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Pancreatic Neoplasms: HELP
Articles by Dik J. Kwekkeboom
Based on 30 articles published since 2008
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Between 2008 and 2019, D. Kwekkeboom wrote the following 30 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 Neuroendocrine gastro-entero-pancreatic tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. 2012

Öberg, K / Knigge, U / Kwekkeboom, D / Perren, A / Anonymous3470737. ·Department of Endocrine Oncology, University Hospital, Uppsala University, Uppsala, Sweden. ·Ann Oncol · Pubmed #22997445.

ABSTRACT: -- No abstract --

3 Review Radiolabeled Somatostatin Analogue Therapy Of Gastroenteropancreatic Cancer. 2016

Bodei, Lisa / Kwekkeboom, Dik J / Kidd, Mark / Modlin, Irvin M / Krenning, Eric P. ·Division of Nuclear Medicine, European Institute of Oncology, Milan, Italy; LuGenIum Consortium, Milan, Rotterdam, London, Bad Berka. Electronic address: lisa.bodei@ieo.it. · LuGenIum Consortium, Milan, Rotterdam, London, Bad Berka; Nuclear Medicine Department, Erasmus Medical Center, Rotterdam, The Netherlands. · Wren Laboratories, Branford, CT. · LuGenIum Consortium, Milan, Rotterdam, London, Bad Berka; Department of Gastroenterological Surgery, Yale School of Medicine, New Haven, CT. · LuGenIum Consortium, Milan, Rotterdam, London, Bad Berka; Wren Laboratories, Branford, CT. ·Semin Nucl Med · Pubmed #27067503.

ABSTRACT: Peptide receptor radionuclide therapy (PRRT) has been utilized for more than two decades and has been accepted as an effective therapeutic modality in the treatment of inoperable or metastatic gastroenteropancreatic neuroendocrine neoplasms (NENs) or neuroendocrine tumors (NETs). The two most commonly used radiopeptides for PRRT, (90)Y-octreotide and (177)Lu-octreotate, produce disease-control rates of 68%-94%, with progression-free survival rates that compare favorably with chemotherapy, somatostatin analogues, and newer targeted therapies. In addition, biochemical and symptomatic responses are commonly observed. In general, PRRT is well tolerated with only low to moderate toxicity in most individuals. In line with the need to place PRRT in the therapeutic sequence of gastroenteropancreatic NENs, a recently sponsored phase III randomized trial in small intestine NENs treated with (177)Lu-octreotate vs high-dose octreotide long-acting release demonstrated that (177)Lu-octreotate significantly improved progression-free survival. Other strategies that are presently being developed include combinations with targeted therapies or chemotherapy, intra-arterial PRRT, and salvage treatments. Sophisticated molecular tools need to be incorporated into the management strategy to more effectively define therapeutic efficacy and for an early identification of adverse events. The strategy of randomized controlled trials is a key issue to standardize the treatment and establish the position of PRRT in the therapeutic algorithm of NENs.

4 Review Peptide Receptor Radionuclide Therapy in the Treatment of Neuroendocrine Tumors. 2016

Kwekkeboom, Dik J / Krenning, Eric P. ·Department of Nuclear Medicine, Erasmus MC, University Medical Center, s-Gravendijkwal 230, Rotterdam 3015CE, The Netherlands. Electronic address: d.j.kwekkeboom@erasmusmc.nl. · Department of Nuclear Medicine, Erasmus MC, University Medical Center, s-Gravendijkwal 230, Rotterdam 3015CE, The Netherlands. ·Hematol Oncol Clin North Am · Pubmed #26614376.

ABSTRACT: Peptide receptor radionuclide therapy (PRRT) is a promising new treatment modality for inoperable or metastasized gastroenteropancreatic neuroendocrine tumors patients. Most studies report objective response rates in 15% to 35% of patients. Progression-free (PFS) and overall survival (OS) compare favorably with that for somatostatin analogues, chemotherapy, or newer, "targeted" therapies. Prospective, randomized data regarding the potential PFS and OS benefit of PRRT compared with standard therapies is anticipated.

5 Review GEPNETs update: Radionuclide therapy in neuroendocrine tumors. 2015

van der Zwan, Wouter A / Bodei, Lisa / Mueller-Brand, Jan / de Herder, Wouter W / Kvols, Larry K / Kwekkeboom, Dik J. ·Department of Nuclear MedicineErasmus MC, University Medical Center, s-Gravendijkwal 230, 3015CE Rotterdam, The NetherlandsDepartment of Nuclear MedicineEuropean Institute of Oncology, Milan, ItalyDepartment of Nuclear MedicineUniversity Hospital Basel, Basel, SwitzerlandDepartment of GI OncologyH. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA w.vanderzwan@erasmusmc.nl. · Department of Nuclear MedicineErasmus MC, University Medical Center, s-Gravendijkwal 230, 3015CE Rotterdam, The NetherlandsDepartment of Nuclear MedicineEuropean Institute of Oncology, Milan, ItalyDepartment of Nuclear MedicineUniversity Hospital Basel, Basel, SwitzerlandDepartment of GI OncologyH. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA. ·Eur J Endocrinol · Pubmed #25117465.

ABSTRACT: Peptide receptor radionuclide therapy (PRRT) is a promising new treatment modality for inoperable or metastasized gastroenteropancreatic neuroendocrine tumors (GEPNETs) patients. Most studies report objective response rates in 15-35% of patients. Also, outcome in terms of progression free survival (PFS) and overall survival compares very favorably with that for somatostatin analogs, chemotherapy, or new, 'targeted' therapies. They also compare favorably to PFS data for liver-directed therapies. Two decades after the introduction of PRRT, there is a growing need for randomized controlled trials comparing PRRT to 'standard' treatment, that is treatment with agents that have proven benefit when tested in randomized trials. Combining PRRT with liver-directed therapies or with targeted therapies could improve treatment results. The question to be answered, however, is whether a combination of therapies performed within a limited time-span from one another results in a better PFS than a strategy in which other therapies are reserved until after (renewed) tumor progression. Randomized clinical trials comparing PRRT with other treatment modalities should be undertaken to determine the best treatment options and treatment sequelae for patients with GEPNETs.

6 Review Neuroendocrine tumours: the role of imaging for diagnosis and therapy. 2014

van Essen, Martijn / Sundin, Anders / Krenning, Eric P / Kwekkeboom, Dik J. ·Department of Nuclear Medicine, Erasmus MC, 's Gravendijkwal 230, Rotterdam, 3015 GD, Netherlands. · Department of Radiology, Karolinska University Hospital, Stockholm, 17176 Stockholm, Sweden. ·Nat Rev Endocrinol · Pubmed #24322649.

ABSTRACT: In patients with neuroendocrine tumours (NETs), a combination of morphological imaging and nuclear medicine techniques is mandatory for primary tumour visualization, staging and evaluation of somatostatin receptor status. CT and MRI are well-suited for discerning small lesions that might escape detection by single photon emission tomography (SPECT) or PET, as well as for assessing the local invasiveness of the tumour or the response to therapy. Somatostatin receptor imaging, by (111)In-pentetreotide scintigraphy or PET with (68)Ga-labelled somatostatin analogues, frequently identifies additional lesions that are not visible on CT or MRI scans. Currently, somatostatin receptor scintigraphy with (111)In-pentetreotide is the more frequently available of the two techniques to determine somatostatin receptor expression and is needed to select patients for peptide receptor radionuclide therapy. In the future, because of its higher sensitivity, PET with (68)Ga-labelled somatostatin analogues is expected to replace somatostatin receptor scintigraphy. Whereas (18)F-FDG-PET is only used in high-grade neuroendocrine cancers, PET-CT with (18)F-dihydroxy-L-phenylalanine or (11)C-5-hydroxy-L-tryptophan is a useful problem-solving tool and could be considered for the evaluation of therapy response in the future. This article reviews the role of imaging for the diagnosis and management of intestinal and pancreatic NETs. Response evaluation and controversies in NET imaging will also be discussed.

7 Review Treatment of gastroenteropancreatic neuroendocrine tumors with peptide receptor radionuclide therapy. 2013

van Vliet, Esther I / Teunissen, Jaap J M / Kam, Boen L R / de Jong, Marion / Krenning, Eric P / Kwekkeboom, Dik J. ·Department of Nuclear Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands. e.i.vanvliet@erasmusmc.nl ·Neuroendocrinology · Pubmed #22237390.

ABSTRACT: The primary treatment of gastroenteropancreatic neuroendocrine tumors (GEPNETs) is surgery with curative intent or debulking of the tumor mass. In case of metastatic disease, cytoreductive options are limited. A relatively new therapeutic modality, peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogs, is currently available in a number of mostly European centers. Complete and partial responses obtained after treatment with [90Y-DOTA0,Tyr3]octreotide are in the same range as after treatment with [177Lu-DOTA0,Tyr3]octreotate (i.e. 10-30%). However, significant nephrotoxicity has been observed after treatment with [90Y-DOTA0,Tyr3]octreotide. Options to improve PRRT may include combinations of radioactive labeled somatostatin analogs, intra-arterial administration, and the use of radiosensitizing drugs combined with PRRT. Other therapeutic applications of PRRT may include additional therapy cycles in patients with progressive disease after benefit from initial therapy, PRRT in adjuvant or neoadjuvant setting, or PRRT combined with new targeted therapies, such as sunitinib or everolimus. Randomized clinical trials comparing PRRT with other treatment modalities, or comparing various radioactive labeled somatostatin analogs should be undertaken to determine the best treatment options and treatment sequelae for patients with GEPNETs.

8 Review Nuclear medicine techniques for the imaging and treatment of neuroendocrine tumours. 2011

Teunissen, Jaap J M / Kwekkeboom, Dik J / Valkema, R / Krenning, Eric P. ·Department of Nuclear Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands. j.teunissen@erasmusmc.nl ·Endocr Relat Cancer · Pubmed #22005114.

ABSTRACT: Nuclear medicine plays a pivotal role in the imaging and treatment of neuroendocrine tumours (NETs). Somatostatin receptor scintigraphy (SRS) with [(111)In-DTPA(0)]octreotide has proven its role in the diagnosis and staging of gastroenteropancreatic NETs (GEP-NETs). New techniques in somatostatin receptor imaging include the use of different radiolabelled somatostatin analogues with higher affinity and different affinity profiles to the somatostatin receptor subtypes. Most of these analogues can also be labelled with positron-emitting radionuclides that are being used in positron emission tomography imaging. The latter imaging modality, especially in the combination with computed tomography, is of interest because of encouraging results in terms of improved imaging quality and detection capabilities. Considerable advances have been made in the imaging of NETs, but to find the ideal imaging method with increased sensitivity and better topographic localisation of the primary and metastatic disease remains the ultimate goal of research. This review provides an overview of the currently used imaging modalities and ongoing developments in the imaging of NETs, with the emphasis on nuclear medicine and puts them in perspective of clinical practice. The advantage of SRS over other imaging modalities in GEP-NETs is that it can be used to select patients with sufficient uptake for treatment with radiolabelled somatostatin analogues. Peptide receptor radionuclide therapy (PRRT) is a promising new tool in the management of patients with inoperable or metastasised NETs as it can induce symptomatic improvement with all Indium-111, Yttrium-90 or Lutetium-177-labelled somatostatin analogues. The results that were obtained with [(90)Y-DOTA(0),Tyr(3)]octreotide and [(177)Lu-DOTA(0),Tyr(3)]octreotate are even more encouraging in terms of objective tumour responses with tumour regression and documented prolonged time to progression. In the largest group of patients receiving PRRT, treated with [(177)Lu-DOTA(0),Tyr(3)]octreotate, a survival benefit of several years compared with historical controls has been reported.

9 Review New therapeutic options for metastatic malignant insulinomas. 2011

de Herder, Wouter W / van Schaik, Ellen / Kwekkeboom, Dik / Feelders, Richard A. ·Department of Internal Medicine, Sector of Endocrinology, Erasmus MC, Rotterdam, the Netherlands. w.w.deherder@erasmusmc.nl ·Clin Endocrinol (Oxf) · Pubmed #21649688.

ABSTRACT: Insulinomas are the most common, functioning, pancreatic neuroendocrine tumours. The great majority (>90%) of insulinomas are nonmetastatic at presentation and can be surgically cured. The <10% patients with distant (liver-bone) metastases have a median survival of < 2 years. Everolimus and sunitinib have been recently introduced as targeted therapies for metastatic pancreatic neuroendocrine tumours. An additional advantage of everolimus in the treatment of patients with metastatic insulinomas is its capability to increase blood glucose levels. Peptide receptor radiotherapy using radiolabelled somatostatin analogues has also been shown to be successful in controlling tumour growth of metastatic pancreatic neuroendocrine tumours. In patients with metastatic insulinomas, this therapeutic modality was also effective in controlling hypoglycaemia, even in the presence of tumour regrowth. With the introduction of these new therapeutic modalities, the therapeutic arsenal for the 'tailor-made' approach of patients with metastatic insulinomas is further expanded.

10 Review Somatostatin receptor-targeted radionuclide therapy in patients with gastroenteropancreatic neuroendocrine tumors. 2011

Kwekkeboom, Dik J / de Herder, Wouter W / Krenning, Eric P. ·Department of Nuclear Medicine, Erasmus Medical Center, 's Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands. d.j.kwekkeboom@erasmusmc.nl ·Endocrinol Metab Clin North Am · Pubmed #21349418.

ABSTRACT: Treatment with radiolabeled somatostatin analogs is a promising tool in the management of patients with inoperable or metastasized neuroendocrine tumors. Symptomatic improvement may occur with all (111)Indium-, (90)Yttrium-, or (177)Lutetium-labeled somatostatin analogs used for peptide receptor radionuclide therapy. If kidney protective agents are used, the side-effects are few and mild, and the median duration of the therapy response is 30 and 40 months, respectively. Overall survival is several years from diagnosis. These data compare favorably with the limited number of alternative treatments. If more widespread use of PRRT can be guaranteed, such therapy may become the therapy of first choice.

11 Review Role of somatostatins in gastroenteropancreatic neuroendocrine tumor development and therapy. 2010

Oberg, Kjell E / Reubi, Jean-Claude / Kwekkeboom, Dik J / Krenning, Eric P. ·Department of Endocrine Oncology, University Hospital, Uppsala, Sweden. kjell.oberg@medsci.uu.se ·Gastroenterology · Pubmed #20637207.

ABSTRACT: The incidence and prevalence of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) have increased in the past 20 years. GEP-NETs are heterogeneous tumors, in terms of clinical and biological features, that originate from the pancreas or the intestinal tract. Some GEP-NETs grow very slowly, some grow rapidly and do not cause symptoms, and others cause hormone hypersecretion and associated symptoms. Most GEP-NETs overexpress receptors for somatostatins. Somatostatins inhibit the release of many hormones and other secretory proteins; their effects are mediated by G protein-coupled receptors that are expressed in a tissue-specific manner. Most GEP-NETs overexpress the somatostatin receptor SSTR2; somatostatin analogues are the best therapeutic option for functional neuroendocrine tumors because they reduce hormone-related symptoms and also have antitumor effects. Long-acting formulations of somatostatin analogues stabilize tumor growth over long periods. The development of radioactive analogues for imaging and peptide receptor radiotherapy has improved the management of GEP-NETs. Peptide receptor radiotherapy has significant antitumor effects, increasing overall survival times of patients with tumors that express a high density of SSTRs, particularly SSTR2 and SSTR5. The multi-receptor somatostatin analogue SOM230 (pasireotide) and chimeric molecules that bind SSTR2 and the dopamine receptor D2 are also being developed to treat patients with GEP-NETs. Combinations of radioactive labeled and unlabeled somatostatin analogues and therapeutics that inhibit other signaling pathways, such as mammalian target of rapamycin (mTOR) and vascular endothelial growth factor, might be the most effective therapeutics for GEP-NETs.

12 Article Persistent Hematologic Dysfunction after Peptide Receptor Radionuclide Therapy with 2018

Bergsma, Hendrik / van Lom, Kirsten / Raaijmakers, Marc H G P / Konijnenberg, M / Kam, B L Boen L R / Teunissen, Jaap J M / de Herder, Wouter W / Krenning, Eric P / Kwekkeboom, Dik J. ·Department of Radiology and Nuclear Medicine, Erasmus Medical Center, Rotterdam, The Netherlands bergsmahb@gmail.com. · Department of Hematology, Erasmus Medical Center, Rotterdam, The Netherlands; and. · Department of Radiology and Nuclear Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. · Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. ·J Nucl Med · Pubmed #28775205.

ABSTRACT: Peptide receptor radionuclide therapy (PRRT) may induce long-term toxicity to the bone marrow (BM). The aim of this study was to analyze persistent hematologic dysfunction (PHD) after PRRT with

13 Article Long-Term Efficacy, Survival, and Safety of [ 2017

Brabander, Tessa / van der Zwan, Wouter A / Teunissen, Jaap J M / Kam, Boen L R / Feelders, Richard A / de Herder, Wouter W / van Eijck, Casper H J / Franssen, Gaston J H / Krenning, Eric P / Kwekkeboom, Dik J. ·Department of Radiology & Nuclear Medicine, Erasmus Medical Center, Rotterdam, the Netherlands. t.brabander@erasmusmc.nl. · Department of Radiology & Nuclear Medicine, Erasmus Medical Center, Rotterdam, the Netherlands. · Department of Internal Medicine, Erasmus Medical Center, ENETS Center of Excellence, Rotterdam, the Netherlands. · Department of Surgery, Erasmus Medical Center, Rotterdam, the Netherlands. ·Clin Cancer Res · Pubmed #28428192.

ABSTRACT:

14 Article Physiological Uptake in the Pancreatic Head on Somatostatin Receptor Scintigraphy Using [111In-DTPA]Octreotide: Incidence and Mechanism. 2017

Brabander, Tessa / Teunissen, Jaap / Kwekkeboom, Dik. ·From the Department of Radiology & Nuclear Medicine, Erasmus Medical Center, Rotterdam, the Netherlands. ·Clin Nucl Med · Pubmed #27775943.

ABSTRACT: PURPOSE: Physiological uptake in the uncinate process or pancreatic head has been described with Ga-labeled PET tracers for somatostatin receptor imaging. In-DTPA-octreotide is the only registered radiopharmaceutical for the imaging of neuroendocrine tumors. We studied the uptake in this region of the pancreatic head on somatostatin receptor scintigraphy (SRS) using In-DTPA-octreotide in a large group of patients. Furthermore, known physiological and clinical characteristics are discussed in an attempt to elucidate this phenomenon. METHODS: Four hundred seven patients underwent SRS using In-DTPA-octreotide in our department in 2014. After excluding patients with a known malignancy in or close to the pancreas, as well as all scans without SPECT/CT of the upper abdomen, we reviewed 178 scans in total. The uptake was graded on a 4-point scale that correlates the uptake in the pancreatic head to physiological uptake in the liver. RESULTS: Uptake in the region of the pancreatic head, including the uncinate process, was seen in 46 (26%) of 178 patients on SPECT/CT and in 12 patients (7%) on planar imaging. On SPECT/CT, uptake was lower than the liver in 26 patients (15%), equal to the liver in 17 patients (10%), and higher than the liver in 3 patients (2%). In patients with diabetes mellitus (DM), the incidence of uptake in the pancreatic head was 50% on SPECT/CT. CONCLUSIONS: Physiological uptake in the pancreatic head is seen on SPECT/CT with In-DTPA-octreotide in 26% of patients, and the incidence is doubled in patients with DM. Previous case reports showed uptake in the pancreatic head due to histologically proven pancreatic polypeptide (PP) cell hyperplasia. Also, patients with DM have elevated serum PP concentrations, which is likely due to PP cell hyperplasia. Because 90% of PP cells are present in the pancreatic head, PP cell hyperplasia is the most likely explanation for visualization of the pancreatic head on SRS in a substantial number of patients.

15 Article Is There an Additional Value of Using Somatostatin Receptor Subtype 2a Immunohistochemistry Compared to Somatostatin Receptor Scintigraphy Uptake in Predicting Gastroenteropancreatic Neuroendocrine Tumor Response? 2016

van Adrichem, Roxanne C S / Kamp, Kimberly / van Deurzen, Carolien H M / Biermann, Katharina / Feelders, Richard A / Franssen, Gaston J H / Kwekkeboom, Dik J / Hofland, Leo J / de Herder, Wouter W. · ·Neuroendocrinology · Pubmed #26536001.

ABSTRACT: BACKGROUND AND AIMS: It is unknown whether tumoral somatostatin receptor subtype 2a (sst2a) immunohistochemistry (IHC) has additional value compared to somatostatin receptor scintigraphy (SRS) uptake using OctreoScan® in predicting response to peptide receptor radiotherapy using 177Lu-octreotate (PRRT) in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs). The aims of this study were: (1) to establish the percentage of sst2a immunopositivity in GEP-NET samples of PRRT-treated patients, (2) to determine the relationship between best GEP-NET response using RECIST 1.0 criteria 1 year after PRRT and tumoral sst2a IHC, and (3) to compare characteristics of patients with sst2a IHC-negative and -positive tumors. METHODS: All 73 consecutive patients were selected for PRRT based on a positive SRS. Radiological response was scored according to RECIST 1.0 criteria. sst2a status was detected on tumor samples by IHC. RESULTS: In total, 93% of GEP-NET samples showed sst2a IHC positivity. No statistically significant relationship was observed between in vitro sst2a expression and in vivo best GEP-NET response 1 year after PRRT (p = 0.47). Sex, primary tumor site, disease stage, ENETS TNM classification, Ki-67 index, highest serum chromogranin-A level, and highest neuron-specific enolase level were not significantly different between patients with negative and positive sst2a tumoral IHC with the exception of age at diagnosis (p = 0.007). CONCLUSIONS: sst2a IHC of tumor samples has no additional value compared to SRS uptake using OctreoScan® in predicting tumor response after PRRT.

16 Article Neoadjuvant Treatment of Nonfunctioning Pancreatic Neuroendocrine Tumors with [177Lu-DOTA0,Tyr3]Octreotate. 2015

van Vliet, Esther I / van Eijck, Casper H / de Krijger, Ronald R / Nieveen van Dijkum, Elisabeth J / Teunissen, Jaap J / Kam, Boen L / de Herder, Wouter W / Feelders, Richard A / Bonsing, Bert A / Brabander, Tessa / Krenning, Eric P / Kwekkeboom, Dik J. ·Department of Nuclear Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands esthervanvliet@yahoo.com. · Department of Surgery, Erasmus Michoacande Ocampo, University Medical Center, Rotterdam, The Netherlands. · Department of Pathology, Erasmus Michoacande Ocampo, University Medical Center, Rotterdam, The Netherlands. · Department of Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. · Department of Nuclear Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands. · Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands; and. · Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands. ·J Nucl Med · Pubmed #26272813.

ABSTRACT: METHODS: We studied 29 Dutch patients with a pathology-proven nonfunctioning pancreatic NET treated with (177)Lu-octreotate. All patients had a borderline or unresectable pancreatic tumor (group 1) or oligometastatic disease (defined as ≤3 liver metastases) (group 2). Progression-free survival (PFS) was analyzed using the Kaplan-Meier method and Cox proportional hazards modeling. RESULTS: After the treatment with (177)Lu-octreotate, successful surgery was performed in 9 of 29 patients (31%). Six patients had a Whipple procedure, 2 patients had a pylorus-preserving pancreaticoduodenectomy, and 1 patient had a distal pancreatectomy and splenectomy. The median PFS was 69 mo for patients with successful surgery and 49 mo for the other patients. For comparison, the median PFS in 90 other patients with a nonfunctioning pancreatic NET with more than 3 liver metastases or other metastases was 25 mo. CONCLUSION: Neoadjuvant treatment with (177)Lu-octreotate is a valuable option for patients with initially unresectable pancreatic NETs.

17 Article Pazopanib: a new drug for pancreatic neuroendocrine tumours. 2015

Kwekkeboom, Dik J. ·Department of Nuclear Medicine, Erasmus Medical Center, Rotterdam 3015 GD, Netherlands. ·Lancet Oncol · Pubmed #25956796.

ABSTRACT: -- No abstract --

18 Article Parathyroid hormone-related peptide (PTHrP) secretion by gastroenteropancreatic neuroendocrine tumors (GEP-NETs): clinical features, diagnosis, management, and follow-up. 2014

Kamp, Kimberly / Feelders, Richard A / van Adrichem, Roxanne C S / de Rijke, Yolanda B / van Nederveen, Francien H / Kwekkeboom, Dik J / de Herder, Wouter W. ·Department of Internal Medicine, Sector of Endocrinology (K.K., R.A.F., R.C.S.v.A., W.W.d.H.), Department of Clinical Chemistry (Y.B.d.R.), Department of Pathology (F.H.v.N.), and Department of Nuclear Medicine (D.J.K.), ENETS Centre of Excellence, Erasmus Medical Center, 3015 CE Rotterdam, The Netherlands. ·J Clin Endocrinol Metab · Pubmed #24905065.

ABSTRACT: CONTEXT: Only a small number of case reports has been published on patients with PTHrP-hypersecreting metastatic gastroenteropancreatic (GEP) neuroendocrine tumors (NETs). OBJECTIVE: The objective of this study was to evaluate the clinical, biochemical, and radiological features, management, and treatment outcome of patients with PTHrP-hypersecreting GEP-NETs. DESIGN: Retrospective case series. SETTING: Tertiary referral hospital. MAIN OUTCOME MEASURES: Clinical, biochemical, and radiological features were measured, as well as response to therapy and survival. PATIENTS: Ten patients with PTHrP-secreting GEP-NETs (nine pancreatic and one unknown primary) with a median age of 50.4 years (range, 38.3-61.1) were studied. Multiple endocrine neoplasia type 1 patients were excluded. RESULTS: The median follow-up was 57.2 months (range, 11.6-204.5 mo). Median overall survival was 86.0 months. In total, 51 different treatment interventions and combinations were applied. In seven of the 10 patients, somatostatin analog (SSA) treatment resulted in a temporary normalization of serum calcium levels with a long-term response observed in two patients (up to 35.2 mo). Peptide receptor radiotherapy (PRRT) with radiolabeled SSAs induced long-term responses ranging from 9.0-49.0 months in four of six patients treated with PRRT. CONCLUSIONS: Hypersecretion of PTHrP by metastatic GEP-NETs is very rare and seems to be exclusively associated with metastatic pancreatic NETs. PTHrP production has major clinical impact because poorly controllable hypercalcemia is associated with increased morbidity and mortality. The most successful treatment options for PTHrP-producing GEP-NETs are SSAs and PRRT using radiolabeled SSAs. Isotonic saline and bisphosphonates can be considered as supportive therapies.

19 Article Comparison of response evaluation in patients with gastroenteropancreatic and thoracic neuroendocrine tumors after treatment with [177Lu-DOTA0,Tyr3]octreotate. 2013

van Vliet, Esther I / Krenning, Eric P / Teunissen, Jaap J / Bergsma, Hendrik / Kam, Boen L / Kwekkeboom, Dik J. ·Department of Nuclear Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands. ·J Nucl Med · Pubmed #24084705.

ABSTRACT: METHODS: Two-hundred sixty-eight Dutch patients with NETs who had been treated with (177)Lu-octreotate between January 2000 and April 2007 were studied. CT or MR imaging scans were analyzed using RECIST, SWOG criteria, mRECIST, and mSWOG criteria (including the tumor response class minor response [decrease of 13%-30% for mRECIST and 25%-50% for mSWOG]). The outcomes were correlated with progression-free survival (PFS) and overall survival (OS). RESULTS: Eleven patients had an unknown tumor response and were excluded. The rates of objective response (OR) (complete response + partial response [+minor response for mRECIST/mSWOG]), stable disease, and progressive disease (PD) were 28%, 49%, and 24%, respectively, according to RECIST; 25%, 49%, and 26%, respectively, according to SWOG; 44%, 33%, and 24%, respectively, according to mRECIST; and 45%, 29%, and 26%, respectively, according to mSWOG. In patients who had OR, stable disease, or PD, the median PFS was 26-30, 27-34, and 8 mo, respectively, with any of the 4 response criteria. In patients who had OR, stable disease, or PD, the median OS was 55-57, 56-74, and 11-12 mo, respectively, with any of the 4 response criteria. Subanalyses for patients who had progression before treatment start were comparable. CONCLUSION: Patients with PD as treatment outcome had significantly shorter PFS and OS than patients with an OR or stable disease with all 4 scoring systems. PFS and OS were comparable for patients with tumor regression and stable disease. The addition of the response class minor response did not improve the correlation with PFS and OS. The 4 scoring systems gave comparable results in terms of PFS and OS per categorized outcome.

20 Article Safety and efficacy of everolimus in gastrointestinal and pancreatic neuroendocrine tumors after (177)Lu-octreotate. 2013

Kamp, Kimberly / Gumz, Brenda / Feelders, Richard A / Kwekkeboom, Dik J / Kaltsas, Gregory / Costa, Frederico P / de Herder, Wouter W. ·Sector of Endocrinology, Department of Internal Medicine Department of Nuclear Medicine, Erasmus Medical Center, 's-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands Centro de Oncologia, Hospital Sírio Libanês, São Paulo, Brazil Department of Pathophysiology, National University of Athens, Athens, Greece. ·Endocr Relat Cancer · Pubmed #24036133.

ABSTRACT: Although (177)Lu-octreotate is an effective treatment for patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs), some patients will fail or develop disease progression necessitating further treatment. We examined whether the safety and efficacy of everolimus after prior treatment with (177)Lu-octreotate is different from the published safety profile of everolimus in GEP-NETs. In this multicenter study, 24 GEP-NET patients were included. Adverse events were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. Tumor response was measured according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.0. Major clinical adverse events (grade 3 or 4) during treatment with everolimus were hyperglycemia (20.8%), fatigue (8.3%), thrombocytopenia (8.3%), and elevated alanine transaminase levels (8.3%). By radiological review, there were four partial responses (16.7%), five patients (62.5%) with stable disease, and three patients (12.5%) with progressive disease. For two patients (8.3%), no data on tumor response were available. Median progression-free survival (PFS) was 13.1 months (95% CI, 11.5-21.2). Median PFS of the current study was longer when compared with the RADIANT-3 trial (13.1 vs 11.4 months) and shorter when compared with the RADIANT-1 trial (13.1 vs 16.7 months). In conclusion, the safety profile of everolimus is not influenced by previous treatment with peptide receptor radiotherapy.

21 Article Tumor response assessment to treatment with [177Lu-DOTA0,Tyr3]octreotate in patients with gastroenteropancreatic and bronchial neuroendocrine tumors: differential response of bone versus soft-tissue lesions. 2012

van Vliet, Esther I / Hermans, John J / de Ridder, Maria A / Teunissen, Jaap J / Kam, Boen L / de Krijger, Ronald R / Krenning, Eric P / Kwekkeboom, Dik J. ·Department of Nuclear Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands. e.i.vanvliet@erasmusmc.nl ·J Nucl Med · Pubmed #22782312.

ABSTRACT: METHODS: Forty-two patients with well-differentiated NETs who had bone metastases that were positive on [(111)In-DTPA(0)]octreotide somatostatin receptor scintigraphy (SRS) before treatment, and who had soft-tissue lesions, were studied. All patients had had a minimum of 1 follow-up CT scan. Lesions were scored on CT and bone lesions also on SRS before and after treatment. Tumor markers (chromogranin A and 5-hydroxyindoleacetic acid) before and after treatment were compared. RESULTS: Because bone lesions were not visible on CT before treatment in 11 of 42 patients (26%), bone and soft-tissue lesions were evaluated in 31 patients. Whereas bone lesions increased in size, soft-tissue lesions decreased in size. The percentage change in bone and soft-tissue lesions was significantly different at all time points up to 12 mo of follow-up (P < 0.001). The intensity or number of bone lesions on SRS decreased after treatment in 19 of 23 patients (83%) in whom SRS after treatment was available. The tumor markers also decreased significantly after treatment. In 1 patient, bone lesions became visible on CT after treatment, mimicking progressive disease with "new" bone lesions, although there was an overall treatment response. CONCLUSION: In patients with NETs, the apparent increase in size of bone lesions or the appearance of new bone lesions on CT after treatment with (177)Lu-octreotate should be interpreted cautiously, as this finding may be therapy-related rather than indicative of tumor progression.

22 Article Neoadjuvant downsizing by internal radiation: a case for preoperative peptide receptor radionuclide therapy in patients with pancreatic neuroendocrine tumors. 2012

Ezziddin, Samer / Lauschke, Holger / Schaefers, Michael / Meyer, Carsten / van Essen, Martijn / Biersack, Hans-Jürgen / Kwekkeboom, Dik J / Ahmadzadehfar, Hojjat. ·Department of Nuclear Medicine, University Hospital Bonn, Bonn, Germany. samer.ezziddin@ukb.uni-bonn.de ·Clin Nucl Med · Pubmed #22157044.

ABSTRACT: -- No abstract --

23 Article Immunohistochemical localization and quantitative expression of somatostatin receptors in normal human spleen and thymus: Implications for the in vivo visualization during somatostatin receptor scintigraphy. 2012

Ferone, D / Pivonello, R / Kwekkeboom, D J / Gatto, F / Ameri, P / Colao, A / de Krijger, R R / Minuto, F / Lamberts, S W J / van Hagen, P M / Hofland, L J. ·Department of Endocrinological and Medical Sciences and Center of Excellence for Biomedical Research, University of Genoa, Viale Benedetto XV, 6-16132-Genoa, Italy. ferone@unige.it ·J Endocrinol Invest · Pubmed #21765239.

ABSTRACT: BACKGROUND: [111In-DTPA-D-Phe1]-octreotide scintigraphy allows the visualization of SRIF receptor (SSR)-expressing tumors, including thymic tumors, and normal tissues. While the spleen is clearly visualized, the thymus is not depicted, although both contain SSR. AIM: We evaluated whether the heterogeneity, the type, and the amount of SSR might explain this contrasting finding. MATERIALS, METHODS, AND RESULTS: By ligand-binding the number of [125I-Tyr11]-SRIF- 14 binding sites resulted comparable between the two tissues, whereas the number of [125I-Tyr3]-octreotide sites was significantly higher in the spleen (p<0.001). Quantitative RTPCR showed a significantly higher expression of sst2A mRNA in the spleen, whereas a significantly higher expression of SRIF and sst3 in the thymus. The highest density of sst2A in the spleen is in line with the in vivo uptake of [111In-DTPA-D-Phe1]- octreotide, which is considered a sst2-preferring ligand. The specificity is confirmed by the evidence that in vivo [111In-DTPA- D-Phe1]-octreotide uptake can be abolished during chronic administration of "cold" octreotide. Immunohistochemistry confirmed a preferential expression of sst2A on microenvironmental cells and of sst3 on lymphoid cells. CONCLUSIONS: The heterogeneity of SSR expression and the higher SRIF content explain the lack of thymus visualization during scintigraphy, whereas thymic tumors, which do not express SRIF, are visualized. Apart from the affinity of the radioligand, also the efficacy of the internalization is crucial for the in vivo uptake, and both heterogeneity and SRIF content affect this process. These observations might have an important impact when interpretating in vivo visualization of SSR-positive lesions, and when treatment with novel SRIF analogs is considered.

24 Article Improved control of severe hypoglycemia in patients with malignant insulinomas by peptide receptor radionuclide therapy. 2011

van Schaik, E / van Vliet, E I / Feelders, R A / Krenning, E P / Khan, S / Kamp, K / Valkema, R / van Nederveen, F H / Teunissen, J J M / Kwekkeboom, D J / de Herder, W W. ·Department of Internal Medicine, Section of Endocrinology, Erasmus Medical Center, 's Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands. ·J Clin Endocrinol Metab · Pubmed #21917872.

ABSTRACT: CONTEXT: Insulinomas are relatively rare neuroendocrine tumors of the pancreas. Only 10% are considered malignant. Control of insulin hypersecretion and hypoglycemia in patients with malignant insulinomas may be extremely difficult. Different medications and chemotherapy schedules have been used. PATIENTS: Five patients with metastatic insulinomas and severe, poorly controllable, hypoglycemia are described. These patients required continuous glucose infusion to control severe hypoglycemia, which were induced by the high levels of insulin secretion. Conventional medications, such as diazoxide, or streptozotocin-based chemotherapies had been used to control hypoglycemia but were ineffective and/or produced adverse effects. All patients were treated with sc octreotide. INTERVENTION: Peptide receptor radionuclide therapy with radiolabeled-somatostatin analogs was used. RESULTS: After the start of radiolabeled somatostatin analog therapy, the five patients with metastatic insulinomas had stable disease for a mean period of 27 months. During these months, the patients were without any hypoglycemic episodes. Finally, three of five patients died because of progressive disease. CONCLUSIONS: Radiolabeled somatostatin analog therapy can stabilize tumor growth and can be very successful in further controlling severe hypoglycemia in malignant insulinomas. In our series, this eventually resulted in improved survival outside the hospital setting.

25 Article Quality of life in 265 patients with gastroenteropancreatic or bronchial neuroendocrine tumors treated with [177Lu-DOTA0,Tyr3]octreotate. 2011

Khan, Saima / Krenning, Eric P / van Essen, Martijn / Kam, Boen L / Teunissen, Jaap J / Kwekkeboom, Dik J. ·Department of Nuclear Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. s.khan@erasmusmc.nl ·J Nucl Med · Pubmed #21795361.

ABSTRACT: METHODS: Two hundred sixty-five Dutch patients completed the QOL questionnaire of the European Organization for the Research and Treatment of Cancer after being treated for NETs. ANOVA was used for statistical analyses, with a P value of 0.05 or less being considered significant. Differences of at least 10 points in global health status (GHS)/QOL scores, symptom scores, and Karnofsky performance scores (KPS) before and after therapy were regarded as indicating an improvement. RESULTS: Regardless of the treatment outcome, GHS/QOL, insomnia, appetite loss, and diarrhea improved significantly in the total group. These improvements were also seen in patients with bone metastases or a decrease of 50% or more in chromogranin A. Improvement in the scores by at least 10 points was also analyzed in a subgroup of patients with decreased GHS/QOL or symptoms at the start of therapy: in 36% of these patients, GHS/QOL improved after therapy; in 49%, fatigue; in 70%, nausea plus vomiting; in 53%, pain; in 44%, dyspnea; in 59%, insomnia; in 63%, appetite loss; in 60%, constipation; and in 67%, diarrhea. Additionally, we did not see a statistically significant deterioration in patients who had GHS/QOL 100, KPS 100, or no symptoms at the start. In patients with initial stable disease or remission after treatment, GHS/QOL and KPS decreased significantly when regrowth of the tumors occurred. CONCLUSION: GHS/QOL, KPS, and symptoms improved significantly after (177)Lu-octreotate therapy, and there was no significant decrease in QOL in patients who had no symptoms before therapy. In patients who had suboptimal scores for GHS/QOL or symptoms before therapy, a clinically significant improvement was demonstrated. Our results indicate that (177)Lu-octreotate therapy not only reduces tumors and prolongs overall survival but also improves the patients' self-assessed QOL.

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