Expression of cell cycle inhibitors p21, p27, p14 and p16 in gliomas. Correlation with classic prognostic factors and patients' outcome.

Gliomas are among the most aggressive and treatment-refractory of all human tumors. The aim of the present study is to evaluate the role of the expression of cell cycle molecules as prognostic indicators in gliomas. We immunohistochemically analyzed the expression of p21, p27, p14, p16, p53 and proliferation marker Ki67, in 67 low and high grade astrocytic tumors. High grade tumors exhibited higher labeling indices for Ki67 (P = 0.004), p53 (P = 0.039) and slightly higher index for p21 (P = 0.07) compared to low grade tumors. p14 and p16 were more frequently present in low grade tumors (P = 0.001 and P = 0.052, respectively). Worse survival was correlated with high grade tumors (P < 0.0001) and higher Ki67 index (P < 0.0001). Cox regression analysis revealed that only age, grade and marginally Ki67 index were independent prognostic factors. Cell cycle alterations are involved in the malignant progression of astrocytomas, but only age, tumor grade and proliferating index can predict the outcome of the patients with glioma.

Neurotrophin receptors expression and JNK pathway activation in human astrocytomas.

BACKGROUND: Neurotrophins are growth factors that regulate cell growth, differentiation and apoptosis in the nervous system. Their diverse actions are mediated through two different transmembrane - receptor signaling systems: Trk receptor tyrosine kinases (TrkA, TrkB, TrkC) and p75NTR neurotrophin receptor. Trk receptors promote cell survival and differentiation while p75NTR induces, in most cases, the activity of JNK-p53-Bax apoptosis pathway or suppresses intracellular survival signaling cascades. Robust Trk activation blocks p75NTR -induced apoptosis by suppressing the JNK-p53-Bax pathway. The aim of this exploratory study was to investigate the expression levels of neurotrophin receptors, Trks and p75NTR, and the activation of JNK pathway in human astrocytomas and in adjacent non-neoplastic brain tissue. METHODS: Formalin-fixed paraffin-embedded serial sections from 33 supratentorial astrocytomas (5 diffuse fibrillary astrocytomas, WHO grade II; 6 anaplastic astrocytomas, WHO grade III; 22 glioblastomas multiforme, WHO grade IV) were immunostained following microwave pretreatment. Polyclonal antibodies against TrkA, TrkB, TrkC and monoclonal antibodies against p75NTR and phosphorylated forms of JNK (pJNK) and c-Jun (pc-Jun) were used. The labeling index (LI), defined as the percentage of positive (labeled) cells out of the total number of tumor cells counted, was determined. RESULTS: Moderate to strong, granular cytoplasmic immunoreactivity for TrkA, TrkB and TrkC receptors was detected in greater than or equal to 10% of tumor cells in the majority of tumors independently of grade; on the contrary, p75NTR receptor expression was found in a small percentage of tumor cells (approximately 1%) in some tumors. The endothelium of tumor capillaries showed conspicuous immunoreactivity for TrkB receptor. Trk immunoreactivity seemed to be localized in some neurons and astrocytes in non-neoplastic tissue. Phosphorylated forms of JNK (pJNK) and c-Jun (pc-Jun) were significantly co-expressed in a tumor grade-dependent manner (p < 0.05). Interestingly, a statistically significant (p < 0.05) reverse relationship between Trk receptors LIs and pc-Jun/pJNK LIs was noted in some glioblastomas multiforme. CONCLUSION: In the context of astrocytomas, Trk receptors (TrkA, TrkB, TrkC) expression may promote tumor growth independently of grade. Furthermore, activation of JNK pathway may contribute to progression towards malignancy. Considering the fact that regional tumor heterogeneity may be a limiting factor for immunohistochemical studies, the significance of the reverse relationship between Trk receptors and pc-Jun/pJNK LIs with respect to biological behavior of human astrocytomas requires further evaluation.

Transcranial cerebral oximetry and transcranial doppler sonography in patients with ruptured cerebral aneurysms and delayed cerebral vasospasm.

BACKGROUND: Vasospasm is a major cause of ischemic neurological deficits developing after subarachnoid hemorrhage. The goal was to identify hemodynamic changes and the presence of clinical vasospasm in patients suffering from subarachnoid hemorrhage secondary to ruptured intracranial aneurysms. MATERIAL/METHODS: Pre- and postoperative serial transcranial cerebral oximetry and transcranial doppler sonography (TCD) examinations were performed in 75 patients operated for aneurysmal subarachnoid hemorrhage. RESULTS: No significant difference (p=0.14) was found in the levels of regional oxygen saturation (rSO2) between patients with vasospasm and those without. In patients who developed clinical vasospasm, the blood flow velocity values were significantly higher compared with those who did not (127.5+/-2.7 versus 92.5+/-1.2 cm/sec, p<0.001). In six patients with clinical vasospasm and low TCCO measurements, the use of triple-H therapy led to oxygen saturation increment and clinical improvement. CONCLUSIONS: Transcranial cerebral oximetry seems to be of limited value for the detection of vasospasm in patients with subarachnoid hemorrhage. However, it may be useful in estimating the clinical impact of triple-H therapy in such patients.