Leonel Ampie

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.

Immunomonitoring in glioma immunotherapy: Current status and future perspectives

Abstract Given the continued poor clinical outcomes and refractory nature of glioblastoma multiforme to traditional interventions, immunotherapy is gaining traction due to its potential for specific tumor-targeting and long-term antitumor protective surveillance. Currently, development of glioma immunotherapy relies on overall survival as an endpoint in clinical trials. However, the identification of surrogate immunologic biomarkers can accelerate the development of successful immunotherapeutic strategies. Immunomonitoring techniques possess the potential to elucidate immunological mechanisms of antitumor responses, monitor disease progression, evaluate therapeutic effect, identify candidates for immunotherapy, and serve as prognostic markers of clinical outcome. Current immunomonitoring assays assess delayed-type hypersensitivity, T cell proliferation, cytotoxic T-lymphocyte function, cytokine secretion profiles, antibody titers, and lymphocyte phenotypes. Yet, no single immunomonitoring technique can reliably predict outcomes, relegating immunological markers to exploratory endpoints. In response, the most recent immunomonitoring assays are incorporating emerging technologies and novel analysis techniques to approach the goal of identifying a competent immunological biomarker which predicts therapy responsiveness and clinical outcome. This review addresses the current status of immunomonitoring in glioma vaccine clinical trials with emphasis on correlations with clinical response.

Prognostic factors for recurrence and complications in the surgical management of primary chordoid gliomas: A systematic review of literature

OBJECTIVE Chordoid gliomas (CG) are rare neoplasms which frequently arise within the third ventricle. Surgery remains the mainstay treatment for CG. The present study comprehensively reviews all reported cases of CG within the literature in order to identify risk factors for surgical complications and tumor recurrence. METHODS A comprehensive search on MEDLINE (OVID and PubMed), Scopus, Embase, and Web of Science was conducted following PRISMA guidelines to identify all reported cases of CG. RESULTS A total of 81 patients met the study criteria which comprised of 33 males and 48 females. Median age at diagnosis was 48 years with a range from 5 to 72 years, and mean tumor size was 3.1cm. Biopsy, subtotal resection (STR), and gross total resection (GTR) were achieved in 8, 34, and 33 patients, respectively, with six cases not reporting extent of resection (EOR). Thirteen patients underwent adjuvant radiotherapy. Postoperative complications were noted in 30 cases (37%), with new onset diabetes insipidus being the most common. Postoperative morbidity was not associated with age, tumor size, or extent of resection. A trans-lamina terminalis approach demonstrated a strong trend towards decreased overall rates of postoperative morbidity compared to other approaches (p=0.051). GTR was associated with improved progression-free survival (PFS; p=0.028), while adjuvant radiotherapy, age, tumor size and proliferative index were not predictive of patient outcomes. CONCLUSION GTR should be the primary goal for the management of CG, as it is associated with improved rates of tumor control without an increased rate of postoperative complications. Surgical approach was a stronger predictor of complication rates than extent of resection. Morbidity remains high, and future studies to further elaborate on factors predictive of postoperative complications are critical.

Immune Modulation in the Treatment of Amyotrophic Lateral Sclerosis: A Review of Clinical Trials

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the degeneration of motor neurons. Though many molecular and genetic causes are thought to serve as predisposing or disease propagating factors, the underlying pathogenesis of the disease is not known. Recent discoveries have demonstrated the presence of inflammation propagating substrates in the central nervous system of patients afflicted with ALS. Over the past decade, this hypothesis has incited an effort to better understand the role of the immune system in ALS and has led to the trial of several potential immune-modulating therapies. Here, we briefly review advances in the role of such therapies. The clinical trials discussed here are currently ongoing or have been concluded at the time of writing.

Clinical attributes and surgical outcomes of angiocentric gliomas

Angiocentric gliomas (AG) are exceedingly rare low-grade neoplasms which often present in the form of intractable epilepsy within younger patients. The current study extensively reviews all reported cases which were pathologically verified as AG in the literature to analyze clinical attributes and surgical outcomes of this neoplasm. There were 88 patients with AG reported in the literature consisting mostly of pediatric cases. The sex distribution consisted of 45 males and 36 females with the remaining seven cases not documenting sex. The average age of initial diagnosis was 16years with almost half of all diagnosed patients being within the first decade of life. In cases where extent of resection was reported, gross total resection (GTR) was achieved in 54 patients, subtotal resection (STR) in 16, and biopsy only in three. Post-operative complications were transient and only occurred in three patients with no reports of death following surgery. Only five cases reported tumor recurrence on follow-up. Eight patients had seizure recurrence post-operatively and GTR offered improved rates of seizure control when compared to STR (p=0.0005). Nearly half of the cases of AG are diagnosed within the first decade of life and they usually manifest with intractable seizures. GTR appears to offer better seizure control in the post-operative period. Surgical resection is the mainstay therapy for AG as post-operative complications and tumor recurrence remain uncommon. Since the number of reported cases is limited, future studies with longer follow-up periods will help elaborate more long-term outcomes.

Safety and outcomes of preoperative embolization of intracranial hemangioblastomas: A systematic review

INTRODUCTION While preoperative embolization is often reserved for large and highly vascular tumors in order to minimize blood loss, its safety and efficacy in the treatment of hemangioblastomas (HB) is unclear. We present the largest systematic review focusing on the safety and outcome of preoperative embolization of intracranial HB. MATERIALS AND METHODS To identify all cases of preoperative embolization for HB, a literature search was conducted via Medline (OVID and PubMed), Scopus, Embase, and Web of Science. Studies that were in English, included intracranial hemangioblastomas treated with preoperative embolization and provided sufficient disaggregated clinical data for each patient were included. Historical control patients with non-embolized intracranial HB undergoing resection were similarly identified. RESULTS A total of 111 patients that underwent preoperative embolization of HB prior to planned resection were identified. Patient age ranged from 12 to 72 years, with a cohort of 63% males and 36% females. Nine studies comprising 392 non-embolized patients were included as controls. Gross total resection was achieved in 83.7% of embolized and 95.6% of non-embolized patients. Intraoperative blood transfusion was required in 15.3% of embolized and 0.51% of non-embolized controls, while rates of post-operative hemorrhage were 8.4% and 1.6%, respectively. Complication rates from embolization were 11.7% and following consequent surgery were 20.7%. DISCUSSION Embolization did not increase rates of gross total resection, decrease estimated blood loss, or decrease incidence of complications. Not only does embolization fail to mitigate surgical risks, the embolization procedure itself carries significant risk for complications. Embolization should not be standard of care for intracranial HB.

The immune checkpoint protein PD-L1 induces and maintains regulatory T cells in glioblastoma

ABSTRACT Glioblastoma (GBM) promotes immunosuppression through upregulation of PD-L1 and regulatory T cell (Treg) expansion, but the association of these suppressive factors has not been well elucidated. Here, we investigate a role of PD-L1 in expanding Tregs and the value of targeting the PD-1 receptor to inhibit Treg expansion. Quantitative RNA sequencing data from The Cancer Genome Atlas were evaluated for an association between CD274 and FOXP3 transcript expressions and impact of FOXP3 on clinical outcomes. Peripheral leukocytes from patients with newly diagnosed GBM were profiled for PD-L1+ myeloid expressions and Treg abundance. Healthy lymphocytes were assessed for impact of recombinant PD-L1 on expansion of the inducible Treg (iTreg) population. iTreg function was evaluated by the capacity to suppress effector T cell proliferation. Specificity of responses were confirmed by pharmacologic inhibition of the PD-1 receptor. Increased PD-L1 mRNA expression in GBM corresponded to increased FOXP3 mRNA (p = 0.028). FOXP3 elevation had a negative impact on overall survival (HR = 2.0; p < 0.001). Peripheral PD-L1 positivity was associated with an increased Treg fraction (p = 0.008). Lymphocyte activation with PD-L1 co-stimulation resulted in greater iTreg expansion compared to activation alone (18.3% vs. 6.5%; p < 0.001) and improved preservation of the Treg phenotype. Suppressive capacity on naïve T cell proliferation was sustained. Nivolumab inhibited PD-L1-induced Treg expansion (p < 0.001). These results suggest that PD-L1 may expand and maintain immunosuppressive Tregs, which are associated with decreased survival in glioma patients. Blockade of the PD-L1/PD-1 axis may reduce Treg expansion and further improve T cell function beyond the direct impact on effector cells.

Role of preoperative embolization for intradural spinal hemangioblastomas

Spinal hemangioblastomas (HB) are relatively rare neoplasms with a high degree of vascularity. Therapy for symptomatic tumors involves total resection when possible. Due to the enriched blood supply of these neoplasms, there is a high risk of significant intraoperative blood loss, which can lead to perioperative complications. Preoperative embolization of HB has been suggested to reduce blood loss and operative morbidity, but its use remains controversial. Data on the risks and benefits of preoperative embolization for this tumor remains limited. We identified and analyzed all 29 reported cases of preoperative embolization of intradural spinal HB within the literature. There were 18 men and nine women, and patients ranged from 24 to 61 years of age. Mean tumor size was 3.5 cm. Cervical and thoracic location was most common, accounting for 48.3% and 20% of cases, respectively. Complications from embolization and surgery were minimal, with no deaths or permanent neurological morbidity. Minimal intraoperative bleeding and excellent rates of gross total resection were reported with preoperative embolization. However, outcomes from microsurgery alone from historical series have similarly reported excellent outcomes. While there is no established standard, preoperative embolization should be reserved for particularly high risk patients with risk of intraoperative bleeding.

Erratum to: Predictors of recurrence in the management of chordoid meningioma.

Fig. 3 Kaplan–Meier curve for all patients included within the study. 3and 5-year PFS was 76.0 and 67.5 %, respectively Fig. 4 Kaplan–Meier analysis of recurrence free survival following either gross (GTR) to subtotal (STR) resection. Greater extent of surgery was associated with improved rates of tumor control. For GTR, 3and 5-year PFS was 85.3 and 80.8 %, respectively. For STR, 3and 5-year PFS was 50.7 and 33.8 %, respectively, p\ 0.001

Sellar plasmacytomas masquerading as pituitary adenomas: A systematic review

Given the rarity of intracranial plasmacytomas, these lesions are frequently misdiagnosed as pituitary adenomas. We report on the distinguishing characteristics of sellar plasmacytomas from cases in the literature and our experience. A literature search was conducted to collect all documented cases of a plasmacytoma originating in the sellar region. Patient characteristics, medical history, presentation, tumor characteristics, and survival data were collected. An additional case from our institution not previously reported was included. Thirty-one patients with sellar plasmacytomas were studied. Presenting symptoms were most commonly headache (68%), diplopia (65%) and visual field disturbances (10%). Fifteen patients (48%) were initially suspected of having a pituitary adenoma. Pathologic diagnosis of plasmacytoma preceded a finding of multiple myeloma in 14 cases (45%). Thirty patients (90%) had surgical intervention. Adjuvant therapy consisted of radiotherapy for twenty-five patients (81%) and chemotherapy for sixteen (52%). Tumor recurrence was reported for 7 cases (23%). Nine deaths were reported (23%). We demonstrate that cranial nerve involvement is far more common in sellar plasmacytomas than conventional pituitary adenomas. Given the successful management of these tumors with radiotherapy, such deficits, particularly in patients with known multiple myeloma, should impact the diagnostic workup and treatment considerations.