Flemming S. Vassbotn

Vestibular schwannomas: clinical results and quality of life after microsurgery or gamma knife radiosurgery.

OBJECTIVE:The aim of the present study was to evaluate the overall treatment efficacy (tumor control, facial nerve function, complications) and quality of life for patients treated primarily for unilateral vestibular schwannomas of 30 mm or less, either by microsurgery or by gamma knife (GK) radiosurgery. The results for the two treatment groups are compared with each other, with main emphasis on the long-term quality of life. METHODS:This is a retrospective study of 189 consecutive patients, 86 treated by microsurgery and 103 by gamma knife. The mean observation time was 5.9 years. All patients had a magnetic resonance imaging scan and clinical evaluation performed toward the end of the study. To evaluate the quality of life, we used two standardized questionnaires, the Glasgow Benefit Inventory and Short-Form 36. The questionnaires were sent to the 168 living patients. The reply rate was 83.3%. RESULTS:A total of 79.8% of the patients in the microsurgery group and 94.8% of the GK patients had a good facial nerve function (House-Brackmann Grade 1–2). Hearing was usually lost after microsurgery, whereas the GK patients had preserved hearing, which often became reduced over the years after the treatment. The treatment efficacy, defined as no need for additional treatment, was similar for the two treatment modalities. Quality of life was reduced compared with normative data, being most reduced in the microsurgery group. Some of the quality of life questions showed an association with facial nerve function and sex. CONCLUSION:Posttreatment facial nerve function, hearing, complication rates, and quality of life were all significantly in favor of GK radiosurgery.

Acute mastoiditis in a Norwegian population: a 20 year retrospective study

We have retrospectively examined the nature of acute mastioditis (in western Norway) during a 20 year period (1980-2000). Sixty-one cases of AM were identified in 57 patients with a mean age of 3.6 years. We found no significant change in the incidence of AM during the last 20 years. Seven patients were treated solely with intravenous antibiotics and myringotomies. Fifty patients also underwent cortical mastoidectomy, four cases with bilateral surgery. Antibiotic treatment was given to 31 of the patients before admission to hospital and this group had a significant longer duration of symptoms (12.4 days) compared to untreated patients (7.3 days). Streptococcus pneumoniae was the most common organism recovered from patient cultures. Surgery was found to correlate to patients with retroauricular fluctuation or to children with at least two of the three clinical signs: protrusion of the ear, retroauricular oedema and swelling of the ear canal. Our data show that clinical examination only reveal 50% of the cases with surgically proven retroauricular subperiostal abscess. We therefore recommend a CT scan of patients treated conservatively.

Conservative Management of Vestibular Schwannoma—A Prospective Cohort Study: Treatment, Symptoms, and Quality of Life

BACKGROUND One hundred ninety-three patients with sporadic unilateral vestibular schwannoma given conservative management were enrolled in a prospective study. OBJECTIVE To evaluate the efficacy of conservative management and to determine the effect of an initial conservative management on the quality of life (QOL) and severity of audio vestibular symptoms. METHODS The patients underwent magnetic resonance imaging scans, clinical examination, and QOL assessment by 2 validated questionnaires, the Short Form-36 (SF-36) and Glasgow Benefit Inventory (GBI). Using regression analysis of clustered data, we analyzed possible associations between tumor growth and symptoms and tested whether our earlier finding that vertigo is associated with reduced QOL could be verified. RESULTS The median follow-up time was 43 months (range, 9-115 months; SD, 21.48 months). Results are based on 703 clinical controls and 642 (SF-36) and 638 (GBI) questionnaires. Seven patients were lost to follow-up. Approximately 40% of patients were in need of treatment during follow-up. We found a statistically significant association between tinnitus and vertigo and tumor growth. Vertigo was found to significantly reduce QOL. There was a significant drop in the Social Function subscales of both SF-36 and GBI, possibly attributable to progressive hearing loss. Otherwise, there was no overall trend toward any change in QOL during the observation period. In addition, QOL seemed to be little affected by treatment. CONCLUSION There was a small but statistically significant improvement in vestibular complaints and no change in the occurrence of tinnitus. Except for hearing loss caused by surgery, treatment did not affect symptoms or QOL significantly. Growth was associated with the occurrence of tinnitus and balance problems.

Identification of functional VEGF receptors on human platelets

Platelets secrete platelet‐derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) upon stimulation. We have demonstrated that platelets have functionally active PDGF α‐receptors, a transmembrane tyrosine kinase involved in negative feedback regulation. Here we demonstrate the presence of the related VEGF receptors fms‐like tyrosine kinase‐1 and kinase‐insert domain region on human platelets. VEGF itself did not cause platelet aggregation. However, addition of exogenous VEGF to SFRLLN or thrombin‐stimulated platelets potentiated platelet aggregation. Moreover, thrombin‐induced phosphoinositide 3‐kinase and mitogen‐activated protein kinase activity were enhanced in the presence of VEGF.

Analysis of vestibular schwannoma size in multiple dimensions: a comparative cohort study of different measurement techniques

Clin. Otolaryngol. 2010, 35, 97–103

A monoclonal antibody against PDGF B-chain inhibits PDGF-induced DNA synthesis in C3H fibroblasts and prevents binding of PDGF to its receptor

A monoclonal antibody (MAb 6D11) against platelet-derived growth factor (PDGF) was studied. We found that the MAb 6D11 in concentrations equimolar to PDGF blocked the [3H]thymidine incorporation in C3H/10T1/2 C18 fibroblasts stimulated by PDGF B-B and PDGF A-B. This inhibition was overcome by high doses of PDGF. The [3H]thymidine incorporation stimulated by other growth factors (aFGF, bFGF and bombesin) was not inhibited by the antibody. The MAb 6D11 blocked receptor binding of PDGF B-B, but not PDGF A-A. These findings suggest that the MAb 6D11 abolishes PDGF-induced DNA synthesis by blocking PDGF receptor binding. In this communication we demonstrate an isoform-specific monoclonal antibody against PDGF.

PI 3-kinase signalling in platelets: the significance of synergistic, autocrine stimulation.

Phosphoinositide 3-kinases (PI 3Ks) play a key role in regulation of intracellular signalling and cellular function, including cell proliferation, apoptosis, chemotaxis, membrane trafficking and platelet activation. The PI 3Ks are grouped into three classes on the basis on their structure and in vitro substrate specificity. Class I are activated by a variety of agonists which mediate their effect through tyrosine kinase-linked or G-proteinlinked receptors. In vivo class I PI 3Ks seem to preferentially phosphorylate the D3 hydroxyls of the inositol moiety of PtdIns(4,5)P 2 to produce PtdIns(3,4,5)P 3 . However, class II PI 3Ks preferentially phosphorylate the D3 hydroxyl of PtdIns and PtdIns(4)P to produce PtdIns(3)P and PtdIns(3,4)P 2 , respectively. The late accumulation of PtdIns(3,4)P 2 has been suggested to play an important role in irreversible platelet aggregation. In human platelets the class II PI 3K isoform HsC2-PI 3K is activated in an integrin alpha Ib beta 3 +fibrinogen dependent manner. Class III PI 3Ks phosphorylate PtdIns to produce PtdIns(3)P, which play a crucial role in vesicular trafficking. Recent work has suggested that crosstalk between individual receptors and their downstream signal pathways play a central role in PI 3K signalling responses. In this review, we will concentrate on recent advances regarding the regulation of platelet PI 3Ks. IPhosphoinositide 3-kinases (PI 3Ks) play a key role in regulation of intracellular signalling and cellular function, including cell proliferation, apoptosis, chemotaxis, membrane trafficking and platelet activation. The PI 3Ks are grouped into three classes on the basis on their structure and in vitro substrate specificity. Class I are activated by a variety of agonists which mediate their effect through tyrosine kinase-linked or G-protein-linked receptors. In vivo class I PI 3Ks seem to preferentially phosphorylate the D3 hydroxyls of the inositol moiety of PtdIns(4,5)P2 to produce PtdIns(3,4,5)P3. However, class II PI 3Ks preferentially phosphorylate the D3 hydroxyl of PtdIns and PtdIns(4)P to produce PtdIns(3)P and PtdIns(3,4)P2, respectively. The late accumulation of PtdIns(3,4)P2 has been suggested to play an important role in irreversible platelet aggregation. In human platelets the class II PI 3K isoform HsC2-PI 3K is activated in an integrin alpha IIb beta 3 + fibrinogen-dependent manner. Class III PI 3Ks phosphorylate PtdIns to produce PtdIns(3)P, which play a crucial role in vesicular trafficking. Recent work has suggested that crosstalk between individual receptors and their downstream signal pathways play a central role in PI 3K signalling responses. In this review, we will concentrate on recent advances regarding the regulation of platelet PI 3Ks.

Adrenaline potentiates PI 3-kinase in platelets stimulated with thrombin and SFRLLN: role of secreted ADP

Adrenaline significantly potentiated late thrombin‐ and SFRLLN‐induced PtdIns(3,4)P2 production. Furthermore, the potentiating effect of adrenaline on thrombin‐induced PtdIns(3,4)P2 production was independent on secreted ADP, whereas, the effect of adrenaline on SFRLLN‐induced PtdIns(3,4)P2 production was completely dependent of secreted ADP. However, the ADP‐dependent accumulation of PtdIns(3,4)P2 was not required for irreversible platelet aggregation induced by SFRLLN in the presence of adrenaline. It is concluded that adrenaline can replace secreted ADP to potentiate PtdIns(3,4)P2 production in thrombin‐stimulated but not in SFRLLN‐stimulated platelets, thus demonstrating a qualitative difference between platelet stimulation by thrombin and the thrombin receptor activating peptide SFRLLN.

Predictors of vertigo in patients with untreated vestibular schwannoma.

Objectives Previous studies have shown that vertigo is the most powerful negative predictor of quality of life in patients with vestibular schwannomas, but the variability in vertigo symptom severity is still poorly understood. We wanted to find out whether vertigo could be related to objective parameters such as tumor size, location, vestibular nerve function, hearing, and postural stability in patients with untreated vestibular schwannomas. Study Design Baseline data from prospective cohort study. Setting Tertiary referral center. Patients Four hundred thirty-four consecutive patients with unilateral VS diagnosed on MRI. Mean age 56 years (range 16–84 yr). Fifty-three percent women. Intervention Diagnostic, with a medical history, otolaryngological examination, pure-tone and speech audiometry, MRI, posturography, and videonystagmography with bithermal caloric tests. Main Outcome Measure Dizziness measured on a 100-mm visual analog scale (VAS). Secondary outcome measures were canal paresis and postural imbalance (static and dynamic posturography). Results Three hundred three patients (70%) completed the VAS. Severe dizziness, defined as VAS 75 or greater, was reported by 9% of the patients. Larger tumors were associated with higher risk of postural instability and canal paresis. Moderate to severe dizziness was associated with postural imbalance and canal paresis, and possibly with small to medium-sized tumors. Postural instability was related to tumor size and canal paresis when measured by dynamic, but not with static, posturography. Conclusion A minority of VS patients experience severe vestibular symptoms related to canal paresis and postural instability. A curvilinear relationship is hypothesized between tumor size and dizziness.

Platelet-Derived Growth Factor Inhibits Platelet Activation in Heparinized Whole Blood

We previously have demonstrated that human platelets have functionally active platelet-derived growth factor alpha-receptors. Studies with gel-filtered platelets showed that an autocrine inhibition pathway is transduced through this tyrosine kinase receptor during platelet activation. The physiological significance of this inhibitory effect of platelet-derived growth factor on gel-filtered platelets activation is, however, not known. In the present study, we investigated whether platelet-derived growth factor inhibits platelet activation under more physiological conditions in heparinized whole blood, which represents a more physiological condition than gel-filtered platelets. Using flow cytometric assays, we demonstrate here that platelet-derived growth factor inhibits thrombin-, thrombin receptor agonist peptide SFLLRN-, and collagen-induced platelet aggregation and shedding of platelet-derived microparticles from the platelet plasma membrane during platelet aggregation in stirred heparinized whole blood. The inhibitory effect of platelet-derived growth factor was dose dependent. However, under nonaggregating conditions (no stirring), we could not demonstrate any significant effect of platelet-derived growth factor on thrombin- and thrombin receptor agonist peptide-induced platelet surface expression of P-selectin. Our results demonstrate that platelet-derived growth factor appears to be a true antithrombotic agent only under aggregating conditions in heparinized whole blood.