Combined-modality therapy for primary central nervous system lymphoma: long-term data from a Phase II multicenter study (Trans-Tasman Radiation Oncology Group)

PURPOSE: To assess, in a multicenter setting, the long-term outcomes of a brief course of high-dose methotrexate followed by radiotherapy for patients with primary central nervous system lymphoma (PCNSL). METHODS AND MATERIALS: Forty-six patients were entered in a Phase II protocol consisting of methotrexate (1 g/m(2) on Days 1 and 8), followed by whole-brain irradiation (45-50.4 Gy). The median follow-up time was 7 years, with a minimum follow-up of 5 years. RESULTS: The 5-year survival estimate was 37% (+/-14%, 95% confidence interval [CI]), with progression-free survival being 36% (+/-15%, 95% CI), and median survival 36 months. Of the original 46 patients, 10 were alive, all without evidence of disease recurrence. A total of 11 patients have developed neurotoxicity, with the actuarial risk being 30% (+/-18%, 95% CI) at 5 years but continuing to increase. For patients aged>60 years the risk of neurotoxicity at 7 years was 58% (+/-30%, 95% CI). CONCLUSION: Combined-modality therapy, based on high-dose methotrexate, results in improved survival outcomes in PCNSL. The risk of neurotoxicity for patients aged>60 years is unacceptable with this regimen, although survival outcomes for patients aged>60 years were higher than in many other series.     

Selective increases in the cytokine, TNFalpha, in the prefrontal cortex of PCP-treated rats and human schizophrenic subjects: influence of antipsychotic drugs

The psychotomimetic drug phencyclidine (PCP) induces symptoms closely related to those of schizophrenia in humans. In order to test the hypothesis that cytokines may be involved in the aetiology and treatment of schizophrenia, this study investigated the levels of cytokine mRNAs in rat brain after acute and chronic administration of PCP, in the presence and absence of antipsychotic drugs. The levels of the mRNAs encoding TNF, IL-2, IL-6, TGF 1, 2, 3, IL-3 and GM-CSF were measured in the prefrontal cortex, cortex, hippocampus, ventral and dorsal striatum regions of male hooded Long Evans rats after acute drug administration. Antipsychotic drugs and PCP significantly reduced the levels of TNF in the prefrontal cortex compared to vehicle-treated animals, whilst other cytokines remained unchanged. In addition, significant reductions in the levels of TNF mRNA in the prefrontal cortex still occurred 24h after acute PCP administration. However, levels of TNF mRNA were restored to control values after chronic PCP treatment, whereas increased expression was detected in animals co-administered with haloperidol. Levels of TNF mRNA were also found to be significantly increased in the prefrontal cortex of schizophrenic subjects. The relationship between TNF levels and schizophrenia are discussed.     

Sound lateralization and interaural discrimination. Effects of brainstem infarcts and multiple sclerosis lesions

Subjects with brainstem lesions due to either an infarct or multiple sclerosis (MS) underwent two types of binaural testing (lateralization testing and interaural discrimination) for three types of sounds (clicks and high and low frequency narrow-band noise) with two kinds of interaural differences (level and time). Two major types of abnormalities were revealed in the lateralization performances: perception of all stimuli, regardless of interaural differences (time and/or level) in the center of the head (center-oriented), or lateralization of all stimuli to one side or the other of the head (side-oriented). Similar patterns of abnormal lateralization (center-oriented and side-oriented) occurred for MS and stroke patients. A subject's pattern of abnormal lateralization testing was the same regardless of the type of stimulus or type of interaural disparity. Lateralization testing was a more sensitive test than interaural discrimination testing for both types of subjects. Magnetic resonance image (MRI) scanning in three orthogonal planes of the brainstem was used to detect lesions. A semi-automated algorithm superimposed the auditory pathway onto each MRI section. Whenever a lesion overlapped the auditory pathway, some binaural performance was abnormal and vice versa. Given a lateralization test abnormality, whether the pattern was center-oriented or side-oriented was mainly determined by lesion site. Center-oriented performance was principally associated with caudal pontine lesions and side-oriented performance with lesions rostral to the superior olivary complex. For lesions restricted to the lateral lemniscus and/or inferior colliculus, whether unilateral or bilateral, just noticeable differences (JNDs) were nearly always abnormal, but for caudal pontine lesions JNDs could be normal or abnormal. MS subjects were more sensitive to interaural time delays than interaural level differences particularly for caudal pontine lesions, while stroke patients showed no differential sensitivity to the two kinds of interaural differences. These results suggest that neural processing of binaural stimuli is multilevel and begins with independent interaural time and level analyzers in the caudal pons.     

Tamoxifen reduces serum insulin-like growth factor I (IGF-I)

Summary Antiestrogens are widely used in the management of hormonally responsive breast cancer in both adjuvant and palliative settings, and are currently being evaluated as chemopreventive agents. The classical mechanism of action of these drugs involves inhibition of estrogen-stimulated neoplastic cell proliferation by blockade of estrogen receptors present on breast cancer cells. This paper reviews recent clinical and laboratory data that suggest that the commonly used antiestrogen tamoxifen also acts to reduce serum IGF-I levels. Estrogens appear to play a permissive role in growth hormone (GH) release by the pituitary gland and GH is known to stimulate IGF-I expression by hepatocytes. It is therefore possible that blockade of estrogen receptors in the hypothalamic-pituitary axis by tamoxifen interferes with GH release, leading to reduced hepatic IGF-I expression. In view of results suggesting that IGF-I is a more potent mitogen than estradiol for breast cancer cells and data demonstrating a positive correlation between estrogen receptor level and IGF-I receptor level of breast cancer cells, the IGF-I lowering effect of tamoxifen may contribute to the cytostatic activity of the drug. The interrelationships between steroid hormone physiology and IGF-I physiology may have relevance to a variety of commonly used treatments for hormonally responsive cancers.     

Lupus anticoagulant activity of autoimmune antiphospholipid antibodies is dependent upon beta 2-glycoprotein I.

It has been reported that antiphospholipid autoantibodies do not recognize phospholipid alone, but rather the plasma protein beta 2-glycoprotein I (beta 2GPI), or a beta 2GPI-phospholipid complex. In vitro beta 2GPI binds to anionic phospholipids and inhibits the prothrombinase activity of procoagulant membranes. In light of the fact that lupus anticoagulants, a type of antiphospholipid antibody, have similar anticoagulant properties, the relationship of beta 2GPI to lupus anticoagulant activity was investigated. IgG from patients with autoimmune diseases or syphilis were tested for anticardiolipin reactivity and lupus anticoagulant activity in the presence and absence of beta 2GPI. As expected, anti-cardiolipin reactivity associated with autoimmune disease was beta 2GPI dependent. In contrast, IgG from a patient with syphilis recognized cardiolipin alone and binding was inhibited by beta 2GPI. Autoimmune antiphospholipid antibodies prolonged the dilute Russell viper venom time of normal plasma, but had no effect on beta 2GPI-depleted plasma. Antiphospholipid antibodies associated with syphilis had no anticoagulant effect. RP-1, an anti-beta 2GPI mAb, had anticoagulant effects similar to those of autoimmune antiphospholipid antibodies. These data demonstrate that antiphospholipid autoantibodies exert lupus anticoagulant activity via an interaction with beta 2GPI. These antibodies and RP-1 appear to amplify the anticoagulant effect of beta 2GPI itself.     

Real-time list-mode processing of gated cardiac blood pool examinations with forward-backward framing

List-mode processing of gated cardiac blood pool data has be shown to been more accurate than standard frame-mode processing, but it has not gained widespread clinical use because of the difficulties associated with post-processing of the acquired data. We therefore investigated the possibility of performing the list-mode processing concurrently with the acquisition of the data, i.e. real-time list-mode processing. A programme for simultaneous acquisition and processing of gated cardiac images was written in assembly code and implemented on a personal computer. The programme was tested in phantom studies, then used in 200 consecutive patient examinations. Data could be concurrently acquired from the gamma-camera and processed with forward-backward framing at a great enough speed so that no loss of information occurred at up to 40000 counts per second, a value exceeding typical count rates observed in clinical practice. The ease-of-use and the clinical benefits of real-time list-mode processing suggest that it may become a standard method for gated examinations of the left ventricle in the near future. Offprint requests to: J.L. Lear