First-in-human phase I study of copanlisib (BAY 80-6946), an intravenous pan-class I phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors and non-Hodgkin's lymphomas.

BACKGROUND: To evaluate the safety, tolerability, pharmacokinetics, and maximum tolerated dose (MTD) of copanlisib, a phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors or non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Phase I dose-escalation study including patients with advanced solid tumors or NHL, and a cohort of patients with type 2 diabetes mellitus. Patients received three weekly intravenous infusions of copanlisib per 28-day cycle over the dose range 0.1-1.2 mg/kg. Plasma copanlisib levels were analyzed for pharmacokinetics. Biomarker analysis included PIK3CA, KRAS, BRAF, and PTEN mutational status and PTEN immunohistochemistry. Whole-body [(18)F]-fluorodeoxyglucose positron emission tomography ((18)FDG-PET) was carried out at baseline and following the first dose to assess early pharmacodynamic effects. Plasma glucose and insulin levels were evaluated serially. RESULTS: Fifty-seven patients received treatment. The MTD was 0.8 mg/kg copanlisib. The most frequent treatment-related adverse events were nausea and transient hyperglycemia. Copanlisib exposure was dose-proportional with no accumulation; peak exposure positively correlated with transient hyperglycemia post-infusion. Sixteen of 20 patients treated at the MTD had reduced (18)FDG-PET uptake; 7 (33%) had a reduction >25%. One patient achieved a complete response (CR; endometrial carcinoma exhibiting both PIK3CA and PTEN mutations and complete PTEN loss) and two had a partial response (PR; both metastatic breast cancer). Among the nine NHL patients, all six with follicular lymphoma (FL) responded (one CR and five PRs) and one patient with diffuse large B-cell lymphoma had a PR by investigator assessment; two patients with FL who achieved CR (per post hoc independent radiologic review) were on treatment >3 years. CONCLUSION: Copanlisib, dosed intermittently on days 1, 8, and 15 of a 28-day cycle, was well tolerated and the MTD was determined to be 0.8 mg/kg. Copanlisib exhibited dose-proportional pharmacokinetics and promising anti-tumor activity, particularly in patients with NHL. CLINICALTRIALSGOV: NCT00962611; https://clinicaltrials.gov/ct2/show/NCT00962611.

Evaluation of a commercial radiochromatography module as an arterial blood activity monitor.

Input functions required for positron emission tomography (PET) tracer kinetic modeling are often obtained from arterial blood. In some situations, using short-lived radiotracers, e.g. [(15)O]water, rapid sample handling is required. A method used at several facilities is to pump blood through a detector system at a constant rate. We investigate the suitability of a commercial radiochromatography module (IN/US Posi-RAM) for this new use. The Posi-RAM consists of two 2.5 cm (length) x 2.5 cm (diameter) cylindrical bismuth germanate (BGO) detectors that can operate in coincidence mode. Arterial blood is transported through the system via a length of tubing with flow rate controlled by a peristalsis pump. A custom-counting loop and support frame were designed for the Posi-RAM for PET studies. System sensitivity was determined to be 1.1 x 10(4) cps/(MBq ml(-1)). Dead time as a function of count-rate was found to be less than 1% for concentrations below 3.5 MBq ml(-1), a range encompassing all human-study values. In a human study, the performance of the device was found to be similar to that of the facility's current blood monitor (Siemens Fluid Monitor). We conclude that the Posi-RAM has the necessary sensitivity and count-rate capabilities to be used as a real-time blood activity monitor.

Nuclear medicine in the rehabilitative treatment evaluation in stroke recovery. Role of diaschisis resolution and cerebral reorganization.

There has recently been a tremendous increase in imaging technology and imaging methodology enabling noninvasive exploration of brain function to such an intricate degree as to enable measurements of very small spatial and short temporal cerebral operations responsible for neurological and functional recovery after stroke. This has allowed conceptualization of rehabilitation strategies designed to maximally enhance rehabilitation protocols tailored to the individual patient's deficits. Rehabilitation strategies may now be designed and optimized by employing methods to synchronize functional training of brain regions ascribed to those areas innately undergoing neuronal plasticity change responsible for stroke recovery. In order to effectively apply these noninvasive imaging methods, one must have a clear understanding of the physics and technique of the imaging methodologies and how these are best applied to understand brain physiology during the stroke recovery process to provide a solid rationale for development of rehabilitation protocols. Nuclear medicine imaging is first presented as a diagnostic method to assess the stroke process. The initial brain damage and resulting neurological disability can be primarily assessed in terms of changes in the vascular and hemodynamic status of the cerebral circulation in addition to alterations in the metabolic status around the infarction region. Techniques for assessing perfusion and metabolism include regional cerebral blood flow (rCBF), single photon emission computed tomography (SPECT), and F-18 2-Fluoro-2-deoxy-D-glucose (F-18 FDG) positron emission tomography (PET). In addition, hemodynamic vascular insufficiency can be assessed using O-15 O2 oxygen extraction PET and rest and Diamox rCBF SPECT. The status of the peri-infarction region can be characterized in terms of components of diaschisis and ischemia using proton magnetic resonance spectroscopy imaging ((1)H MRSI) and rest/stress rCBF assessment of cerebral vascular reserve. As the brain recovers from cerebral infarction, areas of reorganization and energy utilization by the brain can be measured using oxygen extraction methods with PET, F-18 FDG glucose utilization by PET, and functional magnetic resonance imaging (fMRI) measures using the blood oxygenation level dependent (BOLD) technique. In addition, high field MRI imaging of the brain is now able to provide detailed fractional anisotropy (FA) maps to characterize changes in white matter by fiber tracking mapping using diffusion tensor imaging. Imaging of the stroke recovery process focuses on the physiologic model of stroke characterized by rCBF, metabolism, 1H spectroscopic measures of N-acetyl aspartate (NAA), choline (Ch) and creatine (Cr) in the peri-infarction zone as well as in the extended stroke penumbra including areas of distant ''pure'' diaschisis unencumbered with the confound of cerebral ischemia. Data is presented describing the results of application of imaging methodologies as the patient undergoes rehabilitation that demonstrates the importance of blood flow and metabolic changes in the contralesional frontal lobe both during the resting state and during motor and speech activation paradigms. The results of advanced imaging technologies on cerebral damage and cerebral reorganization during rehabilitation are presented in the context of furthering designs of rehabilitation strategies. Success can be monitored to assess the optimization of rehabilitation strategy design to maximize neurological recovery from stroke by employing facilitatory methods to maximally synchronize rehabilitation techniques with recovery of functionally counterpart areas of viable brain.

Specific localization of thallium 201 in human high-grade astrocytoma by microautoradiography.

The ability to accurately distinguish remaining or recurrent high-grade astrocytoma from necrosis or edema following treatment is essential to optimal patient management. Thallium 201 planar gamma-camera imaging has been shown to be helpful in detecting recurrent high-grade astrocytoma; however, due to tissue heterogeneity adjacent to and within tumor, the cellular specificity and quantification of 201Tl uptake are largely unknown. In order to determine which tissues are responsible for the radioisotope uptake, microautoradiographic techniques were used to examine multiple tissue sections from five patients with high-grade astrocytoma. Each patient received 5 mCi of 201Tl i.v. 1 h prior to tumor removal. Additionally, all patients received computerized tomographic and 201Tl planar gamma-camera scans prior to surgery. Following surgery, the excised tissue specimens were tentatively classified by gross pathological examination and then immediately processed for dry mount autoradiography; grain density was determined over regions containing tumor, adjacent and uninvolved brain tissue, necrotic tissue, and background. Highly significant differences were found in grain densities (201Tl uptake) between tumor and uninvolved brain tissue, as well as between uninvolved brain tissue and necrotic tissue; there was no significant difference between background grain density and that in necrotic tissue. Mean grain densities (grains/cm2 +/- 1 SD) across patients were: tumor, 102 +/- 23; adjacent, uninvolved brain tissue, 29 +/- 11; necrotic tissue, 6.2 +/- 1.1; and background, 7.0 +/- 4.1. We conclude that the ability of 201Tl to selectively image high-grade astrocytoma is due to its preferential uptake into tumor cells.

Positron emission tomographic evaluation of cerebral blood flow during state anxiety in simple phobia.

The present study was undertaken to clarify some of the conflicting findings of previous reports on the effect of state anxiety on cerebral blood flow (CBF). Seven subjects with simple phobia of small animals were studied to permit the generation of wide ranges of anxiety. Each subject received five positron emission tomography (PET) scans in a rest-fear-rest-fear-rest, repeated-measures paradigm. A population of eight normal controls was employed. The phobic stimuli produced significant increases in state anxiety during fear and significant differences in physiologic measurements between the fear and rest scans. Absolute global and regional CBF was significantly lower during fear scans than during rest scans; however, when hypocapnia resulting from anxiety-induced hyperventilation was taken into account, the pattern vanished, and all global and regional CBF differences among scans became not significant. Resting global and regional CBF values in the phobic subjects did not significantly differ from those of the normal controls. That a relationship between anxiety and CBF was not found in 35 scans among seven subjects strongly suggests that CBF changes induced by state anxiety are either not presently measurable by PET techniques or that such a relationship may not exist. These findings should also reduce concerns that subject anxiety may confound CBF measurements during routine PET scanning.

99mTc-hexamethylpropyleneamine oxime single photon emission CT in poststroke depression.

In this pilot study of poststroke depression, the authors evaluated regional cerebral blood flow and depression in 14 stroke patients. Volume of ischemia was measured by two methods, which were highly correlated. Depression scores correlated with lesion volume as measured by single photon emission CT.

Blood flow imaging of a posterior circulation stroke. Use of technetium Tc 99m hexamethylpropyleneamine oxime and single photon emission computed tomography.

Regional cerebellar perfusion was imaged using technetium Tc 99m hexamethylpropylene amine oxime and single photon emission computed tomography (HM-PAO-SPECT) in a patient with chronic left lateral medullary syndrome with contralateral weakness due to traumatically induced thrombosis of the left vertebral artery. Despite continued neurologic deficits, x-ray transmission computed tomography was normal. However, HM-PAO-SPECT demonstrated that blood flow to the left cerebellar hemisphere was significantly impaired. This abnormality was still apparent after correction for atrophy as estimated by magnetic resonance imaging. Technetium Tc 99m hexamethyl-propyleneamine oxime and single photon emission computed tomography effectively imaged regional blood flow in the vertebrobasilar circulation and appears to more clearly reflect the nature and extent of the neurologic deficit than either x-ray transmission computed tomography or magnetic resonance scanning.

Normal T-cell response and in vivo magnetic resonance imaging of T cells loaded with HIV transactivator-peptide-derived superparamagnetic nanoparticles.

The present study analyzed the feasibility of using magnetic resonance imaging (MRI) to monitor T-cell homing in vivo after loading T cells with superparamagnetic iron oxide (CLIO) nanoparticles derivatized with a peptide sequence from the transactivator protein (Tat) of HIV-1. T cells were isolated from C57BL/6 (B6) mice and loaded with 0, 400, 800, 1600, or 8000 ng/ml of FITC conjugated CLIO-Tat (FITC-CLIO-Tat). There was a dose-dependent uptake of FITC-CLIO-Tat by T cells. Stimulation of FITC-CLIO-Tat loaded T cells with anti-CD3 (0.1 microg/ml) plus IL-2 (5 ng/ml) elicited normal activation and activation-induced cell death (AICD) responses, and normal upregulation of CD69, ICAM-1 (CD54), L-selectin (CD62L), and Fas. The FITC-CLIO-Tat loaded T cells (3 x 10(7)) were transferred intravenously (i.v.) into B6 mice and the in vivo MRI of mice was acquired using a spin-echo pulse sequence at 4.7 T with a Bruker Biospec system. Homing of T cells into the spleen was observed by a decrease in MRI signal intensity within 1 h after the transfer, which remained decreased for 2-24 h after transfer. These homing data were confirmed by FACS analysis and biodistribution analysis using 125I-CLIO-Tat. Thus, T cells can be efficiently loaded with FITC-CLIO-Tat without interfering with their normal activation and AICD, or homing to the spleen, and the biodistribution of FITC-CLIO-Tat loaded T cells can be monitored in vivo over time by MRI.

Technetium-99m-HMPAO brain SPECT evaluation of neurotoxicity due to manganese toxicity.

UNLABELLED: We performed initial and follow-up regional cerebral blood flow (rCBF) studies using 99mTc-hexamethylpropyleneamine oxime (HMPAO) SPECT on a patient with manganese-induced central nervous system (CNS) neurotoxicity. METHODS: The patient had a history of long-term exposure to manganese at the time of the first scan, while the follow-up scan was performed 9 mo after removal from the toxic environment. The patient's serum level of manganese was five- to tenfold greater than normal at the time of the initial rCBF brain SPECT scan. RESULTS: The rCBF brain SPECT scan demonstrated significantly decreased rCBF in the right caudate nucleus and both thalami. A MRI scan obtained at the same time was normal. The follow-up rCBF brain SPECT scan was normal. CONCLUSIONS: This report supports the utilization of functional rCBF brain SPECT imaging to provide objective evidence of a function CNS abnormality due to neurotoxicity at an early clinical stage. Our results emphasize that rCBF brain SPECT may provide a confirmational test to support the diagnosis of neurotoxicity in the appropriate clinical setting.

Functional deficits in autistic disorder: characterization by technetium-99m-HMPAO and SPECT.

UNLABELLED: Autistic disorder is an early and severe developmental disorder characterized by deficits in verbal and nonverbal language, social skills, cognitive functioning and an abnormal repertoire of behaviors. Current research, however, has failed to identify the neurobiological mechanisms that underlie autism or those cortical brain regions, if any, that are abnormal. METHODS: We examined regional cerebral blood flow (rCBF) in six young, severely autistic patients. High-resolution brain SPECT with 99mTc-HMPAO was performed while five of the six patients were under general anesthesia. The scans reflected the subjects' rCBF in their usual alert behavioral state, since the tracer was injected at least 15 min prior to anesthesia and is rapidly extracted and fixed in the brain. A computer-automated cortical region of interest (ROI) generator was used to define 12 annular cortical regions (region 1 = left frontal, clockwise to region 12 = right frontal) for count data acquisition. The ratio of average counts in each ROI to whole-slice counts for the autistic patients was compared to age-matched controls using repeated measures (splt-plot) ANOVA statistical analysis for three representative brain levels. RESULTS: In the autistic patients, cortical regions 3, 4, and 10 were abnormally low at the cortical level canthomeatal (CM) + 3.5 cm. At level CM + 5.5 cm, regions 3, 4, 5 and 10 were abnormally low, and at level CM + 7.5 cm, regions 7 and 9 were also abnormally low. These regions correspond to abnormally low rCBF values located predominately in the temporal and parietal lobes, with the left cerebral hemisphere showing greater rCBF abnormalities than the right. CONCLUSION: Our findings suggest that the temporal and parietal lobes have abnormal rCBF in autism. HMPAO brain SPECT in combination with general anesthesia is particularly useful for imaging severely noncompliant patients.

Regional stability of cerebral blood flow measured by repeated technetium-99m-HMPAO SPECT: implications for the study of state-dependent change.

UNLABELLED: The replicability of resting state rCBF has implications for the analysis of cerebral activation protocols and the interpretation of rCBF in disease states. This study examined the stability of rCBF as measured by two resting state 99mTc-HMPAO brain SPECT scans with an emphasis on examining the contribution of specific cerebral regions to within and between subjects variance. METHODS: Nine normal, medically healthy subjects underwent two 99mTc-HMPAO brain SPECT scans under identical conditions separated by 48 hr. A reference system and semiautomated computer ROI method was used to enable accurate alignment and cortical analysis of the two scans. RESULTS: Mean within-subject difference between Scans 1 and 2 was 2.8% (range 0%-7.8%) for the 36 cortical ROIs. The mean between-subject coefficient of variation was 10% (range 7%-15%) for these ROIs. Correlation analysis of rCBF pattern replication for all slice levels yielded a highly significant overall consistency of pattern within subjects (Pearson r = 0.698, p = 0.0001). Variance component analysis revealed regional heterogeneity in between-subjects variance, with significantly greater variability found in frontal regions. The within-subject repeated measures variability was not significantly different across regions. CONCLUSION: Good within-subject 48-hr replicability indicates that individual resting state rCBF reflects fairly stable, subject-specific factors. This also justifies comparing state-dependent studies separated by a modest length of time. Although individual patterns of rCBF replicate well, the larger contribution of frontal regions to normal between-subjects variance makes evaluating the frontal effects of disease or activation more difficult.

Frontotemporal decreases in rCBF correlate with degree of dysnomia in primary progressive aphasia.

UNLABELLED: Primary progressive aphasia (PPA) is an uncommon degenerative dementia characterized by gradual impairment of language function with initial sparing of the memory domain. Using semiquantitative 99mTc-hexamethyl propyleneamine oxime (HMPAO) brain SPECT as a measure of regional cerebral blood flow (rCBF), we investigated the relationship between reduced 99mTc-HMPAO uptake and the severity of dysnomia in PPA. METHODS: Seven right-handed patients with PPA had their dysnomia assessed by the Boston Naming Test (BNT), a subtest of the Boston Diagnostic Aphasia Examination. Neuroimaging studies, including 99mTc-HMPAO brain SPECT, CT, and MRI, were performed. Correlational analysis between reduced rCBF and BNT was performed. RESULTS: Brain SPECT showed a reduction in 99mTc-HMPAO uptake involving the frontal and temporal lobes in all 7 patients. CT and MRI showed mild to moderate cerebral atrophy in 4 patients. Low scores on the BNT correlated with low frontotemporal 99mTc-HMPAO (Spearman r = 0.97, P = 0.004) in the 5 patients with left-hemisphere involvement. CONCLUSION: Decreased rCBF to the frontotemporal region characterized the cerebral abnormalities associated with PPA. The finding of focal rCBF abnormalities in the right hemisphere of 2 right-handed women corroborates that PPA symptoms may arise from a "non-left-dominant"-hemisphere degenerative process. Our results support the usefulness of rCBF SPECT imaging as a diagnostic aid in PPA.

Scintigraphic localization of ovarian dysfunction.

To assess the potential role of scintigraphy in the evaluation of clinically and biochemically suspect ovarian hyperandrogenism (HA), dexamethasone suppression 131I-6 beta-iodomethyl-19-norcholesterol (NP-59) scans were performed to characterize ovarian function in nine patients. Pelvic ultrasound and/or computed tomography (CT) identified anatomic abnormalities in the adnexal region in six women in whom there was discernible pelvic accumulation(s) of NP-59. In the remaining three patients testosterone levels were normal or only slightly elevated and the NP-59 scan did not demonstrate abnormal adrenal or pelvic uptake. CT and/or ultrasound studies failed to demonstrate an abnormality in the pelvis suggesting excessive peripheral conversion or abnormal end organ sensitivity of androgen precursors as potential etiologies of their HA. In three women with androgen secreting lipoid tumors of the ovary, unilateral, pelvic NP-59 activity was noted; these tumors were subsequently resected. Two women with bilateral pelvic NP-59 uptake were later shown to have hyperthecosis with markedly asymmetric and enlarged ovaries. In one woman the extent of asymmetric NP-59 uptake was anticipated by the asymmetry of ovarian vein androgen levels at selective venous catheterization. In another woman with markedly asymmetric polycystic ovary disease, intense focal uptake of NP-59 localized to the side of the anatomically abnormal, enlarged ovary. Thus, our preliminary study reviews our experience to date and suggests that NP-59 scintigraphy may be used to localize both tumorous and nontumorous ovarian dysfunction in states of HA and virilization.

Noninvasive monitoring of gene transfer using a reporter receptor imaged with a high-affinity peptide radiolabeled with 99mTc or 188Re.

UNLABELLED: Gene therapy protocols require better modalities to monitor the location and level of transferred gene expression. One potential in vivo mechanism to assess gene expression would be to image the binding of a radiolabeled peptide to a reporter receptor that is expressed in targeted tissues. This concept was tested in a tumor model using a replication-incompetent adenoviral vector encoding the human type 2 somatostatin receptor (Ad5-CMVhSSTr2). Expression of the hSSTr2 reporter was imaged using a radiolabeled, somatostatin-avid peptide (P829). METHODS: Bilateral subcutaneous A427 tumor xenografts were established on the flanks of athymic nude mice. These human-origin, non-small cell lung tumors are normally negative for hSSTr2 expression. One tumor was injected directly with Ad5-CMVhSSTr2, whereas the second tumor was injected directly with a control Ad5 vector. The mice were injected intravenously 48 h later with P829 peptide that was radiolabeled to high specific activity with 99mTc (half-life, 6 h) or 188Re (half-life, 17 h). Tumors were frozen and evaluated for somatostatin receptor expression using fluorescein-labeled somatostatin. RESULTS: The accumulation of radiolabeled P829 in hSSTr2-expressing tumors was easily visualized by gamma camera imaging 3 h after injection. Imaging region of interest analyses and biodistribution studies confirmed a 5- to 10-fold greater accumulation of both radiolabeled P829 peptides in the Ad5-CMVhSSTr2-injected tumors versus control tumors injected with control Ad5 vectors. Ad5-CMVhSSTr2-injected tumors accumulated 2.5-3.8 percentage injected dose per gram 3 h after injection. Only Ad5-CMVhSSTr2-injected tumors expressed somatostatin receptors, as determined by immunohistochemistry. CONCLUSION: These studies show the feasibility of imaging a 99mTc-labeled peptide's binding to a reporter receptor after in vivo gene transfer to tumor cells. The 188Re-labeled peptide worked equally well for this imaging approach and offers the additional advantage of energetic beta decay with potential therapeutic efficacy. 99mTc and 188Re are generator produced, an advantage for widespread availability and low cost, and both radioisotopes can be imaged with existing, high-resolution modalities. There is great potential for using 99mTc-labeled peptides for imaging gene transfer with the hSSTr2 reporter receptor, especially when the reporter correlates with the expression of therapeutic genes that can be included simultaneously in the gene therapy vector.

Prognostication of recovery following stroke using the comparison of CT and technetium-99m HM-PAO SPECT.

This study investigated the possibility that a relationship between the anatomic defects observed on computed tomography (CT) and the functional defects observed on single photon emission computed tomography (SPECT) might be used as an outcome measure to predict clinical recovery from the neurologic deficits induced by stroke. Twenty-seven patients with stroke location limited primarily to cerebral cortex were included in the study: each patient underwent a cranial CT scan, 99mTc hexamethylpropyleneamineoxime SPECT cerebral perfusion scan, and an initial and 1-yr follow-up neurologic examination. A strongly positive correlation between the ratio of the SPECT to CT volume defect sizes (SPECT divided by CT) and recovery following stroke was found, such that the greater the SPECT to CT ratio, the better the subsequent recovery of neurological deficits. Discriminant function analysis revealed that the best predictor of clinical outcome following stroke was the log-transformation of SPECT divided by CT. The results suggest that the relationship between the perfusion defects and tissue loss measured by SPECT and CT imaging may have prognostic utility following stroke limited primarily to cerebral cortex.

A reference method for correlation of anatomic and functional brain images: validation and clinical application.

We describe a reference device that provides accurate correlation between anatomic and functional brain images. The reference device, which generates fiduciary reference points on sequential scan planes, is positioned adjacent to the canthomeatal line of the subject and held in place by a glasses-like framework anchored to the external auditory meatus. The reference system was tested on 17 subjects undergoing 99mTc hexamethylpropylene amine oxime ([99mTc]HMPAO) brain single-photon emission computed tomography (SPECT) and cranial computed tomography (CT) scans. The centers of the caudate nuclei, thalami, brain stem, and cerebellar vermis were identified independently on CT and SPECT. The average difference +/- 1 SD between structure locations (x, y, and z) on SPECT and CT were calculated as 1.86 +/- 1.5, 2.16 +/- 1.4, and 1.83 +/- 1.9 mm, respectively. The clinical application of the method is showed by coregistration of images from SPECT to MRI. An example of sequential [99mTc]HMPAO brain SPECT scan sections precisely coregistered with MRI scan sections oriented parallel to and sequentially above the canthomeatal line illustrates the correlation between regional cerebral blood flow (rCBF) tracer activity on SPECT and normal anatomic structures. Test-retest activation paradigms in brain SPECT requires precise SPECT-to-SPECT image coregistration to evaluate changes in rCBF during activation. Precisely coregistered rest, 48-hour repeat rest [99mTc]HMPAO SPECT studies are shown to illustrate the normal intrasubject variability of tracer uptake. An example of the usefulness of image coregistration for evaluation of viable residual brain tumor and its application to tumor biopsy is presented. An example of developmental abnormalities identified by [99mTc]HMPAO brain SPECT is illustrated by a case of autistic disorder. An example of image coregistration in stroke and evaluation of cerebrovascular disease with Diamox (Lederle Laboratory Division, Pearl River, NY) cerebrovasculature stress testing is presented. The usefulness in epilepsy using a protocol whereby the tracer is injected during the ictal phase of seizure is presented. We conclude that the reference system provides an accurate, rapid, and noninvasive patient-specific method for correlating brain structure with brain function.

Thalamic thought disorder: on being "a bit addled".

Humans can generate and maintain relatively coherent trains of thought in natural discourse. The neural mediation of this ability and the phenomenology of its breakdown are not well understood. We report a case of a woman with paramedian thalamic strokes involving the mammillothalamic tract, intralaminar nuclei, parts of the dorsomedial and ventral lateral nuclei bilaterally. She presented with a dense amnesia and confusion typical of the syndrome of bilateral paramedian thalamic infarcts. Her Tc-99m HMPAO brain SPECT scan showed decreased thalamic and basal ganglia blood flow. General diminution of cerebral blood flow and areas of further diminution in the right frontal, left temporal and left temporoparietal regions were also observed. Although her amnesia was characteristic of diencephalic amnesia, her most striking clinical feature was a bizarre, disconnected and at times incoherent speech output. Analysis of her speech revealed relatively preserved lexical and morpho-syntactic linguistic production. By contrast, analysis of the macrostructure of her discourse revealed frequent unpredictable topic shifts that were completely unconstrained by contextual factors. Many of her shifts were intrusions from previous topics. We interpret her severely disordered speech output as representing the surface manifestations of a thought disorder (rather than as a language disorder per se) characterized by an inability to maintain and appropriately shift themes that normally guide discourse. Median and intralaminar thalamic nuclei appear to be critical for the neurophysiologic regulation of thalamocortical and striatocortical circuits, which in turn may be critical for the functional regulation of contextually appropriate transitions of thought.

Imaging Tc-99m-labeled FGF-1 targeting in rats.

Recombinant human acidic fibroblast growth factor (FGF-1) was radiolabeled with (99m)Tc by the HYNIC method. The (99m)Tc-FGF-1 retained its representative molecular mass, heparin affinity, cellular binding to both low (Kd = 9.5 nM) and high (Kd = 125 pM) affinity sites, and mitogenic activity. Gamma camera imaging after intravenous dosing in rats confirmed high liver and kidney binding. Heparin significantly decreased (99m)Tc-FGF-1 liver uptake and increased urinary excretion. These studies illustrate a new method for imaging FGF-1 targeting under various conditions.

Simultaneous evaluation of dual gene transfer to adherent cells by gamma-ray imaging.

A gamma camera imaging method was developed to detect dual gene transfer to adherent cells growing as monolayers in cell culture plates. Human cancer cells were infected with replication-incompetent adenoviral vectors encoding the human type 2 somatostatin receptor (Ad-hSSTr2) and/or herpes virus thymidine kinase (Ad-TK). The hSSTr2 and TK reporter proteins were detected by imaging internally bound (99m)Tc-P2045 peptide (Diatide, Inc.) and radioiodinated 2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl-5-iodouracil (FIAU), respectively. Following gene transfer, expression of hSSTr2 and TK were accurately imaged in vitro.

Thallium-201 tumor/cardiac ratio estimation of residual astrocytoma.

Treatment of high-grade astrocytoma includes surgery, chemotherapy, and various methods of irradiation. Radiation therapy usually results in necrosis and edema around the primary tumor site. Contrast-enhanced computerized tomography (CT) and standard radionuclide imaging techniques are unable to reliably distinguish recurrent tumor from necrosis or edema since these images depict localization of contrast material or tracer, which primarily depends on blood-brain barrier breakdown. Thallium-201 (201Tl) appears to incorporate into viable tumor cells more rapidly than into normal brain cells. This report describes a new method to quantify the uptake of 201T1 in the tumor: the tumor-to-cardiac uptake ratio (T/C). Twenty-three 201T1 brain scans were performed on eight patients to differentiate recurrent viable high-grade astrocytoma from posttherapy changes. Planar images of the head and heart were obtained in order to calculate the ratio of tumor counts to cardiac counts. This ratio represents a numerical estimation of 201T1 uptake in the brain tumor relative to cardiac counts and is expressed as the T/C index. The T/C index correlated well with the clinical course in all eight patients. In general, however, CT suggested more extensive regrowth of tumor than the actual clinical status suggested. In one patient's course of radiological monitoring, tumor recurrence was detected by means of 201T1 imaging four months prior to its appearance on CT. In conclusion, when performed serially, the T/C index can provide an accurate estimate of residual tumor burden or recurrence, and detect and quantify viable tumor during therapy.