|Year : 2011 | Volume
| Issue : 1 | Page : 60-72
Abstracts of Oral Presentations
|Date of Web Publication||16-Jun-2011|
|How to cite this article:|
. Abstracts of Oral Presentations. World J Nucl Med 2011;10:60-72
PET Imaging Using Ga-68-labelled Somatostatin Antagonists is Influenced by the Choice of the Chelator
Melpomeni Fani, Luigi Del Pozzo, Maria Luisa Tamma, Guillaume Nicolas, Friederike Deininger, Wolfgang A. Weber, Jean Claude Reubi, Helmut R. Maecke
University Hospital Freiburg, Germany, University Hospital Basel, Switzerland, University of Bern, Switzerland
Aim: Radiolabelled somatostatin analogs play an important role in molecular imaging and targeted radiotherapy of somatostatin receptor (sst)-positive tumors. Many patients are studied nowadays with Ga-68-labelled somatostatin agonists, such as Ga-68-DOTA-TOC or Ga-68-DOTA-TATE. Recent studies showed that somatostatin antagonists have higher tumor uptake and improved pharmacokinetics, compared to agonists. Factors determining the performance of radioantagonists have only very scarcely been studied. The aim of our work was to study the influence of the chelator in the pharmacological properties, and as a consequence in the image contrast, of this new class of compounds.
Materials and Methods: Two somatostatin antagonists, named BASS and LM3, were synthesized on solid phase using standard Fmoc strategy and were coupled to the macrocyclic chelators, DOTA and NODAGA. Labelling with Ga-68 was performed in sodium acetate buffer 0.2 mol/L, pH 4.0 at room temeprature (NODAGA-conjugates) or at 95°C (DOTA-conjugates). Biodistribution and microPET studies were performed for all four radiotracers in sst2-tumor xenografts. Blocking studies were done with an excess of cold peptide.
Results: All radiotracers were prepared with labelling yield >95% and specific activity 100-120 MBq/nmol. Pharmacokinetics strongly depended on the chelators. Ga-68-NODAGA-LM3 had higher tumor uptake (37.3±5.5%IA/g) than Ga-68-DOTA-LM3 (28.7±5.5%IA/g), 1 h p.i., and also 2-fold higher tumor-to-blood and tumor-to-kidney ratios. Ga-68-NODAGA-BASS showed much higher tumor uptake than Ga-68-DOTA-BASS (33.3±5.7 and 14.2±4.9%IA/g, respectively, 1 h p.i.), which resulted in a significantly higher tumor-to-background contrast (e.g. tumor-to-blood 35 vs. 23, tumor-to-liver 35 vs. 6 and tumor-to-kidney 2 vs. 0.8, for Ga-68-NODAGA-BASS vs. Ga-68-DOTA-BASS). Quantitative analysis of microPET images confirmed the biodistribution results. Blood clearance and also clearance from normal organs was faster for Ga-68-NODAGA-BASS compared to Ga-68-DOTA-BASS. On the contrary, tumor washout was slower for Ga-68-NODAGA-BASS which remained in the tumor at about 90% at 4 h, while more than 60% of Ga-68-DOTA-BASS is washed out. As a consequence, tumor-to-background contrast was significantly increasing over time for Ga-68-NODAGA-BASS (e.g. tumor-to-liver 133, tumor-to-kidney 10, 4 h p.i.) and decreasing for Ga-68-DOTA-BASS (e.g. tumor-to-liver 1.5, tumor-to-kidney 0.6, 4 h p.i.). MicroPET images of all radiotracers showed clear tumor localisation as well as significantly improved image contrast for Ga-68-NODAGA-conjuagets compared to the corresponding Ga-68-DOTA-conjugates.
Summary: NODAGA-conjugates can be labelled with Ga-68 at room temperature while elevated temperature is necessary for the DOTA-conjugates. The Ga-68-NODAGA-conjugates of somatostatin antagonists have better in vivo performance as PET imaging probes than the corresponding Ga-68-DOTA-conjugates.
A Novel Ga-68 Labeled Pteroic Acid-based PET Tracer for Tumor Imaging Via the Folate Receptor
Berit Kühle, Cristina Müller, Tobias L. Ross
Institute of Nuclear Chemistry, Johannes Gutenberg-University Mainz; Fritz Strassmann Weg 2, D-55128 Mainz, Germany
Aim of the Study: The folate receptor (FR) is an ideal target for oncological imaging as it is highly overexpressed by several cancer forms (e.g. ovary, cervix, endometrium, lung, kidney and breast cancer) but shows only a very limited expression in healthy tissue.  The glutamic acid moiety of folic acid is widely used for drug or radionuclide conjugation. Few examples [2,3] show that even derivatives of pteroic acid (folic acid lacking glutamic acid) retain a high affinity to the FR. The development of a DOTA-connected derivative of pteroic acid, ready for labelling with 68 Ga, is expected to ease the synthetic effort towards a molecule with suitable in vivo characteristics significantly.
Materials and Methods: Starting from 2-aminoethanol as a spacer between pteroic acid and the chelator DO3A, the precursor was synthesized in seven steps. The radiolabelling was performed in 0.13M HEPES buffer for 10 min at 95°C conventional heating or under microwave support (300 W, max. 120°C, 1 min ramp, 2 min hold, constant cooling). The generator eluate used for labelling was purified via a cation exchange column based post-processing.  Radiochemical yields were examined by radio-TLC. Determination of lipophilicity was performed by 1-octanol/PBS extraction of the labelled compound. The in vitro stability was tested in PBS at 37°C and against in vivo transchelation by incubation in a transferrin solution (3 mg/mL PBS).
Results: The synthesis of the new DO3A-pteroate was successfully achieved. Preliminary radiolabelling using 68 Ga showed high radiochemical yields by using 30 nmol precursor and conventional heating or 10 nmol precursor and microwave-assisted heating. Three hours incubation of the new radiotracer in PBS at 37°C did not show significant degradation. Similarly, the addition of transferrin did not affect the 68 Ga-labelled pteroate and no transchelation was observed. The lipophilicity assay resulted in a logD value of 0.1±0.1.
Summary: A new pteroic acid-based 68 Ga-radiotracer is available via a convenient and efficient (radio)synthesis. The new 68 Ga-DO3A-pteroate exhibits an adequate logD regarding folate receptor-based PET imaging. First in vitro and in vivo evaluations of the new compound are currently being performed. Another derivative connecting the pteroic acid with DO3A via a triethylene glycol spacer, in order to further increase hydrophilicity and the distance between the chelator and the pteroic acid moiety, will be available soon. The most promising candidate will be further evaluated and developed as new radiopteroate for PET imaging of folate receptor positive tissues.
Acknowledgement: We thank Merck and Cie Schaffhausen for kindly providing protected pteroic acid.
1. Müller, Cristina et al., (2011), J. Nucl. Med., 52, 1-4
2. Ke, Chun-Yen et al., (2005), J. Am. Chem. Soc., 127, 7421-7426
3. Müller, Cristina et al., (2006), Eur. J. Nucl. Med. Mol. Imag., 33, 1007-1016
4. Zhernosekov, Konstantin P. et al., (2007), J. Nucl. Med., 48, 1741-1748.
Molecular Imaging of HER2 Expression in Breast Cancer Using 68 Ga-NOTA-Anti-HER2 Nanobodies
Catarina Xavier, Mathias D'huyvetter, Ilse Vaneycken, Nick Devoogdt, Tony Lahoutte, Vicky Caveliers
In vivo Cellular and Molecular Imaging Lab, ICMI, Vrije Universiteit Brussel, Brussels, Belgium and Laboratory of Cellular and Molecular Immunology, VUB, Brussels, Belgium
Aim of the Study: Nanobodies are small (15 kDa) antibody fragments with beneficial pharmacokinetic properties that are ideally suited to be used as probes in molecular imaging. Within this project, we develop new 68 Ga-nanobodies labeled via the macrocyclic chelator NOTA, that could be used for in vivo radioimmunodetection of HER2 antigen using positron emission tomography (PET).
Materials and Methods: In this study, two nanobodies differing only in the C terminal 6-histidine tag, were chemically modified with S-2-(4-Isothiocyanatobenzyl)-1, 4, 7-triazacyclononane-1, 4, 7-triacetic acid (p-SCN-Bn-NOTA) and analysed by mass spectrometry. The resulting modified nanobodies, NOTA-nanobodies, were radiolabeled with 68 Ga, an important PET radionuclide which half-life fits with the short biological half-life of the nanobodies. Labeling efficiencies were checked by Instant Thin Layer Chromatography (ITLC) and Reverse Phase-High Performance Liquid Chromatography (RP-HPLC). Stability of 68 Ga-NOTA-nanobodies was evaluated in PBS, human serum and in the presence of excess EDTA. Biodistribution was evaluated in mice bearing HER2 positive or negative tumors.
Results: Mass Spectrometry results showed conjugation of 1 to 1,2 molecules of NOTA per nanobody. After incubation with 68 Ga for 7 min at room temperature, ITLC and RP-HPLC showed a radiochemical purity >98%. The labeled nanobodies showed to be stable in PBS, human serum, and 500 fold excess EDTA presenting only one major peak of radioactivity (>98%), with the same retention time as that of intact 68 Ga-NOTA-nanobodies. The uptake of 68 Ga-NOTA-nanobodies in HER2 positive tumors was 3.13±0.06%IA/g for the His tag form and 4.34±0.90%IA/g for the no tag with a tumor-to-muscle ratio of 12.96±1.88 and 28.49±1.87, respectively, at 1 hour after injection. The uptake in the negative tumor was 0.45±0.1 and 0.26±0.07 for the His tag and no tag, respectively. The major difference between the two different nanobodies was the kidney retention, decreasing from 116.67±1.83 to 45.00±11.42% IA/g for the no tag nanobody.
Summary: We showed for the first time the successful labeling of anti-HER2 nanobodies with 68 Ga through the bifunctional chelator p-SCN-Bn-NOTA. High tumor uptake with high tumor-to-muscle ratio is observed early after administration. The removal of the 6-histidine tag showed a significant impact on kidney uptake being more than 60% lower. 68 Ga-anti-HER2-Nanobody PET imaging of breast cancer should enable non-invasive assessment of HER2 receptor status in breast cancer patients.
Radiolabelling and biodistribution of Ga-68-AMBA in zr75-1 human breast cancer tumors
Aurélie Prignon, Valérie Nataf, Jimmy Rose, Claire Provost, Lucile Durand, Adrian D. Nunn 1 , Françoise Montravers, Jean-Noël Talbot
Plateforme LIMP, Hôpital Tenon, Paris, 75020, France; 1 Bracco Research USA, Princeton, USA
Objectives: Breast cancer is the most diagnosed carcinomas in women and for instance imaging detection of lobular breast cancer is difficult with 18FDG. AMBA (Do3A-Ch2Co-G-(4-aminobenzoyl)-QWAVGHLM-NH2) is a bombesin (BN)-like peptide having high affinity with gastrin-releasing peptide receptors (GRPR) which are overexpressed in a variety of human tumors including prostate, breast, and lung cancer. GRPR is a promising target for molecular imaging.
The aim of the present study was to develop an automated radiolabelling method of AMBA peptide and to evaluate the biodistribution of the 68 Ga-AMBA compared to 18FDG reference tracer for imaging breast cancer with positron emission tomography (PET).
Materials and Methods: A fully-automatic, PC-controlled, radiopharmaceutical synthesis device (SynChrom R&D, Raytest) was used for all steps in the synthesis. 68 Ga (t1/2 68 min) was eluted from a 68 Ge/ 68 Ga-generator (Eckert and Ziegler) with fractionated method. Sodium acetate was used as buffer. The reaction was heating 10 min at 95°C and the product was purified using a Sep-Pack cartridge (Waters) The presence of two reactors gave the possibility to evaporate the final product to increase the volumic activity. PET studies were performed with both 68 Ga-AMBA and 18FDG in ZR75-1 tumor-bearing mice which are known to overexpress the GRPR. Static PET scans were reconstructed and analysed quantitatively.
Results: 68 Ga-AMBA could be labeled with 68 Ga within 30 min. After the purification and the evaporation, the radiochemical yield was >98% and the specific activity was 8,75 MBq/nmol. Biodistribution data 45 min post-injection in mice confirmed receptor-specific tumor accumulation with 68 Ga-AMBA. SUVmean/SUV background ratio in mice (n=8) was 6,84(±1,58) with 68 Ga-AMBA and 1,5 (±0,5) with 18FDG.
Conclusions: Fully automated radiolabelling with Raytest module was fast and easy with high radiochemical yield. All tumors were clearly visualized using 68 Ga-AMBA with high and fast tumor uptake, while 18FDG showed poor uptake and poor tumor-to-background ratios. 68 Ga-AMBA may be considered as a promising candidate for 68 Ga-PET imaging of breast cancer.
Design, Synthesis and Preclinical Evaluation of Ga(III)-DOTA-modified-Ranatensin Analogues for SPECT/PET Imaging
Raunak 1 , Puja Panwar Hazari 1 , Philippe Frandez 2 , Jurgen Schulz 2 , Michele Allard 2 , Anil K. Mishra 1
1 Division of Cyclotron and Radiopharmaceutical Sciences, Institute of nuclear medicine and Allied Sciences, Brig. S. K. Mazumdar Road, Delhi-110054, India, 2 UMR-CNRS-5231, University of Bordeaux-2, France
Aim: The application of 68 Ga labeled peptides has attracted considerable interest for cancer imaging, because of its physical characteristics and compatibility with the pharmacokinetics of many peptides. The study of peptide receptors has provided valuable information on the development of radiopharmaceuticals that bind to site and disease-specific receptors for the diagnosis and therapy of cancer. The aim of this study was to obtain novel Gastrin-Releasing Peptide (GRP) analogues for cancer imaging by convenient solid phase synthesis.
Materials and Methods: We have synthesized novel DOTA-Ranatensin peptide analogue and its radiocomplexation with 68 Ga. Ranatensisn peptide analogue was synthesized by Fmoc solid phase strategy and alkylated with chloroacetyl chloride and was reacted with trisubstituted cyclen to yield the final DOTA-peptide. The compound was radiolabeled with 68 Ga in aqueous solution at pH 6.5 (ammonium acetate buffer). Radiochemical analysis by Radio-HPLC demonstrated single species with 68 Ga.
Results: DOTA- Ranatensin was prepared with more than 85% yield by solid phase synthesis and was characterized by mass spectroscopy. DOTA- Ranatensin binds with 68 Ga with high specific activity (1.48 MBq/μg). MTT assay have been performed to determine the cytotoxicity of the compound. Cell uptake studies carried out on prostrate cancer (PC12) cell line known to express GRP-type receptors exhibited saturable binding of the radioconjugate in picomolar range. The in vivo biodistribution and blood kinetics studies exhibited rapid clearance of the radiolabeled complex and excretion through the hepatobilliary and renal route. The production of high-specific-activity 68 Ga-DOTA-Ranatensin resulted in substantial accumulation at tumor site with 5.41±2.1%ID/g at 30 min postinjection and tumor retention (4.12±0.92%ID/g at 4 h p.i.). Receptor-mediated tumor uptake was verified by administration of blocking dose.
Summary: An attempt was made to develop BN-like peptide, Ranatensin radiopharmaceutical for targeting GRPR expressing tumors derived from the universal sequence of BN and conjugated to DOTA. The present studies demonstrated the potential applications of high-specific-activity 68 Ga-DOTA- Ranatensin as a PET radiopharmaceutical for GRPR expression as well as early diagnosis of a large number of mammalian carcinomas.
In vivo Comparison of 68 Ga and 111In Labelled Affibody Molecule Analogues
Irina Velikyan, Vladimir Tolmachev, Mattias Sandström, Anna Orlova
Uppsala Applied Science Lab, GE Healthcare; Division of Biomedical Radiation Sciences, Department of Radiology, Oncology, and Radiation Science, Uppsala University, Sweden
Aim: The imaging and estimation of the extent of receptor overexpression in tumors may improve the therapeutic efficiency on the bases of individualized patient management. HER2 receptor over-expression is a prognostic and predictive biomarker in breast cancer. The first generation Affibody molecule analogue (DOTA-ZHER2:342-pep2, ABY-002) has previously been labelled with 111In and the resulting tracer demonstrated excellent imaging of HER2-expressing xenografts in mice. The substitution of the gamma emitting 111In with 68 Ga would improve the sensitivity and enable more accurate quantification of the receptor expression. The aim of the study was the direct in vivo comparison of the tracers in the same animal.
Materials and Methods: The labeling synthesis of ABY-002 with 68 Gawas optimized. In vitro cell-binding and procession of [ 68 Ga]Ga-ABY-002 was evaluated. Biodistribution and tumor targeting of [ 68 Ga]Ga-ABY-002and [111In]In-ABY-002 was compared in vivo by paired-label experiments.
Results: ABY-002 was efficiently labelled with 68 Ga (>95%) within 10 min. The maintenance of the specific binding to HER2-expressing cells was assessed and confirmed. Both [ 68 Ga]Ga-ABY-002 and [111In]In-ABY-002 demonstrated high and specific uptake in SKOV-3 xenograft in mice. However, the clearance of radioactivity from blood, lung, gastrointestinal tract and muscle was more rapid for [ 68 Ga]Ga-ABY-002 as compared to [111In]In-ABY-002.
Summary: The preparation of [ 68 Ga]Ga-ABY-002 was simple and efficient. The binding of [ 68 Ga]Ga-ABY-002 was specific to HER2 receptors expressed in SKOV-3 cell line and respective xenograft. [ 68 Ga]Ga-ABY-002 demonstrated faster clearance and consequently higher contrast as compared to [111In]In-ABY-002 thus making the former a promising candidate for clinical molecular imaging of HER2-expression in malignant tumors with added value of higher sensitivity and accurate quantification provided by PET technique.
Novel DOTA-Neurotensin Analogue and Ga 68 PET Imaging of Neurotensin Receptor-positive Tumor in Mice
Anne Gruaz-Guyon, Aurélie Prignon, Faisal Al Shoukr, Luc Brans, Abdelhak Jallane, Sandra Mendes, Jean-Noël Talbot, Dirk Tourwé, Jacques Barbet
Faculté de Médecine Xavier Bichat, 16 rue Henri Huchard, 75890 PARIS CEDEX 18, France
Aim of the Study : Over-expression of the high affinity neurotensin receptor, NTSR1, demonstrated in several human cancers, has been proposed as a new marker for human ductal pancreatic carcinoma and as an independent factor of poor prognosis for ductal breast cancer, head and neck squamous cell carcinoma and non-small cell lung cancer. The aim of the present study was to develop new DOTA-neurotensin analogues for positron emission tomography (PET) imaging with 68 Ga and for targeted radiotherapy with 90Y or 177Lu.
Materials and Methods: We synthesized a DOTA-neurotensin analogue series. DOTA-NT-20.3 shares the same peptide sequence as the previously described DTPA-NT-20.3. In the sequence of DOTA-NT-20.4 the Arg8-Arg9 bond was N-methylated instead of the Pro7-Arg8 bond in DOTA-NT-20.3. An additional sequence modification was introduced in DOTA-LB119 to increase stability. A spacer was added between DOTA and the peptide sequence to increase affinity. The affinity, in vivo stability and biodistribution of the various analogues were compared. The best candidate was used to image tumors of various sizes with the microPET in a model of male nude mice grafted with the HT29 human colorectal cancer cell line, that expresses NTSR1.
Results: DOTA(111In)-NT-20.3, in spite of a relatively high uptake in kidneys, showed specific tumor uptake and elevated tumor to other organ uptake ratios at a time interval post-injection appropriate for imaging with the short lived radionuclide 68 Ga. The decay-corrected labeling yield of 68 Ga obtained was 67±9% with a specific activity of 2.5-4.5 MBq/nmol at the end of the labeling. One hour after injection of DOTA( 68 Ga)-NT-20.3 (250-500 pmol, n=6) tumor and kidney uptakes were not significantly different from those of DOTA(111In)-NT-20.3 (n=7). The high contrast PET images obtained with DOTA( 68 Ga)-NT-20.3 allowed the detection of very small tumors as soon as 25-45 minutes post-injection.
Summary: DOTA-NT-20.3 may be considered as a promising candidate for 68 Ga-PET imaging of neurotensin receptor-positive tumors. DOTA-NT-20.3 could also be considered for therapy as the yttrium-labeled peptide has higher affinity than that of the gallium-labeled one. If therapeutic application of this neurotensin analogue is developed, infusion of basic aminoacids, gelofusin and albumin fragments may be considered to prevent nephrotoxicity, as with radiolabeled somatostatin analogues.
Lu-177/90Y- Intermediate Affinity Monoclonal Antibodies Targeting EGFR and HER2/c-neu: Preparation and Preclinical Evaluation
Denis R. Beckford Vera, Sebastian Eigner, Katerina Eigner Henke, Frantisek Melichar, Milos Beran
Department of Radiopharmaceuticals, Nuclear Physics Institute of the AS CR, Czech Republic
Objectives: The encouraging results observed in the radioimmunotherapy of hematologic tumors have not yet been translated to solid tumors. For tumors associated antigents like EGFR, monoclonal antibodies (mAbs) with intermediate affinity might have preferential uptake in target tissues overexpressing target antigen while might have low uptake in normal tissue.  Nimotuzumab (h-R3) and Trastuzumab (Herceptin) are monoclonal antibodies with intermedia affinity which recognize the EGFR and HER2/c-neu, respectively. Residualizing radionuclides, such as 90Y and 177Lu, are potentially more suitable radionuclides for RIT.  The aim of this study was to prepare and evaluate the targeting properties of radioimmunoconjugates formed by Lu-177/Y-90 and monoclonal antibodies with intermedia affinity to EGFR and HER2/c-neu.
Materials and Methods: Nimotuzumab and Trastuzumab were labeled with n.c.a. Lu-177/Y-90 using p-SCN-Bz-DOTA. Radioimmunoconjugates were characterized by HPLC and SDS-PAGE. In vitro binding properties of Lu-177/Y-90-immunoconjugates were studied in human cancirnoma and normal cultured cell lines with varying EGFR and HER2/c-neu expression levels. Immunoreactive fraction, IC50 and Kd were determined. Toxicity of 90Y-h-R3/Herceptin was evaluated in vitro. Tumor-targeting properties of 177Lu-h-R3 were evaluated in athymic mice bearing human cancer xenografts with varying EGFR expression levels. Preliminary dosimetric evaluation was performed using OLINDA/EXM.
Results: Complexation of Lu-177/Y-90 to h-R3/Herceptin resulted in radiolabeling efficiencies higher than 95% and specific activities up to 1.3 GBq/mg without considerable loss of immunoreactivity (IF>90%). In vitro studies showed that the binding of the radioimmunoconjugates was receptor specific and the affinities was similar than those for the unmodified mAbs. 90Y-h-R3/Herceptin increased cell growth inhibition compared to unmodified mAbs or 90YCl 3 alone in cell lines with overexpression of the target antigen, while no significant differences were observed in cell lines with lower expression of the target antigen. In vivo studies performed with 177Lu-hR3 showed significantly higher uptake in A431 (22.8±3.1%ID/g) than in SNU-C2B (8.8±4.1%ID/g) xenografts at 72h post injection. 177Lu-h-R3 showed strong association between tumor uptake and EGFR expression levels. Tumor to normal tissue ratio increased markedly with increasing EGFR expression levels.
Summary: Antibodies with intermediate affinity, preferentially targeting overexpressing target antigen, labeled with radiometals might offer a potential radiopharmaceuticals for assessing and/or radioimmunotherapy of tumors associated antigens like EGFRs.
1. Garrido G, Tikhomirov IA, Rabasa A, et al. Bivalent binding by intermediate affinity of nimotuzumab: a contribution to explain antibody clinical profile. Cancer Biol Ther. Feb 15 2011;11(4):373-382.
2. Brouwers AH, van Eerd JE, Frielink C, et al. Optimization of radioimmunotherapy of renal cell carcinoma: labeling of monoclonal antibody cG250 with 131I, 90Y, 177Lu, or 186Re. J Nucl Med. Feb 2004;45(2):327-337.
Automated and cGMP-consistent Synthesis of Lu-177 and Ga-68 Labeled Peptides
Milos Petrik, Peter Knetsch, Meltem Ocak, Roger Knopp, Elisabeth Von Guggenberg, Roland Haubner, Clemens Decristoforo
Department of Nuclear Medicine, Innsbruck Medical Universtíty Innsbruck (Austria) and Eckert and Ziegler Eurotope GmbH, Berlin, Germany
Purpose Radiolabelled Somatostatin analogues have found extensive clinical use in Nuclear Medicine both for diagnostic and therapeutic applications. Initially staring from manual preparation approaches, high regulatory demands and radiation protection requirements makes the full automation of the process desirable. Use of different radionuclides can only be implemented if cross contamination can be avoided. This can be guaranteed by using single use, sterile cassettes also improving pharmaceutical standards. We developed system for fully automated synthesis allowing radiolabelling of DOTA-derivatized peptides with 68 Ga/ 111 In/ 177 Lu and 90 Y meeting radiation safety and pharmaceutical requirements. Cross-contamination is prevented by using disposable cassettes also ensuring cGMP standards. Methods The system consists of a syringe pump and a holder for insertion of single use multi-valve cassettes. 68 Ga was obtained from a commercially available generator (IGG, Eckart & Ziegler, 1110MBq) by elution with 0.1 M HCl. Two methods were employed for 68 Ga labelling of DOTATOC. One is based on preconcentration on a commercial cation exchange cartridge (Strata X-C, Phenomenex, USA) and extraction with acetone/HCl solution (Method 1). Method 2 was based on direct elution of a fraction of the eluate. Radiolabelling was performed in Acetate buffer with heating at 90°C for 7 min followed by transfer to a C18 cartridge for purification. 177 Lu/ 90 Y/ 111 In labelling was performed in ascorbate buffer by transfer of activity to the reaction vial, heating and C18 cartridge for purification. Overall yields were calculated and 68 Ge breakthrough was determined. Radiochemical yield (RCY) and radiochemical purity (RCP) were determined by ITLC-SG and RP-HPLC (ACN/H 2 O/0.1% TFA), other pharmaceutical parameters were tested according to European Pharmacopeia standards. Results 68 Ga-DOTA-peptides could be prepared with high RCP and yields (>80% d.c.) using two different labelling strategies (direct labelling and post processing of generator eluate), 68 Ge content was <0.0001% in all cases and synthesis times did not exceed 30 min. 111 In, 177 Lu and 90 Y labelling of DOTATOC, DOTATATE or DOTALAN resulted in yields (~90%) with high RCP and total synthesis time of ~45 min. The system has been used for more than one year in a busy clinical department giving reliable radiolabelling results for PET, but particularly also for therapeutic applications. Conclusions The described system allows fully automated, aseptic preparation of DOTA-peptides radiolabelled with different radionuclides in high radiochemical yields and pharmaceutical quality suitable for clinical application avoiding cross-contaminations by using single use, sterile cassettes.
Performance of DOTATOC PET/CT for the Detection of Insulinomas in Adults
Françoise Montravers 1 , Valérie Nataf 1 , Aurélie Prignon 1 , Jimmy Rose 1 , Sona Balogova 1 , Marie Calzada 2 , Gérard Maurel 2 , Khaldoun Kerrou 1 , Odile Pascal 1 , Virginie Huchet 1 , Laure Michaud 1 , Jean-Yves Devaux 2 , Jean-Noël Talbot 1
1 Hôpital Tenon , 4 rue de la Chine, F75020 Paris, 2 Hôpital S aint-Antoine, 184 Rue du Faubourg Saint Antoine, F75012 Paris, France
Aim: The purpose of this study was to evaluate the performance of DOTATOC-( 68 Ga) PET/CT in comparison with Somatostatin Receptor Scintigraphy (SRS) and in 2 cases with FDOPA PET/CT for the detection of insulinomas in adults.
Patients and Methods: Between February 2008 and February 2011, 10 adult patients were referred for localisation of a suspected sporadic insulinoma (6 patients), for localisation of insulinoma in one patient with Multiple Endocrine Neoplasia type 1 (MEN-1), for staging of a proven insulinoma in one patient and for re-staging of metastatic insulinoma in 2 patients. DOTATOC PET/CT and SRS were performed in all patients and FDOPA PET/CT was also performed in 2 patients.
Results: Localisation of a suspected sporadic insulinoma: The diagnosis of insulinoma was finally excluded in 3 patients and confirmed in 3 patients. DOTATOC PET/CT and SRS were true negative (TN) for the 3 patients without insulinoma. In the 3 patients with confirmed insulinoma, DOTATOC PET/CT was true positive (TP) in the 3 patients, SRS was TP in 1 patient and false negative (FN) in 2 patients and the FDOPA PET/CT performed in 1 patient was FN.
In the patient with MEN-1, DOTATOC PET/CT was superior to SRS and FDOPA PET/CT, showing clearly the insulinoma and leading to the detection of an unexpected second functioning tumor in the pancreas (glucagonoma), while SRS was positive only for the insulinoma and FDOPA PET/CT was positive only for the glucagonoma.- In the patient referred for staging of a proven insulinoma, DOTATOC PET/CT was TP for the insulinoma and TN for the distant extension and SRS was FN for the insulinoma.- In the 2 patients referred for re-staging, DOTATOC PET/CT and SRS were both TP on a per-patient basis but DOTATOC PET/CT showed more lesions than SRS.
Conclusion: In this prelimary series of insulinomas in adults, DOTATOC PET/CT appeared as superior to SRS to detect the primary tumors with a sensitivity (Se) of 5/5 vs 3/5 for SRS. The specificity of DOTATOC PET/CT and SRS was 3/3. DOTATOC PET/CT and SRS were TP on a per patient basis in the 2 patients with a metastatic insulinoma but DOTATOC PET/CT was clearly superior to SRS on a per-site basis. FDOPA PET/CT was FN for the localisation on the primary insulinoma in 2 patients. - In the 2 patients referred for re-staging, DOTATOC PET/CT and SRS were both TP on a per-patient basis but DOTATOC PET/CT showed more lesions than SRS.
Automated Synthesis of 68 Ga-exendin-4 for PET imaging of beta cell activity in diabetes mellitus
Mario De Decker, J. Harvey Turner
University of Western Australia, Fremantle Hospital - Nuclear medicine department, Fremantle, Australia
Objectives: To automate radiolabelling og 689 Ga-peptides for PET imaging and minimise radiation exposure to radiopharmaceutical chemists.
Materials and Methods: Elution of the 68 Ge/ 68 Ga generator was performed with 0.1 M Ultrapure HCl. DOTA-peptides were dissolved in 0.01 M acetic acid in Milli-Q water, with a final peptide concentration of 10-3 M. The peptide (20 - 40 nmol) and the radioactivity were mixed with 1.25 M sodium acetate. The vials were placed in a temperature-controlled heating block at 98°C for 10 minutes. After heating, 4mM EDTA was added. Radiochemical yield and purity was measured by instant thin-layer chromatography and high-performance liquid chromatography. A biodistribution study was performed in male Wistar rats (3 rats per time point). Animals were euthanized at 3 time points between 15 minutes and 3 hours. Tissues were dissected, weighed and counted for measurement of radioactivity in a gamma-well counter. The percentage of injected activity per gram was calculated for each organ. The Synthera® module (IBA Molecular, Belgium) was programmed for routine fully automated preparation of diagnostic 68 Ga-radiopharmaceuticals under remote, shielded, sterile conditions. Radiation exposure was measured for both manual and automated synthesis using dosemeters worn by the radiopharmacist.
Results: 68 Ga-Exendin-4 was synthesized in high radiochemical yield and radiochemical purity greater than 99%.Blood clearance was fast, only 0.13% remaining in blood 3 hours after injection. The highest uptake was in the kidneys (51.71% 3 hours after injection). Uptake in other organs was insignificant. In particular there was no discernible pancreatic activity in normal rats. Based on the biodistribution data mean radiation dose estimates were calculated for the human reference adult. The kidneys (229mGy) received the highest absorbed radiation dose. The predicted radiation dose for the total body was in the range of 1.39 mGy for an administration of 200Mbq of 68 Ga to humans. Using 200 MBq 68 GaCl 3 per synthesis, the median absorbed body dose for a manual synthesis was 90 μSv, contrasting with automated synthesis exposure of 8 μSv.
Summary: Automated synthesis of 68 Ga peptides on the Synthera® module achieves high yield, sterile preparations for routine PET imaging and minimises radiation exposure of the radiopharmaceutical chemist.
Role of Ga-68 DOTA-SMS-R PET/CT in the Detection of Cardiac Metastases in Patients with Neuroendocrine Tumors
Vikas Prasad, Ali Salavati, Harshad Kulkarni, Maria-Anna Secknus, Bernward Lauer, Richard P. Baum
Zentralklinik, Bad Berka, Germany
Aim: We investigated the diagnostic accuracy of Ga-68 DOTA-SMS-R PET/CT in comparison to the other imaging modalities for the detection of heart metastases (HM) in neuroendocrine tumor (NET) patients.
Materials and Methods: Overall, 713 progressive NET patients were examined with Ga-68 DOTA-Somatostatin-Receptor (SMS-R) PET/CT (using mainly DOTA-NOC and DOTA-TATE) and 2D echocardiography (echo). 28 patients had HM (incidence 4%). In 12 patients, also cardiac MRI was performed; FDG PET/CT was available in 24 patients. All imaging studies were reviewed separately by two independent experts. Cases were classified based on confirmation of HM in functional and morphological studies. The diagnostic accuracy of SMS-R-PET/CT, cardiac MRI, echo and thoracic CT scan studies was compared.
Results: Cardiac metastases were confirmed in at least 2 functional and morphological imaging studies in 22 patients (mean age 53.6+11.9 yrs) and by one modality (more than twice) in 6 patients. The time from diagnosis of NET to diagnosis of HM was 7.6+5.9 years. The primary NET was located in small intestine in 18 (64%); pancreas in 4 (14%); adrenals in 2; and in one each of stomach, liver, and thymus. One patient had CUP. Sites of cardiac metastases were: 15 pericardial (P), 17 myocardial (M), 1 intracardiac (I) and 1 epicardial (E). Detection rate (positive+/negative-) of different imaging modalities according to sites of metastases were echo: 16+/12-; M: 10, P: 6, I: 1, E:1; SMS-R PET/CT: 26+/2-; M: 15, P: 14, I: 1,E:1; MRI: 9+/2- ; M: 5, P: 4, I: 1; FDG PET/CT: 3+/21 ; M: 1, P: 2; CT: 9+/19- ; M: 5, P: 5, I: 1. Echo detected 2 HM which were not receptor positive. MRI and SMS-R PET/CT were concordant in 91% of the cases, whereas echo-MRI and CT-MRI were concordant in only 63% of the cases. In one case, MRI was nonconclusive because of the presence of intractable cardiac arrhythmias. The median SUV max of HM was 6.9 (2.8 to 36.1). In patient-based analysis, sensitivity of SMS-R PET/CT, echo, CT, and FDG PET/CT were 92% (CI 77-98), 57% (CI 39-73), 32% (CI 17-50) and 12% (CI 4-31), respectively. Four patients had fibrotic changes of the free wall of the right ventricle. In 6 cases LVEF was less than 55%, but the other patients had good LV function. Bulky abdominal lymph node metastases were present in 15 patients with HM; 4 cases had also mediastinal metastases.
Conclusion: Ga-68 SMS-R PET/CT is highly sensitive and far superior to echo, or CT alone in the detection of heart metastases. Although MRI is a very good method for the detection of HM, the presence of arrhythmias in 2/3 of patients with cardiac metastases can reduce its diagnostic accuracy. Echocardiography is very useful in NET patients not only to detect carcinoid heart disease, but also for the exact localization of cardiac metastases.
Does the Addition of Gelofusin in the Renal Protection of Patients Undergoing PRRNT Make a Difference?
Paul Maltby, S. Vinjamuri, J. Jorga, P. Vikas, H. Kulkarni, S. Senftleben, R. Baum
Royal Liverpool University Hospital, Nuclear Medicine Department, Prescot St Liverpool L7 8XP, UK
Aim of the Study: To determine the effect of changes to the renal protection procedure in patients who have undergone PRRNT by retrospective review of their renal function as measured by eGFR.
Materials and Methods: Patients undergoing PRRNT are routinely co-administered with LysArg infusion (1 litre) as a renal protective measure to reduce the radiation dose to the kidneys. Recently we added a second agent (gelofusin) into our standard patient treatment procedure. We have investigated the effect on renal function in patients who have completed therapy with either Lu177 or 90Y DOTATATE in order to verify if this additional agent has any additive or synergistic potential. Electronic-GFR measurements were taken prior to commencing the first cycle of therapy and after the final cycle at 3-6 months. Changes were recorded as increas, decrease or stable.
Patients and Methods: 62 patients completed treatment in this cohort. 59 with 90Y DOTATATE and 3 with 177Lu DOTATATE. All had LysArg as standard renal protection. 18 patients additionally received gelofusine.
Results: Of the 62 patients, only 28 data sets were available for analysis. 8 patients had 90Y with LysArg alone (Group A); 17 had 90Y and additional gelofusin (Group B);1 had Lu177 with LysArg alone (Group C) and 2 had Lu177 and additional gelofusin. At 3-6 months following completion of PRRNT, 6 patients in Group A showed a decrease in eGFR with 2 stable or increased; in GroupB 4 showed a decrease with 13 stable or increased; in Group C one patient showed a decrease and in Group D 2 were stable
Summary: Early indications appear to show that the addition of gelofusin to the regime for renal protection in patients undergoing PRRNT has a beneficial effect in the short term compared to standard protection measures. Longer term follow up in these patients and standardisation of the new regime are in progress.
The Possibility to Use Peptide Receptor Radionuclide Therapy as a Neoadjuvant Therapy in Patients with Inoperable Neuroendocrine Tumors
A. Sowa-Staszczak 1 , A. Stefańska1 , D. Pach 1 , M. Tomaszuk 1, R. Mikołajczak2 , D. Pawlak 2, M. Kołodziej2 , R. Chrzan 3 , A.B. Hubalewska-Dydejczyk 1
1 Nuclear Medicine Unit Endocrinology Department, Jagiellonian University, Medical College, Krakow, Poland; 2 Research and Development, IAE Radioisotope Centre POLATOM, Otwock-Swierk, Poland and 3 Department of Radiology, Jagiellonian University, Medical College, Krakow, Poland
Aim: The aim of the study was to assess the usage of peptide receptor radionuclide therapy (PRRT) as a neoadjuvant treatment leading to downstaging the tumor and enabling surgical intervention in primary inoperable NET.
Materials and Methods: Within the group of 47 patients treated with PRRT, 6 patients were chosen with large, inoperable tumors, for whom enabling of complete surgical excision of the lesions might be the prospect for a cure. Among the patients included in the therapy with 90Y-DOTA-TATE due to inoperable NET, there were 5 patients with foregut tumors, among them 3 with pancreatic neuroendocrine tumors (PNT) and 1 with midgut tumor. Every patient received a dose of 7.4 GBq/m 2 90Y-DOTA-TATE in 4-5 cycles every 6-9 weeks. The mean dose was 13.6 GBq (min 11.1 GBq, max 14.8 GBq). Response to the therapy was assessed according to RECIST criteria. Only one patient had metastases to the liver. Cytoreduction chemiotherapy was not used.
Results: After the treatment, mean tumor size decreased to 6.9 (min 3.1 cm, max 9.6 cm) to 5.39 (min 3.1 cm, max 9.5 cm). According to RECIST criteria, stabilization of the disease was observed in 4, and partial responses in 2 patients. In two patients, reduction of the tumor size enabled surgical intervention. PRRT did not cause mielotoxicity or nephrotoxicity.
Conclusions/Summary: 1) PRRT might be considered a neoadjuvant therapy in primary inoperable neuroendocrine tumors. 2) According to RECIST criteria stabilization of the disease was observed in the majority of patients. 3) We suggest that not only tumor' diameter changes, but also tumor' volume and contrast enhancement changes in computed tomography (CT) should be taken into consideration in assessment of the response to the therapy.
Ga-68 DOTA-somatostatin Analogues PET in Neuroendocrine Tumors: First year Experience in Turkey
Emre Demirci 1 , Meltem Ocak 2 , Levent Kabasakal 1 , Clemens Decristoforo 3, Burçak Güneş1, İlhami Uslu1
1Department of Nuclear Medicine, Cerrahpaşa Medical Faculty, Aksaray Istanbul, Turkey; 2 Department of Pharmaceutical Technology, Pharmacy Faculty, Istanbul University, Istanbul, Turkey and 3 Clinical Department of Nuclear Medicine, Medical University Innsbruck, Austria
Aim of the Study: In January 2010, we set up fully automated 68 Ga-DOTA-peptides Moduler Synthesis device with the 68 Ge/ 68 Ga generator to diagnose patients suspected from neuroendocrine tumors (NETs) in Cerrahpasa Medical Faculty, Nuclear Medicine Department in Istanbul. Therefore in this study we aimed to report diagnostic value of 68 Ga-DOTA-TATE and 68 Ga-DOTA-NOC in patients who applied in our department for PET scintigrapy in last one year.
Materials and Methods: 137 patients with NETs (38 unknown primary, 24 pancreatic, 12 lung, 12 gastric, 7 small bowel, 7 colon, 6 gastrinoma, 5 insulinoma, 5 Mercel, 4 MEN, 4 paraganglioma, 13 others), 9 search for the primary site (high chromogranin), 1 prostate, 2 acromegaly, 4 thyroid carcinoma (papillary and follicular), 2 germ cell carcinoma, 1 ectopic cushing, 1 hepatocellulary carcinoma, 1 glial tumor, totally 158 patients (mean age 51.77±14.22, F/M: 91/67) were injected with 161.3±43.42MBq 68 Ga-DOTA-TATE (n=131) or Ga-68-DOTA-NOC (n=27) (which was synthesized by using Fractionated Moduler System with 30 mCi 68 Ga/ 68 Ge Generator, Eckert& Ziegler Eurotope, Berlin, Germany). 30-60 min. after injection PET/CT images were obtained and evaluated.
Results: 91 patients had positive 68 Ga-DOTA-peptides and 67 patients had negative 68 Ga-DOTA-peptides scan. In 46 patients lesions were located in liver, in 41 patients in area of abdomen and pelvis, in 24 patients in lymph lenf node stations, in 20 patients in bone system, in 8 patients in lung and in 16 patients in other parts of the body. There were no significant differences (P>0.05) between Ki67 proliferation indexes in 68 Ga-DOTA-TATE/DOTA-NOC positive (32) and negative (17) patients.
Summary: In all our cases the image quality was excellent and most of them provided clinically useful information. The fully automated synthesis module with cyclotrone independent Ga-68 allowed us successfully, reliably and reproducibly preparation of 68 Ga-DOTA-sst analogues for routine preparations in clinical applications.
Acknowledgement: This work was supported by Scientific Research Projects Coordination Unit of Istanbul University. Project number 3264
PET Lung Ventilation/Perfusion Imaging using Gallium-68 Labeled Aerosol and Gallium-68 Labeled Macroaggregated Albumin
S.J. Ament, S. Maus, H.G. Buchholz, H. Reber, N. Bausbacher, M. Schreckenberger
Department of Nuclear Medicine, Johannes Gutenberg University, Mainz, Germany
Aim: Pulmonary imaging with ventilation/perfusion single photon emission tomography (V/P Scan) is a well-established diagnostic tool for suspected pulmonary embolism (PE). Ga-68 labeled aerosol and Ga-68 labeled macroaggregated albumin (MAA) are potential tracers for PET lung ventilation/perfusion imaging and could be in times of the worldwide shortage of Mo-99 an effective widening and upgrading in the diagnosis of clinically suspected PE. After preclinical studies and in the abscence of alternatives the clinical applicability of Ga-68 labeled tracer for PET lung ventilation/ perfusion imaging was investigated in form of an exploratory study of 5 patients with clinical suspicion of PE.
Materials and Methods: Five patients with suspicion on pulmonary embolism underwent PET/CT (Philips TF) after inhalation of Ga-68 labeled aerosol and application of 42-116 MBq Ga-68 labeled MAA (injected activity was calculated compared to the activity inhaled). PET scans were acquired with an acquisition time of 5 min per bed position. The acquisition protocol included a low-dose CT for attenuation correction (AC). Dosimetry calculations and continuative phantom measurements for validation of the quantification were performed.
Results: PET lung ventilation/perfusion imaging using Ga-68 labeled aerosol and Ga-68 labeled MAA is clinically feasible. In one case a clinically suspected PE could be detected and verified. Radiation exposure (0.7 mSV / 6 MBq Ga-68 labeled aerosol, coinc rate 71000) was comparable to the SPECT technique with Tc-99m labeled aerosol (0.6 mSV / 40 MBq, ICRP 80) for lung ventilation imaging and 50% higher (3.7 mSV / 42 MBq Ga-68 labeled MAA, coinc rate 415000) as Tc-99m labeled MAA for lung perfusion imaging (2.2 mSV / 200 MBq, IRCP 80). Extrapulmonal activity but no free Ga-68 activity could be detected. In phantom measurements using a torso phantom with Ga-68 free water we found 15% measurable (but "not existing") activity of the total applied activity dose from the closed hollow cylinder with lung mass density equivalent material (inside of the torso phantom). This effects could be caused by the high kinetic energy of Ga-68 positrons.
Conclusions: Ga-68 aerosol and Ga-68 labeled MAA are principally adequate surrogate markers for clinical use and could be an interesting alternative with high accuracy to lung ventilation/perfusion imaging with Tc-99m labeled radiotracers in times of Mo-99 shortages. Further studies on broad reach of positrons due to high kinetic energy of Ga-68 are needed to investigate the possible effects on PET lung ventilation/perfusion imaging.
Ga-68 DOTATOC vs. Ga-68 DOTATATE PET/CT in Functional Imaging of Neuroendocrine Tumors
Thorsten D. Poeppe, I. Binse, S. Petersenn, H. Lahner, M. Schott, G. Antoch, W. Brandau, A. Bockisch, C. Boy
Nuklearmedizinische Klinik, Universitatsklinikum Essen. Hufelandstr. 55, 45122 Essen, Germany
Aim: The two compounds most often used in functional imaging of NET with positron emission tomography (PET) are 68 Ga-DOTATATE and 68 Ga-DOTATOC. Both ligands share a quite similar sst binding profile. However, the in-vitro affinity of 68 Ga-DOTATATE in binding the sst subtype 2 (sst2) is approximately tenfold higher than that of 68 Ga-DOTATOC. This difference may affect efficiency in the detection of NET lesions as it is the sst2 that is predominantly overexpressed in NET. We thus compared the diagnostic value of PET/CT with both radiolabelled somatostatin analogues ( 68 Ga-DOTATATE and 68 Ga-DOTATOC) in the same neuroendocrine tumor patients.
Patients and Methods: 40 patients with metastatic neuroendocrine tumors underwent 68 Ga-DOTATOC and 68 Ga-DOTATATE PET/CT as part of the work-up before prospective peptide radio receptor therapy. The performance of both imaging methods was analysed and compared for the detection of individual lesions per patient and for eight defined body regions. A region was regarded positive if at least one lesion was detected in that region. In addition, maximal radiopeptide uptake in terms of the maximal standardised uptake value (SUV max ) was compared for concordant lesions and renal parenchyma.
Results: 78 regions were found positive with DOTATATE vs. 79 regions with DOTATOC (n.s.). Overall, however, significantly fewer lesions were detected with DOTATATE in comparison with DOTATOC (254 vs. 262, P<0.05). Mean DOTATATE SUV max across all lesions was significantly lower compared to DOTATOC (16.0±10.8 vs. 20.4±14.7, P <0.01). Mean SUV max for renal parenchyma was not significantly different between DOTATATE and DOTATOC (12.7±3.0 vs. 13.2±3.3).
Summary: DOTATOC and DOTATATE possess a comparable diagnostic accuracy for detection of NET lesions with a minor advantage of DOTATOC. The approximately tenfold higher affinity for the sst2 of DOTATATE does not prove to be clinically relevant. Quite unexpectedly, maximal binding of DOTATOC tended to be higher than its DOTATATE counterpart.
Comparison of Lesion Detection and Characterisation in Patients with Neuroendocrine Tumors Using DOTATOC-PET in Correlation with Contrast-enhanced MRI and Contrast-enhanced CT
Frederik L. Giesel, C. Kratochwil, A. Mehndiratta, S. Wulfert, C. Zechmann, H.U. Kauczor, U. Haberkorn, S. Ley
University Hospital Heidelberg, INF 400, 69120 Heidelberg, Germany
Purpose: Most of the gastroenteropancreatic neuroendocrine tumors (GEP-NETs) present an increased somatostatin receptor expression. Therefore, PET with 68 Ga-DOTATOC has both high sensitivity and specificy in tumor staging. However, additional morphologic characterisation of tumor lesions is often essential, e.g. the relation to adjacent structures to determine weather the lesion is resectable. We evaluated the rate of successful lesion characterisation comparing contrast enhanced CT with MRI each in correlation with DOTATOC-PET.
Materials and Methods: 8 patients with GEP-NET were investigated using late enhanced MRI (1.5-Tesla, T2w-BLADE and T1w-VIBE, before and 15 min after injection of Eovist® ), contrast enhanced CT (in arterial and portal venous phase) and DOTATOC-PET imaging. DOTATOC-PET and ce-CT were performed in a BIOGRAPH-6 PET/CT. Contrast enhancement of normal liver and metastatic lesions was quantified with ROI technique. Tumor delineation was assessed with a visual score in a blind read analysis performed by two experienced radiologist.
Results: Using DOTATOC-PET as a standard of reference, 40 liver metastases in eight patients were detected. All 40 liver metastases were also detected by late enhanced MRI and the lesion extent could be adequately assessed in all lesions. In contrast to MRI, CT failed to detect 20% of the hepatic metastases. The blind read score of the CT in the arterial phase was -0.65 while the portal phase was scored with a mean of -1.4. In contrast the delayed MRI was considered superior to CT with a median score of 2.7. For CT, the quantitative ROI analysis presented an improved contrast enhancement ratio with a mean ratio of 1.2 while during the portal phase, lesion mean enhancement improved to 1.6. Delayed MRI presented with a median of 3.3. The difference in MRI in comparison to both CT scans was statistically significant (P<0.05).
Conclusion: Late ce-MRI was superior to ce-CT in providing additional morphologic characterisation and exact lesion extension of hepatic metastases from neuroendocrine tumor detected with DOTATOC-PET. Therefore, late enhanced EOVIST® -MRI seems to be the adequate imaging modality for combination with DOTATOC-PET to provide complementary (macroscopic and molecular) tumor characterisation in hepatic metastasised GEP-NETs.
Diagnostic Impact of 68 Ga-DOTA-TATE PET/CT Imaging in the Detection of Recurrent or Metastatic Medullary Thyroid Carcinoma and Elevated Calcitonin Levels
Anar Aliyev, Meltem Ocak, Levent Kabasakal, Clemens Decristoforo, Emre Demirci, Sabire Yılmaz, Ahmet Araman, İlhami Uslu
Departments of Nuclear Medicine, Cerrahpasa Medical Faculty, University of Istanbul, Turkey Kocamustafapasa Fatih, Istanbul, Turkey
Aim: Medullary thyroid cancer (MTC) is a neuroendocrine tumor of the parafollicular or C cells of the thyroid gland. MTC is a rare thyroid tumor that accounts for 5- 10% of thyroid malignancies. MTC is more difficult to treat and has higher rates of recurrence and mortality. Total thyroidectomy is the preferred initial treatment for patients with MTC. In one large series who were biochemically cured, the five-year recurrence rate was 5 percent. The diagnosis and treatment of recurrent tumor show specific features. Nuclear medicine imaging is particularly useful in the postoperative follow-up to detect recurrent tumor. A great number of radiopharmaceutical have been used with advantage of specific expression of receptors or molecular targets by MTC lesions. In patients with MTC, rising level of the tumor marker calcitonin after primary surgery relate with tumor recurrence or metastases incidence. The only chance of cure is the resection of localised tumor tissue. For conventional scintigraphic procedures (i.e. somatostatin receptor scintigraphy, DMSA, MIBI), varying but low sensitivities between 25% and 50% are reported. 68 Ga-DOTA-TATE is a new PET tracer and it has already shown satisfactory sensitivity in neuroendocrine tumor imaging. We tried to investigate 68 Ga-DOTA-TATE PET/CT imaging's diagnostic performance in the detection of recurrent or metastatic MTC.
Materials and Methods: This evaluation contains data from 15 patients (nine female, six male, mean age 45.2 years, range 23-64 years) with previously surgically treated MTC (all the patients with sporadic MTC). All patients had elevated calcitonin levels. Whole body 68 Ga-DOTA-TATE PET/CT was performed in 15 patients with MTC to detect recurrences or metastases.
Results: With 68 Ga-DOTA-TATE PET/CT, eight of 15 patients showed small foci suspicious for MTC in the neck, mediastinum or bone. Postoperative calcitonin concentrations ≤500 pg/ml, generally indicate a small residual disease in the neck or mediastinal lymph nodes, not easily detectable by conventional imaging. In our study, 68 Ga-DOTA-TATE PET/CT has 100% sensitivity associated with calcitonin serum concentrations higher than 316.5 pg/ml (specificity 72%, P<0.05).
Summary: 68 Ga-DOTA-TATE PET/CT can be useful imaging's detection at postoperative recurrent or metastatic MTC.
Acknowledgement: This work is supported by; Scientific Research Projects Coordination Unit (BAP) of Istanbul University with Project number 3264.
Comparison of 68 Ga-somatostatin analogues, 18F-DOPA and 18F-FDG PET-CT in Patients with Recurrent Medullary Thyroid Carcinoma: Also Ferrari Does Not Always Win!
Giorgio Treglia 1 , Paola Castaldi 1 , Maria Felicia Villani 1 , Angelina Filice 2 , Valentina Ambrosini 3 , Nadia Cremonini 4 , Diana Salvo 2 , Stefano Fanti 3 , Maria Lucia Calcagni 1 , Alessandro Giordano 1 , Vittoria Rufini 1
1 Nuclear Medicine Institute, Catholic University of Sacred Heart, Rome, Italy; 2 Nuclear Medicine Unit, Santa Maria Nuova Hospital, Reggio Emilia, Italy, 3 Nuclear Medicine Institute, PET Center, Policlinico S. Orsola-Malpighi, Bologna, Italy, 4 Endocrinology Unit, Maggiore Hospital, Bologna, Italy Largo Gemelli, 8; zip code: 00168; Rome, Italy
Aim: Although surgery is curative in the vast majority of patients with medullary thyroid carcinoma (MTC), disease can persist or recur and the early detection of malignant lesions is a crucial step in the therapeutic management of these patients. Several morphological and functional imaging techniques have been used to detect recurrent MTC with variable results. Among nuclear medicine techniques, currently there is growing interest for positron emission tomography (PET) methodology, which offers higher image quality and higher spatial resolution, and for PET tracers such as: 18F-FDG, which reflects tumor glucose metabolism and proliferative activity; 18F-DOPA, which reflects a metabolic pathway (amine decarboxylation) that is typical of neuroendocrine tumors; 68 Ga-somatostatin analogues which reflect the expression of somatostatin receptors. The aim of our study was to compare PET/CT with 68 Ga-somatostatin analogues, 18F-DOPA and 18F-FDG in a small series of patients with suspected recurrent MTC on the basis of increased calcitonin levels during follow up but with conventional imaging (CI) inconclusive for loco-regional and/or metastatic spread.
Materials and Methods: Among 40 patients previously operated for MTC (total thyroidectomy and loco-regional lymphadenectomy), who were submitted to 18F-DOPA PET/CT for increasing calcitonin serum levels and inconclusive CI, 11 patients (5 males and 6 females; mean age 51.4 years; mean calcitonin value 973 ng/L, range 66-2043) who had performed also PET/CT with 68 Ga-somatostatin analogues (DOTANOC or DOTATOC) and 18F-FDG within 3 months were selected. PET/CT findings were classified as positive or negative on visual interpretation on a patient based analysis. Verification of positive PET findings was achieved by cyto-histopathology (in 6 cases) and/or imaging follow-up (in 5 cases).
Results: Foci of abnormal uptake were observed in 7/11 patients at 18F-DOPA PET/CT, in 3/11 at 68 Ga-somatostatin analogues PET/CT and in 0/11 at 18F-FDG PET/CT. In particular, 4 patients (with liver and bone, cervical lymph node and mediastinal involvement) were positive at 18F-DOPA PET/CT alone. In three cases both 8F-DOPA PET/CT and 68 Ga-somatostatin analogues PET/CT were positive, even though in one patient 18F-DOPA PET/CT showed mediastinal lymph node and liver involvement, whereas 68 Ga-somatostatin analogues PET/CT showed only mediastinal lymph node uptake. Despite increasing levels of calcitonin, 4 out of 11 patients were negative with all procedures and no disease was detected after one year of clinical and imaging follow-up.
All foci of uptake observed at 18F-DOPA PET/CT and 68 Ga-somatostatin analogues PET/CT were confirmed to be malignant by histopathology (6 cases) and by subsequent follow-up (one case).
Summary: From our preliminary experience, 18F-DOPA PET/CT seems to be the most useful imaging method to detect metastatic lesions in patients with recurrent MTC, but studies investigating larger patient population are needed to confirm these results and to explain the lack of abnormal uptake of all tracers in some cases. In any case, the different uptake patterns observed with the various PET tracers reflect different metabolic pathways (uptake of hormone precursors, receptor expression, glucose metabolism); this information may help to broaden knowledge of MTC and potentially to select the most appropriate treatment.
Comparison of Positron Emission Tomography with 68 Ga -DOTA-TATE and 18F FDG in Neuroendocrine Tumors
Sabire Yılmaz, Emre Demirci, Meltem Ocak, Burcak Günes, Levent Kabasakal, Metin Halac, Ahmet Araman, Ilhami Uslu, Clemens Decristoforo
Departments of Nuclear Medicine, Cerrahpasa Medical Faculty, University of Istanbul, Turkey
Aim: Neuroendocrine tumors (NETs) are rare tumors originating from the neural crest and typically characterized by peptide receptors and neuroamine uptake mechanism on their cell membrane. Most frequently, NET arise in the gastrointestinal tract, the pancreas, the lung and rarely in other organs. NET are generally asymptomatic and slow-growing tumors. The diagnosis of NET relies on radiological-scintigraphic imaging methods and tumor marker levels. Is's difficult to detect NET by positron emission tomography (PET) with 18F FDG because of low metabolic activity. However, PET using 68 Ga DOTA peptides is a promising imaging method in diagnosis and follow-up of NET because NET typically express somatostatin receptor. The aim of this study is to compare the diagnostic efficacy of 68 Ga-DOTA-TATE and 18F-FDG PET scintigraphy.
Materials and Methods: 29 patients (14 men, 15 women, range:11-64 mean age:46 y) with diagnosis of NET who underwent 68 Ga-DOTA-TATE and 18F-FDG PET /CT at our institution were enrolled in this study. Maximum interval between the two study was 2 months (median interval: 16,7 d). The imaging findings were recorded per region in 7 regions (thyroid bed, lymphatic stations, lungs, liver, bones, pancreas and other) for every patient. PET images were evaluated visually.
Result: Of 29 patients with NET (1 urinary-bladder NET, 3 gastric carcinoid, 3 pheochromacytoma, 4 lung carcinoid tm, 9 metastasis of unknown primary, 5 pancreatic NET, 2 medullary thyroid tm, 1 paraganglioma, 1 MEN-1 disease). 9 patients had no uptake; 14 patients had uptake by either modality. On a lesion basis, 68 Ga-DOTA-TATE PET detected more lesion than 18F-FDG PET. In 4 patients (14,3%), 68 Ga-DOTA-TATE PET was positive but 18F-FDG PET was negative. On the other hand, 2 patients (7%) had 18F-FDG positive but 68 Ga-DOTA-TATE negative lesions. 68 Ga-DOTA-TATE PET is found to be superior to 18F-FDG PET for detection of NET (P=0,002). There was significant correlation with FDG SUV and Ki-67 index (r=0,810; P=0,008) The correlation with 68 Ga SUV and Ki-67 index was nas statisticaly significant (r=0,287; P=0,453).
Conclusion: 68 Ga-DOTA-TATE PET/CT is a valuable imaging modality for diagnosis and follow-up of NETs and is superior to 18F-FDG PET /CT.
Acknowledgement: This work is supporting by; Scientific Research Projects Coordination Unit (BAP) of Istanbul University with Project number 3264.
PRRT with 177Lu-DOTATATE for GEP-NET - Initial Results in Brazil
Aron J. Belfer, Lisiane N. Hilario, Marycel Barbosa
Hospital Israelita Albert Einstein, R Dr. Renato Paes de barros 188 ap.211 - S.Paulo CEP 04530-000, Brazil
Introduction: Well differentiated GEP-NET express somatostatin (ST) receptor and the ST analogs have been used for symptomatic relieve, although, with limited cytostatic effect.
The ST analog octreotate, labeled with 177Lutécio, concentrate in those ST receptor positive tumors, and promotes cytostatic effect.
Aim: To show the feasibility and early results after PRRT with 177Lu-DOTATATE in GEP-NET tumors in Brazil.
Patients and Methods: 32 GEP-NET patients with progressive, metastatic, inoperable or nonresponders to conventional regime treatments were treated with 177Lu-DOTATATE. All patients had measurable disease in MRI or CT and a positive Octreoscan. Life expectance >12 months, KI >50%, renal, hepatic and hematologic function preserved.
The patients received 3 to 4 7400 MBq cycles of 177Lu-DOTATATE with 6 to 12 weeks interval and had amino acid solution infusion for renal protection, according the Rotterdam protocol. Whole body scans and blood tests were acquired after each cycle. MRI or CT, following SWOG criteria, analyzed the therapeutic results after 3 months.
Results: Partial response in 10 (31%) patients, minor response in 6 (19%), stable disease in 10 (31%) and progression in 6 (19%). No complete remission was achieved. The acute collateral effects were nausea in 23 (19%) cycles, vomiting in 7(6%) and abdominal pain in 7 (6%). Subacute collateral effect: leukopenia (grade 3 or 4) in 1(0,8%), thrombocytopenia (grade 3 e 4) in 1(0,8%) cycles.
Conclusion: PRRT is feasible in Brazil, with few collateral effects and a good response.
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