Comparison of F-18 FET-PET with F-18 FDG-PET for biopsy planning of non-contrast-enhancing gliomas.

OBJECTIVE: The management of non-contrast-enhancing brain tumours largely depends on biopsy, which allows a differentiation of low-grade gliomas (LGG) from high-grade gliomas (HGG). The aim of this study was to compare positron emission tomography using 2-[(18)F]-fluoro-2-deoxy-D: -glucose (FDG-PET) and O-(2-[(18)F]-fluoroethyl)-L: -tyrosine (FET-PET) in terms of providing target regions for biopsies. MATERIALS AND METHODS: Fifteen consecutive patients with newly diagnosed brain tumours (n = 11) or suspected recurrence of a known LGG (n = 4), in whom MRI demonstrated no contrast enhancement, were studied by both FET-PET and FDG-PET. FET-PET, FDG-PET and MRI data were fused, and then transferred to the neurosurgical navigation system, prior to neurosurgical interventions. RESULTS: Histology showed HGG (WHO grade III) in 6/15 and LGG (WHO grade II) in 9/15 patients. FET-PET revealed an increased intratumoural tracer uptake in 8/9 LGG and in 5/6 HGG. FDG-PET depicted hypermetabolic spots in 2/9 LGG and in 4/6 HGG. In 6 patients we observed an increased intratumoural uptake of both tracers. In 4 of them, the area of highest FET accumulation in the tumour corresponded to the focus of increased FDG uptake. CONCLUSIONS: FET-PET appears to be superior to FDG-PET for biopsy planning in non-contrast-enhancing brain tumours. FDG-PET does not provide any additional information in this issue.

Implication of macrophages in tumor rejection induced by CpG-oligodeoxynucleotides without antigen.

Phosphorothioate oligodeoxynucleotides containing CpG motifs (CpG-ODNs) display broad immunostimulating activity and have potential applications in cancer immunotherapy. To investigate the antitumor activity of CpG-ODNs and to study the role of macrophages and lymphocytes in tumor rejection, CpG-ODN's effects on 9 L glioma cells were assessed in Fisher rats, depleted or not in macrophages, in nude mice, and in SCID mice. In nondepleted rats, intratumoral injections with 100 microg of CpG-ODNs on days 5, 12, and 19, after s.c. 9 L cell inoculations, resulted in an 84% reduction of the tumor volumes, when compared with controls injected with saline (P < 0.0001). Whereas all control animals developed tumors, more than one-third of the treated rats remained tumor free. Rejection of established glioma induced a specific long-term immunity, as cured rats were protected against a subsequent 9 L injection, but not a RG2 cell inoculation, another syngenic glioma in Fischer rats. Macrophages played a critical role in the early phase of tumor rejection, because the CpG-ODN's effects were significantly decreased in the rats depleted in macrophages, and none of the macrophage-depleted rats treated with CpG-ODNs rejected the tumor. On the contrary, both nude and SCID mice, which have normal innate immunity, showed a significant decrease of tumor volume when treated with CpG-ODNs when compared with controls. T cells were however involved in a later phase of the tumor rejection, as all nude mice eventually developed tumors despite the initial tumor growth inhibition. Altogether, these data suggest that immunostimulatory CpG-ODNs induced tumor rejections through an early activation of innate immunity and priming of a specific immune response against glioma cells.

Characterization and measurement of cytoplasmic and nuclear oestradiol-17 beta-receptor proteins in benign hypertrophied human prostate.

The demonstration and partial characterization of a high-affinity saturable binding component for oestradiol-17 beta in the cytosol and nuclear extract of the benign hypertrophied human prostate is reported. This binding component was found to precipitate with protamine sulphate and to exhibit marked specificity for oestradiol and diethylstilboestrol (DES) but not dihydrotestosterone (DHT) or progesterone. Analysis of oestradiol-labelled cytosol on low ionic strength glycerol gradients revealed a binding component with a sedimentation coefficient of 4S which was inhibited with DES but not DHT and destroyed either by preheating labelled cytosol at 45 degrees C for 30 min or by treatment with the sulphydryl blocking agent, parachloromercureobenzoate. The oestradiol-binding complex precipitated by ammonium sulphate was found to have an isoelectric point (pI) of 6.3 as analysed on polyacrylamide-gel plates. The oestradiol-binding component in the nuclear extract also exhibited similar steroid specificity and sedimented with a coefficient of 2.8S on high ionic strength glycerol gradients. Isoelectric focusing of the heparin-extracted nuclear oestradiol-binding complex revealed a pI of 6.0. The dissociation constants (Kd) and the concentrations of the cytoplasmic and nuclear oestradiol-binding sites in 19 samples of benign hypertrophied prostates were estimated by Scatchard plot analyses. The mean Kd and concentration of binding sites in the cytosol were 2.9 +/- 2.6 (S.D.) nmol/l and 11.7 +/- 8.4 fmol/mg protein respectively. The corresponding values for nuclear extract were 4.1 +/- 7.5 nmol/l and 347.1 +/- 415.5 fmol/mg DNA respectively. There was no significant difference between the mean concentration of oestradiol-binding sites in the two cellular fractions.

[Subacute neuropathy, multiple cancers, and Gougerot-Sjögren syndrome: contribution of anti-Hu antibody]. / Neuropathie subaiguë, cancers multiples et syndrome de Gougerot-Sjögren: intérêt des anticorps anti-Hu.

We report the case of a patient presenting a subacute, predominantly sensory neuropathy. The work up revealed a Sjögren's syndrome and a breast carcinoma. The presence of anti-Hu antibodies, identified by Western Blot using purified recombinant HuD protein, and the absence of the Hu antigen in the breast carcinoma ruled out the responsibility of the Sjögren's syndrome or breast carcinoma. In this context, the most likely diagnosis was a subacute neuropathy associated with small cell lung cancer, which was indeed discovered 3 years later.

Combined temozolomide and sunitinib treatment leads to better tumour control but increased vascular resistance in O6-methylguanine methyltransferase-methylated gliomas.

INTRODUCTION: Combined antiangiogenic and cytotoxic treatment represents an appealing treatment approach for malignant glioma. In this study we characterised the antitumoural and microvascular consequences of sunitinib (Su) and temozolomide (TMZ) therapy and verified the ideal treatment protocol, with special focus on a potential therapeutic window for combined scheduling. MATERIALS AND METHODS: O(6)-Methylguanine methyltransferase (MGMT) status was analysed by pyrosequencing. Tumour growth of subcutaneous xenografts was assessed under different treatment protocols (TMZ, SU, SU followed by TMZ, TMZ followed by SU, combined TMZ/SU). Intravital microscopy (dorsal skinfold chamber model) assessed microvascular consequences. Immunohistochemistry included tumour and endothelial cell proliferation, apoptosis and vascular pericyte coverage. Real-time polymerase chain reaction (RT-PCR) analysed the expression of angiogenesis-related pathways in response to therapy. RESULTS: Combined TMZ/SU resulted in significantly reduced tumour growth compared to either monotreatment (TMZ: 106 ± 13 mm(3); SU: 114 ± 53 mm(3); TMZ/SU: 34 ± 7 mm(3)) by additional antiangiogenic effects and synergistic induction of apoptosis versus TMZ monotreatment. Sequential treatment protocols did not show additive antitumour responses. TMZ/SU aggravated vascular resistance mechanisms characterised by significantly higher blood flow rate (TMZ: 74 ± 34 µl/s; SU: 164 ± 36 µl/s; TMZ/SU: 254 ± 95 µl/s), reduced permeability (TMZ: 1.05 ± 0.02; SU: 0.99 ± 0.07; TMZ/SU: 0.89 ± 0.05) and recovery of pericyte-endothelial interactions (TMZ: 89 ± 7%; SU: 67 ± 9%, TMZ/SU:80 ± 10%) versus either monotreatment. Vascular resistance was paralleled by an increase in Ang-1 and Tie-2 and by the downregulation of Dll4. CONCLUSION: Sequential application of TMZ and SU in the angiogenic window does not add antitumour efficacy to monotherapy. Simultaneous application yields beneficial tumour control due to additive antiangiogenic and proapoptotic effects. Combined treatment may aggravate pericyte-mediated vascular resistance mechanisms by altering Ang-1-Tie-2 and Dll4/Notch pathways.

Relationship between prostatic cytoplasmic and nuclear androgen receptors in patients with carcinoma of the prostate.

Cytoplasmic and nuclear androgen receptors were measured in benign prostatic hypertrophy, untreated malignant prostates and diethylstilboestrol-treated malignant prostates. The levels of total androgen receptors in benign prostatic hypertrophy were not statistically different from those in the untreated or treated malignant prostates. Free cytoplasmic androgen receptors constituted only a small proportion of the total receptor concentration. A significantly higher level of free cytoplasmic receptors were present in the treated malignant prostates in comparison to the untreated ones. A significant positive correlation was observed between the total cytoplasmic and nuclear androgen receptors in both treated and untreated patients. A significant correlation was also observed between free cytoplasmic and total nuclear androgen receptors in untreated patients.

Androgen receptors in the prostate of the Rhesus monkey.

The presence of an androgen receptor protein in the supernatant preparation of the prostate from Rhesus monkey (macaca mulatta) is described. The molecular weight of this receptor protein was found to be 2.8 - 2.9 X 10(5) daltons. The levels of free and bound androgen receptors were measured in the caudal and cranial lobes of the prostate by an exchange assay using methyltrienolone (R1881). The concentration of the free binding sites in the caudal lobe ranged between 3.7 - 23.7 fmol/mg proteial binding sites in the caudal lobe ranged between 36.0 - 112.7 and in the cranial between 21.2 - 55.0 fmol/mg. The bound receptor ranged between 43.3 - 109.0 and 19.1 - 47.3 fmol/mg protein for caudal and cranial lobes respectively. The level of both bound and free receptors was found to be significantly higher in the caudal lobe. This data suggests that the two lobes of the prostate in the Rhesus monkey can be equated with the two zones of the human prostate in respect of androgen responsiveness.

Receptor proteins for androgens in prostatic disease.

The suitability of an exchange assay with methyltrienolone (R1881) for the measurement of androgen receptors in human prostatic tumours has been investigated. Having established the specificity of this compound for androgen receptor assay, a pilot study was carried out to measure dihydrotestosterone (DHT) receptor in 27 cases of benign hypertrophy and 18 cases of malignant tumour of the prostate.