Radioimmunotherapy using 131I-labeled anti-CD22 monoclonal antibody (LL2) in patients with previously treated B-cell lymphomas.

Experience in using rapidly internalizing antibodies, such as the anti-CD22 antibody, for radioimmunotherapy of B-cell lymphomas is still limited. The present study was conducted to assess the efficacy and toxicity of a 131I-labeled anti-CD22 monoclonal antibody (mAb), LL2, in patients with B-cell lymphomas failing first- or second-line chemotherapy. Eligible patients were required to have measurable disease, less than 25% B cells in unseparated bone marrow, and an uptake of 99mTc-labeled LL2Fab' in at least one lymphoma lesion on immunoscintigram. Eight of nine patients examined with immunoscintigraphy were unequivocally found to have an uptake, and therapy with 131I-labeled anti-CD22 [1330 MBq/m2 (36 mCi/m2)] preceded by 20 mg of naked anti-CD22 mAb was administered. Three patients achieved partial remission (duration, 12, 3, and 2 months), and one patient with progressive lymphoma showed stable disease for 17 months. Four patients exhibited progressive disease. The toxicity was hematological. Patients with subnormal counts of neutrophils or platelets before therapy seemed to be more at risk for hematological side effects. Radioimmunotherapy in patients with B-cell lymphomas using 131I-labeled mouse anti-CD22 can induce objective remission in patients with aggressive as well as indolent lymphomas who have failed prior chemotherapy.

Central nervous system effects of subdissociative doses of (S)-ketamine are related to plasma and brain concentrations measured with positron emission tomography in healthy volunteers.

Plasma concentrations, maximum regional brain concentrations, and specific regional binding in the brain after administration of 0, 0.1, and 0.2 mg/kg doses of (S)-ketamine were measured in a randomized, double-blind, crossover study in five volunteers and were related to induced effects such as analgesia, amnesia, and mood changes. Specific binding in the brain was assessed by simultaneous administration of (S)-[N-methyl-11C]ketamine quantified by positron emission tomography. High radioactivities in the brain corresponded to regional distribution of N-methyl-D-aspartate receptor complexes. A significant and dose-dependent reduction of binding was measured as a result of displacement of (S)-[N-methyl-11C]ketamine. Memory impairment and psychotomimetic effects were related to dose, plasma concentration 4 minutes after administration, and decreased regional binding of (S)-ketamine in the brain and were consistently seen at plasma and maximum regional brain (S)-ketamine concentrations higher than 70 and 500 ng/ml, respectively. The magnitude of specific binding of (S)-ketamine, measured with positron emission tomography, can be related directly to drug effects.

In vivo demonstration of enzyme activity in endocrine pancreatic tumors: decarboxylation of carbon-11-DOPA to carbon-11-dopamine.

METHODS: We used PET to characterize the uptake and decarboxylation of 11C-L-DOPA in vivo in two patients with endocrine pancreatic tumors: one glucagonoma and one gastrinoma. RESULTS: With L-DOPA labeled with 11C in the beta position, in which the radioactive label follows the molecule through decarboxylation to dopamine, significant uptake was observed in the tumors. With L-DOPA labeled in the carboxyl group, in which the label is rapidly eliminated from the tissue as 11CO2 if decarboxylation takes place, an almost complete lack of uptake is noted. CONCLUSION: This study shows that, using selective position labeling, an in vivo action of enzymatic activity can be observed with PET and that significant decarboxylation occurs in the tested endocrine pancreatic tumors. Also, marked retention of radioactivity occurs after treatment with somatostatin analogs. It is hypothesized that this is a reflection of a reduction of exocytosis which is induced by this treatment.

Effect of 6R-L-erythro-5,6,7,8-tetrahydrobiopterin on the extracellular levels of dopamine and serotonin in the rat striatum: a microdialysis study with tyrosine or tryptophan infusion.

The present study demonstrates the effects of 6R-L-erythro-5,6,7,8-tetrahydrobiopterin (6R-BH4) on turnover of dopamine and serotonin (5-HT) in rat striatum during continuous infusion of the amino acids tyrosine and tryptophan. By monitoring with microdialysis, it was found that the increase in dopamine and homovanillic acid (HVA) concentrations in rat striatal extracellular fluid (ECF) induced by 6R-BH4 was further enhanced by the continuous infusion of tyrosine at a relatively low dose (1 mumol/min/kg) as compared with the concentration which saturates tyrosine hydroxylation. This dose of tyrosine alone did not induce the elevation of dopamine and HVA concentrations in ECF. In contrast, though the concentration of 5-HT and 5-HIAA in striatal ECF was gradually increased by tryptophan infusion, 6R-BH4 had no further effect. Although the higher output of dopamine into ECF was induced by the dialytic perfusion of 6R-BH4 via the microdialysis probe into striatum, tyrosine infusion had no further effect on dopamine concentration in the dialysates. The in vivo measurement of DOPA accumulation during NSD 1015 perfusion suggests that the enhancement of dopamine concentration in ECF induced by tyrosine infusion and 6R-BH4 might be attributable to an increase in tyrosine hydroxylase activity in striatum. Tryptophan hydroxylase was also activated by tryptophan infusion and/or 6R-BH4, however, it did not induce an increase in 5-HT concentration in striatal ECF.

Effect of 6R-L-erythro-5,6,7,8-tetrahydrobiopterin and infusion of L-tyrosine on the in vivo L-[beta-11C] DOPA disposition in the monkey brain.

The effect of 6R-L-erythro-5,6,7,8-tetrahydrobiopterin (6R-BH4) and L-tyrosine infusion on [11C]dopamine synthesis was analyzed in the striatum of Rhesus using positron emission tomography (PET). The rate for decarboxylation from L-[beta-11C]DOPA to [11C]dopamine was calculated using a graphical method with cerebellum as a reference region. Although the peripheral administration of 6R-BH4 at low dose (2 mg/kg) did not provide a significant increase in the rate of dopamine biosynthesis, a high dose of 6R-BH4 (20 mg/kg) induced an elevation of the rate. This 6R-BH4-induced elevation of the dopamine synthesis rate was further dose-dependently enhanced by the continuous infusion of L-tyrosine (0.2 and 1.0 mumol/min/kg). L-Tyrosine infusion with a rate of 1.0 mumol/min/kg caused an enhancement of the rate even during low dose administration of 6R-BH4 (2 mg/kg). L-Tyrosine infusion alone did not induce any elevation of the dopamine biosynthesis rate. The analysis of plasma indicated that the metabolic ratios of L-[beta-11C]DOPA to each metabolite were not affected by 6R-BH4 and/or L-tyrosine infusion. The results suggest that the low dose loading of tyrosine facilitates the activity of 6R-BH4 on the presynaptic dopamine biosynthesis, and also that the combined effects can be monitored by PET using L-[beta-11C]DOPA as a biochemical probe.

Determination of 5-hydroxy-L-[beta-11C]tryptophan and its in vivo-formed radiolabeled metabolites in brain tissue using high performance liquid chromatography: a study supporting radiotracer kinetics obtained with positron emission tomography.

A high performance liquid chromatographic system was developed for separation of 11C-labeled 5-hydroxy-L-tryptophan ([11C]HTP) and in vivo formed radiolabeled metabolites in rat brain tissue. Analysis of brain homogenate revealed that the main part of the radioactivity was associated with 11C-labeled 5-hydroxyindole-3-acetic acid after intravenous injection of [11C]HTP to the rat. The serotonin synthesis rate in the brain was calculated and closely correlated to the serotonin synthesis rate in monkey and human measured using positron emission tomography.

Demonstration of [11C] 5-hydroxy-L-tryptophan uptake and decarboxylation in carcinoid tumors by specific positioning labeling in positron emission tomography.

In three patients with carcinoid liver and/or lymph node metastases, we studied the process of tumor tracer uptake and decarboxylation by means of positron emission tomography (PET) using 5-hydroxy-L-tryptophan (5-HTP) 11C-labeled in the beta-position (HTP) and later the same day with 5-HTP 11C-labeled in the carboxyl group (HTC). With HTP, in which the 11C-label follows the molecule through decarboxylation to form 11C-serotonin, a high tumor accumulation of the tracer was found. With HTC, in which the label is rapidly eliminated from the tissues as 11CO2 if decarboxylation takes place, there was virtually no uptake by the tumors. By utilizing data from PET scanning with both tracers, we could quantify the decarboxylation rate and tissue accumulation of [11C]-serotonin and hence the enzymatic action of aromatic amino acid decarboxylase.

An automated liquid chromatographic plasma analysis of amino acids used in combination with positron emission tomography (PET) for determination of in vivo plasma kinetics.

Quantification of physiological processes measured with positron emission tomography (PET) requires an "input" function which can be the concentration of administered radio-tracer in plasma. Radioactive nuclides used in PET have short half lives (2-20 min) and a limited time is available for the PET investigation including analysis of the composition of the radioactive signal in plasma. Therefore, an automated method for the analysis and separation of beta-[11C]-L-5-hydroxy-tryptophan ([11C]-L-5-HTP), beta-[11C]-L-3,4-dihydroxy-phenylalanine ([11C]-L-DOPA) and L-[methyl-11C]-methionine and their respective metabolites in plasma was developed. A size exclusion exclusion column was used for isolation of the low molecular weight fraction. In the case of [11C]-L-5-HTP and [11C]-L-DOPA, the low molecular weight fraction was injected onto a liquid chromatographic system for separation of radioactive tracer from in vivo formed radio-labelled metabolites. The elution volume from the size exclusion column was 7.0, 5.0 and 3.5 ml for [11C]-L-5-HTP, [11C]-L-DOPA and L-[methyl-11C]-methionine, respectively. An interaction with the column matrix and the solutes was observed for both [11C]-L-5-HTP and [11C]-L-DOPA. The yield in the isolation step was > 98%. Separation of [11C]-L-5-HTP and [11C]-L-DOPA from their respective metabolites was performed with high-performance liquid chromatography with automated collection of fractions of the eluate corresponding to those of administered tracer and metabolites. The fractions were measured for radioactivity in a well counter.(ABSTRACT TRUNCATED AT 250 WORDS)

Liquid chromatographic analysis of brain homogenates and microdialysates for the quantification of L-[beta-11C]DOPA and its metabolites for the validation of positron emission tomography studies.

The clinical use of positron emission tomography, PET, with selected radiolabelled tracer molecules visualizing and quantitating physiological processes in the tissue relies in many situations on compartmental models for the interpretation of the radiosignal. Validation of such models must, therefore, include chromatographic analysis of the radioactivity composition of the signal. Rapid and sensitive liquid chromatographic methods amenable for automation for the analysis of [11C] labelled L-DOPA and its metabolites were therefore developed and validated for the quantitation of radioactivity composition in rat brain microdialysates as well as homogenates. Analysis included a simple isolation step, separation using reversed phase liquid chromatography with radiometric detection and permitted assay following tracer doses with an analysis time of 15 min. The analysis of radioactivity composition in the rat striatum showed that peripherally formed O-methyl L-DOPA constituted less than 20% of the radioactivity 40 min after injection of L-[beta-11C]DOPA. In the extracellular space the main component was [11C]-homovanillic acid which increased with time indicating rapid formation but slow elimination. The cumulation of radioactivity in the striatum corresponded to the radioactivity signal of dopamine and derived metabolites. The formation rate of dopamine in the rat corresponded closely to the utilization rate in the striatum of monkey and man measured with PET. This indicated that the rate constants measured with PET correlates well to the dopamine synthesis rate.

PET with hydroxytryptophan as tracer in hormone-refractory prostatic adenocarcinoma: evaluation of decarboxylation in vivo.

Position emission tomography (PET) was performed on two patients with hormone-refractory prostatic adenocarcinoma in order to characterize the mechanism behind an earlier observed increased uptake of tracer hydroxytryptophan (5-HTP) in bone metastases. The osseous metastases were investigated with 5-hydroxytryptophan, radio-labelled with 11C in the carboxyl group (5-HTC), and with 5-HTP in order to elucidate in vivo the presence of hydroxytryptophan decarboxylation. An increased uptake, measured as standard uptake value (SUV), in the metastatic lesions was observed using 5-HTP. The uptake varied between lesions. Using 5-HTC a corresponding uptake was observed. The time-activity rates were similar. The congruence in uptake patterns between 5-HTP and 5-HTC in the investigated lesions, demonstrates that decarboxylation of 5-hydroxytryptophan to serotonin is not a dominant factor in the uptake. It was concluded that 5-HTC could be used in vivo to investigate the chemical event of decarboxylation of 5-hydroxytryptophan and provide information about characteristics in metastatic lesions.

Age changes in assembly performance: a component analysis.

100 children from Kindergarten to Grade 9 (i.e., 5 to 15 yr.) performed a one-handed manual dexterity assembly task. The videotaped performances were analyzed for the components, Grasping, Transporting, Positioning, Reaching, and Pauses. All five components contributed significantly to the improvements in the lower grades. The Grasping component deteriorated significantly in the older children, but Reaching and Positioning continued to improve up to Grade 9. There were no sex differences.

Overuse Injuries of Growing Bones: The Young Female Gymnast at Risk?

In brief: While exercise and physical training generally have a beneficial effect on bone growth, excessive physical loading may disrupt normal osseous development and inflict injury. The latter is particularly applicable to young female gymnasts, who seem predisposed because of their physical immaturity and for whom the injury rate is astonishingly high when they train and compete at advanced levels. This literature review indicates grounds for concern and points to the need for research that will provide a more extensive data base. It also indicates the need to examine the relationships between an injury and the athlete's characteristics, types of skills, and training regimens. The authors recommend a longitudinal approach to such research.

Injury patterns of female competitive club gymnasts.

Gymnast and injury information on 178 competitive female gymnasts was collected through questionnaires and interviews in a 3-year prospective epidemiologic study. The injury rate was 30/100 gymnasts/year, .52 injuries/1000 h. Injury rates excluding risk exposure increased with competitive level, but the top level gymnasts had the lowest rate per 1000 h of practice. Fractures of the wrist, fingers and toes were most common, followed by sprains of ankle and knee. Nearly 40% of the sudden-onset injuries occurred in the floor event. 'Missed move' was most frequently cited as the injury mechanism, while somersaults and handsprings were the most injury-producing moves. Most injuries happened with moves that were basic or moderately difficult and well-established. There was an increased chance of injury when the gymnast had been on the apparatus for an extended period of time. One major source of injury is loss of concentration, and a key to injury prevention may be the reorganization of the practice session.

Withdrawal predictors among physical and performance characteristics of female competitive gymnasts.

Future drop-outs (n = 27) and continuing (n = 41) female competitive gymnasts were compared with respect to their physical, performance and injury characteristics measured through a large battery of tests completed while they were participants in competition. Included were anthropometric variables, body composition and somatotype, strength, flexibility, endurance, power, speed and balance measurements, and previous injury information. Differences were examined through t-tests and through discriminant analyses of principal components. The results indicate that the drop-outs were as a group distinguishable from the continuing gymnasts: they were significantly older, taller and heavier which may account for the finding that they were significantly stronger, more powerful and faster, and had greater endurance. They also had a slightly more linear/ectomorphic physique with less muscularity, and performed better on most flexibility tests. Only in a gymnastic-specific flexibility variable did the continuing gymnasts out-perform the drop-outs. It was concluded that it was mainly the age factor, and presumably the social and psychological factors associated with it, that distinguished the future drop-outs from the continuing gymnasts, and that factors related to the physical make-up and performance capacities of gymnasts cannot readily predict withdrawal from the sport.

Regional brain kinetics of 6-fluoro-(beta-11C)-L-dopa and (beta-11C)-L-dopa following COMT inhibition. A study in vivo using positron emission tomography.

The regional brain kinetics of (beta-11C)-L-dopa and 6-fluoro-(beta-11C)-L-dopa was measured in six Rhesus monkeys using positron emission tomography (PET). Radioactivity accumulated specifically in the striatal region and the increase in L-dopa-derived radioactivity utilization with time was calculated using surrounding brain as a reference area, this being devoid of dopaminergic activity. The rate constant for selective striatal utilization i.e. grossly decarboxylation was 0.0110 +/- 0.0007 (S.D) and 0.0057 +/- 0.0006 min-1 for (beta-11C)-L-dopa and 6-fluoro-(beta-11C)-L-dopa, respectively. After pretreatment of the monkeys with the peripherally and centrally active catecholamine-O-methyl transferase (COMT) inhibitor Ro 40-7592 10 mg/kg, the decarboxylation rate remained unchanged (0.0112 +/- 0.0015 min-1) for (beta-11C)-L-dopa, whereas an increase in rate was measured for 6-fluoro-(beta-11C)-L-dopa (0.0092 +/- 0.0015 min-1). Differences in the distribution of radiolabelled metabolites i.e. the corresponding O-methyl-L-dopa in the reference area is most probably the reason for the difference in calculated decarboxylation rate seen between the radiotracers. The higher decarboxylation rate measured for 6-fluoro-(beta-11C)-L-dopa after blockade of COMT shows that the radiolabelled metabolites i.e. 6-fluoro-O-methyl-(beta-11C)-L-dopa significantly contributes to background radioactivity.

Brain kinetics of 11 C-labelled L-tryptophan and 5-hydroxy-L-tryptophan in the rhesus monkey. A study using positron emission tomography.

5-Hydroxy-L-tryptophan labelled with 11 C is introduced as a tracer for the in vivo assessment of brain serotonin synthesis in the Rhesus monkey using positron emission tomography, PET. Increasing radioactivities were seen in the striatal area in contrast to that seen in other brain regions. Following 11 C-labelled L-tryptophan an even spread of brain radioactivity was seen. This selective increase most probably results from the decarboxylation of tracer and retention of formed products since no striatal increase of radioactivity was seen when 5-hydroxy-L-tryptophan labelled with 11 C in the carboxy-position was administered. Furthermore, pretreatment of the monkey with a centrally active decarboxylase inhibitor (NSD 1015, 10 mg/kg) did not lead to increased striatal radioactivities after the administration of 5-hydroxy-(beta-11 C)-L-tryptophan. The selective utilization of the radiotracer in the striatal area increased with a rate constant calculated to be 0.0055 +/- 0.0015 min-1 (n = 5) using the surrounding brain as reference area. A non-significant influence of radiolabelled metabolites to the rate constants measured was shown after pretreatment of the monkeys with selective and non-selective monoamine oxidase inhibitors, respectively. These results may give a basis for the use of the new tracer 5-hydroxy-(beta-11 C)-L-tryptophan in PET-studies of brain serotonin metabolism in health and disease.

Analysis of L-[methyl-11C]methionine and metabolites in human plasma by an automated solid-phase extraction and a high-performance liquid chromatographic procedure.

A fully automated method for separation of L-[methyl-11C]Methionine from metabolites in patient plasma was developed. L-[methyl-11C]Methionine was isolated from plasma by solid-phase extraction (SPE). The radioactivity retained on the SPE column was eluted and injected onto the HPLC system for separation of in vivo formed L-[methyl-11C]methionine radiolabeled metabolites. The yield through the isolation procedure and HPLC analysis was greater than 95% with a precision better than 5% (R.S.D.). The calculated rate of L-[methyl-11C]methionine transport into tumor tissue was markedly different with and without compensation for radiolabeled metabolites in patient plasma.

Pyridoxine effect on synthesis rate of serotonin in the monkey brain measured with positron emission tomography.

The influence of the co-factor pyridoxine, vitamin B6, on the activity of aromatic amino acid decarboxylase enzyme was studied by positron emission tomography, PET in the brain of the Rhesus monkey using the precursor for serotonin synthesis 5-hydroxy-L-tryptophan (5-HTP) radiolabelled with 11C in the beta-position. The rate constant for the formation of serotonin in the corpus striatum was calculated using a two tissue compartment model with reference area in the brain. In baseline investigations, the mean rate constants (+/-S.D:) for selective utilization of [11C]5-HTP to form [11C]serotonin in the corpus striatum was 0.0080 +/- 0.0011 min(-1). Pretreatment with intravenous pyridoxine hydrochloride 10 mg/kg bodyweight before doing a second PET study resulted in an enhanced rate constant by a mean of 20%. The rate increase was statistically significant. The increase varied considerably in different monkeys from no effect to more than 60%. The effect of pyridoxine on aromatic amino acid decarboxylase activity supported a regulatory role of pyridoxine on the synthesis of neurotransmitter in vivo, and may be of importance in diseases with deficiencies in neurotransmitter function.

Positron emission tomographic studies on aromatic L-amino acid decarboxylase activity in vivo for L-dopa and 5-hydroxy-L-tryptophan in the monkey brain.

The regional brain kinetics following 5-hydroxy-L-(beta-11 C)tryptophan and L-(beta-11 C)DOPA intravenous injection was measured in twelve Rhesus monkeys using positron emission tomography (PET). The radiolabelled compounds were also injected together with various doses of unlabelled 5-hydroxy-L-tryptophan or D-DOPA. The radioactivity accumulated in the striatal region and the rate of increased utilization with time was calculated using a graphical method with back of the brain as a reference region. The rate constants for decarboxylation were 0.0070 +/- 0.0007 (S. D) and 0.0121 +/- 0.0010 min-1 for 5-hydroxy-L-(beta-11 C)tryptophan and L-(beta-11 C)DOPA, respectively. After concomitant injection with unlabelled 5-hydroxy-L-tryptophan, the rate constant of 5-hydroxy-L-(beta-11 C)tryptophan decreased dose-dependently and a 50 percent reduction was seen with a dose of about 4 mg/kg of unlabelled compound. A decreased utilization rate of L-(beta-11 C)DOPA was seen only after simultaneous injection of 30 mg/kg of either L-DOPA or 5-hydroxy-L-tryptophan. This capacity limitation was most likely interpreted as different affinity of the striatal aromatic amino acid decarboxylase for L-DOPA and 5-hydroxy-L-tryptophan, respectively.