Ann Liu

Polymeric Nanoparticles for Nonviral Gene Therapy Extend Brain Tumor Survival in Vivo

Biodegradable polymeric nanoparticles have the potential to be safer alternatives to viruses for gene delivery; however, their use has been limited by poor efficacy in vivo. In this work, we synthesize and characterize polymeric gene delivery nanoparticles and evaluate their efficacy for DNA delivery of herpes simplex virus type I thymidine kinase (HSVtk) combined with the prodrug ganciclovir (GCV) in a malignant glioma model. We investigated polymer structure for gene delivery in two rat glioma cell lines, 9L and F98, to discover nanoparticle formulations more effective than the leading commercial reagent Lipofectamine 2000. The lead polymer structure, poly(1,4-butanediol diacrylate-co-4-amino-1-butanol) end-modified with 1-(3-aminopropyl)-4-methylpiperazine, is a poly(β-amino ester) (PBAE) and formed nanoparticles with HSVtk DNA that were 138 ± 4 nm in size and 13 ± 1 mV in zeta potential. These nanoparticles containing HSVtk DNA showed 100% cancer cell killing in vitro in the two glioma cell lines when combined with GCV exposure, while control nanoparticles encoding GFP maintained robust cell viability. For in vivo evaluation, tumor-bearing rats were treated with PBAE/HSVtk infusion via convection-enhanced delivery (CED) in combination with systemic administration of GCV. These treated animals showed a significant benefit in survival (p = 0.0012 vs control). Moreover, following a single CED infusion, labeled PBAE nanoparticles spread completely throughout the tumor. This study highlights a nanomedicine approach that is highly promising for the treatment of malignant glioma.

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.

Local delivery methods of therapeutic agents in the treatment of diffuse intrinsic brainstem gliomas

Brainstem gliomas comprise 10-20% of all pediatric central nervous system (CNS) tumors and diffuse intrinsic pontine gliomas (DIPGs) account for the majority of these lesions. DIPG is a rapidly progressive disease with almost universally fatal outcomes and a median survival less than 12 months. Current standard-of-care treatment for DIPG includes radiation therapy, but its long-term survival effects are still under debate. Clinical trials investigating the efficacy of systemic administration of various therapeutic agents have been associated with disappointing outcomes. Recent efforts have focused on improvements in chemotherapeutic agents employed and in methods of localized and targeted drug delivery. This review provides an update on current preclinical and clinical studies investigating treatment options for brainstem gliomas.

Clinical outcomes after ventriculoatrial shunting for idiopathic normal pressure hydrocephalus

INTRODUCTION Idiopathic normal pressure hydrocephalus (iNPH) is a neurological disorder that classically presents with a triad of progressive gait impairment, urinary incontinence, and cognitive deterioration. Treatment predominantly involves ventriculoperitoneal (VP) shunting, but one alternative is ventriculoatrial (VA) shunting. This study sought to describe and evaluate the clinical outcomes of patients with iNPH primarily treated with VA shunting. MATERIALS AND METHODS A retrospective review of patients with iNPH who were treated with VA shunting at a single institution, from 2003 to 2013, was performed. RESULTS 58 patients with iNPH underwent primary VA shunting at a median age of 74 (IQR: 70-80) years. The most common comorbidities included hypertension (n=39, 67%) and diabetes mellitus (n=11, 19%). Median duration of symptoms prior to VA shunting was 24 (IQR: 12-36) months. All patients had gait impairment, 52 (90%) had cognitive decline, and 43 (74%) had urinary incontinence. Forty-three (74%) patients had all three symptoms. At a median last follow-up of 16 (IQR: 7-26) months, median iNPH score improved from 6 to 3 (p<0.0001), mini mental status exam (MMSE) tended to increase from 26 to 29 (p=0.082), timed up-and-go (TUG) improved from 18 to 13s (p<0.0001), and Tinetti score improved from 19 to 25 (p<0.0001) after VA shunting. 78% of patients had improvement in at least one of their symptoms with 66% of patients having improvement in gait, 53% having improvement in their cognition, and 52% having improved urinary incontinence. A total of 21 patients (36%) had improvement in all 3 symptoms. CONCLUSIONS There were significant improvements in functional outcomes as evaluated via the iNPH score, TUG, and Tinetti score, while improvement in MMSE trended toward significance. Patients also had improvement of clinical symptoms related to gait, urinary function and cognition. These results suggest that VA shunting can be an effective primary treatment alternative to VP shunting for iNPH.

A systematic review of clinical outcomes for patients diagnosed with skin cancer spinal metastases

OBJECT Surgical procedures and/or adjuvant therapies are effective modalities for the treatment of symptomatic spinal metastases. However, clinical results specific to the skin cancer spinal metastasis cohort are generally lacking. The purpose of this study was to systematically review the literature for treatments, clinical outcomes, and survival following the diagnosis of a skin cancer spinal metastasis and evaluate prognostic factors in the context of spinal skin cancer metastases stratified by tumor subtype. METHODS The authors performed a literature review using PubMed, Embase, CINAHL, and Web of Science to identify articles since 1950 that reported survival, clinical outcomes, and/or prognostic factors for the skin cancer patient population with spinal metastases. The methodological quality of reviews was assessed using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) tool. RESULTS Sixty-five studies met the preset criteria and were included in the analysis. Of these studies, a total of 25, 40, 25, and 12 studies included patients who underwent some form of surgery, radiotherapy, chemotherapy, or observation alone, respectively. Sixty-three of the 65 included studies were retrospective in nature (Class of Evidence [CoE] IV), and the 2 prospective studies were CoE II. Based on the studies analyzed, the median overall survival for a patient with a spinal metastasis from a primary skin malignancy is 4.0 months; survival by tumor subtype is 12.5 months for patients with basal cell carcinoma (BCC), 4.0 months for those with melanoma, 4.0 months for those with squamous cell carcinoma, 3.0 months for those with pilomatrix carcinoma, and 1.5 months for those with Merkel cell carcinoma (p < 0.0001). The overall percentage of known continued disease progression after spine metastasis diagnosis was 40.1% (n = 244/608, range 25.0%-88.9%), the rate of known recurrence of the primary skin cancer lesion was 3.5% (n = 21/608, range 0.2%-100.0%), and the rate of known spine metastasis recurrence despite treatment for all skin malignancies was 2.8% (n = 17/608, range 0.0%-33.3%). Age greater than 65 years, sacral spinal involvement, presence of a neurological deficit, and nonambulatory status were associated with decreased survival in patients diagnosed with a primary skin cancer spinal metastasis. All other clinical or prognostic parameters were of low or insufficient strength. CONCLUSIONS Patients diagnosed with a primary skin cancer metastasis to the spine have poor overall survival with the exception of those with BCC. The median duration of survival for patients who received surgical intervention alone, medical management (chemotherapy and/or radiation) alone, or the combination of therapies was similar across interventions. Age, spinal region, and neurological status may be associated with poor survival following surgery.

Are shunt series and shunt patency studies useful in patients with shunted idiopathic intracranial hypertension in the emergency department

OBJECTIVES Shunt series and shunt patency studies can be performed in the emergency department (ED) to evaluate for shunt malfunction in patients with idiopathic intracranial hypertension (IIH). Here, we examine the utility of these studies in this specific patient population. METHODS We retrospectively reviewed the ED visits of all shunted patients diagnosed with IIH from 2003 to 2014. ED visits for symptoms not related to the patients IIH were excluded from the study. Collected variables included demographics, symptoms, IIH diagnosis and treatment history, imaging findings, and management changes. RESULTS Twenty-five (81%) patients had a total of 105 visits involving a shunt series, with four (3.9%) showing problems with the catheter. The majority of shunt series (n=101, 96%) showed no catheter pathology. Based on results of the shunt series alone, in 3 instances, management changes in the form of shunt revision or shunt reprogramming occurred. Of the 105 visits with a shunt series, 17 (16%) resulted in a change in management as compared to 12 out of 66 (18%) visits without a shunt series (p=0.83). Nine patients had a total of 10 visits involving a shunt patency study: five were normal, four were abnormal, and one was inconclusive. Based on findings on the shunt patency study alone, changes in management leading to shunt adjustment or revision occurred in 4 instances. Of the 10 visits with shunt patency studies, 5 resulted in a change in management as compared to 24 out of 161 visits without a shunt patency study (p=0.014). CONCLUSIONS Shunt series detected catheter pathology only 3.9% of the time, and there was no difference in the rate of management changes between those patients who underwent a shunt series and those who did not. There was a significant difference in the rate of management changes in patients who received shunt patency studies as compared to those who did not. Shunt series may not be a useful screening tool to be used universally to diagnose shunt malfunction in IIH patients in the ED, and should be utilized when there is concern for impending visual loss. Shunt patency studies should be reserved for patients with inconclusive diagnostic imaging and clinical findings to decide whether to proceed to surgical exploration and revision.

Sporadic intramedullary hemangioblastoma of the spine: a single institutional review of 21 cases

Introduction: Sporadic intramedullary spinal cord hemangioblastomas are rare, vascular tumours that can present with significant neurological dysfunction. Surgical resection is the standard treatment for these lesions, and we report our institutions experience with patients who underwent surgery for sporadic intramedullary spinal cord hemangioblastomas. Methods: We retrospectively reviewed 21 patients (14 male, 7 female) who underwent a total of 23 surgeries for sporadic intramedullary spinal cord hemangioblastoma between 1996 and 2014.We recorded demographic, operative and postoperative factors. Results: The median age was 45 years (IQR: 28). All tumours were present in the cervical (13 of 21, 62%) or thoracic (nine of 21, 43%) spine (one patient had tumours in both locations). Thirteen patients (62%) also had concurrent syringomyelia spanning a median of 11 vertebral levels (IQR: 5). Total resection was achieved in all but one surgery, and no cases involved intraoperative complications. However, postoperative complications occurred after five cases. Median follow-up was 12 months (IQR: 38). Twelve patients (57%) experienced long-term dysfunction after surgery, and two patients experienced recurrence requiring a second surgery. Conclusions: Maximal safe surgical resection should be considered as a primary treatment modality for individuals with intramedullary spinal cord hemangioblastomas.

Postoperative survival and functional outcomes for patients with metastatic gynecological cancer to the spine: case series and review of the literature.

OBJECTIVE Spinal metastases from gynecological cancers are rare, with few cases reported in the literature. In this study, the authors examine a series of patients with spinal metastases from gynecological cancer and review the literature. METHODS The cases of 6 consecutive patients who underwent spine surgery for metastatic gynecological cancer between 2007 and 2012 at a single institution were retrospectively reviewed. The recorded demographic, operative, and postoperative factors were reviewed, and the functional outcomes were determined by change in Karnofsky Performance Scale and the American Spine Injury Association (ASIA) score during follow-up. A systematic review of the literature was also performed to evaluate outcomes for patients with similar gynecological metastases to the spine. RESULTS In this series, details regarding metastatic gynecological cancers to the spine are as follows: 2 patients with cervical cancer (both presented at age 46 years, mean postoperative survival of 32 months), 2 patients with endometrial cancer (mean age of 40 years, mean postoperative survival of 26 months), and 2 patients with leiomyosarcoma (mean age of 44 years, mean postoperative survival of 20 months). All patients presented with pain, and no complications were noted following surgery. All patients with known follow-up had stable or improved neurological outcomes, performance status, and improved pain, without local recurrence of tumor. Overall median survival after diagnosis of metastatic spine lesions for all cases in the literature as well as those treated by the authors was 15 months. When categorized by type, median survival of patients with cervical cancer (n = 2), endometrial cancer (n = 26), and leiomyosarcoma (n = 16) was 32, 10, and 22.5 months, respectively. CONCLUSIONS Gynecological cancers metastasizing to the spine are rare. In this series, overall survival following diagnosis of spinal metastasis and surgery was 27 months, with cervical cancer, endometrial cancer, and leiomyosarcoma survival being 32, 26, and 20 months, respectively. Combined with literature cases, survival differs depending on primary histology, with decreasing survival from cervical cancer (32 months) to leiomyosarcoma (22.5 months) to endometrial cancer (10 months). Integrating such information with other patient factors may more accurately guide decision making regarding management of such spinal lesions.

The Utility of Computed Tomography in Shunted Patients with Idiopathic Intracranial Hypertension Presenting to the Emergency Department

BACKGROUND Shunted patients with idiopathic intracranial hypertension (IIH) often present to the emergency department (ED) for symptoms related to their disease. Although brain imaging with computed tomography (CT) is often performed, particularly in the current medicolegal environment, its utility during these ED visits is unclear. METHODS The ED visits of all shunted adult patients with IIH from 2003-2015 were retrospectively reviewed. ED visits not related to IIH were excluded from our study. RESULTS Thirty-one patients visited the ED 171 times for IIH symptoms. Five patients had greater than 10 ED visits. Twenty-five (81%) patients had 131 visits involving a CT scan, while six (19%) patients were not scanned. The majority of scans (n = 126, 96%) showed no change; five (4%) scans detected new noncritical pathologies. On the basis of CT findings alone, treatment changes occurred in three (2.3%) instances. Of the 131 visits with a CT scan, twenty-five (19%) visits resulted in management changes; of the 40 ED visits without a CT scan, four (10%) visits resulted in a management change (P = 0.23). CONCLUSIONS In our cohort, CT imaging rarely showed a change in pathology or affected the management of patients with IIH. There was no difference in the rate of management changes between those patients who underwent a CT scan and those who did not. Given the risk of cumulative radiation exposure and cost of CT scans, CT imaging should be used when there is concern for visual dysfunction and the utility of CT imaging in the ED for the workup of other symptoms related to IIH must be explored further.

Poor prognosis despite aggressive treatment in adults with intramedullary spinal cord glioblastoma

We report our institutions experience with adult patients who underwent surgery for intramedullary spinal cord glioblastoma. Spine involvement of glioblastoma is rare, representing 7.5% of all intramedullary gliomas and 1-3% of all spinal cord tumors. We performed a retrospective review of five male patients with intramedullary spinal cord glioblastoma who underwent surgical resection from 1990 to 2014. Demographic, operative, and postoperative factors were recorded. The median age at treatment was 31 years (range: 18-61) and all men presented with motor or sensory dysfunction. Two had prior surgical resection of an intramedullary World Health Organization Grade III anaplastic astrocytoma lesion with adjuvant chemoradiation. All tumors were present in the cervical (n=2; 40%) or thoracic (n=3; 60%) spine, spanning a median of three levels (range: 2-4). Gross total resection was achieved in three men (60%), and there were no intraoperative mortalities or complications. Although one had improvement in his neurological status postoperatively, all five men died with a median time to death of 20 months (range: 2-31). Adult intramedullary spinal cord glioblastoma is rare, and despite aggressive treatment, prognosis is poor, with a median survival in our series of only 20 months. New treatment strategies are necessary to improve survival in this patient population.