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The purpose of these guidelines is to assist physicians caring for patients with neuroendocrine neoplasia in considering eligibility criteria for peptide receptor radionuclide therapy (PRRT) and in defining the minimum requirements for PRRT. It is not these guidelines' aim to give recommendations on the use of specific radiolabelled somatostatin analogues for PRRT as different analogues are being used, and their availability is governed by varying international regulations. However, a recent randomized controlled trial, NETTER-1, has provided evidence that may establish 177Lu-DOTA-octreotate (LutaThera®) as the first widely approved agent. It also makes recommendations on what minimal patient, tumour, and treatment outcome characteristics should be reported for PRRT to facilitate robust comparisons between studies. [ABSTRACT FROM AUTHOR]

Prostate-specific antigen (PSA)-based screening for prostate cancer (PC) has dramatically increased early diagnosis. Current imaging techniques are not optimal to stage early PC adequately. A promising alternative to PC imaging is peptide-based scintigraphy using radiolabelled bombesin (BN) analogues that bind to gastrin-releasing peptide receptors (GRPR) being overexpressed in PC. When labelled to appropriate radionuclides BN targeting of GRPRs may also provide applications for peptide radionuclide receptor therapy (PRRT). Assessment studies under identical experimental conditions allowing a reliable comparison of the potential of such analogues are lacking. This study was performed to evaluate and directly compare five promising radiolabelled BN analogues for their targeting efficacy for PC under standardised conditions. The BN agonists [111In]DOTA-PESIN, [111In]AMBA, [111In]MP2346 and [111In]MP2653 and one antagonist [99mTc]Demobesin-1 were evaluated in GRPR-overexpressing human PC-3 tumour-bearing mice to determine peptide stability in vivo, biodistribution and GRPR targeting potential by animal SPECT/CT imaging and ex vivo autoradiography. HPLC analysis of blood showed intact Demobesin-1 at 5 and 15 min after injection (64.1 ± 1.6% and 41.0 ± 01%, respectively) being much less for the other compounds. AMBA, the second most stable analogue, showed 36.1 ± 2.7% and 9.8 ± 1.1% intact peptide after 5 and 15 min. PC-3 tumour uptake at 1 h was comparable for Demobesin-1, AMBA, PESIN and MP2346 (3.0 ± 0.4, 2.7 ± 0.5, 2.3 ± 0.5 and 2.1 ± 0.9%ID/g, respectively), but very low for MP2653 (0.9 ± 0.2%ID/g). In addition, MP2346 showed undesirably high uptake in the kidneys (7.9 ± 1.9%ID/g) being significantly less for the other analogues. AMBA, MP2346 and PESIN revealed favourable increases in tumour to blood ratios over time while changes in tumour to kidney and pancreas ratios for Demobesin-1 from 1 to 24 h after injection were significantly better than for the other analogues. All analogues visualised PC-3 tumours by SPECT/CT and autoradiography. In the present study the BN antagonist Demobesin-1 was the best performing analogue showing superior in vivo stability, highest tumour uptake and retention while pancreatic and renal clearance were rapid. PESIN and AMBA were the best GRP agonists with sufficient in vivo stabilities as well as high tumour uptake and retention. Based on these results all three analogues deserve further evaluation for clinical use in PC patients. [ABSTRACT FROM AUTHOR]

The purpose of this guideline is to assist physicians caring for patients with neuroendocrine tumors in considering eligibility criteria for peptide receptor radionuclide therapy (PRRT), and in defining the minimum requirements for PRRT. This guideline also makes recommendations on what minimal patient, tumor, and treatment outcome characteristics should be reported for PRRT in order to make comparisons between studies possible. It is not this guideline’s aim to give specific recommendations on the use of specific radiolabeled somatostatin analogs for PRRT because different analogs are being used, and their availability depends on national law and local permissions. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The article presents guidelines formulated at the 2007 European Neuroendocrine Tumor Society (ENETS) Standards of Care Conference on the performance, interpretation and reporting of results of somatostatin receptor scintigraphy with 111In-pentetreotide. The action of somatostatin is mediated through membrane-bound receptors. Visualization of the thyroid, spleen, liver and kidneys are some of the normal scintigraphic features.

Adequate dosimetry is mandatory for effective and safe peptide receptor radionuclide therapy (PRRT). Besides the kidneys, the bone marrow is a potentially dose-limiting organ. The radiation dose to the bone marrow is usually calculated according to the MIRD scheme, where the accumulated activity in the bone marrow is calculated from the accumulated radioactivity of the radiopharmaceutical in the blood. This may underestimate the absorbed dose since stem cells express somatostatin receptors. We verified the blood-based method by comparing the activity in the blood with the radioactivity in bone marrow aspirates. Also, we evaluated the absorbed cross-dose from the source organs (liver, spleen, kidneys and blood), tumours and the so-called “remainder of the body” to the bone marrow. Bone marrow aspirates were drawn in 15 patients after treatment with [177Lu-DOTA0,Tyr3]octreotate. Radioactivity in the bone marrow was compared with radioactivity in the blood drawn simultaneously. The nucleated cell fraction was isolated from the bone marrow aspirate and radioactivity was measured. The absorbed dose to the bone marrow was calculated. The results were correlated to the change in platelet counts 6 weeks after treatment. A strong linear correlation and high agreement between the measured radioactivities in the bone marrow aspirates and in the blood was found ( r=0.914, p<0.001). No correlation between the calculated absorbed dose in the bone marrow and the change in platelets was found. There was a considerable contribution from other organs and the remainder of the body to the bone marrow absorbed dose. (1) After PRRT with [177Lu-DOTA0,Tyr3]octreotate, the radioactivity concentration in the bone marrow is identical to that in the blood; (2) There is no significant binding of the radiopharmaceutical to bone marrow precursor stem cells; (3) The contribution of the cross dose from source organs and tumours to the bone marrow dose is significant; and (4) There is considerable variation in bone marrow absorbed dose between patients. These findings imply that for individual dose optimization, individual calculation of the bone marrow absorbed dose is necessary. [ABSTRACT FROM AUTHOR]

Peptide Receptor Radionuclide Therapy (PRRT) with radiolabelled somatostatin analogues is a promising treatment option for patients with inoperable or metastasised neuroendocrine tumours. Symptomatic improvement may occur with all of the various 111In, 90Y, or 177Lu-labelled somatostatin analogues that have been used. Since tumour size reduction was seldom achieved with 111Indium labelled somatostatin analogues, radiolabelled somatostatin analogues with beta-emitting isotopes like 90Y and 177Lu were developed. Reported anti-tumour effects of [90Y-DOTA0,Tyr3]octreotide vary considerably between various studies: Tumour regression of 50% or more was achieved in 9 to 33% (mean 22%). With [177Lu-DOTA0,Tyr3]octreotate treatments, tumour regression of 50% or more was achieved in 28% of patients and tumour regression of 25 to 50% in 19% of patients, stable disease was demonstrated in 35% and progressive disease in 18%. Predictive factors for tumour remission were high tumour uptake on somatostatin receptor scintigraphy and limited amount of liver metastases. The side-effects of PRRT are few and mostly mild, certainly when using renal protective agents: Serious side-effects like myelodysplastic syndrome or renal failure are rare. The median duration of the therapy response for [90Y-DOTA0,Tyr3]octreotide and [177Lu-DOTA0,Tyr3]octreotate is 30 months and more than 36 months respectively. Lastly, quality of life improves significantly after treatment with [177Lu-DOTA0,Tyr3]octreotate. These data compare favourably with the limited number of alternative treatment approaches, like chemotherapy. If more widespread use of PRRT is possible, such therapy might become the therapy of first choice in patients with metastasised or inoperable gastroenteropancreatic neuroendocrine tumours. Also the role in somatostatin receptor expressing non-GEP tumours, like metastasised paraganglioma/pheochromocytoma and non-radioiodine-avid differentiated thyroid carcinoma might become more important. [ABSTRACT FROM AUTHOR]

Purpose: Peptide receptor scintigraphy with the radioactive somatostatin analogue 111In-DTPA-octreotide is a sensitive and specific technique to show in vivo the presence of somatostatin receptors on various tumours. Since 111In emits not only gamma rays but also therapeutic Auger and internal conversion electrons with a medium to short tissue penetration (0.02–10 μm and 200–550 μm, respectively), 111In-DTPA-octreotide is also being used for peptide receptor radionuclide therapy (PRRT). In this study we investigated the therapeutic effects of 111In-DTPA-octreotide in tumours of various sizes. Regrowth of a tumour despite PRRT with 111In-DTPA-octreotide may be due to the lack of crossfire from 111In, whereby any possible receptor-negative tumour cell can multiply. We therefore also investigated the somatostatin receptor status of the tumour before and after PRRT. Methods: The radiotherapeutic effects of different doses of 111In-DTPA-octreotide in vivo were investigated in Lewis rats bearing small (≤1 cm²) or large (≥8 cm²) somatostatin receptor-positive rat pancreatic CA20948 tumours expressing the somatostatin receptor subtype 2 (sst2). In addition, the somatostatin receptor density on the tumour after injection of a therapeutic labelled somatostatin analogue was investigated when the tumour was either declining in size or regrowing after an initial reduction in size. To initiate a partial response of the tumour (so that regrowth would follow) and not a complete response, a relatively low dose was administered. Results: Impressive radiotherapeutic effects of 111In-labelled octreotide were observed in this rat tumour model. Complete responses (up to 50%) were found in the animals bearing small (≤1 cm²) tumours after at least three injections of 111 MBq or a single injection of 370 MBq 111In-DTPA-octreotide, leading to a dose of 6.3–7.8 mGy/MBq (1–10 g tumour). In the rats bearing the larger (≥8 cm²) tumours, the effects were much less pronounced and only partial responses were achieved in these groups. Clear sst2 expression was found in the control as well as in the treated tumours. A significantly higher tumour receptor density (p«0.001) was found when the tumours regrew after an initial decline in size after low-dose PRRT in comparison with the untreated tumours. Conclusion: Therapy with 111In-labelled somatostatin analogues is feasible but should preferably start as early as possible during tumour development. One might also consider the use of radiolabelled somatostatin analogues in an adjuvant setting after surgery of somatostatin receptor-positive tumours in order to eradicate occult metastases. We showed that PRRT led to an increase in the density of somatostatin receptors when the tumours regrew after an initial decline in size because of PRRT. Upregulation of the somatostatin receptor may lead to higher uptake of radiolabelled peptides in therapeutic applications, which would probably make repeated injections of radiolabelled peptides more effective. [ABSTRACT FROM AUTHOR]

Peptide receptor radionuclide therapy is a new treatment modality for patients with inoperable or metastasised neuroendocrine gastroenteropancreatic tumours. After the successful implementation of somatostatin receptor scintigraphy in daily clinical practice, the next logical step was to increase the radiation dose of the administered radiolabelled somatostatin analogue in an attempt to induce tumour shrinkage. Since then, an increasing number of patients has been successfully treated with this approach, resulting in a substantial numbers of patient with objective tumour shrinkage. Serious side-effects have been rare. This article reviews the effectiveness of the different radiolabelled somatostatin analogues used, the currently known side-effects and the survival data available. Furthermore, clinical issues, including indication and timing of therapy, are discussed. Finally, important directions for future research are briefly mentioned to illustrate that, although the currently available results already suggest a favourable outcome compared with other systemic therapies, new strategies are being developed to increase efficacy. [Copyright &y& Elsevier]

Earlier studies have shown that modification of the octapeptide octreotide in positions 3 and 8 may result in compounds with increased somatostatin receptor affinity that, if radiolabelled, display improved uptake in somatostatin receptor-positive tumours. The aim of a recent research study in our laboratory was to employ the parallel peptide synthesis approach by further exchanging the amino acid in position 3 of octreotide and coupling the macrocyclic chelator DOTA(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) to these peptides for labelling with radiometals like gallium-67 or -68, indium-111, yttrium-90 and lutetium-177. The purpose was to find radiopeptides with an improved somatostatin receptor binding profile in order to extend the spectrum of targeted tumours. A first peptide, [[sup111]In,[sup90]Y-DOTA]-1-Nal3-octreo- tide (111In,90Y-DOTA-NOC), was isolated which showed an improved profile. In[supIII]-DOTA-NOC exhibited the following IC[sup50] values (nM) when studied in competition with [sup[125I]][Leu[sup8], D-Trp[sup22], Tyr[sup25]]somatostatin-28 (values for Y[supIII]-DOTA-NOC are shown in parentheses): sstr2, 2.9±0.1 (3.3±0.2); sstr3, 8±2 (26±1.9); sstr5, 11.2±3.5 (10.47plusmn;1.6). Affinity towards sstr1 and 4 was very low or absent. In[supIII]-DOTA-NOC is superior to all somatostatin-based radiopeptides having this particular type of binding profile, including DOTA-lanreotide, and has three to four times higher binding affinity to sstr2 than In[supIII],Y[supIII]-DOTA-Tyr3-octreotide (InIII,YIII-DOTA-TOC). In addition, [[sup111]In]DOTA-NOC showed a specific and high rate of internalization into AR4–2J rat pancreatic tumour cells which, after 4 h, was about two times higher than that of [[sup111]In]DOTA-TOC and three times higher than that of [[sup111]In]DOTA-octreotide ([[sup111]In]DOTA-OC). The internalized radiopeptides were externalized intact upon 2 h of internalization followed by an acid wash. After 2–3 h of externalization a plateau is reached, indicating a steady-state situation explained by reactivation of the receptors followed by re-endocytosis. Biodistribution studies in CA 20948 tumour-bearing rats showed rapid clearance from all sstr-negative tissues except the kidneys. At 4 h the up-take of [[sup111]In]DOTA-NOC in the tumour and sstr-positive tissues, such as adrenals, stomach and pancreas, was three to four times higher than that of [[sup111]In]DOTA-TOC. Differential blocking studies indicate that this is at least partially due to the uptake mediated by sstr3 and sstr5. These very promising preclinical data justify the use of this new radiopeptide for imaging and potentially internal radiotherapy studies in patients. [ABSTRACT FROM AUTHOR]

Evaluates the pharmacokinetics and dosimetry of [sup 86]Y-DOTA[sup 0]-D-Phe[sup 1]-Tyr[sup 3]-octreotide in a phase I positron emission tomography study of patients with somatostatin receptor-positive neuroendocrine tumors. Effect of amino acid co-infusion on renal and tumor uptake; Suggestion that the prolongation of the infusion enhances the protective effect on the kidneys.

Radiolabelled tumour receptor-binding peptides can be used for in vivo scintigraphic imaging. Recently, the somatostatin analogue [Tyr[sup 3] ]octreotide (d-Phe-c(Cys-Tyr-d-Trp-Lys-Thr-Cys)-Thr(ol)) was derivatized with the chelator DOTA (tetra-azacyclododecane-tetra-acetic acid), enabling stable radiolabelling with both the high-energy beta particle-emitter yttrium-90 and the Auger electron-emitter indium-111. The thus produced radiolabelled compounds are promising for peptide receptor radionuclide therapy. Our previous in vitro and in vivo (rat) experiments with these radiolabelled compounds showed favourable binding and biodistribution characteristics with high uptake and retention in the target organs. We also demonstrated receptor-specific, time- and temperature-dependent internalization of radiolabelled [DOTA[sup 0] ,Tyr[sup 3] ]octreotide in somatostatin receptor subtype 2 (sst[sub 2] )-positive rat pancreatic tumour cell lines. In this study we have investigated the effects of differences in the amount of injected peptide on tissue distribution of [sup 111] In-labelled [DOTA[sup 0] ,Tyr[sup 3] ]octreotide in normal, i.e. non-tumour-bearing, and CA20948 tumour-bearing rats. This was done in order to find the amount of peptide at which the highest uptake in target tissues is achieved, and thereby to increase the potential of radionuclide therapy while simultaneously ensuring the lowest possible radiotoxicity in normal organs. Uptake of radiolabelled [DOTA[sup 0] ,Tyr[sup 3] ]octreotide in sst[sub 2] -positive organs showed different bell-shaped functions of the amount of injected peptide, being highest at 0.05 (adrenals), 0.05-0.1 (pituitary and stomach) and 0.25 (pancreas) µg. Uptake in the tumour was highest at 0.5 µg injected peptide. The highest uptake was found at peptide amounts that were lower than those reported for [[sup 111] In-DTPA[sup 0] ]octreotide ((d-Phe-c(Cys-Phe-d-Trp-Lys-Thr-Cys)-Thr(ol), DT... [ABSTRACT FROM AUTHOR]

Background: Peptide radioligands may serve as radionuclide carriers to tumor sites overexpressing their cognate receptor for diagnostic or therapeutic purposes. Treatment of mice with the neprilysin (NEP)-inhibitor phosphoramidon was previously shown to improve the metabolic stability and tumor uptake of biodegradable radiopeptides. Aiming to clinical translation of this methodology, we herein investigated the impact of the approved pill Entresto, releasing the potent NEP-inhibitor LBQ657 in vivo, on the stability and tumor uptake of two radiopeptides. Methods: The metabolic stability of [99mTc]Tc-DB4 (DB4, N4-Pro-Gln-Arg-Tyr-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Nle-NH2) and [111In]In-SG4 (SG4, DOTA-DGlu-Ala-Tyr-Gly-Trp-Nle-Asp-Phe-NH2) was tested in LBQ657/Entresto-treated mice vs. untreated controls. The uptake in gastrin-releasing peptide receptor (GRPR)-, or cholecystokinin subtype 2 receptor (CCK2R)-positive tumors respectively, was compared between LBQ657/Entresto-treated mice and untreated controls. Results: LBQ657/Entresto treatment induced marked stabilization of [99mTc] Tc-DB4 and [111In]In-SG4 in peripheral mice blood, resulting in equally enhanced tumor uptake at 4 h post-injection. Accordingly, the [99mTc]Tc-DB4 uptake of 7.13 ± 1.76%IA/g in PC-3 tumors increased to 16.17 ± 0.71/17.50 ± 3.70%IA/g (LBQ657/Entresto) and the [111In]In-SG4 uptake of 3.07 ± 0.87%IA/g in A431-CCK2R(+) tumors to 8.11 ± 1.45/9.61 ± 1.70%IA/g. Findings were visualized by SPECT/CT. Conclusions: This study has shown the efficacy of Entresto to notably improve the profile of [99mTc]Tc-DB4 and [111In]In-SG4 in mice, paving the way for clinical translation of this approach. [ABSTRACT FROM AUTHOR]

Neurotensin subtype 1 receptors (NTS1R) represent attractive molecular targets for directing radiolabeled neurotensin (NT) analogs to tumor lesions for diagnostic and therapeutic purposes. This approach has been largely undermined by the rapid in vivo degradation of linear NT-based radioligands. Herein, we aim to increase the tumor targeting of three 99mTc-labeled NT analogs by the in-situ inhibition of two key proteases involved in their catabolism. DT1 ([N4-Gly7]NT(7-13)), DT5 ([N4-βAla7,Dab9]NT(7-13)), and DT6 ([N4-βAla7,Dab9,Tle12]]NT(7-13)) were labeled with 99mTc. Their profiles were investigated in NTS1R-positive colon adenocarcinoma WiDr cells and mice treated or not with the neprilysin (NEP)-inhibitor phosphoramidon (PA) and/or the angiotensin converting enzyme (ACE)-inhibitor lisinopril (Lis). Structural modifications led to the partial stabilization of 99mTc-DT6 in peripheral mice blood (55.1 ± 3.9% intact), whereas 99mTc-DT1 and 99mTc-DT5 were totally degraded within 5 min. Coinjection of PA and/or Lis significantly stabilized all three analogs, leading to a remarkable enhancement of tumor uptake for 99mTc-DT1 and 99mTc-DT5, but was less effective in the case of poorly internalizing 99mTc-DT6. In conclusion, NEP and/or ACE inhibition represents a powerful tool to improve tumor targeting and the overall pharmacokinetics of NT-based radioligands, and warrants further validation in the field of NTS1R-targeted tumor imaging and therapy. [ABSTRACT FROM AUTHOR]

The overexpression of gastrin-releasing peptide receptors (GRPRs) in frequently occurring human tumors has provided the opportunity to use bombesin (BBN) analogs as radionuclide carriers to cancer sites for diagnostic and therapeutic purposes. We have been alternatively exploring human GRP motifs of higher GRPR selectivity compared to frog BBN sequences aiming to improve pharmacokinetic profiles. In the present study, we compared two differently truncated human endogenous GRP motifs: GRP(14–27) and GRP(18–27). An acyclic tetraamine was coupled at the N-terminus to allow for stable binding of the SPECT radionuclide 99mTc. Their biological profiles were compared in PC-3 cells and in mice without or with coinjection of phosphoramidon (PA) to induce transient neprilysin (NEP) inhibition in vivo. The two 99mTc-N4-GRP(14/18–27) radioligands displayed similar biological behavior in mice. Coinjection of PA exerted a profound effect on in vivo stability and translated into notably improved radiolabel localization in PC-3 experimental tumors. Hence, this study has shown that promising 99mTc-radiotracers for SPECT imaging may indeed derive from human GRP sequences. Radiotracer bioavailability was found to be of major significance. It could be improved during in situ NEP inhibition resulting in drastically enhanced uptake in GRPR-expressing lesions. [ABSTRACT FROM AUTHOR]

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 In-pentetreotide scintigraphy or PET with Ga-labelled somatostatin analogues, frequently identifies additional lesions that are not visible on CT or MRI scans. Currently, somatostatin receptor scintigraphy with mln-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 Ga-labelled somatostatin analogues is expected to replace somatostatin receptor scintigraphy. Whereas F-FDG-PET is only used in high-grade neuroendocrine cancers, PET-CT with F-dihydroxy-L-phenylalanine or C-5-hydroxy-L-tryptophan is a useful problem-solving too! 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 o intestinal and pancreatic NETs. Response evaluation and controversies in NET imaging will also be discussed. [ABSTRACT FROM AUTHOR]

Introduction: Gastrin-releasing peptide receptors (GRPR) and GRP-derived analogs have attracted attention due to high receptor expression in frequently occurring human neoplasia. The authors recently synthesized a series of GRPR-affine peptide analogs based on the 27-mer GRP and derivatized with the DOTA chelator at the N-terminus for 111In-labeling. In this study, the authors evaluated the most promising from these series, DOTA-GRP(13-27), after radiolabeling with 177Lu for future therapeutic applications. In addition, to improve in vivo stability of the peptide against in vivo degradation by the protease neutral endopeptidase (NEP), the authors coinjected [177Lu]DOTA-GRP(13-27) with the potent NEP inhibitor phosphoramidon (PA). The authors also aimed at reducing renal uptake by coadministration of lysine. Methods: In vivo stability studies were performed in Swiss albino mice. Biodistribution studies were conducted in NMRI nu/nu mice bearing prostate cancer (PC)-3 xenografts. Ex vivo autoradiography was performed using frozen sections from PC-3 xenografts and kidneys. Results and Discussion: Coadministration of PA significantly increased the percentage of intact radiopeptide in the mouse circulation. From biodistribution and ex vivo autoradiography studies, coadministration of both lysine and PA with [177Lu]DOTA-GRP(13-27) appeared to induce a clear improvement of tumor uptake as well as lower levels of renal radioactivity, causing a promising ninefold increase in tumor/kidney ratios. [ABSTRACT FROM AUTHOR]

Summary: Gastroenteropancreatic (GEP) neuroendocrine tumours (NETs) are fairly rare neoplasms that present many clinical challenges. They secrete peptides and neuroamines that cause distinct clinical syndromes, including carcinoid syndrome. However, many are clinically silent until late presentation with mass effects. Investigation and management should be highly individualised for a patient, taking into consideration the likely natural history of the tumour and general health of the patient. Management strategies include surgery for cure (which is achieved rarely) or for cytoreduction, radiological intervention (by chemoembolisation and radiofrequency ablation), chemotherapy, and somatostatin analogues to control symptoms that result from release of peptides and neuroamines. New biological agents and somatostatin-tagged radionuclides are under investigation. The complexity, heterogeneity, and rarity of GEP NETs have contributed to a paucity of relevant randomised trials and little or no survival increase over the past 30 years. To improve outcome from GEP NETs, a better understanding of their biology is needed, with emphasis on molecular genetics and disease modeling. More-reliable serum markers, better tumour localisation and identification of small lesions, and histological grading systems and classifications with prognostic application are needed. Comparison between treatments is currently very difficult. Progress is unlikely to occur without development of centers of excellence, with dedicated combined clinical teams to coordinate multicentre studies, maintain clinical and tissue databases, and refine molecularly targeted therapeutics. [Copyright &y& Elsevier]

Abstract: Introduction: The folate receptor (FR) is frequently overexpressed in tumors and can be targeted with folate-based (radio)pharmaceuticals. However, significant accumulation of radiofolates in FR-positive kidneys represents a drawback. We have shown that preadministration of the antifolate pemetrexed (PMX) significantly improved the tumor-to-kidney ratio of radiofolates in mice. The aim of this study was to investigate the dose dependence of these effects and whether the same results could be achieved with folic acid (FA) or 5-methyl-tetrahydrofolate (5-Me-THF). Methods: Biodistribution was assessed 4 h postinjection of the organometallic 99mTc-picolylamine monoacetic acid folate in nude mice bearing FR-positive KB tumor xenografts. PMX (50–400 μg/mouse) was injected 1 h previous to radioactivity. The effects of FA and 5-Me-THF (0.5–50 μg/mouse) were investigated likewise. Tissues and organs were collected and counted for radioactivity and the values tabulated as percentage of injected dose per gram tissue (% ID/g). Results: PMX administration reduced renal retention (<1.6% ID/g vs. control: >10% ID/g), while the tumor uptake (average 1.35%±0.40% ID/g vs. control: 1.79%±0.49% ID/g) was only slightly affected independent of the PMX dose. Replacement of PMX by FA or 5-Me-THF (50 μg/mouse) resulted in a significant renal blockade (<0.1% ID/g) but at the same time in an undesired reduction of tumor uptake (<0.2% ID/g). Conclusions: Selective reduction of radiofolate uptake in kidneys under retention of high tumor accumulation could be achieved in combination with PMX over a broad dose range but not with FA or 5-Me-THF. [Copyright &y& Elsevier]

Aim: The aim of this study was to investigate the influence of a diagnostic versus therapeutic dose of [(177)Lu-DOTA-Tyr(3)]octreotate on the uptake, effects, and dosimetry in somatostatin receptor subtype 2(sst2)-positive tumors and normal organs in a rat tumor model.Materials and Methods: Lewis rats bearing rat pancreatic CA20948-tumor grafts were injected intravenously with different amounts of radioactivity and peptide of [(177)Lu-DOTA-Tyr(3)]octreotate: 3 MBq/0.5 microg (group A), 3 MBq/15 microg (group B), 300 MBq/15 microg (group C), and 555 MBq/15 microg (group D). Biodistribution studies were performed at several time points between 3 and 13 days post injection. Ex vivo and in vitro autoradiography was performed with frozen tumor sections.Results: Normal sst2-positive tissues showed a significantly higher uptake of radioactivity [%IA/g] when a low peptide amount was injected. On the other hand, the radioactivity concentration [%IA/g] in sst2-negative tissues and organs (blood, muscles, kidney, and liver) were comparable (groups A and B), independent of the injected peptide amount. Initially, this held true for the tumors as well. Yet, over time, we found a decrease in the radioactivity concentration in the tumors of groups A and B, because of tumor growth. On the other hand, therapeutic amounts of radioactivity (groups C and D) resulted in a significant reduction of tumor size, where radioactivity concentration remained higher than in groups A and B, despite the use of the high peptide amounts. Ex vivo autoradiograms of tumor sections confirmed these results. In vitro autoradiography performed on adjacent tumor sections revealed a reduced density of sst2 in tumors from animals that received a therapeutic radioactivity dose. Ki67-antibody immunohistochemistry showed an absence of proliferating tumor cells after therapy.Conclusions: The differences in radioactivity retention in tumors after diagnostic or therapeutic doses, depending on a change in tumor kinetics, have to be taken into account when calculating tumor-absorbed radiation doses. [ABSTRACT FROM AUTHOR]