Boron Neutron Capture Therapy of Brain Tumors: Clinical Trials at the Finnish Facility Using Boronophenylalanine

Two clinical trials are currently running at the Finnish dedicated boron neutron capture therapy (BNCT) facility. Between May 1999 and December 2001, 18 patients with supratentorial glioblastoma were treated with boronophenylalanine (BPA)-based BNCT within a context of a prospective clinical trial (protocol P-01). All patients underwent prior surgery, but none had received conventional radiotherapy or cancer chemotherapy before BNCT. BPA-fructose was given as 2-h infusion at BPA-dosages ranging from 290 to 400mg/kg prior to neutron beam irradiation, which was given as a single fraction from two fields. The average planning target volume dose ranged from 30 to 61Gy (W), and the average normal brain dose from 3 to 6Gy (W). The treatment was generally well tolerated, and none of the patients have died during the first months following BNCT. The estimated 1-year overall survival is 61%. In another trial (protocol P-03), three patients with recurring or progressing glioblastoma following surgery and conventional cranial radiotherapy to 50–60Gy, were treated with BPA-based BNCT using the BPA dosage of 290mg/kg. The average planning target dose in these patients was 25–29Gy (W), and the average whole brain dose 2–3Gy (W). All three patients tolerated brain reirradiation with BNCT, and none died during the first three months following BNCT. We conclude that BPA-based BNCT has been relatively well tolerated both in previously irradiated and unirradiated glioblastoma patients. Efficacy comparisons with conventional photon radiation are difficult due to patient selection and confounding factors such as other treatments given, but the results support continuation of clinical research on BPA-based BNCT.     

Treatment improves serotonin transporter binding and reduces binge eating

Rationale Serotonin (5-HT) is involved in the control of eating behaviour by inhibiting food intake. Obese women with binge-eating disorder (OB-BED) were recently found to have reduced 5-HT transporter binding. Objectives The aim of this study was to investigate the effect of a successful treatment on 5-HT transporters in OB-BED. Methods The 5-HT transporter binding of seven OB-BED was measured by single-photon emission computed tomography (SPECT), by using iodine-123-labelled nor-β-CIT as a tracer, before treatment and after successful treatment, when the OB-BED were asymptomatic. Treatment consisted of group psychotherapy and fluoxetine medication. The control subjects, six obese women without eating disorders, were also studied twice by using SPECT. Results The 5-HT transporter binding of the symptomatically recovered OB-BED increased significantly (24±22%) after treatment, whereas in the control group, binding remained unchanged. Conclusions The results tentatively suggest that 5-HT transporter binding in OB-BED is an adaptive mechanism, which can be affected by treatment. Furthermore, there seems to be a link between improved 5-HT transporter binding and reduced binge eating.     

Dose-dependent suppression by ethanol of transient auditory 40-Hz response

Rationale: Acute alcohol (ethanol) challenge is known to induce various cognitive disturbances, yet the neural basis of the effect is poorly known. The auditory transient evoked gamma-band (40-Hz) oscillatory responses have been suggested to be associated with various perceptual and cognitive functions in humans; however, alcohol effects on auditory 40-Hz responses have not been investigated to date. Objectives: The objective of the study was to test the dose-related impact of alcohol on auditory transient evoked 40-Hz responses during a selective-attention task. Methods: Ten healthy social drinkers ingested, in four separate sessions, 0.00, 0.25, 0.50, or 0.75 g/kg of 10% (v/v) alcohol solution. The order of the sessions was randomized and a double-blind procedure was employed. During a selective attention task, 300-Hz standard and 330-Hz deviant tones were presented to the left ear, and 1000-Hz standards and 1100-Hz deviants to the right ear of the subjects (P=0.425 for each standard, P=0.075 for each deviant). The subjects attended to a designated ear, and were to detect the deviants therein while ignoring tones to the other ear. Results: The auditory transient evoked 40-Hz responses elicited by both the attended and unattended standard tones were significantly suppressed by the 0.50 and 0.75 g/kg alcohol doses. Conclusions: Alcohol suppresses auditory transient evoked 40-Hz oscillations already with moderate blood alcohol concentrations. Given the putative role of gamma-band oscillations in cognition, this finding could be associated with certain alcohol-induced cognitive deficits. Received: 20 January 1999 / Final version: 9 August 1999     

Cholesterol metabolism and non-cholesterol sterol distribution in lipoproteins of type 1 diabetes: the effect of improved glycemic control

In type 1 diabetes, the ratios to cholesterol of serum absorption markers, e.g., cholestanol, are elevated and those of synthesis markers, e.g., lathosterol, are reduced suggesting perturbed cholesterol metabolism. We studied 17 subjects with type 1 diabetes in poor glycemic control at baseline to assess whether improvement of glycemic control affects lathosterol and cholestanol ratios to cholesterol and their distribution in lipoproteins. Cholesterol and the non-cholesterol sterols were assayed directly from serum, and free and ester fractions after thin-layer chromatographic separation of lipoprotein sterols with gas-liquid chromatography. After the 2-6 months follow-up, the mean value of HbA1(c) decreased from 10.8% to 8.6% (p=0.001). Even though the concentrations of serum and lipoprotein cholesterol remained unchanged, the serum lathosterol to cholesterol ratio increased by 28% (p<0.05) and the lathosterol/cholestanol proportion by 23% (p<0.05). The ratios of total and esterified lathosterol to cholesterol in serum, chylomicrons and LDL, and free lathosterol to cholesterol in serum and IDL, were negatively associated with HbA1(c) at baseline and after follow-up, suggesting that the better glycemic control, the higher was cholesterol synthesis. The absorption markers were less consistently associated with HbA1(c). About half of the serum lathosterol and cholestanol was carried in LDL and one-fourth to one-fifth in HDL, but the lathosterol ratios were roughly similar in all lipoproteins. In contrast, cholestanol accumulated in chylomicrons and HDL. Glycemic control did not affect the distributions of lathosterol and cholestanol. In conclusion, improvement in glycemic control increased cholesterol synthesis, but had no effect on cholesterol absorption as measured by the serum or lipoprotein cholestanol to cholesterol ratio. From a clinical point of view, the better the glycemic control, the more antiatherogenic cholesterol metabolism may be in type 1 diabetes.     

Structure of needs among persons with schizophrenia

Abstract Background The importance of needs assessment for service development has been widely recognised. Several studies have focused on the associations between ratings of needs by patients and staff and have found clear differences, especially concerning the unmet needs. Methods The present study is part of a Nordic Multicentre study that investigates the life and care of outpatients with a schizophrenia group illness in all the Nordic countries. The aim of this paper is to study the patterns of needs as identified by patients and staff according to the Camberwell Assessment of Needs (CAN). Quality of life, level of functioning, and psychiatric symptoms were assessed. Results The sample includes 300 patients, 194 (65%) men and 106 (35%) women. The factor analysis identified five factors for patients and four factors for staff in the questionnaire on ratings of needs. In four of the five patient-related factors a meaningful interpretation was possible, and the factors were named skills, illness, coping, and substance abuse. The staff-related factors were named skills, impairment, symptom, and substance abuse. There were significant associations between the sum scores constructed from the factors and measures of functioning level and symptoms. Conclusions It seems that the sum factor reflecting secondary needs was the most important of the identified factors among both patient and staff ratings. The item-by-item comparisons in previous studies have emphasised differences between patient and staff ratings, but our analysis of the structure of needs also found similarities in the structures and in the associations between the identified sum scores and measures of symptoms, functioning level, and quality of life.     

Temporal cortex dopamine D2/3 receptor binding in major depression

The aim of this study was to assess the dopamine function of the temporal cortex in major depressive disorder using [¹²³I]epidepride to image D_2/3 receptor binding sites. Ten major depressives and 10 healthy controls were selected from a general population sample for single-photon emission computed tomography imaging. Among the major depressives there was a strong bilateral correlation between the scores on the 21-item Hamilton Depression Rating Scale and D_2/3 receptor binding. Dopaminergic abnormalities may be present in the temporal cortices of major depressives.     

Dobutamine compensates deleterious hemodynamic and metabolic effects of vasopressin in the splanchnic region in endotoxin shock

BACKGROUND: Vasopressin is a potent vasopressor in septic shock, but it may impair splanchnic perfusion. We compared the effects of vasopressin alone and in combination with dobutamine on systemic and splanchnic circulation and metabolism in porcine endotoxin shock. METHODS: Twelve pigs were randomized to receive either vasopressin (VASO, n = 6) or vasopressin in combination with dobutamine (DOBU, n = 6) during endotoxin shock (E. coli endotoxin infusion). Endotoxin infusion rate was increased to induce hypotension after which vasoactive drugs were started. We aimed to keep systemic mean arterial pressure (MAP) >70 mmHg by vasopressin; the goal of dobutamine infusion was to prevent decrease in cardiac output often associated with vasopressin infusion. Regional blood flows, oxygen delivery and consumption, arterial and regional lactate concentrations were measured. RESULTS: Mean arterial pressure >70 mmHg was achieved in both the VASO and DOBU groups. After the primary decrease of cardiac output by vasopressin, systemic blood flow remained stable in vasopressin-treated animals. However, vasopressin as a monotherapy decreased portal venous blood flow. This was prevented by dobutamine. Vasopressin also induced splanchnic lactate release and arterial hyperlactatemia, which were not observed when dobutamine was combined with vasopressin. CONCLUSION: Dobutamine prevents adverse hemodynamic and metabolic effects of vasopressin in septic shock.     

N-Glucuronidation of some 4-arylalkyl-1H-imidazoles by rat, dog, and human liver microsomes.

N-Glucuronidation in vitro of six 4-arylalkyl-1H-imidazoles (both enantiomers of medetomidine, detomidine, atipamezole, and two other closely related compounds) by rat, dog, and human liver microsomes and by four expressed human UDP-glucuronosyltransferase isoenzymes was studied. Human liver microsomes formed N-glucuronides of 4-arylalkyl-1H-imidazoles with high activity, with apparent V(max) values ranging from 0.59 to 1.89 nmol/min/mg of protein. In comparison, apparent V(max) values for two model compounds forming the N-glucuronides 4-aminobiphenyl and amitriptyline were 5.07 and 0.56 nmol/min/mg of protein, respectively. Atipamezole showed an exceptionally low apparent K(m) value of 4.0 microM and a high specificity constant (V(max)/K(m)) of 256 compared with 4-aminobiphenyl (K(m), 265 microM; V(max)/K(m), 19) and amitriptyline (K(m), 728 microM; V(max)/K(m), 0.8). N-Glucuronidation of medetomidine was highly enantioselective in human liver microsomes; levomedetomidine exhibited a 60-fold V(max)/K(m) value compared with dexmedetomidine. Furthermore, two isomeric imidazole N-glucuronides were formed from dexmedetomidine, but only one was formed from levomedetomidine. Dog liver microsomes formed N-glucuronides of 4-arylalkyl-1H-imidazoles at a low rate and affinity, with apparent V(max) values ranging from 0.29 to 0.73 nmol/min/mg of protein and apparent K(m) values from 279 to 1640 microM. Rat liver microsomes glucuronidated these compounds at a barely detectable rate. Four expressed human UDP-glucuronosyltransferase isoenzymes (UGT1A3, UGT1A4, UGT1A6, and UGT1A9) were studied for 4-arylalkyl-1H-imidazole-conjugating activity. Only UGT1A4 glucuronidated these compounds at an activity of about 5% of that measured for 4-aminobiphenyl. The observed activity of UGT1A4 does not explain the high efficiency of glucuronidation of 4-arylalkyl-1H-imidazoles in human liver microsomes.     

Quality of myocardial perfusion single-photon emission tomography imaging: multicentre evaluation with a cardiac phantom

The aim of the study was to evaluate quality of myocardial perfusion single-photon emission tomography (SPET) imaging in Finnish hospitals. Nineteen nuclear medicine departments participated in the study. A myocardial phantom simulating clinical stress and rest conditions was filled with routinely used isotope solution (technetium-99m or thallium-201). The cardiac insert included three reversible defects (simulating ischaemia): 30×30×14 mm³ septal (90% recovery at rest), 30×20×14 mm³ posterobasal (full recovery) and 20×20×14 mm³ lateral (full recovery). There were two fixed defects (simulating infarct): 30×20×14 mm³ postero-apical and 10×10×6 mm³ apical. The phantom was imaged and interpreted as a myocardial perfusion patient. Reconstruction, printout and reporting were performed according to the clinical routine of each centre. Three nuclear medicine specialists anonymously evaluated the quality of the image sets. The visual scores of the experts were ranked from 1 to 5. Additionally, points from 0 to 8 were given to research reports according to how well perfusion defects were detected. Quantitative points were calculated by comparing background-subtracted and -normalized counts from 12 regions of interest between stress and rest images. Results for technetium studies (12 departments) were better than those for thallium (7 departments). The average visual scores of the experts were 3.7±0.9 for all image sets, 3.2±0.5 for thallium users and 3.9±0.6 for technetium users (P=0.003). Five laboratories received a low score which, according to the specialists, is barely sufficient for limited clinical use. Average points for the reports were 5.6±2.1, 4.9±1.5 and 6.5±1.7 (P=0.051), and for the quantitation 8.2±1.0, 7.9±0.4 and 8.4±1.1 (P=0.185), respectively. Seven out of 22 interpreters did not detect the lateral 20×20×14 mm³ defect; five of them used thallium. This study demonstrated the heterogeneity of myocardial perfusion SPET in Finland. The participating laboratories used a wide scale of methods and, sometimes, inappropriate imaging protocols. The need for quality assurance in nuclear cardiology, correct use of SPET instrumentation and objective comparison of clinical studies is evident. The method described is suitable for external quality assurance and quality improvement of myocardial SPET imaging, and is recommended for regular use in nuclear medicine. Reiceived 15 March and in revised form 9 May 1999