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Pancreatic Neoplasms: HELP
Articles by Tim Meyer
Based on 12 articles published since 2010
(Why 12 articles?)
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Between 2010 and 2020, Tim Meyer wrote the following 12 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Review Streptozocin-based chemotherapy is not history in neuroendocrine tumours. 2012

Weatherstone, Katie / Meyer, Tim. ·Department of Oncology, Royal Free Hospital, London, UK. ·Target Oncol · Pubmed #22899468.

ABSTRACT: Streptozocin (STZ)-based chemotherapy has been used for over 30 years in the treatment of neuroendocrine tumours (NET); however, there have been few randomised trials in homogeneous and well-characterised patient populations. With the recent approval of sunitinib and everolimus for pancreatic NET (PNET) and the emergence of a more stratified approach to cancer therapy, it is timely to reevaluate the role of chemotherapy. Here we review the evidence base for STZ-based chemotherapy, the toxicity associated with treatment and the role of predictive markers such as Ki67 to select patients who may benefit most from therapy. Although there are no trials comparing chemotherapy with best supportive care, there is evidence that multi-agent STZ-containing regimens are associated with improved survival compared with control therapy. Compared with other therapies, chemotherapy appears to be associated with the highest response rate, particularly in PNET and remains the first-line treatment of choice for those patients in whom response is required. This includes those who are symptomatic from tumour burden and those with locally advanced disease who may be down-staged for resection. The role of Ki67 and other predictive markers requires further assessment in prospective studies as does the relative efficacy of alternative agents such as temozolomide.

2 Review Role of everolimus in pancreatic neuroendocrine tumors. 2011

Goldstein, Robert / Meyer, Tim. ·UCL Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London, WC1E 6BT, UK. ·Expert Rev Anticancer Ther · Pubmed #21932937.

ABSTRACT: Survival from pancreatic neuroendocrine tumors has not improved over the past two decades and, until recently, streptozocin was the last therapeutic agent approved for this malignancy. Everolimus blocks mTOR, which plays an integral role in cell growth, mitosis and angiogenesis. Abnormal PI3K-Akt/PKB-mTOR pathway signaling has been implicated in the pathogenesis of pancreatic neuroendocrine tumors. In a Phase III study, patients with low- and intermediate-grade advanced pancreatic neuroendocrine tumors were randomized to receive everolimus 10 mg/day or placebo. Median progression-free survival was significantly greater in patients treated with everolimus than placebo - 11 versus 4.6 months - and drug-related adverse events were consistent with the known side-effect profile of everolimus. Everolimus represents a significant treatment development for pancreatic neuroendocrine tumors.

3 Review Malignant somatostatinoma presenting with diabetic ketoacidosis and inhibitory syndrome: pathophysiologic considerations. 2010

Theodoraki, Aikaterini / Khoo, Bernard / Hamda, Arif / Grillo, Frederica / Meyer, Tim / Bouloux, Pierre-Marc Gilles. ·Department of Endocrinology, Royal Free Hampstead NHS Trust, London, United Kingdom. aikaterini.theodoraki@royalfree.nhs.uk ·Endocr Pract · Pubmed #20497932.

ABSTRACT: OBJECTIVE: To describe a patient with diabetic ketoacidosis secondary to a malignant somatostatinoma. METHODS: We present the clinical, laboratory, radiologic, and pathologic findings of a patient with diabetic ketoacidosis secondary to a malignant somatostatinoma. We also review the potential effects of somatostatin on glucose homeostasis and discuss the underlying pathophysiologic mechanisms. RESULTS: A 30-year-old woman presented with diabetic ketoacidosis and had a malignant somatostatinoma with hepatic, bone, and lymph node metastasis. She exhibited features of somatostatinoma "inhibitory syndrome" characterized by mild nonketotic hyperglycemia, hypochlorhydria, cholelithiasis, steatorrhea, anemia, and weight loss. In these tumors, the absence of ketoacidosis is thought to arise from the somatostatin-induced simultaneous suppression of the secretion of insulin and glucagon. The patient's primary tumor could not be located. CONCLUSIONS: Diabetic ketoacidosis may occur in somatostatinomas. The secretion of larger molecular weight forms of somatostatin from the tumor may contribute to the ketogenesis.

4 Clinical Trial Phase II Study of BEZ235 versus Everolimus in Patients with Mammalian Target of Rapamycin Inhibitor-Naïve Advanced Pancreatic Neuroendocrine Tumors. 2018

Salazar, Ramon / Garcia-Carbonero, Rocio / Libutti, Steven K / Hendifar, Andrew E / Custodio, Ana / Guimbaud, Rosine / Lombard-Bohas, Catherine / Ricci, Sergio / Klümpen, Heinz-Josef / Capdevila, Jaume / Reed, Nicholas / Walenkamp, Annemiek / Grande, Enrique / Safina, Sufiya / Meyer, Tim / Kong, Oliver / Salomon, Herve / Tavorath, Ranjana / Yao, James C. ·Department of Medical Oncology, Institut Català d'Oncologia-IDIBELL-CIBERONC, Universitat de Barcelona, Barcelona, Spain ramonsalazarsole@iconcologia.net. · Department of Medical Oncology, Hospital Universitario 12 de Octubre, Madrid, Spain. · Albert Einstein College of Medicine, New York City, New York, USA. · David Geffen School of Medicine and Cedars Sinai Medical Center, Los Angeles, California, USA. · Department of Medical Oncology, Hospital Universitario La Paz, Madrid, Spain. · Department of Digestive Medical Oncology (IUCT-RL), Centre Hospitalier Universitaire de Toulouse, Toulouse, France. · Centre Hospitalier Lyon Sud, Pierre-Bénite, France. · Division of Medical Oncology, S Chiara University Hospital, Pisa, Italy. · Department of Medical Oncology, Academic Medical Center, Amsterdam, The Netherlands. · Vall Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. · Beatson West of Scotland Cancer Centre, Glasgow, Scotland. · University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. · Department of Medical Oncology, Hospital Universitario Ramón y Cajal, Madrid, Spain. · Department of Biochemistry, Kazan State Medical University, Kazan, Russia. · Royal Free Hospital, London, United Kingdom. · Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA. · Novartis Pharma S.A.S., Rueil-Malmaison, France. · The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. ·Oncologist · Pubmed #29242283.

ABSTRACT: LESSONS LEARNED: Treatment with BEZ235 has not been shown to demonstrate increased efficacy compared with everolimus and may be associated with a poorer tolerability profile.The hypothesis of dual targeting of the phosphatidylinositol 3-kinase and mammalian target of rapamycin pathways in patients with advanced pancreatic neuroendocrine tumors may warrant further study using other agents. BACKGROUND: This phase II study investigated whether targeting the phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway via PI3K, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) inhibition using BEZ235 may be more effective than mTORC1 inhibition with everolimus in patients with advanced pancreatic neuroendocrine tumors (pNET) who are naïve to mTOR inhibitor therapy. METHODS: Patients with advanced pNET were randomized (1:1) to oral BEZ235 400 mg twice daily or oral everolimus 10 mg once daily on a continuous dosing schedule. The primary endpoint was progression-free survival (PFS). Secondary endpoints included safety, overall response rate (ORR), overall survival (OS), and time to treatment failure. RESULTS: Enrollment in this study was terminated early (62 enrolled of the 140 planned). The median PFS was 8.2 months (95% confidence interval [CI]: 5.3 to not evaluable [NE]) with BEZ235 versus 10.8 months (95% CI: 8.1-NE) with everolimus (hazard ratio 1.53; 95% CI: 0.72-3.25). The most commonly reported all-grade adverse events (>50% of patients regardless of study treatment relationship) with BEZ235 were diarrhea (90.3%), stomatitis (74.2%), and nausea (54.8%). CONCLUSION: BEZ235 treatment in mTOR inhibitor-naïve patients with advanced pNET did not demonstrate increased efficacy compared with everolimus and may be associated with a poorer tolerability profile.

5 Clinical Trial Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. 2017

Neoptolemos, John P / Palmer, Daniel H / Ghaneh, Paula / Psarelli, Eftychia E / Valle, Juan W / Halloran, Christopher M / Faluyi, Olusola / O'Reilly, Derek A / Cunningham, David / Wadsley, Jonathan / Darby, Suzanne / Meyer, Tim / Gillmore, Roopinder / Anthoney, Alan / Lind, Pehr / Glimelius, Bengt / Falk, Stephen / Izbicki, Jakob R / Middleton, Gary William / Cummins, Sebastian / Ross, Paul J / Wasan, Harpreet / McDonald, Alec / Crosby, Tom / Ma, Yuk Ting / Patel, Kinnari / Sherriff, David / Soomal, Rubin / Borg, David / Sothi, Sharmila / Hammel, Pascal / Hackert, Thilo / Jackson, Richard / Büchler, Markus W / Anonymous3241111. ·University of Liverpool, Liverpool, UK; The Royal Liverpool University Hospital, Liverpool, UK. Electronic address: j.p.neoptolemos@liverpool.ac.uk. · University of Liverpool, Liverpool, UK; The Clatterbridge Cancer Centre, Wirral, UK. · The Royal Liverpool University Hospital, Liverpool, UK. · University of Liverpool, Liverpool, UK. · University of Manchester/The Christie NHS Foundation Trust, Manchester, UK. · University of Liverpool, Liverpool, UK; The Royal Liverpool University Hospital, Liverpool, UK. · The Clatterbridge Cancer Centre, Wirral, UK. · Manchester Royal Infirmary, Manchester, UK. · Royal Marsden Hospital, London, UK. · Weston Park Hospital, Sheffield, UK. · Royal Free Hospital, London, UK. · St James's University Hospital, Leeds, UK. · Karolinska Institute, Stockholm, Sweden; Clinical Research Sörmland, Eskilstuna, Sweden. · University of Uppsala, Uppsala, Sweden. · Bristol Haematology and Oncology Centre, Bristol, UK. · University of Hamburg Medical institutions UKE, Hamburg, Germany. · Royal Surrey County Hospital, Guildford, UK. · Guy's Hospital, London, UK. · Hammersmith Hospital, London, UK. · The Beatson West of Scotland Cancer Centre, Glasgow, UK. · Velindre Hospital, Cardiff, UK. · Queen Elizabeth Hospital, Birmingham, UK. · Churchill Hospital, Oxford, UK. · Derriford Hospital, Plymouth, UK. · Ipswich Hospital, Ipswich, UK. · Skåne University Hospital, Lund, Sweden. · University Hospital Coventry, Coventry, UK. · Hôpital Beaujon, Clichy, France. · University of Heidelberg, Germany. ·Lancet · Pubmed #28129987.

ABSTRACT: BACKGROUND: The ESPAC-3 trial showed that adjuvant gemcitabine is the standard of care based on similar survival to and less toxicity than adjuvant 5-fluorouracil/folinic acid in patients with resected pancreatic cancer. Other clinical trials have shown better survival and tumour response with gemcitabine and capecitabine than with gemcitabine alone in advanced or metastatic pancreatic cancer. We aimed to determine the efficacy and safety of gemcitabine and capecitabine compared with gemcitabine monotherapy for resected pancreatic cancer. METHODS: We did a phase 3, two-group, open-label, multicentre, randomised clinical trial at 92 hospitals in England, Scotland, Wales, Germany, France, and Sweden. Eligible patients were aged 18 years or older and had undergone complete macroscopic resection for ductal adenocarcinoma of the pancreas (R0 or R1 resection). We randomly assigned patients (1:1) within 12 weeks of surgery to receive six cycles of either 1000 mg/m FINDINGS: Of 732 patients enrolled, 730 were included in the final analysis. Of these, 366 were randomly assigned to receive gemcitabine and 364 to gemcitabine plus capecitabine. The Independent Data and Safety Monitoring Committee requested reporting of the results after there were 458 (95%) of a target of 480 deaths. The median overall survival for patients in the gemcitabine plus capecitabine group was 28·0 months (95% CI 23·5-31·5) compared with 25·5 months (22·7-27·9) in the gemcitabine group (hazard ratio 0·82 [95% CI 0·68-0·98], p=0·032). 608 grade 3-4 adverse events were reported by 226 of 359 patients in the gemcitabine plus capecitabine group compared with 481 grade 3-4 adverse events in 196 of 366 patients in the gemcitabine group. INTERPRETATION: The adjuvant combination of gemcitabine and capecitabine should be the new standard of care following resection for pancreatic ductal adenocarcinoma. FUNDING: Cancer Research UK.

6 Article Retrospective study on mixed neuroendocrine non-neuroendocrine neoplasms from five European centres. 2019

Frizziero, Melissa / Wang, Xin / Chakrabarty, Bipasha / Childs, Alexa / Luong, Tu V / Walter, Thomas / Khan, Mohid S / Morgan, Meleri / Christian, Adam / Elshafie, Mona / Shah, Tahir / Minicozzi, Annamaria / Mansoor, Wasat / Meyer, Tim / Lamarca, Angela / Hubner, Richard A / Valle, Juan W / McNamara, Mairéad G. ·Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, United Kingdom. · Department of Analytics and Development, The Christie NHS Foundation Trust, Manchester M20 4BX, United Kingdom. · Department of Pathology, The Christie NHS Foundation Trust, Manchester M20 4BX, United Kingdom. · Department of Medical Oncology, Royal Free London NHS Foundation Trust, London NW3 2QG, United Kingdom. · Department of Histopathology, Royal Free London NHS Foundation Trust, London NW3 2QG, United Kingdom. · Department of Gastroenterology and Medical Oncology, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon 69003, France. · Department of Gastroenterology, Cardiff and Vale University Health Board, University Hospital of Wales, Cardiff CF14 4XW, United Kingdom. · Department of Cellular Pathology, Cardiff and Vale University Health Board, University Hospital of Wales, Cardiff CF14 4XW, United Kingdom. · Department of Pathology, University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2TH, United Kingdom. · Department of Hepatology, University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2TH, United Kingdom. · Department of Surgical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, United Kingdom. · Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, United Kingdom. mairead.mcnamara@christie.nhs.uk. ·World J Gastroenterol · Pubmed #31660035.

ABSTRACT: BACKGROUND: Mixed neuroendocrine non-neuroendocrine neoplasm (MiNEN) is a rare diagnosis, mainly encountered in the gastro-entero-pancreatic tract. There is limited knowledge of its epidemiology, prognosis and biology, and the best management for affected patients is still to be defined. AIM: To investigate clinical-pathological characteristics, treatment modalities and survival outcomes of a retrospective cohort of patients with a diagnosis of MiNEN. METHODS: Consecutive patients with a histologically proven diagnosis of MiNEN were identified at 5 European centres. Patient data were retrospectively collected from medical records. Pathological samples were reviewed to ascertain compliance with the 2017 World Health Organisation definition of MiNEN. Tumour responses to systemic treatment were assessed according to the Response Evaluation Criteria in Solid Tumours 1.1. Kaplan-Meier analysis was applied to estimate survival outcomes. Associations between clinical-pathological characteristics and survival outcomes were explored using Log-rank test for equality of survivors functions (univariate) and Cox-regression analysis (multivariable). RESULTS: Sixty-nine consecutive patients identified; Median age at diagnosis: 64 years. Males: 63.8%. Localised disease (curable): 53.6%. Commonest sites of origin: colon-rectum (43.5%) and oesophagus/oesophagogastric junction (15.9%). The neuroendocrine component was; predominant in 58.6%, poorly differentiated in 86.3%, and large cell in 81.25%, of cases analysed. Most distant metastases analysed (73.4%) were occupied only by a poorly differentiated neuroendocrine component. Ninety-four percent of patients with localised disease underwent curative surgery; 53% also received perioperative treatment, most often in line with protocols for adenocarcinomas from the same sites of origin. Chemotherapy was offered to most patients (68.1%) with advanced disease, and followed protocols for pure neuroendocrine carcinomas or adenocarcinomas in equal proportion. In localised cases, median recurrence free survival (RFS); 14.0 mo (95%CI: 9.2-24.4), and median overall survival (OS): 28.6 mo (95%CI: 18.3-41.1). On univariate analysis, receipt of perioperative treatment ( CONCLUSION: MiNEN is most commonly driven by a poorly differentiated neuroendocrine component, and has poor prognosis. Advances in its biological understanding are needed to identify effective treatments and improve patient outcomes.

7 Article Observational Study to Assess Quality of Life in Patients with Pancreatic Neuroendocrine Tumors Receiving Treatment with Everolimus: The OBLIQUE Study (UK Phase IV Trial). 2019

Ramage, John K / Punia, Pankaj / Faluyi, Olusola / Frilling, Andrea / Meyer, Tim / Saharan, Ruby / Valle, Juan W. ·Kings College Hospital, London and Hampshire Hospitals, London, United Kingdom, john.ramage@hhft.nhs.uk. · Queen Elizabeth Hospital, Birmingham, United Kingdom. · Clatterbridge Cancer Centre, The Wirral, United Kingdom. · Imperial College London, London, United Kingdom. · Royal Free Hospital, London, United Kingdom. · Novartis Pharmaceuticals Ltd., Camberley, United Kingdom. · University of Manchester, Division of Cancer Sciences/The Christie NHS Foundation Trust, Manchester, United Kingdom. ·Neuroendocrinology · Pubmed #30699423.

ABSTRACT: BACKGROUND/AIMS: To assess health-related quality of life (HRQoL), treatment patterns, and clinical outcomes of adult (≥18 years) patients with advanced (unresectable or metastatic) pancreatic neuroendocrine neoplasms (PanNENs) treated with everolimus in routine clinical practice. METHODS: In a prospective, non-interventional, multi-center study patients administered at least one 10 mg dose of everolimus were evaluated for change in HRQoL (EORTC QLQ-C30 Global Health Status scale) from baseline after 6 months treatment (primary endpoint). Secondary endpoints included disease-specific HRQoL measures (EORTC QLQ-G.I.NET21), clinical outcomes, everolimus treatment patterns, and safety. RESULTS: Forty-eight patients were recruited (between August 2013 and March 2015); the median treatment duration was 27.8 months. EORTC QLQ-C30 Global Health score was not significantly different from baseline after 6 months of treatment (mean difference -1.9 points, p = 0.660, n = 30). In pairwise analyses, the only significant changes in HRQoL from baseline were for EORTC QLQ-C30 physical functioning score at month 3 (adjusted mean difference -8.8 points, p = 0.002, n = 36) and the EORTC QLQ-G.I.NET21 disease-related worries scores at months 1 and 2 (adjusted mean differences: -11.5 points [p = 0.001, n = 44] and -8.8 points [p = 0.017, n = 43], respectively). Disease progression or death was recorded in 44.4% (n = 20/45) patients during follow-up; median progression-free survival was 25.1 months and the cumulative survival rate at 3 years was 71%. No new safety signals were detected. CONCLUSIONS: The OBLIQUE study demonstrates that HRQoL is maintained in patients with PanNENs during treatment with everolimus in a UK real-world setting. This study adds to the limited HRQoL data available in this patient group.

8 Article The VAR2CSA malaria protein efficiently retrieves circulating tumor cells in an EpCAM-independent manner. 2018

Agerbæk, Mette Ø / Bang-Christensen, Sara R / Yang, Ming-Hsin / Clausen, Thomas M / Pereira, Marina A / Sharma, Shreya / Ditlev, Sisse B / Nielsen, Morten A / Choudhary, Swati / Gustavsson, Tobias / Sorensen, Poul H / Meyer, Tim / Propper, David / Shamash, Jonathan / Theander, Thor G / Aicher, Alexandra / Daugaard, Mads / Heeschen, Christopher / Salanti, Ali. ·Centre for Medical Parasitology at Department of Immunology and Microbiology, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital, 2200, Copenhagen, Denmark. · Vancouver Prostate Centre, Vancouver, BC, V6H 3Z6, Canada. · Department of Urologic Sciences, University of British Columbia, Vancouver, BC, V5Z 1M9, Canada. · Stem Cells in Cancer & Ageing, Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ, United Kingdom. · Division of Urology, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, 11490, Taipei, Taiwan. · Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, BC, V5Z 1L3, Canada. · UCL Cancer Institute, University College London, London, WC1E 6BT, United Kingdom. · Department of Medical Oncology, Barts Health NHS, London, EC1A 7BE, United Kingdom. · Stem Cells in Cancer & Ageing, Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ, United Kingdom. c.heeschen@unsw.edu.au. · School of Medical Sciences, University of New South Wales, Sydney, NSW, 2052, Australia. c.heeschen@unsw.edu.au. · Centre for Medical Parasitology at Department of Immunology and Microbiology, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital, 2200, Copenhagen, Denmark. salanti@sund.ku.dk. ·Nat Commun · Pubmed #30115931.

ABSTRACT: Isolation of metastatic circulating tumor cells (CTCs) from cancer patients is of high value for disease monitoring and molecular characterization. Despite the development of many new CTC isolation platforms in the last decade, their isolation and detection has remained a challenge due to the lack of specific and sensitive markers. In this feasibility study, we present a method for CTC isolation based on the specific binding of the malaria rVAR2 protein to oncofetal chondroitin sulfate (ofCS). We show that rVAR2 efficiently captures CTCs from hepatic, lung, pancreatic, and prostate carcinoma patients with minimal contamination of peripheral blood mononuclear cells. Expression of ofCS is present on epithelial and mesenchymal cancer cells and is equally preserved during epithelial-mesenchymal transition of cancer cells. In 25 stage I-IV prostate cancer patient samples, CTC enumeration significantly correlates with disease stage. Lastly, rVAR2 targets a larger and more diverse population of CTCs compared to anti-EpCAM strategies.

9 Article Capecitabine and streptozocin ± cisplatin in advanced gastroenteropancreatic neuroendocrine tumours. 2014

Meyer, Tim / Qian, Wendi / Caplin, Martyn E / Armstrong, Graham / Lao-Sirieix, Si-Houy / Hardy, Richard / Valle, Juan W / Talbot, Denis C / Cunningham, David / Reed, Nick / Shaw, Ashley / Navalkissoor, Shaunak / Luong, Tu-Vinh / Corrie, Pippa G. ·Neuroendocrine Tumour Unit, The Royal Free Hospital, Pond Street, London, UK; UCL Cancer Institute, London, UK. · Cambridge Cancer Trials Centre, Cambridge Clinical Trials Unit - Cancer Theme, Addenbrooke's Hospital, Cambridge, UK; Medical Research Council Biostatistics Unit Hub for Trials Methodology, Cambridge, UK. · Neuroendocrine Tumour Unit, The Royal Free Hospital, Pond Street, London, UK. · Cambridge Cancer Trials Centre, Cambridge Clinical Trials Unit - Cancer Theme, Addenbrooke's Hospital, Cambridge, UK. · Department of Medical Oncology, The Christie, Manchester, UK. · Oxford Neuroendocrine Tumour Centre, Churchill Hospital, Oxford, UK. · Gastrointestinal Unit, The Royal Marsden, London, UK. · Beatson Oncology Centre, Glasgow, UK. · Oncology Centre, Addenbrooke's Hospital, Cambridge, UK. · Cambridge Cancer Trials Centre, Cambridge Clinical Trials Unit - Cancer Theme, Addenbrooke's Hospital, Cambridge, UK; Oncology Centre, Addenbrooke's Hospital, Cambridge, UK. Electronic address: pippa.corrie@addenbrookes.nhs.uk. ·Eur J Cancer · Pubmed #24445147.

ABSTRACT: BACKGROUND: Cytotoxic chemotherapy is widely used for advanced, unresectable pancreatic and other gastrointestinal foregut neuroendocrine tumours (NETs) and the most commonly used regimen combines 5-fluorouracil with streptozocin. The NET01 trial was designed to investigate whether capecitabine combined with streptozocin was an acceptable regimen with or without adding cisplatin. METHODS: Patients with advanced, unresectable NETs of pancreatic, gastrointestinal foregut or unknown primary site were randomised to receive three-weekly capecitabine (Cap) 625 mg/m(2) twice daily orally, streptozocin (Strep) 1.0 g/m(2) intravenously on day 1, with or without cisplatin (Cis) 70 mg/m(2) intravenously on day 1. The primary outcome measure was objective response. Secondary outcome measures included progression-free and overall survival, quality of life, toxicity and biochemical response. RESULTS: 86 (44 CapStrep, 42 CapStrepCis) patients were randomised. Best objective response rate was 12% (95% confidence interval (CI)=2-22%) with CapStrep and 16% (95% CI=4-27.4%) with CapStrepCis. Disease-control rate was 80% with CapStrep and 74% with CapStrepCis. The estimated median progression-free and overall survival were 10.2 and 26.7 months for CapStrep and 9.7 and 27.5 months for CapStrepCis. 44% of CapStrep and 68% of CapStrepCis patients experienced grade ≥3 adverse events. INTERPRETATION: The efficacies of the novel CapStrep±Cis regimens were very similar. CapStrep was better tolerated than CapStrepCis. The trial was registered as EudraCT: 2004-005202-71 and ISRCTN: 35124268.

10 Article CCK-2/gastrin receptor signaling pathway is significant for gemcitabine-induced gene expression of VEGF in pancreatic carcinoma cells. 2011

Kato, Hiroki / Seto, Koichi / Kobayashi, Nobuyoshi / Yoshinaga, Koji / Meyer, Tim / Takei, Mineo. ·Department of Clinical Research, Zeria Pharmaceutical Co., Ltd., Tokyo, Japan. ·Life Sci · Pubmed #21839751.

ABSTRACT: AIMS: As activation and overexpression of the cholecystokinin-2 (CCK-2)/gastrin receptor can lead to carcinogenesis, it has been explored as a therapeutic target in pancreatic cancer. We demonstrated that Z-360, a CCK-2/gastrin receptor antagonist, combined with gemcitabine prolonged survival and reduced gemcitabine-induced vascular endothelial growth factor (VEGF) expression in a pancreatic carcinoma orthotopic xenograft mouse. In this study, we investigated the role of the CCK-2/gastrin signaling pathway on gemcitabine-induced VEGF expression in PANC-1 human pancreatic carcinoma cells. MAIN METHODS: In PANC-1 cells treated with Z-360, anti-gastrin IgG or kinase inhibitors, the gene expression levels were analyzed by quantitative real-time RT-PCR, and the protein levels of Akt and phosphorylated Akt (p-Akt) in cellular extracts were measured by ELISA. KEY FINDINGS: Gemcitabine-induced expression of VEGF and hypoxia-inducible factor-1 alpha (HIF-1 alpha) were suppressed by the treatment with an anti-gastrin antibody. In addition, VEGF and HIF-1 alpha gene expression was inhibited by treatment with an inhibitor of phosphatidylinositol 3-kinase (PI3K), which is involved in the downstream signaling pathway of the CCK-2/gastrin receptor, and was also suppressed by treatment with Z-360. Moreover, although Akt phosphorylation was increased by treatment with gemcitabine, this elevation was partially, but significantly, inhibited by an exposure of Z-360. SIGNIFICANCE: Gemcitabine might induce gene expression of VEGF via the PI3K/Akt signaling pathway in the downstream of the CCK-2/gastrin receptor. The suppression of the CCK-2/gastrin signaling pathway by treatment with Z-360 could be a useful approach for potentiating prolonged survival of pancreatic cancer patients receiving gemcitabine therapy.

11 Article Z-360, a novel therapeutic agent for pancreatic cancer, prevents up-regulation of ephrin B1 gene expression and phosphorylation of NR2B via suppression of interleukin-1 β production in a cancer-induced pain model in mice. 2010

Orikawa, Yuki / Kato, Hiroki / Seto, Koichi / Kobayashi, Nobuyoshi / Yoshinaga, Koji / Hamano, Hiroki / Hori, Yuko / Meyer, Tim / Takei, Mineo. ·Central Research Laboratories, Zeria Pharmaceutical Co,, Ltd,, 2512-1 Numagami, Oshikiri, Kumagaya-shi, Saitama, Japan. yuki-orikawa@zeria.co.jp ·Mol Pain · Pubmed #20979661.

ABSTRACT: BACKGROUND: Z-360 is an orally active cholecystokinin-2 (CCK2)/gastrin receptor antagonist currently under development as a therapeutic drug for pancreatic cancer. It was previously reported that Z-360 treatment in combination with gemcitabine prolonged the survival period in a lethal pancreatic cancer xenograft model in mice. In a phase Ib/IIa clinical study, Z-360 treatment displayed a trend of reduced pain in patients with advanced pancreatic cancer in combination with gemcitabine including analgesics such as opioids. Here, we investigated the mechanism of analgesic action of Z-360 in a severe cancer-induced pain model in mice, which is considered to be opioid-resistant, by examining ephrin B1 gene expression, N-methyl-D-aspartate receptor NR2B subunit phosphorylation, and interleukin-1β (IL-1β) production. RESULTS: In a mouse model of cancer-induced pain, ephrin B1 gene expression in dorsal root ganglia (DRGs) and the phosphorylation of NR2B in the spinal cord were induced. Z-360 treatment inhibited both ephrin B1 gene expression and the phosphorylation of NR2B. In addition, IL-1β production increased in the cancer-inoculated hind paw of mice, but could be suppressed by treatment with Z-360. Moreover, we observed that the CCK1 receptor antagonist devazepide similarly suppressed up-regulation of ephrin B1 gene expression and IL-1β production, and that the intraperitoneal injection of sulfated CCK-8 induced the production of IL-1β in the cancer-inoculated region. CONCLUSIONS: We have identified a novel pain cascade, in which IL-1β production in cancer-inoculated regions induces ephrin B1 gene expression in DRGs and then ephrin B1 enhances the tyrosine phosphorylation of NR2B via Eph B receptor in the spinal cord. Notably, Z-360 relieves cancer-induced pain by preventing this pain cascade through the suppression of IL-1β production, likely via the blockade of CCK1 receptor. The pre-clinical results presented here support the analgesic action of Z-360 in pancreatic cancer patients with severe, opioid-resistant pain. Pre-clinical and clinical results have demonstrated that Z-360 combined with gemcitabine represents a promising pancreatic cancer therapy approach with characteristic analgesic effects in addition to the prolongation of survival.

12 Minor Epigenetic dysregulation and poorer prognosis in DAXX-deficient pancreatic neuroendocrine tumours. 2015

Pipinikas, Christodoulos P / Dibra, Harpreet / Karpathakis, Anna / Feber, Andrew / Novelli, Marco / Oukrif, Dahmane / Fusai, Guiseppe / Valente, Roberto / Caplin, Martyn / Meyer, Tim / Teschendorff, Andrew / Bell, Christopher / Morris, Tiffany J / Salomoni, Paolo / Luong, Tu-Vinh / Davidson, Brian / Beck, Stephan / Thirlwell, Christina. ·Medical Genomics Laboratory, University College London Cancer Institute, University College London72 Huntley Street, London, WC1E 6BT, UK. · Medical Genomics Laboratory, University College London Cancer Institute, University College London72 Huntley Street, London, WC1E 6BT, UK Medical Genomics Laboratory, University College London Cancer Institute, University College London72 Huntley Street, London, WC1E 6BT, UK. · Medical Genomics Laboratory, University College London Cancer Institute, University College London72 Huntley Street, London, WC1E 6BT, UK Medical Genomics Laboratory, University College London Cancer Institute, University College London72 Huntley Street, London, WC1E 6BT, UK christina.thirlwell@ucl.ac.uk. ·Endocr Relat Cancer · Pubmed #25900181.

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