Integrated boost IMRT with FET-PET-adapted local dose escalation in glioblastomas. Results of a prospective phase II study.

PURPOSE: Dose escalations above 60 Gy based on MRI have not led to prognostic benefits in glioblastoma patients yet. With positron emission tomography (PET) using [(18)F]fluorethyl-L-tyrosine (FET), tumor coverage can be optimized with the option of regional dose escalation in the area of viable tumor tissue. METHODS AND MATERIALS: In a prospective phase II study (January 2008 to December 2009), 22 patients (median age 55 years) received radiochemotherapy after surgery. The radiotherapy was performed as an MRI and FET-PET-based integrated-boost intensity-modulated radiotherapy (IMRT). The prescribed dose was 72 and 60 Gy (single dose 2.4 and 2.0 Gy, respectively) for the FET-PET- and MR-based PTV-FET((72 Gy)) and PTV-MR((60 Gy)). FET-PET and MRI were performed routinely for follow-up. Quality of life and cognitive aspects were recorded by the EORTC-QLQ-C30/QLQ Brain20 and Mini-Mental Status Examination (MMSE), while the therapy-related toxicity was recorded using the CTC3.0 and RTOG scores. RESULTS: Median overall survival (OS) and disease-free survival (DFS) were 14.8 and 7.8 months, respectively. All local relapses were detected at least partly within the 95% dose volume of PTV-MR((60 Gy)). No relevant radiotherapy-related side effects were observed (excepted alopecia). In 2 patients, a pseudoprogression was observed in the MRI. Tumor progression could be excluded by FET-PET and was confirmed in further MRI and FET-PET imaging. No significant changes were observed in MMSE scores and in the EORTC QLQ-C30/QLQ-Brain20 questionnaires. CONCLUSION: Our dose escalation concept with a total dose of 72 Gy, based on FET-PET, did not lead to a survival benefit. Acute and late toxicity were not increased, compared with historical controls and published dose-escalation studies.

Brain stem activation in spontaneous human migraine attacks.

Evidence from animal experiments shows that the brain stem is involved in the pathophysiology of migraine. To investigate human migraine, we used positron emission tomography to examine the changes in regional cerebral blood flow as an index of neuronal activity in the human brain during spontaneous migraine attacks. During the attacks, increased blood flow was found in the cerebral hemispheres in cingulate, auditory and visual association cortices and in the brain stem. However, only the brain stem activation persisted after the injection of sumatriptan had induced complete relief from headache and phono- and photophobia. These findings support the idea that the pathogenesis of migraine is related to an imbalance in activity between brain stem nuclei regulating antinociception and vascular control.

High resolution BrainPET combined with simultaneous MRI.

UNLABELLED: After the successful clinical introduction of PET/CT, a novel hybrid imaging technology combining PET with the versatile attributes of MRI is emerging. At the Forschungszentrum Jülich, one of four prototypes available worldwide combining a commercial 3T MRI with a newly developed BrainPET insert has been installed, allowing simultaneous data acquisition with PET and MRI. The BrainPET is equipped with LSO crystals of 2.5 mm width and Avalanche photodiodes (APD) as readout electronics. Here we report on some performance characteristics obtained by phantom studies and also on the initial BrainPET studies on various patients as compared with a conventional HR+ PET-only scanner. MATERIAL, METHODS: The radiotracers [18F]-fluoro-ethyl-tyrosine (FET), [11C]-flumazenil and [18F]-FP-CIT were applied. RESULTS: Comparing the PET data obtained with the BrainPET to those of the HR+ scanner demonstrated the high image quality and the superior resolution capability of the BrainPET. Furthermore, it is shown that various MR images of excellent quality could be acquired simultaneously with BrainPET scans without any relevant artefacts. DISCUSSION, CONCLUSION: Initial experiences with the hybrid MRI/BrainPET indicate a promising basis for further developments of this unique technique allowing simultaneous PET imaging combined with both anatomical and functional MRI.

[German guidelines for brain tumour imaging by PET and SPECT using labelled amino acids]. / PET- und SPECT-Untersuchungen von Hirntumoren mit radioaktiv markierten Aminosäuren.

For the primary diagnosis of brain tumours, morphological imaging by means of magnetic resonance imaging (MRI) is the current method of choice. The complementary use of functional imaging by positron emitting tomography (PET) and single photon emitting computerized tomography (SPECT) with labelled amino acids can provide significant information on some clinically relevant questions, which are beyond the capacity of MRI. These diagnostic issues affect in particular the improvement of biopsy targeting and tumour delineation for surgery and radiotherapy planning. In addition, amino acid labelled PET and SPECT tracers are helpful for the differentiation between tumour recurrence and non-specific post-therapeutic tissue changes, in predicting prognosis of low grade gliomas, and for metabolic monitoring of treatment response. The application of dynamic PET examination protocols for the assessment of amino acid kinetics has been shown to enable an improved non-invasive tumour grading. The purpose of this guideline is to provide practical assistance for indication, examination procedure and image analysis of brain PET/SPECT with labelled amino acids in order to allow for a high quality standard of the method. After a short introduction on pathobiochemistry and radiopharmacy of amino acid labelled tracers, concrete and detailed information is given on the several indications, patient preparation and examination protocols as well as on data reconstruction, visual and quantitative image analysis and interpretation. In addition, possible pitfalls are described, and the relevant original publications are listed for further information.

Production of the therapeutic radionuclides 193mPt and 195mPt with high specific activity via alpha-particle-induced reactions on 192Os.

For the production of therapy-relevant radionuclides (193m)Pt (T(1/2)=4.33 d) and (195m)Pt (T(1/2)=4.03 d) with a high specific activity, the (192)Os(alpha,n)(195m)Pt and (192)Os(alpha,3n)(193m)Pt nuclear reactions were investigated for the first time from their respective thresholds up to 28 MeV. Thin samples of enriched (192)Os were prepared by electrodeposition on Ni, and the conventional stacked-foil technique was used for cross-section measurements. The calculated thick target yields were found to be 0.013 MBq/microA h for the (192)Os(alpha,n)(195m)Pt reaction in the energy range of E(alpha)=24-->18 MeV, and 0.25 MBq/microA h for the (192)Os(alpha,3n)(193m)Pt reaction in the energy range of E(alpha)=28-->24 MeV. The two radionuclides could not be detected in the interactions of (3)He particles with (192)Os. A production method involving high-current alpha-particle irradiation of enriched (192)Os and efficient chemical separation of radioplatinum was developed. Batch yields of about 1 MBq (195m)Pt and 8.7 MBq (193m)Pt were achieved. Compared to the reactor production these batch yields are very low, but the (192)Os(alpha,n)(195m)Pt and (192)Os(alpha,3n)(193m)Pt reactions are superior with respect to the specific activity of the products which is higher by two orders of magnitude.

Evaluation of novel tropane analogues in comparison with the binding characteristics of [18F]FP-CIT and [131I]beta-CIT.

This study evaluated novel potential dopamine transporter (DAT) inhibitors as ligands for positron emission tomography. Five new tropane analogs were synthesized and compared with the known ligand 2beta-carbomethoxy-3beta-(4-iodophenyl)tropane (beta-CIT) and the recently characterized ligands N-(3-iodoprop-2E-enyl)-2beta-carbomethoxy-3beta-(4-methylphenyl)-nortropane (PE2I) and 2beta-carbofluoroethoxy-3beta-(4-methylphenyl)tropane (FETT). Evaluation with autoradiography measured the ability to antagonize the binding of [(131)I]iodine-labeled beta-CIT and [(18)F]fluorine-labeled N-(3-fluoropropyl)-2beta-carbomethoxy-3beta-(4-iodo-phenyl) nortropane in rat and pig brains. The standards for comparison (PE2I and FETT) competed strongly in all regions investigated (striatum, cortex, superior colliculus and cerebellum). Of the new compounds, 2alpha-amido-fluoroethyl-3beta-(4-iodophenyl)tropane (4) and 2beta-amido-fluoroethyl-3beta-(4-iodophenyl)tropane (4a) competed strongly with [(131)I]beta-CIT in DAT-rich striatum, but also in other brain regions suggesting poor DAT selectivity. Because [(131)I]beta-CIT binds unselectively both to DAT and serotonin transporters, no definite conclusion about the selectivity of the new compounds is possible. However, preclinical studies using the compounds and labeled with fluorine-18 or iodine-131 are encouraged.

Fluorine-18 labeling methods: Features and possibilities of basic reactions.

Many experimental and established tracers make fluorine- 18 the most widely used radionuclide in positron emission tomography with an increasing demand for new or simpler 18F-labeling procedures. After a brief summary of the advantages of the nuclide and its major production routes, the basic features of the principal radiofluorination methods are described. These comprise direct electrophilic and nucleophilic processes, or in case of more complex molecules, the labeling of synthons and prosthetic groups for indirect built-up syntheses. While addressing the progress of no-carrier-added 18F-labeling procedures, the following chapters on more specific topics in this book are introduced. Emphasis is given to radiofluorination of arenes--especially with iodonium leaving groups. Examples of radiopharmaceutical syntheses are mentioned in order to illustrate strategic concepts of labeling with fluorine-18.

Yield and purity of 82Sr produced via the natRb(p,xn) 82Sr process.

The recently reported cross-section data for the production of 82Sr via the natRb(p,xn) 82Sr process were evaluated. For the natRb(p,xn) 85Sr process, cross-sections were measured experimentally over the proton energy range of 25-45 MeV, a region where very few data existed. An evaluation of the recently published data on the formation of 85Sr was then also performed. From the recommended data curves, the integral yields of the desired radionuclide 82Sr and the impurity 85Sr were calculated. Yields were also determined experimentally over several energy ranges using thick natRbCl targets. The experimental and calculated yields were found to be in agreement within 15%. These integral tests add confidence to the evaluated cross-section data. For the production of 82Sr, an incident proton energy of 60 MeV or above is recommended; the 85Sr impurity then corresponds to <20%.

Excitation functions of natGe(p,xn)71,72,73,74 As reactions up to 100 MeV with a focus on the production of 72 As for medical and 73 As for environmental studies.

Excitation functions for the formation of the arsenic radionuclides (71)As, (72)As, (73)As and (74)As in the interaction of protons with (nat)Ge were measured from the respective threshold energy up to 100 MeV. The conventional stacked-foil technique was used and the needed thin samples were prepared by sedimentation. Irradiations were done at three cyclotrons: CV 28 and injector of COSY at Forschungszentrum Jülich, and Separate Sector Cyclotron at iThemba LABS, Somerset West. The radioactivity was measured via high-resolution gamma-ray spectrometry. The measured cross section data were compared with the literature data as well as with the nuclear model calculations. In both cases, the results generally agree but there are discrepancies in some areas, the results of nuclear model calculation and some of the literature data being somewhat higher than our data. The integral yields of the four radionuclides were calculated from the measured excitation functions. The beta(+) emitting nuclide (72)As (T(1/2)=26.01 h) can be produced with reasonable radionuclidic purity ((71)As impurity: <10%) over the energy range E(p) = 18-->8 MeV; the yield of 93 MBq/microAh is, however, low. The radionuclide (73)As (T(1/2)=80.30 d), a potentially useful indicator in environmental studies, could be produced with good radionuclidic purity ((74)As impurity: <11%) over the energy range E(p) = 30 --> 18 MeV, provided, a decay time of about 60 days is allowed. Its yield would then correspond to 2.4 MBq/microAh, and GBq amounts could be produced when using a high current target.

Excitation functions of (alpha,xn) reactions on (nat)Rb and (nat)Sr from threshold up to 26 MeV: possibility of production of (87)Y, (88)Y and (89)Zr.

Excitation functions were measured by the stacked-foil technique for (nat)Rb(alpha,xn)(87m,87m+g,88)Y and (nat)Sr(alpha,xn)(86,88,89)Zr reactions from their respective thresholds up to 26 MeV. The samples for irradiation were prepared by sedimentation and pellet pressing techniques. The measured data were compared with those available in the literature. From the excitation functions, integral yields of the products were calculated. The suitable energy ranges for the production of (87)Y and (88)Y via (nat)Rb(alpha,xn) processes and of (89)Zr via the (nat)Sr(alpha,xn) process are E(alpha)=26-->20 MeV, E(alpha)=26-->5 MeV and E(alpha)=20-->8.5 MeV, respectively. The respective yields amount to 8.2, 0.08 and 0.9 MBq/microA h. Production of (88)Y is feasible if a waiting time of about 2 months is allowed to let the impurities decay out. Also, (87)Y can be produced with a relatively low impurity of (88)Y. The yields of both (88)Y and (87)Y via the present routes are, however, appreciably lower than those via the (nat)Sr(p,xn) processes. There is a possibility to produce (89)Zr via the alpha-particle irradiation of (nat)Sr. The yield is rather low but would be considerably increased if enriched (86)Sr would be used as target material. The radionuclidic impurity levels in all the three products are discussed.

Bone regeneration induced by a 3D architectured hydrogel in a rat critical-size calvarial defect.

Bone regeneration can be stimulated by implantation of biomaterials, which is especially important for larger bone defects. Here, healing potency of the porous ArcGel was evaluated in a critical-size calvarial bone defect in rats in comparison with clinical standard autologous bone and Bio-Oss® Collagen (BioOss), a bone graft material frequently used in clinics. Bone healing and metabolic processes involved were monitored longitudinally by [18F]-fluoride and [18F]-FDG µ-PET/CT 1d, 3d, 3w, 6w, and 12w post implantation. Differences in quality of bone healing were assessed by ex vivo µ-CT, mechanical tests and histomorphometry. The amount of bone formed after implantation of ArcGel was comparable to autologous bone and superior to BioOss (histomorphometry). Furthermore, microarchitecture of newly formed bone was more physiological and better functional in case of ArcGel (push-out tests). [18F]-FDG uptake increased until 3d after implantation, and decreased until 12w for both ArcGel and BioOss. [18F]-fluoride uptake increased until 3w post implantation for all materials, but persisted significantly longer at higher levels for BioOss, which indicates a prolonged remodelling phase. The study demonstrates the potential of ArcGel to induce restitutio ad integrum comparable with clinical standard autologous bone and better bone regeneration in large defects compared to a commercial state-of-the-art biomaterial.

No-carrier-added nucleophilic 18F-labelling in an electrochemical cell exemplified by the routine production of [18F]altanserin.

A new type of electrochemical cell with anodic deposition of no-carrier-added [(18)F]fluoride and variable reaction volume has been developed. The reactor is designed for small reaction volumes and non-thermal drying of [(18)F]fluoride. The implementation of this reactor into a complete remotely controlled synthesis device is described for the routine production of [(18)F]altanserin. A radiochemical yield of 23+/-5% was obtained via cryptate-mediated nucleophilic (18)F-fluorination. Batches of up to 6 GBq [(18)F]altanserin, suitable for human application, with a molar activity of >500 GBq/micromol were obtained within 75 min.

Alpha-particle induced reactions on natSb and 121Sb with particular reference to the production of the medically interesting radionuclide 124I.

Excitation functions of the reactions (nat)Sb(alpha,xn)(123,124,125,126)I and (121)Sb(alpha,xn)(123,124)I were measured from their respective thresholds up to 26 MeV, with particular emphasis on data for the production of the medically important radionuclide (124)I. The conventional stacked-foil technique was used, and the samples for irradiation were prepared by a sedimentation process. The measured excitation curves were compared with the data available in the literature. From the experimental data the theoretical yields of the investigated radionuclides were calculated as a function of the alpha-particle energy. The calculated yield of (124)I from the (nat)Sb(alpha,xn)(124)I process over the energy range E(alpha) = 22-->13 MeV amounts to 1.02 MBq/microA x h and from the (121)Sb(alpha,n)(124)I reaction over the same energy range to 2.11 MBq/microA x h. The radionuclidic impurity levels are discussed. Use of (nat)Sb as target material would not lead to high-purity (124)I. Using highly enriched (121)Sb as target, production of (124)I of high radionuclidic purity is possible; the batch yield, however, is low.

(3)He-particle-induced reactions on (nat)Sb for production of (124)I.

Excitation functions of the reactions (nat)Sb((3)He,xn)(124,123,121)I were measured from their respective thresholds up to 35 MeV, with particular emphasis on data for the production of the medically important radionuclide (124)I. The conventional stacked-foil technique was used. From the experimental data the theoretical yields of the three investigated radionuclides were calculated. The yield of (124)I over the energy range E9(30He) = 35 --> 13 MeV amounts to 0.95 MBq/microA h. The radionuclidic impurities are discussed. A comparison of (3)He- and alpha-particle-induced reactions on antimony for production of (124)I is given. The alpha-particle-induced reaction on enriched (121)Sb and the (3)He-particle-induced reaction on enriched (123)Sb would lead to comparable (124)I yields, but the level of impurities in the latter case would be somewhat higher.

Nuclear data for production of the therapeutic radionuclides 32P, 64Cu, 67Cu, 89Sr, 90Y and 153Sm via the (n,p) reaction: evaluation of excitation function and its validation via integral cross-section measurement using a 14 MeV d(Be) neutron source.

Nuclear data for production of the therapeutic radionuclides 32P, 64Cu, 67Cu, 89Sr, 90Y and 153Sm via (n,p) reactions on the target nuclei 32S, 64Zn, 67Zn, 89Y, (90)Zr and 153Eu, respectively, are discussed. The available information on each excitation function was analysed. From the recommended data set for each reaction the average integrated cross section for a standard 14 MeV d(Be) neutron field was deduced. The spectrum-averaged cross section was also measured experimentally. A comparison of the integrated value with the integral measurement served to validate the excitation function within about 15%. A fast neutron source appears to be much more effective than a fission reactor for production of the above-mentioned radionuclides in a no-carrier-added form via the (n,p) process. In particular, the possibility of production of high specific activity 153Sm is discussed.

Cross-section measurement of the 169 Tm p,n reaction for the production of the therapeutic radionuclide 169 Yb and comparison with its reactor-based generation.

The radionuclide (169)Yb (T(1/2)=32.0 d) is potentially important for internal radiotherapy. It is generally produced using a nuclear reactor. In this work the possibility of its production at a cyclotron was investigated. A detailed determination of the excitation function of the (169)Tm(p,n)(169)Yb reaction was done over the proton energy range up to 45 MeV using the stacked-foil technique and high-resolution gamma-ray spectrometry. The integral yield of (169)Yb was calculated. Over the optimum energy range E(P)=16-->7 MeV the yield amounts to 1.5 MBq/micro Ah and is thus rather low. A comparison of this production route with the established (168)Yb(n,gamma)(169)Yb reaction at a nuclear reactor is given. The (169)Yb yield via the reactor route is by several orders of magnitude higher than by the cyclotron method. The latter procedure, however, leads to "no-carrier-added" product.

Labelling of manganese-based magnetic resonance imaging (MRI) contrast agents with the positron emitter 51Mn, as exemplified by manganese-tetraphenyl-porphin-sulfonate (MnTPPS4).

The potential tumor seeking MRI contrast agent MnTPPS(4) was labelled with the positron emitting nuclide (51)Mn in no-carrier-added (n.c.a.) form. The complex formation kinetics were investigated and the apparent rate constants were determined under pseudo-first-order conditions. The derived bimolecular rate constants gave the Arrhenius parameters E(A)=84 kJ mol(-1) and A=2 x 10(12)s(-1)M(-1). Optimum labelling conditions were derived (radiochemical yields >99% possible, effective yields about 32%). Separation and purification of n.c.a. (51)MnTPPS(4) were performed for potential human use. All impurities were <1%.

Target development for diversified irradiations at a medical cyclotron.

The irradiation facility at an old medical cyclotron (Ep=17 MeV; Ed=10 MeV) was upgraded by extending the beam line and incorporation of solid state targetry. Tests performed to check the quality of the available beam are outlined. Results on nuclear data measurements and improvement of radiochemical separations are described. Using solid targets, with the proton beam falling at a slanting angle of 20°, a few radionuclides, e.g. (75)Se, (120)I, (124)I, etc. were produced with medium currents (up to 20 µA) in no-carrier-added form in quantities sufficient for local use. The extended irradiation facility has considerably enhanced the utility of the medical cyclotron.

The quantitative analysis of D2-dopamine receptors in baboon striatum in vivo with 3-N-[2'-18F]fluoroethylspiperone using positron emission tomography.

We used the ligand 3-N-[2'-18F]fluoroethylspiperone (FESP), which binds to D2-dopamine receptors in the striatum, and positron emission tomography (PET) to quantify striatal D2-dopamine densities (Bmax) and binding kinetics in baboon brain in vivo. Sequential PET scans were obtained for 4 h post injection. Various similar models based on a nonlinear kinetic four-compartment model that takes into account the effect of ligand specific activity were used. We investigated the effect of exact model configuration on the reliability of Bmax and other kinetic transfer coefficients. We found that with the ligand FESP and dynamic PET studies, the estimated values of Bmax and other model parameters are sensitive to the choice of model configuration, ligand specific activity, and data analysis technique. The limitations of the reliability of parameter estimates in a complex kinetic model for receptor ligands were studied in simulation calculations. Results showed that the accuracy of estimated values of Bmax is affected by both the ligand binding properties and the injected dose of ligand. The estimated average value of kinetic model parameters was as follows: ligand-receptor dissociation constant k4 = 0.0080 min-1; the product of ligand-receptor association constant and fraction of ligand available to bind to specific receptors f2ka = 0.0052 (min nM)-1; and D2-dopamine receptor density Bmax = 37.5 pmol g-1.

Efficient stereospecific synthesis of no-carrier-added 2-[18F]-fluoro-2-deoxy-D-glucose using aminopolyether supported nucleophilic substitution.

An aminopolyether mediated synthesis of fluorine-18 (18F) 2-fluoro-2-deoxy-D-glucose (FDG) has been developed. The nucleophilic fluorination with accelerator-produced [18F]fluoride works at the no-carrier-added level and gives epimerically pure 2-18FDG with an uncorrected radiochemical yield of a maximum 50% in a synthesis time of approximately 50 min from EOB.