David C. Price

Melatonin augments hypothermic neuroprotection in a perinatal asphyxia model

Despite treatment with therapeutic hypothermia, almost 50% of infants with neonatal encephalopathy still have adverse outcomes. Additional treatments are required to maximize neuroprotection. Melatonin is a naturally occurring hormone involved in physiological processes that also has neuroprotective actions against hypoxic-ischaemic brain injury in animal models. The objective of this study was to assess neuroprotective effects of combining melatonin with therapeutic hypothermia after transient hypoxia-ischaemia in a piglet model of perinatal asphyxia using clinically relevant magnetic resonance spectroscopy biomarkers supported by immunohistochemistry. After a quantified global hypoxic-ischaemic insult, 17 newborn piglets were randomized to the following: (i) therapeutic hypothermia (33.5°C from 2 to 26 h after resuscitation, n = 8) and (ii) therapeutic hypothermia plus intravenous melatonin (5 mg/kg/h over 6 h started at 10 min after resuscitation and repeated at 24 h, n = 9). Cortical white matter and deep grey matter voxel proton and whole brain (31)P magnetic resonance spectroscopy were acquired before and during hypoxia-ischaemia, at 24 and 48 h after resuscitation. There was no difference in baseline variables, insult severity or any physiological or biochemical measure, including mean arterial blood pressure and inotrope use during the 48 h after hypoxia-ischaemia. Plasma levels of melatonin were 10 000 times higher in the hypothermia plus melatonin than hypothermia alone group. Melatonin-augmented hypothermia significantly reduced the hypoxic-ischaemic-induced increase in the area under the curve for proton magnetic resonance spectroscopy lactate/N-acetyl aspartate and lactate/total creatine ratios in the deep grey matter. Melatonin-augmented hypothermia increased levels of whole brain (31)P magnetic resonance spectroscopy nucleotide triphosphate/exchangeable phosphate pool. Correlating with improved cerebral energy metabolism, TUNEL-positive nuclei were reduced in the hypothermia plus melatonin group compared with hypothermia alone in the thalamus, internal capsule, putamen and caudate, and there was reduced cleaved caspase 3 in the thalamus. Although total numbers of microglia were not decreased in grey or white matter, expression of the prototypical cytotoxic microglial activation marker CD86 was decreased in the cortex at 48 h after hypoxia-ischaemia. The safety and improved neuroprotection with a combination of melatonin with cooling support phase II clinical trials in infants with moderate and severe neonatal encephalopathy.

Malignant pheochromocytomas and paragangliomas: a phase II study of therapy with high-dose 131I-metaiodobenzylguanidine (131I-MIBG).

Abstract:  Thirty patients with malignant pheochromocytoma (PHEO) or paraganglioma (PGL) were treated with high‐dose 131I‐MIBG. Pa tients were 11–62 (mean 39) years old: 19 patients males and 11 females. Nineteen patients had PGL, three of which were multifocal. Six PGLs were nonsecretory. Eleven patients had PHEO. All 30 patients had prior surgery. Fourteen patients were refractory to prior radiation or chemotherapy before 131I‐MIBG. Peripheral blood stem cells (PBSCs) were collected and cryopreserved. 131I‐MIBG was synthesized on‐site, by exchange‐labeling 131I with 127I‐MIBG in a solid‐phase Cu2+‐catalyzed exchange reaction. 131I‐MIBG was infused over 2 h via a peripheral IV. Doses ranged from 557 mCi to 1185 mCi (7.4 mCi/kg to 18.75 mCi/kg). Median dose was 833 mCi (12.55 mCi/kg). Marrow hypoplasia commenced 3 weeks after 131I‐MIBG therapy. After the first 131I‐MIBG therapy, 19 patients required platelet transfusions; 19 received GCSF; 12 received epoeitin or RBCs. Four patients received a PBSC infusion. High‐dose 131I‐MIBG resulted in the following overall tumor responses in 30 patients: 4 sustained complete remissions (CRs); 15 sustained partial remissions (PRs); 1 sustained stable disease (SD); 5 progressive disease (PD); 5 initial PRs or SD but relapsed to PD. Twenty‐three of the 30 patients remain alive; deaths were from PD (5), myelodysplasia (1), and unrelated cause (1). Overall predicted survival at 5 years is 75% (Kaplan Meier estimate). For patients with metastatic PHEO or PGL, who have good *I‐MIBG uptake on diagnostic scanning, high‐dose 131I‐MIBG therapy was effective in producing a sustained CR, PR, or SD in 67% of patients, with tolerable toxicity.

Quantitative aspects of computed tomography of the blood and cerebrospinal fluid.

Computed tomographic (CT) scans of fresh and coagulated blood in vitro as well as calcium and iron solutions demonstrate that the increased absorption seen in hematomas is primarily a reflection of hemoconcentration: calcium plays essentially no role in this increased absorption, while iron makes a minimal contribution. In vitro studies of cerebrospinal fluid (CSF) indicate that CT scanning is insensitive to pathological elevations of CSF protein.

An Improved Method for in Vivo Tracing and Imaging of Liposomes Using a Gallium 67-Deferoxamine Complex

AbstractWe have developed a new method for tracing and imaging liposomes in vivo based on the encapsulation of a gallium 67-deferoxamine 67Ga-DF) complex in the liposomal water phase. This method combines several advantages over other published methods: extremely high affinity of 67Ga for DF, thus avoiding the problem of metal translocation to various plasma proteins; rapid renal clearance rate of67Ga-DF complex, thus minimizing the background of radioactivity in non-liposome-associated form; and use of67Ga, a readily available, short half-life gamma-emitter convenient for dosimetry and imaging, which can be efficiently loaded into preformed liposomes.

Dual-Modality Imaging of Cancer with SPECT/CT

Dual-modality imaging is an in vivo diagnostic technique that obtains structural and functional information directly from patient studies in a way that cannot be achieved with separate imaging systems alone. Dual-modality imaging systems are configured by combining computed tomography (CT) with radionuclide imaging (using positron emission tomography (PET) or single-photon emission computed tomography (SPECT)) on a single gantry which allows both functional and structural imaging to be performed during a single imaging session without having the patient leave the imaging system. A SPECT/CT system developed at UCSF is being used in a study to determine if dual-modality imaging offers advantages for assessment of patients with prostate cancer using111 In-ProstaScint®, a radiolabeled antibody for the prostate-specific membrane antigen.111 In-ProstaScint® images are reconstructed using an iterative maximum-likelihood expectation-maximization (ML-EM) algorithm with correction for photon attenuation using a patient-specific map of attenuation coefficients derived from CT. The ML-EM algorithm accounts for the dual-photon nature of the111 In-labeled radionuclide, and incorporates correction for the geometric response of the radionuclide collimator. The radionuclide image then can be coregistered and overlaid in color on a grayscale CT image for improved localization of the functional information from SPECT. Radionuclide images obtained with SPECT/CT and reconstructed using ML-EM with correction for photon attenuation and collimator response improve image quality in comparison to conventional radionuclide images obtained with filtered backprojection reconstruction. These results illustrate the potential advantages of dual-modality imaging for improving the quality and the localization of radionuclide uptake for staging disease, planning treatment, and monitoring therapeutic response in patients with cancer.

Magnetic Resonance Imaging Detection of an Experimental Pulmonary Perfusion Deficit Using a Macromolecular Contrast Agent Polylysine-Gadolinium-DTPA40

RATIONALE AND OBJECTIVES.This study was designed to evaluate the potential of a blood–pool magnetic resonance (MR) contrast agent, polylysine–gadolinium-DTPA4O (polylysine–G-DTPA40) for detecting pulmonary perfusion defects. MATERIALS AND METHODS.Pulmonary emboli were induced in 10 rats by venous injection of 0.2 mL of air. Axial spin-echo images were acquired (TR = 800 mseconds; TE = 6 mseconds) before and after air injection and serially after the administration of polylysine–Gd-DTPA40. The embolism model was confirmed by scintigraphy using 99mTc-macroaggregated albumin. RESULTS.Signal intensity differences between normal and embolized lungs before and after the air injection were less than 25%. After polylysine–Gd-DTPA40 administration, signal intensity of the perfused lung increased more than 200%, whereas the embolized lung increased by only 25%. Signal intensities of the perfused lung remained stable for 1 hour, whereas signal intensities of the embolized lung gradually increased for 20 minutes as the air embolus dissolved. CONCLUSION.Magnetic resonance imaging (MRI) enhanced with a macromolecular blood–pool contrast agent can be used to detect acute pulmonary embolism in a confirmed animal model.

An automated fluorescent excitation analysis system for medical applications.

The use of stable tracers assayed by x-ray fluorescent excitation analysis has proven advantageous over other stable or radioisotopic techniques in a number of clinical and investigative situations. An automated fluorescent excitation analysis system for medical application has developed. Its design parameters and performance are described.

Implementation of a combined X-ray CT-scintillation camera imaging system for localizing and measuring radionuclide uptake: experiments in phantoms and patients

We have developed and demonstrated an imaging system that couples an X-ray CT scanner to a scintillation camera for the localization and absolute measurement of radionuclide uptake. We use the registered CT images to provide physical information to overcome the quantitative errors in nuclear imaging due to attenuation, scatter, and limited spatial resolution. The registration accuracy and precision in phantom experiments was 0.0/spl plusmn/0.4 mm. Preliminary patient scans suggest that the registration techniques developed for phantom studies can be used. Conversion of X-ray CT image data to attenuation maps was accomplished by the scaling of calibration data and includes extensions to account for the presence of iodinated contrast agents. Experimental phantom studies show absolute quantitation with less than 10% error for up to 2:1 target:background activity concentration for objects as small as 2.7 ml. We are evaluating the localization and absolute quantitation of /sup 131/I-MIBG in neuroblastoma patients to determine if the techniques improve correlation between tumor dose and response.

Brain mitochondrial oxidative metabolism during and after cerebral hypoxia-ischemia studied by simultaneous phosphorus magnetic-resonance and broadband near-infrared spectroscopy☆

Background Multimodal measurements combining broadband near-infrared spectroscopy (NIRS) and phosphorus magnetic resonance spectroscopy (31P MRS) assessed associations between changes in the oxidation state of cerebral mitochondrial cytochrome-c-oxidase (Δ[oxCCO]) and 31P metabolite peak-area ratios during and after transient cerebral hypoxia–ischemia (HI) in the newborn piglet. Methods Twenty-four piglets (aged < 24 h) underwent transient HI (inspired oxygen fraction 9% and bilateral carotid artery occlusion for ~ 20 min). Whole-brain 31P MRS and NIRS data were acquired every minute. Inorganic phosphate (Pi)/epp, phosphocreatine (PCr)/epp, and total nucleotide triphosphate (NTP)/epp were measured by 31P MRS and were plotted against Δ[oxCCO] during HI and recovery (epp = exchangeable phosphate pool = Pi + PCr + 2γ-NTP + β-NTP). Results During HI Δ[oxCCO], PCr/epp and NTP/epp declined and Pi/epp increased. Significant correlations were seen between 31P ratios and Δ[oxCCO]; during HI a threshold point was identified where the relationship between Δ[oxCCO] and both NTP/epp and Pi/epp changed significantly. Outcome at 48 h related to recovery of Δ[oxCCO] and 31P ratios 1 h post-HI (survived: 1-h NTP/epp 0.22 ± 0.02, Δ[oxCCO] − 0.29 ± 0.50 μM; died: 1-h NTP/epp 0.10 ± 0.04, Δ[oxCCO] − 2.41 ± 1.48 μM). Conclusions Both lowered Δ[oxCCO] and NTP/epp 1 h post-HI indicated mitochondrial impairment. Animals dying before 48 h had slower recovery of both Δ[oxCCO] and 31P ratios by 1 h after HI.

Metrizamide and radionuclide cisternography in communicating hydrocephalus.

Simultaneous 111In-DPTA and metrizamide CT cisternography correlated closely in the qualitative imaging of cerebrospinal fluid (CSF) dynamics in 9 normal patients and in 11 patients thought to have communicating hydrocephalus. CSF clearance of both tracers was similar; significant absorption occurred in the spinal dural sac. Although delayed elevated serum iodine levels correlated highly with abnormal persistent ventricular penetration (detection at 48 hours), these levels cannot be used to predict abnormal ventricular stasis. The pattern of ventricular and cortical sulcus enlargement on the plain CT scan did not indicate whether the dynamic metrizamide cisternogram would be normal or abnormal.