Initial experience with an electron FLASH research extension (FLEX) for the Clinac system.

PURPOSE: Radiotherapy delivered at ultra-high-dose-rates (≥40 Gy/s), that is, FLASH, has the potential to effectively widen the therapeutic window and considerably improve the care of cancer patients. The underlying mechanism of the FLASH effect is not well understood, and commercial systems capable of delivering such dose rates are scarce. The purpose of this study was to perform the initial acceptance and commissioning tests of an electron FLASH research product for preclinical studies. METHODS: A linear accelerator (Clinac 23EX) was modified to include a non-clinical FLASH research extension (the Clinac-FLEX system) by Varian, a Siemens Healthineers company (Palo Alto, CA) capable of delivering a 16 MeV electron beam with FLASH and conventional dose rates. The acceptance, commissioning, and dosimetric characterization of the FLEX system was performed using radiochromic film, optically stimulated luminescent dosimeters, and a plane-parallel ionization chamber. A radiation survey was conducted for which the shielding of the pre-existing vault was deemed sufficient. RESULTS: The Clinac-FLEX system is capable of delivering a 16 MeV electron FLASH beam of approximately 1 Gy/pulse at isocenter and reached a maximum dose rate >3.8 Gy/pulse near the upper accessory mount on the linac gantry. The percent depth dose curves of the 16 MeV FLASH and conventional modes for the 10 × 10 cm2 applicator agreed within 0.5 mm at a range of 50% of the maximum dose. Their respective profiles agreed well in terms of flatness but deviated for field sizes >10 × 10 cm2 . The output stability of the FLASH system exhibited a dose deviation of <1%. Preliminary cell studies showed that the FLASH dose rate (180 Gy/s) had much less impact on the cell morphology of 76N breast normal cells compared to the non-FLASH dose rate (18 Gy/s), which induced large-size cells. CONCLUSION: Our studies characterized the non-clinical Clinac-FLEX system as a viable solution to conduct FLASH research that could substantially increase access to ultra-high-dose-rate capabilities for scientists.

Effects of isoflurane anesthesia on hyperpolarized (13)C metabolic measurements in rat brain.

PURPOSE: Commonly used anesthetic agents such as isoflurane are known to be potent cerebral vasodilators, with reported dose-dependent increase in cerebral blood flow and cerebral blood volume. Despite the widespread use of isoflurane in hyperpolarized (13)C preclinical research studies, a quantitative assessment of its effect on metabolic measurements is limited. This work investigates the effect of isoflurane anesthesia dose on hyperpolarized (13)C MR metabolic measurements in rat brain for [1-(13)C]pyruvate and 2-keto[1-(13)C]isocaproate. METHODS: Dynamic 2D and 3D spiral chemical shift imaging was used to acquire metabolic images of rat brain as well as kidney and liver following bolus injections of hyperpolarized [1-(13)C]pyruvate or 2-keto[1-(13)C]isocaproate. The impact of a "low dose" vs. a "high dose" of isoflurane on cerebral metabolite levels and apparent conversion rates was examined. RESULTS: The cerebral substrate signal levels, and hence the metabolite-to-substrate ratios and apparent conversion rates, were found to depend markedly on isoflurane dose, while signal levels of metabolic products and their ratios, e.g. bicarbonate/lactate, were largely insensitive to isoflurane levels. No obvious dependence on isoflurane was observed in kidney or liver for pyruvate. CONCLUSION: This study highlights the importance of careful attention to the effects of anesthesia on the metabolic measures for hyperpolarized (13)C metabolic imaging in brain.

In vivo MRSI of hyperpolarized [1-(13)C]pyruvate metabolism in rat hepatocellular carcinoma.

Hepatocellular carcinoma (HCC), the primary form of human adult liver malignancy, is a highly aggressive tumor with average survival rates that are currently less than 1 year following diagnosis. Most patients with HCC are diagnosed at an advanced stage, and no efficient marker exists for the prediction of prognosis and/or response(s) to therapy. We have reported previously a high level of [1-(13)C]alanine in an orthotopic HCC using single-voxel hyperpolarized [1-(13)C]pyruvate MRS. In the present study, we implemented a three-dimensional MRSI sequence to investigate this potential hallmark of cellular metabolism in rat livers bearing HCC (n = 7 buffalo rats). In addition, quantitative real-time polymerase chain reaction was used to determine the mRNA levels of lactate dehydrogenase A, nicotinamide adenine (phosphate) dinucleotide dehydrogenase quinone 1 and alanine transaminase. The enzyme levels were significantly higher in tumor than in normal liver tissues within each rat, and were associated with the in vivo MRSI signal of [1-(13)C]alanine and [1-(13)C]lactate after a bolus intravenous injection of [1-(13)C]pyruvate. Histopathological analysis of these tumors confirmed the successful growth of HCC as a nodule in buffalo rat livers, revealing malignancy and hypervascular architecture. More importantly, the results demonstrated that the metabolic fate of [1-(13)C]pyruvate conversion to [1-(13)C]alanine significantly superseded that of [1-(13)C]pyruvate conversion to [1-(13)C]lactate, potentially serving as a marker of HCC tumors.

Hydrogen NMR of H2-TDF-D2O clathrate.

The three-component clathrate H2-TDF-D2O offers hydrogen storage at lower pressure, but with reduced weight fraction of H2, compared to H2-H2O clathrate. In H2-TDF-D2O, H2 resides exclusively and singly in the small cages of structure II, allowing the rotational behavior of H2 in this nominally uniform environment to be probed. Here we report NMR measurements of the H2 line shape and relaxation times T1, T2, and T1rho. The principal differences in the results, compared to the H2-D2O binary system, are the dips in T2 and T1rho near 28 K due to thermally activated reorientation of TDF molecules, line-narrowing and decreases in T2 and T1rho near 175 K due to D2O reorientations and diffusion, and the apparent absence of H2 diffusion between small cages.

Hydrogen nuclear spin relaxation in hydrogen-ice clathrate.

H2 in D2O ice clathrate has been studied by hydrogen NMR. In a previous report, the H2 line shape was shown to be due to incompletely averaged intramolecular dipolar interactions. Here the relaxation times T1, T1rho, and T2 are reported. T1 passes through a minimum at 10 K, indicating that the rotational transition rate Gamma between the three sublevels of J = 1 passes through the resonance frequency at this temperature. On the cold side, T1 varies as T(-2.6); on the hot side, the rate T1(-1) varies as T(-2) plus a constant (due to paramagnetic impurities). These indicate a two-phonon process drives the rotational transitions Gamma. The spin-echo T2 is nearly independent of temperature and in reasonable agreement with the Van Vleck intermolecular H2-H2 second moment. T1rho deviates from the expected T1rho = T1 behavior above 85 K, revealing an additional slow-motion source of relaxation. The deviation is driven by the hopping of H2 between large cages. Ortho-para conversion is measured to be much slower in the clathrate than in the bulk solid, reflecting the greater distances between the H2 molecules.

Rotation and diffusion of H2 in hydrogen-ice clathrate by 1H NMR.

A recently reported hydrogen-ice clathrate carries up to four H(2) in each large cage and one H(2) in each small cage. We report pulsed proton NMR line shape measurements on H(2)-D(2)O clathrate formed at 1500 bar and 250 K. The behavior of the two-pulse spin-echo amplitude with respect to the nutation angle of the refocusing pulse shows that intramolecular dipolar broadening, modulated by H(2) molecular reorientations, dominates the line width of the ortho-H(2). Dipolar interaction between H(2) guests and host D atoms explains the echo variation with the relative phases of the pulses. From 12 to 120 K, the line width varies as 1/T, demonstrating that the three sublevels of J = 1 are split by a constant energy, epsilon. The splitting arises from distortion in the otherwise high-symmetry cages from frozen-out D(2)O orientational disorder. Above 120 K, further line-narrowing signals the onset of H(2) diffusion from cage to cage. At the lowest temperature, 1.9 K, the spectrum has Pake powder doublet-like features; the doublet is not fully developed, indicating a broad distribution of order parameters and energies epsilon.