Clinical efficacy of dual-phase scanning using (68)Ga-DOTATOC-PET/CT in the detection of neuroendocrine tumours.

AIM: To investigate whether delayed scanning at approximately 90 minutes post-injection of (68)Ga-labelled 1,4,7,10-tetraazacyclododecane-N,N',N″,N‴-tetraacetic acid-d-Phe(1)-Tyr(3)-octreotide (DOTATOC) had any clinical benefits regarding the evaluation of neuroendocrine tumours (NETs), relative to conventional combined positron-emission tomography (PET) and computed tomography (CT) at 60 minutes post-injection. MATERIALS AND METHODS: Fifty-four patients who underwent DOTATOC-PET/CT for suspected or known NETs were retrospectively reviewed. PET/CT was performed twice at approximately 60 and 90 minutes post-injection. For visual analysis, a five-point grading scale (0: definitely normal to 4: definitely abnormal) was used, and grade 3-4 lesions were regarded as positive. For quantitative analysis, the time course of the maximum standardised uptake value (SUVmax) in each lesion and the mean SUV of physiological uptake in the liver were evaluated. RESULTS: Of the 54 patients, 43 had a total of 132 lesions. In interpreting the early images, there were four grade 3 lesions, and the remaining 128 lesions were grade 4. All 132 lesions were grade 4 in the delayed images. SUVs and tumour-to-liver ratios for hepatic lesions were slightly higher in delayed scanning than in early scanning (SUV, 26.8±21.2 versus 28.2±21.2 [p<0.01]; tumour-to-liver ratio, 5.9±4.5 versus 6.2±4.6 [p<0.01]), which did not affect the detection rate. Additionally, bone and peritoneal metastases had slightly higher SUVs at delayed imaging (p<0.05), but there was no difference in diagnostic performance. No significant difference in the SUVs for pancreatic lesions and primary sites in the bowel were observed between the early and delayed scans. CONCLUSION: Delayed scanning may be helpful for improving diagnostic confidence in some cases, although it provided no specific merits for diagnostic accuracy in detecting primary or metastatic NETs.

Alternaric acid stimulates phosphorylation of His-tagged RiCDPK2, a calcium-dependent protein kinase in potato plants.

Calcium-dependent protein kinases (CDPK) are an essential component of plant defense mechanisms against pathogens. We investigated the effect of alternaric acid, a host-specific toxin produced by the plant fungal pathogen Alternaria solani (Pleosporaceae), on a putative plasma membrane and cytosolic kinase RiCDPK2 of potato (Solanum tuberosum) and on hypersensitive cell death of host potato cells. Alternaric acid, in the presence of Ca²âº and Mg²âº, stimulated in vitro phosphorylation of His-tagged RiCDPK2, a Ca²âº-dependent protein kinase found in potato plants. We concluded that Ca²âº and Mg²âº play an important role in the interaction between alternaric acid and RiCDPK2. Based on our observations, alternaric acid regulates RiCDPK2 kinase during the infection process in an interaction between host and A. solani, leading to the inhibition of hypersensitive cell death in the host. We suggest that alternaric acid is a primary determinant by which A. solani stimulates CDPK activity in the host, suppressing hypersensitive cell death.

Dynamic micro-magnetic resonance imaging of liver micrometastasis in mice with a novel liver macromolecular magnetic resonance contrast agent DAB-Am64-(1B4M-Gd)(64).

DAB-Am64-(1B4M-Gd)(64) is a newly synthesized macromolecular liver magnetic resonance imaging (MRI) contrast agent with a polypropylenimine diaminobutane (DAB) dendrimer conjugated with a bifunctional diethylenetriaminepentaacetic acid (DTPA) derivative for complexing Gd(III) atoms. The characteristics of DAB-Am64-(1B4M-Gd)(64), which quickly accumulated in the liver, have been reported recently. In the present study, the dynamic micro-MRI with DAB-Am64-(1B4M-Gd)(64) was obtained in the mouse liver metastasis model using colon carcinoma cells to evaluate the ability to visualize the micrometastatic tumors compared with that using Gd-DTPA. The dynamic micro-MRI with DAB-Am64-(1B4M-Gd)(64) was able to homogeneously enhance the normal liver parenchyma and visualize micrometastatic tumors of 0.3-mm diameter in the liver of the mice with better contrast than that with Gd-DTPA. In conclusion, DAB-Am64-(1B4M-Gd)(64) is a new liver MRI contrast agent potentially useful for diagnosis of micrometastasis in the liver.

Variability in coronary hemodynamics in response to ergonovine in patients with normal coronary arteries and atypical chest pain.

Because an increase in coronary vascular resistance in response to ergonovine maleate has been suggested as a possible diagnostic aid for variant angina, changes were evaluated in coronary hemodynamics and serial myocardial thallium-201 perfusion scans in 15 patients without angina and with normal coronary arteries in response to ergonovine (0.05, 0.10 and 0.20 mg intravenously). For the group, heart rate-blood pressure product increased significantly (p less than 0.001) without any change in coronary sinus flow, coronary vascular resistance, myocardial oxygen extraction, arterial-coronary sinus oxygen difference and lactate extraction. In 7 of 15 patients, however, coronary vascular resistance increased (mean 39%, range 11 to 75%, probability [p] less than 0.001), and coronary sinus flow decreased (14%, p less than 0.001), despite an increase in heart rate-blood pressure product (36%, p less than 0.02). No electrocardiographic, metabolic or thallium-201 scan abnormalities occurred. Therefore, significant increases in coronary vascular resistance in response to ergonovine may occur in patients with normal coronary arteries and atypical chest pain.

Tumor targeting and imaging of intraperitoneal tumors by use of antisense oligo-DNA complexed with dendrimers and/or avidin in mice.

To establish an effective nonviral gene delivery and a corresponding imaging method for i.p.-disseminated tumors, various oligonucleotide-carrier complexes were synthesized, and their in vitro and in vivo properties were examined. The 20-mer multiamino-linked oligonucleotide (oligo), synthesized as antisense against the c-erbB-2 sequence, and the 3'-biotinylated form of the same oligonucleotide (oligo-Bt) were (111)In labeled through a diethylenetriaminepentaacetic acid chelate. (111)In-oligo was mixed with generation 4 polyamidoamine dendrimer (G4) or with biotinylated G4 (G4-Bt), which are positively charged to form electrostatic complexes. (111)In-oligo/G4-Bt and (111)In-oligo-Bt were conjugated to avidin ((111)In-oligo/G4-Av and (111)In-oligo-Av, respectively). (111)In-oligo/G4, (111)In-oligo/G4-Av, (111)In-oligo-Av, and carrier-free (111)In-oligo (2.96 kBq/22.4-45.9 ng of oligo) were examined for internalization in vitro in human ovarian cancer cells (SHIN3). Biodistribution of (111)In-oligo-carrier complexes or (111)In-oligo was examined in normal (n = 4-7) or i.p. SHIN3 tumor-bearing (n = 6-10) mice 2-24 h after i.p. injection (74 kBq/125-300 ng). Scintigraphy of i.p. tumor-bearing and normal mice was performed at various times postinjection of (111)In-oligo-carrier complex or (111)In-oligo (1.85 MBq/2.2 ng). (111)In-oligo-carrier complexes bound to the tumor cells were internalized at a rate of 34-56% at 24 h. In vivo, G4, G4-Av, and Av significantly enhanced tumor delivery of (111)In-oligo [9.1, 14.5, and 24.4% of injected dose per g of tissue (ID/g) at 24 h; P < 0.05, < 0.01, and < 0.0001, respectively] compared with delivery without carrier (0.8% ID/g). Scintigrams of (111)In-oligo delivered to the i.p.-disseminated tumors by the carriers were successfully obtained. In conclusion, G4, G4-Av, and Av can effectively deliver (111)In-oligo to i.p.-disseminated tumors. (111)In-oligo-carrier complexes also have potential as tracers for imaging and monitoring of gene delivery.

Enhancement of the therapeutic outcome of radio-immunotherapy by combination with whole-body mild hyperthermia.

To enhance the effect of radio-immunotherapy for solid cancers, whole-body mild hyperthermia was added, and its effects on the pharmacokinetics of radiolabelled antibody, outcome of radio-immunotherapy, and radiosensitivity of the tumour were investigated. Nude mice bearing human colon cancer xenografts were heated to 40 degrees C for 3 or 6 h. After heating, mice received intravenous (i.v.) injections of [131I]-labelled anti-carcinoembryonic antigen (CEA) monoclonal antibody. Although 6-h heating did not alter the biodistribution of the radiolabelled antibody, and alone did not show any therapeutic effect on tumour growth, when combined with radio-immunotherapy, the therapeutic effect on tumour growth was significantly enhanced. Three-hour heating also significantly enhanced the effect of radio-immunotherapy. Colony formation assay showed that the radiosensitivity of the tumour was significantly enhanced after heating, which was achieved by a reduction of the hypoxic fraction of the tumour. In conclusion, the addition of whole-body mild hyperthermia significantly enhanced the therapeutic effect of radio-immunotherapy by increasing the radiosensitivity of the tumour.

Establishment and characterization of a breast cancer cell line expressing Na+/I- symporters for radioiodide concentrator gene therapy.

UNLABELLED: 131I therapy is a widely accepted treatment for metastatic differentiated thyroid cancer. To investigate the feasibility of 131I therapy for breast cancer, we established breast cancer cells stably expressing Na-/I- symporter (NIS) gene that can be modulated and studied in vitro and in vivo. METHODS: We transfected rat NIS genes into a human breast cancer cell line (MCF7) by electroporation. Iodide accumulation was evaluated under various extracellular concentrations of sodium and iodide, and iodide efflux was also assessed. Biodistribution and tumor imaging were studied using tumor-bearing mice. RESULTS: A novel cell line (MCF3B), stably expressing the NIS gene, was established from MCF7. MCF3B took up 44 times more radioiodide in vitro than MCF7 did. Iodide uptake was completely inhibited by 1 mmol/L perchlorate and was dependent on external sodium and iodide concentrations. Iodide efflux from MCF3B cells was slower (half-life [T 1/2] > 27 min) than from FRTL5 thyroid cells (T 1/2 = 4 min). In the biodistribution study using MCF3B-xenografted mice, high tumor uptake of 125I was shown (16.73%) at 1 h after injection, and tumor-to-normal tissue ratios were also high (4.84-21.28), except in the stomach (0.47). However, the iodide accumulation in the tumor lessened with time, reaching less than 1% at 24 h after injection. CONCLUSION: Our preliminary data indicate that NIS-based gene therapy may be applied by concentrating a lethal dose of radiation in tumor cells in vivo, but further investigation is necessary to determine a method of maintaining radioiodine in the cells to allow greater therapeutic effects.

Exercise-induced coronary arterial spasm: angiographic demonstration, documentation of ischemia by myocardial scintigraphy and results of pharmacologic intervention.

Exercise-induced coronary arterial spasm is an infrequently recognized phemonemon whose mechanism and management are not well established. In two patients with reproducible exercise-induced S-T segment elevation and angina pectoris thallium-201 scintigraphy showed areas of reversible anteroapical hypoperfusion, and gated radionuclide ventriculography revealed anteroapical hypokinesia with a decrease in left ventricular ejection fraction at peak exercise. During coronary arteriography supine exercise provoked occlusive spasm of the left anterior descending coronary artery, which at rest had only minimal plaques. Consequently, treadmill testing was performed with five different pharmacologically provoked interventions: direct vasodilatation (nitrates), alpha adrenergic blockade (phenmoxybenzamine), beta adrenergic blockade (propranolol), calcium flux blockade (verapamil), and prostaglandin inhibition (indomethacin). Exercise-induced coronary arterial spasm, manifested as S-T segment elevation and angina, was prevented by nitrates, but was not eliminated by short-term oral administration of an alpha or beta blocking agent, a calcium antagonist or a prostaglandin inhibitor. Further, beta adrenergic blockade appeared to be detrimental. Thus, this study demonstrates (1) that coronary arterial spasm may be the underlying mechanism of at least some cases of exertional angina associated with transient perfusion deficits and left ventricular dysfunction, and (2) that it may be prevented by oral nitrates.

Analysis of the vasodilator action of alprenolol.

The effect of alprenolol and other beta-adrenoceptor antagonists, including d-isomers, on blood flow in femoral, coronary and mesenteric vascular beds was measured in anesthetized dogs. Under conditions of constant perfusion pressure, intra-arterial injection of beta-adrenoceptor antagonists produced vasodilation. Propranolol and alprenolol were approximately equipotent in coronary and mesenteric beds but alprenolol was significantly more potent in the femoral bed. Practolol was virtually inactive in all beds. The vasodilating potency of d-alprenolol and d-propranolol was not significantly different from that of the respective racemic mixtures. The vasodilator response to alprenolol was not affected by pretreatment with atropine, diphenhydramine or propranolol. In conscious normotensive dogs i.v. injections of d,l- and d-alprenolol produced dose-dependent decreases in blood pressure and increases in heart rate. Under similar conditions, i.v. d,l-propranolol was without effect on either measurement. The results suggest that the hypotensive action of alprenolol in dogs may derive from its vasodilator activity.

Duration and selectivity in beta-adrenoceptor blocking action of a beta-adrenoceptor blocking drug, D-32 in conscious dogs.

In conscious dogs, the selectivity and duration of beta-blocking activity, and serum concentration of a beta-blocking agent, D-32 [dl-1-tert-butylamino-3-(2,3-dimethylphenoxy)-2-propanol hydrochloride] was compared to that of propranolol, pindolol, atenolol and IPS-339 [dl-1-tert-butylamino-3-(-9-fluorenylideneaminoxy)-2-propanol hydrochloride]. Ratios of doses causing a 50% inhibition of tachycardia to that on hypotension induced by isoprenaline were as follows: D-32 (0.69), propranolol (0.67), atenolol (0.03) and IPS-339 (6.3). Thus, present experiments indicate that, unlike atenolol and IPS-339, D-32, propranolol and pindolol are non-selective beta-adrenoceptor blocking agents. Atenolol and IPS-339, however, selectively blocked cardiac beta1, receptors and vascular beta2-receptors respectively, as would be expected. In an optimal dose range these two drugs can be used satisfactorily as a pharmacological tool for inhibiting responses mediated via the respective beta-receptors. After oral administration, the pharmacological half-life (time required for 50% recovery of beta-blocking action) was 15.8 +/- 4.5 h for propranolol (3 mg/kg), 21.8 +/- 6.4 h for D-32 (0.5 mg/kg), 30.5 +/- 3.1 h for atenolol (6 mg/kg) and 30-35 h for pindolol (0.2 mg/kg). The pharmacological half-life after i.v. administration was 4.4 +/- 0.7 h for propranolol (300 microgram/kg) and 5.9 +/- 0.4 h for D-32 (150 microgram/kg), whereas the serum half-like (time required for 50% decrease in serum concentration) of propranolol was 1.4 h and that of D-32 was 1.3 h. The values for pharmacological half-life and serum half-life were significantly different. Thus, for determination of administration frequency and dosage of beta-adrenoceptor blocking drugs, not only pharmacokinetic but also pharmacological data (duration of action) are essential.

Role of beta 2-adrenoceptor blockade and circulating adrenaline level for the pressor responses to beta-adrenoceptor blocking drugs in rats.

The present experiments were designed to elucidate what mechanism(s) would be responsible for beta-adrenoceptor blocking drugs (beta-blockers)-induced pressor responses in rats. In urethane-anaesthetized rats, 6 beta-blockers at i.v. doses ranging from 0.3 to 300 micrograms/kg evoked the pressor response in a dose-dependent manner. The relative potency in causing the pressor action was correlated not to their beta 1-blocking activities (r = 0.374, P greater than 0.05) but to their beta 2-blocking ones (r = 0.856, P less than 0.05). In pithed or adrenalectomized rats with low levels of plasma catecholamines, however, propranolol failed to exert its sustained pressor action. Propranolol (300 micrograms/kg i.v.) distinctly potentiated the pressor responses not to noradrenaline but to adrenaline and to electrical stimulation of the sympathetic outflow (E.S.) in pithed rats. On the contrary, there was not any potentiation of pressor response to E.S. in pithed, adrenalectomized rats treated with propranolol (300 micrograms/kg i.v.). In rats treated with phenoxybenzamine (5 mg/kg i.v.), adrenaline was shown to have much more potent vasodilating action resulting from beta 2-stimulation than noradrenaline, the dose difference for causing the diastolic blood pressure decrease by a 25 mm Hg being almost 80 times. In pithed rats, infusion of adrenaline at the rate of 0.02 micrograms/min caused a significant increase in plasma adrenaline level from 0.02 +/- 0.01 to 0.45 +/- 0.048 ng/ml, being close to basal level obtained in urethane-anaesthetized rats. Under this situation, propranolol (1-100 micrograms/kg i.v.) showed a distinct pressor response in a dose-dependent fashion as observed in adrenal intact rats anaesthetized with urethane.(ABSTRACT TRUNCATED AT 250 WORDS)

Determination of small amounts of TBP and DBP in uranyl nitrate solutions.

Tri- and dibutylphosphate (TBP and DBP) in concentrated uranyl nitrate solution are determined by a method based on the solvent extraction of zirconium-95. The distribution ratio of zirconium-95 between dilute solutions of TBP and DBP in dodecane and 10M hydrochloric acid and 1Mnitric acid respectively is measured. There is a logarithmic relationship between the distribution ratio and concentration of TBP and DBP, which enables them to be determined rapidly and with an error of +/- 10% over the range 1-100ppm of TBP and 40-600 ppm of DBP. The lower limit is 0.5 ppm for TBP and 10 ppm for DBP.

Gravimetric determination of the abundance ratio of zirconium and hafnium, based on the in situ thermal decomposition of K(4)[(Zr,Hf)(C(2)O(4))(4)].5H(2)O.

Careful heating of K(4)[(Zr,Hf)(C(2)O(4))(4)].5H(2)O results in a two-step thermal decomposition which can be written as: K(4)[(Zr,Hf(C(2)O(4))(4)].5H(2)O --> K(4)[(Zr,Hf)(C(2)O(4))(4)] --> {2K(2)CO(3)+(Zr,Hf)O(2)}. The weight-ratio of the successive decomposition products depends on the abundance ratio of Zr and Hf, and forms the basis for the present method of gravimetric determination.

Prospective community evaluation of the signal-averaged electrocardiogram in predicting malignant ventricular arrhythmias: beneficial outcome with electrophysiology guided therapy.

The role of the signal-averaged ECG was prospectively assessed in 517 patients in whom there was a suspicion for malignant ventricular arrhythmias. Patients were divided into Group I with a normal surface QRS width less than 120 ms (426 patients) and Group II with a prolonged QRS duration greater than or equal to 120 ms (91 patients). Late potentials were present in 42 (10%) Group I patients and in 24 (26%) Group II patients. Programmed ventricular stimulation was performed for standard indications in 55 patients without late potentials and in 42 patients with late potentials, combining both groups. The sudden death or recurrent sustained ventricular tachycardia rate in follow-up was evaluated based on the presence or absence of late potentials and whether programmed ventricular stimulation was performed. In the patients without late potentials, these rates were 4 patients (1.0%) in the no EP group and 3 patients (5.5%) in the EP group (p less than .05), respectively (overall 1.6%). In the patients with late potentials, these rates were 7 patients (29%) in the no EP group and 7 patients (17%) in the EP group (p = .19), respectively (overall 21%). In addition, appropriate automatic defibrillator shocks were present in 1 patient without late potentials and in 8 patients with late potentials which were not included in the recurrent sudden death or sustained ventricular tachycardia statistics. The signal-averaged ECG accurately defines patients at a higher risk for malignant ventricular arrhythmias regardless of unfiltered QRS duration.(ABSTRACT TRUNCATED AT 250 WORDS)

The magnitude of exercise-induced ST segment depression and the predictive value of exercise testing.

The assess whether the magnitude of exercise induced ST segment depression improves the predictive values of symptom limited exercise tests, and helps in the recognition of patients with more severe coronary heart disease, 90 consecutive patients with positive treadmill tests who also underwent selective coronary arteriography were reviewed. The predictive value improved progressively with the increasing ST depression and was most reliable in a select group of patients with normal electrocardiographic baseline who were not receiving digitalis (73% with ST depression greater than or equal to 1 mm to 100% with ST depression greater than or equal to 4 mm). The incidence of 2 and 3 vessel disease increased from 61% with ST depression greater than or equal to 1 mm in the overall population to 100% with ST depression greater than or equal to 4 mm in the select group, and the incidence of left main trunk lesions increased, respectively from 6 to 30%. The prediction of 2 and 3 vessels disease was found to be significantly greater when patients were dichotomized into those with ST depression greater than or equal to 4 mm compared to less than 4 mm. It is concluded that the magnitude of ST segment depression definitely improves the predictive values of exercise tests as well as the ability to recognize the patients with more severe disease. However, the markedly positive exercise tests cannot be utilized to accurately predict the presence of 2 or 3 vessel disease in individual cases unless ST depression attains 4 mm or more in patients with normal electrocardiographic baseline who are not taking digitalis. In this group, the ability to predict left main trunk lesion is approximately 30%.

Hypopituitarism due to pituitary metastasis of lung cancer: case of a 21-year-old man.

A 21-year-old man presented persistent dry cough, general malaise, loss of appetite, decreased sexual desire and double vision. Chest radiograph revealed a mass shadow in the left upper lobe. Histopathological diagnosis of the tumor was squamous cell carcinoma. Brain computed tomography and magnetic resonance imaging revealed a metastasis to the pituitary gland. Hypopituitarism was diagnosed by pituitary function tests. Diabetes insipidus was absent and the function of the posterior lobe of the pituitary gland was preserved. Hypopituitarism due to pituitary metastasis is a rare complication of lung cancer, and has never been reported in a patient as young as 21 years old.

Diastolic mitral regurgitation in patients with hypertrophic cardiomyopathy.

An analysis of the left ventricular angiograms of 31 patients with hypertrophic cardiomyopathy revealed diastolic mitral regurgitation in 4, a prevalence of 12.9%. The clinical, echocardiographic, angiographic, and hemodynamic data of these patients were reviewed. Diastolic mitral regurgitation could not be attributed to arrhythmia, PR interval prolongation, atrioventricular dissociation, aortic insufficiency, or aortic stenosis. Reduced left ventricular compliance was evidenced by elevated end-diastolic pressure following angiography and reduced diastolic E-F slope on echocardiography. It is speculated that the rapid inflow of blood into a poorly compliant ventricle established a turbulent flow pattern that resulted in the "floating" of blood back into the left atrium.

[Clinical usefulness of fat suppression technique for MR cholangiopancreatography (MRCP)].

In order to obtain high quality of MRCP image, it is important to reduce the background signal intensity and increase the contrast of the pancreatobiliary ducts relative to surrounding fat tissue. The combination of long effective-TE and fat suppression technique including the short-TI inversion recovery and chemical-selective fat suppression enables to suppress the background signal intensity enough to obtain high quality MR cholangiopancreatogram. However, susceptibility artifacts from the metal, gastroduodenal gas, and vascular pulsation can be augmented by using the chemical-selective fat suppression technique, which may result in signal loss of the pancreatobiliary ducts. This potential diagnostic pitfalls can be avoided by interpreting the coronal source images obtained with long effective-TE and without fat suppression technique.

Heating characteristics with a re-entrant type applicator in consideration of tissue blood flow rate.

We have proposed the heating system based on a re-entrant cavity that can heat a localized deep region in a living body noninvasively. This system is superior in a local heating characteristic. However, when the living body was treated as a heating object during thermotherapy (hyperthermia), the effect of blood flow changes on a heating characteristic has to be examined. The purpose of this study was to establish the quantitative evaluation method of heating characteristics for a re-entrant type applicator. The numerical analyses by using three-dimensional finite element method in consideration of a blood flow and fundamental experiments with prototype system were carried out. Since the difference of numerical analyses and experiments was as small as about 4.2 [%] by evaluation with full width at half maximum (FWHM), the validity of this numerical analysis was confirmed.