Phase I clinical trial of a TGF-beta antisense-modified tumor cell vaccine in patients with advanced glioma.

We performed a phase I clinical trial in grade IV astrocytoma to assess the safety of a whole-cell vaccine comprising autologous tumor cells genetically modified by a transforming growth factor-beta2 (TGF-beta2) antisense vector. Blocking secretion of the immunosuppressive molecule TGF-beta in this manner should inhibit one of the major mechanisms by which tumor cells evade immune surveillance and should lead to clinically effective antitumor immunity. Six patients with progressive WHO grade IV astrocytoma were enrolled in the trial. Patients received 2-7 subcutaneous injections of 5 x 10(6)-2 x 10(7) autologous tumor cells per injection. TGF-beta2 secretion by the tumor cells used to vaccinate patients was inhibited by 53-98%. Treatment was well tolerated with only low-grade, transient treatment-related toxicities reported. Two patients had partial regressions and two had stable disease following therapy. The overall median survival was 68 weeks. Median survival of the responding patients was 78 weeks, compared to a historic value of 47 weeks for glioma patients treated conventionally. There were indications of humoral and cellular immunity induced by the vaccine. These findings support further clinical evaluation of vaccines comprised of TGF-beta antisense-modified tumor cells.

Prediction of pathology and survival by FDG PET in gliomas.

OBJECTIVES: Despite being in use for nearly two decades, the utility of [18F]2-fluoro-2deoxy-D-glucose positron emission tomography (FDG PET) in the evaluation and treatment of brain tumors remains controversial. We retrospectively analyzed all patients with histologically proven gliomas, between the years 1990 and 2000, who underwent FDG PET studies at various stages of their treatment and who were followed till either death or for a minimum period of 1 year in an attempt to bring resolution to this controversy. METHODS: All PET scans prior to 1997 were acquired on an ECAT 951/31 scanner in 2D. Scans since 1997 were obtained on a Siemens HR+ scanner in 3D mode. The majority of FDG PET scans were co-registered with the magnetic resonance imaging (MRI) scans to aid in diagnosis and therapy. Based on independent visual inspection, two board certified nuclear medicine physicians graded the highest activity level of the tumor using the metabolic grading: 0 = no uptake; 1 = uptake less or equal to normal white matter; 2 = uptake greater than normal white matter and less than gray matter; 3 = uptake equal to or greater than gray mater. The measure of association of lambda (lambda) was used to measure the strength of predictive ability of FDG PET for pathological grading of the gliomas. The Cox proportional hazards regression model was used to assess the significance of grade of uptake on survival. RESULTS: A total of 331 patients were analyzed of which 137 had a PET scan prior to histological diagnosis and therapeutic intervention (mean age = 46.5 years; M:F = 1.7:1). Eighty six percent (143/166) of the patients with low uptake (metabolic scores 0,1) had low-grade gliomas (grade I,II) and 14% (23/166) high-grade gliomas (grade III,IV) on histologic examination. Ninety four percent (154/165) of the patients with high uptake (metabolic scores 2,3) on PET had high-grade gliomas and 7% (11/165) had low-grade gliomas on histologic examination. The grade of uptake had increasing significance on survival as the level increased from 'low' to 'high' (P = 0.0009). Ninety four percent (156/166) of the patients with low uptake survived for > 1 year (median survival of 28 months) and 19% survived for > 5 years. Only 29% (48/165) of patients with high uptake survived for > 1 year, (median survival of 11 months) and none survived for > 5 years. Irrespective of when the scan showed a high uptake of FDG, before or after intervention, the prognosis following that scan was poor. CONCLUSIONS: Our observations confirm the utility of FDG PET as a prognostic tool for the histological grading and survival in patients with gliomas and appears to more than complement pathological grading.

Cerebral metabolism of the remote area after epilepsy surgery.

To clarify whether epilepsy surgery improves cerebral metabolism, pre- and postoperative positron emission tomography (PET) scans were performed, with special reference to hypometabolism outside the resected epileptogenic zones in nine patients (8 males, 1 female) with medically intractable complex partial seizures and multiple hypometabolic zones. Seven patients underwent unilateral anterior temporal lobectomy, one patient underwent selective amygdalohippocampectomy, and one patient underwent parieto-occipital cortical resection and anterior temporal lobectomy. PET scans were obtained at least 6 months after surgery. Eight patients became seizure-free, and one patient had fewer than three seizures per year. Four patients showed improved glucose metabolism in the formerly hypometabolic zones, which were remote to the surgical site and ipsilateral to the epileptogenic foci. Five patients, who showed bilateral temporal hypometabolism preoperatively, had contralateral temporal hypometabolism after surgery. The relative glucose uptake in four of these patients showed increased metabolism of the adjacent lobes ipsilateral to the surgical site. The lobes that showed increased glucose metabolism after surgery were mostly frontal. Hypometabolism is reversible in the ipsilateral remote area, and may be caused by inhibition via the intercortical pathway. Contralateral temporal hypometabolic zones that persist after surgery may be caused by a different mechanism, and neither indicate the presence of seizure foci nor affect the seizure outcome.

Synthesis and in vivo disposition studies of 18F-labeled HFA-134a.

A rapid synthesis of the chlorofluorocarbon replacement compound 1,1,1,2-tetrafluoroethane (HFA-134a) was identified and utilized to prepare 99+% radiochemically pure [18F]HFA-134a in 20-35% radiochemical yield. Four rats were then exposed to no-carrier-added (NCA) [18F]HFA-134a, and monitored via coincidence detection. Following withdrawal of the test atmosphere of [18F]HFA-134a, the mean half-life of [18F]HFA-134a in four rats was determined to be 7.8 +/- 1.5 min following a 10 s exposure and 8.1 +/- 1.7 minutes following a 10 min exposure.

The clinical utility of provocative radionuclide oesophageal transit in the evaluation of non-cardiac chest pain.

We combined edrophonium provocative testing with the technique of radionuclide oesophageal transit (RET) in 30 consecutive patients with non-cardiac chest pain (NCCP) and 12 controls. The oesophageal transit time of aqueous technetium-99m sulfur colloid was determined before and after intravenous infusion of 80 micrograms/kg edrophonium chloride (ED). Patient symptoms during provocative RET (P-RET) were recorded. Thirteen (43%) of the patients had abnormal study results, whereas all control subjects had normal results. Three groups considered abnormal were observed: (a) in two patients (6%), the pain was reproduced and transit pre- and post-ED administration was prolonged (greater than 15 s); (b) in six patients (20%), the pain was reproduced, but transit was normal pre- and post-ED; (c) in five patients (17%), transit pre- and post-ED was prolonged, but no pain was reproduced. In five patients (17%), ED prolonged the transit time greater than 15 s without pain, but the baseline transit was normal. Transit time was measurable in 23 patients. Mean pre-ED transit time was 10.2 +/- 7.4 s (mean +/- SD) and post-ED, 12.4 +/- 8.0 s (P = 0.3). We conclude that ED has no significant effect on transit time, and the pain induced by ED rarely correlates with an abnormal transit; P-RET provides additional information to baseline RET, increasing sensitivity, and may be a useful screening method in the evaluation of patients with NCCP.

Intense pyrophosphate heart uptake with insignificant coronary stenosis.

A patient with intense technetium pyrophosphate myocardial activity is presented. The scintigraphic findings are unique in that a pattern consistent with extensive myocardial necrosis was present, but no significant coronary artery stenosis was present by coronary cineangiography.

Effects of dynamic and isometric exercise on the radionuclide-determined regurgitant fraction in aortic insufficiency.

Twenty-five patients with aortic insufficiency and eight asymptomatic control subjects underwent radionuclide ventriculography at rest and during dynamic and isometric exercise to clarify the mechanisms for preservation of exercise capacity in aortic insufficiency. Regardless of symptomatic state or severity of regurgitation, patients with aortic insufficiency had no significant increase in left ventricular ejection fraction or relative left ventricular end-diastolic volume during dynamic or isometric exercise. The radionuclide stroke count ratio (ratio of left ventricular to right ventricular stroke counts) progressively decreased in patients with aortic insufficiency from 2.98 +/- 1.14 (mean +/- 1 standard deviation) at a mean heart rate at rest of 69.6 beats/min to 2.48 +/- 0.59 (p = not significant [NS]) at a mean submaximal bicycle exercise heart rate of 129 beats/min and to 1.97 +/- 0.57 (p less than 0.005) at a mean maximal bicycle exercise heart rate of 145 beats/min. The decrease in stroke count ratio with bicycle exercise was significantly related to the severity of valvular regurgitation at rest (p less than 0.005). Although achieving lower bicycle exercise heart rates and comparable diastolic blood pressures, symptomatic patients had a lower mean stroke count ratio compared with asymptomatic patients with aortic insufficiency, suggesting that an elevation left ventricular diastolic pressure significantly decreased the regurgitant fraction in symptomatic patients during bicycle exercise. In patients with aortic insufficiency, the mean heart rate (92 beats/min) was significantly lower with isometric exercise than during the submaximal stage of bicycle exercise (129 beats/min). However, diastolic blood pressures, left ventricular diastolic counts and ejection fractions were comparable.(ABSTRACT TRUNCATED AT 250 WORDS)