Bilateral Fascicular Third Nerve Palsy in Posterior Circulation Stroke.

Third nerve palsy is bilateral in only about 10% of cases, of which one in five cases is due to brainstem stroke. Bilateral oculomotor nerve palsy as an isolated clinical finding after brainstem stroke is extremely rare. We present a case of severe bilateral fascicular oculomotor nerve palsy due to distal basilar occlusion and subsequent midbrain infarction of cardioembolic origin. The patient required mechanical aids and subsequent ptosis surgery to relieve complete ptosis at least unilaterally.

Effective long-term treatment with bevacizumab for relapsed glioblastoma: case report and review of the literature.

Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor in adults. Despite the use of optimized first-line therapy, GBM is still associated with a poor prognosis and an effective second-line therapy remains an important challenge in this patient population. In 2009, the US Food and Drug Administration (FDA) approved the monoclonal anti-VEGF-antibody bevacizumab for the treatment of relapsed GBM after two phase-II studies showed its efficacy and safety, alone or in combination with irinotecan, in relapsed GBM. In contrast, the European Medicines Agency (EMA) concluded from the same published data that a clear benefit in terms of overall survival was not shown and subsequently did not grant approval for bevacizumab in this setting. Here, we report on a 53-year old patient with relapsed GBM who was treated with bevacizumab as single agent. After three months, the tumor volume was reduced and the Karnofsky performance status was substantially improved compared to the baseline at the time of relapse. After continued long-term treatment for 26 months, the patient remains in an excellent general condition. Moreover, the measurement of the tumor volume using multiple imaging modalities shows a sustained treatment response. In conclusion, this case supports the notion that individual patients respond exceptionally well to treatment with anti-VEGF therapy and suggests that future trials are needed to better identify the patient population that responds to bevacizumab.

Intravenous and oral levetiracetam in patients with a suspected primary brain tumor and symptomatic seizures undergoing neurosurgery: the HELLO trial.

BACKGROUND: Levetiracetam (LEV) is a newer anticonvulsant with a favorable safety profile. There seem to be no relevant drug interactions, and an intravenous formulation is available. Therefore, LEV might be a suitable drug for the perioperative anticonvulsive therapy of patients with suspected brain tumors undergoing neurosurgery. METHODS: In this prospective study (NCT00571155) patients with suspected primary brain tumors and tumor-related seizures were perioperatively treated with oral and intravenous LEV up to 4 weeks before and until 4 weeks after a planned neurosurgical procedure. FINDINGS: Thirty patients with brain tumor-related seizures and intended neurosurgery were included. Three patients did not undergo the scheduled surgery after enrollment, and two patients were lost to follow-up. Therefore, 25 patients were fully evaluable. After initiation of therapy with LEV, 100% of the patients were seizure-free in the pre-surgery phase (3 days up to 4 weeks before surgery), 88% in the 48 h post-surgery phase and 84% in the early follow-up phase (48 h to 4 weeks post surgery). Treatment failure even after dose escalation to 3,000 mg/day occurred in three patients. No serious adverse events related to the treatment with LEV occurred. CONCLUSION: Our data show the feasibility and safety of oral and intravenous LEV in the perioperative treatment of tumor-related seizures. Although this was a single arm study, the efficacy of LEV appears promising. Considering the side effects and interactions of other anticonvulsants, LEV seems to be a favorable option in the perioperative treatment of brain tumor-related seizures.

Phase I/IIa study of cilengitide and temozolomide with concomitant radiotherapy followed by cilengitide and temozolomide maintenance therapy in patients with newly diagnosed glioblastoma.

PURPOSE: Invasion and migration are key processes of glioblastoma and are tightly linked to tumor recurrence. Integrin inhibition using cilengitide has shown synergy with chemotherapy and radiotherapy in vitro and promising activity in recurrent glioblastoma. This multicenter, phase I/IIa study investigated the efficacy and safety of cilengitide in combination with standard chemoradiotherapy in newly diagnosed glioblastoma. PATIENTS AND METHODS: Patients (age > or = 18 to < or = 70 years) were treated with cilengitide (500 mg) administered twice weekly intravenously in addition to standard radiotherapy with concomitant and adjuvant temozolomide. Treatment was continued until disease progression or for up to 35 weeks. The primary end point was progression-free survival (PFS) at 6 months. RESULTS: Fifty-two patients (median age, 57 years; 62% male) were included. Six- and 12-month PFS rates were 69% (95% CI, 54% to 80%) and 33% (95% CI, 21% to 46%). Median PFS was 8 months (95% CI, 6.0 to 10.7 months). Twelve- and 24-month overall survival (OS) rates were 68% (95% CI, 53% to 79%) and 35% (95% CI, 22% to 48%). Median OS was 16.1 months (95% CI, 13.1 to 23.2 months). PFS and OS were longer in patients with tumors with O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation (13.4 and 23.2 months) versus those without MGMT promoter methylation (3.4 and 13.1 months). The combination of cilengitide with temozolomide and radiotherapy was well tolerated, with no additional toxicity. No pharmacokinetic interactions between temozolomide and cilengitide were identified. CONCLUSION: Compared with historical controls, the addition of concomitant and adjuvant cilengitide to standard chemoradiotherapy demonstrated promising activity in patients with glioblastoma with MGMT promoter methylation.

O6-methylguanine DNA methyltransferase and p53 status predict temozolomide sensitivity in human malignant glioma cells.

Temozolomide (TMZ) is a methylating agent which prolongs survival when administered during and after radiotherapy in the first-line treatment of glioblastoma and which also has significant activity in recurrent disease. O6-methylguanine DNA methyltransferase (MGMT) is a DNA repair enzyme attributed a role in cancer cell resistance to O6-alkylating agent-based chemotherapy. Using a panel of 12 human glioma cell lines, we here defined the sensitivity to TMZ in acute cytotoxicity and clonogenic survival assays in relation to MGMT, mismatch repair and p53 status and its modulation by dexamethasone, irradiation and BCL-X(L). We found that the levels of MGMT expression were a major predictor of TMZ sensitivity in human glioma cells. MGMT activity and clonogenic survival after TMZ exposure are highly correlated (p < 0.0001, r2 = 0.92). In contrast, clonogenic survival after TMZ exposure does not correlate with the expression levels of the mismatch repair proteins mutS homologue 2, mutS homologue 6 or post-meiotic segregation increased 2. The MGMT inhibitor O6-benzylguanine sensitizes MGMT-positive glioma cells to TMZ whereas MGMT gene transfer into MGMT-negative cells confers protection. The antiapoptotic BCL-X(L) protein attenuates TMZ cytotoxicity in MGMT-negative LNT-229 but not in MGMT-positive LN-18 cells. Neither ionizing radiation (4 Gy) nor clinically relevant concentrations of dexamethasone modulate MGMT activity or TMZ sensitivity. Abrogation of p53 wild-type function strongly attenuates TMZ cytotoxicity. Conversely, p53 mimetic agents designed to stabilize the wild-type conformation of p53 sensitize glioma cells for TMZ cytotoxicity. Collectively, these results suggest that the determination of MGMT expression and p53 status will help to identify glioma patients who will or will not respond to TMZ.

Pharmacotherapy of epileptic seizures in glioma patients: who, when, why and how long?

BACKGROUND: The risk for patients with primary brain tumors of experiencing an epileptic seizure at least once in the course of disease probably exceeds 50%, depending on tumor location and tumor type. Several aspects regarding the role of anticonvulsants in the treatment of brain tumor patients have remained controversial. PATIENTS AND METHODS: We reviewed the seizure history in 107 patients undergoing a surgical procedure for glioma at our institution. RESULTS: The overall seizure incidence was 68%. Pre-operative seizures did not predict the occurrence of post-operative seizures. After surgery, postoperative chemo- or radiotherapy and anticonvulsive therapy one third of patients was seizure-free whereas one third showed frequent seizures despite this treatment. Seizure frequency increased regardless of anticonvulsive treatment with progressive or recurrent tumor growth. CONCLUSIONS: Based on a literature review and our institutional experience, we delineate some recommendations for the management of seizures in patients with brain tumors.

Neoadjuvant gemcitabine/treosulfan chemotherapy for newly diagnosed glioblastoma: a phase II study.

The median survival for patients with glioblastoma is 12 months. The authors evaluated whether preirradiation gemcitabine/treosulfan (GeT) chemotherapy followed by standard radiotherapy improved outcome in patients with glioblastoma. Seventeen patients with newly diagnosed glioblastoma were enrolled in a prospective, unicenter trial of preirradiation GeT chemotherapy. Chemotherapy included up to 4 cycles of intravenous gemcitabine (1000 mg/m2 body surface) and treosulfan (3500 mg/m2 body surface) on days 1 and 8 of 28 days treatment cycles. Involved field radiotherapy (60 Gy in 30 fractions) was given after chemotherapy or earlier in the case of disease progression or drug intolerance. There was no specific treatment-related neurotoxicity reported, but in 3 of 17 patients (18%) chemotherapy was stopped because of World Health Organization (WHO) IV hematological toxicity. With GeT chemotherapy alone, there was a median progression-free survival of 12 weeks and a progression-free survival rate at 4 months of 29%. In 16 of 17 patients who subsequently received a full course of radiotherapy, the median progression-free survival from the time of diagnosis was 8 months, and the progression-free survival rate at 12 months was 25% (4 of 16 patients). The median overall survival was 12 months. Neither age nor extent of the residual postoperative tumor predicted the duration of progression-free survival after chemotherapy alone or after chemotherapy followed by radiotherapy. The combination of gemcitabine and treosulfan produced significant hematological toxicity in patients with newly diagnosed glioblastoma. The schedule used in the present study did not confer any significant survival advantage compared with standard involved field radiotherapy alone.