Immunohistochemical assessment of the peripheral benzodiazepine receptor in breast cancer and its relationship with survival.

PURPOSE: The peripheral benzodiazepine receptor (PBR) expression has been shown dramatically increased in neoplastic tissues and tumor cell lines originated from ovary, liver, colon, breast, or brain relative to untransformed tissues. Its expression has been also associated with tumor progression and aggressiveness. To explore whether PBR expression level could be of prognostic value in invasive breast cancer, we studied a series of 117 patients who underwent surgery for primary breast carcinomas and were followed-up for 8 years. EXPERIMENTAL DESIGN: Using an immunohistochemical approach, we first compared PBR expression in normal and tumoral tissues, then we studied PBR expression together with clinicopathological variables (histological type, histological grade, lymph node, estrogen and progesterone receptor status), and biological markers such as BclII, Ki-67, and HER2/Neu. RESULTS: Our results revealed a significant increase of PBR expression in tumoral versus normal breast cells. We found a negative correlation between PBR expression and estrogen receptor status (P = 0.03) as well as a positive correlation between PBR and Ki-67 (P = 0.044). Although the disease-free survival was not affected by PBR in the whole population, high PBR expression level was significantly correlated with a shorter disease-free survival in the lymph node-negative patients, P = 0.038. CONCLUSIONS: As the axillary lymph node-negative status is generally considered as a good prognosis factor, the high expression of PBR in this patient subgroup may be used to identify a new high risk population, for which a more specific therapy would be beneficial.

Assessment of outcome by EC/IC bypass with 123I-iomazenil brain SPECT.

We report two patients with occlusive cerebrovascular disease who were examined by means of benzodiazepine receptor SPECT(BZR-SPECT) with 123I-iomazenil (IMZ) before extracranial-intracranial bypass surgery (EC/IC bypass). Preoperative low perfusion areas detected by cerebral blood flow SPECT (CBF-SPECT) were divided into two parts on BZR-SPECT images. In the low perfusion areas where the BZR were preserved, regional cerebral blood flow (rCBF) increased on postoperative CBF-SPECT, but where the BZR were not preserved, rCBF did not increase on postoperative CBF-SPECT. On visual inspection, the SPECT images of postoperative CBF-SPECT appeared similar to those of preoperative BZR-SPECT. For evaluation of the ischemic brain condition itself, instead of the cerebral metabolism, the distribution and activity of cerebral neurons indicated by BZR-SPECT with IMZ might be utilized.

Assessment of the peripheral benzodiazepine receptors in human gliomas by two methods.

This study was designed to evaluate the density of peripheral benzodiazepine receptor (PBR) sites as a function of tumor malignancy in human gliomas, and to compare the results obtained with autoradiographic and liquid scintillation measurements performed on the same tissue specimens. In vitro binding of [3H]PK-11195[1-(2-chlorophenyl)-N-methyl-(1-methylpropyl)-3-isoguinol ine carboxamide] to human gliomas in radioligand binding studies revealed a significantly higher level (about 3 fold) of PBR binding sites in both low grade and high grade gliomas as compared to normal cortex. The Bmax (mean +/- SD) of high and low grade gliomas, when entire tissue sections were measured by autoradiography, was 5.5 +/- 0.3 pmol/mg-tissue (n = 5) and 1.8 +/- 0.9 pmol/mg-tissue (n = 6), respectively, although it was evident that there was area of hot spots in the high grade tumors. This difference was significant (p < 0.05; two-tailed t-test). Similarly, the KD values (dissociation constant; nM) between the high (KD = 20.4 +/- 1.3 nM) and low (KD = 14.3 +/- 2.1 nM) grade gliomas were significantly different. A significant difference in binding site density (Bmax) between the two types of gliomas was also obtained in liquid scintillation measurements. The hot spot areas which showed the most intense binding of [3H]PK-11195 had KD of 24.5 +/- 1.0 nM and Bmax of 6.2 +/- 0.42 pmol/mg-tissue, values significantly higher (p < 0.05, two-tailed t-test) than those obtained when the entire tissue section was measured. The data on the Bmax/KD ratios presented here suggest that it might be possible to differentiate high from low grade gliomas in human by in vivo imaging with 11C-labelled PK-11195.

Tracer kinetic modelling of receptor data with mathematical metabolite correction.

Quantitation of metabolic processes with dynamic positron emission tomography (PET) and tracer kinetic modelling relies on the time course of authentic ligand in plasma, i.e. the input curve. The determination of the latter often requires the measurement of labelled metabolites, a laborious procedure. In this study we examined the possibility of mathematical metabolite correction, which might obviate the need for actual metabolite measurements. Mathematical metabolite correction was implemented by estimating the input curve together with kinetic tissue parameters. The general feasibility of the approach was evaluated in a Monte Carlo simulation using a two tissue compartment model. The method was then applied to a series of five human carbon-11 iomazenil PET studies. The measured cerebral tissue time-activity curves were fitted with a single tissue compartment model. For mathematical metabolite correction the input curve following the peak was approximated by a sum of three decaying exponentials, the amplitudes and characteristic half-times of which were then estimated by the fitting routine. In the simulation study the parameters used to generate synthetic tissue time-activity curves (K1-k4) were refitted with reasonable identifiability when using mathematical metabolite correction. Absolute quantitation of distribution volumes was found to be possible provided that the metabolite and the kinetic models are adequate. If the kinetic model is oversimplified, the linearity of the correlation between true and estimated distribution volumes is still maintained, although the linear regression becomes dependent on the input curve. These simulation results were confirmed when applying mathematical metabolite correction to the [11C]iomazenil study. Estimates of the distribution volume calculated with a measured input curve were linearly related to the estimates calculated using mathematical metabolite correction with correlation coefficients >0.990. However, the slope of the regression line displayed considerable variability among the subjects (0.33-0.95), demonstrating that absolute quantitation of the distribution volume was impaired. Mathematical metabolite correction is a feasible method and may prove useful in cases where actual metabolite data cannot be obtained. The potential for absolute quantitation seems limited, but the method allows the quantitative assessment of regional ratios of receptor measures.