Ankit I. Mehta

Glioblastoma multiforme: a review of where we have been and where we are going

Malignant gliomas such as glioblastoma multiforme (GBM) present some of the greatest challenges in the management of cancer patients worldwide, despite notable recent achievements in oncology. Even with aggressive surgical resections using state-of-the-art preoperative and intraoperative neuroimaging, along with recent advances in radiotherapy and chemotherapy, the prognosis for GBM patients remains dismal: median survival after diagnosis is about 14 months. Established good prognostic factors are limited, but include young age, high Karnofsky Performance Status (KPS), high mini-mental status examination score, O6-methylguanine methyltransferase promoter methylation, and resection of > 98% of the tumor. Standard treatment includes resection, followed by concurrent chemotherapy and radiotherapy. GBM research is being conducted worldwide at a remarkable pace, with some of the more recent promising studies focused on identification of aberrant genetic events and signaling pathways, tumor stem cell identification and characterization, modulation of tumor immunological responses, combination therapies, and understanding of the rare long-term survivors. Past treatment strategies have failed for various reasons; however, newer strategies in trials today and on the horizon encourage optimism. To help illustrate ‘where we have been’ with this fatal disease and ‘where we are going’ with contemporary studies, we include in this review a detailed history of Phase III clinical trials for GBM, with a final emphasis on exciting new treatment strategies that offer hope for future GBM therapy.

Glioblastoma multiforme: a review of therapeutic targets

Glioblastoma is the commonest primary brain tumor, as well as the deadliest. Malignant gliomas such as glioblastoma multiforme (GBM) present some of the greatest challenges in the management of cancer patients worldwide, despite notable recent achievements in oncology. Even with aggressive surgical resections using state-of-the-art preoperative and intraoperative neuroimaging, along with recent advances in radiotherapy and chemotherapy, the prognosis for GBM patients remains dismal: survival after diagnosis is about 1 year. Established prognostic factors are limited, but include age, Karnofsky performance status, mini-mental status examination score, O6-methylguanine methyltransferase promoter methylation and extent of surgery. Standard treatment includes resection of > 95% of the tumor, followed by concurrent chemotherapy and radiotherapy. Nevertheless, GBM research is being conducted worldwide at a remarkable pace, in the laboratory and at the bedside, with some of the more recent promising studies focused on identification of aberrant genetic events and signaling pathways to develop molecular-based targeted therapies, tumor stem cell identification and characterization, modulation of tumor immunological responses and understanding of the rare long-term survivors. With this universally fatal disease, any small breakthrough will have a significant impact on survival and provide hope to the thousands of patients who receive this diagnosis annually. This review describes the epidemiology, clinical presentation, pathology and tumor immunology, with a focus on understanding the molecular biology that underlies the current targeted therapeutics being tested.

Bispecific antibodies engage T cells for antitumor immunotherapy

Introduction: Although considerable evidence supports the hypothesis that T cells play a critical role in the immune response against cancer, the ability to mount and sustain tumor-specific cellular responses in vivo remains a challenge. A strategy that harnesses the cytotoxic advantage of T cell therapy is the use of bispecific antibodies designed to engage and activate endogenous polyclonal T cell populations via the CD3 complex, but only in the presence of a tumor antigen. While antibody constructs with dual specificity were first described as anticancer therapeutics over 25 years ago, it was not until recently that one subclass of bispecific single-chain antibody, the bispecific T cell engager (BiTE), emerged as superior to previous iterations in achieving efficacy in animal models and early clinical trials. Areas covered: The evolution of bispecific antibodies in antitumor immunotherapy is reviewed and the greatest hurdles impeding their clinical translation are discussed, specifically in the context of immunoprivileged sites as is the case for intracerebral malignancy. Expert opinion: The BiTE platform has great potential in the treatment of malignant disease. Despite burgeoning interest in bispecific antibodies and permutations thereof, the issues of stability and cost-effective production persist as obstacles.

2012 Young Investigator Award winner: The distribution of body mass as a significant risk factor for lumbar spinal fusion postoperative infections.

Study Design. A retrospective review. Objective. The purpose of this study was to determine the role in body habitus and weight distribution on developing a surgical site infection (SSI). Summary of Background Data. SSI after lumbar spine surgery remains a significant cause of morbidity. The literature demonstrates an increased risk of postoperative infections associated with obesity, diabetes, and multilevel surgeries. Methods. A retrospective review was performed on a consecutive cohort of 298 adult patients who underwent lumbar spine fusion surgeries between 2006 and 2008 at the Duke University Medical Center. Previously identified risk factors (i.e., number of levels, diabetes, body mass index [BMI]) were collected, as well as the horizontal distance from the lamina to the skin surface (measured at L4) and thickness of subcutaneous fat at the surgical site. Results. Among the 298 patients, 24 (8%) had postoperative infections. Of the previously identified risk factors, number of levels (P = 0.0078) was found to be significantly associated with infections, whereas BMI (P = 0.16) and diabetes (P = 0.13) were found not to be statistically significant. Obesity (BMI ≥30) (P = 0.025), skin to lamina distance (P = 0.046), and thickness of the subcutaneous fat (P = 0.035) were found to be significant risk factors for SSI. Conclusion. Our findings suggest that in obese patients, the distribution of body mass is more predictive of SSI than the absolute BMI and deserves attention in preoperative evaluation.

Extreme lateral interbody fusion approach for isolated thoracic and thoracolumbar spine diseases: initial clinical experience and early outcomes.

Study Design Retrospective review of prospective collected data on 22 patients. Objective To describe our initial clinical experience and outcomes with the extreme lateral interbody fusion (XLIF) approach for spinal diseases requiring access to the thoracic cavity. Summary of Background Data Minimally invasive anterior approaches to the thoracic spine have traditionally consisted of thoracoscopic and mini-open thoracotomy techniques. We present our initial experience with employing the XLIF technique to treat thoracic spine diseases. Methods Clinical, radiographic, operative, postoperative, and functional outcomes were analyzed. Results A total of 22 patients (15 females, 7 males, average age 64.6 y) with isolated thoracic and thoracolumbar spine diseases were treated between 2005 and 2009. The indications for surgery included degenerative scoliosis (11), pathological fractures from tumors (2), adjacent level disease from prior fusions (5), thoracic disc herniations (3), and discitis/osteomyelitis (1). A total of 47 levels were treated. In the subset of patients treated for degenerative scoliosis, the mean preoperative and postoperative coronal Cobb angles were 22 and 14, respectively. The mean preoperative and postoperative sagittal angles were 39 and 44, respectively. The average estimated blood loss and length of stay were 227.5 mL and 4.8 d, respectively. Three complications consisting of wound infection, subsidence, and adjacent level disease requiring additional procedures were encountered. There were no neural, vascular, visceral injuries, or death. At a mean follow-up of 16.4 months (range, 3-50), we observed a 95.5% substantial clinical benefit. All patients who had reached a minimum of 6 months (95.5%) demonstrated radiographic evidence of fusion. Conclusions The XLIF technique can be expanded to treat diseases in the thoracic spine. Although the magnitude of deformity correction achieved is less than that of the traditional open approaches, the lesser invasiveness of this technique may be tolerable for the elderly and in patients with significant medical comorbidities.

Management of a spontaneous spinal epidural abscess: a single-center 10-year experience.

OBJECTIVEThere is significant debate in the literature regarding the optimal management of patients with the diagnosis of a spinal epidural abscess (SEA). Although some have advocated conservative treatment with intravenous antibiotics alone in select patients, recent studies have shown that patients treated without early surgery are more likely to have poor outcomes. METHODSIn this study, we review patients treated at a tertiary medical center with a spontaneous SEA. A total of 104 patients had a diagnosis of an SEA over a 10-year period. More than half of these patients presented with back pain alone and no objective motor weakness. Sixty-four patients (61.5%) were treated conservatively with computed tomography-guided aspiration or antibiotics alone based on blood cultures, whereas 40 patients (38.5%) underwent surgical decompression. RESULTSOf the patients managed nonoperatively, 11% improved, 64% remained stable, and 17% died. Conversely, of the patients treated with surgery, 25% improved, 43% remained stable, and 23% died. Review of the imaging studies revealed that 65.4% of patients had a ventral SEA, whereas 34.6% had a dorsal SEA. Although there were no statistically significant differences between these 2 groups in terms of management or outcome, 30.6% of the patients with a dorsal SEA were paraplegic or quadriplegic, and only 7.3% of the patients with a ventral SEA were paraplegic or quadriplegic (P = 0.003). CONCLUSIONOur data do not support the hypothesis that patients treated without early surgery are more likely to have a poor outcome. Furthermore, we propose that the anatomy of the SEA (ventral or dorsal) should play an important role in determining the treatment plan.

Impact of tumor histology on resectability and neurological outcome in primary intramedullary spinal cord tumors: a single-center experience with 102 patients.

BACKGROUND Surgical outcomes for intramedullary spinal cord tumors are affected by many variables including tumor histology and preoperative neurological function. OBJECTIVE To analyze the impact of tumor histology on neurological outcome in primary intramedullary spinal cord tumors. METHODS A retrospective review of 102 consecutive patients with intramedullary spinal cord tumors treated at a single institution between January 1998 and March 2009. RESULTS Ependymomas were the most common tumors with 55 (53.9%), followed by 21 astrocytomas (20.6%), 12 hemangioblastomas (11.8%), and 14 miscellaneous tumors (13.7%). Gross total resection was achieved in 50 ependymomas (90.9%), 3 astrocytomas (14.3%), 11 hemangioblastomas (91.7%), and 12 miscellaneous tumors (85.7%). At a mean follow-up of 41.8 months (range, 1-132 months), we observed recurrences in 4 ependymoma cases (7.3%), 10 astrocytoma cases (47.6%), 1 miscellaneous tumor case (7.1%), and no recurrence in hemangioblastoma cases. When analyzed by tumor location, there was no difference in neurological outcomes (P = .66). At the time of their last follow-up visit, 11 patients (20%) with an ependymoma improved, 38 (69%) remained the same, and 6 (10.9%) worsened. In patients with an astrocytoma, 1 (4.8%) improved, 10 (47.6%) remained the same, and 10 (47.6%) worsened. One patient (8.3%) with a hemangioblastoma improved and 11 (91.7%) remained the same. No patient with a hemangioblastoma worsened. In the miscellaneous tumor group, 2 (14.3%) improved, 10 (71.4%) remained the same, and 2 (14.3%) worsened. Preoperative neurological status (P = .02), tumor histology (P = .005), and extent of resection (P < .0001) were all predictive of functional neurological outcomes. CONCLUSION Tumor histology is the most important predictor of neurological outcome after surgical resection because it predicts resectability and recurrence.

Colocalization of Gadolinium-Diethylene Triamine Pentaacetic Acid With High-Molecular-Weight Molecules After Intracerebral Convection-Enhanced Delivery in Humans

BACKGROUND:Convection-enhanced delivery (CED) permits site-specific therapeutic drug delivery within interstitial spaces at increased dosages through circumvention of the blood-brain barrier. CED is currently limited by suboptimal methodologies for monitoring the delivery of therapeutic agents that would permit technical optimization and enhanced therapeutic efficacy. OBJECTIVE:To determine whether a readily available small-molecule MRI contrast agent, gadolinium-diethylene triamine pentaacetic acid (Gd-DTPA), could effectively track the distribution of larger therapeutic agents. METHODS:Gd-DTPA was coinfused with the larger molecular tracer, 124I-labeled human serum albumin (124I-HSA), during CED of an EGFRvIII-specific immunotoxin as part of treatment for a patient with glioblastoma. RESULTS:Infusion of both tracers was safe in this patient. Analysis of both Gd-DTPA and 124I-HSA during and after infusion revealed a high degree of anatomical and volumetric overlap. CONCLUSION:Gd-DTPA may be able to accurately demonstrate the anatomic and volumetric distribution of large molecules used for antitumor therapy with high resolution and in combination with fluid-attenuated inversion recovery (FLAIR) imaging, and provide additional information about leaks into cerebrospinal fluid spaces and resection cavities. Similar studies should be performed in additional patients to validate our findings and help refine the methodologies we used.

Therapeutic approaches for HER2-positive brain metastases: circumventing the blood-brain barrier.

We aim to summarize data from studies of trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) and brain metastasis and to describe novel methods being developed to circumvent the blood-brain barrier (BBB). A literature search was conducted to obtain data on the clinical efficacy of trastuzumab and lapatinib in patients with HER2-positive MBC and brain metastasis, as well as the transport of therapeutic molecules across the BBB. Trastuzumab-based therapy is the standard of care for patients with HER2-positive MBC. Post hoc and retrospective analyses show that trastuzumab significantly prolongs overall survival when given after the diagnosis of central nervous system (CNS) metastasis; this is probably attributable to its control of extracranial disease, although trastuzumab may have a direct effect on CNS disease in patients with local or general perturbation of the BBB. In patients without a compromised BBB, trastuzumab is thought to have limited access to the brain, because of its relatively large molecular size. Several approaches are being developed to enhance the delivery of therapeutic agents to the brain. These include physical or pharmacologic disruption of the BBB, direct intracerebral drug delivery, drug manipulation, and coupling drugs to transport vectors. Available data suggest that trastuzumab extends survival in patients with HER2-positive MBC and brain metastasis. Novel methods for delivery of therapeutic agents into the brain could be used in the future to enhance access to the CNS by trastuzumab, thereby improving its efficacy in this setting.

A novel method for volumetric MRI response assessment of enhancing brain tumors.

Current radiographic response criteria for brain tumors have difficulty describing changes surrounding postoperative resection cavities. Volumetric techniques may offer improved assessment, however usually are time-consuming, subjective and require expert opinion and specialized magnetic resonance imaging (MRI) sequences. We describe the application of a novel volumetric software algorithm that is nearly fully automated and uses standard T1 pre- and post-contrast MRI sequences. T1-weighted pre- and post-contrast images are automatically fused and normalized. The tumor region of interest is grossly outlined by the user. An atlas of the nasal mucosa is automatically detected and used to normalize levels of enhancement. The volume of enhancing tumor is then automatically calculated. We tested the ability of our method to calculate enhancing tumor volume with resection cavity collapse and when the enhancing tumor is obscured by subacute blood in a resection cavity. To determine variability in results, we compared narrowly-defined tumor regions with tumor regions that include adjacent meningeal enhancement and also compared different contrast enhancement threshold levels used for the automatic calculation of enhancing tumor volume. Our method quantified enhancing tumor volume despite resection cavity collapse. It detected tumor volume increase in the midst of blood products that incorrectly caused decreased measurements by other techniques. Similar trends in volume changes across scans were seen with inclusion or exclusion of meningeal enhancement and despite different automated thresholds for tissue enhancement. Our approach appears to overcome many of the challenges with response assessment of enhancing brain tumors and warrants further examination and validation.