D-dimer elevation and paresis predict thromboembolic events during bevacizumab therapy for recurrent malignant glioma.

BACKGROUND: The major side-effects of bevacizumab in glioma treatment are venous thromboembolic events (VTE). We retrospectively evaluated factors potentially predictive of thromboembolic events. PATIENTS AND METHODS: Bevacizumab, alone or in combination with chemotherapy was used as salvage therapy for recurrence in malignant glioma every two weeks. None but one patient received anti-coagulants. Before each bevacizumab cycle differential blood cell count, kidney and liver parameters, D-dimers, neurological status, body-mass index, vital signs and signs of venous thrombosis were assessed. RESULTS: Thirty-eight patients received 428 cycles of bevacizumab. In five patients (13%), six VTE were observed. These complications were preceded four weeks before the onset of symptoms by D-dimer elevation above 0.865 mg/l [p<0.0001; sensitivity=89% (95% confidence interval=83-93%); specificity=89% (95% CI=52-100%)]. An existing hemiparesis constituted a 27-fold risk elevation for thrombotic complication (p<0.0001, χ(2)-test). CONCLUSION: D-Dimer elevation or hemiparesis predict VTE under bevacizumab and chemotherapy, four weeks before the event becomes clinically apparent. Future investigations should determine if prophylactic anti-coagulants for patients at risk may reduce the risk of VTE.

NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide.

PURPOSE: The standard of care for anaplastic gliomas is surgery followed by radiotherapy. The NOA-04 phase III trial compared efficacy and safety of radiotherapy followed by chemotherapy at progression with the reverse sequence in patients with newly diagnosed anaplastic gliomas. PATIENTS AND METHODS: Patients (N = 318) were randomly assigned 2:1:1 (A:B1:B2) to receive conventional radiotherapy (arm A); procarbazine, lomustine (CCNU), and vincristine (PCV; arm B1); or temozolomide (arm B2) at diagnosis. At occurrence of unacceptable toxicity or disease progression, patients in arm A were treated with PCV or temozolomide (1:1 random assignment), whereas patients in arms B1 or B2 received radiotherapy. The primary end point was time to treatment failure (TTF), defined as progression after radiotherapy and one chemotherapy in either sequence. RESULTS: Patient characteristics in the intention-to-treat population (n = 274) were balanced between arms. All histologic diagnoses were centrally confirmed. Median TTF (hazard ratio [HR] = 1.2; 95% CI, 0.8 to 1.8), progression-free survival (PFS; HR = 1.0; 95% CI, 0.7 to 1.3, and overall survival (HR = 1.2; 95% CI, 0.8 to 1.9) were similar for arms A and B1/B2. Extent of resection was an important prognosticator. Anaplastic oligodendrogliomas and oligoastrocytomas share the same, better prognosis than anaplastic astrocytomas. Hypermethylation of the O(6)-methylguanine DNA-methyltransferase (MGMT) promoter (HR = 0.59; 95% CI, 0.36 to 1.0), mutations of the isocitrate dehydrogenase (IDH1) gene (HR = 0.48; 95% CI, 0.29 to 0.77), and oligodendroglial histology (HR = 0.33; 95% CI, 0.2 to 0.55) reduced the risk of progression. Hypermethylation of the MGMT promoter was associated with prolonged PFS in the chemotherapy and radiotherapy arm. CONCLUSION: Initial radiotherapy or chemotherapy achieved comparable results in patients with anaplastic gliomas. IDH1 mutations are a novel positive prognostic factor in anaplastic gliomas, with a favorable impact stronger than that of 1p/19q codeletion or MGMT promoter methylation.

Blood oxygen level-dependent MRI of tissue oxygenation: relation to endothelium-dependent and endothelium-independent blood flow changes.

OBJECTIVES: The contribution of endothelial function to tissue oxygenation is not well understood. Muscle blood oxygen level-dependent MRI (BOLD MRI) provides data largely dependent on hemoglobin (Hb) oxygenation. We used BOLD MRI to assess endothelium-dependent signal intensity (SI) changes. METHODS AND RESULTS: We investigated mean BOLD SI changes in the forearm musculature using a gradient-echo technique at 1.5 T in 9 healthy subjects who underwent a protocol of repeated acetylcholine infusions at 2 different doses (16 and 64 microg/min) and N(G)-monomethyl-L-arginine (L-NMMA; 5 mg/min) into the brachial artery. Sodium nitroprusside was used as a control substance. For additional correlation with standard methods, the same protocol was repeated, and forearm blood flow was measured by strain gauge plethysmography. We obtained a significant increase in BOLD SI during acetylcholine infusion (64 microg/min) and a significant decrease for L-NMMA infusion (P<0.005 for both). BOLD SI showed a different kinetic signal than did blood flow, particularly after intermittent ischemia and at high flow rates. CONCLUSIONS: In standard endothelial function tests, BOLD MRI detects a dissociation of tissue Hb oxygenation from blood flow. BOLD MRI may be a useful adjunct in assessing endothelial function.

Riluzole and blood pressure in multiple system atrophy.

Riluzole is a neuroprotective agent that is currently tested for the treatment of multiple system atrophy (MSA). Riluzole may influence afferent and efferent parts of the baroreflex due to glutamate antagonistic effects. The effect of riluzole on the efferent part may be unmasked in MSA patients with dysfunction of afferent structures of the baroreflex. We compared the effect of a single dose of 200 mg riluzole with placebo in 10 patients with probable MSA. Brachial blood pressure and heart rate were recorded at baseline and for 120 minutes every 5 minutes after ingestion of riluzole. For determination of spontaneous baroreflex sensitivity, continuous finger blood pressure and ECG were recorded. Cardiac stroke volume was monitored using impedance cardiography. The change in blood pressure over a two hour period was significantly greater with riluzole than with placebo (5 +/- 5/2 +/- 3 mmHg with placebo, 16 +/- 6/10 +/- 2 mmHg with riluzole, p < 0.001 by ANOVA). Systemic vascular resistance increased 32 +/- 6% with riluzole. Baroreflex sensitivity, the high and low frequency components of heart rate variability, and the low frequency component of systolic blood pressure variability were not different between placebo and riluzole treatment. We conclude that in MSA patients, manipulation of glutamatergic transmission with riluzole elicits a moderate pressor response. The response is explained by a marked increase in systemic vascular resistance. We propose that decreased inhibition of efferent sympathetic neurons may contribute to the response.

Pressor effect of water drinking in tetraplegic patients may be a spinal reflex.

Water drinking elicits a profound sympathetically mediated pressor response in patients with autonomic failure. To further elucidate the mechanism of the response, we assessed the acute effect of drinking water on supine blood pressure and heart rate in 13 tetraplegic patients (12 men, 1 woman; 39+/-4 years of age; body mass index, 25+/-1 kg/m2) with complete spinal cord injury (C2 to C7). Heart rate and finger blood pressure were recorded continuously. Brachial blood pressure was measured every 5 minutes. Baroreflex sensitivity was assessed by the sequence method. Stroke volume was calculated by use of transthoracic bioimpedance. Patients were placed in the supine position with the upper body elevated by 15 degrees. After 30 minutes, supine patients ingested 500 mL of water and the following 60 minutes were monitored. Finger blood pressure at baseline was 123+/-8/65+/-4 mm Hg. Water drinking elicited a pressor response that was apparent within 5 minutes and reached a maximum of 138+/-8/73+/-4 mm Hg after 35 to 40 minutes (P<0.05). Heart rate decreased from 64+/-2 bpm at baseline to 60+/-2 bpm (P<0.001). The mean area under the curve for brachial systolic blood pressure changes differed significantly from zero (364+/-151 mm Hg/min). Total peripheral resistance increased by 15+/-4% (P<0.05). Baroreflex sensitivity increased from 18+/-5 ms/mm Hg at baseline to 23+/-6 ms/mm Hg at 35 minutes after water drinking (P<0.01). Water drinking elicits a pressor response even if the direct connection between brain stem cardiovascular centers and spinal sympathetic neurons is interrupted. This observation might suggest that water drinking activates postganglionic sympathetic neurons either directly or through a spinal reflex mechanism.

Tissue-specific response to interstitial angiotensin II in humans.

Angiotensin II is synthesized locally in various tissues; however, the role of interstitial angiotensin II in the regulation of regional metabolism and tissue perfusion is not clear. We characterized the effect of interstially applied angiotensin II in skeletal muscle and subcutaneous adipose tissue of young, normal-weight, healthy subjects by using the microdialysis technique. Furthermore, we tested the hypothesis that the effect of interstitial angiotensin II is modulated by nitric oxide. Tissues were perfused with 0.01, 0.1, and 1 micro mol/L angiotensin II in the presence of the L- or D-isomer of N(G)-nitro-arginine-methyl ester (L- or D-NAME), the effective and noneffective isomer, respectively, for blocking nitric oxide synthase. Dialysate ethanol, glycerol, glucose, lactate, and pyruvate concentrations were measured to assess changes in blood flow (ethanol dilution technique), lipolysis, and glycolysis, respectively. Baseline blood flow and dialysate concentrations of the metabolites were similar with L- and D-NAME in both tissues. Blood flow and dialysate glucose and lactate did not change significantly in both tissues during perfusion with angiotensin II. Dialysate glycerol dose-dependently increased in adipose tissue (P<0.0438) but decreased in muscle (P<0.007). In muscle, dialysate pyruvate increased (P<0.0002), whereas lactate/pyruvate ratio decreased (P<0.001), both dose-dependently. All effects were similar with L- and D-NAME and could be reversed by nitroprusside. We conclude that in contrast to the profound hemodynamic effect of intravascular angiotensin II, interstitial angiotensin II has a minimal acute effect on blood flow in both tissues. However, interstitial angiotensin II modulates lipid and carbohydrate metabolism in a tissue specific fashion. Thus, the physiology of interstitial angiotensin II cannot be predicted from intravascular studies.

Catechol-o-methyltransferase and blood pressure in humans.

BACKGROUND: Whether catechol-O-methyltransferase (COMT), the enzyme that metabolizes extraneuronal norepinephrine, contributes to blood pressure regulation in humans is unknown. METHODS AND RESULTS: We studied incremental doses of the COMT inhibitor entacapone, the sympathetic stimulant yohimbine, and placebo in 7 patients with multiple system atrophy (Shy Drager syndrome). We selected these unique subjects because norepinephrine exerts an exaggerated increase in blood pressure in these patients. Autonomic regulation was characterized with intravenous phenylephrine, nitroprusside, and trimethaphan. Patients were extremely hypersensitive to phenylephrine and nitroprusside. Trimethaphan elicited a profound depressor response. Phenylephrine sensitivity increased only slightly during ganglionic blockade. Entacapone increased systolic blood pressure dose-dependently; however, the pressor response to yohimbine was approximately 3.5 times greater than the maximal response to entacapone. CONCLUSIONS: COMT inhibition elicits a moderate, dose-dependent pressor response in the setting of severely impaired baroreflex buffering. Patients with multiple system atrophy allow for the characterization of subtle manipulations of norepinephrine turnover and blood pressure regulation in small numbers of subjects.