Eric W. Sankey

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.

Impact of indocyanine green videoangiography on rate of clip adjustments following intraoperative angiography.

BACKGROUND Intraoperative angiography (IA) is used to evaluate the adequacy of clip reconstruction of intracranial aneurysms. Alternative imaging such as indocyanine green videoangiography (ICG-VA) has been proposed. The additional benefit of ICG-VA when IA is routinely used has not been previously determined. OBJECTIVE To report our experience with the use of ICG-VA in combination with IA vs IA alone. METHODS We retrospectively reviewed cases of aneurysm clipping during a 21-month period by a single surgeon in which ICG-VA was performed after clip reconstruction prior to IA, or IA alone was performed to verify optimal clipping. Records were reviewed for age, sex, race, length of stay, rupture status, Hunt and Hess grade, aneurysm size, location, and temporary clipping. Intraoperative decision making was determined for each group. RESULTS Ninety-four patients who underwent 97 craniotomies for 128 aneurysms met inclusion criteria for this study. ICG-VA+IA was performed in 37 craniotomies; IA alone was performed for 60 craniotomies. Baseline characteristics were similar with the exception that median aneurysm size was slightly larger in the ICG-VA group (5.6 mm vs 4.3 mm, P = .04). ICG-VA produced 4 false negatives, which required clip adjustments following IA (10.8%), vs 7 patients (11.7%) in the IA-alone group requiring clip adjustments (P = .897). CONCLUSION When IA is routinely performed, the additional use of ICG-VA does not eliminate the need for post-IA clip adjustments owing to the possibility of false negatives. When ICG-VA suggests optimal clipping, but is followed by IA, the rate of post-IA modifications in this study did not differ significantly than if ICG-VA had not been performed.

Time Interval Reduction for Delayed Implant-Based Cranioplasty Reconstruction in the Setting of Previous Bone Flap Osteomyelitis

Background: Reinfections following implant-based cranioplasty, in the setting of previous bone flap osteomyelitis, are common and associated with significant morbidity. The timing of reconstruction following initial osteomyelitic bone flap removal remains controversial; most advocate for prolonged time intervals of approximately 6 to 12 months. Thus, the authors investigated their delayed cranioplasty outcomes following both early (between 90 and 179 days) and late (≥180 days) time intervals with custom craniofacial implants to determine whether timing affected outcomes and rates of reinfection. Methods: An institutional review board–approved retrospective cohort review of 25 consecutive cranioplasties, from 2012 to 2014, was conducted. A nonparametric bivariate analysis compared variables and complications between the two different time interval groups, defined as early cranioplasty (between 90 and 179 days) and cranioplasty (≥180 days). Results: No significant differences were found in primary and secondary outcomes in patients who underwent early versus late cranioplasty (p > 0.29). The overall reinfection rate was only 4 percent (one of 25), with the single reinfection occurring in the late group. Overall, the major complication rate was 8 percent (two of 25). Complete and subgroup analyses of specific complications yielded no significant differences between the early and late time intervals (p > 0.44). Conclusions: The results suggest that early cranioplasty is a viable treatment option for patients with previous bone flap osteomyelitis and subsequent removal. As such, a reduced time interval of 3 months—with equivalent outcomes and reinfection rates—represents a promising area for future study aiming to reduce the morbidity surrounding prolonged time intervals. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Outcomes and Experience with Lumbopleural Shunts in the Management of Idiopathic Intracranial Hypertension.

OBJECTIVE To report five patients who underwent lumbopleural (LPl) shunting for the treatment of idiopathic intracranial hypertension (IIH) and to describe the considerations, complications, and outcomes related to this rarely described procedure. METHODS The clinical data of five patients treated with LPl shunting over a 23-year period were retrospectively analyzed. Factors including the age at diagnosis of IIH, age at time of LPl shunting, body mass index (BMI), reason for LPl shunt placement, number of revisions before LPl shunt placement, valve type, time to first revision, presence of overdrainage and its management, complications and their management, survival time of LPl shunt, and clinical course at last follow-up were analyzed. RESULTS All patients were morbidly obese females with an average of 4.6 shunt revisions before an LPl shunt. The average overall survival time of the LPl shunt was 48 months. Two patients experienced failure of their LPl shunts with subsequent replacement within the first year. Four patients experienced complications related to shunt overdrainage, requiring placement of an antisiphon device (ASD) or additional valve. One patient developed a symptomatic pleural effusion, and one patient developed a small pneumothorax, which was managed conservatively. CONCLUSIONS LPl shunting, though rarely used, is a viable option in the treatment of IIH refractory to standard peritoneal shunting. When pursuing this treatment, a valve and ASD are recommended to mitigate the risks of overdrainage and pleural effusion. Chest imaging should be obtained if the patient becomes symptomatic but can be deferred if the patient remains asymptomatic and is doing well.

Factors Associated with Life Expectancy in Patients with Metastatic Spine Disease from Adenocarcinoma of the Lung

Study Design Retrospective study. Objective Our objective was to identify preoperative prognostic factors associated with survival in patients with spinal metastasis from lung carcinoma. Methods A retrospective analysis of 26 patients diagnosed with lung carcinoma metastatic to the spinal column was performed to determine factors associated with survival. We used 3 months survival as the clinical cutoff for whether surgical intervention should be performed. We analyzed patients who survived less than 3 months compared with those who survived more than 3 months. Demographic, preoperative, operative, and postoperative factors including functional scores were collected for analysis. Results The median survival for all patients in our study was 3.5 months. We found a statistically significant difference between the group that survived less than 3 months and the group that survived greater than 3 months in terms of extrathoracic metastasis, visceral metastasis, and average postoperative modified Rankin score. Conclusion Determining which patients with lung cancer spinal metastases will benefit from surgical intervention is often dictated by the patients predicted life expectancy. Factors associated with poorer prognosis include age, functional status, visceral metastases, and extrathoracic metastases. Although the prognosis for patients with lung cancer spinal metastases is poor, some patients may experience long-term benefit from surgical intervention.

Surgical Outcomes in Patients with High Spinal Instability Neoplasm Score Secondary to Spinal Giant Cell Tumors

Study Design Retrospective review. Objective To describe the surgical outcomes in patients with high preoperative Spinal Instability Neoplastic Score (SINS) secondary to spinal giant cell tumors (GCT) and evaluate the impact of en bloc versus intralesional resection and preoperative embolization on postoperative outcomes. Methods A retrospective analysis was performed on 14 patients with GCTs of the spine who underwent surgical treatment prior to the use of denosumab. A univariate analysis was performed comparing the patient demographics, perioperative characteristics, and surgical outcomes between patients who underwent en bloc marginal (n = 6) compared with those who had intralesional (n = 8) resection. Results Six patients underwent en bloc resections and eight underwent intralesional resection. Preoperative embolization was performed in eight patients. All patients were alive at last follow-up, with a mean follow-up length of 43 months. Patients who underwent en bloc resection had longer average operative times (p = 0.0251), higher rates of early (p = 0.0182) and late (p = 0.0389) complications, and a higher rate of surgical revision (p = 0.0120). There was a 25% (2/8 patients) local recurrence rate for intralesional resection and a 0% (0/6 patients) local recurrence rate for en bloc resection (p = 0.0929). Conclusions Surgical excision of spinal GCTs causing significant instability, assessed by SINS, is associated with high intraoperative blood loss despite embolization and independent of resection method. En bloc resection requires a longer operative duration and is associated with a higher risk of complications when compared with intralesional resection. However, the increased morbidity associated with en bloc resection may be justified as it may minimize the risk of local recurrence.

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.

Functional gait outcomes for idiopathic normal pressure hydrocephalus after primary endoscopic third ventriculostomy

We evaluated if patients with idiopathic normal pressure hydrocephalus (iNPH) showed functional improvement after primary endoscopic third ventriculostomy (ETV). The efficacy of ETV for iNPH remains controversial. We retrospectively reviewed 10 consecutive patients treated between 2009 and 2011 with ETV for iNPH. Seven patients with a median age of 73 years (range: 60-80) who underwent a primary ETV for iNPH were included for analysis. Median follow-up was 39 months (range: 26-46). Post-ETV stoma and aqueductal and cisternal flows were confirmed via high resolution, gradient echo and phase contrast MRI. Post-ETV timed up and go (TUG) and Tinetti performance oriented mobility assessment scores were compared to pre- and post-lumbar puncture (LP) values. A second LP was performed if ETV failed to sustain the observed improvement after initial LP. Patients who demonstrated ETV failure were subsequently shunted. Compared to pre-LP TUG and Tinetti values of 14.00 seconds (range: 12.00-23.00) and 22 (range: 16-24), post-LP scores improved to 11.00 seconds (range: 8.64-15.00; p=0.06) and 25 (range: 24-28; p=0.02), respectively. ETV failed to sustain this improvement with slight worsening between pre-LP and post-ETV TUG and Tinetti scores. Improvement from pre-LP assessment was regained after shunting and at last follow-up with TUG and Tinetti scores of 12.97 seconds (range: 9.00-18.00; p=0.250) and 25 (range: 18-27; p=0.07), and 11.87 seconds (range: 8.27-18.50; p=0.152) and 23 (range: 18-26; p=0.382), respectively. Despite stoma patency, ETV failed to sustain functional improvement seen after LP, however, improvement was regained after subsequent shunting suggesting that shunt placement remains the preferred treatment for iNPH.

Successful anterior fusion following posterior cervical fusion for revision of anterior cervical discectomy and fusion pseudarthrosis

Pseudarthrosis occurs after approximately 2-20% of anterior cervical discectomy and fusion (ACDF) procedures; it is unclear if posterior or anterior revision should be pursued. In this study, we retrospectively evaluate the outcomes in 22 patients with pseudarthrosis following ACDF and revision via posterior cervical fusion (PCF). Baseline demographics, preoperative symptoms, operative data, time to fusion failure, symptoms of pseudarthrosis, and revision method were assessed. Fusion outcome and clinical outcome were determined at last follow-up (LFU). Thirteen females (59%) and 9 (41%) males experienced pseudarthrosis at a median of 11 (range: 3-151)months after ACDF. Median age at index surgery was 51 (range: 33-67)years. All patients with pseudarthrosis presented with progressive neck pain, with median visual analog scale (VAS) score of 8 (range: 0-10), and/or myeloradiculopathy. Patients with pseudarthrosis <12 months compared to >12 months after index surgery were older (p=0.013), had more frequent preoperative neurological deficits (p=0.064), and lower baseline VAS scores (p=0.006). Fusion was successful after PCF in all patients, with median time to fusion of 10 (range: 2-14)months. Eighteen patients fused both anteriorly and posteriorly, two patients fused anteriorly only, and two patients fused posteriorly only. Median VAS neck score at LFU significantly improved from the time of pseudarthrosis (p=0.012). While uncommon, pseudarthrosis may occur after ACDF. All patients achieved successful fusion after subsequent posterior cervical fusion, with 91% fusing a previous anterior pseudarthrosis after posterior stabilization. Neck pain significantly improved by LFU in the majority of patients in this study.

A Systematic Review of Metastatic Hepatocellular Carcinoma to the Spine

BACKGROUND Hepatocellular carcinoma (HCC) frequently metastasizes to the spine. The impact of medical and/or surgical intervention on overall survival has been examined in a limited number of clinical studies, and herein we systematically review these data. METHODS We performed a literature review using PubMed, Embase, CINAHL, and Web of Science to identify articles that reported survival, clinical outcomes, and/or prognostic factors associated with patients diagnosed with spinal metastases. The methodologic quality of each review was assessed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses tool. RESULTS There were 26 articles (152 patients) that met the inclusion criteria and were treated with either surgery, radiotherapy, chemotherapy, and/or observation. There were 3 retrospective cohort studies, 17 case reports, 5 case series, and 1 longitudinal observational study. Of the patients with known overall survival after diagnosis of spinal metastasis, survival at 3 months, 6 months, 1 year, 2 years, and 5 years was 95.2%, 83.0%, 28.6%, 2.0%, and 1.4%, respectively. The median survival after diagnosis of the metastasis was 0.7 months in the patients who received no treatment, 7 months in the patients treated with surgical intervention alone, 6 months for patients who received chemotherapy and/or radiation, and 13.5 months in the patients treated with a combination of surgery and medical management. All other clinical or prognostic parameters were of low or insufficient strength. CONCLUSIONS Patients diagnosed with HCC spinal metastasis have a 10.6-month overall survival. Further analysis of patients in prospective controlled trials will be essential to the development of treatment algorithms for these patients in the future.