EJNMMI Research - Latest Articles

Hemoglobin level significantly impacts the tumor cell survival fraction in humans after internal radiotherapy

Stephan Walrand — 2012-05-19T00:00:00Z

Background: Anemia is usually not taken into account in internal radiotherapy. We investigated whetherthe hemoglobin (Hb) level could have an impact on the tumor response, as observed inexternal beam radiotherapy (EBRT). Methods: Absorbed doses of 25 hepatic metastatic sites in eight patients who underwent a liverselective internal radiotherapy (SIRT) were computed by a 3D convolution of a dosedeposition kernel with the 90Y time-of-flight positron emission tomography (TOF-PET)images acquired following therapy. Early tumor response was assessed by comparing afollow-up FDG TOF-PET scan with a baseline scan. Hb level was measured on the day of theSIRT procedure. Results: All patients displayed early tumor response increasing with the tumor-absorbed dose.Significant differences between patients were noted, the response slope correlating with theHb level. After applying a global fit on all metastases using a tumor radiosensitivitymodulated by a Hb enhancement factor (HEF) linearly dependent on the Hb level, a strongcorrelation (R = 0.96) was observed between the early response and the absorbed dose. Hblevel had a major impact on tumor response by modulating HEF by a factor 6. Conclusions: These results prove the significant impact of Hb level on the tumor response and support thestudy of methods for correcting tumor hypoxia, such as intensively performed in EBRT. Thequantitative analysis of the relationship between tumor doses and early response has thepower to allow fast screening of such correction methods in limited patient series. Internalradiotherapy could be more efficient if performed earlier in the therapy line, when thedisease- and treatment-related anemia remains limited.

Co-registration of glucose metabolism with positron emission tomography and vascularity with fluorescent diffuse optical tomography in mouse tumors

Xiao Tong — 2012-05-07T00:00:00Z

Background: Bimodal molecular imaging with fluorescence diffuse optical tomography (fDOT) and positron emission tomography (PET) has the capacity to provide multiple molecular information of mouse tumors. The objective of the present study is to co-register fDOT and PET molecular images of tumors in mice automatically. Methods: The coordinates of bimodal fiducial markers (FM) in regions of detection were automatically detected in planar optical images (x, y positions) in laser pattern optical surface images (z position) and in 3-D PET images. A transformation matrix was calculated from the coordinates of the FM in fDOT and in PET and applied in order to co-register images of mice bearing neuroendocrine tumors. Results: The method yielded accurate non-supervised co-registration of fDOT and PET images. The mean fiducial registration error was smaller than the respective voxel sizes for both modalities, allowing comparison of the distribution of contrast agents from both modalities in mice. Combined imaging depicting tumor metabolism with PET-[18 F]2-deoxy-2-fluoro-D-glucose and blood pool with fDOT demonstrated partial overlap of the two signals. Conclusions: This automatic method for co-registration of fDOT with PET and other modalities is efficient, simple and rapid, opening up multiplexing capacities for experimental in vivo molecular imaging.

Sorafenib increases 18-FDG colic uptake: demonstration in patients with differentiated thyroid cancer

Renaud Ciappuccini — 2012-05-07T00:00:00Z

Background: To assess 18-fluorodeoxyglucose (FDG) bowel uptake in patients with differentiated thyroidcancer (DTC) treated with sorafenib.FindingsVisual (5-point scale) and high maximum standard uptake value (SUVmax) semi-quantitativeanalyses were conducted in 63 positron emission tomography (PET) studies performed inpatients on sorafenib (group 1, n = 20), in a control group (group 2, n = 28) and in patients onsunitinib or vandetanib (group 3, n = 15).Moderate or high and diffuse bowel uptake (grade 4 or 5) was observed in 90% of the PETscans of group 1 versus none in group 2. Only 20% of PET scans in group 3 were scoredgrade 4. SUVmax values were significantly higher for all colic segments in group 1 than ingroup 2 (P < 0.0001) or 3 (P < 0.0004). This uptake pattern appeared rapidly (one month) anddisappeared after sorafenib withdrawal. Conclusions: FDG uptake is increased in the colon of DTC patients treated by sorafenib.

Straightforward thiol-mediated protein labelling with DTPA: Synthesis of a highly active 111In-annexin A5-DTPA tracer

Harald Kratz — 2012-04-27T00:00:00Z

Background: Annexin A5 (anxA5) has been found useful for molecular imaging of apoptosis and other biological processes. Methods: Here, we report an optimised two-step synthesis of annexin A5-diethylene triamine pentaacetic acid (DTPA) (anxA5-DTPA) for positron emission tomography (PET) and single-photon emission computed tomography (SPECT) imaging with a single purification step. The use of a recombinant annexin A5 (cys-anxA5) with a single thiol group allowed regionally specific coupling, without affecting the binding domain of cys-anxA5. Results: The metal complexing capacity of anxA5-DTPA was investigated by labelling with 111In3+ and Eu3+. Binding of modified anxA5-DTPA to apoptotic cells was tested in competition experiments with a fluorescent anxA5 derivative (anxA5-FITC) using flow cytometry and compared with that of wildtype anxA5 or non-binding anxA5-DTPA (M1234-anxA5-DTPA). The binding affinity to apoptotic cells of the anxA5-DTPA conjugate does not differ from that of wildtype anxA5. Conclusions: This two-step synthesis of annexin A5-DTPA resulted in biologically active anxA5-DTPA, which can be labelled with radionuclides for use in SPECT and PET imaging.

A method for model-free partial volume correction in oncological PET

Frank Hofheinz — 2012-04-24T00:00:00Z

Background: As is well known, limited spatial resolution leads to partial volume effects (PVE) and consequently to limited signal recovery. Determination of the mean activity concentration of a target structure is thus compromised even at target sizes much larger than the reconstructed spatial resolution. This leads to serious size-dependent underestimates of true signal intensity in hot spot imaging. For quantitative PET in general and in the context of therapy assessment in particular it is, therefore, mandatory to perform an adequate partial volume correction (PVC). The goal of our work was to develop and to validate a model-free PVC algorithm for hot spot imaging. Methods: The algorithm proceeds in two automated steps. Step 1: estimation of the actual object boundary with a threshold based method and determination of the total activity A measured within the enclosed volume V. Step 2: determination of the activity fraction B, which is measured outside the object due to the partial volume effect (spill-out). The PVE corrected mean value is then given by Cmean = (A+B)/V. For validation simulated tumours were used which were derived from real patient data (liver metastases of a colorectal carcinoma and head and neck cancer, respectively). The simulated tumours have characteristics (regarding tumour shape, contrast, noise, etc.) which are very similar to those of the underlying patient data, but the boundaries and tracer accumulation are exactly known. The PVE corrected mean values of 37 simulated tumours were determined and compared with the true mean values. Results: For the investigated simulated data the proposed approach yields PVE corrected mean values which agree very well with the true values (mean deviation (+/- s.d.): (0.8 +/- 2.5)% Conclusions: The described method enables accurate quantitative partial volume correction in oncological hot spot imaging.

Kinetic analysis and test-retest variability of the radioligand [11C](R)-PK11195 binding to TSPO in the human brain - a PET study in control subjects

Aurelija Jucaite — 2012-04-23T00:00:00Z

Background: Positron-emission tomography and the radioligand [11C](R)-PK11195 have been used for the imaging of the translocator protein (TSPO) and applied to map microglia cells in the brain in neuropsychiatric disorders. [11C](R)-PK11195 binding has been quantified using reference region approaches, with the reference defined anatomically or using unsupervised or supervised clustering algorithms. Kinetic compartment modelling so far has not been presented. In the present test-retest study, we examine the characteristics of [11C](R)-PK11195 binding in detail, using the classical compartment analysis with a metabolite-corrected arterial input function. Methods: [11C](R)-PK11195 binding was examined in six control subjects at two separate occasions, 6 weeks apart. Results of one-tissue and two-tissue compartment models (1TCM, 2TCM) were compared using the Akaike criteria and F-statistics. The reproducibility of binding potential (BPND) estimates was evaluated by difference in measurements (error in percent) and intraclass correlation coefficients (ICCs). Results: [11C](R)-PK11195 binding could be described by 2TCM which was the preferred model. Measurement error (in percent) indicated good reproducibility in large brain regions (mean error: whole brain 4%, grey matter 5%), but not in smaller subcortical regions (putamen 25%, caudate 55%). The ICC values were moderate to low, highest for the white matter (0.73), whole brain and thalamus (0.57), and cortical grey matter (0.47). Sizeable [11C](R)-PK11195 BPND could be identified throughout the human brain (range 1.11 to 2.21). Conclusions: High intra-subject variability of [11C](R)-PK11195 binding limits longitudinal monitoring of TSPO changes. The interpretation of [11C](R)-PK11195 binding by 2TCM suggests that the presence of specific binding to TSPO cannot be excluded at physiological conditions.

High resolution tumor targeting in living mice by means of multispectral optoacoustic tomography

Andreas Buehler — 2012-04-01T00:00:00Z

Background: Tumor targeting is of high clinical and biological relevance, and major efforts have been made to develop molecular imaging technologies for visualization of the disease markers in tissue. Of particular interest is apoptosis which has a profound role within tumor development and has significant effect on cancer malignancy. Methods: Herein, we report on targeting of phosphatidylserine-exposing cells within live tumor allograft models using a synthetic near infrared zinc(II)-dipicolylamine probe. Visualization of the probe biodistribution is performed with whole body multispectral optoacoustic tomography (MSOT) system and subsequently compared to results attained by planar and tomographic fluorescence imaging systems. Results: Compared to whole body optical visualization methods, MSOT attains remarkably better imaging capacity by delivering high-resolution scans of both disease morphology and molecular function in real time. Enhanced resolution of MSOT clearly showed that the probe mainly localizes in the vessels surrounding the tumor, suggesting that its tumor selectivity is gained by targeting the phosphatidylserine exposed on the surface of tumor vessels. Conclusions: The current study demonstrates the high potential of MSOT to broadly impact the fields of tumor diagnostics and preclinical drug development.

Bone-seeking TRAP conjugates: surprising observations and their implications on the development of gallium-68-labeled bisphosphonates

Johannes Notni — 2012-03-30T00:00:00Z

Background: Bisphosphonates possess strong affinity to bone. 99mTc bisphosphonate complexes are widely used for bone scintigraphy. For positron emission tomography (PET) bone imaging, Ga-68-based PET tracers based on bisphosphonates are highly desirable.FindingsTwo trimeric bisphosphonate conjugates of the triazacyclononane-phosphinate (TRAP) chelator were synthesized, labeled with Ga-68, and used for microPET imaging of bone in male Lewis rats. Both Ga-68 tracers show bone uptake and, thus, are suitable for PET bone imaging. Surprisingly, Ga-71 nuclear magnetic resonance data prove that Ga(III) is not located in the chelating cavity of TRAP and must therefore be bound by the conjugated bisphosphonate units. Conclusion: The intrinsic Ga-68 chelating properties of TRAP are not needed for Ga-68 PET bone imaging with TRAP-bisphosphonate conjugates. Here, TRAP serves only as a trimeric scaffold. For preparation of Ga-68-based bone seekers for PET, it appears sufficient to equip branched scaffolds with multiple bisphosphonate units, which serve both Ga-68-binding and bone-targeting purposes.

[11C]Flumazenil brain uptake is influenced by the blood-brain barrier efflux transporter P-glycoprotein

Femke Froklage — 2012-03-28T00:00:00Z

Background: [11C]Flumazenil and positron emission tomography (PET) are used clinically to assess gamma-aminobutyric acid (GABA)-ergic function and to localize epileptic foci prior to resective surgery. Enhanced P-glycoprotein (P-gp) activity has been reported in epilepsy and this may confound interpretation of clinical scans if [11C]flumazenil is a P-gp substrate. The purpose of this study was to investigate whether [11C]flumazenil is a P-gp substrate. Methods: [11C]Flumazenil PET scans were performed in wild type (WT) (n = 9) and Mdr1a/1b, (the genes that encode for P-gp) double knockout (dKO) (n = 10) mice, and in naive rats (n = 10). In parallel to PET scanning, [11C]flumazenil plasma concentrations were measured in rats. For 6 of the WT and 6 of the dKO mice a second, [11C]flumazenil scan was acquired after administration of the P-gp inhibitor tariquidar. Cerebral [11C]flumazenil concentrations in WT and Mdr1a/1b dKO mice were compared (genetic disruption model). Furthermore, pre and post P-gp-blocking cerebral [11C]flumazenil concentrations were compared in all animals (pharmacological inhibition model). Results: Mdr1a/1b dKO mice had approximately 70% higher [11C]flumazenil uptake in the brain than WT mice. After administration of tariquidar, cerebral [11C]flumazenil uptake in WT mice increased by about 80% in WT mice, while it remained the same in Mdr1a/1b dKO mice. In rats, cerebral [11C]flumazenil uptake increased by about 60% after tariquidar administration. Tariquidar had only a small effect on plasma clearance of flumazenil. Conclusions: The present study showed that [11C]flumazenil is a P-gp substrate in rodents. Consequently, altered cerebral [11C]flumazenil uptake, as observed in epilepsy, may not reflect solely GABAA receptor density changes but also changes in P-gp activity.

Evaluation of limited blood sampling population input approaches for kinetic quantification of [18F]fluorothymidine PET data

Kaiyumars Contractor — 2012-03-24T00:00:00Z

Background: Quantification of kinetic parameters of positron emission tomography (PET) imaging agents normally requires collecting arterial blood samples which is inconvenient for patients and difficult to implement in routine clinical practice. The aim of this study was to investigate whether a population-based input function (POP-IF) reliant on only a few individual discrete samples allows accurate estimates of tumour proliferation using [18F]fluorothymidine (FLT). Methods: Thirty-six historical FLT-PET data with concurrent arterial sampling were available for this study. A population average of baseline scans blood data was constructed using leave-one-out cross-validation for each scan and used in conjunction with individual blood samples. Three limited sampling protocols were investigated including, respectively, only seven (POP-IF7), five (POP-IF5) and three (POP-IF3) discrete samples of the historical dataset. Additionally, using the three-point protocol, we derived a POP-IF3M, the only input function which was not corrected for the fraction of radiolabelled metabolites present in blood. The kinetic parameter for net FLT retention at steady state, Ki, was derived using the modified Patlak plot and compared with the original full arterial set for validation. Results: Small percentage differences in the area under the curve between all the POP-IFs and full arterial sampling IF was found over 60 min (4.2%-5.7%), while there were, as expected, larger differences in the peak position and peak height.A high correlation between Ki values calculated using the original arterial input function and all the population-derived IFs was observed (R2 = 0.85-0.98). The population-based input showed good intra-subject reproducibility of Ki values (R2 = 0.81-0.94) and good correlation (R2 = 0.60-0.85) with Ki-67. Conclusions: Input functions generated using these simplified protocols over scan duration of 60 min estimate net PET-FLT retention with reasonable accuracy.