Multicenter, Prospective, Phase II and Biomarker Study of High-Dose Bevacizumab as Induction Therapy in Patients With Neurofibromatosis Type 2 and Progressive Vestibular Schwannoma.

PURPOSE: Bevacizumab treatment at 7.5 mg/kg every 3 weeks results in improved hearing in approximately 35%-40% of patients with neurofibromatosis type 2 (NF2) and progressive vestibular schwannomas (VSs). However, the optimal dose is unknown. In this multicenter phase II and biomarker study, we evaluated the efficacy and safety of high-dose bevacizumab in pediatric and adult patients with NF2 with progressive VS. PATIENTS AND METHODS: Bevacizumab was given for 6 months at 10 mg/kg every 2 weeks, followed by 18 months at 5 mg/kg every 3 weeks. The primary end point was hearing response defined by word recognition score (WRS) at 6 months. Secondary end points included toxicity, radiographic response, quality of life (QOL), and plasma biomarkers. RESULTS: Twenty-two participants with NF2 (median age, 23 years) with progressive hearing loss in the target ear (median baseline WRS, 53%) were enrolled. Nine (41%) of 22 participants achieved a hearing response at 6 months (1 of 7 children and 8 of 15 adults; P = .08). Radiographic response was seen in 7 (32%) of 22 patients with VS at 6 months (7 of 15 adults and 0 of 7 children; P = .05). Common mild to moderate adverse events included hypertension, fatigue, headache, and irregular menstruation. Improvement in NF2-related QOL and reduction in tinnitus-related distress were reported in 30% and 60% of participants, respectively. Paradoxically, high-dose bevacizumab treatment was not associated with a significant decrease in free vascular endothelial growth factor but was associated with increased carbonic anhydrase IX, hepatocyte growth factor, placental growth factor, stromal cell-derived factor 1α, and basic fibroblast growth factor concentrations in plasma. CONCLUSION: High-dose bevacizumab seems to be no more effective than standard-dose bevacizumab for treatment of patients with NF2 with hearing loss. In contrast to adults, pediatric participants did not experience tumor shrinkage. However, adult and pediatric participants reported similar improvement in QOL during induction. Novel approaches using bevacizumab should be considered for children with NF2.

Meniere's attacks occur in the inner ear with excessive vasopressin type-2 receptors.

Meniere's disease is peculiar to humans and is characterised by episodic vertigo, fluctuating hearing loss and tinnitus, and attacks of the affliction occurring under conditions of stress. Its pathology was first revealed to be inner ear hydrops through temporal bone studies in 1938. Although subsequently proposed as a disorder of water metabolism in the inner ear, its pathogenesis remains unsolved. The present study aimed to assess the link between the inner ear pathology in Meniere's disease and vasopressin, an anti-diuretic stress hormone with a potential role in inner ear fluid homeostasis. Blood samples were obtained from Meniere's disease patients in the morning, before any surgical treatment, to examine plasma vasopressin (pAVP) levels, and then from inner ear tissue during surgical treatment, to examine vasopressin type-2 receptor (V2R) in the endolymphatic sac. pAVP and the relative V2R mRNA expression in the endolymphatic sac were examined using a real-time polymerase chain reaction. Relative cAMP activity in the endolymphatic sac was also examined using tissue culture and cAMP assay. Both pAVP (1.6-fold versus controls; P = 0.048) and inner ear V2R mRNA expression (41.5-fold versus controls; P = 0.022) were significantly higher in Meniere's patients. cAMP activity was basally up-regulated (2.1-fold versus controls) and cAMP sensitivity to vasopressin application was largely elevated (4.9-fold versus controls) in Meniere's patients. We conclude that, in the pathogenesis of inner ear hydrops, resulting in Meniere's attacks, elevation of pAVP levels (probably as a result of stress) may present as a matter of consequence, but susceptibility of the V2R-overexpressed and cAMP-hypersensitized inner ear to pAVP elevation might be essential as the basis of this disease. Further experimental and clinical studies are needed to better clarify the relationship between Meniere's disease and stress.

Stress hormones in Ménière's disease and acoustic neuroma.

Stress has been postulated to trigger or contribute to inner ear pathologies but there is little objective evidence. We investigated stress hormones in Ménière's patients and patients with acoustic neuroma. Data were compared with those from a control group of patients with facial spasm. We assayed classic stress hormones including adrenocorticotropic hormone, cortisol, growth hormone and prolactin. We found a strong positive correlation between cortisol and adrenocorticotropic hormone in Ménière patients and patients with acoustic neuroma but no correlation in patients with facial spasm. The data also revealed in female patients with Ménière's disease or with acoustic neuroma an unexpected significant positive correlation between cortisol and prolactin. The data showed the expected negative correlation or no correlation between cortisol and prolactin associated with males and females in the other patient groups. Both cortisol and prolactin increases are known to represent alternative strategies to cope with stress, and our data point to prolactin being possibly more dominant in Ménière's disease and cortisol in acoustic neuroma. These data provide further evidence for modification of different stress hormones in audiovestibular pathologies, which might provide a valuable diagnostic or prognostic tool in the future.

[The permeability of the hemato-encephalic barrier in neurological cancer patients in the postoperative period]. / Pronitsaemost' gematoéntsefalicheskogo bar'era u neiroonkologicheskikh bol'nykh v posleoperatsionnom periode.

The permeability of the blood-brain barrier was studied in 48 patients by examining the protein indices of cerebrospinal fluid. The types of changes in the indices were identified, which reflected the level of the permeability and correlate with good and poor postoperative outcomes. Possible ways of correcting hypertransudation across the barrier were defined.

Infectious retrovirus is inactivated by serum but not by cerebrospinal fluid or fluid from tumor bed in patients with malignant glioma.

Intravenous gene transfer using recombinant retroviruses tends to suffer from a low infectious viral titer when conducted in vivo. This is, in part, caused by complement-mediated proteolytic inactivation of the retrovirus in human serum. However, if the retroviruses were directly injected into the brain, they might not be inactivated. Supernatant from amphotropic retrovirus-producing cells harboring the BAG vectors was incubated with sera or cerebrospinal fluid (CSF) of patients with gliomas or unrelated disorders. The retroviruses were severely inactivated in sera. However, no such inactivation was noted in CSF or fluid from the tumor bed of glioma patients. These data suggest that gene transfer using recombinant retroviruses could be done into the cavity after removal of the tumor in glioma patients.

Aluminum concentrations in serum of patients with intracranial tumors.

The concentration of serum aluminum was measured by electrothermal atomic absorption spectrometry in 71 patients with intracranial tumors. The data were compared with those from a reference group of 15 healthy adult individuals. The serum concentrations of aluminum were significantly increased (p < 0.01) in patients with malignant gliomas and meningiomas. The concentrations of serum calcium, known as an antagonist of aluminum, were normal in the same patients.

Elevation of serum ceruloplasmin levels in brain tumours.

Serum ceruloplasmin levels have been estimated in 80 patients with various intracranial space occupying lesions and in 30 controls. The ceruloplasmin levels were significantly increased in all brain tumours except in meningiomas. After therapy, the ceruloplasmin levels were still significantly increased when compared to controls and their respective preoperative values. However, the rise in levels of ceruloplasmin in malignant tumours compared to benign was statistically not significant. It is concluded that ceruloplasmin may have a role to play as an acute phase reactant protein in brain tumours.

Long term monitoring of immunoreactive endothelin-1 and endothelin-3 in ventricular cerebrospinal fluid, plasma, and 24-h urine of patients with subarachnoid hemorrhage.

Endothelins (ETs), peptides that were originally isolated from endothelial cells, have extremely potent and long-lasting vasoconstricting effects on cerebral vessels in vitro and in vivo. Observations that astrocytes produce these peptides and that their ET production can be stimulated, e.g. by thrombin, and potentiated via a self-enhancing autoregulatory mechanism may have shed new light upon the pathogenesis of cerebrovasospasm (CVS). ETs are present at low levels in normal human cerebrospinal fluid (CSF). Few and contradictory reports exist on ET levels in subarachnoid hemorrhage (SAH)-associated CVS. We monitored ventricular CSF, plasma, and 24-h urine levels of immunoreactive endothelin-1 (ET-1) and endothelin-3 (ET-3) in seven patients with SAH, who did (five) or did not (two) develop CVS in the course of their disease, as well as in two patients with different conditions (acoustic neuroma/postoperative meningitis; hydro-/hematocephalus) over 7-19 days. A distinct peak of both ET-1 and ET-3 in CSF of patients with SAH coincided with clinically documented signs of CVS and was absent in CSF of patients with SAH but no CVS. CSF levels of ET-1 and ET-3 displayed a striking parallelism in all subjects. Plasma ET-1 levels were essentially in the normal range. ET-3 was not detectable in plasma under our assay conditions. The excretion profiles of ET-1 and ET-3 in 24-h urine revealed again a predominantly parallel behavior of the two peptides. Interestingly, patients with high ET levels in CSF showed simultaneous peaks in urinary ET excretion, expressed as nanograms per gram of creatinine. Our findings support an association of ETs with the pathogenic events following SAH. The well-documented effects of these peptides on cerebral vessels suggest they are mediators rather than markers of disease.

Serological analysis of tumor antigens in malignant glioma patients.

Sera from 27 malignant glioma patients were tested for antibodies to surface antigens of cultured human glioma cells using enzyme-linked immunosorbent assay. Average antibody titer for glioma cell lines was 0.558 +/- 0.123, which was significantly higher than in the normal control group (0.165 +/- 0.082). Surprisingly, average antibody titer for autologous glioma cells was low (0.207 +/- 0.154) in these patients. The results suggest that various surface antigens in glioma cells include specific autologous antigens, antigens associated with gliomas, and common antigens present on cultured normal and malignant cells. These analyses are important in the evaluation of monoclonal antibodies and explanation of escape mechanisms.

Identification of perilymph proteins by two-dimensional gel electrophoresis.

Perilymph has a total protein component that is quantitatively distinct from serum and cerebrospinal fluid (CSF). The goal of this research was to determine if perilymph contains any qualitatively unique protein constituents that will distinguish it from serum or CSF. To test this hypothesis, matched sets of perilymph, serum, and CSF were obtained from 18 guinea pigs and seven human subjects. The purity of each sample was assured by measurement of the protein concentration of each sample and comparison of this parameter to known normal values for perilymph, serum, and CSF. Each sample was then subjected to two-dimensional gel electrophoresis, separating proteins by isoelectric point in the horizontal dimension and by relative molecular weight in the vertical dimension. All gels were processed under precisely identical physical conditions by use of a diamine silver stain. A small number of perilymph proteins not found in plasma were identified in both the guinea pig and the human specimens. The finding of unique perilymph proteins may permit the development of a sensitive marker that will aid in the diagnosis of perilymph fistula.

[Practical significance of middle molecules of the blood in assessing the severity of the status of neurosurgical patients]. / Prikladnoe znachenie srednikh molekul krovi dlia otsenki tiazhesti sostonianiia neirokhirugicheskikh bol'nykh.

Study of the content of medium-size molecules (MM), residual nitrogen, creatinine, and urea in the blood of 80 neurosurgical patients with various diseases showed correlation between the severity of the patient's general condition and the MM level. No correlation was noted between the content of MM, creatinine, and urea. The MM level in the blood correlated with that of residual nitrogen in 20% of cases. The MM dynamics may serve as a prognostic sign of the course and outcome of the disease. The MM content corresponds to the severity of the patient's general condition and is not dependent on the etiological and pathogenetic factors.

Central neurofibromatosis with bilateral acoustic neuroma: genetic, clinical and biochemical distinctions from peripheral neurofibromatosis.

Neurofibromatosis includes the common "peripheral" form and a recently documented "central" form. We describe the central form in 130 cases from 9 kindreds personally studied and 15 reported kindreds. Central neurofibromatosis with bilateral acoustic neuroma is an autosomal dominant disorder beginning about 20 years of age, accompanied by mild skin changes. In three kindreds with central neurofibromatosis, we measured nerve growth factor in serum by radioimmunoassay and radioreceptor assay. Only the antigenic activity of nerve growth factor was increased. In contrast, in peripheral neurofibromatosis, only the functional activity of nerve growth factor has been reported increased. Central and peripheral forms of neurofibromatosis are closely related but discrete diseases which appear to have separate alterations in nerve growth factor activity.

Increased levels of a nerve-growth-factor cross-reacting protein in "central" neurofibromatosis.

Nerve-growth factor (N.G.F.) from serum was assayed in 9 affected individuals from three kindreds with the trait "central neurofibromatosis". The hallmark of this disease is bilateral acoustic neuromas. Antigenic activity, as measured by radioimmunoassay, was significantly elevated. However, functional activity for N.G.F.; as measured by radioreceptor assay, was normal or low. This indicates that the central form of neurofibromatosis is characterised by high circulating N.G.F. levels which show low to normal function. These changes in N.G.F. differ from those in peripheral neurofibromatosis and suggest that the two hereditary conditions involve different alterations in N.G.F. synthesis and/or regulation.