followed by capecitabine ± nelfinavir with high- or standard-dose radiotherapy for locally advanced pancreatic cancer (SCALOP-2). 2019

Strauss, Victoria Y / Shaw, Rachel / Virdee, Pradeep S / Hurt, Christopher N / Ward, Elizabeth / Tranter, Bethan / Patel, Neel / Bridgewater, John / Parsons, Philip / Radhakrishna, Ganesh / O'Neill, Eric / Sebag-Montefiore, David / Hawkins, Maria / Corrie, Pippa G / Maughan, Timothy / Mukherjee, Somnath. ·Centre for Statistics in Medicine, University of Oxford, Oxford, UK. · Oncology Clinical Trials Office, University of Oxford, Oxford, UK. · Centre for Trials Research, Cardiff University, Cardiff, UK. · Clinical Trials and Evaluation Unit, Bristol Royal Infirmary, Bristol, UK. · Pharmacy Department, Velindre Cancer Centre, Velindre NHS University Trust, Cardiff, UK. · Department of Radiology, Oxford University Hospitals NHS Foundation Trust, Churchill Hospital, Oxford, UK. · Department of Oncology, University College London Hospitals, London, UK. · Cardiff NCRI RTTQA group, Department of Medical Physics, Velindre Cancer Centre, Cardiff, UK. · Oncology Department, The Christie NHS Foundation Trust, Wilmslow Road, Manchester, UK. · Department of Oncology, University of Oxford, CRUK MRC Oxford Institute for Radiation Oncology, Oxford, UK. · University of Leeds, Leeds Cancer Centre, St James's University Hospital, Leeds, UK. · Cambridge Cancer Centre, Addenbrooke's Hospital, Cambridge, UK. · Department of Oncology, University of Oxford, CRUK MRC Oxford Institute for Radiation Oncology, Oxford, UK. somnath.mukherjee@oncology.ox.ac.uk. ·BMC Cancer · Pubmed #30717707.

ABSTRACT: BACKGROUND: Induction chemotherapy followed by chemoradiation is a treatment option for patients with locally advanced pancreatic cancer (LAPC). However, overall survival is comparable to chemotherapy alone and local progression occurs in nearly half of all patients, suggesting chemoradiation strategies should be optimised. SCALOP-2 is a randomised phase II trial testing the role of radiotherapy dose escalation and/or the addition of the radiosensitiser nelfinavir, following induction chemotherapy of gemcitabine and nab-paclitaxel (GEMABX). A safety run-in phase (stage 1) established the nelfinavir dose to administer with chemoradiation in the randomised phase (stage 2). METHODS: Patients with locally advanced, inoperable, non-metastatic pancreatic adenocarcinoma receive three cycles of induction GEMABX chemotherapy prior to radiological assessment. Those with stable/responding disease are eligible for further trial treatment. In Stage 1, participants received one further cycle of GEMABX followed by capecitabine-chemoradiation with escalating doses of nelfinavir in a rolling-six design. Stage 2 aims to register 262 and randomise 170 patients with responding/stable disease to one of five arms: capecitabine with high- (arms C + D) or standard-dose (arms A + B) radiotherapy with (arms A + C) or without (arms B + D) nelfinavir, or three more cycles of GEMABX (arm E). Participants allocated to the chemoradiation arms receive another cycle of GEMABX before chemoradiation begins. Co-primary outcomes are 12-month overall survival (radiotherapy dose-escalation question) and progression-free survival (nelfinavir question). Secondary outcomes include toxicity, quality of life, disease response rate, resection rate, treatment compliance, and CA19-9 response. SCALOP-2 incorporates a detailed radiotherapy quality assurance programme. DISCUSSION: SCALOP-2 aims to optimise chemoradiation in LAPC and incorporates a modern induction regimen. TRIAL REGISTRATION: Eudract No: 2013-004968-56; ClinicalTrials.gov : NCT02024009.

15 Clinical Trial A phase I trial of the γ-secretase inhibitor MK-0752 in combination with gemcitabine in patients with pancreatic ductal adenocarcinoma. 2018

Cook, Natalie / Basu, Bristi / Smith, Donna-Michelle / Gopinathan, Aarthi / Evans, Jeffry / Steward, William P / Palmer, Daniel / Propper, David / Venugopal, Balaji / Hategan, Mirela / Anthoney, D Alan / Hampson, Lisa V / Nebozhyn, Michael / Tuveson, David / Farmer-Hall, Hayley / Turner, Helen / McLeod, Robert / Halford, Sarah / Jodrell, Duncan. ·Cancer Research UK, Cambridge Research Institute, University of Cambridge Robinson Way, Cambridge CB2 0RE, UK. · Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0RE, UK. · Beatson West of Scotland Cancer Centre, University of Glasgow, Glasgow G12 0YN, United Kingdom. · Department of Oncology, University of Leicester, Leicester LE2 7LX, UK. · Clatterbridge Cancer Centre, Clatterbridge Road, Bebington, Wirral CH63 4JY, UK. · Bart's Cancer Institute, Queen Mary University of London EC1M 6BQ, London, UK. · Cancer Research UK, Centre for Drug Development, Angel Building, 407 St. John Street, London EC1V 4AD, UK. · St James Institute of Oncology, University of Leeds & Leeds Teaching Hospitals Trust, Leeds LS9 7TF, UK. · Department of Mathematics and Statistics, Fylde College, Lancaster University, Lancaster LA1 4YF, UK. · Merck & Co., Inc., Kenilworth, NJ 07033, USA. · Cold Spring Harbor Laboratories, Cold Spring Harbor, NY 11724, USA. ·Br J Cancer · Pubmed #29438372.

ABSTRACT: BACKGROUND: The Notch pathway is frequently activated in cancer. Pathway inhibition by γ-secretase inhibitors has been shown to be effective in pre-clinical models of pancreatic cancer, in combination with gemcitabine. METHODS: A multi-centre, non-randomised Bayesian adaptive design study of MK-0752, administered per os weekly, in combination with gemcitabine administered intravenously on days 1, 8 and 15 (28 day cycle) at 800 or 1000 mg m RESULTS: Overall, 44 eligible patients (performance status 0 or 1 with adequate organ function) received gemcitabine and MK-0752 as first or second line treatment for pancreatic cancer. RP2Ds of MK-0752 and gemcitabine as single agents could be combined safely. The Bayesian algorithm allowed further dose escalation, but pharmacokinetic analysis showed no increase in MK-0752 AUC (area under the curve) beyond 1800 mg once weekly. Tumour response evaluation was available in 19 patients; 13 achieved stable disease and 1 patient achieved a confirmed partial response. CONCLUSIONS: Gemcitabine and a γ-secretase inhibitor (MK-0752) can be combined at their full, single-agent RP2Ds.

16 Clinical Trial HALO-109-301: a Phase III trial of PEGPH20 (with gemcitabine and nab-paclitaxel) in hyaluronic acid-high stage IV pancreatic cancer. 2018

Doherty, Gary J / Tempero, Margaret / Corrie, Pippa G. ·Department of Oncology, University of Cambridge, Box 193, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0QQ, UK. · Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, Box 193, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0QQ, UK. · Pancreas Center, University of California, San Francisco, CA 94158, USA. ·Future Oncol · Pubmed #29235360.

ABSTRACT: The outlook for patients with advanced pancreatic cancer remains poor, despite significant advances in our understanding of pancreatic tumor biology. One emerging theme highlights the distinct composition of the pancreatic tumor microenvironment. Hyaluronic acid is a hydrophilic glycosaminoglycan whose production within the tumor leads to increased interstitial tumor pressure, thereby limiting the access of potentially effective circulating anticancer drugs via reduced tumor perfusion. PEGylated rHuPH20 is a multiply PEGylated recombinant human hyaluronidase that has shown promising efficacy in preclinical models and early phase clinical trials in pancreatic cancer patients. Here, we discuss these findings, and the rationale for the ongoing randomized Phase III trial (HALO-109-301), which seeks to definitively define the efficacy of PEGylated rHuPH20 alongside gemcitabine and nab-paclitaxel in previously untreated, hyaluronic acid-high, stage IV pancreatic cancer.

17 Clinical Trial Vandetanib plus gemcitabine versus placebo plus gemcitabine in locally advanced or metastatic pancreatic carcinoma (ViP): a prospective, randomised, double-blind, multicentre phase 2 trial. 2017

Middleton, Gary / Palmer, Daniel H / Greenhalf, William / Ghaneh, Paula / Jackson, Richard / Cox, Trevor / Evans, Anthony / Shaw, Victoria E / Wadsley, Jonathan / Valle, Juan W / Propper, David / Wasan, Harpreet / Falk, Stephen / Cunningham, David / Coxon, Fareeda / Ross, Paul / Madhusudan, Srinivasan / Wadd, Nick / Corrie, Pippa / Hickish, Tamas / Costello, Eithne / Campbell, Fiona / Rawcliffe, Charlotte / Neoptolemos, John P. ·University of Birmingham, Edgbaston, Birmingham, UK. · Liverpool Cancer Research UK Cancer Trials Unit and LCTU-GCPLabs, University of Liverpool, Liverpool, UK; Clatterbridge Cancer Centre NHS Foundation Trust, Wirral, UK. · Liverpool Cancer Research UK Cancer Trials Unit and LCTU-GCPLabs, University of Liverpool, Liverpool, UK. · Weston Park Hospital, Sheffield Teaching Hospital NHS Foundation Trust, Sheffield, UK. · Division of Molecular and Clinical Cancer Sciences, University of Manchester, Manchester, UK; Christie NHS Foundation Trust, Manchester, UK. · Centre for Cancer and Inflammation, Barts Cancer Institute, London, UK. · Hammersmith Hospital, London, UK. · Bristol Haematology and Oncology Centre, University Hospital Bristol NHS Foundation Trust, Bristol, UK. · Royal Marsden, Royal Marsden NHS Foundation Trust, London, UK. · Northern Centre for Cancer Care, Newcastle upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK. · Guy's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, UK. · Nottingham City Hospital, Nottingham University Hospitals NHS Trust, Nottingham, UK. · James Cook University Hospital, South Tees Hospitals NHS Foundation Trust, Middlesborough, UK. · Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK. · Poole Hospital NHS Foundation Trust, Bournemouth University, Poole, UK. · Liverpool Cancer Research UK Cancer Trials Unit and LCTU-GCPLabs, University of Liverpool, Liverpool, UK. Electronic address: j.p.neoptolemos@liverpool.ac.uk. ·Lancet Oncol · Pubmed #28259610.

ABSTRACT: BACKGROUND: Erlotinib is an EGFR tyrosine kinase inhibitor that has shown a significant but only marginally improved median overall survival when combined with gemcitabine in patients with locally advanced and metastatic pancreatic cancer. Vandetanib is a novel tyrosine kinase inhibitor of VEGFR2, RET, and EGFR, all of which are in involved in the pathogenesis of pancreatic cancer. We investigated the clinical efficacy of vandetanib when used in combination with gemcitabine in patients with advanced pancreatic cancer. METHODS: The Vandetanib in Pancreatic Cancer (ViP) trial was a phase 2 double-blind, multicentre, randomised placebo-controlled trial in previously untreated adult patients (aged ≥18 years) diagnosed with locally advanced or metastatic carcinoma of the pancreas confirmed by cytology or histology. Patients had to have an Eastern Cooperative Oncology Group (ECOG) score of 0-2 and a documented life expectancy of at least 3 months. Patients were randomly assigned 1:1 to receive vandetanib plus gemcitabine (vandetanib group) or placebo plus gemcitabine (placebo group) according to pre-generated sequences produced on the principle of randomly permuted blocks with variable block sizes of two and four. Patients were stratified at randomisation by disease stage and ECOG performance status. All patients received gemcitabine 1000 mg/m FINDINGS: Patients were screened and enrolled between Oct 24, 2011, and Oct 7, 2013. Of 381 patients screened, 142 eligible patients were randomly assigned to treatment (72 to the vandetanib group and 70 to the placebo group). At database lock on July 15, 2015, at a median follow-up of 24·9 months (IQR 24·3 to not attainable), 131 patients had died: 70 (97%) of 72 in the vandetanib group and 61 (87%) of 70 in the placebo group. The median overall survival was 8·83 months (95% CI 7·11-11·58) in the vandetanib group and 8·95 months (6·55-11·74) in the placebo group (hazard ratio 1·21, 80·8% CI 0·95-1·53; log rank χ INTERPRETATION: The addition of vandetanib to gemcitabine monotherapy did not improve overall survival in advanced pancreatic cancer. Tyrosine kinase inhibitors might still have potential in the treatment of pancreatic cancer but further development requires the identification of biomarkers to specifically identify responsive cancer subtypes. FUNDING: Cancer Research UK and AstraZeneca.

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

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

ABSTRACT: BACKGROUND: Immune Modulation and Gemcitabine Evaluation-1, a randomised, open-label, phase II, first-line, proof of concept study (NCT01303172), explored safety and tolerability of IMM-101 (heat-killed Mycobacterium obuense; NCTC 13365) with gemcitabine (GEM) in advanced pancreatic ductal adenocarcinoma. METHODS: Patients were randomised (2 : 1) to IMM-101 (10 mg ml(-l) intradermally)+GEM (1000 mg m(-2) intravenously; n=75), or GEM alone (n=35). Safety was assessed on frequency and incidence of adverse events (AEs). Overall survival (OS), progression-free survival (PFS) and overall response rate (ORR) were collected. RESULTS: IMM-101 was well tolerated with a similar rate of AE and serious adverse event reporting in both groups after allowance for exposure. Median OS in the intent-to-treat population was 6.7 months for IMM-101+GEM v 5.6 months for GEM; while not significant, the hazard ratio (HR) numerically favoured IMM-101+GEM (HR, 0.68 (95% CI, 0.44-1.04, P=0.074). In a pre-defined metastatic subgroup (84%), OS was significantly improved from 4.4 to 7.0 months in favour of IMM-101+GEM (HR, 0.54, 95% CI 0.33-0.87, P=0.01). CONCLUSIONS: IMM-101 with GEM was as safe and well tolerated as GEM alone, and there was a suggestion of a beneficial effect on survival in patients with metastatic disease. This warrants further evaluation in an adequately powered confirmatory study.

19 Clinical Trial Long-term efficacy of (90)Y-DOTATATE in patients with nonresectable pancreatic and small bowel neuroendocrine neoplasms. 2016

Rogowski, Wojciech / Wachuła, Ewa / Lewczuk, Anna / Buscombe, John R / Seklecka, Nina / Sankowski, Artur / Ćwikła, Jarosław B. ·Clinical Department of Chemotherapy, Hospital Ministry of the Interior & Administration & Warmia & Mazury Oncology Centre, Olsztyn, Poland. · Department of Endocrinology, Medical University of Gdansk, Gdansk, Poland. · Department of Nuclear Medicine & PET, Addenbrooke's Hospital, Cambridge, UK. · Department of Radiology & Diagnostic Imaging, Central Clinical Hospital of the Ministry of Interior, Warsaw, Poland. · Faculty of Medical Science, University of Varmia & Masuria, Olsztyn, Poland. ·Future Oncol · Pubmed #27156864.

ABSTRACT: AIM: To determine the efficacy of (90)Y [DOTA(0), D-Phe(1), Tyr(3)]-octreotate (DOTATATE) in 67 patients with pancreatic and small bowel neuroendocrine tumors (NETs). PATIENTS & METHODS: The primary efficacy end point was overall survival (OS) and secondary end points were progression-free survival (PFS) and tumor response. RESULTS: Median PFS in pancreatic and small bowel NETs was 25 and 28 months, respectively, and median OS was 42 and 38.5 months, respectively. No intergroup differences in median OS (p = 0.945) or PFS (p = 0.174) were found, also after adjustment for tumor origin, secretory status and grade, and patient's gender. CONCLUSION: (90)Y-DOTATATE may have similar efficacy in pancreatic and small bowel NETs. Better WHO performance status at baseline seems to be associated with more favorable outcomes.

20 Clinical Trial A phase 3 randomized, double-blind, placebo-controlled trial of ganitumab or placebo in combination with gemcitabine as first-line therapy for metastatic adenocarcinoma of the pancreas: the GAMMA trial. 2015

Fuchs, C S / Azevedo, S / Okusaka, T / Van Laethem, J-L / Lipton, L R / Riess, H / Szczylik, C / Moore, M J / Peeters, M / Bodoky, G / Ikeda, M / Melichar, B / Nemecek, R / Ohkawa, S / Świeboda-Sadlej, A / Tjulandin, S A / Van Cutsem, E / Loberg, R / Haddad, V / Gansert, J L / Bach, B A / Carrato, A. ·Department of Medical Oncology/Solid Tumor Oncology, Dana-Farber Cancer Institute, Boston, USA charles_fuchs@dfci.harvard.edu. · Oncology Service, Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil. · Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan. · Department of Gastroenterology, Erasme University Hospital, Brussels, Belgium. · Medical Oncology, Royal Melbourne Hospital, Parkville, VIC, Australia. · Department of Hematology, Oncology, and Tumor Immunology, Charité University, Berlin, Germany. · Department of Oncology, Military Institute of Health Services, Warsaw, Poland. · Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada. · Department of Oncology, Antwerp University Hospital, Edegum, Belgium. · Department of Oncology, St László Hospital, Budapest, Hungary. · Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan. · Department of Oncology, Palacký University Medical School and Teaching Hospital, Olomouc. · Department of Oncology, Masaryk University Medical School and Masaryk Memorial Cancer Institute, Brno, Czech Republic. · Department of Gastroenterology, Kanagawa Cancer Center, Yokohama, Japan. · Department of Haematology, Oncology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland. · Department of Clinical Pharmacology and Chemotherapy, Russian Cancer Research Center, Moscow, Russia. · Digestive Oncology, University Hospitals Gasthuisberg/Leuven and KU Leuven, Leuven, Belgium. · Medical Sciences, Amgen Inc., Thousand Oaks, USA. · Global Biostatistical Science, Amgen Ltd, Cambridge, UK. · Global Development, Thousand Oaks. · Development Oncology Therapeutics, Amgen Inc., Thousand Oaks, USA. · Medical Oncology Department, University Hospital Ramon y Cajal, Madrid, Spain. ·Ann Oncol · Pubmed #25609246.

ABSTRACT: BACKGROUND: This double-blind, phase 3 study assessed the efficacy and safety of ganitumab combined with gemcitabine as first-line treatment of metastatic pancreatic cancer. PATIENTS AND METHODS: Patients with previously untreated metastatic pancreatic adenocarcinoma were randomly assigned 2 : 2 : 1 to receive intravenous gemcitabine 1000 mg/m(2) (days 1, 8, and 15 of each 28-day cycle) plus placebo, ganitumab 12 mg/kg, or ganitumab 20 mg/kg (days 1 and 15 of each cycle). The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), safety, and efficacy by levels of circulating biomarkers. RESULTS: Overall, 322 patients were randomly assigned to placebo, 318 to ganitumab 12 mg/kg, and 160 to ganitumab 20 mg/kg. The study was stopped based on results from a preplanned futility analysis; the final results are reported. Median OS was 7.2 months [95% confidence interval (CI), 6.3-8.2] in the placebo arm, 7.0 months (95% CI, 6.2-8.5) in the ganitumab 12-mg/kg arm [hazard ratio (HR), 1.00; 95% CI, 0.82-1.21; P = 0.494], and 7.1 months (95% CI, 6.4-8.5) in the ganitumab 20-mg/kg arm (HR, 0.97; 95% CI, 0.76-1.23; P = 0.397). Median PFS was 3.7, 3.6 (HR, 1.00; 95% CI, 0.84-1.20; P = 0.520), and 3.7 months (HR, 0.97; 95% CI, 0.77-1.22; P = 0.403), respectively. No unexpected toxicity was observed with ganitumab plus gemcitabine. The circulating biomarkers assessed [insulin-like growth factor-1 (IGF-1), IGF-binding protein-2, and -3] were not associated with a treatment effect on OS or PFS by ganitumab. CONCLUSION: Ganitumab combined with gemcitabine had manageable toxicity but did not improve OS, compared with gemcitabine alone in unselected patients with metastatic pancreatic cancer. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01231347.

21 Clinical Trial A phase I open-label study investigating the disposition of [14C]-cabazitaxel in patients with advanced solid tumors. 2015

Ridoux, Laurence / Sémiond, Dorothée R / Vincent, Carine / Fontaine, Hélène / Mauriac, Christine / Sanderink, Ger-Jan / Oprea, Corina / Kelly, Lindsay / Clive, Sally. ·aSanofi R&D, Chilly-Mazarin bSanofi R&D, Vitry-sur-Seine, France cSanofi R&D, Cambridge, Massachusetts, USA dCharles River Biopharmaceutical Services, Tranent eEdinburgh Cancer Centre, Western General Hospital, Edinburgh, UK. ·Anticancer Drugs · Pubmed #25462133.

ABSTRACT: Cabazitaxel is a semisynthetic taxane approved for the treatment of patients with hormone-refractory metastatic prostate cancer (now known as metastatic castration-resistant prostate cancer) treated previously with a docetaxel-containing treatment regimen. The human plasma pharmacokinetics of cabazitaxel have been described previously, but detailed analyses of the metabolism and excretion pathways of cabazitaxel have not yet been published. Metabolite profiling, quantification, and identification as well as excretion analyses were carried out on samples from patients with advanced solid tumors who received an intravenous infusion of 25 mg/m [C]-cabazitaxel (50 μCi, 1.85 MBq) over 1 h. In plasma, cabazitaxel was the main circulating compound. Seven metabolites were detected, but with each accounting for 5% or less of the parent drug exposure, none were considered relevant metabolites. In excreta, 76.0% of the administered dose was recovered in feces within 2 weeks and 3.7% of the dose was excreted in urine within 1 week. Approximately 20 metabolites were detected in excreta; the main metabolites corresponded to combined mono-O-demethyl or di-O-demethyl derivatives on the taxane ring, with hydroxyl or cyclized derivatives on the lateral chain. Docetaxel (di-O-demethyl-cabazitaxel) was only detected at trace levels in excreta. These results suggest an extensive hepatic metabolism and biliary excretion of cabazitaxel in humans.

22 Clinical Trial Gemcitabine and capecitabine with or without telomerase peptide vaccine GV1001 in patients with locally advanced or metastatic pancreatic cancer (TeloVac): an open-label, randomised, phase 3 trial. 2014

Middleton, Gary / Silcocks, Paul / Cox, Trevor / Valle, Juan / Wadsley, Jonathan / Propper, David / Coxon, Fareeda / Ross, Paul / Madhusudan, Srinivasan / Roques, Tom / Cunningham, David / Falk, Stephen / Wadd, Nick / Harrison, Mark / Corrie, Pippa / Iveson, Tim / Robinson, Angus / McAdam, Karen / Eatock, Martin / Evans, Jeff / Archer, Caroline / Hickish, Tamas / Garcia-Alonso, Angel / Nicolson, Marianne / Steward, William / Anthoney, Alan / Greenhalf, William / Shaw, Victoria / Costello, Eithne / Naisbitt, Dean / Rawcliffe, Charlotte / Nanson, Gemma / Neoptolemos, John. ·University of Birmingham, Edgbaston, Birmingham, UK. · Liverpool Cancer Research UK Cancer Trials Unit and GCLP Facility, University of Liverpool, Liverpool, UK. · Manchester Academic Health Sciences Centre, Christie Hospital NHS Foundation Trust and University of Manchester, Manchester UK. · Weston Park Hospital, Sheffield Teaching Hospital NHS Foundation Trust, Sheffield, UK. · St Bartholomew's Hospital, Barts Health NHS Trust, West Smithfield, London, UK. · Northern Centre for Cancer Care, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK. · Guy's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, UK. · Nottingham City Hospital, Nottingham University Hospitals NHS Trust, Nottingham, UK. · Norfolk and Norwich University Hospital, Norfolk and Norwich University Hospital NHS Foundation Trust, Norwich, UK. · The Royal Marsden, The Royal Marsden NHS Foundation Trust, London, UK. · Bristol Haematology And Oncology Centre, University Hospital Bristol NHS Foundation Trust, Bristol, UK. · The James Cook University Hospital, South Tees Hospitals NHS Foundation Trust, Middleborough, UK. · Mount Vernon Hospital, The Hillingdon Hospitals NHS Foundation Trust, Northwood, UK. · Addenbrookes Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK. · Southampton General Hospital, University Hospital Southampton NHS Foundation Trust, Southampton, Hampshire, UK. · Conquest Hospital, East Sussex Healthcare NHS Trust, The Ridge, St Leonards-on-Sea, East Sussex, UK. · Peterborough City Hospital, Peterborough and Stamford Hospitals NHS Foundation Trust, Edith, Cavell Campus, Peterborough, UK. · Belfast City Hospital, Belfast Health and Social Care Trust, Belfast, UK. · University of Glasgow, Beatson West of Scotland Cancer Centre, Glasgow, UK. · Queen Alexandra Hospital, Portsmouth Hospitals NHS Trust, Cosham, Portsmouth, UK. · Royal Bournemouth Hospital, The Royal Bournemouth and Christchurch Hospitals NHS Foundation Trust, Bournemouth, UK. · Glan Clwyd Hospital, University Health Board, Rhyl, Denbighshire, UK. · Abderdeen Royal Infirmary, NHS Grampian, Aberdeen, UK. · Leicester Royal Infirmary, University Hospitals of Leicester NHS Trust, Leicester, UK. · St James University Hospital, The Leeds Teaching Hospital Trust, Beckett Street, Leeds, UK. · Liverpool Cancer Research UK Cancer Trials Unit and GCLP Facility, University of Liverpool, Liverpool, UK. Electronic address: j.p.neoptolemos@liverpool.ac.uk. ·Lancet Oncol · Pubmed #24954781.

ABSTRACT: BACKGROUND: We aimed to assess the efficacy and safety of sequential or simultaneous telomerase vaccination (GV1001) in combination with chemotherapy in patients with locally advanced or metastatic pancreatic cancer. METHODS: TeloVac was a three-group, open-label, randomised phase 3 trial. We recruited patients from 51 UK hospitals. Eligible patients were treatment naive, aged older than 18 years, with locally advanced or metastatic pancreatic ductal adenocarcinoma, and Eastern Cooperative Oncology Group performance status of 0-2. Patients were randomly assigned (1:1:1) to receive either chemotherapy alone, chemotherapy with sequential GV1001 (sequential chemoimmunotherapy), or chemotherapy with concurrent GV1001 (concurrent chemoimmunotherapy). Treatments were allocated with equal probability by means of computer-generated random permuted blocks of sizes 3 and 6 in equal proportion. Chemotherapy included six cycles of gemcitabine (1000 mg/m(2), 30 min intravenous infusion, at days 1, 8, and 15) and capecitabine (830 mg/m(2) orally twice daily for 21 days, repeated every 28 days). Sequential chemoimmunotherapy included two cycles of combination chemotherapy, then an intradermal lower abdominal injection of granulocyte-macrophage colony-stimulating factor (GM-CSF; 75 μg) and GV1001 (0·56 mg; days 1, 3, and 5, once on weeks 2-4, and six monthly thereafter). Concurrent chemoimmunotherapy included giving GV1001 from the start of chemotherapy with GM-CSF as an adjuvant. The primary endpoint was overall survival; analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN4382138. FINDINGS: The first patient was randomly assigned to treatment on March 29, 2007, and the trial was terminated on March 27, 2011. Of 1572 patients screened, 1062 were randomly assigned to treatment (358 patients were allocated to the chemotherapy group, 350 to the sequential chemoimmunotherapy group, and 354 to the concurrent chemoimmunotherapy group). We recorded 772 deaths; the 290 patients still alive were followed up for a median of 6·0 months (IQR 2·4-12·2). Median overall survival was not significantly different in the chemotherapy group than in the sequential chemoimmunotherapy group (7·9 months [95% CI 7·1-8·8] vs 6·9 months [6·4-7·6]; hazard ratio [HR] 1·19, 98·25% CI 0·97-1·48, p=0·05), or in the concurrent chemoimmunotherapy group (8·4 months [95% CI 7·3-9·7], HR 1·05, 98·25% CI 0·85-1·29, p=0·64; overall log-rank of χ(2)2df=4·3; p=0·11). The commonest grade 3-4 toxic effects were neutropenia (68 [19%] patients in the chemotherapy group, 58 [17%] patients in the sequential chemoimmunotherapy group, and 79 [22%] patients in the concurrent chemoimmunotherapy group; fatigue (27 [8%] in the chemotherapy group, 35 [10%] in the sequential chemoimmunotherapy group, and 44 [12%] in the concurrent chemoimmunotherapy group); and pain (34 [9%] patients in the chemotherapy group, 39 [11%] in the sequential chemoimmunotherapy group, and 41 [12%] in the concurrent chemoimmunotherapy group). INTERPRETATION: Adding GV1001 vaccination to chemotherapy did not improve overall survival. New strategies to enhance the immune response effect of telomerase vaccination during chemotherapy are required for clinical efficacy. FUNDING: Cancer Research UK and KAEL-GemVax.

23 Clinical Trial Targeted metabolomics identifies perturbations in amino acid metabolism that sub-classify patients with COPD. 2012

Ubhi, Baljit K / Cheng, Kian Kai / Dong, Jiyang / Janowitz, Tobias / Jodrell, Duncan / Tal-Singer, Ruth / MacNee, William / Lomas, David A / Riley, John H / Griffin, Julian L / Connor, Susan C. ·Department of Biochemistry and the Cambridge Systems Biology Centre, University of Cambridge, UK. bs405@cam.ac.uk ·Mol Biosyst · Pubmed #23051772.

ABSTRACT: BACKGROUND: COPD, a leading cause of mortality is currently assessed by spirometry (forced expiratory volume in 1 second, FEV(1)). However FEV(1) does not correlate with patient mortality. ECLIPSE (Evaluation of Chronic obstructive pulmonary disease to Longitudinally Identify Predictive Surrogate Endpoints) aims to identify biomarkers that correlate with clinically relevant COPD subtypes, and to assess how these may predict disease progression. New methods were developed and validated to evaluate small molecules as potential diagnostic tools in patients with COPD, COPD related cachexia and cancer related cachexia. METHODS AND FINDINGS: quantitative LC-MS/MS was developed to measure 34 amino acids and dipeptides for stratification of patient groups. Subsets of the ECLIPSE patients were used to assess biomarkers of lung obstruction; GOLD IV (n = 30) versus control (n = 30); emphysema (n = 38) versus airways disease (n = 21) and cachexia (n = 30) versus normal body mass index (n = 30). Serum from cachexic (n = 7) and non-cachexic (n = 5) pancreatic cancer patients were included as controls. Targeted LC-MS/MS distinguished GOLD IV patients from controls, patients with and without emphysema and patients with and without cachexia. Glutamine, aspartate and arginine were significantly increased (p < 0.05; FDR adjustment α < 0.1) in cachexia, emphysema and GOLD IV patients and aminoadipate was decreased. Several amino acid concentrations were significantly altered in patients with COPD but not patients with pancreatic cancer (serine, sarcosine, tryptophan, BCAAs and 3-methylhistdine). Increased γ-aminobutyrate (GABA, p < 0.01) levels were specific to cachexia in patients with pancreatic cancer. β-aminoisobutyrate, 1-methylhistidine and asparagine (p < 0.05) were common across the patients with cachexia from both the COPD and pancreatic cancer cohorts. CONCLUSION: these results demonstrate that a metabolomic fingerprint has potential to stratify patients for the treatment of COPD and may provide a means of assessing response to therapy. GOLD IV patients were distinguished from smoker control subjects, patients with emphysema were distinguished from those without emphysema and COPD patients displaying cachexia were distinguished from those not displaying cachexia. General markers of cachexia were discovered reflecting both COPD- and pancreatic cancer-related cachexia (increased glutamine, aspartate, arginine, and asparagine and decreased aminoadipate, β-aminoisobutyrate and 1-methylhistidine). Metabolomic biomarkers, particularly altered levels of GABA, could be exploited as a way of monitoring treatment efficacy and tumour recurrence for patients with pancreatic cancer experiencing cachexia.

24 Article Acromegaly associated with GIST, non-small cell lung carcinoma, clear cell renal carcinoma, multiple myeloma, medulla oblongata tumour, adrenal adenoma, and follicular thyroid nodules. 2019

Jawiarczyk-Przybyłowska, Aleksandra / Wojtczak, Beata / Whitworth, James / Sutkowski, Krzysztof / Bidlingmaier, Martin / Korbonits, Márta / Bolanowski, Marek. ·Department of Endocrinology, Diabetes, and Isotope Therapy, Medical University Wroclaw, Wrocław, Poland. aleksandra.olczur@gmail.com. · Department of Endocrinological Surgery, Medical University Wroclaw, Wrocław, Poland. · Department of Medical Genetics, University of Cambridge Cancer Research UK Cambridge Centre, Cambridge, United Kingdom. · Endocrine Laboratory, Ludwig-Maximilians-University of Munich, Munich, Germany. · Centre for Endocrinology, Barts and the London School of Medicine, Queen Mary University of London, London, United Kingdom. · Department of Endocrinology, Diabetes, and Isotope Therapy, Medical University Wroclaw, Wrocław, Poland. ·Endokrynol Pol · Pubmed #30742299.

ABSTRACT: Acromegaly is associated with increased growth hormone (GH) and insulin-like growth factor-I (IGF-I) secretion which may support tumour development and growth. A 68-year-old woman was diagnosed with acromegaly due to typical clinical and hormonal characteristics. While contrast-enhanced MRI at diagnosis did not reveal a pituitary adenoma, a 5-mm lesion was identified on repeat scanning 13 months later. Abdominal and chest CT showed tumours of the stomach, right adrenal gland, and right lung. The CT also showed a hypodense lesion in the liver and heterogeneous echostructure of the thyroid gland with left lobe solid-cystic tumour. Somatostatin receptor scintigraphy revealed increased tracer accumulation in the right thyroid lobe. No tracer accumulation was noted at the location of the other tumours. The resected stomach, adrenal, chest, and thyroid lesions did not show GH secretion. The patient refused pituitary surgery, and her acromegaly is currently well-controlled with somatostatin analogue therapy. A CT scan 19 months later revealed a contrast-enhancing left kidney tumour that was a G1-grade clear cell carcinoma. Four years after the acromegaly diagnosis multiple myeloma were diagnosed with secondary renal amyloidosis. Genetic screening for a paraganglioma gene panel, AIP, MEN1, and CDKN1B mutations were negative. A next-generation cancer panel containing 94 cancer genes did not identify any possible unifying gene abnormality in her germline DNA. Coexistence of acromegaly and numerous other tumours suggests a common aetiology of these disorders. However, no genetic abnormality could be identified with the tests that have been performed.

25 Article Cytosolic 5'-nucleotidase 1A is overexpressed in pancreatic cancer and mediates gemcitabine resistance by reducing intracellular gemcitabine metabolites. 2019

Patzak, Melanie S / Kari, Vijayalakshmi / Patil, Shilpa / Hamdan, Feda H / Goetze, Robert G / Brunner, Marius / Gaedcke, Jochen / Kitz, Julia / Jodrell, Duncan I / Richards, Frances M / Pilarsky, Christian / Gruetzmann, Robert / Rümmele, Petra / Knösel, Thomas / Hessmann, Elisabeth / Ellenrieder, Volker / Johnsen, Steven A / Neesse, Albrecht. ·University Medical Center Goettingen, Department of Gastroenterology and Gastrointestinal Oncology, Goettingen, Germany. · University Medical Center Goettingen, Department of General, Visceral and Pediatric Surgery, Goettingen, Germany. · University Medical Center Goettingen, Institute of Pathology, Goettingen, Germany. · Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom. · University Medical Center Erlangen, Department of Surgery, Erlangen, Germany. · University Medical Center Erlangen, Institute of Pathology, Erlangen, Germany. · Ludwig Maximilian University Munich, Institute of Pathology, Munich, Germany. · University Medical Center Goettingen, Department of Gastroenterology and Gastrointestinal Oncology, Goettingen, Germany. Electronic address: albrecht.neesse@med.uni-goettingen.de. ·EBioMedicine · Pubmed #30709769.

ABSTRACT: BACKGROUND: Cytosolic 5'-nucleotidase 1A (NT5C1A) dephosphorylates non-cyclic nucleoside monophosphates to produce nucleosides and inorganic phosphates. Here, we investigate NT5C1A expression in pancreatic ductal adenocarcinoma (PDAC) and its impact on gemcitabine metabolism and therapeutic efficacy. METHODS: NT5C1A expression was determined by semiquantitative immunohistochemistry using tissue microarrays. Gemcitabine metabolites and response were assessed in several human and murine PDAC cell lines using crystal violet assays, Western blot, viability assays, and liquid chromatography tandem mass-spectrometry (LC-MS/MS). FINDINGS: NT5C1A was strongly expressed in tumor cells of a large subgroup of resected PDAC patients in two independent patient cohorts (44-56% score 2 and 8-26% score 3, n = 414). In contrast, NT5C1A was expressed at very low levels in the tumor stroma, and neither stromal nor tumoral expression was a prognostic marker for postoperative survival. In vitro, NT5C1A overexpression increased gemcitabine resistance by reducing apoptosis levels and significantly decreased intracellular amounts of cytotoxic dFdCTP in +NT5C1A tumor cells. Co-culture experiments with conditioned media from +NT5C1A PSCs improved gemcitabine efficacy in tumor cells. In vivo, therapeutic efficacy of gemcitabine was significantly decreased and serum levels of the inactive gemcitabine metabolite dFdU significantly increased in mice bearing NT5C1A overexpressing tumors. INTERPRETATION: NT5C1A is robustly expressed in tumor cells of resected PDAC patients. Moreover, NT5C1A mediates gemcitabine resistance by decreasing the amount of intracellular dFdCTP, leading to reduced tumor cell apoptosis and larger pancreatic tumors in mice. Further studies should clarify the role of NT5C1A as novel predictor for gemcitabine treatment response in patients with PDAC.

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