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.
Although isolated lower motor neuron disease has been reported as a paraneoplastic complication, it has not been previously described, in association with anti-Hu antibody. We report a 51-year-old man in whom weakness heralded the presence of a small-cell cancer of the lung. His neurological disorder was characterized by an unremitting progression of limb, neck, and chest wall weakness and wasting that commenced and remained predominant in the upper limbs. Electrophysiological studies demonstrated widespread denervation and examination of a muscle biopsy specimen showed evidence of acute and chronic denervation. High titers of anti-Hu antibody were detected in the serum and cerebrospinal fluid. Neither objective measures of strength nor titers of anti-Hu antibody responded to corticosteroids, cyclophosphamide, intravenous immunoglobulins, or plasmapheresis. Death from the complications of motor neuron disease ensued 23 months after the onset of weakness. Autopsy revealed tumor in the lung and on pleural and peritoneal surfaces. There was a loss of anterior horn cells in the spinal cord. Despite the absence of symptomatic cerebellar disease, a decrease in the number of Purkinje cells was also detected.
Human T-cell lymphotropic virus type one (HTLV-1) is associated with tropical spastic paraparesis or HTLV-I--associated myelopathy. We report 2 women with a spastic ataxic illness similar to HTLV-I--associated myelopathy infected solely with HTLV-II. Identification of HTLV-II infection was made serologically, by polymerase chain reaction, and by viral culture (in 1 woman). One woman, treated with 200 mg of danazol orally, three times daily, had pronounced improvement in ambulation, nocturnal spasticity, and nighttime urinary frequency. It appears that infection with HTLV-II may cause an illness similar to HTLV-I--associated myelopathy, but distinguished by the presence of ataxia.
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