Eli T. Sayegh

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.

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.

Adjuvant radiotherapy delays recurrence following subtotal resection of spinal cord ependymomas

BACKGROUND Ependymoma is the most common glial tumor of the adult spinal cord. Current consensus recommends surgical resection with gross total resection (GTR) whenever possible. We performed a comprehensive review of the literature to evaluate whether adjuvant radiotherapy after subtotal resection (STR) has any benefit. METHODS A PubMed search was performed to identify adult patients with spinal cord ependymoma who underwent surgical resection. Only patients who had clearly defined extent of resection with or without adjuvant radiotherapy were included for analysis. Kaplan-Meier and multivariate Cox regression survival analyses were performed to determine the effects of adjuvant radiotherapy on progression-free survival (PFS) and overall survival (OS). RESULTS A total of 348 patients underwent surgical resection of spinal cord ependymomas, where GTR was obtained in 77.0% (268/348) of patients. Among those who received STR, 58.8% (47/80) received adjuvant radiotherapy. PFS was significantly prolonged among those who received adjuvant radiotherapy after STR (log rank; P < .001). This prolonged PFS with adjuvant radiotherapy remained significant in multivariate Cox regression analysis (STR versus STR + RT group; hazard ratio (HR) = 2.26, P = .047). By contrast, improved OS was only associated with GTR (GTR versus STR + RT group; HR = 0.07, P = .001) and benign ependymomas (HR = 0.16, P = .001). CONCLUSIONS Surgery remains the mainstay treatment for spinal cord ependymomas, where GTR provides optimal outcomes with longest PFS and OS. Adjuvant radiotherapy prolongs PFS after STR significantly, and OS is improved by GTR and benign tumor grade only.

Survival impact of time to initiation of chemoradiotherapy after resection of newly diagnosed glioblastoma.

OBJECT There are few and conflicting reports on the effects of delayed initiation of chemoradiotherapy on the survival of patients with glioblastoma. The standard of care for newly diagnosed glioblastoma is concurrent radiotherapy and temozolomide chemotherapy after maximal safe resection; however, the optimal timing of such therapy is poorly defined. Given the lack of consensus in the literature, the authors performed a retrospective analysis of The Cancer Genome Atlas (TCGA) database to investigate the effect of time from surgery to initiation of therapy on survival in newly diagnosed glioblastoma. METHODS Patients with primary glioblastoma diagnosed since 2005 and treated according to the standard of care were identified from TCGA database. Kaplan-Meier and multivariate Cox regression analyses were used to compare overall survival (OS) and progression-free survival (PFS) between groups stratified by postoperative delay to initiation of radiation treatment. RESULTS There were 218 patients with newly diagnosed glioblastoma with known time to initiation of radiotherapy identified in the database. The median duration until therapy was 27 days. Delay to radiotherapy longer than the median was not associated with worse PFS (HR = 0.918, p = 0.680) or OS (HR = 1.135, p = 0.595) in multivariate analysis when controlling for age, sex, KPS score, and adjuvant chemotherapy. Patients in the highest and lowest quartiles for delay to therapy (≤ 20 days vs ≥ 36 days) did not statistically differ in PFS (p = 0.667) or OS (p = 0.124). The small subset of patients with particularly long delays (> 42 days) demonstrated worse OS (HR = 1.835, p = 0.019), but not PFS (p = 0.74). CONCLUSIONS Modest delay in initiation of postoperative chemotherapy and radiation does not appear to be associated with worse PFS or OS in patients with newly diagnosed glioblastoma, while significant delay longer than 6 weeks may be associated with worse OS.

Complement anaphylatoxins as immune regulators in cancer.

The role of the complement system in innate immunity is well characterized. However, a recent body of research implicates the complement anaphylatoxins C3a and C5a as insidious propagators of tumor growth and progression. It is now recognized that certain tumors elaborate C3a and C5a and that complement, as a mediator of chronic inflammation and regulator of immune function, may in fact foster rather than defend against tumor growth. A putative mechanism for this function is complement‐mediated suppression of immune effector cells responsible for immunosurveillance within the tumor microenvironment. This paradigm accords with models of immune dysregulation, such as autoimmunity and infectious disease, which have defined a pathophysiological role for abnormal complement signaling. Several types of immune cells express the cognate receptors for the complement anaphylatoxins, C3aR and C5aR, and demonstrate functional modulation in response to complement stimulation. In turn, impairment of antitumor immunity has been intimately tied to tumor progression in animal models of cancer. In this article, the literature was systematically reviewed to identify studies that have characterized the effects of the complement anaphylatoxins on the composition and function of immune cells within the tumor microenvironment. The search identified six studies based upon models of lymphoma and ovarian, cervical, lung, breast, and mammary cancer, which collectively support the paradigm of complement as an immune regulator in the tumor microenvironment.

Systematic review of protein biomarkers of invasive behavior in glioblastoma.

Glioblastoma (GBM) is an aggressive and incurable brain tumor with a grave prognosis. Recurrence is inevitable even with maximal surgical resection, in large part because GBM is a highly invasive tumor. Invasiveness also contributes to the failure of multiple cornerstones of GBM therapy, including radiotherapy, temozolomide chemotherapy, and vascular endothelial growth factor blockade. In recent years there has been significant progress in the identification of protein biomarkers of invasive phenotype in GBM. In this article, we comprehensively review the literature and survey a broad spectrum of biomarkers, including proteolytic enzymes, extracellular matrix proteins, cell adhesion molecules, neurodevelopmental factors, cell signaling and transcription factors, angiogenic effectors, metabolic proteins, membrane channels, and cytokines and chemokines. In light of the marked variation seen in outcomes in GBM patients, the systematic use of these biomarkers could be used to form a framework for better prediction, prognostication, and treatment selection, as well as the identification of molecular targets for further laboratory investigation and development of nascent, directed therapies.

Prognosis by tumor location in adults with intracranial ependymomas

Intracranial ependymomas are rare tumors in adults. Thus, factors affecting prognosis are poorly understood. We performed a study to investigate whether tumor location is an important prognostic factor in adults who undergo surgery for intracranial ependymomas. PubMed was searched to identify studies that reported clinical outcomes in adult patients with intracranial ependymoma. Data were extracted for patient and tumor characteristics, extent of resection, progression-free survival (PFS), and overall survival (OS). Tumors were categorized as supratentorial or infratentorial and extraventricular or intraventricular. Presenting clinical features and tumor characteristics were tabulated. Kaplan-Meier and multivariate Cox regression survival analyses were performed to determine PFS and OS by tumor location. Extent of resection was also analyzed by tumor location. A total of 183 patients were included in the meta-analysis. Patients presented at a mean of 8.2months with a myriad of clinical features. The mean tumor size was 3.38 cm, and 19.3% of tumors were cystic. Supratentorial tumors were most commonly located in the frontal and parietal lobes, and infratentorial tumors in the fourth ventricle. Supratentorial tumors demonstrated significantly poorer PFS (p<0.001) and OS (p=0.003) than infratentorial tumors, despite a higher rate of gross total resection (GTR) for the supratentorial tumors (72.6% versus 42.1%). Extraventricular ependymomas displayed significantly poorer PFS than intraventricular ependymomas (p=0.009). In summary, supratentorial ependymomas have significantly poorer PFS and OS than their infratentorial counterparts, despite being more conducive to GTR, suggesting increased clinical aggressiveness. Extraventricular location is also associated with significantly poorer PFS than intraventricular location.

Prognosis by tumor location for pediatric spinal cord ependymomas

OBJECT Ependymoma is a common CNS tumor in children, with spinal cord ependymomas making up 13.1% of all ependymomas in this age group. The clinical features that affect prognosis in pediatric spinal cord ependymomas are not well understood. A comprehensive literature review was performed to determine whether a tumor location along the spinal cord is prognostically significant in children undergoing surgery for spinal cord ependymomas. METHODS A PubMed search was performed to identify all papers that contained data on patients with spinal cord ependymomas. Only pediatric patients (age < 18 years) who underwent resection with a clearly reported tumor location were included in the analysis. Myxopapillary tumors were excluded from study. Tumor location was subdivided into 6 regions: cervicomedullary, cervical, cervicothoracic, thoracic, thoracolumbar, and conus medullaris. Kaplan-Meier survival and Cox regression analyses were performed to determine the effects of tumor location on progression-free survival (PFS) and overall survival (OS). RESULTS Fifty-eight patients who underwent resection of spinal cord ependymomas were identified. Ependymomas were located all along the spinal cord but occurred with the highest frequency in the cervical region (29.3%). Progression-free survival was significantly better in patients with tumors arising in the upper portion of the spinal cord (p = 0.031), which remained significant in the multivariate Cox regression analysis (p < 0.05). Moreover, OS was significantly better in patients with upper spinal cord ependymomas than in those harboring ependymomas in the lower spinal cord (p = 0.048). CONCLUSIONS Although more common in adults, spinal ependymomas can occur anywhere along the spinal cord in the pediatric population; however, tumors occurring in the lower half of the spinal cord carry a worse prognosis with shorter PFS and OS. By comparison, ependymomas in the upper spinal cord recur later and less frequently, with little or no mortality in this patient group.

Fractionated radiation therapy for vestibular schwannoma

Vestibular schwannomas are the most common tumors of the cerebellopontine angle. Multiple management paradigms exist for patients with these benign tumors, including observation, microsurgery, stereotactic radiosurgery, and fractionated radiation therapy, or some combination of these. While the proper course of management is controversial, the goals of therapy are to achieve excellent local tumor control and optimize functional outcomes with as little treatment-related morbidity as possible. Decision-making is tailored to patient-specific factors such as tumor size, clinical presentation, patient age, and goals of hearing preservation. We review the literature in order to summarize the application of fractionated radiation therapy to this tumor entity, where it is used as a primary treatment or, more commonly, as an adjunct therapy. We also provide an overview of the use of fractionated radiation therapy for the preservation of hearing and facial function, and dosing and other technical considerations, in light of the indolent natural history of vestibular schwannomas. We also discuss potential risks associated with this treatment modality, including its effects on temporal bone structures and cranial nerves among other possible complications. Lastly, we outline future directions in this rapidly evolving segment of vestibular schwannoma therapy, which has benefited from the advent of intensity-modulated radiation therapy coupled with stereotactic localization.

Tumor-to-tumor metastasis: Breast carcinoma to meningioma

Metastasis of breast carcinoma to meningioma is a rare phenomenon with relatively few reports in the literature, although it is the most common type of carcinoma-to-meningioma metastasis. Several factors have been implicated in the pathogenesis of these lesions, including the microenvironment and vascular network of the meningioma, expression of cell-cell adhesion molecules, local immunosuppression, and hormonal factors, including estrogen and progesterone, whose receptors have been well-characterized in these two tumor types. While histopathologic study is the cornerstone of diagnosis of these lesions, newer radiological modalities such as magnetic resonance spectroscopy and perfusion MRI have shown promise, particularly in screening patients at risk for developing these lesions. Because their detection is problematic, it is imperative that clinicians thoroughly examine tissue samples of resected meningiomas, as this may alter the patients treatment plan and prognosis. Furthermore, as both of these neoplasms often co-occur in women with breast cancer, clinicians should be vigilant of the potential for intrameningioma metastasis when neurological involvement becomes apparent in late-stage disease. While these unusual lesions should be managed surgically, as with meningiomas, it is unclear whether proposed adjuvants such as hormonal and radiation therapy improve survival.