Sajeel Chowdhary

Phase I trial of vorinostat combined with bevacizumab and CPT-11 in recurrent glioblastoma.

A phase I study was conducted to determine the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) for the combination of vorinostat with bevacizumab and CPT-11 in recurrent glioblastoma. Vorinostat was combined with bevacizumab and CPT-11 and was escalated using a standard 3 + 3 design. Vorinostat was escalated up to 2 actively investigated doses of this compound or until the MTD was identified on the basis of DLTs. Correlative science involving proteomic profiling of serial patient plasma samples was performed. Nineteen patients were treated. The MTD of vorinostat was established at 400 mg on days 1-7 and 15-21 every 28 days when combined with bevacizumab and CPT-11. Common toxicities were fatigue and diarrhea. DLTs included fatigue, hypertension/hypotension, and central nervous system ischemia. Although the MTD was established, CPT-11 dose reductions were common early in therapy. High-dose vorinostat had an improved progression-free survival and overall survival when compared with low-dose vorinostat. Serum proteomic profiling identified IGFBP-5 and PDGF-AA as markers for improved PFS and recurrence, respectively. A MTD for the combination of vorinostat with bevacizumab and CPT-11 has been established, although it has poor long-term tolerability. With the increased toxicities associated with CPT-11 coupled with its unclear clinical significance, investigating the efficacy of vorinostat combined with bevacizumab alone may represent a more promising strategy to evaluate in the context of a phase II clinical trial.

Clinical utility and pharmacology of high-dose methotrexate in the treatment of primary CNS lymphoma

Primary CNS non-Hodgkin lymphoma (PCNSL) has been shown to be increasing in incidence. This appears to be a consequence of the increasing population of those older than 65 years of age in whom PCNSL occurs most often. PCNSL often has a favorable response to treatment and aggressive management may result in extended survival and, in a proportion of patients less than 65 years of age, cure. The majority of neuro-oncologist’s advocate utilizing high-dose methotrexate (HD-MTX) as a platform for the chemotherapy treatment of these neoplasms. In this review, the literature regarding HDHMTX as a treatment for PCNSL is summarized as are the pharmacological principles of HD-MTX.

A Progressive Neurologic Disorder with Multiple CNS Lesions: A Neuroimaging Clinicopathologic Correlation

A 51‐year‐old man with a diagnosis of myelodysplasia and non‐Hodgkins lymphoma underwent an unmatched allogenic bone marrow transplantation and was treated posttransplant with chronic immunosuppressive medication. Eight months following transplantation, he presented with progressive dysarthria, cognitive and visual decline. Evaluation included brain magnetic resonance (MR) imaging demonstrating multifocal areas of increased T2 and FLAIR (fluid attenuated inversion recovery) signals involving the left frontal, parietal, and occipital lobes. The MR lesions demonstrated diffuse increased signal on DWI (diffusion‐weighted images) and normal to low signal on ADC (apparent diffusion coefficients). Contrast‐enhanced T1 images were unremarkable. Lumbar puncture revealed a mild elevation in cerebrospinal fluid (CSF) protein. CSF PCR assay for viral DNA fragments were negative on two occasions. Serum serology for HIV was negative as well. A brain biopsy was subsequently performed. The clinical and neuroimaging differential diagnoses as well as neuropathologic correlation are presented.

Anaplastic astrocytomas: biology and treatment.

Anaplastic astrocytomas (AA), WHO grade III gliomas, comprise 10–15% of all glial neoplasms. Currently, the only factors that have been shown to influence prognosis in patients with AA are age and Karnofsky performance status. Attempts have been made to identify biological prognostic factors for response to therapy and clinical outcome, as well as potential targets for new therapies. The most important predictor of response to therapy and survival in AA tumors is the presence or absence of the 1p19q co-deletion, a translocation that defines a subset of oligodendroglial tumors, and anaplastic oligodendrogliomas in particular. A further likely prognostic biomarker is the methylation status of O6-methylguanine-DNA-methyltranferase gene (the predominant DNA repair enzyme following alkylator-based chemotherapy-induced injury). Owing to a paucity of clinical trials specifically in patients with AA, most patients receive temozolomide-containing regimens, based on data acquired from patients with glioblastoma multiforme. At present, there are no cooperative group trials being conducted for the adjuvant treatment of AA, although several randomized trials have been proposed. Evidence-based management of patients with AA supports maximum safe resection followed by involved-field radiotherapy for newly diagnosed patients, and temozolomide for recurrent disease. This treatment paradigm varies considerably from actual practice.

Non‐HIV‐Related Progressive Multifocal Leukoencephalopathy (PML): A Tertiary Cancer Center Experience

In the course of 1 year at a tertiary cancer center, 3 patients (2 men; 1 woman; age 51‐75 years) were seen in neurological consultation (1.5% of all consultations). Clinical course in all patients was of a progressive neurologic disorder not consistent with either a primary or secondary malignancy. Magnetic resonance (MR) imaging was most informative with respect to diagnosis and subsequent management. Brain biopsy was performed in all patients to assist in both diagnosis and prognostication. All patients were determined to have progressive multifocal leukoencephalopathy (PML) by brain biopsy.

Feasibility, phase I, and phase II studies of tandutinib, an oral platelet-derived growth factor receptor-β tyrosine kinase inhibitor, in patients with recurrent glioblastoma

Background Platelet-derived growth factor (PDGF) signaling is important in gliomagenesis and PDGF receptor-β is expressed on most endothelial cells in glioblastoma specimens. Methods We report the results of feasibility, phase I, and phase II studies of tandutinib (MLN518), an orally bioavailable inhibitor of type III receptor tyrosine kinases including PDGF receptor-β, Fms-like tyrosine kinase 3, and c-Kit in patients with recurrent glioblastoma. Results In an initial feasibility study, 6 patients underwent resection for recurrent glioblastoma after receiving tandutinib 500mg twice daily for 7 days. The mean ratio of tandutinib concentration in brain tumor-to-plasma was 13.1±8.9 in 4 of the 6 patients. In the phase I study, 19 patients were treated at 500, 600, and 700mg twice daily dose levels. The maximum tolerated dose was found to be 600mg twice daily, and 30 patients were treated with this dose in the phase II study. The trial was closed after interim analysis, as the prespecified goal of patients alive and progression-free survival at 6 months was not achieved. Biomarker studies suggested that tandutinib treatment could lead to vascular disruption rather than normalization, which was associated with rapid progression. Conclusions Tandutinib readily distributed into the brain following oral administration and achieved concentrations within the tumor that exceed the corresponding concentration in plasma. The phase II study was closed at interim analysis due to lack of efficacy, although this study was not enriched for glioblastomas with alterations of the PDGF pathway.

Neuroradiographic variant of posterior reversible leukoencephalopathy

with acute confusion. Neurological examination was remarkable for a mild encephalopathy without focal or lateralizing features. Six weeks prior, she underwent unsuccessful induction treatment with adriamycin and high-dose cytarabine. Ten days previously, she received a bone marrow transplantation preceded by fludarabine and busulfan. Following transplantation, she received tacrolimus. At presentation, MRI sequences revealed multiple areas of abnormal signal intensity not appreciated on T1-weighted preand post-contrast sequences (Fig. 1). Tacrolimus was discontinued (serum levels were elevated on admission) and within several days, the patient’s encephalopathy markedly improved. Repeat MRI imaging was normal. The cardinal features of the posterior reversible leukoencephalopathy syndrome (PRES) are both clinical (i.e. hypertension, headaches, seizures, altered mental status and visual disturbances) and radiological [1–3]. The cortical gyriform appearance and topography of involvement (frontoparietal lobes and thalami) in this case are unusual as PRES usually is limited to the white matter of the parietal and occipital lobes [4, 5]. Most often PRES is associated with malignant hypertension or eclampsia however PRES is a well-described complication in normotensive patients (although an increase in mean arterial pressure is very often observed at onset of the syndrome) and in patients treated with tacrolimus and related immunophilins (i.e. cyclosporin). An additional consideration in the differential diagnosis of PRES in this case is high-dose chemotherapy administered in conjunction with stem cell transplantation. The presumed precipitating event in the development of PRES is acute endothelial cell damage resulting in a microangiopathy, cerebrovascular dysregulation and vasogenic edema. However the pathophysiology of PRES remains largely unknown.

Myelopathy from Intradural Extramedullary Metastasis as an Initial Presentation of Metastatic Melanoma

The incidence of metastatic melanoma (MM) has been steadily rising, and it is the third most common metastatic lesion to the central nervous system (CNS). Spinal intradural extramedullary (IDEM) MM is rare, and it is associated with coexisting or antecedent brain metastasis. Metastatic disease to the CNS is a complication of advanced disease, and it generally occurs months to years after initial diagnosis and treatment. We describe the first case of an initial presentation of MM, presenting as cervical myelopathy secondary to spinal cord compression from IDEM spinal metastasis. Further work-up revealed additional lesions in the temporal lobe and cauda equina region as well as a scalp lesion that was presumed to be the primary site. MM should be considered in the differential of myelopathy secondary to a spinal intradural mass, particularly in those with a history of or risk factors for melanoma.

Case Reports of Pembrolizumab-induced Acute Inflammatory Demyelinating Polyneuropathy

Pembrolizumab is a humanized monoclonal antibody that blocks the programmed cell death 1 (PD-1) pathway, thereby enhancing antitumor immunity. As the use of immune checkpoint inhibitors becomes more prevalent, so do immune-related adverse events associated with their use. The immune-related adverse events linked with this class of drugs are commonly seen and most of the time are classified as mild adverse events. These are easily treated with steroids if recognition of symptomatology and treatment are promptly established. However, neurologic immune-related adverse events are less understood and have been infrequently cited in the medical literature, thus representing a challenge for clinicians.

Abstract 233: Evaluating glioma risk associated with extent of European admixture in African-Americans and Latinos

Glioma incidence is highest in non-Hispanic Whites, where it occurs ~2x as frequently compared with other race/ethnicity groups. Glioma GWAS to date have included European ancestry populations only ...