A. Dennis Nelson

Measurement of Human Cerebral Blood Flow with [15O]Butanol and Positron Emission Tomography

Although H215O is widely used for CBF measurement by positron tomography, it underestimates CBF, especially at elevated flow rates. Several tracers, including butanol, overcome this problem, but the short half-life of 15O provides advantages that cause water to remain the tracer of choice. We report the first use and evaluation of 15O–labeled butanol for CBF measurement. Flow measurements made in a similar fashion with water and butanol at 10-min intervals were compared in normal volunteers under resting and hypercapnic conditions. Regional analysis showed good agreement between the tracers at low flows, and significant underestimation of flow by water relative to butanol in regions of elevated flow. The observed relationship between the tracers and the curve-fitted permeability-surface area product for water (133 ml · 100 g−1 · min−1) follow the known relationship between water and true flow. These observations indicate that [15O]-butanol provided accurate measurements of human regional CBF under conditions of elevated perfusion. We conclude that butanol is a convenient and accurate method for routine CBF determination by positron emission tomography.

Phase II Trial of Radiosurgery to Magnetic Resonance Spectroscopy-Defined High-Risk Tumor Volumes in Patients With Glioblastoma Multiforme

PURPOSE To determine the efficacy of a Gamma Knife stereotactic radiosurgery (SRS) boost to areas of high risk determined by magnetic resonance spectroscopy (MRS) functional imaging in addition to standard radiotherapy for patients with glioblastoma (GBM). METHODS AND MATERIALS Thirty-five patients in this prospective Phase II trial underwent surgical resection or biopsy for a GBM followed by SRS directed toward areas of MRS-determined high biological activity within 2 cm of the postoperative enhancing surgical bed. The MRS regions were determined by identifying those voxels within the postoperative T2 magnetic resonance imaging volume that contained an elevated choline/N-acetylaspartate ratio in excess of 2:1. These voxels were marked, digitally fused with the SRS planning magnetic resonance image, targeted with an 8-mm isocenter per voxel, and treated using Radiation Therapy Oncology Group SRS dose guidelines. All patients then received conformal radiotherapy to a total dose of 60 Gy in 2-Gy daily fractions. The primary endpoint was overall survival. RESULTS The median survival for the entire cohort was 15.8 months. With 75% of recursive partitioning analysis (RPA) Class 3 patients still alive 18 months after treatment, the median survival for RPA Class 3 has not yet been reached. The median survivals for RPA Class 4, 5, and 6 patients were 18.7, 12.5, and 3.9 months, respectively, compared with Radiation Therapy Oncology Group radiotherapy-alone historical control survivals of 11.1, 8.9, and 4.6 months. For the 16 of 35 patients who received concurrent temozolomide in addition to protocol radiotherapeutic treatment, the median survival was 20.8 months, compared with European Organization for Research and Treatment of Cancer historical controls of 14.6 months using radiotherapy and temozolomide. Grade 3/4 toxicities possibly attributable to treatment were 11%. CONCLUSIONS This represents the first prospective trial using selective MRS-targeted functional SRS combined with radiotherapy for patients with GBM. This treatment is feasible, with acceptable toxicity and patient survivals higher than in historical controls. This study can form the basis for a multicenter, randomized trial.

The effect of scatter and attenuation on aerosol deposition as determined by gamma scintigraphy.

Gamma scintigraphy is often used to quantify deposition patterns from aerosol inhalers. The errors caused by scatter and tissue attenuation in planar Tc-99m gamma scintigraphy were investigated based on the data collected from four subjects in this study. Several error correction methods were tested. The results from two scatter correction methods, Jaszczaks method and factor analysis of dynamic sequences (FADS), were similar. Scatter accounted for 20% of raw data in the whole lung, 20% in the oropharynx, and 43% in the central airways and esophagus. Three attenuation correction methods were investigated and compared. These were: uniform attenuation correction (UAC), a known method used for inhalation drug imaging work; the broad-beam attenuation correction used for organ imaging in nuclear medicine; and a narrow-beam inhomogeneous tissue attenuation correction proposed in this study. The three methods differed significantly (p < 0.05), but all indicated that attenuation is a severe quantification problem. The narrow beam attenuation correction with scatter correction, showed that raw data underestimated tracer deposition by 44% in the lung, 137% in the oropharynx, and 153% in the trachea/esophageal region. To quantify aerosol lung deposition using planar scintigraphy even in relative terms, corrections are necessary. Much of the literature concerning quantified aerosol dose distributions measured by gamma scintigraphy needs to be interpreted carefully.

Comparison of the effect of temafloxacin, ciprofloxacin, or placebo on cerebral blood flow, glucose, and oxygen metabolism in healthy subjects by means of positron emission tomography

Study objective: To determine the cause of the central nervous system effect of the fluorinated quinolones temafloxacin and ciprofloxacin by measuring cerebral blood flow and metabolism by use of positron emission tomography.

Comparative Assessment of the Effect of Lomefloxacin, Ciprofloxacin, and Placebo on Cerebral Blood Flow, and Glucose and Oxygen Metabolism in Healthy Subjects by Positron Emission Tomography

The mechanism by which the fluorinated quinolones produce central nervous system (CNS) effects is currently unknown. We measured the effect of lomefloxacin on cerebral blood flow and metabolism using positron emission tomography. Eighteen healthy, nonsmoking volunteers were randomized to receive lomefloxacin 400 mg, ciprofloxacin 750 mg, or placebo given in a single‐blind fashion every 12 hours for 72 hours, the time window for maximum lomefloxacin CNS effects. Subjects receiving lomefloxacin had a mean (± SEM) cerebral blood flow (CBF) of 46 (2.9) ml/min/100 g, glucose metabolism (FDG) 4.7 (0.4) mg/min/100 g, oxygen metabolism (OM) 3.3 (0.3) ml/min/100 g, and oxygen extraction (%OM) 0.4 (0.04). Posttreatment values were 43 (3.6) ml/min/100 g, 4.2 (0.4) mg/min/100 g, 2.6 (0.3) ml/min/100 g, and 0.4 (0.03), respectively. Values for subjects receiving ciprofloxacin were CBF 44.8 (1.6) ml/min/100 g, FDG 4.9 (0.7) mg/min/100 g, OM 4.1 (0.4) ml/min/100 g, and %OM 0.6 (0.03) at baseline, and 40.3 (3.5), 4.5 (0.6), 3.4 (0.4), and 0.5 (0.09), respectively, after treatment. For placebo‐treated subjects, baseline values were CBF 41.4 (1.9) ml/min/100 g, FDG 4.9 (0.5) mg/min/100 g, OM 3.3 (0.4) ml/min/100 g, and %OM 0.5 (0.07), and respective posttreatment values were 42.1 (2.3), 5.0 (0.6), 3.5 (0.3), and 0.5 (0.02). No effect was observed on visual (qualitative), blinded reading of the scans. No significant effect on cerebral blood flow or metabolism was detected. We conclude that short‐term administration of lomefloxacin or ciprofloxacin to healthy volunteers does not have a significant effect on cerebral blood flow, or on oxygen or glucose metabolism. Trends toward decreased metabolism in the quinolone‐treated subjects are consistent with findings from other published trials, although their significance is unclear.

An Assessment of Cerebral Blood Flow and Metabolism After Fleroxacin Therapy

Cerebral blood flow (CBF), glucose (FDG), and oxygen metabolism (OM) were evaluated by positron emission tomography (PET) in 18 healthy volunteers who were randomized to a 72‐hour course of either 600 mg/d of fleroxacin or placebo. Such studies attempted to assess potentially serious, yet unexplained, central nervous system adverse effects of the fluorinated quinolone class. Baseline and postplacebo values for CBF (mL/min/100 g) and FDG (mg/min/100 g) were: 53 ± 6 and 5.7 ± 1.8; and 49.6 ± 4.4 and 5.2 ± 1.2, respectively. Identical values for fleroxacin were: 53.9 ± 4.8 and 6.3 ± 1.1; and 54.4 ± 2.2 and 6.8 ± 1.5, respectively. The differences between fleroxacin and placebo were not significant. There was also no effect seen in OM between placebo and the active drug. The authors conclude that short‐term administration of fleroxacin does not alter CBF, FDG, or OM in healthy volunteers.

Fluid Flow Effects on Readings from the Mass Spectrometer with Diffusion Membrane Catheter

The diffusion membrane catheter coupled to the mass spectrometer has previously been used to measure partial pressures of gases in blood. However, measurement errors arise due to depletion of gases in the vicinity of the catheter. The nature of these errors in oxygen and argon partial pressure measurement is described for in vitro and in vivo studies. The in vitro setup consisted of a catheter having a silicone or Teflon membrane at its tip and located within a tube surrounded by flowing blood or water. The effects of tube diameter and bulk fluid flow rate on mass spectrometer readings of oxygen and argon partial pressures were examined. It was found that a log-linear relationship closely described the effect of flow rate on readings in the region of flow dependence. Also flow dependence for argon closely paralleled that for oxygen. The in vivo study which followed was an examination of the errors in mass spectrometer readings under conditions which cause varying flow rates in blood vessels. Substantial errors in oxygen readings were found which could be compensated for by using argon readings as a correction factor.

MONITORING OF ARGON GAS TRANSPORT IN TISSUE

Publisher Summary This chapter presents details of experiments conducted to study monitoring of argon gas transport in tissue. In the study, the diffusion process is employed in a technique for withdrawing gas from tissues to challenge the tissue environment around a monitoring probe. Withdrawal is accomplished using silicone or Teflon membrane tipped probes coupled by a high vacuum line to a mass spectrometer. Argon is the monitored gas in this study. Because it is not metabolized, any changes in argon gas tension readings must be because of the changes in supply of inspired argon or alteration in delivery to the probe due to changes in perfusion and/or diffusion. The mass spectrometer probes consisted of slotted stainless steel tubes covered with a silicone or Teflon membrane. The slits in the steel tubes allow gases to diffuse into the inner part of the tube that is maintained at a high vacuum by the mass spectrometer.