Jennifer E. Kim

Combination therapy with anti-PD-1, anti-TIM-3, and focal radiation results in regression of murine gliomas

Purpose: Checkpoint molecules like programmed death-1 (PD-1) and T-cell immunoglobulin mucin-3 (TIM-3) are negative immune regulators that may be upregulated in the setting of glioblastoma multiforme. Combined PD-1 blockade and stereotactic radiosurgery (SRS) have been shown to improve antitumor immunity and produce long-term survivors in a murine glioma model. However, tumor-infiltrating lymphocytes (TIL) can express multiple checkpoints, and expression of ≥2 checkpoints corresponds to a more exhausted T-cell phenotype. We investigate TIM-3 expression in a glioma model and the antitumor efficacy of TIM-3 blockade alone and in combination with anti-PD-1 and SRS. Experimental Design: C57BL/6 mice were implanted with murine glioma cell line GL261-luc2 and randomized into 8 treatment arms: (i) control, (ii) SRS, (iii) anti-PD-1 antibody, (iv) anti-TIM-3 antibody, (v) anti-PD-1 + SRS, (vi) anti-TIM-3 + SRS, (vii) anti-PD-1 + anti-TIM-3, and (viii) anti-PD-1 + anti-TIM-3 + SRS. Survival and immune activation were assessed. Results: Dual therapy with anti-TIM-3 antibody + SRS or anti-TIM-3 + anti-PD-1 improved survival compared with anti-TIM-3 antibody alone. Triple therapy resulted in 100% overall survival (P < 0.05), a significant improvement compared with other arms. Long-term survivors demonstrated increased immune cell infiltration and activity and immune memory. Finally, positive staining for TIM-3 was detected in 7 of 8 human GBM samples. Conclusions: This is the first preclinical investigation on the effects of dual PD-1 and TIM-3 blockade with radiation. We also demonstrate the presence of TIM-3 in human glioblastoma multiforme and provide preclinical evidence for a novel treatment combination that can potentially result in long-term glioma survival and constitutes a novel immunotherapeutic strategy for the treatment of glioblastoma multiforme. Clin Cancer Res; 23(1); 124–36. ©2016 AACR.

Immediate and follow-up results for 44 consecutive cases of small (<10 mm) internal carotid artery aneurysms treated with the pipeline embolization device

Background: The pipeline embolization device (PED) provides effective, durable and safe endovascular reconstruction of large and giant intracranial aneurysms. However, 80% of all cerebral aneurysms found in the general population are less than 10 mm in size. Treatment of small aneurysms (<10 mm) with flow diverters may be advantageous over endosaccular modalities that carry risks of procedural rupture during aneurysm access or coil placement. Methods: We retrospectively reviewed a prospective, single-center aneurysm database to identify all patients with small (<10 mm) internal carotid artery (ICA) aneurysms who underwent endovascular treatment using the PED. Patient demographics, aneurysm characteristics, procedural details, complications, and technical and clinical outcomes were analyzed. Results: Forty-four cases were performed in 41 patients (age range 31-78 years). PED was successfully implanted in 42 cases. A single PED was used in 37/42 (88%) cases. Mean postprocedure hospital stay was 1.7 ± 0.3 days and 98% of patients were discharged home. Major complication occurred in one patient (2.3%), who died of early subarachnoid hemorrhage. Transient neurological deficit, delayed intracerebral hemorrhage (asymptomatic), and delayed groin infection occurred in one patient each. Follow-up rate was 91.8% (45 aneurysms in 35 patients) with a mean follow-up of 4.0 ± 1.9 months. By 6 months post-PED implantation, angiographic success (complete or near complete aneurysm occlusion) was observed in 80%. Mild (<50%), asymptomatic, nonflow limiting in-stent stenosis was observed in 5.4% (2/37 cases). All the 35 patients with follow-up remained at preprocedure neurological baseline. Conclusion: Small (<10 mm) ICA aneurysm treatment with PED implantation is safe and carries a high rate of early angiographic success.

STAT3 Activation in Glioblastoma: Biochemical and Therapeutic Implications

Signal transducer and activator of transcription 3 (STAT3) is a potent regulator of gliomagenesis through its induction of angiogenesis, host immunosuppression, and tumor invasion. Gain of function mutations result in constitutive activation of STAT3 in glioma cells, making STAT3 an attractive target for inhibition in cancer therapy. Nevertheless, some studies show that STAT3 also participates in terminal differentiation and apoptosis of various cell lines and in glioma with phosphatase and tensin homolog (PTEN)-deficient genetic backgrounds. In light of these findings, the utility of STAT3 as a prognostic indicator and as a target of drug therapies will be contingent on a more nuanced understanding of its pro- and anti-tumorigenic effects.

The Future of Glioblastoma Therapy: Synergism of Standard of Care and Immunotherapy

The current standard of care for glioblastoma (GBM) is maximal surgical resection with adjuvant radiotherapy and temozolomide (TMZ). As the 5-year survival with GBM remains at a dismal <10%, novel therapies are needed. Immunotherapies such as the dendritic cell (DC) vaccine, heat shock protein vaccines, and epidermal growth factor receptor (EGFRvIII) vaccines have shown encouraging results in clinical trials, and have demonstrated synergistic effects with conventional therapeutics resulting in ongoing phase III trials. Chemoradiation has been shown to have synergistic effects when used in combination with immunotherapy. Cytotoxic ionizing radiation is known to trigger pro-inflammatory signaling cascades and immune activation secondary to cell death, which can then be exploited by immunotherapies. The future of GBM therapeutics will involve finding the place for immunotherapy in the current treatment regimen with a focus on developing strategies. Here, we review current GBM therapy and the evidence for combination of immune checkpoint inhibitors, DC and peptide vaccines with the current standard of care.

Assessing recollection and familiarity of similar lures in a behavioral pattern separation task.

The relationship between recollection‐mediated recognition memory and behavioral pattern separation is poorly understood. In two separate experiments, we modified a well‐validated object discrimination task with previously demonstrated sensitivity to neural pattern separation with instructions to assess recollection and familiarity. In the first experiment, we included a Remember/Know (R/K) judgment, and in the second we included a source memory judgment. We found that both “Remember” and correct source judgments were higher for lures labeled “similar” (where pattern separation is engaged) but also higher on lures called “old” (where pattern separation is absent), suggesting that false alarms in pattern separation tasks are frequently mediated by recollection. As one might expect, “Remember” judgments and correct source decisions increased with greater dissimilarity for “similar” responses and increased with greater similarity for “old” responses. This suggests that recollection can occur in the presence and in the absence of pattern separation and that false alarms to similar lures are not simply driven by familiarity.

Intracranial hemorrhage after spine surgery Clinical article

OBJECT The authors describe the largest case series of 8 patients with intracranial hemorrhage (ICH) after spinal surgery and identify associated pre-, intra-, and postoperative risk factors in relation to outcome. METHODS The authors retrospectively reviewed the cases of 8 patients treated over 16 years at a single institution and also reviewed the existing literature and collected demographic, treatment, and outcome information from 33 unique cases of remote ICH after spinal surgery. RESULTS The risk factors most correlated with ICH postoperatively were the presence of a CSF leak intraoperatively and the use of drains postoperatively with moderate hourly serosanguineous output in the early postoperative period. CONCLUSIONS Intracranial hemorrhage is a rare complication of spinal surgery that is associated with CSF leakage and use of drains postoperatively, with moderate serosanguinous output. These associations do not justify a complete avoidance of drains in patients with CSF leakage but may guide the treating physician to keep in mind drain output and timing of drain removal, while noting any changes in neurological examination status in the meantime. Additionally, continued and worsening neurological symptoms after spinal surgery may warrant cranial imaging to rule out intracranial hemorrhage, usually within the first 24 hours after surgery. The presence of cerebellar hemorrhage and hydrocephalus indicated a trend toward worse outcome.

Non-virally engineered human adipose mesenchymal stem cells produce BMP4, target brain tumors, and extend survival

There is a need for enabling non-viral nanobiotechnology to allow safe and effective gene therapy and cell therapy, which can be utilized to treat devastating diseases such as brain cancer. Human adipose-derived mesenchymal stem cells (hAMSCs) display high anti-glioma tropism and represent a promising delivery vehicle for targeted brain tumor therapy. In this study, we demonstrate that non-viral, biodegradable polymeric nanoparticles (NPs) can be used to engineer hAMSCs with higher efficacy (75% of cells) than leading commercially available reagents and high cell viability. To accomplish this, we engineered a poly(beta-amino ester) (PBAE) polymer structure to transfect hAMSCs with significantly higher efficacy than Lipofectamine™ 2000. We then assessed the ability of NP-engineered hAMSCs to deliver bone morphogenetic protein 4 (BMP4), which has been shown to have a novel therapeutic effect by targeting human brain tumor initiating cells (BTIC), a source of cancer recurrence, in a human primary malignant glioma model. We demonstrated that hAMSCs genetically engineered with polymeric nanoparticles containing BMP4 plasmid DNA (BMP4/NP-hAMSCs) secrete BMP4 growth factor while maintaining their multipotency and preserving their migration and invasion capacities. We also showed that this approach can overcome a central challenge for brain therapeutics, overcoming the blood brain barrier, by demonstrating that NP-engineered hAMSCs can migrate to the brain and penetrate the brain tumor after both intranasal and systemic intravenous administration. Critically, athymic rats bearing human primary BTIC-derived tumors and treated intranasally with BMP4/NP-hAMSCs showed significantly improved survival compared to those treated with control GFP/NP-hAMCSs. This study demonstrates that synthetic polymeric nanoparticles are a safe and effective approach for stem cell-based cancer-targeting therapies.

Immune Checkpoint Modulators: An Emerging Antiglioma Armamentarium

Immune checkpoints have come to the forefront of cancer therapies as a powerful and promising strategy to stimulate antitumor T cell activity. Results from recent preclinical and clinical studies demonstrate how checkpoint inhibition can be utilized to prevent tumor immune evasion and both local and systemic immune suppression. This review encompasses the key immune checkpoints that have been found to play a role in tumorigenesis and, more specifically, gliomagenesis. The review will provide an overview of the existing preclinical and clinical data, antitumor efficacy, and clinical applications for each checkpoint with respect to GBM, as well as a summary of combination therapies with chemotherapy and radiation.

High incidence of morbidity following resection of metastatic pheochromocytoma in the spine

Pheochromocytomas of the spine are uncommon and require careful preoperative planning. The authors retrospectively reviewed the charts of 5 patients with metastatic spinal pheochromocytoma who had undergone surgical treatment over the past 10 years at their medical center. They reviewed patient age, history of pheochromocytoma resection, extent and location of metastases, history of alpha blockage, surgical level, surgical procedure, postoperative complications, tumor recurrence, and survival. Metastases involved the cervical (1 patient), thoracic (3 patients), and lumbar (2 patients) levels. Preoperative treatment included primary pheochromocytoma resection, chemotherapy, alpha blockade, embolization, and radiation. Three patients had tumor recurrence, and 2 underwent 2-stage reoperations for tumor extension. Hemodynamic complications were common: 2 patients developed pulseless electrical activity arrest within 4 months after surgery, 1 patient had profound postoperative tachycardia with fever and an elevated creatine kinase level, and 1 patient experienced transient postoperative hypotension and paraplegia. One patient died of complications related to disseminated cerebral and spinal disease. With careful preoperative and surgical management, patients with symptomatic metastatic spinal pheochromocytoma can benefit from aggressive surgical treatment. Postoperative cardiovascular complications are common even months after surgery, and patients should be closely monitored long term.

Clay-shoveler's fracture during indoor rock climbing.

Indoor rock climbing is becoming more popular for people of all ages. Despite the tremendous interest in this competitive sport, participants are made aware of the dangers associated with participating. The authors present the first reported case of a clay-shovelers fracture at the T1 spinous process during indoor rock climbing. They describe the management and natural history of this fracture and discuss management strategies for this increasingly popular recreational sport.A 14-year-old competitive indoor rock climber presented with acute-onset midline thoracic pain at T1 while indoor rock climbing. He reported no recent falls or trauma but stated that the pain came on abruptly while rock climbing. On examination, he was neurologically intact except for significant tenderness to palpation at the T1 spinous process. Magnetic resonance imaging demonstrated a minimally displaced T1 spinous process fracture with evidence of significant surrounding muscular edema, suggesting an acute fracture. He was treated conservatively with anti-inflammatory drugs, complete climbing restriction, and rest. He continued to have focal upper back pain at the level of the fracture over the next 4 months. He was unable to climb for 4 months until his pain resolved after conservative treatment of climbing restriction, pain control, and rest.This is the first documented case of a clay-shovelers fracture sustained in a pediatric patient directly attributable to indoor rock climbing.