Quasi-real-time range monitoring by in-beam PET: a case for 15O.

A fast and reliable range monitoring method is required to take full advantage of the high linear energy transfer provided by therapeutic ion beams like carbon and oxygen while minimizing damage to healthy tissue due to range uncertainties. Quasi-real-time range monitoring using in-beam positron emission tomography (PET) with therapeutic beams of positron-emitters of carbon and oxygen is a promising approach. The number of implanted ions and the time required for an unambiguous range verification are decisive factors for choosing a candidate isotope. An experimental study was performed at the FRS fragment-separator of GSI Helmholtzzentrum für Schwerionenforschung GmbH, Germany, to investigate the evolution of positron annihilation activity profiles during the implantation of [Formula: see text]O and [Formula: see text]O ion beams in a PMMA phantom. The positron activity profile was imaged by a dual-panel version of a Siemens Biograph mCT PET scanner. Results from a similar experiment using ion beams of carbon positron-emitters [Formula: see text]C and [Formula: see text]C performed at the same experimental setup were used for comparison. Owing to their shorter half-lives, the number of implanted ions required for a precise positron annihilation activity peak determination is lower for [Formula: see text]C compared to [Formula: see text]C and likewise for [Formula: see text]O compared to [Formula: see text]O, but their lower production cross-sections make it difficult to produce them at therapeutically relevant intensities. With a similar production cross-section and a 10 times shorter half-life than [Formula: see text]C, [Formula: see text]O provides a faster conclusive positron annihilation activity peak position determination for a lower number of implanted ions compared to [Formula: see text]C. A figure of merit formulation was developed for the quantitative comparison of therapy-relevant positron-emitting beams in the context of quasi-real-time beam monitoring. In conclusion, this study demonstrates that among the positron emitters of carbon and oxygen, [Formula: see text]O is the most feasible candidate for quasi-real-time range monitoring by in-beam PET that can be produced at therapeutically relevant intensities. Additionally, this study demonstrated that the in-flight production and separation method can produce beams of therapeutic quality, in terms of purity, energy, and energy spread.

Production and separation of positron emitters for hadron therapy at FRS-Cave M.

The FRagment Separator FRS at GSI is a versatile spectrometer and separator for experiments with relativistic in-flight separated short-lived exotic beams. One branch of the FRS is connected to the target hall where the bio-medical cave (Cave M) is located. Recently a joint activity between the experimental groups of the FRS and the biophysics at the GSI and Department of physics at LMU was started to perform biomedical experiments relevant for hadron therapy with positron emitting carbon and oxygen beams. This paper presents the new ion-optical mode and commissioning results of the FRS-Cave M branch where positron emitting 15O-ions were provided to the medical cave for the first time. An overall conversion efficiency of 2.9±0.2×10-4 15O fragments per primary 16O ion accelerated in the synchrotron SIS18 was reached.

Precision of the PET activity range during irradiation with10C,11C, and12C beams.

Objective. Beams of stable ions have been a well-established tool for radiotherapy for many decades. In the case of ion beam therapy with stable12C ions, the positron emitters10,11C are produced via projectile and target fragmentation, and their decays enable visualization of the beam via positron emission tomography (PET). However, the PET activity peak matches the Bragg peak only roughly and PET counting statistics is low. These issues can be mitigated by using a short-lived positron emitter as a therapeutic beam.Approach.An experiment studying the precision of the measurement of ranges of positron-emitting carbon isotopes by means of PET has been performed at the FRS fragment-separator facility of GSI Helmholtzzentrum für Schwerionenforschung GmbH, Germany. The PET scanner used in the experiment is a dual-panel version of a Siemens Biograph mCT PET scanner.Main results.High-quality in-beam PET images and activity distributions have been measured from the in-flight produced positron emitting isotopes11C and10C implanted into homogeneous PMMA phantoms. Taking advantage of the high statistics obtained in this experiment, we investigated the time evolution of the uncertainty of the range determined by means of PET during the course of irradiation, and show that the uncertainty improves with the inverse square root of the number of PET counts. The uncertainty is thus fully determined by the PET counting statistics. During the delivery of 1.6 × 107ions in 4 spills for a total duration of 19.2 s, the PET activity range uncertainty for10C,11C and12C is 0.04 mm, 0.7 mm and 1.3 mm, respectively. The gain in precision related to the PET counting statistics is thus much larger when going from11C to10C than when going from12C to11C. The much better precision for10C is due to its much shorter half-life, which, contrary to the case of11C, also enables to include the in-spill data in the image formation.Significance. Our results can be used to estimate the contribution from PET counting statistics to the precision of range determination in a particular carbon therapy situation, taking into account the irradiation scenario, the required dose and the PET scanner characteristics.

Dominance of Tensor Correlations in High-Momentum Nucleon Pairs Studied by (p,pd) Reaction.

The isospin character of p-n pairs at large relative momentum has been observed for the first time in the ^{16}O ground state. A strong population of the J,T=1,0 state and a very weak population of the J,T=0,1 state were observed in the neutron pickup domain of ^{16}O(p,pd) at 392 MeV. This strong isospin dependence at large momentum transfer is not reproduced by the distorted-wave impulse approximation calculations with known spectroscopic amplitudes. The results indicate the presence of high-momentum protons and neutrons induced by the tensor interactions in the ground state of ^{16}O.

Measurement of Excitation Spectra in the

Excitation spectra of ^{11}C are measured in the ^{12}C(p,d) reaction near the η^{'} emission threshold. A proton beam extracted from the synchrotron SIS-18 at GSI with an incident energy of 2.5 GeV impinges on a carbon target. The momenta of deuterons emitted at 0° are precisely measured with the fragment separator (FRS) operated as a spectrometer. In contrast to theoretical predictions on the possible existence of deeply bound η^{'}-mesic states in carbon nuclei, no distinct structures are observed associated with the formation of bound states. The spectra are analyzed to set stringent constraints on the formation cross section and on the hitherto barely known η^{'}-nucleus interaction.

Experimental study of nuclear fragmentation of 200 and 400 MeV/u (12)C ions in water for applications in particle therapy.

Carbon ion beams in the energy range of about 100-450 MeV/u offer excellent conditions for tumour therapy, in particular for the treatment of deep-seated radio-resistant tumours. Their depth-dose distribution is characterized by a low dose in the entrance channel, small lateral beam spread and an elevated biological effectiveness in the Bragg peak region. In comparison to protons the radiation field of heavier ions stopping in tissue is however more complex due to nuclear fragmentation reactions occurring along their stopping path. This results in an attenuation of the primary beam flux and a build-up of lower-Z fragments with longer ranges causing the characteristic dose tail beyond the Bragg peak. In the present work the characteristics of secondary charged particles at various depths of water were investigated experimentally using (12)C ion beams of 200 and 400 MeV/u delivered by the heavy-ion synchrotron SIS-18 at GSI Darmstadt. The nuclear charge Zf of secondary fragments was identified by combining energy loss and time-of-flight (TOF) measurements. Energy spectra and yields were recorded at lab angles of 0° - 10° and at seven different water depths corresponding to the entrance channel, the Bragg peak region and the tail of the Bragg curve.

Direct mapping of nuclear shell effects in the heaviest elements.

Quantum-mechanical shell effects are expected to strongly enhance nuclear binding on an "island of stability" of superheavy elements. The predicted center at proton number Z = 114, 120, or 126 and neutron number N = 184 has been substantiated by the recent synthesis of new elements up to Z = 118. However, the location of the center and the extension of the island of stability remain vague. High-precision mass spectrometry allows the direct measurement of nuclear binding energies and thus the determination of the strength of shell effects. Here, we present such measurements for nobelium and lawrencium isotopes, which also pin down the deformed shell gap at N = 152.

Mass measurements of very neutron-deficient Mo and Tc isotopes and their impact on rp process nucleosynthesis.

The masses of ten proton-rich nuclides, including the N=Z+1 nuclides 85Mo and 87Tc, were measured with the Penning trap mass spectrometer SHIPTRAP. Compared to the Atomic Mass Evaluation 2003 a systematic shift of the mass surface by up to 1.6 MeV is observed causing significant abundance changes of the ashes of astrophysical x-ray bursts. Surprisingly low α separation energies for neutron-deficient Mo and Tc are found, making the formation of a ZrNb cycle in the rp process possible. Such a cycle would impose an upper temperature limit for the synthesis of elements beyond Nb in the rp process.

Direct mass measurements above uranium bridge the gap to the island of stability.

The mass of an atom incorporates all its constituents and their interactions. The difference between the mass of an atom and the sum of its building blocks (the binding energy) is a manifestation of Einstein's famous relation E = mc(2). The binding energy determines the energy available for nuclear reactions and decays (and thus the creation of elements by stellar nucleosynthesis), and holds the key to the fundamental question of how heavy the elements can be. Superheavy elements have been observed in challenging production experiments, but our present knowledge of the binding energy of these nuclides is based only on the detection of their decay products. The reconstruction from extended decay chains introduces uncertainties that render the interpretation difficult. Here we report direct mass measurements of trans-uranium nuclides. Located at the farthest tip of the actinide species on the proton number-neutron number diagram, these nuclides represent the gateway to the predicted island of stability. In particular, we have determined the mass values of (252-254)No (atomic number 102) with the Penning trap mass spectrometer SHIPTRAP. The uncertainties are of the order of 10 keV/c(2) (representing a relative precision of 0.05 p.p.m.), despite minute production rates of less than one atom per second. Our experiments advance direct mass measurements by ten atomic numbers with no loss in accuracy, and provide reliable anchor points en route to the island of stability.

Discovery of highly excited long-lived isomers in neutron-rich hafnium and tantalum isotopes through direct mass measurements.

A study of cooled ¹97Au projectile-fragmentation products has been performed with a storage ring. This has enabled metastable nuclear excitations with energies up to 3 MeV, and half-lives extending to minutes or longer, to be identified in the neutron-rich nuclides ¹8³(,)¹84(,)¹86Hf and ¹86(,)¹87Ta. The results support the prediction of a strongly favored isomer region near neutron number 116.

Experimental and theoretical study of the neutron dose produced by carbon ion therapy beams.

High-energy (12)C ions offer favourable conditions for the treatment of deep-seated local tumours. Several facilities for the heavy ion therapy are planned or under construction, for example the new clinical ion-therapy unit HIT at the Radiological University Clinics in Heidelberg. In order to improve existing treatment planning models, it is essential to evaluate the secondary fragment production and to include these contributions to the therapy dose with higher accuracy. Secondary neutrons are most abundantly produced in the reactions between (12)C beams and tissues. The dose contribution to tissues by a neutron is fairly small compared with the projectile and the other charged fragments due to no ionisation and the small reaction cross-sections; however, it distributes in a considerably wider region beyond the bragg-peak because of the strong penetrability. Systematic data on energy spectra and doses of secondary neutrons produced by (12)C beams using water targets of different thicknesses for various detection angles have therefore been measured in this study at GSI Darmstadt.

Measurement of the beta+ and orbital electron-capture decay rates in fully ionized, hydrogenlike, and heliumlike 140Pr ions.

We report on the first measurement of the beta+ and orbital electron-capture decay rates of 140Pr nuclei with the simplest electron configurations: bare nuclei, hydrogenlike, and heliumlike ions. The measured electron-capture decay constant of hydrogenlike 140Pr58+ ions is about 50% larger than that of heliumlike 140Pr57+ ions. Moreover, 140Pr ions with one bound electron decay faster than neutral 140Pr0+ atoms with 59 electrons. To explain this peculiar observation one has to take into account the conservation of the total angular momentum, since only particular spin orientations of the nucleus and of the captured electron can contribute to the allowed decay.

Experimental fragmentation studies with 12C therapy beams.

High-energy beams of (12)C ions in the range of 80-430 MeV u(-1) delivered by the heavy-ion synchrotron SIS-18 are used for radiotherapy of deep-seated localized tumors at the treatment unit at GSI Darmstadt. In order to improve the physical database, the fragmentation characteristics along the penetration path in tissue were investigated experimentally by using a water phantom as tissue-equivalent absorber. Measurements were performed at specific energies of 200 and 400 MeV u(-1) of the incident (12)C ions and at six different depths before and behind the Bragg peak. Secondary fragments with nuclear charges Z(f) = 1-5 were identified by scintillation detectors using DeltaE-E and time-of-flight techniques. The preliminary results include energy- and angular distributions, fragment yields, build-up curves and attenuation of the primary carbon projectiles.

Modifications of transthyretin in amyloid fibrils: analysis of amyloid from homozygous and heterozygous individuals with the Met30 mutation.

The finding of individuals homozygous for FAP I (familial amyloidotic polyneuropathy, transthyretin TTRMet30) with amyloid deposits in the vitreous body, gave us access to a unique material lacking wild type transthyretin and contaminating proteins. Amyloid TTR is modified in several ways. Besides the full-length protein and its dimer form, two smaller bands were identified by SDS-PAGE and protein sequencing. One corresponded to a peptide starting at amino acid Thr49, the other was a mixture of two peptides starting at positions 1 and 3 in a 3:1 ratio. Upon reduction the amount of the TTR dimer decreased, the monomer amount increased, and the resulting monomers became available for carboxymethylation. Moreover, the mobility of the small band, which includes Cys10, increased upon reduction. This cysteine seemed to be involved in an interchain disulfide bridge both between intact TTR molecules and between small fragments. The same pattern was found in heterozygous fibril material although smaller amounts of the truncated peptides were found. Fibrils were formed both from normal and mutated TTR in heterozygotes. The significance of our results for amyloid formation is discussed.

Homozygosity for the transthyretin-met30-gene in two Swedish sibs with familial amyloidotic polyneuropathy.

Familial amyloidotic polyneuropathy (FAP) is an autosomal dominant inherited disorder. Recent biochemical studies have revealed that amyloid protein in FAP of Japanese, Swedish and Portuguese origin mainly consists of a variant transthyretin (TTR) (formerly called prealbumin) with one amino acid substitution of methionine for valine at position 30. In a 56-year-old man with typical polyneuropathy, gastrointestinal problems and vitreous amyloid, we diagnosed homozygosity for the TTR-met30-gene using RFLP analysis. In a family study, a sister presented the same homozygous RFLP pattern; however, in a careful clinical investigation we were not able to demonstrate any of the typical symptoms of FAP, nor could we demonstrate amyloid deposits in a biopsy skin specimen. This is the first report of homozygosity for the TTR-met30-gene, and it shows that the mutation of the protein involved in amyloid formation may be necessary but is clearly not sufficient for the clinical symptoms.