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Pancreatic Neoplasms: HELP
Articles by Eric P. Krenning
Based on 20 articles published since 2009
(Why 20 articles?)
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Between 2009 and 2019, E. Krenning wrote the following 20 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Guideline ENETS Consensus Guidelines Update for the Management of Distant Metastatic Disease of Intestinal, Pancreatic, Bronchial Neuroendocrine Neoplasms (NEN) and NEN of Unknown Primary Site. 2016

Pavel, M / O'Toole, D / Costa, F / Capdevila, J / Gross, D / Kianmanesh, R / Krenning, E / Knigge, U / Salazar, R / Pape, U-F / Öberg, K / Anonymous6880853. ·Charite Virchow Klinikum, Berlin, Germany. ·Neuroendocrinology · Pubmed #26731013.

ABSTRACT: -- No abstract --

2 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.

3 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.

4 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.

5 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.

6 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.

7 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.

8 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.

9 Article Salvage peptide receptor radionuclide therapy with [ 2019

van der Zwan, W A / Brabander, T / Kam, B L R / Teunissen, J J M / Feelders, R A / Hofland, J / Krenning, E P / de Herder, W W. ·Department of Radiology & Nuclear Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands. w.vanderzwan@erasmusmc.nl. · Department of Radiology & Nuclear Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands. · Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands. · Cyclotron Rotterdam BV, Erasmus Medical Centre, Rotterdam, The Netherlands. ·Eur J Nucl Med Mol Imaging · Pubmed #30267116.

ABSTRACT: PURPOSE: Therapy with [ METHODS: Patients with progressive bronchial NET or GEP-NET were selected for re-(re)treatment if they had benefited from initial peptide receptor radionuclide therapy (I-PRRT) with a minimal progression-free survival (PFS) of 18 months. Patients received an additional cumulative dose of 14.8 GBq of [ RESULTS: The safety and efficacy analyses included 181 patients and 168 patients, respectively, with bronchial NET or GEP-NET. Overall median follow-up was 88.6 months (95% CI 79.0-98.2). Median cumulative doses were 44.7 GBq (range 26.3-46.4 GBq) during R-PRRT (168 patients) and 59.7 GBq (range 55.2-≤60.5 GBq) during RR-PRRT (13 patients). Objective response and stable disease, as best response, were observed in 26 patients (15.5%) and 100 patients (59.5%) following R-PRRT, and in 5 patients (38.5%) and 7 patients (53.8%) following RR-PRRT, respectively. Median PFS was 14.6 months (95% CI 12.4-16.9) following R-PRRT and 14.2 months (95% CI 9.8-18.5) following RR-PRRT. Combined overall survival (OS) after I-PRRT plus R-PRRT and RR-PRRT was 80.8 months (95% CI 66.0-95.6). Grade III/IV bone marrow toxicity occurred in 6.6% and 7.7% of patients after R-PRRT and RR-PRRT, respectively. Salvage therapy resulted in a significantly longer OS in patients with bronchial NET, GEP-NET and midgut NET than in a nonrandomized control group. The total incidence of acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) was 2.2%. No PRRT-related grade III/IV nephrotoxicity was observed. CONCLUSION: A cumulative dose of up to 60.5 GBq salvage PRRT with [

10 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

11 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:

12 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.

13 Article [(111)In-DTPA]octreotide tumor uptake in GEPNET liver metastases after intra-arterial administration: an overview of preclinical and clinical observations and implications for tumor radiation dose after peptide radionuclide therapy. 2014

Pool, Stefan E / Kam, Boen L R / Koning, Gerben A / Konijnenberg, Mark / Ten Hagen, Timo L M / Breeman, Woulter A P / Krenning, Eric P / de Jong, Marion / van Eijck, Casper H J. ·1 Department of Nuclear Medicine, Erasmus MC , Rotterdam, The Netherlands . ·Cancer Biother Radiopharm · Pubmed #24820805.

ABSTRACT: AIMS: With the aim to improve peptide receptor radionuclide therapy effects in patients with gastroenteropancreatic neuroendocrine tumor (GEPNET) liver metastases we explored the effect of intra-arterial (IA) administration of [(111)In-DTPA]octreotide ((111)In-DTPAOC) on tumor uptake in an animal model and in a patient study. METHODS: Preclinical study: After administering (111)In-DTPAOC intra-venously (IV) or IA, biodistribution studies were performed in rats with a hepatic somatostatin receptor subtype 2 (sst2)-positive tumor. Clinical study: 3 patients with neuroendocrine liver metastases were injected twice with (111)In-DTPAOC. The first injection was given IV, and 2 weeks later, the second was injected IA (hepatic artery). Planar images of the abdomen were made up to 72 hours after injection. Blood samples were taken and urine was collected. Pharmacokinetic modeling was performed on the IV and IA data of the same patient. Based on this model, additional (177)Lu dosimetry calculations for IV and IA administrations were performed. RESULTS: The preclinical study showed a two-fold higher (111)In-DTPAOC tumor uptake after IA administration than after IV injection. Patient data showed a large variability in radioactivity increment in liver metastases after IA administration compared with IV administration. Renal radioactivity was not significantly lower after IA administration; (177)Lu dosimetry simulations in 1 patient using a maximum kidney radiation dose of 23 Gy showed IA administration resulted in a mean increase in tumor radiation dose of 2.9-fold. CONCLUSION: Preclinical and clinical data both indicate that IA administration of radiolabeled somatostatin analogs via the hepatic artery can significantly increase radionuclide uptake in GEPNET, sst2-positive, liver metastases up to 72 hours postinjection, although the effect of IA administration can differ between patients.

14 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.

15 Article mTOR inhibitor RAD001 promotes metastasis in a rat model of pancreatic neuroendocrine cancer. 2013

Pool, Stefan E / Bison, Sander / Koelewijn, Stuart J / van der Graaf, Linda M / Melis, Marleen / Krenning, Eric P / de Jong, Marion. ·Department of Nuclear Medicine and Radiology, Erasmus MC, Rotterdam, The Netherlands. s.pool@erasmusmc.nl ·Cancer Res · Pubmed #23149918.

ABSTRACT: Inhibition of mTOR is commonly considered a valid target in cancer treatment, but this assertion does not address effects on the immune microenvironment that may be detrimental to cancer treatment. Here we show how administration of the mTOR inhibitor RAD001 (everolimus) results in the occurrence of distant metastasis in a rat model of pancreatic cancer. RAD001 was administered twice weekly for 4.5 weeks as a single treatment or combined with [(177)Lu-DOTA,Tyr3]octreotate ((177)Lu-DOTATATE), where the latter targets the somatostatin receptor-2. The hypothesized synergistic therapeutic effect of RAD001 combined with (177)Lu-DOTATATE was, however, not observed in our experiments. The combination was shown to be less effective than (177)Lu-DOTATATE alone. Unexpectedly, tumor metastasis was observed in 77% of the subjects treated with RAD001, either alone or as part of the combination treatment. This was a striking effect, because metastasis did not occur in control or (177)Lu-DOTATATE-treated animals, including those where the primary tumor was surgically removed. These findings may be important clinically among noncompliant patients or patients that discontinue RAD001 therapy because of adverse effects.

16 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.

17 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.

18 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.

19 Article Dose-response effect of Gelofusine on renal uptake and retention of radiolabelled octreotate in rats with CA20948 tumours. 2009

Melis, Marleen / Bijster, Magda / de Visser, Monique / Konijnenberg, Mark W / de Swart, Jan / Rolleman, Edgar J / Boerman, Otto C / Krenning, Eric P / de Jong, Marion. ·Department of Nuclear Medicine, Erasmus MC Rotterdam, 's Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands. m.melis@erasmusmc.nl ·Eur J Nucl Med Mol Imaging · Pubmed #19585115.

ABSTRACT: PURPOSE: Peptide receptor radionuclide therapy using β-emitting radiolabelled somatostatin analogues like DOTA,Tyr3-octreotate shows beneficial results in patients suffering from somatostatin receptor overexpressing tumours. However, after high-dose therapy partial renal reabsorption of radiopeptides may lead to nephrotoxicity. Co-infusion of lysine/arginine lowers renal retention of these radiopeptides without affecting tumour uptake. Recently co-administration of Gelofusine has been described to have a comparable kidney-protecting effect in rats. In the present study optimal dosing of Gelofusine co-administration was studied in tumour-bearing rats. METHODS: Doses of 40, 80, 120 or 160 mg/kg Gelofusine were co-injected with 15 µg DOTA,Tyr3-octreotate, labelled with 3 MBq 111In for biodistribution (24 h post-injection, n = 4 per group) and with 60 MBq 111In for microSPECT imaging experiments at 3, 24 and 48 h post-injection. An additional group of rats received 80 mg/kg Gelofusine plus 400 mg/kg lysine co-injection. Biodistribution studies were performed both in older (475 g) and younger (300 g) rats, the latter bearing CA20948 tumours. RESULTS: Co-injection of 40 mg/kg Gelofusine resulted in 40-50% reduction of renal uptake and retention of 111In-DOTA,Tyr3-octreotate, whereas higher doses further increased the reduction to 50-60% in both groups of rats. Combining Gelofusine and lysine caused 70% reduction of renal uptake. The uptake of radiolabelled octreotate both in somatostatin receptor-expressing normal tissues and tumours was not affected by Gelofusine co-injection. CONCLUSION: In rats co-injection of 80 mg/kg Gelofusine resulted in maximum reduction of renal retention of 111In-DOTA,Tyr3-octreotate, which was further improved when combined with lysine. Tumour uptake of radiolabelled octreotate was not affected, resulting in an increased tumour to kidney ratio.

20 Article Tumor imaging and therapy using radiolabeled somatostatin analogues. 2009

de Jong, Marion / Breeman, Wout A P / Kwekkeboom, Dik J / Valkema, Roelf / Krenning, Eric P. ·Department of Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands. m.hendriks-dejong@erasmusmc.nl ·Acc Chem Res · Pubmed #19445476.

ABSTRACT: Molecular imaging plays an essential role in balancing the clinical benefits and risks of radionuclide-based cancer therapy. To effectively treat individual patients, careful assessment of biodistribution, dosimetry, and toxicity is essential. In this Account, we describe advances that combine features of molecular imaging and radionuclide therapy to provide new avenues toward individualized cancer treatment. Selective receptor-targeting radiopeptides have emerged as an important class of radiopharmaceuticals for molecular imaging and therapy of tumors that overexpress peptide receptors on the cell membrane. After such peptides labeled with gamma-emitting radionuclides bind to their receptors, they allow clinicians to visualize receptor-expressing tumors non-invasively. Peptides labeled with beta-particle emitters could also eradicate receptor-expressing tumors. The somatostatin receptors, which are overexpressed in a majority of neuroendocrine tumors, represent the first and best example of targets for radiopeptide-based imaging and radionuclide therapy. The somatostatin analogue (111)In-octreotide permits the localization and staging of neuroendocrine tumors that express the appropriate somatostatin receptors. Newer modified somatostatin analogues, including Tyr(3)-octreotide and Tyr(3)-octreotate, are successfully being used for tumor imaging and radionuclide therapy. Because there are few effective therapies for patients with inoperable or metastasized neuroendocrine tumors, this therapy is a promising novel treatment option for these patients. Peptide receptor imaging and radionuclide therapy can be combined in a single probe, called a "theranostic". To select patients who are likely to benefit from this type of intervention, we first use a peptide analogue labeled with a diagnostic radionuclide to obtain a scan. Selected patients will be treated using the same or a similar peptide analogue labeled with a therapeutic radionuclide. The development of such theranostics could greatly advance the development of personalized treatments. Apart from patient selection for radionuclide therapy, other imaging applications of targeted radiopeptides include localization of primary tumors, detection of metastatic disease (staging/restaging), dosimetry (prediction of response and radiotoxicity), monitoring effects of surgery, radio(nuclide)therapy or chemotherapy, and detection of progression of disease or relapse (follow up). For further evaluation of tumor receptor expression and to increase the value of cancer targeting using radiopeptides, researchers have introduced and evaluated different radiolabeled analogues of other peptide families, such as cholecystokinin (CCK), gastrin, bombesin, substance P, vasoactive intestinal peptide (VIP), and neuropeptide (NP)-Y analogues. We expect improvements in the development of new peptide analogues: such advances could reduce side effects and allow for the use of combination therapy (for example, combining radiopeptide analogues with chemotherapeutics).