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Pancreatic Neoplasms: HELP
Articles by Martyn Evan Caplin
Based on 29 articles published since 2009
(Why 29 articles?)
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Between 2009 and 2019, M. Caplin wrote the following 29 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Guideline ENETS Consensus Guidelines Update for the Management of Patients with Functional Pancreatic Neuroendocrine Tumors and Non-Functional Pancreatic Neuroendocrine Tumors. 2016

Falconi, M / Eriksson, B / Kaltsas, G / Bartsch, D K / Capdevila, J / Caplin, M / Kos-Kudla, B / Kwekkeboom, D / Rindi, G / Klöppel, G / Reed, N / Kianmanesh, R / Jensen, R T / Anonymous1590854. · ·Neuroendocrinology · Pubmed #26742109.

ABSTRACT: -- No abstract --

2 Guideline ENETS Consensus Guidelines for High-Grade Gastroenteropancreatic Neuroendocrine Tumors and Neuroendocrine Carcinomas. 2016

Garcia-Carbonero, R / Sorbye, H / Baudin, E / Raymond, E / Wiedenmann, B / Niederle, B / Sedlackova, E / Toumpanakis, C / Anlauf, M / Cwikla, J B / Caplin, M / O'Toole, D / Perren, A / Anonymous6950853. ·Medical Oncology Department, Hospital Universitario Doce de Octubre, Madrid, Spain. ·Neuroendocrinology · Pubmed #26731334.

ABSTRACT: -- No abstract --

3 Guideline Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours (NETs). 2012

Ramage, John K / Ahmed, A / Ardill, J / Bax, N / Breen, D J / Caplin, M E / Corrie, P / Davar, J / Davies, A H / Lewington, V / Meyer, T / Newell-Price, J / Poston, G / Reed, N / Rockall, A / Steward, W / Thakker, R V / Toubanakis, C / Valle, J / Verbeke, C / Grossman, A B / Anonymous3000709. ·Basingstoke and North Hampshire Hospital, Aldermaston Road, Basingstoke RG24 9NA, UK. john.ramage@bnhft.nhs.uk ·Gut · Pubmed #22052063.

ABSTRACT: These guidelines update previous guidance published in 2005. They have been revised by a group who are members of the UK and Ireland Neuroendocrine Tumour Society with endorsement from the clinical committees of the British Society of Gastroenterology, the Society for Endocrinology, the Association of Surgeons of Great Britain and Ireland (and its Surgical Specialty Associations), the British Society of Gastrointestinal and Abdominal Radiology and others. The authorship represents leaders of the various groups in the UK and Ireland Neuroendocrine Tumour Society, but a large amount of work has been carried out by other specialists, many of whom attended a guidelines conference in May 2009. We have attempted to represent this work in the acknowledgements section. Over the past few years, there have been advances in the management of neuroendocrine tumours, which have included clearer characterisation, more specific and therapeutically relevant diagnosis, and improved treatments. However, there remain few randomised trials in the field and the disease is uncommon, hence all evidence must be considered weak in comparison with other more common cancers.

4 Review Treatment challenges in and outside a specialist network setting: Pancreatic neuroendocrine tumours. 2019

Lykoudis, Panagis M / Partelli, Stefano / Muffatti, Francesca / Caplin, Martyn / Falconi, Massimo / Fusai, Giuseppe K / Anonymous971001. ·Department of Hepato-Pancreato-Biliary Surgery & Liver Transplantation, Royal Free Hospital, London, UK. Electronic address: p.lykoudis@ucl.ac.uk. · Pancreatic Surgery Unit, Pancreas Translational & Research Institute, Scientific Institute San Raffaele Hospital & University "Vita e Salute", Milan, Italy. · Department of Gastroenterology and G.I. & Tumour Neuroendocrinology, Royal Free Hospital, London, UK. · Department of Hepato-Pancreato-Biliary Surgery & Liver Transplantation, Royal Free Hospital, London, UK. ·Eur J Surg Oncol · Pubmed #29126671.

ABSTRACT: Pancreatic Neuroendocrine Neoplasms comprise a group of rare tumours with special biology, an often indolent behaviour and particular diagnostic and therapeutic requirements. The specialized biochemical tests and radiological investigations, the complexity of surgical options and the variety of medical treatments that require individual tailoring, mandate a multidisciplinary approach that can be optimally achieved through an organized network. The present study describes currents concepts in the management of these tumours as well as an insight into the challenges of delivering the pathway in and outside a Network.

5 Review Nutrition and pancreatic cancer. 2014

Pericleous, Marinos / Rossi, Roberta Elisa / Mandair, Dalvinder / Whyand, Tara / Caplin, Martyn Evan. ·Department of Gastroenterology, Royal Free Hospital, Pond Street, London, NW3 2QG, U.K. m.caplin@ucl.ac.uk. ·Anticancer Res · Pubmed #24403441.

ABSTRACT: BACKGROUND: Pancreatic cancer is the fourth leading cause of cancer death in men and women. Prognosis is poor with a 5-year survival rate of less than 5%. As there is no effective screening modality, the best way to reduce morbidity and mortality due to pancreatic cancer is by effective primary prevention. AIM: To evaluate the role of dietary components in pancreatic cancer. MATERIALS AND METHODS: Bibliographical searches were performed in PubMed using the terms "pancreatic cancer", together with "nutrition", "diet", "dietary factors", "lifestyle", "smoking", "alcohol" and "epidemiology". RESULTS: Fruits (particularly citrus) and vegetable consumption may be beneficial. The consumption of whole grains has been shown to reduce pancreatic cancer risk and fortification of whole grains with folate may confer further protection. Red meat, cooked at high temperatures, should be avoided, and replaced with poultry or fish. Total fat should be reduced. The use of curcumin and other flavonoids should be encouraged in the diet. There is no evidence for benefit from vitamin D supplementation. There may be benefit for dietary folate. Smoking and high Body Mass Index have both been inversely associated with pancreatic cancer risk. CONCLUSION: The lack of randomized trials and the presence of confounding factors including smoking status, physical activity, distance of habitat from the equator, obesity, and diabetes may often result in inconclusive results. There is evidence to encourage the use of whole grain in the staple diet and supplementation within the diet of folate, curcumin and other flavanoids. Carefully designed randomized trials are required to further elucidate these important matters.

6 Review Update on the role of somatostatin analogs for the treatment of patients with gastroenteropancreatic neuroendocrine tumors. 2013

Toumpanakis, Christos / Caplin, Martyn E. ·Neuroendocrine Tumour Unit, ENETS Centre of Excellence, Royal Free Hospital, London, UK. ·Semin Oncol · Pubmed #23391113.

ABSTRACT: Somatostatin analogs (SA) are the standard of care for controlling symptoms of patients with functional gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs). SA control symptoms in more than 70% of patients with carcinoid syndrome. Similar results are obtained in patients with functional, hormone-secreting, pancreatic NETs. The use of SA as antiproliferative agents has been established only recently. Retrospective studies have shown stabilization of tumor growth in >50% of patients with progressive disease. The results of a recent randomized phase III trial (PROMID) demonstrated that the median time to progression in patients with midgut carcinoid tumors treated with octreotide LAR (Long-Acting-Repeatable, Novartis, Basel, Switzerland) was more than twice as long compared to that of patients treated with placebo. The results of a phase III study of lanreotide versus placebo in nonfunctional NETs are not yet available. More studies are needed to determine whether combining SA with novel targeted treatments will result in enhanced antiproliferative activity compared to treatment with a SA alone. Studies are ongoing using pan-receptor agonists (eg, pasireotide) and chimeric dimers, which possess features of somatostatin and dopamine agonists (dopastatins) and are thought to enhance symptom control by binding multiple receptors (somatostatin and dopamine receptors). Somatostatin receptor antagonists are also currently being developed for clinical use. Peptide receptor radionuclide therapy (PRRT), consisting of yttrium-90 and lutetium-177 isotopes conjugated with SA appear to be efficacious in advanced NETs. Randomized studies are needed to definitively establish the safety and efficacy of this strategy compared to other available treatments, and to determine which radiolabeled isotopes or combinations are most effective.

7 Review Therapeutic management of patients with gastroenteropancreatic neuroendocrine tumours. 2011

Khan, Mohid S / Caplin, Martyn E. ·Neuroendocrine Tumour Unit, Centre for Gastroenterology, Royal Free Hospital, London NW3 2QG, UK. ·Endocr Relat Cancer · Pubmed #22005115.

ABSTRACT: Patients with neuroendocrine tumours (NETs) are best managed in a specialist centre as part of a multidisciplinary team comprising gastroenterologists, oncologists, endocrinologists, gastrointestinal and hepatopancreaticobiliary surgeons, pathologists, nuclear medicine physicians and technicians, radiologists, specialist nurses, pharmacists, biochemists and dieticians. This should ideally be led by a clinician with experience and interest in NETs. Although the number of medical treatments and clinical trials has increased in the decade, there is still a lack of prospective randomised trials; thus, management is mainly based on limited often single-centre studies, although there are now formal guidelines based on consensus expert opinion. We have outlined the current optimal management of patients with NETs. We have reviewed therapeutic options including surgery, somatostatin analogues and other biotherapies and peptide receptor-targeted therapy. We have discussed the challenge in managing hepatic metastases including hepatic artery embolisation, ablation and orthotopic liver transplant. In addition, we have briefly reviewed the emerging therapies such as the mammalian target of rapamycin and angiogenic inhibitors and the newer somatostatin analogues.

8 Review Management of gastroentero-pancreatic neuroendocrine tumors (GEP-NETs). 2009

Desai, K K / Khan, M S / Toumpanakis, C / Caplin, M E. ·Neuroendocrine Tumor Unit, Royal Free Hospital, London, UK. ·Minerva Gastroenterol Dietol · Pubmed #19942827.

ABSTRACT: Neuroendocrine tumors (NETs) are relatively rare neoplasms that often present as diagnostic dilemmas due to obscure or non-specific symptoms. The ability of carcinoid tumors to cause clinical symptoms by secretion of hormones or biogenic amines is best recognised in the form of the carcinoid syndrome. Although generally slow growing, a significant minority demonstrate aggressive tumor growth. Ten-twenty percent of pancreatic NETs may be associated with hereditary disorders such as multiple endocrine neoplasia-1 (MEN-1) and less frequently, Von Hippel Lindau, which should be considered in the investigation and management of these patients. A small percentage of NETs are associated with co-existing synchronous non-carcinoid neoplasm. The aim of this paper was to review the optimal management in patients with NETs. The therapeutic options which are reviewed, including the use of somatostatin analogues, the role of surgery, the use of chemotherapy, biotherapy using interferon, peptide receptor targeted therapy. In addition, the challenging interventional management of liver metastases is discussed, including the role of hepatic-artery embolization, radiofrequency ablation and the place of orthotoptic liver transplantation in selected patients. Authors have focused on the newest therapeutic modalities, e.g., radionuclide peptide receptor targeted therapy with Yttrium-90 and Lutetium-177, the newest somatostatin analogues such as pasireotide and angiogenic inhibitors. In conclusion, with the increasing number of investigative procedures and therapeutic options available to diagnose and treat carcinoid tumors, it is vital to have a multidisciplinary approach. Furthermore, additional scientific research and controlled clinical trials are needed to determine the efficacy of the many treatment options, which for these rare tumors can only be achieved by collaboration.

9 Review Review article: future therapies for management of metastatic gastroenteropancreatic neuroendocrine tumours. 2009

Srirajaskanthan, R / Toumpanakis, C / Meyer, T / Caplin, M E. ·Neuroendocrine Tumour Unit, Royal Free Hospital, London, UK. m.caplin@medsch.ucl.ac.uk ·Aliment Pharmacol Ther · Pubmed #19298583.

ABSTRACT: BACKGROUND: Gastroenteropancreatic neuroendocrine tumours (GEP NETs) are relatively uncommon tumours that occur anywhere within the gastrointestinal tract. The prevalence of GEP NETs is estimated to be 35 per 100 000 population. Patients often present with metastatic disease and consequently, palliative treatments form the mainstay of therapy. AIM: To review the current and novel therapeutic options for management of GEP NETs. METHODS: Searches for all studies related to GEP NETs, NETs and carcinoid tumours in Medline and abstracts from international meetings. RESULTS: Somatostatin analogues remain the first line therapy for management of symptoms of GEP NETs and may have anti-proliferative action. New somatostatin analogues with different somatostatin receptor affinity have been developed. Radionuclide peptide receptor therapy is established in patients with positive somatostatin scintigraphy. A number of new agents and targeted therapies are currently being evaluated in a phase I and II studies and these include angiogenic inhibitors, mammalian target of rapamycin inhibitors and immune therapies. CONCLUSIONS: A number of nonsurgical therapies are available for management of gastroenteropancreatic neuroendocrine tumours. It is hoped, the development of some of these promising novel therapies will expand the therapeutic armamentarium.

10 Clinical Trial Anti-tumour effects of lanreotide for pancreatic and intestinal neuroendocrine tumours: the CLARINET open-label extension study. 2016

Caplin, Martyn E / Pavel, Marianne / Ćwikła, Jarosław B / Phan, Alexandria T / Raderer, Markus / Sedláčková, Eva / Cadiot, Guillaume / Wolin, Edward M / Capdevila, Jaume / Wall, Lucy / Rindi, Guido / Langley, Alison / Martinez, Séverine / Gomez-Panzani, Edda / Ruszniewski, Philippe / Anonymous721030. ·Royal Free HospitalLondon, UKCharité University Medicine BerlinBerlin, GermanyUniversity of Warmia and MazuryOlsztyn, PolandUniversity of Texas MD Anderson Cancer CenterHouston, Texas, USAUniversity HospitalVienna, AustriaDepartment of Oncology of the First Faculty of Medicine and General Teaching HospitalPrague, Czech RepublicRobert-Debré HospitalReims, FranceMarkey Cancer CenterUniversity of Kentucky, Lexington, Kentucky, USAVall d'Hebron University HospitalBarcelona, SpainWestern General HospitalEdinburgh, UKUniversità Cattolica del Sacro CuoreRome, ItalyIpsenLes Ulis, FranceIpsenBasking Ridge, New Jersey, USABeaujon HospitalClichy, FranceParis Diderot UniversityParis, France m.caplin@ucl.ac.uk. · Royal Free HospitalLondon, UKCharité University Medicine BerlinBerlin, GermanyUniversity of Warmia and MazuryOlsztyn, PolandUniversity of Texas MD Anderson Cancer CenterHouston, Texas, USAUniversity HospitalVienna, AustriaDepartment of Oncology of the First Faculty of Medicine and General Teaching HospitalPrague, Czech RepublicRobert-Debré HospitalReims, FranceMarkey Cancer CenterUniversity of Kentucky, Lexington, Kentucky, USAVall d'Hebron University HospitalBarcelona, SpainWestern General HospitalEdinburgh, UKUniversità Cattolica del Sacro CuoreRome, ItalyIpsenLes Ulis, FranceIpsenBasking Ridge, New Jersey, USABeaujon HospitalClichy, FranceParis Diderot UniversityParis, France. · Royal Free HospitalLondon, UKCharité University Medicine BerlinBerlin, GermanyUniversity of Warmia and MazuryOlsztyn, PolandUniversity of Texas MD Anderson Cancer CenterHouston, Texas, USAUniversity HospitalVienna, AustriaDepartment of Oncology of the First Faculty of Medicine and General Teaching HospitalPrague, Czech RepublicRobert-Debré HospitalReims, FranceMarkey Cancer CenterUniversity of Kentucky, Lexington, Kentucky, USAVall d'Hebron University HospitalBarcelona, SpainWestern General HospitalEdinburgh, UKUniversità Cattolica del Sacro CuoreRome, ItalyIpsenLes Ulis, FranceIpsenBasking Ridge, New Jersey, USABeaujon HospitalClichy, FranceParis Diderot UniversityParis, France Royal Free HospitalLondon, UKCharité University Medicine BerlinBerlin, GermanyUniversity of Warmia and MazuryOlsztyn, PolandUniversity of Texas MD Anderson Cancer CenterHouston, Texas, USAUniversity HospitalVienna, AustriaDepartment of Oncology of the First Faculty of Medicine and General Teaching HospitalPrague, Czech RepublicRobert-Debré HospitalReims, FranceMarkey Cancer CenterUniversity of Kentucky, Lexington, Kentucky, USAVall d'Hebron University HospitalBarcelona, SpainWestern General HospitalEdinburgh, UKUniversità Cattolica del Sacro CuoreRome, ItalyIpsenLes Ulis, FranceIpsenBasking Ridge, New Jersey, USABeaujon HospitalClichy, FranceParis Diderot UniversityParis, France. ·Endocr Relat Cancer · Pubmed #26743120.

ABSTRACT: In the CLARINET study, lanreotide Autogel (depot in USA) significantly prolonged progression-free survival (PFS) in patients with metastatic pancreatic/intestinal neuroendocrine tumours (NETs). We report long-term safety and additional efficacy data from the open-label extension (OLE). Patients with metastatic grade 1/2 (Ki-67 ≤ 10%) non-functioning NET and documented baseline tumour-progression status received lanreotide Autogel 120 mg (n = 101) or placebo (n = 103) for 96 weeks or until death/progressive disease (PD) in CLARINET study. Patients with stable disease (SD) at core study end (lanreotide/placebo) or PD (placebo only) continued or switched to lanreotide in the OLE. In total, 88 patients (previously: lanreotide, n = 41; placebo, n = 47) participated: 38% had pancreatic, 39% midgut and 23% other/unknown primary tumours. Patients continuing lanreotide reported fewer adverse events (AEs) (all and treatment-related) during OLE than core study. Placebo-to-lanreotide switch patients reported similar AE rates in OLE and core studies, except more diarrhoea was considered treatment-related in OLE (overall diarrhoea unchanged). Median lanreotide PFS (core study randomisation to PD in core/OLE; n=101) was 32.8 months (95% CI: 30.9, 68.0). A sensitivity analysis, addressing potential selection bias by assuming that patients with SD on lanreotide in the core study and not entering the OLE (n=13) had PD 24 weeks after last core assessment, found median PFS remaining consistent: 30.8 months (95% CI: 30.0, 31.3). Median time to further PD after placebo-to-lanreotide switch (n=32) was 14.0 months (10.1; not reached). This OLE study suggests long-term treatment with lanreotide Autogel 120 mg maintained favourable safety/tolerability. CLARINET OLE data also provide new evidence of lanreotide anti-tumour benefits in indolent and progressive pancreatic/intestinal NETs.

11 Clinical Trial Lanreotide in metastatic enteropancreatic neuroendocrine tumors. 2014

Caplin, Martyn E / Pavel, Marianne / Ćwikła, Jarosław B / Phan, Alexandria T / Raderer, Markus / Sedláčková, Eva / Cadiot, Guillaume / Wolin, Edward M / Capdevila, Jaume / Wall, Lucy / Rindi, Guido / Langley, Alison / Martinez, Séverine / Blumberg, Joëlle / Ruszniewski, Philippe / Anonymous1220800. ·From Royal Free Hospital, London (M.E.C.) · Charité University Medicine Berlin, Berlin (M.P.) · University of Warmia and Mazury, Olsztyn, Poland (J.B.Ć.) · University of Texas M.D. Anderson Cancer Center, Houston (A.T.P.) · University Hospital, Vienna (M.R.) · Department of Oncology of the First Faculty of Medicine and General Teaching Hospital, Prague, Czech Republic (E.S.) · Robert-Debré Hospital, Reims (G.C.), Ipsen, Les Ulis, (A.L., S.M., J.B.), Beaujon Hospital, Clichy (P.R.), and Paris Diderot University, Paris (P.R.) - all in France · Samuel Oschin Cancer Center, Cedars-Sinai Medical Center, Los Angeles (E.M.W.) · Vall d'Hebron University Hospital, Barcelona (J.C.) · Western General Hospital, Edinburgh (L.W.) · and Università Cattolica del Sacro Cuore, Rome (G.R.). ·N Engl J Med · Pubmed #25014687.

ABSTRACT: BACKGROUND: Somatostatin analogues are commonly used to treat symptoms associated with hormone hypersecretion in neuroendocrine tumors; however, data on their antitumor effects are limited. METHODS: We conducted a randomized, double-blind, placebo-controlled, multinational study of the somatostatin analogue lanreotide in patients with advanced, well-differentiated or moderately differentiated, nonfunctioning, somatostatin receptor-positive neuroendocrine tumors of grade 1 or 2 (a tumor proliferation index [on staining for the Ki-67 antigen] of <10%) and documented disease-progression status. The tumors originated in the pancreas, midgut, or hindgut or were of unknown origin. Patients were randomly assigned to receive an extended-release aqueous-gel formulation of lanreotide (Autogel [known in the United States as Depot], Ipsen) at a dose of 120 mg (101 patients) or placebo (103 patients) once every 28 days for 96 weeks. The primary end point was progression-free survival, defined as the time to disease progression (according to the Response Evaluation Criteria in Solid Tumors, version 1.0) or death. Secondary end points included overall survival, quality of life (assessed with the European Organization for Research and Treatment of Cancer questionnaires QLQ-C30 and QLQ-GI.NET21), and safety. RESULTS: Most patients (96%) had no tumor progression in the 3 to 6 months before randomization, and 33% had hepatic tumor volumes greater than 25%. Lanreotide, as compared with placebo, was associated with significantly prolonged progression-free survival (median not reached vs. median of 18.0 months, P<0.001 by the stratified log-rank test; hazard ratio for progression or death, 0.47; 95% confidence interval [CI], 0.30 to 0.73). The estimated rates of progression-free survival at 24 months were 65.1% (95% CI, 54.0 to 74.1) in the lanreotide group and 33.0% (95% CI, 23.0 to 43.3) in the placebo group. The therapeutic effect in predefined subgroups was generally consistent with that in the overall population, with the exception of small subgroups in which confidence intervals were wide. There were no significant between-group differences in quality of life or overall survival. The most common treatment-related adverse event was diarrhea (in 26% of the patients in the lanreotide group and 9% of those in the placebo group). CONCLUSIONS: Lanreotide was associated with significantly prolonged progression-free survival among patients with metastatic enteropancreatic neuroendocrine tumors of grade 1 or 2 (Ki-67 <10%). (Funded by Ipsen; CLARINET ClinicalTrials.gov number, NCT00353496; EudraCT 2005-004904-35.).

12 Clinical Trial Glucagon-like peptide-1 receptor imaging for the localisation of insulinomas: a prospective multicentre imaging study. 2013

Christ, Emanuel / Wild, Damian / Ederer, Susanne / Béhé, Martin / Nicolas, Guillaume / Caplin, Martyn E / Brändle, Michael / Clerici, Thomas / Fischli, Stefan / Stettler, Christoph / Ell, Peter J / Seufert, Jochen / Gloor, Beat / Perren, Aurel / Reubi, Jean Claude / Forrer, Flavio. ·Division of Endocrinology, Diabetology and Clinical Nutrition, University Hospital of Berne, Inselspital, Berne, Switzerland. · Department of Radiology, Division of Nuclear Medicine, University of Basel Hospital, Switzerland; Department of Nuclear Medicine, University Hospital Freiburg, Germany; Institute of Nuclear Medicine, University College Hospital, London, UK. Electronic address: damian.wild@usb.ch. · Department of Radiology, Division of Nuclear Medicine, University of Basel Hospital, Switzerland. · Department of Nuclear Medicine, University Hospital Freiburg, Germany; Center for Radiopharmaceutical Science ETH-PSI-USZ, Paul Scherrer Institute, Villingen, Switzerland. · Neuroendocrine Tumour Unit, Royal Free Hospital, London, UK. · Division of Endocrinology, Diabetes and Osteology, Kantonsspital, St Gallen, Switzerland. · Division of Visceral Surgery, Kantonsspital, St Gallen, Switzerland. · Division of Endocrinology, Diabetes and Osteology, Kantonsspital Luzern, Switzerland. · Institute of Nuclear Medicine, University College Hospital, London, UK. · Division of Endocrinology and Diabetology, University Hospital Freiburg, Germany. · Division of Visceral Surgery, University Hospital of Berne, Inselspital, Berne, Switzerland. · Institute of Pathology, University of Berne, Berne, Switzerland. ·Lancet Diabetes Endocrinol · Pubmed #24622317.

ABSTRACT: BACKGROUND: Small benign insulinomas are hard to localise, leading to difficulties in planning of surgical interventions. We aimed to prospectively assess the insulinoma detection rate of single-photon emission CT in combination with CT (SPECT/CT) with a glucagon-like peptide-1 receptor avid radiotracer, and compare detection rates with conventional CT/MRI techniques. METHODS: In our prospective imaging study, we enrolled adults aged 25-81 years at centres in Germany, Switzerland, and the UK. Eligible patients had proven clinical and biochemical endogenous hyperinsulinaemic hypoglycaemia and no evidence for metastatic disease on conventional imaging. CT/MRI imaging was done at referring centres according to standard protocols. At three tertiary nuclear medicine centres, we used whole body planar images and SPECT/CT of the abdomen up to 168 h after injection of (111)In-[Lys40(Ahx-DTPA-(111)In)NH2]-exendin-4 ((111)In-DTPA-exendin-4) to identify insulinomas. Consenting patients underwent surgery and imaging findings were confirmed histologically. FINDINGS: Between Oct 1, 2008, and Dec 31, 2011, we recruited 30 patients. All patients underwent (111)In-DTPA-exendin-4 imaging, 25 patients underwent surgery (with histological analysis), and 27 patients were assessed with CT/MRI. (111)In-DTPA-exendin-4 SPECT/CT correctly detected 19 insulinomas and four additional positive lesions (two islet-cell hyperplasia and two uncharacterised lesions) resulting in a positive predictive value of 83% (95% CI 62-94). One true negative (islet-cell hyperplasia) and one false negative (malignant insulinoma) result was identified in separate patients by (111)In-DTPA-exendin-4 SPECT/CT. Seven patients (23%) were referred to surgery on the basis of (111)In-DTPA-exendin-4 imaging alone. For 23 assessable patients, (111)In-DTPA-exendin-4 SPECT/CT had a higher sensitivity (95% [95% CI 74-100]) than did CT/MRI (47% [27-68]; p=0.011). INTERPRETATION: (111)In-DTPA-exendin-4 SPECT/CT could provide a good second-line imaging strategy for patients with negative results on initial imaging with CT/MRI. FUNDING: Oncosuisse, the Swiss National Science Foundation, and UK Department of Health.

13 Clinical Trial Glucagon-like peptide-1 versus somatostatin receptor targeting reveals 2 distinct forms of malignant insulinomas. 2011

Wild, Damian / Christ, Emanuel / Caplin, Martyn E / Kurzawinski, Tom R / Forrer, Flavio / Brändle, Michael / Seufert, Jochen / Weber, Wolfgang A / Bomanji, Jamshed / Perren, Aurel / Ell, Peter J / Reubi, Jean Claude. ·Institute of Nuclear Medicine, University College Hospital, London, United Kingdom. ·J Nucl Med · Pubmed #21680696.

ABSTRACT: METHODS: Eleven patients with malignant insulinoma were prospectively included. (111)In-[Lys(40)(Ahx-diethylenetriaminepentaacetic acid [DTPA])NH(2)]-exendin-4 SPECT/CT, (68)Ga- DOTATATE PET/CT, and in vitro receptor autoradiography were performed to assess the receptor status and to evaluate the detection rate. RESULTS: GLP-1 receptor targeting was positive in 4 of 11 patients, and sst(2) receptor expression was positive in 8 of 11. In only 1 patient were both receptors expressed. In 1 patient, GLP-1 receptor imaging was the only method that successfully localized the primary tumor in the pancreas. In 3 patients with sst(2)-expressing tumors, DOTATATE radiotherapy was effectively applied. CONCLUSION: As opposed to benign insulinomas, malignant insulinomas often lack GLP-1 receptors. Conversely, malignant insulinomas often express sst(2), which can be targeted therapeutically.

14 Clinical Trial A phase Ib/IIa trial to evaluate the CCK2 receptor antagonist Z-360 in combination with gemcitabine in patients with advanced pancreatic cancer. 2010

Meyer, T / Caplin, M E / Palmer, D H / Valle, J W / Larvin, M / Waters, J S / Coxon, F / Borbath, I / Peeters, M / Nagano, E / Kato, H. ·UCL, London, UK. t.meyer@ucl.ac.uk ·Eur J Cancer · Pubmed #20006921.

ABSTRACT: AIM: To evaluate the combination of the gastrin antagonist Z-360 and gemcitabine for advanced pancreatic cancer. METHODS: Previously untreated patients with PC were randomly allocated to Z-360 120 mg, 240 mg or placebo. Z-360/placebo was given on day -3 and gemcitabine 1000 mg/m(2) commenced on day 1 followed by Z-360 on day 2. Thereafter Z-360/placebo was given twice daily concurrently with standard dose of gemcitabine. Pharmacokinetics for both drugs was measured alone and in combination. Toxicity, response and quality of life were also recorded. RESULTS: Thirty-three patients with a median age of 62 years were randomised of which six had locally advanced disease and 26 had metastatic disease. Analysis of the area under the plasma concentration versus time curve (AUC), the maximum observed concentration (Cmax(obs)) and the time of the maximum observed concentration (Tmax(obs)) for Z-360, gemcitabine and 2,2-difluorodeoxyuridine (dFdU), could not exclude an effect on the systemic exposure to Z-360, gemcitabine and dFdU when co-administration of Z-360 and gemcitabine was compared with single agent administration. The most commonly reported adverse events were nausea, abdominal pain, vomiting and fatigue. At the end of the study, 62.5%, 25% and 60% had stable disease in the 120 mg, 240 mg and placebo group, respectively. A higher proportion of patients in Z-360 groups reported improvement in pain. CONCLUSIONS: Z-360 is safe and well tolerated when combined with gemcitabine. A Phase III trial is needed to determine whether the combination of Z-360 and gemcitabine is superior to gemcitabine alone in advanced PC.

15 Article Tumor growth rate as a metric of progression, response, and prognosis in pancreatic and intestinal neuroendocrine tumors. 2019

Dromain, Clarisse / Pavel, Marianne E / Ruszniewski, Philippe / Langley, Alison / Massien, Christine / Baudin, Eric / Caplin, Martyn E / Anonymous2211132. ·Department of Diagnostic and Interventional Radiology, CHUV University Hospital, Lausanne, Switzerland. Clarisse.Dromain@chuv.ch. · Department of Medicine 1, Division of Endocrinology and Diabetology, Friedrich-Alexander Universität Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany. · Division of Gastroenterology and Pancreatology, Beaujon Hospital, Clichy, France. · Faculty of Medicine, Paris Diderot University, Paris, France. · Ipsen, Boulogne-Billancourt, France. · APHP, Hypertension unit, Georges Pompidou European Hospital, F-75015, Paris, France. · Endocrine Tumour and Nuclear Medicine Unit, Gustave-Roussy Cancer Campus, Villejuif, France. · Neuroendocrine Tumour Unit, Department of Gastroenterology, Royal Free Hospital, London, UK. ·BMC Cancer · Pubmed #30642293.

ABSTRACT: BACKGROUND: Lanreotide depot/autogel antitumor activity in intestinal/pancreatic neuroendocrine tumors (NETs) was demonstrated in the phase-3 CLARINET study (NCT00353496), based on significantly prolonged progression-free survival (PFS) versus placebo. METHODS: During CLARINET, patients with metastatic intestinal/pancreatic NETs received lanreotide depot/autogel 120 mg or placebo every 4 weeks for 96 weeks. Imaging data (response evaluation criteria in solid tumors [RECIST] v1.0, centrally reviewed) were re-evaluated in this post hoc analysis of tumor growth rate (TGR) in NETs. TGR (%/month) was calculated from two imaging scans during relevant periods: pre-treatment (TGR RESULTS: TGR CONCLUSIONS: TGR provides valuable information on tumor activity and prognosis in patients with metastatic intestinal/pancreatic NETs, and identifies early lanreotide depot/autogel antitumor activity. TRIAL REGISTRATION: Retrospective registration, 18 July 2006; EudraCT: 2005-004904-35; ClinicalTrials.gov: NCT00353496 .

16 Article A Case Series of Molecular Imaging of Glucagonoma After Initial Therapy-68Ga-DOTATATE PET/CT Reveals Similar Results as in Neuroendocrine Tumors of Other Origin in Follow-up and Re-evaluation. 2018

Rottenburger, Christof / Papantoniou, Dimitrios / Mandair, Dalvinder / Caplin, Martyn / Navalkissoor, Shaunak. · ·Clin Nucl Med · Pubmed #29432346.

ABSTRACT: Glucagonoma is an extremely rare, glucagon-secreting neuroendocrine tumor of the pancreas. Only sparse data are available about the characteristics of this tumor in somatostatin receptor imaging and only for the situation of initial diagnosis. We present a series of 3 glucagonoma patients who underwent at least 1 Ga-DOTATATE PET/CT scan. All patients were diagnosed by either histology and/or elevated serum levels of glucagon. The presented cases suggest that somatostatin receptor-based imaging can probably be used for re-evaluation of disease status in patients with glucagonoma in a similar way as it is already established for neuroendocrine tumors of other origin.

17 Article Major postoperative complications after pancreatic resection for P-NETS are not associated to earlier recurrence. 2017

Valente, R / Lykoudis, P / Tamburrino, D / Inama, M / Passas, I / Toumpanakis, C / Luong, T V / Davidson, B / Imber, C / Malagò, M / Rahman, S H / Shankar, A / Sharma, D / Caplin, M / Fusai, G. ·Department of Hepatopancreatobiliary and Liver Transplantation Surgery, Royal Free and University College London, NW32QG, UK; Hepatopancreatobiliary Service, Barts Health NHS Trust, The Royal London Hospital, E1 1BZ, UK. Electronic address: r.valente@ucl.ac.uk. · Department of Hepatopancreatobiliary and Liver Transplantation Surgery, Royal Free and University College London, NW32QG, UK. · Neuroendocrine Tumour Unit, Royal Free and University College London, NW32QG, UK. · Histopathology Unit, Royal Free and University College London, NW32QG, UK. ·Eur J Surg Oncol · Pubmed #28821361.

ABSTRACT: BACKGROUND: The oncological impact of surgical complications has been studied in visceral and pancreatic cancer. AIM: To investigate the impact of complications on tumour recurrence after resections for pancreatic neuroendocrine tumours. METHODS: We have retrospectively analysed 105 consecutive resections performed at the Royal Free London Hospital from 1998 to 2014, and studied the long-term outcome of nil-minor (<3) versus major (≥3) Clavien-Dindo complications (CD) on disease-free (DFS) and overall survival (OS). RESULTS: The series accounted for 41 (39%) pancreaticoduodenectomies, two (1.9%) central, 48 (45.7%) distal pancreatectomies, eight (7.6%) enucleations, four (3.8%) total pancreatectomies. Sixteen (15.2%) were extended to adjacent organs, 13 (12.3%) to minor liver resections. Postoperative complications presented in 43 (40.1%) patients; CD grade 1 or 2 in 23 (21.9%), grades ≥3 in 20 (19%). Among 25 (23.8%) pancreatic fistulas, 14 (13.3%) were grades B or C. Thirty-four (32.4%) patients developed exocrine, and 31 (29.5%) endocrine insufficiency. Seven patients died during a median 27 (0-175) months follow up. Thirty-day mortality was 0.9%. OS was 94.1% at 5 years. Thirty tumours recurred within 11.7 (0.8-141.5) months. DFS was 44% at 5 years. At univariate analysis, high-grade complications were not associated with shorter DFS (p = 0.744). At multivariate analysis, no parameter was independent predictor for DFS or OS. The comparison of nil-minor versus major complications showed no DFS difference (p = 0.253). CONCLUSION: From our series, major complications after P-NETs resection are not associated to different disease recurrence; hence do not require different follow up or adjuvant regimens.

18 Article Long-Term Outcomes of Surgical Management of Pancreatic Neuroendocrine Tumors with Synchronous Liver Metastases. 2015

Partelli, Stefano / Inama, Marco / Rinke, Anja / Begum, Nehara / Valente, Roberto / Fendrich, Volker / Tamburrino, Domenico / Keck, Tobias / Caplin, Martyn E / Bartsch, Detlef / Thirlwell, Christina / Fusai, Giuseppe / Falconi, Massimo. ·Pancreatic Surgery Unit, University Hospital of Ancona, Ancona, Italy. ·Neuroendocrinology · Pubmed #26043944.

ABSTRACT: BACKGROUND: The value of surgical resection in the management of pancreatic neuroendocrine tumors (PNET) with liver metastases (LM) is still debated. The aim of this study was to evaluate the outcomes of surgery of PNET with LM. METHODS: Patients with PNET with synchronous LM between 2000 and 2011 from 4 high-volume institutions were included. The patients were divided into 3 groups: curative resection, palliative resection, and no resection. RESULTS: Overall, 166 patients were included. Eighteen patients (11%) underwent curative resection, 73 patients (43%) underwent palliative resection, and 75 patients (46%) underwent conservative treatment. The median overall survival (OS) from the time of diagnosis was 73 months. Patients who underwent curative resection had a significantly better median OS from the initial diagnosis compared with those who underwent palliative resection and those who were conservatively treated (97 vs. 89 vs. 36 months, p = 0.0001). The median OS from the time of diagnosis in those patients who underwent radical or palliative resection was 97 months, with a 5-year survival rate of 76%. On multivariate analysis, factors associated with OS from the time of diagnosis were the presence of bilobar metastases, tumor grading, and curative resection in a first model. On a second model, curative or palliative surgery was an independent predictor of OS. Among 91 patients who underwent surgery, the presence of pancreatic neuroendocrine carcinoma G3 was the only factor independently associated with a poorer survival after surgery (median OS: 35 vs. 97 months, p < 0.0001). CONCLUSIONS: Patients with LM from PNET benefit from surgical resection, although surgery should be reserved to well- or moderately differentiated forms.

19 Article Case report of multimodality treatment for metastatic parathyroid hormone-related peptide-secreting pancreatic neuroendocrine tumour. 2014

Rossi, Roberta Elisa / Naik, Keval / Navalkissoor, Shaunak / Imber, Charles / O'Beirne, James / Toumpanakis, Christos / Caplin, Martyn Evan. · ·Tumori · Pubmed #25296608.

ABSTRACT: AIMS AND BACKGROUND: Hypercalcaemia due to metastatic parathyroid hormone-related peptide-secreting pancreatic neuroendocrine tumour is challenging to manage and requires a multimodality approach. METHODS: We present a case of a woman undergoing liver transplantation for metastatic parathyroid hormone-related peptide-secreting pancreatic neuroendocrine tumour. RESULTS: A young woman with a history of parathyroid hormone-related peptide-secreting pancreatic neuroendocrine tumour (Ki-67 5%) removed in 1998 developed bilobar liver metastases in 2004 and underwent repeated transarterial embolisations of liver tumour and therapy with somatostatin analogue. In view of symptomatic hypercalcaemia refractory to medical therapy, she underwent liver transplantation in 2006. In 2012, follow-up imaging showed a 3-cm hypervascular lesion in the posterior wall of the stomach, which was confirmed on endoscopic ultrasound and on gallium-68-octreotate positron emission tomography scan. A gastric wall resection was performed in February 2013, and biopsies showed a neuroendocrine tumour of intermediate grade (Ki-67 15%). In June 2013, a restaging imaging showed a 2.4 cm lesion in the left breast, which was reported as a primary breast cancer on biopsies, and a 14-mm tissue lesion anterior to the gastric antrum. The patient underwent surgical excision of the breast cancer followed by hormone treatment and radiotherapy. She had surgical removal of the gastric recurrence with adjuvant chemotherapy postoperatively. CONCLUSIONS: Hypercalcaemia related to parathyroid hormone-related peptide-secreting neuroendocrine tumour can be life-threatening, and liver transplantation may be a viable option in case of liver only diffuse neuroendocrine metastases refractory to other therapies. The risk of tumour recurrence remains a significant clinical problem after liver transplantation, and only a few patients might be considered tumour-free 5 years after liver transplantation.

20 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.

21 Article A comparison of Ki-67 and mitotic count as prognostic markers for metastatic pancreatic and midgut neuroendocrine neoplasms. 2013

Khan, M S / Luong, T V / Watkins, J / Toumpanakis, C / Caplin, M E / Meyer, T. ·Neuroendocrine Tumour Unit, Centre for Gastroenterology, Royal Free Hospital, London NW3 2QG, UK. ·Br J Cancer · Pubmed #23579216.

ABSTRACT: BACKGROUND: The aim of this study was to compare mitotic count (MC) and Ki-67 proliferation index as prognostic markers in pancreatic and midgut neuroendocrine neoplasms (NENs). METHODS: Two hundred eighty-five patients with metastatic NENs were recruited. Concordance between histological grade according to either Ki-67 or MC as defined by the European Neuroendocrine Tumour Society guidelines was assessed and the prognostic significance of Ki-67 or MC were evaluated. RESULTS: There was a discrepancy of 44 and 38% in grade assignment when using Ki-67 or MC in pancreatic and midgut NENs, respectively. In multivariate analysis, grade using Ki-67, but not MC, was a significant prognostic factor in determining overall survival (hazard ratios: midgut G2 2.34, G3 15.1, pancreas G2 2.08, G3 11.3). The prognostic value of Ki-67 was improved using a modified classification (hazard ratios: midgut G2 3.02, for G3 22.1, pancreas G2 5.97, G3 33.8). CONCLUSION: There is a lack of concordance between Ki-67 and MC in assigning tumour grade. Grade according to Ki-67 was a better prognostic marker than MC for metastatic pancreatic and midgut NENs. We suggest that Ki-67 alone should be used for grading pancreatic and midgut NENs and that the current threshold for classifying G1/G2 tumours should be revised from 2 to 5%.

22 Article TNM staging of neoplasms of the endocrine pancreas: results from a large international cohort study. 2012

Rindi, G / Falconi, M / Klersy, C / Albarello, L / Boninsegna, L / Buchler, M W / Capella, C / Caplin, M / Couvelard, A / Doglioni, C / Delle Fave, G / Fischer, L / Fusai, G / de Herder, W W / Jann, H / Komminoth, P / de Krijger, R R / La Rosa, S / Luong, T V / Pape, U / Perren, A / Ruszniewski, P / Scarpa, A / Schmitt, A / Solcia, E / Wiedenmann, B. ·Institute of Anatomic Pathology, Università Cattolica del Sacro Cuore, Histopathology and Cytodiagnosis Unit, Policlinico Gemelli, Largo A. Gemelli, 8, Roma I-00168, Italy. guido.rindi@rm.unicatt.it ·J Natl Cancer Inst · Pubmed #22525418.

ABSTRACT: BACKGROUND: Both the European Neuroendocrine Tumor Society (ENETS) and the International Union for Cancer Control/American Joint Cancer Committee/World Health Organization (UICC/AJCC/WHO) have proposed TNM staging systems for pancreatic neuroendocrine neoplasms. This study aims to identify the most accurate and useful TNM system for pancreatic neuroendocrine neoplasms. METHODS: The study included 1072 patients who had undergone previous surgery for their cancer and for which at least 2 years of follow-up from 1990 to 2007 was available. Data on 28 variables were collected, and the performance of the two TNM staging systems was compared by Cox regression analysis and multivariable analyses. All statistical tests were two-sided. RESULTS: Differences in distribution of sex and age were observed for the ENETS TNM staging system. At Cox regression analysis, only the ENETS TNM staging system perfectly allocated patients into four statistically significantly different and equally populated risk groups (with stage I as the reference; stage II hazard ratio [HR] of death = 16.23, 95% confidence interval [CI] = 2.14 to 123, P = .007; stage III HR of death = 51.81, 95% CI = 7.11 to 377, P < .001; and stage IV HR of death = 160, 95% CI = 22.30 to 1143, P < .001). However, the UICC/AJCC/WHO 2010 TNM staging system compressed the disease into three differently populated classes, with most patients in stage I, and with the patients being equally distributed into stages II-III (statistically similar) and IV (with stage I as the reference; stage II HR of death = 9.57, 95% CI = 4.62 to 19.88, P < .001; stage III HR of death = 9.32, 95% CI = 3.69 to 23.53, P = .94; and stage IV HR of death = 30.84, 95% CI = 15.62 to 60.87, P < .001). Multivariable modeling indicated curative surgery, TNM staging, and grading were effective predictors of death, and grading was the second most effective independent predictor of survival in the absence of staging information. Though both TNM staging systems were independent predictors of survival, the UICC/AJCC/WHO 2010 TNM stages showed very large 95% confidence intervals for each stage, indicating an inaccurate predictive ability. CONCLUSION: Our data suggest the ENETS TNM staging system is superior to the UICC/AJCC/WHO 2010 TNM staging system and supports its use in clinical practice.

23 Article Use of molecular imaging to differentiate liver metastasis of colorectal cancer metastasis from neuroendocrine tumor origin. 2011

Desai, Kiran / Watkins, Jennifer / Woodward, Nicholas / Quigley, Anne Marie / Toumpanakis, Christos / Bomanji, Jamshed / Caplin, Martyn. ·Royal Free Hampstead NHS trust, UK. ·J Clin Gastroenterol · Pubmed #20861802.

ABSTRACT: Synchronous malignant neoplasms in a single patient are well documented in the literature. It is also recognized that there is increasing incidence of synchronous non-neuroendocrine neoplasm in patients with neuroendocrine tumor (NET). We present a case, of a patient with synchronous colorectal cancer and pancreatic NET, both cancers presenting with liver metastasis. By using 18F-FDG PET and 68Ga-DOTATATE PET imaging, we showed 2 different tumor types within the liver, which was subsequently confirmed on liver biopsy. This case report shows the utility of molecular imaging using different PET peptides. These newer modalities are useful in understanding the biology of the NET and in determining the best patient management.

24 Article Identification of Mac-2-binding protein as a putative marker of neuroendocrine tumors from the analysis of cell line secretomes. 2010

Srirajaskanthan, Rajaventhan / Caplin, Martyn E / Waugh, Mark G / Watkins, Jennifer / Meyer, Tim / Hsuan, J Justin / Beaumont, Nicholas J. ·Centre of Gastroenterology, Royal Free Hospital, London, United Kingdom. rs3856@doctors.org.uk ·Mol Cell Proteomics · Pubmed #20019050.

ABSTRACT: Neuroendocrine tumors (NETs) can arise from a variety of organs. They can vary widely in clinical behavior; consequently, optimizing their treatment plan can be problematic. NETs display diverse tumor biology; however, most secrete peptides such as chromogranin A into the circulation, consistent with their neuroendocrine origin. In this study, we sought to identify other potential markers for NETs by analyzing the secreted proteomes of three neuroendocrine cell lines. BON-1, NCI-H727, and SHP-77 cells were grown in serum-free media, and the secreted proteins were separated by SDS-PAGE and identified by LC-MS/MS. We identified 205 proteins of which 61 were secreted by two or more of the cell lines and 19 were secreted by all three lines. Mac-2-binding protein (Mac-2BP) was found to be secreted by all three cell lines, and this was confirmed by Western blotting. Immunohistochemical analysis found 29 of 33 NET cases from different primary sites to be positive for Mac-2BP. Serum Mac-2BP was significantly elevated in NET patients compared with healthy controls (p < 0.001). This study demonstrated that analysis of the secreted proteomes of neuroendocrine cell lines can identify potential biomarkers for NET. Initial assessment showed that serum Mac-2BP is significantly elevated in patients with NET and is expressed by the majority of NET tissues.

25 Article Circulating angiopoietin-2 is elevated in patients with neuroendocrine tumours and correlates with disease burden and prognosis. 2009

Srirajaskanthan, R / Dancey, G / Hackshaw, A / Luong, T / Caplin, M E / Meyer, T. ·Neuroendocrine Tumour Unit, Royal Free Hospital, London NW3 2QG, UK. ·Endocr Relat Cancer · Pubmed #19502452.

ABSTRACT: Angiogenesis is an essential process in the development and growth of tumours. There are a large number of angiogenic mediators including the angiopoietin (Ang) family and vascular endothelial growth factor, which play an important role in both physiological and pathological angiogenesis. This study examines serum levels of Ang-1 and Ang-2 in patients with neuroendocrine tumour (NET) compared healthy controls. ELISA for Ang-1 and Ang-2 was performed in 47 patients with histologically proven NETs and 44 healthy controls. Immunohistochemical staining for Ang-2 was performed in patients to demonstrate cellular location of Ang-2. Serum Ang-2 levels were significantly elevated in patients compared controls (median 4756 vs 2495 pg/ml, P<0.001), while there was no significant difference in Ang-1 levels. The ratio of Ang-2:Ang-1 was significantly elevated in patients compared controls (0.13 vs 0.066, P<0.001). Serum Ang-2 levels were significantly elevated in patients with distant metastases compared with those without metastasis (median 5080 vs 3360 pg/ml, P=0.01). There was also a significant increase between Ang-2 levels and volume of liver metastases (P=0.014). Time to disease progression was worse in patients with serum Ang-2 levels >4756 pg/ml (P=0.04). Serum Ang-2 but not Ang-1 is elevated in NET patients. Ang-2 may be a useful serum marker for monitoring and assessment of prognosis in patients with NETs.

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