Central neurogenic hyperventilation: pharmacologic intervention with morphine sulfate and correlative analysis of respiratory, sleep, and ocular motor dysfunction.

Journal ArticleCentral neurogenic hyperventilation (CNH), for which there is no effective therapy, can eventually result in respiratory fatigue and death. This report describes a patient with CNH due to a brainstem anaplastic astrocytoma who also exhibited disturbances of sleep and ocular motor function. The CNH responded clinically to morphine sulfate and methadone. Analysis of ventilatory response to CO2 before and after morphine demonstrated a depression of ventilatory response (49 to 53% of baseline) and occlusion pressure response (35 to 50% of baseline) to CO2, with a requirement for high doses of naloxone (10 mg IV) to reverse the effect. Polysomnography revealed sustained hyperventilation, elevated O2 saturation, and low end-tidal CO2 throughout all stages of non-rapid eye movement (NREM) sleep, and absence of rapid eye movement (REM) sleep. Ocular motor evaluation disclosed absence of horizontal and reflexive saccades with compensatory head thrusts. Correlation of the clinical and physiologic data with the MRI abnormalities suggested that the lesion responsible for CNH in this patient might reside in the medial tegmental parapontine reticular formation. Since recurrent episodes of hyperventilation responded in a sustained fashion to IV and oral opiates, this treatment may warrant consideration in other patients with CNH

Isocitrate Dehydrogenase Mutant Grade II and III Glial Neoplasms

Mutations in isocitrate dehydrogenase (IDH) 1 or IDH2 occur in the majority of adult low-grade gliomas and, less commonly, in cholangiocarcinoma, chondrosarcoma, acute myeloid leukemia, and other human malignancies. Cancer-associated mutations alter the function of the enzyme, resulting in production of R(-)-2-hydroxyglutarate (R-2-HG) and broad epigenetic dysregulation. Small molecule IDH inhibitors have received regulatory approval for the treatment of IDH mutant (mIDH) leukemia and are under development for the treatment of mIDH solid tumors. This article provides a current view of IDH mutant adult astrocytic and oligodendroglial tumors, including their clinical presentation and treatment, and discusses novel approaches and challenges toward improving the treatment of these tumors

Phase I/randomized phase II trial of TRC105 plus bevacizumab versus bevacizumab in recurrent glioblastoma: North Central Cancer Treatment Group N1174 (Alliance)

Background Patients with glioblastoma (GBM) have a poor prognosis and limited effective treatment options. Bevacizumab has been approved for treatment of recurrent GBM, but there is questionable survival benefit. Based on preclinical and early clinical data indicating that CD105 upregulation may represent a mechanism of resistance to bevacizumab, we hypothesized that combining bevacizumab with the anti-CD105 antibody TRC105 may improve efficacy in recurrent GBM.Methods Phase I dose-escalation/comparative randomized phase II trial in patients with GBM. During phase I, the maximum tolerated dose (MTD) of TRC105 in combination with bevacizumab was determined. In phase II, patients were randomized 1:1 to TRC105 and bevacizumab or bevacizumab monotherapy. Patients receivedTRC105 (10 mg/kg) weekly and bevacizumab (10 mg/kg) every 2 weeks. Efficacy, as assessed by progression-free survival (PFS), was the primary endpoint; safety, quality of life, and correlative outcomes were also evaluated.Results In total, 15 patients were enrolled in phase I and 101 in phase II; 52 patients were randomized to TRC105 with bevacizumab and 49 to bevacizumab monotherapy. The MTD was determined to be 10 mg/kg TRC105 weekly plus bevacizumab 10 mg/kg every 2 weeks. An increased occurrence of grade >= 3 adverse events was seen in the combination arm, including higher incidences of anemia. Median PFS was similar in both treatment arms: 2.9 months for combination versus 3.2 months for bevacizumab monotherapy (HR = 1.16, 95% CI = 0.75-1.78, P = .51). Quality of life scores were similar for both treatment arms.Conclusions TRC105 in combination with bevacizumab was well tolerated in patients with recurrent GBM, but no difference in efficacy was observed compared to bevacizumab monotherapy

A randomized trial of bevacizumab for newly diagnosed glioblastoma.

BACKGROUND: Concurrent treatment with temozolomide and radiotherapy followed by maintenance temozolomide is the standard of care for patients with newly diagnosed glioblastoma. Bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor A, is currently approved for recurrent glioblastoma. Whether the addition of bevacizumab would improve survival among patients with newly diagnosed glioblastoma is not known. METHODS: In this randomized, double-blind, placebo-controlled trial, we treated adults who had centrally confirmed glioblastoma with radiotherapy (60 Gy) and daily temozolomide. Treatment with bevacizumab or placebo began during week 4 of radiotherapy and was continued for up to 12 cycles of maintenance chemotherapy. At disease progression, the assigned treatment was revealed, and bevacizumab therapy could be initiated or continued. The trial was designed to detect a 25% reduction in the risk of death and a 30% reduction in the risk of progression or death, the two coprimary end points, with the addition of bevacizumab. RESULTS: A total of 978 patients were registered, and 637 underwent randomization. There was no significant difference in the duration of overall survival between the bevacizumab group and the placebo group (median, 15.7 and 16.1 months, respectively; hazard ratio for death in the bevacizumab group, 1.13). Progression-free survival was longer in the bevacizumab group (10.7 months vs. 7.3 months; hazard ratio for progression or death, 0.79). There were modest increases in rates of hypertension, thromboembolic events, intestinal perforation, and neutropenia in the bevacizumab group. Over time, an increased symptom burden, a worse quality of life, and a decline in neurocognitive function were more frequent in the bevacizumab group. CONCLUSIONS: First-line use of bevacizumab did not improve overall survival in patients with newly diagnosed glioblastoma. Progression-free survival was prolonged but did not reach the prespecified improvement target. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00884741.)

Ototoxicity of cisplatin plus standard radiation therapy vs. accelerated radiation therapy in glioblastoma patients

Purpose : To assess the effect of cisplatin (CDDP) plus concurrent radiation therapy on hearing loss. Methods : 451 patients with glioblastoma multiforme (GBM) were randomly assigned after surgery to: Arm A: Carmustine (BCNU) + standard radiation therapy (SRT); Arm B: BCNU + accelerated radiation therapy (ART: 160 cGy twice daily for 15 days); Arm C: CDDP + BCNU + SRT; or Arm D: CDDP + BCNU + ART. Patients on arms C and D received audiograms at baseline, and prior to the start of RT, and prior to cycles 3 and 6. Otologic toxicities were recorded at each visit. Results : 56% of patients had hearing loss at baseline. 13% and 50% of patients experienced worsening ototoxicity after 1 year of treatment in arms A and B vs. C and D, respectively, with 13% of those on arms C and D experiencing significant ototoxicity (≥ grade 3) at 6 months. Increasing age was associated with an increased risk of ototoxicity. Conclusions : Increased exposure to CDDP increases the risk of ototoxicity over time. Older patients are more susceptible to hearing loss with CDDP. The low proportion of patients with clinically significant ototoxicity suggests that baseline screening is unnecessary in GBM patients.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/43476/1/11060_2005_Article_9049.pd

Isocitrate Dehydrogenase Mutant Grade II and III Glial Neoplasms

Mutations in isocitrate dehydrogenase (IDH) 1 or IDH2 occur in most of the adult low-grade gliomas and, less commonly, in cholangiocarcinoma, chondrosarcoma, acute myeloid leukemia, and other human malignancies. Cancer-associated mutations alter the function of the enzyme, resulting in production of R(-)-2-hydroxyglutarate and broad epigenetic dysregulation. Small molecule IDH inhibitors have received regulatory approval for the treatment of IDH mutant (mIDH) leukemia and are under development for the treatment of mIDH solid tumors. This article provides a current view of mIDH adult astrocytic and oligodendroglial tumors, including their clinical presentation and treatment, and discusses novel approaches and challenges toward improving the treatment of these tumors