Jacob J. Mandel

Lambrolizumab induced central nervous system (CNS) toxicity

Programmed death 1(PD-1) is a strategic receptor on activated T-cells that mediates immunosuppression in cancer. Lambrolizumab is a humanized monoclonal IgG4–kappa isotype antibody designed to block the negative immune regulatory signaling of the PD-1 receptor expressed by T cells.1 Anti–PD-1 monoclonal antibodies have activity against several solid tumors.2 Recently, the FDA designated lambrolizumab as a breakthrough therapy for patients with advanced melanoma. We describe a patient with metastatic melanoma placed on a clinical trial with lambrolizumab who developed CNS toxicity.

Update on Anti-angiogenic Treatment for Malignant Gliomas

Malignant gliomas are the most common primary brain tumor found in adults. Unfortunately, the prognosis for these type of tumors remains dismal despite aggressive treatment with surgical resection, radiation and chemotherapy. Therefore, therapeutics aimed at disrupting the angiogenesis of these tumors is being utilized in to improve survival outcomes and quality of life. This paper reviews the history of antiangiogenic agents in malignant gliomas, discusses the FDA approval of bevacizumab as monotherapy in recurrent glioblastoma and the subsequent controversy, and analyzes the most recent newly diagnosed trials of RTOG 0825 and AVAglio. Additionally, the results of the latest trials with antiangiogenic agents and possible biomarkers are reviewed. Multiple questions remain regarding the potential benefit of antiangiogenic treatments in patients with glioblastoma. Future clinical trials should be designed to learn more about these drugs, to optimize their future use.

Neurologic complications of immune checkpoint inhibitors

Immune checkpoint inhibitors (ICPIs) have recently emerged as a novel treatment for cancer. These agents, transforming the field of oncology, are not devoid of toxicity and cause immune-related side effects which can involve any organ including the nervous system. In this study, we present 9 patients (7 men and 2 women) with neurologic complications secondary to ICPI treatment. These included meningoencephalitis, limbic encephalitis, polyradiculitis, cranial polyneuropathy, myasthenic syndrome and myositis. Four patients received dual ICPI therapy comprised of programmed cell death-1 and cytotoxic lymphocyte associated protein-4 blocking antibodies. Median time to onset of neurologic adverse event during immune checkpoint inhibitor treatment was 8 weeks (range 5 days–19 weeks). In all patients ICPIs were stopped and corticosteroids were initiated, resulting in a marked improvement in seven out of nine patients. Two patients, one with myositis and one with myasthenic syndrome, died. In two patients ICPI therapy was resumed after resolution of the neurological adverse event with no additional neurologic complications. This series highlights the very broad spectrum of neurological complications of ICPIs, emphasizes the need for expedited diagnosis and suggests that withholding treatment early, accompanied with steroid therapy, carries the potential of complete resolution of the neurological immune-mediated condition. Thus, a high level of suspicion and rapid initiation of corticosteroids are mandatory to prevent uncontrolled clinical deterioration, which might be fatal.

Radiographic patterns of progression with associated outcomes after bevacizumab therapy in glioblastoma patients

Treatment response and survival after bevacizumab failure remains poor in patients with glioblastoma. Several recent publications examining glioblastoma patients treated with bevacizumab have described specific radiographic patterns of disease progression as correlating with outcome. This study aims to scrutinize these previously reported radiographic prognostic models in an independent data set to inspect their reproducibility and potential for clinical utility. Sixty four patients treated at MD Anderson matched predetermined inclusion criteria. Patients were categorized based on previously published data by: (1) Nowosielski et al. into: T2-diffuse, cT1 Flare-up, non-responders and T2 circumscribed groups (2) Modified Pope et al. criteria into: local, diffuse and distant groups and (3) Bahr et al. into groups with or without new diffusion-restricted and/or pre-contrast T1-hyperintense lesions. When classified according to Nowosielski et al. criteria, the cT1 Flare-up group had the longest overall survival (OS) from bevacizumab initiation, with non-responders having the worst outcomes. The T2 diffuse group had the longest progression free survival (PFS) from start of bevacizumab. When classified by modified Pope at al. criteria, most patients did not experience a shift in tumor pattern from the pattern at baseline, while the PFS and OS in patients with local-to-local and local-to-diffuse/distant patterns of progression were similar. Patients developing restricted diffusion on bevacizumab had worse OS. Diffuse patterns of progression in patients treated with bevacizumab are rare and not associated with worse outcomes compared to other radiographic subgroups. Emergence of restricted diffusion during bevacizumab treatment was a radiographic marker of worse OS.

Inability of positive phase II clinical trials of investigational treatments to subsequently predict positive phase III clinical trials in glioblastoma

Background Glioblastoma is the most common primary malignant brain tumor in adults, but effective therapies are lacking. With the scarcity of positive phase III trials, which are increasing in cost, we examined the ability of positive phase II trials to predict statistically significant improvement in clinical outcomes of phase III trials. Methods A PubMed search was conducted to identify phase III clinical trials performed in the past 25 years for patients with newly diagnosed or recurrent glioblastoma. Trials were excluded if they did not examine an investigational chemotherapy or agent, if they were stopped early owing to toxicity, if they lacked prior phase II studies, or if a prior phase II study was negative. Results Seven phase III clinical trials in newly diagnosed glioblastoma and 4 phase III clinical trials in recurrent glioblastoma met the inclusion criteria. Only 1 (9%) phase III study documented an improvement in overall survival and changed the standard of care. Conclusion The high failure rate of phase III trials demonstrates the urgent need to increase the reliability of phase II trials of treatments for glioblastoma. Strategies such as the use of adaptive trial designs, Bayesian statistics, biomarkers, volumetric imaging, and mathematical modeling warrant testing. Additionally, it is critical to increase our expectations of phase II trials so that positive findings increase the probability that a phase III trial will be successful.

Intracranial epithelioid hemangioendothelioma causing subacute loss of vision

A 37-year-old woman presented with left eye pain, headaches, and vision loss. MRI showed a left sphenoid mass, with optic nerve compression and proptosis (figure 1). The left eye had minimal reactivity to light, scleral erythema, and proptosis. A metastatic lesion or a lymphoma was suspected; however, pathology showed an epithelioid hemangioendothelioma (figure 2). There was no extracranial disease. Intracranial epithelioid hemangioendothelioma is rare, with around 40 reports. Thirty-two percent show local invasion, mortality is 15%, 24% recur, and 15% metastasize.1 It is associated with the WWTR1/CAMTA1 fusion protein.2 The treatment is surgery, with unclear roles for adjuvant therapy.1

Highlighting the need for reliable clinical trials in glioblastoma

ABSTRACT Introduction: Several recent phase III studies have attempted to improve the dismal survival seen in glioblastoma patients, with disappointing results despite prior promising phase II data. Areas covered: A literature review of prior phase II and phase III studied in glioblastoma was performed to help identify possible areas of concern. Numerous issues in previous phase II trials for glioblastoma were found that may have contributed to these discouraging outcomes and discordant results. Expert commentary: These concerns include the improper selection of therapeutics warranting investigation in a phase III trial, suboptimal design of phase II studies (often lacking a control arm), absence of molecular data, the use of imaging criteria as a surrogate endpoint, and a lack of pharmacodynamic testing. Hopefully, by recognizing prior phase II trial limitations that contributed to failed phase III trials, we can adapt quickly to improve our ability to accurately discover survival-prolonging treatments for glioblastoma patients.

Spinal Dural Arteriovenous Fistula and Concomitant Intramedullary Spinal Lesion

2. Koenig E, Thron A, Schrader V, Dichgans J. Spinal arteriovenous malformations and fistulae: clinical, neuroradiological and neurophysiologic findings. J Neurol. 1989;236(5):260-266. 3. Kim DJ, Willinsky R, Geibprasert S, et al. Angiographic characteristics and treatment of cervical spinal dural arteriovenous shunts. AJNR Am J Neuroradiol. 2010;31(8):1512-1515. 4. Morris JM. Imaging of dural arteriovenous fistula. Radiol Clin North Am. 2012;50(4):823-839. Spinal Dural Arteriovenous Fistula and Concomitant Intramedullary Spinal Lesion Fábio A. Nascimento1, Peter Kan2, Lydia Sharp1, Jacob J. Mandel1

Targeting Aberrant Signaling Pathways

Malignant gliomas are the most common primary brain tumors in adults. Prognosis remains dismal despite aggressive treatment with surgical resection, radiation, and chemotherapy. The use of advanced sequencing technologies and large-scale gene expression studies has provided an in-depth description of the distinct molecular and genetic alterations in glioblastoma inspiring interest in the development of targeted therapies. Unfortunately, despite trials with several agents and different pathways, targeted therapies have currently failed to improve the overall survival of glioblastoma patients. New therapies examining novel targets and innovative drug combinations are presently under investigation that will hopefully prove more beneficial.

Recent Advances for Targeted Therapies in Glioblastoma

Glioblastoma (GBM) is the most common primary brain tumors in adults. Despite aggressive multimodality therapies, GBM unfortunately remains among the most resistant cancers to treatment. In the past, traditional chemotherapy which works by impeding DNA synthesis or cell metabolism has been used to try and slow the progression of GBM with little success. Recently, research has become more focused into the development of targeted therapies in which drugs (small molecules or antibodies) effect specific molecular and genetic alterations in GBM attempting to inhibit and deregulate cell signaling pathways. The Cancer Genome Atlas (TCGA) GBM project has provided an in depth description of the distinct molecular and genetic alterations in GBM stimulating interest in the development of targeted molecular therapies. While the results of targeted therapy studies to date have failed to improve the overall survival of GBM patients, there continues to be enthusiasm in this approach with numerous clinical trials currently underway. Hopefully, knowledge from the previous failed trials will help provide further insight and assist future clinicians in designing new novel targeted treatments to overcome these barriers.