Imaging features and clinical significance of perineural spread or extension of head and neck tumors

Perineural spread of head and neck tumors is a form of metastatic disease in which tumor disseminates to noncontiguous regions along the endoneurium or perineurium. Both computed tomography (CT) and magnetic resonance (MR) imaging can help detect perineural spread, although MR imaging is the modality of choice because of its multiplanar capability, its superior soft-tissue contrast, and the decreased amount of artifact from dental hardware. Perineural spread most commonly occurs in adenoid cystic carcinoma and squamous cell carcinoma. Nerve enlargement may lead to foraminal enlargement and, ultimately, to foraminal destruction, findings that are best seen at CT. Extension through the foramen ovale and involvement of the Meckel cave is best seen on coronal T1-weighted MR images, and nerve enhancement is best seen on fat-suppressed T1-weighted MR images. Other radiologic findings include obliteration of fat planes at foraminal openings, neuropathic atrophy, cavernous sinus enlargement, and replacement of the trigeminal subarachnoid cistern with soft tissue. The pathway of perineural tumor spread is predictable with knowledge of the pertinent cranial nerve anatomy; however, patients with radiologically or pathologically proved perineural spread may have normal nerve function at clinical examination. Therefore, it is imperative that the radiologist be familiar with both normal cranial nerve anatomy and the radiologic appearance and assessment of perineural tumor extension.     

Pharmacokinetics of tablet huperzine A in six volunteers

AIM: To study pharmacokinetics of tablet huperzine A (Hup-A) in Chinese volunteers to help establishing its drug administration schedule. METHODS: For 6 volunteers after a single oral dose of 0.99 mg, drug concentrations in plasma were assayed by reverse phase high pressure liquid chromatography (HPLC) at 0.5, 0.75, 1.0, 1.25, 1.5, 2, 4, 6, 8, and 10 h. The pharmacokinetic parameters were calculated with a 3P87 program by computer. RESULTS: The time course of plasma concentrations conformed to a one-compartment open model with a first order absorption. The pharmacokinetic parameters were as follows: T 1/2ka = 12.6 min, T 1/2ke = 288.5 min, Tmax = 79.6 min, Cmax = 8.4 micrograms L-1, AUC = 4.1 mg L-1 min. CONCLUSION: Hup-A was absorbed rapidly, distributed widely in the body, and eliminated at a moderate rate.     

The carcinogenic potential of the gas phase of environmental tobacco smoke

Female strain A/J mice were exposed to unfiltered or HEPA-filtered environmental tobacco smoke (ETS). Total suspended particulates (TSP) in the full smoke exposure chamber was 78.5 mg/m3 and in the filtered smoke chamber 0.1 mg/m3; nicotine concentrations in the full and filtered smoke chamber were 13.4 and 3.1 mg/m3, respectively. Animals exposed to filtered ETS (6 h a day, 5 days a week) and killed after 5 months had a higher lung tumor incidence and multiplicity than controls maintained in filtered air, although the differences were not statistically significant. Animals exposed to filtered and full ETS and allowed to recover in air for 4 months had an average of 1.2 +/- 0.3 tumors per lung and 1.3 +/- 0.3 tumors per lung, respectively. Air exposed control animals had an average tumor multiplicity 0.5 +/- 0.1 tumors per lung. Increased immunostaining for CYP 1A1 was not evident in the lung of animals exposed to filtered smoke. Based on the chamber concentrations of selected nitrosamines and polycyclic aromatic hydrocarbons, the possible maximum uptakes by the mice of NNK, NNN and benzo[a]pyrene during the 5 months exposure period were three to six orders of magnitude below doses reported in the literature to produce 1 lung tumor in strain A/J mice. It was concluded that the gas phase of ETS is as carcinogenic as is full ETS. The carcinogenicity of the gas phase may be due to some as yet unidentified, yet highly potent carcinogens or by placing a substantial, possibly free radical-mediated oxidative stress on the lung.     

Evidence for an alternative mechanism for maintaining telomere length in human tumors and tumor-derived cell lines

The gradual loss of DNA from the ends of telomeres has been implicated in the control of cellular proliferative potential. Telomerase is an enzyme that restores telomeric DNA sequences, and expression of its activity was thought to be essential for the immortalization of human cells, both in vitro and in tumor progression in vivo. Telomerase activity has been detected in 50-100% of tumors of different types, but not in most normal adult somatic tissues. It has also been detected in about 70% of human cell lines immortalized in vitro and in all tumor-derived cell lines examined to date. It has previously been shown that in vitro immortalized telomerase-negative cell lines acquire very long and heterogeneous telomeres in association with immortalization presumably via one or more novel telomere-lengthening mechanisms that we refer to as ALT (alternative lengthening of telomeres). Here we report evidence for the presence of ALT in a subset of tumor-derived cell lines and tumors. The maintenance of telomeres by a mechanism other than telomerase, even in a minority of cancers, has major implications for therapeutic uses of telomerase inhibitors.     

Activation of transducin guanosine triphosphatase by two proteins of the RGS family

RGS proteins (regulators of G protein signaling) constitute a newly appreciated group of negative regulators of G protein signaling. Several members of this group stimulate the guanosine triphosphatase (GTPase) activity of various G protein alpha-subunits, including the photoreceptor G protein, transducin. In photoreceptor cells transducin GTPase is known to be substantially accelerated by the coordinated action of the gamma-subunit of its effector enzyme, cGMP phosphodiesterase (PDE gamma), and another yet unidentified membrane-associated protein factor. Here we test the possibility that this factor belongs to the RGS family of GTPase stimulators. We report a detailed kinetic analysis of transducin GTPase activation by two members of the RGS family, RGS4 and G alpha interacting protein (GAIP). RGS4, being at least 5-fold more potent than GAIP, stimulates the rate of transducin GTPase by 2 orders of magnitude. Neither RGS4 nor GAIP requires PDE gamma for activating transducin. Rather, PDE gamma causes a partial reversal of transducin GTPase activation by RGS proteins. The effect of PDE gamma is based on a decreased apparent affinity of RGS for the alpha-subunit of transducin. Our observations indicate that GTPase activity of transducin can be activated by at least two distinct mechanisms, one based on the action of RGS proteins alone and another involving the cooperative action of the effector enzyme and another protein.     

Beta-1-integrin expression in adult acute lymphoblastic leukemia: possible relationship with the stem cell antigen CD34

In the hemopoietic system, interactions between stem cells and components of the bone marrow microenvironment play a pivotal role in blood cell proliferation and differentiation. Among the adhesion molecules, the integrins of the beta 1-subfamily are known to direct cell-cell and cell-matrix interactions and evidence has been provided that CD34-positive stem cells bind either to the bone marrow stroma or to the extracellular matrix proteins through the beta 1-integrins. It seems that changes in their expression pattern or signalling function are likely to reflect disturbances at the hemopoietic bone marrow microenvironmental level. Any alteration of their biological functions makes them attractive candidates for playing decisive roles in the leukemic processes. In this view, beta 1-integrins have been recognized to mediate those cellular interactions and migrations that are important in the biology of leukemia. In this paper we review some aspects of the role played by beta 1-integrins, especially VLA-4 and VLA-5, in adult acute lymphoblastic leukemia in relation with the expression rate of the stem cell antigen CD34.     

Benzodiazepine receptors in the post-mortem brain of suicide victims and schizophrenic subjects

To examine the role of benzodiazepine (BZ) receptors in suicide and schizophrenia, we determined BZ receptors in post-mortem brain (Brodmann's area 10) obtained from suicide victims, schizophrenic patients, and control subjects using [3H]RO15-1788 as the radioligand. The maximum number of binding sites (Bmax) of BZ receptors in the cortex of suicide victims was significantly higher compared with controls, but this increase was mainly due to those suicide victims who died by violent means and whose Bmax was significantly higher than of those who died by non-violent means or control subjects. In schizophrenic patients, Bmax was not significantly different from that of control subjects. When the schizophrenic subjects were separated into two groups, those on neuroleptics and those off neuroleptics for at least 12 months, however, the mean Bmax of BZ receptors in the prefrontal cortex in post-mortem brain obtained from schizophrenic patients on neuroleptics was significantly lower than Bmax in drug-free schizophrenic patients or normal controls. There were no significant differences among groups in values of the apparent dissociation constant (KD) of [3H]RO15-1788 binding. These results suggest that BZ receptors are up-regulated in the cortex of suicide victims, specifically those who used violent means, and that neuroleptic treatment may result in decreased central BZ receptor binding in the cortex of schizophrenic patients. Thus, the method of suicide and previous exposure to neuroleptics should be considered in the interpretation of data on BZ receptors.