Quantitative PET of EGFR expression in xenograft-bearing mice using <Superscript>64</Superscript>Cu-labeled cetuximab,a chimeric anti-EGFR monoclonal antibody

Purpose Cetuximab, a chimeric monoclonal antibody targeting epidermal growth factor receptor (EGFR) on the surface of cancer cells, was approved by the FDA to treat patients with metastatic colorectal cancer. It is currently also in advanced-stage development for the treatment of several other solid tumors. Here we report for the first time the quantitative positron emission tomography (PET) imaging of EGFR expression in xenograft-bearing mice using ⁶⁴Cu-labeled cetuximab. Methods We conjugated cetuximab with macrocyclic chelating agent 1,4,7,10-tetraazadodecane-N,N′,N′′,N′′′-tetraacetic acid (DOTA), labeled with ⁶⁴Cu, and tested the resulting ⁶⁴Cu-DOTA-cetuximab in seven xenograft tumor models. The tracer uptake measured by PET was correlated with the EGFR expression quantified by western blotting. The estimated human dosimetry based on the PET data in Sprague-Dawley rats was also calculated. Results MicroPET imaging showed that ⁶⁴Cu-DOTA-cetuximab had increasing tumor activity accumulation over time in EGFR-positive tumors but relatively low uptake in EGFR-negative tumors at all times examined (<5%ID/g). There was a good correlation (R ² = 0.80) between the tracer uptake (measured by PET) and the EGFR expression level (measured by western blotting). Human dosimetry estimation indicated that the tracer may be safely administered to human patients for tumor diagnosis, with the dose-limiting organ being the liver. Conclusion The success of EGFR-positive tumor imaging using ⁶⁴Cu-DOTA-cetuximab can be translated into the clinic to characterize the pharmacokinetics, to select the right population of patients for EGFR-targeted therapy, to monitor the therapeutic efficacy of anti-EGFR treatment, and to optimize the dosage of either cetuximab alone or cetuximab in combination with other therapeutic agents. Weibo Cai and Kai Chen contributed equally to this work.     

PET imaging of apoptosis with <Superscript>64</Superscript>Cu-labeled streptavidin following pretargeting of phosphatidylserine with biotinylated annexin-V

Purpose In vivo detection of apoptosis is a diagnostic tool with potential clinical applications in cardiology and oncology. Radiolabeled annexin-V (anxV) is an ideal probe for in vivo apoptosis detection owing to its strong affinity for phosphatidylserine (PS), the molecular flag on the surface of apoptotic cells. Most clinical studies performed to visualize apoptosis have used ^99mTc-anxV; however, its poor distribution profile often compromises image quality. In this study, tumor apoptosis after therapy was visualized by positron emission tomography (PET) using ⁶⁴Cu-labeled streptavidin (SAv), following pre-targeting of apoptotic cells with biotinylated anxV. Methods Apoptosis was induced in tumor-bearing mice by photodynamic therapy (PDT) using phthalocyanine dyes as photosensitizers, and red light. After PDT, mice were injected i.v. with biotinylated anxV, followed 2 h later by an avidin chase, and after another 2 h with ⁶⁴Cu-DOTA-biotin-SAv. PET images were subsequently recorded up to 13 h after PDT. Results PET images delineated apoptosis in treated tumors as early as 30 min after ⁶⁴Cu-DOTA-biotin-SAv administration, with tumor-to-background ratios reaching a maximum at 3 h post-injection, i.e., 7 h post-PDT. Omitting the administration of biotinylated anxV or the avidin chase failed to provide a clear PET image, confirming that all three steps are essential for adequate visualization of apoptosis. Furthermore, differences in action mechanisms between photosensitizers that target tumor cells directly or via initial vascular stasis were clearly recognized through differences in tracer uptake patterns detecting early or delayed apoptosis. Conclusion This study demonstrates the efficacy of a three-step ⁶⁴Cu pretargeting procedure for PET imaging of apoptosis. Our data also confirm the usefulness of small animal PET to evaluate cancer treatment protocols.     

Quantitative PET imaging of Met-expressing human cancer xenografts with <Superscript>89</Superscript>Zr-labelled monoclonal antibody DN30

Purpose  Targeting the c-Met receptor with monoclonal antibodies (MAbs) is an appealing approach for cancer diagnosis and treatment because this receptor plays a prominent role in tumour invasion and metastasis. Positron emission tomography (PET) might be a powerful tool for guidance of therapy with anti-Met MAbs like the recently described MAb DN30 because it allows accurate quantitative imaging of tumour targeting (immuno-PET). We considered the potential of PET with either ⁸⁹Zr-labelled (residualising radionuclide) or ¹²⁴I-labelled (non-residualising radionuclide) DN30 for imaging of Met-expressing tumours. Materials and methods  The biodistribution of co-injected ⁸⁹Zr-DN30 and iodine-labelled DN30 was compared in nude mice bearing either the human gastric cancer line GLT-16 (high Met expression) or the head-and-neck cancer line FaDu (low Met expression). PET images were acquired in both xenograft models up to 4 days post-injection (p.i.) and used for quantification of tumour uptake. Results  Biodistribution studies in GTL-16-tumour-bearing mice revealed that ⁸⁹Zr-DN30 achieved much higher tumour uptake levels than iodine-labelled DN30 (e.g. 19.6%ID/g vs 5.3%ID/g, 5 days p.i.), while blood levels were similar, indicating internalisation of DN30. Therefore, ⁸⁹Zr-DN30 was selected for PET imaging of GLT-16-bearing mice. Tumours as small as 11 mg were readily visualised with immuno-PET. A distinctive lower ⁸⁹Zr uptake was observed in FaDu compared to GTL-16 xenografts (e.g. 7.8%ID/g vs 18.1%ID/g, 3 days p.i.). Nevertheless, FaDu xenografts were also clearly visualised with ⁸⁹Zr-DN30 immuno-PET. An excellent correlation was found between PET-image-derived ⁸⁹Zr tumour uptake and ex-vivo-assessed ⁸⁹Zr tumour uptake (R ² = 0.98). Conclusions  The long-lived positron emitter ⁸⁹Zr seems attractive for PET-guided development of therapeutic anti-c-Met MAbs.     

Comparison of <Superscript>18</Superscript>F-FLT PET and <Superscript>18</Superscript>F-FDG PET for preoperative staging in non-small cell lung cancer

Purpose The nucleoside analog 3′-deoxy-3′-¹⁸F-fluorothymidine (FLT) has been introduced for imaging cell proliferation with positron emission tomography (PET). We prospectively compared the diagnostic efficacy of FLT PET with that of 2-deoxy-2-¹⁸F-fluoro-d-glucose (FDG) PET for the preoperative nodal and distant metastatic staging of non-small cell lung cancer (NSCLC). Methods A total of 34 patients with NSCLC underwent FLT PET and FDG PET. PET imaging was performed at 60 min after each radiotracer injection. The PET images were evaluated qualitatively for regions of focally increased metabolism. For visualized primary tumors, the maximum standardized uptake value (SUV) was calculated. Nodal stages were determined by using the American Joint Committee on Cancer staging system and surgical and histologic findings reference standards. Results For the depiction of primary tumor, sensitivity of FLT PET was 67%, compared with 94% for FDG PET (P = 0.005). Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for lymph node staging on a per-patient basis were 57, 93, 67, 89, and 85%, respectively, with FLT PET and 57, 78, 36, 91, and 74%, respectively, with FDG PET (P > 0.1 for all comparisons). Two of the three distant metastases were detected with FLT and FDG PET. Conclusion In NSCLC, FLT PET showed better (although not statistically significant) specificity, positive predictive value and accuracy for N staging on a per-patient basis than FDG PET. However, FDG PET was found to have higher sensitivity for depiction of primary tumor than FLT PET.     

<Superscript>68</Superscript>Ga-labeled NOTA-RGD-BBN peptide for dual integrin and GRPR-targeted tumor imaging

Purpose  Radiolabeled Arg-Gly-Asp (RGD) and bombesin (BBN) peptide analogs have been extensively investigated for the imaging of tumor integrin α_vβ₃ and gastrin-releasing peptide receptor (GRPR) expression, respectively. Recently, we designed and synthesized a RGD-BBN heterodimeric peptide from c(RGDyK) and BBN(7–14) through a glutamate linker. The goal of this study was to investigate the dual receptor-targeting property and tumor diagnostic value of RGD-BBN heterodimeric peptide labeled with generator-eluted ⁶⁸Ga (t_1/2 68 min, β⁺ 89% and EC 11%), ⁶⁸Ga-NOTA-RGD-BBN. Methods  RGD-BBN heterodimer was conjugated with 1,4,7-triazacyclononanetriacetic acid (NOTA) and labeled with ⁶⁸Ga. The dual receptor binding affinity was investigated by a radioligand competition binding assay. The in vitro and in vivo dual receptor targeting of ⁶⁸Ga-NOTA-RGD-BBN was evaluated and compared with that of ⁶⁸Ga-NOTA-RGD and ⁶⁸Ga-NOTA-BBN. Results  NOTA-RGD-BBN had integrin α_vβ₃ and GRPR binding affinities comparable to those of the monomeric RGD and BBN, respectively. The dual receptor targeting property of ⁶⁸Ga-NOTA-RGD-BBN was validated by blocking studies in a PC-3 tumor model. ⁶⁸Ga-NOTA-RGD-BBN showed higher tumor uptake than ⁶⁸Ga-NOTA-RGD and ⁶⁸Ga-NOTA-BBN. ⁶⁸Ga-NOTA-RGD-BBN can also image tumors with either integrin or GRPR expression. Conclusion   ⁶⁸Ga-NOTA-RGD-BBN exhibited dual receptor targeting properties both in vitro and in vivo. The favorable characterizations of ⁶⁸Ga-NOTA-RGD-BBN such as convenient synthesis, high specific activity, and high tumor uptake, warrant its further investigation for clinical cancer imaging. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Steroid hormones affect binding of the sigma ligand <Superscript>11</Superscript>C-SA4503 in tumour cells and tumour-bearing rats

Purpose  Sigma receptors are implicated in memory and cognitive functions, drug addiction, depression and schizophrenia. In addition, sigma receptors are strongly overexpressed in many tumours. Although the natural ligands are still unknown, steroid hormones are potential candidates. Here, we examined changes in binding of the sigma-1 agonist ¹¹C-SA4503 in C6 glioma cells and in living rats after modification of endogenous steroid levels. Methods   ¹¹C-SA4503 binding was assessed in C6 monolayers by gamma counting and in anaesthetized rats by microPET scanning. C6 cells were either repeatedly washed and incubated in steroid-free medium or exposed to five kinds of exogenous steroids (1 h or 5 min before tracer addition, respectively). Tumour-bearing male rats were repeatedly treated with pentobarbital (a condition known to result in reduction of endogenous steroid levels) or injected with progesterone. Results  Binding of ¹¹C-SA4503 to C6 cells was increased (~50%) upon removal and decreased (~60%) upon addition of steroid hormones (rank order of potency: progesterone > allopregnanolone = testosterone = androstanolone > dehydroepiandrosterone-3-sulphate, IC₅₀ progesterone 33 nM). Intraperitoneally administered progesterone reduced tumour uptake and tumour-to-muscle contrast (36%). Repeated treatment of animals with pentobarbital increased the PET standardized uptake value of ¹¹C-SA4503 in tumour (16%) and brain (27%), whereas the kinetics of blood pool radioactivity was unaffected. Conclusions  The binding of ¹¹C-SA4503 is sensitive to steroid competition. Since not only increases but also decreases of steroid levels affect ligand binding, a considerable fraction of the sigma-1 receptor population in cultured tumour cells or tumour-bearing animals is normally occupied by endogenous steroids.     

Tumor hypoxia imaging in orthotopic liver tumors and peritoneal metastasis: a comparative study featuring dynamic <Superscript>18</Superscript>F-MISO and <Superscript>124</Superscript>I-IAZG PET in the same study cohort

Purpose The purpose of this paper is to compare the uptake of two clinically promising positron emission tomography (PET) hypoxia targeting agents, ¹²⁴I-iodoazomycin galactopyranoside (¹²⁴I-IAZG) and ¹⁸F-fluoromisonidazole (¹⁸F-FMISO), by dynamic microPET imaging, in the same rats bearing liver tumors and peritoneal metastasis. Methods Morris hepatoma (RH7777) fragments were surgically implanted into the livers of four nude rats. Tumors formed in the liver and disseminated into the peritoneal cavity. Each rat had a total of two to three liver tumors and peritoneal metastasis measuring 10–15 mm in size. Animals were injected with ¹⁸F-FMISO, followed on the next day (upon complete ¹⁸F decay) by ¹²⁴I-IAZG. The animals were imaged in list mode on the microPET system from the time of injection of each tracer for 3 h and then again at 6 h and 24 h for the long-lived ¹²⁴I-IAZG tracer (4.2-day half-life). Micro computed tomography (CT) scans of each rat were performed for co-registration with the microPET scans acquired with a liver contrast agent, allowing tumor identification. Regions of interest (ROIs) were drawn over the heart, liver, muscle, and the hottest areas of the tumors. Time–activity curves (TACs) were drawn for each tissue ROI. Results The ¹⁸F-FMISO signal increased in tumors over the 3-h time course of observation. In contrast, after the initial injection, the ¹²⁴I-IAZG signal slowly and continuously declined in the tumors. Nevertheless, the tumor-to-normal-tissue ratios of ¹²⁴I-IAZG increased, but more slowly than those of ¹⁸F-FMISO and as a result of the differentially faster clearance from the surrounding normal tissues. These pharmacokinetic patterns were seen in all 11 tumors of the four animals. Conclusions ¹⁸F-FMISO localizes in the same intra-tumor regions as ¹²⁴I-IAZG. The contrast ratios (tumor/background) reach similar values for the two hypoxia tracers, but at later times for ¹²⁴I-IAZG than for ¹⁸F-FMISO and, therefore, with poorer count statistics. As a consequence, the ¹⁸F-FMISO images are of superior diagnostic image quality to the ¹²⁴I-IAZG images in the Morris hepatoma McA-R-7777 tumor model. Supported in part by R25-CA096945-3 (C.C.R., P.B., H.H., J.L.H.) and by NCI grant PO1 CA115675 on the Detection of Tumor Hypoxia by Non Invasive Nuclear Imaging Methods (C.C.L and J.L.H).     

Noninvasive imaging of tumor integrin expression using <Superscript>18</Superscript>F-labeled RGD dimer peptide with PEG<Subscript>4</Subscript> linkers

Purpose  Various radiolabeled Arg-Gly-Asp (RGD) peptides have been previously investigated for tumor integrin α_vβ₃ imaging. To further develop RGD radiotracers with enhanced tumor-targeting efficacy and improved in vivo pharmacokinetics, we designed a new RGD homodimeric peptide with two PEG₄ spacers (PEG₄ = 15-amino-4,7,10,13-tetraoxapentadecanoic acid) between the two monomeric RGD motifs and one PEG₄ linker on the glutamate α-amino group (¹⁸F-labeled PEG₄-E[PEG₄-c(RGDfK)]₂, P-PRGD2), as a promising agent for noninvasive imaging of integrin expression in mouse models. Methods  P-PRGD2 was labeled with ¹⁸F via 4-nitrophenyl 2-¹⁸F-fluoropropionate (¹⁸F-FP) prosthetic group. In vitro and in vivo characteristics of the new dimeric RGD peptide tracer ¹⁸F-FP-P-PRGD2 were investigated and compared with those of ¹⁸F-FP-P-RGD2 (¹⁸F-labeled RGD dimer without two PEG₄ spacers between the two RGD motifs). The ability of ¹⁸F-FP-P-PRGD2 to image tumor vascular integrin expression was evaluated in a 4T1 murine breast tumor model. Results  With the insertion of two PEG₄ spacers between the two RGD motifs, ¹⁸F-FP-P-PRGD2 showed enhanced integrin α_vβ₃-binding affinity, increased tumor uptake and tumor-to-nontumor background ratios compared with ¹⁸F-FP-P-RGD2 in U87MG tumors. MicroPET imaging with ¹⁸F-FP-P-PRGD2 revealed high tumor contrast and low background in tumor-bearing nude mice. Biodistribution studies confirmed the in vivo integrin α_vβ₃-binding specificity of ¹⁸F-FP-P-RGD2. ¹⁸F-FP-P-PRGD2 can specifically image integrin α_vβ₃ on the activated endothelial cells of tumor neovasculature. Conclusion   ¹⁸F-FP-P-PRGD2 can provide important information on integrin expression on the tumor vasculature. The high integrin binding affinity and specificity, excellent pharmacokinetic properties and metabolic stability make the new RGD dimeric tracer ¹⁸F-FP-P-PRGD2 a promising agent for PET imaging of tumor angiogenesis and for monitoring the efficacy of antiangiogenic treatment. Electronic supplementary material  The online version of this article (doi: ) contains supplementary material, which is available to authorized users.     

Detection of bone metastases in patients with lung cancer: <Superscript>99m</Superscript>Tc-MDP planar bone scintigraphy, <Superscript>18</Superscript>F-fluoride PET or <Superscript>18</Superscript>F-FDG PET/CT

Purpose  

The aim of the study was to compare the diagnostic accuracy of ¹⁸F-fluorodeoxyglucose (FDG) PET/CT versus standard planar bone scintigraphy (BS) and ¹⁸F-labelled NaF (¹⁸F) PET for the detection of bone metastases (BM) in non-small cell lung cancer (NSCLC).     

<Superscript>18</Superscript>F-FDG PET imaging of progressive massive fibrosis

Purpose  

This study was to evaluate ¹⁸F-FDG PET features of progressive massive fibrosis (PMF) and to determine the ability of FDG PET to differentiate pure PMF from PMF-associated lung cancer.     

<Superscript>18</Superscript>F-fluorothymidine kinetics of malignant brain tumors

Purpose ¹⁸F-labeled deoxy-fluorothymidine (FLT), a marker of cellular proliferation, has been used in PET tumor imaging. Here, the FLT kinetics of malignant brain tumors were investigated. Methods Seven patients with high-grade tumors and two patients with metastases had 12 studies. After 1.5 MBq/kg ¹⁸F-FLT had been administered intravenously, dynamic PET studies were acquired for 75 min. Images were reconstructed with iterative algorithms, and corrections applied for attenuation and scatter. Parametric images were generated with factor analysis, and vascular input and tumor output functions were derived. Compartmental models were used to estimate the rate constants. Results The standard three-compartment model appeared appropriate to describe ¹⁸F-FLT uptake. Corrections for blood volume, metabolites, and partial volume were necessary. Kinetic parameters were correlated with tumor pathology and clinical follow-up data. Two groups could be distinguished: lesions that were tumor predominant (TumP) and lesions that were treatment change predominant (TrcP). Both groups had a widely varying k ₁ (transport across the damaged BBB, range 0.02–0.2). Group TrcP had a relatively low k ₃ (phosphorylation rate, range 0.017–0.027), whereas k ₃ varied sevenfold in group TumP (range 0.015–0.11); the k ₃ differences were significant (p < 0.01). The fraction of transported FLT that is phosphorylated [k ₃/(k ₂+k ₃)] was able to separate the two groups (p < 0.001). Conclusion A three-compartment model with blood volume, metabolite, and partial volume corrections could adequately describe ¹⁸F-FLT kinetics in malignant brain tumors. Patients could be distinguished as having: (1) tumor-predominant or (2) treatment change-predominant lesions, with significantly different phosphorylation rates.     

<Superscript>89</Superscript>Zr-Onartuzumab PET imaging of c-MET receptor dynamics

Purpose

c-MET and its ligand hepatocyte growth factor are often dysregulated in human cancers. Dynamic changes in c-MET expression occur and might predict drug efficacy or emergence of resistance. Noninvasive visualization of c-MET dynamics could therefore potentially guide c-MET-directed therapies. We investigated the feasibility of ⁸⁹Zr-labelled one-armed c-MET antibody onartuzumab PET for detecting relevant changes in c-MET levels induced by c-MET-mediated epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib resistance or heat shock protein-90 (HSP90) inhibitor NVP-AUY-922 treatment in human non-small-cell lung cancer (NSCLC) xenografts.

Methods

In vitro membrane c-MET levels were determined by flow cytometry. HCC827ErlRes, an erlotinib-resistant clone with c-MET upregulation, was generated from the exon-19 EGFR-mutant human NSCLC cell line HCC827. Mice bearing HCC827 and HCC827ErlRes tumours in opposite flanks underwent ⁸⁹Zr-onartuzumab PET scans. The HCC827-xenografted mice underwent ⁸⁹Zr-onartuzumab PET scans before treatment and while receiving biweekly intraperitoneal injections of 100 mg/kg NVP-AUY-922 or vehicle. Ex vivo, tumour c-MET immunohistochemistry was correlated with the imaging results.

Results

In vitro, membrane c-MET was upregulated in HCC827ErlRes tumours by 213?±?44% in relation to the level in HCC827 tumours, while c-MET was downregulated by 69?±?9% in HCC827 tumours following treatment with NVP-AUY-922. In vivo, ⁸⁹Zr-onartuzumab uptake was 26% higher (P?<?0.05) in erlotinib-resistant HCC827ErlRes than in HCC827 xenografts, while HCC827 tumour uptake was 33% lower (P?<?0.001) following NVP-AUY-922 treatment.

Conclusion

The results show that ⁸⁹Zr-onartuzumab PET effectively discriminates relevant changes in c-MET levels and could potentially be used clinically to monitor c-MET status.

     

<Superscript>124</Superscript>I-L19-SIP for immuno-PET imaging of tumour vasculature and guidance of <Superscript>131</Superscript>I-L19-SIP radioimmunotherapy

Purpose  The human monoclonal antibody (MAb) fragment L19-SIP is directed against extra domain B (ED-B) of fibronectin, a marker of tumour angiogenesis. A clinical radioimmunotherapy (RIT) trial with ¹³¹I-L19-SIP was recently started. In the present study, after GMP production of ¹²⁴I and efficient production of ¹²⁴I-L19-SIP, we aimed to demonstrate the suitability of ¹²⁴I-L19-SIP immuno-PET for imaging of angiogenesis at early-stage tumour development and as a scouting procedure prior to clinical ¹³¹I-L19-SIP RIT. Methods   ¹²⁴I was produced in a GMP compliant way via ¹²⁴Te(p,n)¹²⁴I reaction and using a TERIMO™ module for radioiodine separation. L19-SIP was radioiodinated by using a modified version of the IODO-GEN method. The biodistribution of coinjected ¹²⁴I- and ¹³¹I-L19-SIP was compared in FaDu xenograft-bearing nude mice, while ¹²⁴I PET images were obtained from mice with tumours of <50 to ∼700 mm³. Results   ¹²⁴I was produced highly pure with an average yield of 15.4 ± 0.5 MBq/μAh, while separation yield was ∼90% efficient with <0.5% loss of TeO₂. Overall labelling efficiency, radiochemical purity and immunoreactive fraction were for ¹²⁴I-L19-SIP: ∼80 , 99.9 and >90%, respectively. Tumour uptake was 7.3 ± 2.1, 10.8 ± 1.5, 7.8 ± 1.4, 5.3 ± 0.6 and 3.1 ± 0.4%ID/g at 3, 6, 24, 48 and 72 h p.i., resulting in increased tumour to blood ratios ranging from 6.0 at 24 h to 45.9 at 72 h p.i.. Fully concordant labelling and biodistribution results were obtained with ¹²⁴I- and ¹³¹I-L19-SIP. Immuno-PET with ¹²⁴I-L19-SIP using a high-resolution research tomograph PET scanner revealed clear delineation of the tumours as small as 50 mm³ and no adverse uptake in other organs. Conclusions   ¹²⁴I-MAb conjugates for clinical immuno-PET can be efficiently produced. Immuno-PET with ¹²⁴I-L19-SIP appeared qualified for sensitive imaging of tumour neovasculature and for predicting ¹³¹I-L19-SIP biodistribution. Bernard M. Tijink and Lars R. Perk contributed equally to this article.     

Peptide receptor radionuclide therapy with <Superscript>90</Superscript>Y-DOTATOC in recurrent meningioma

Purpose  Meningiomas are generally benign and in most cases surgery is curative. However, for high-grade histotypes or partially resected tumours, recurrence is fairly common. External beam radiation therapy (EBRT) is usually given in such cases but is not always effective. We assessed peptide receptor radionuclide therapy (PRRT) using ⁹⁰Y-DOTATOC in a group of patients with meningioma recurring after standard treatments in all of whom somatostatin receptors were strongly expressed on meningioma cell surfaces. Methods  Twenty-nine patients with scintigraphically proven somatostatin subtype 2 receptor-positive meningiomas were enrolled: 14 had benign (grade I), 9 had atypical (grade II) and 6 had malignant (grade III) disease. Patients received intravenous ⁹⁰Y-DOTATOC for 2–6 cycles for a cumulative dose in the range of 5–15 GBq. Clinical and neuroradiological evaluations were performed at baseline, during and after PRRT. Results  The treatment was well tolerated in all patients. MRI 3 months after treatment completion showed disease stabilization in 19 of 29 patients (66%) and progressive disease in the remaining 10 (34%). Better results were obtained in patients with grade I meningioma than in those with grade II–III, with median time to progression (from beginning PRRT) of 61 months in the low-grade group and 13 months in the high-grade group. Conclusion  PRRT with ⁹⁰Y-DOTATOC can interfere with the growth of meningiomas. The adjuvant role of this treatment, soon after surgery, especially in atypical and malignant histotypes, deserves further investigation.     

Mean and maximum standardized uptake values in [<Superscript>18</Superscript>F]FDG-PET for assessment of histopathological response in oesophageal squamous cell carcinoma or adenocarcinoma after radiochemotherapy

Purpose  To evaluate the potential of [¹⁸F]fluorodeoxyglucose positron emission tomography (FDG-PET) for the assessment of histopathological response and survival after neoadjuvant radiochemotherapy in patients with oesophageal cancer. Patients and methods  In 2005 and 2006, 55 patients (43 men, 12 women; median age 60 years) with locally advanced oesophageal cancer (cT3-4 Nx M0; 24 with squamous cell carcinoma, 31 with adenocarcinoma) underwent transthoracic en bloc oesophagectomy after completion of treatment with cisplatin, 5-fluorouracil, and radiotherapy ad 36 Gy in a prospective clinical trial. Of the 55 patients, 21 (38%) were classified as histopathological responders (<10% vital residual tumour cells) and 34 (62%) as nonresponders. FDG-PET was performed before (PET 1) and 3–4 weeks after the end (PET 2) of radiochemotherapy with assessment of maximum and average standardized uptake values (SUV) for correlation with histopathological response and survival. Results  Histopathological responders had a slightly higher baseline SUV than nonresponders (p<0.0001 between PET 1 and PET 2 for responders and nonresponders) and the decrease was more prominent in responders. Except for SUVmax in patients with squamous cell carcinoma neither baseline nor preoperative SUV nor percent SUV reduction correlated significantly with histopathological response. Histopathological responders had a 2-year overall survival of 91 ± 9% and nonresponders a survival of 53 ± 10% (p = 0.007). Conclusion  Our study does not support recent reports that FDG-PET predicts histopathological response and survival in patients with locally advanced oesophageal cancer treated by neoadjuvant radiochemotherapy. An erratum to this article can be found at     

The clinical efficacy of <Superscript>18</Superscript>F-FDG-PET/CT in benign and malignant musculoskeletal tumors

Objective  Most of the current clinical data on the role of 2-[¹⁸F]fluoro-2-deoxy-d-glucose positron emission tomography (¹⁸F-FDG-PET) in musculoskeletal tumors come from patients studied with PET and less frequently with hardware fusion PET/computed tomography (CT). And the number of cases in each report is too small to clarify the exact clinical efficacy of PET or PET/CT. This prompted us to analyze our experience with ¹⁸F-FDG-PET/CT in a relatively large group of patients with musculoskeletal tumors. Methods   ¹⁸F-FDG-PET/CT was performed on 91 patients from May 2004 to June 2007. The final diagnosis was obtained from surgical biopsy in 83 patients (91%) and clinical follow-up in 8 (9%). We analyzed the characteristics and amount of ¹⁸F-FDG uptake in soft tissue and bone tumors, and investigated the ability of ¹⁸F-FDG-PET/CT to differentiate malignant from benign tumors. The cutoff maximum standardized uptake value (SUV_max) was calculated using the receiver-operation characteristic curve method. Sensitivity, specificity, and diagnostic accuracy were calculated with cutoff SUV_max and the final diagnosis. Unpaired t test was used for the statistical analysis. Results  Final diagnosis revealed 19 benign soft tissue tumors (mean SUV_max 4.7), 27 benign bone tumors (5.1), 25 malignant soft tissue tumors (8.8), and 20 malignant bone tumors (10.8). There was a significant difference in SUV_max between benign and malignant musculoskeletal tumors in total (P < 0.002), soft tissue tumors (P < 0.05), and bone tumors (P < 0.02). Sensitivity, specificity, and diagnostic accuracy were 80%, 65.2%, and 73% in total with cutoff SUV_max 3.8, 80%, 68.4%, and 75% in the soft tissue tumors with cutoff SUV_max 3.8, and 80%, 63%, and 70% in the bone tumors with cutoff SUV_max 3.7. Conclusions   ¹⁸F-FDG-PET/CT reliably differentiated malignant soft tissue and bone tumors from benign ones, although there were many false-positive and falsenegative lesions. Further studies with all kinds of musculoskeletal tumors in large numbers are needed to improve the diagnostic accuracy of ¹⁸F-FDG-PET/CT.     

<Superscript>18</Superscript>F-FDG PET independently predicts survival in patients with cholangiocellular carcinoma treated with <Superscript>90</Superscript>Y microspheres

Purpose  

⁹⁰Y radioembolization has emerged as a valuable therapy for intrahepatic cholangiocellular carcinomas (ICC). We aimed to evaluate the prognostic power of FDG PET/CT and that of pretherapeutic scintigraphy with ^99mTc-labelled macroagglutinated albumin (MAA), an index of tumour vascularization.     

<Superscript>11</Superscript>C-methylaminoisobutyric acid (MeAIB) PET for evaluation of prostate cancer: compared with <Superscript>18</Superscript>F-fluorodeoxyglucose PET

Objective

α-N-methyl-¹¹C-methylaminoisobutyric acid (¹¹C-MeAIB) is a selective substrate of system A amino acid transport, and known to accumulate in malignant lesions. The aim of this study was to evaluate the utility of MeAIB PET for the assessment of prostate cancer, compared with FDG PET.

Methods

Thirty-four men (age range 57–77 years) with prostate cancer were prospectively enrolled, and underwent MeAIB PET and FDG PET between January 2011 and January 2013. MeAIB PET and FDG PET were performed at 20 and 50 min post-injection, respectively. SUVmax of the prostate was calculated, and visual analysis was conducted for MeAIB and FDG PET studies. MRI images were visually evaluated if available. All patients received total prostatectomy subsequently, and imaging findings were compared with pathological results, including T stage, Gleason score, and tumor size. The patient-based and lesion-based sensitivity and specificity were calculated according to pathological significant cancer.

Results

Mean value of SUVmax of ¹¹C-MeAIB PET and ¹⁸F-FDG PET in prostate cancer were 3.18 (±1.90, range; 1.55–9.57) and 3.88 (±2.85, range; 2.04–14.47). MeAIB PET and FDG PET were positive by visual analysis in 47.1 % (16/34) and 44.1 % (15/34) of the patients. MRI was positive in 51.5 % (17/33). Pathological stage and Gleason score were as follows: Stage 2 (n = 23), 3 (n = 8), and 4 (n = 3); Gleason score 6 (n = 13), 7 (n = 16), 8 (n = 3), and 9 (n = 2). The sensitivities tended to be higher according to higher pathological T stage or Gleason sum score for both MeAIB and FDG PET studies. Visual analysis of both MeAIB PET and FDG PET had significant correlation with extraprostatic extension (p < 0.05). MeAIB PET and FDG PET had complementary results by visual analysis in the assessment of prostate cancer. The patient-based sensitivity of MeAIB PET, FDG PET, and MRI were 51.6, 48.4, and 56.7 %, respectively. The patient-based specificity of these modalities was 100 % for each modality.

Conclusions

MeAIB PET has better diagnostic results than FDG PET for the assessment of significant prostate cancer, and these PET studies showed complementary results. MRI has even better diagnostic results than ¹¹C-MeAIB PET. MeAIB accumulates in prostate cancer, which indicates that the system A amino acid transport pathway is activated in prostate cancer.

     

A novel <Superscript>18</Superscript>F-labeled two-helix scaffold protein for PET imaging of HER2-positive tumor

Purpose  

Two-helix scaffold proteins (~ 5 kDa) against human epidermal growth factor receptor type 2 (HER2) have been discovered in our previous work. In this research we aimed to develop an ¹⁸F-labeled two-helix scaffold protein for positron emission tomography (PET) imaging of HER2-positive tumors.     

Cyclosporine,a P-glycoprotein modulator,increases [<Superscript>18</Superscript>F]MPPF uptake in rat brain and peripheral tissues: microPET and ex vivo studies

Purpose  Pretreatment with cyclosporine, a P-glycoprotein (P-gp) modulator increases brain uptake of 4-(2'-methoxyphenyl)-1-[2'-(N-2"-pyridinyl)-p-[¹⁸F]fluorobenzamido]ethylpiperazine ([¹⁸F]MPPF) for binding to hydroxytryptamine_1A (5-HT_1A) receptors. Those increases were quantified in rat brain with in vivo microPET and ex vivo tissue studies. Materials and methods  Each Sprague–Dawley rat (n = 4) received a baseline [¹⁸F]MPPF microPET scan followed by second scan 2–3 weeks later that included cyclosporine pretreatment (50 mg/kg, i.p.). Maximum a posteriori reconstructed images and volumetric ROIs were used to generate dynamic radioactivity concentration measurements for hippocampus, striatum, and cerebellum, with simplified reference tissue method (SRTM) analysis. Western blots were used to semiquantify P-gp regional distribution in brain. Results  MicroPET studies showed that hippocampus uptake of [¹⁸F]MPPF was increased after cyclosporine; ex vivo studies showed similar increases in hippocampus and frontal cortex at 30 min, and for heart and kidney at 2.5 and 5 min, without concomitant increases in [¹⁸F]MPPF plasma concentration. P-gp content in cerebellum was twofold higher than in hippocampus or frontal cortex. Conclusions  These studies confirm and extend prior ex vivo results (J. Passchier, et al., Eur J Pharmacol, 2000) that showed [¹⁸F]MPPF as a substrate for P-gp. Our microPET results showed that P-gp modulation of [¹⁸F]MPPF binding to 5-HT_1A receptors can be imaged in rat hippocampus. The heterogeneous brain distribution of P-gp appeared to invalidate the use of cerebellum as a nonspecific reference region for SRTM modeling. Regional quantitation of P-gp may be necessary for accurate PET assessment of 5-HT_1A receptor density when based on tracer uptake sensitive to P-gp modulation.