Shayan Fakurnejad

Immunocompetent murine models for the study of glioblastoma immunotherapy

Glioblastoma remains a lethal diagnosis with a 5-year survival rate of less than 10%. (NEJM 352:987-96, 2005) Although immunotherapy-based approaches are capable of inducing detectable immune responses against tumor-specific antigens, improvements in clinical outcomes are modest, in no small part due to tumor-induced immunosuppressive mechanisms that promote immune escape and immuno-resistance. Immunotherapeutic strategies aimed at bolstering the immune response while neutralizing immunosuppression will play a critical role in improving treatment outcomes for glioblastoma patients. In vivo murine models of glioma provide an invaluable resource to achieving that end, and their use is an essential part of the preclinical workup for novel therapeutics that need to be tested in animal models prior to testing experimental therapies in patients. In this article, we review five contemporary immunocompetent mouse models, GL261 (C57BL/6), GL26 (C57BL/6) CT-2A (C57BL/6), SMA-560 (VM/Dk), and 4C8 (B6D2F1), each of which offer a suitable platform for testing novel immunotherapeutic approaches.

Heat shock protein vaccines against glioblastoma: from bench to bedside

Current adjuvant treatment regimens available for the treatment of glioblastoma are widely ineffective and offer a dismal prognosis. Advancements in conventional treatment strategies have only yielded modest improvements in overall survival. Immunotherapy remains a promising adjuvant in the treatment of GBM through eliciting tumor specific immune responses capable of producing sustained antitumor response while minimizing systemic toxicity. Heat shock proteins (HSP) function as intracellular chaperones and have been implicated in the activation of both innate and adaptive immune systems. Vaccines formulated from HSP-peptide complexes, derived from autologous tumor, have been applied to the field of immunotherapy for glioblastoma. The results from the phase I and II clinical trials have been promising. Here we review the role of HSP in cellular function and immunity, and its application in the treatment of glioblastoma.

Anticonvulsant prophylaxis for brain tumor surgery: determining the current best available evidence

Patients who undergo craniotomy for brain tumor resection are prone to experiencing seizures, which can have debilitating medical, neurological, and psychosocial effects. A controversial issue in neurosurgery is the common practice of administering perioperative anticonvulsant prophylaxis to these patients despite a paucity of supporting data in the literature. The foreseeable benefits of this strategy must be balanced against potential adverse effects and interactions with critical medications such as chemotherapeutic agents and corticosteroids. Multiple disparate metaanalyses have been published on this topic but have not been applied into clinical practice, and, instead, personal preference frequently determines practice patterns in this area of management. Therefore, to select the current best available evidence to guide clinical decision making, the literature was evaluated to identify meta-analyses that investigated the efficacy and/or safety of anticonvulsant prophylaxis in this patient population. Six meta-analyses published between 1996 and 2011 were included in the present study. The Quality of Reporting of Meta-analyses and Oxman-Guyatt methodological quality assessment tools were used to score these meta-analyses, and the Jadad decision algorithm was applied to determine the highest-quality meta-analysis. According to this analysis, 2 metaanalyses were deemed to be the current best available evidence, both of which conclude that prophylactic treatment does not improve seizure control in these patients. Therefore, this management strategy should not be routinely used.

Evidence-based management of traumatic thoracolumbar burst fractures: a systematic review of nonoperative management

OBJECT The overall evidence for nonoperative management of patients with traumatic thoracolumbar burst fractures is unknown. There is no agreement on the optimal method of conservative treatment. Recent randomized controlled trials that have compared nonoperative to operative treatment of thoracolumbar burst fractures without neurological deficits yielded conflicting results. By assessing the level of evidence on conservative management through validated methodologies, clinicians can assess the availability of critically appraised literature. The purpose of this study was to examine the level of evidence for the use of conservative management in traumatic thoracolumbar burst fractures. METHODS A comprehensive search of the English literature over the past 20 years was conducted using PubMed (MEDLINE). The inclusion criteria consisted of burst fractures resulting from a traumatic mechanism, and fractures of the thoracic or lumbar spine. The exclusion criteria consisted of osteoporotic burst fractures, pathological burst fractures, and fractures located in the cervical spine. Of the studies meeting the inclusion/exclusion criteria, any study in which nonoperative treatment was used was included in this review. RESULTS One thousand ninety-eight abstracts were reviewed and 447 papers met inclusion/exclusion criteria, of which 45 were included in this review. In total, there were 2 Level-I, 7 Level-II, 9 Level-III, 25 Level-IV, and 2 Level-V studies. Of the 45 studies, 16 investigated conservative management techniques, 20 studies compared operative to nonoperative treatments, and 9 papers investigated the prognosis of conservative management. CONCLUSIONS There are 9 high-level studies (Levels I-II) that have investigated the conservative management of traumatic thoracolumbar burst fractures. In neurologically intact patients, there is no superior conservative management technique over another as supported by a high level of evidence. The conservative technique can be based on patient and surgeon preference, comfort, and access to resources. A high level of evidence demonstrated similar functional outcomes with conservative management when compared with open surgical operative management in patients who were neurologically intact. The presence of a neurological deficit is not an absolute contraindication for conservative treatment as supported by a high level of evidence. However, the majority of the literature excluded patients with neurological deficits. More evidence is needed to further classify the appropriate burst fractures for conservative management to decrease variables that may impact the prognosis.

Evidence-Based Medicine of Traumatic Thoracolumbar Burst Fractures: A Systematic Review of Operative Management across 20 Years.

Study Design Systematic literature review. Objective The management of traumatic thoracolumbar burst fractures (TLBF) remains challenging, and analyzing the levels of evidence (LOEs) for treatment practices can reform the decision-making process. However, no review has yet evaluated the operative management of traumatic thoracolumbar burst fractures with particular attention placed on LOE from an established methodology. The objective of the present study was to characterize the literature evidence for TLBF, specifically for operative management. Methods A comprehensive search of the English literature over the past 20 years was conducted using PubMed (MEDLINE). The inclusion criteria consisted of (1) traumatic burst fractures (2) in the thoracic or lumbar spine. Exclusion criteria included (1) osteoporotic burst fractures, (2) pathologic burst fractures, (3) cervical fractures, (4) biomechanical studies or those involving cadavers, and (5) computer-based studies. Studies were assigned an LOE and those meeting level 1 or 2 were included. Results From 1,138 abstracts, 272 studies met the criteria. Twenty-three studies (8.5%) met level 1 (n = 4, 1.5%) or 2 (n = 19, 7.0%) criteria. All 23 studies were reported. Conclusions The literature contains a high LOE to support the operative management of traumatic thoracolumbar burst fractures. For patients who are neurologically intact, a high LOE demonstrated similar functional outcomes, lower complication rates, and less costs with conservative management when compared with surgical management. There is a high LOE for short- or long-segment pedicle instrumentation without fusion and less invasive (percutaneous and paraspinal) approaches. Furthermore, the posterior approaches are associated with lower complications as opposed to the anterior or combined approaches.

The likelihood of reaching minimum clinically important difference and substantial clinical benefit at 2 years following a 3-column osteotomy: analysis of 140 patients

OBJECT Three-column osteotomies (3COs) are technically challenging techniques for correcting severe rigid spinal deformities. The impact of these interventions on outcomes reaching minimum clinically important difference (MCID) or substantial clinical benefit (SCB) is unclear. The objective of this study was to determine the rates of MCID and SCB in standard health-related quality of life (HRQOL) measures after 3COs in patients with adult spinal deformity (ASD). The impacts of location of the uppermost instrumented vertebra (UIV) on clinical outcomes and of maintenance on sagittal correction at 2 years postoperatively were also examined. METHODS The authors conducted a retrospective multicenter analysis of the records from adult patients who underwent 3CO with complete 2-year radiographic and clinical follow-ups. Cases were categorized according to established radiographic thresholds for pelvic tilt (> 22°), sagittal vertical axis (> 4.7 cm), and the mismatch between pelvic incidence and lumbar lordosis (> 11°). The cases were also analyzed on the basis of a UIV in the upper thoracic (T1-6) or thoracolumbar (T9-L1) region. Patient-reported outcome measures evaluated preoperatively and 2 years postoperatively included Oswestry Disability Index (ODI) scores, the Physical Component Summary and Mental Component Summary (MCS) scores of the 36-Item Short Form Health Survey, and Scoliosis Research Society-22 questionnaire (SRS-22) scores. The percentages of patients whose outcomes for these measures met MCID and SCB were compared among the groups. RESULTS Data from 140 patients (101 women and 39 men) were included in the analysis; the average patient age was 57.3 ± 12.4 years (range 20-82 years). Of these patients, 94 had undergone only pedicle subtraction osteotomy (PSO) and 42 only vertebral column resection (VCR); 113 patients had a UIV in the upper thoracic (n = 63) orthoracolumbar region (n = 50). On average, 2 years postoperatively the patients had significantly improved in all HRQOL measures except the MCS score. For the entire patient cohort, the improvements ranged from 57.6% for the SRS-22 pain score MCID to 24.4% for the ODI score SCB. For patients undergoing PSO or VCR, the likelihood of their outcomes reaching MCID or SCB ranged from 24.3% to 62.3% and from 16.2% to 47.8%, respectively. The SRS-22 self-image score of patients who had a UIV in the upper thoracic region reached MCID significantly more than that of patients who had a UIV in the thoracolumbar region (70.6% vs 41.9%, p = 0.0281). All other outcomes were similar for UIVs of upper thoracic and thoracolumbar regions. Comparison of patients whose spines were above or below the radiographic thresholds associated with disability indicated similar rates of meeting MCID and SCB for HRQOL at the 2-year follow-up. CONCLUSIONS Outcomes for patients having UIVs in the upper thoracic region were no more likely to meet MCID or SCB than for those having UIVs in the thoracolumbar region, except for the MCID in the SRS-22 self-image measure. The HRQOL outcomes in patients who had optimal sagittal correction according to radiographic thresholds determined preoperatively were not significantly more likely to reach MCID or SCB at the 2-year follow-up. Future work needs to determine whether the Schwab preoperative radiographic thresholds for severe disability apply in postoperative settings.

Proportional Upregulation of CD97 Isoforms in Glioblastoma and Glioblastoma-Derived Brain Tumor Initiating Cells

CD97 is a novel glioma antigen that confers an invasive phenotype and poor survival in patients with glioblastoma (GBM), the most aggressive primary malignant brain tumor. The short isoform of CD97, known as EGF(1,2,5), has been shown to promote invasion and metastasis, but its role in gliomas and GBM-derived brain tumor initiating cells (BTICs) has not been studied. We sought to characterize CD97 expression among gliomas and identify the specific isoforms expressed. The short isoform of CD97 was identified in GBM and GBM-derived BTICs, but not low grade or anaplastic astrocytomas. All samples expressing the EGF(1,2,5) isoform were also found to express the EGF(1,2,3,5) isoform. These isoforms are believed to possess similar ligand binding patterns and interact with chondroitin sulfate, a component of the extracellular matrix, and the integrin α5β1. Using data acquired from the Cancer Genome Atlas (TCGA), we show that CD97 is upregulated among the classical and mesenchymal subtypes of GBM and significantly decreased among IDH1 mutant GBMs. Given its proven roles in tumor invasion, expression among aggressive genetic subtypes of GBM, and association with overall survival, CD97 is an attractive therapeutic target for patients with GBM.

Biomechanics of thoracolumbar burst fractures: Methods of induction and treatments

Much controversy exists regarding the mechanism of burst fracture (BF) induction and the proper techniques to treat such fractures. As such, there is a great need for validated preclinical models in which to study these injuries. In this study, an electronic search of the PubMed database (MEDLINE) was performed and the results were filtered to obtain only studies with a biomechanical focus. Forty five biomechanical studies were obtained, from which four distinct methods of injury induction were identified. Twenty one (46.7%) involved clinically relevant techniques for treating BF, involving anterior, posterior, circumferential, or a combination of approaches. Fifteen (71.4%) of the treatment studies used unstable spine specimens that do not fit the classical characteristics of BF. Given the consistent use of BF models that do not adhere to classical definitions, the clinical value of ex vivo induction is uncertain.

Minimally invasive spinal surgery for the treatment of traumatic thoracolumbar burst fractures

The optimum management of traumatic thoracolumbar burst fractures is cause for much debate in the literature. Although minimally invasive surgery (MIS) approaches are increasingly used in the management of degenerative spinal pathology, their role in treating burst fractures is unknown. Assessing the level of evidence (LOE) for use of MIS approaches in vertebral burst fractures may impart better understanding of how to integrate MIS in the treatment schema for these fractures. A comprehensive literature review was conducted using MEDLINE for all articles published on traumatic thoracolumbar burst fractures through to July 2013. LOE was assigned according to the standards set forth by the Journal of Clinical Orthopaedics and Related Research and the Oxford Centre for Evidence Based Medicine. Full texts were reviewed to select only those articles discussing MIS approaches as a treatment modality. A total of 501 articles met both inclusion and exclusion criteria, and 403 of those were published within the past two decades. Among those, 35 articles detailed the use of MIS approaches in the management of traumatic thoracolumbar burst fractures. Only three studies provided high LOE: one level 1 study and two level 2 studies. Thirteen studies described the use of vertebroplasty or kyphoplasty, but all were level 4 or level 5 studies. Currently, the LOE for utilization of MIS approaches to manage traumatic thoracolumbar burst fractures is low. Further work in the form of prospective randomized controlled trials is needed to ascertain how MIS may be integrated into the treatment scheme for thoracolumbar burst fractures.

Vaccine Therapies in Malignant Glioma

Glioblastoma is a grade IV astrocytoma that is widely accepted in clinical neurosurgery as being an extremely lethal diagnosis. Long-term survival rates remain dismal, and even when tumors undergo gross resection with confirmation of total removal on neuroimaging, they invariably recur with even greater virulence. Standard therapeutic modalities as well as more contemporary treatments have largely resulted in disappointing improvements. However, the therapeutic potential of vaccine immunotherapy for malignant glioma should not be underestimated. In contrast to many of the available treatments, vaccine immunotherapy is unique because it offers the means of delivering treatment that is highly specific to both the patient and the tumor. Peptide, heat-shock proteins, and dendritic cell vaccines collectively encapsulate the majority of research efforts involving vaccine-based treatment modalities. In this review, important recent findings for these vaccine types are discussed in the context of ongoing clinical trials. Broad challenges to immunotherapy are also considered.