Phase I study of panobinostat in combination with bevacizumab for recurrent high-grade glioma.

Bevacizumab is frequently used to treat patients with recurrent high-grade glioma (HGG), but responses are generally not durable. Panobinostat is a histone deacetylase inhibitor with anti-neoplastic and anti-angiogenic effects and may work synergistically with VEGF inhibitors. We performed a phase I study to evaluate the safety and tolerability of the combination of orally administered panobinostat with bevacizumab in patients with recurrent HGG. Patients with recurrent HGG were treated on a 3 + 3 trial design. Patients received bevacizumab 10 mg/kg every other week in combination with oral panobinostat. The starting dose of panobinostat was 20 mg three times per week, weekly (cohort 1). Due to concerns for thrombocytopenia with the weekly dosing regimen, the protocol was amended to examine an every other week regimen. Cohort 2 received panobinostat 20 mg three times per week, every other week, and cohort 3 received 30 mg three times per week, every other week. Dose-limiting toxicity during the first 30 days was used to determine the maximum-tolerated dose. Twelve patients (median age 50, median KPS 90) with recurrent HGG were enrolled. One dose-limiting toxicity (DLT) (Grade 3 thrombocytopenia) was observed in cohort 1. No DLTs were observed in cohorts 2 and 3. The following grade 3 toxicities were seen in one patient each: thrombocytopenia, hypophosphatemia, esophageal hemorrhage, and deep venous thrombosis. There were no grade 4 or 5 toxicities. There were three patients with partial responses and seven with stable disease. The recommended doses for further study are oral panobinostat 30 mg three times per week, every other week, in combination with bevacizumab 10 mg/kg every other week. A phase II clinical trial in recurrent HGG is underway.

Delayed, transient encephalopathy after marrow transplantation: case reports and MRI findings in four patients.

Subacute encephalopathy developed in four patients within one to two months after undergoing high-dose chemotherapy and bone marrow transplantation or peripheral blood progenitor (stem) cell transplantation for breast cancer, acute myeloid leukemia, and non-Hodgkin's lymphoma. None of the patients had previously known neurologic disorders, central nervous tumor or infection. Two patients presented with generalized tonic, clonic seizures, and two with confusion and lethargy. In all patients lumbar puncture and CT scans of the brain were normal, while magnetic resonance imaging (MRI) demonstrated multifocal predominantly white matter lesions. Phenytoin therapy was given to the two patients with seizures and all four patients improved without specific therapeutic intervention. Repeat MRIs became normal within three months. We report a delayed and transient encephalopathy which appears to be a unique complication of high-dose cytotoxic chemotherapy. The corresponding brain lesions may not be appreciated on CT scans, suggesting an expanded role for MRI studies in patients who develop neurologic findings while undergoing high-dose cytotoxic therapy.

The role of steroids in the management of metastatic carcinoma to the brain. A pilot prospective trial.

This prospective study attempted to evaluate the indications for glucocorticoids which are commonly given to patients with brain metastases. Twelve patients with histologically confirmed malignancies and radiographically documented brain metastases were enrolled. Patients were scored for general performance status and neurologic function class. All subjects were given high-dose dexamethasone (HDD) for 48 hours and then randomized to receive either intermediate-dose dexamethasone (IDD) or no steroids with cranial radiotherapy. Of these 12 study patients, 3 achieved a complete response, 1 partial response, and 8 nonresponses to HDD. Seven patients had IDD, while five received no IDD. Although a small sample size prevented any statistical analysis, this study does suggest that the place for using glucocorticoids in treating patients with metastatic carcinoma to the brain remains uncertain and should be evaluated in a cooperative prospective trial.

Neurologic complications of Merkel cell carcinoma.

We describe a 61-year-old man with a multiple neurologic complication of Merkel cell carcinoma, a rare skin cancer. An enhancing brain mass, and cytologically proven leptomeningeal disease produced a succession of symptoms including seizures, bilateral radiculopathies, myoclonus, a cauda equina syndrome and altered mental status. Aggressive treatment prolonged his survival marginally.

Clinical significance of periodic lateralized epileptiform discharges: relationship with status epilepticus.

A retrospective study was carried out in 147 patients who had been found to have periodic lateralized epileptiform discharges (PLEDs). Clinical, laboratory, radiological, and pathological correlation was performed for all patients. As in previously published works, we found a high correlation with cerebrovascular accidents in our population. A large number of patients, however, had no evidence of focal central nervous system pathology. An attempt was made to find a temporal relationship between the onset of seizure activity (or neurological dysfunction in those patients without seizure activity) and the recording of an EEG with PLEDs. We found that most of the EEGs with PLEDs were obtained within the first 4 days of seizure activity or status epilepticus condition. We postulate that the EEG phenomenon of PLEDs could be considered a part of the status epilepticus condition. Suggestive of this was the fact that the first EEG record obtained in one-third of our patients showed electrographic partial status epilepticus. In a small percentage of our patients, a transitional record showed first status epilepticus and then PLEDs. We found that PLEDs usually disappeared from the EEG tracing within 9 days post-ictus flash status. They were most frequently replaced by focal slowing or random spike activity.