Alexander Tucker

Xenon and Hypothermia Combine Additively, Offering Long-Term Functional and Histopathologic Neuroprotection After Neonatal Hypoxia/Ischemia

Background and Purpose— Hypoxic/ischemic (HI) brain injury affects 1 to 6 per 1000 live human births, with a mortality of 15% to 20%. A quarter of survivors have permanent disabilities. Hypothermia is the only intervention that improves outcome; however, further improvements might be obtained by combining hypothermia with additional treatments. Xenon is a noble anesthetic gas with an excellent safety profile, showing great promise in vitro and in vivo as a neuroprotectant. We investigated combinations of 50% xenon (Xe50%) and hypothermia of 32°C (HT32°C) as a post-HI therapy. Methods— An established neonatal rat HI model was used. Serial functional neurologic testing into adulthood 10 weeks after injury was performed, followed by global and regional brain histopathology evaluation. Results— In the combination Xe50%HT32°C group, complete restoration of long-term functional outcomes was seen. Hypothermia produced improvement on short- (P<0.001) and long- (P<0.001) term functional testing, whereas Xe50% alone predominantly improved long-term function (P<0.05), suggesting that short-term testing does not always predict eventual outcome. Similarly, the Xe50%HT32°C combination produced the greatest (71%) improvement in global histopathology scores, a pattern mirrored in the regional scores, whereas Xe50% and HT32°C individually produced smaller improvements (P<0.05 and P<0.001, respectively). The interaction between the 2 treatments was additive. Conclusions— The xenon/hypothermia combination additively confers greater protection after HI than either treatment alone. The functional improvement is almost complete, is sustained long term, and is accompanied by greatly improved histopathology. The unique safety profile differentiates xenon as an attractive combination therapy with hypothermia to improve the otherwise bleak outcome from neonatal HI.

Neurobehavioral abnormalities in the dysbindin-1 mutant, sandy, on a C57BL/6J genetic background.

Sandy mice have a deletion mutation in the gene encoding dysbindin‐1, Dtnbp1, with consequent reduction of the protein in heterozygotes and its loss in homozygotes. The sandy mouse thus serves as an animal model of dysbindin‐1 function. As this protein is concentrated in synaptic tissue and affects transmitter release, it may affect neuronal processes that mediate behavior. To investigate the neurobehavioral effects of the Dtnbp1 mutation, we studied littermate sandy and wild‐type controls on a C57BL/6J genetic background. The three animal groups were indistinguishable in their external physical characteristics, sensorimotor skills and indices of anxiety‐like behaviors. In the open field, however, homozygous animals were hyperactive and appeared to show less habituation to the initially novel environment. In the Morris water maze, homozygous animals displayed clear deficits in spatial learning and memory with marginal deficits in visual association learning. Apart from the last mentioned deficits, these abnormalities are consistent with hippocampal dysfunction and in some cases with elevated dopaminergic transmission via D2 dopamine receptors. As similar deficits in spatial learning and memory have been found in schizophrenia, where decreased dysbindin‐1 has been found in the hippocampus, the sandy mouse may also model certain aspects of cognition and behavior relevant to schizophrenia.

Development of Amplitude-Integrated Electroencephalography and Interburst Interval in the Rat

Continuous monitoring of electrocortical brain activity with amplitude-integrated electroencephalography (aEEG) is important in neonatology. aEEG is affected by, for example, maturity, encephalopathy, and drugs. Neonatal research uses rat pups of different ages. Postnatal day (P) 7 rats are suggested to be equivalent neurodevelopmentally to near-term infants. We hypothesized that electroencephalography (EEG) and aEEG in P1–P21 rats follow the same developmental pattern with respect to background activity and the longest interburst interval (IBI) as that seen in infants from 23-wk gestational age (GA) to post-term. We examined aEEG and EEG on 49, unsedated rat pups with two clinical monitors. aEEG traces were analyzed for lower and upper margin amplitude, bandwidth and the five longest IBI in each trace were measured from the raw EEG. The median longest IBI decreased linearly with age by 5.24 s/d on average. The lower border of the aEEG trace was <5 μV until P7 and rose exponentially reaching 10 μV by P12. This correlated strongly with the decrease in IBI; both reflect increased continuity of brain activity with postnatal age. Based on aEEG trace analysis, the rat aEEG pattern at P1 corresponds to human aEEG at 23-wk gestation; P7 corresponds to 30–32 wk and P10 to 40–42 wk.

A neonatal piglet model of intraventricular hemorrhage and posthemorrhagic ventricular dilation

OBJECT The combination of intraventricular hemorrhage (IVH) and posthemorrhagic ventricular dilation (PHVD) remains an important cause of disability in children surviving prematurity. Currently, there is no clear agreement on the management of neonatal IVH, apart from the eventual insertion of a shunt to control PHVD. Cerebrospinal fluid (CSF) shunts are associated with a relatively high complication rate in this population. The development of new treatment options requires greater understanding of the pathophysiological mechanisms of IVH and PHVD, as well as an opportunity to monitor closely their effects on the immature brain. The authors have developed a neonatal large animal model of IVH with long-term survival, allowing the full development of PHVD. METHODS Fourteen piglets that were 3 to 24 hours old were randomized to receive slow injections of autologous blood, autologous blood with elevated hematocrit, or artificial CSF after induction of general anesthesia. A fourth group served as controls. All animals underwent surgery to form an artificial fontanelle at the bregma. Physiological parameters, including intracranial pressure and electroencephalography, were monitored during injection. RESULTS Serial cranial ultrasonography studies performed during the 23- to 44-day survival period demonstrated progressive ventricular dilation in the animals injected with blood. Ventricular volumes, measured with image analysis software, confirmed the highest dilation after injection of blood with an elevated hematocrit. Histological evaluation showed fibrosis in the basal subarachnoid space of hydrocephalic piglets. CONCLUSIONS This piglet model closely replicates human neonatal IVH and PHVD. It allows detailed physiological and ultrasonographic monitoring over a prolonged survival period. It is suitable for evaluation of noninvasive as well as surgical options in the management of IVH and PHVD.

Immunosuppressive tumor-infiltrating myeloid cells mediate adaptive immune resistance via a PD-1/PD-L1 mechanism in glioblastoma

Background Adaptive immune resistance in the tumor microenvironment appears to attenuate the immunotherapeutic targeting of glioblastoma (GBM). In this study, we identified a tumor-infiltrating myeloid cell (TIM) population that expands in response to dendritic cell (DC) vaccine treatment. The aim of this study was to understand how this programmed death ligand 1 (PD-L1)-expressing population restricts activation and tumor-cytolytic function of vaccine-induced tumor-infiltrating lymphocytes (TILs). Methods To test this hypothesis in our in vivo preclinical model, we treated mice bearing intracranial gliomas with DC vaccination ± murine anti-PD-1 monoclonal antibody (mAb) blockade or a colony stimulating factor 1 receptor inhibitor (CSF-1Ri) (PLX3397) and measured overall survival. We then harvested and characterized the PD-L1+ TIM population and its role in TIL activation and tumor cytolysis in vitro. Results Our data indicated that the majority of PD-L1 expression in the GBM environment is contributed by TIMs rather than by tumor cells themselves. While PD-1 blockade partially reversed the TIL dysfunction, targeting TIMs directly with CSF-1Ri altered TIM expression of key chemotactic factors associated with promoting increased TIL infiltration after vaccination. Neither PD-1 mAb nor CSF-1Ri had a demonstrable therapeutic benefit alone, but when combined with DC vaccination, a significant survival benefit was observed. When the tripartite regimen was given (DC vaccine, PD-1 mAb, PLX3397), long-term survival was noted together with an increase in the number of TILs and TIL activation. Conclusion Together, these studies elucidate the role that TIMs play in mediating adaptive immune resistance in the GBM microenvironment and provide evidence that they can be manipulated pharmacologically with agents that are clinically available. Development of immune resistance in response to active vaccination in GBM can be reversed with dual administration of CSF-1Ri and PD-1 mAb.

Do drugs that block transforming growth factor beta reduce posthaemorrhagic ventricular dilatation in a neonatal rat model

Aim: Posthaemorrhagic ventricular dilatation (PHVD) after intraventricular haemorrhage (IVH) remains a significant problem in preterm infants. No treatment has reduced the need for cerebrospinal fluid (CSF) diversion. Considerable evidence implicates transforming growth factor‐β (TGF‐β) in the pathogenesis of PHVD. Pirfenidone and losartan reduce TGF‐β expression and decrease postinflammatory fibrosis in the lungs, kidneys, heart and liver. They have excellent CSF and brain penetration. We hypothesized that administration of pirfenidone or losartan would reduce ventricular dilatation.

TCR sequencing can identify and track glioma-infiltrating T cells after DC vaccination

A clinically translatable platform was developed to track T-cell populations without prior knowledge of their specificity. TCR sequencing data could be used to distinguish patients with glioblastoma who will benefit and are benefitting from immunotherapy. Although immunotherapeutic strategies are emerging as adjunctive treatments for cancer, sensitive methods of monitoring the immune response after treatment remain to be established. We used a novel next-generation sequencing approach to determine whether quantitative assessments of tumor-infiltrating lymphocyte (TIL) content and the degree of overlap of T-cell receptor (TCR) sequences in brain tumors and peripheral blood were predictors of immune response and overall survival in glioblastoma patients treated with autologous tumor lysate–pulsed dendritic cell immunotherapy. A statistically significant correlation was found between a higher estimated TIL content and increased time to progression and overall survival. In addition, we were able to assess the proportion of shared TCR sequences between tumor and peripheral blood at time points before and after therapy, and found the level of TCR overlap to correlate with survival outcomes. Higher degrees of overlap, or the development of an increased overlap following immunotherapy, was correlated with improved clinical outcome, and may provide insights into the successful, antigen-specific immune response. Cancer Immunol Res; 4(5); 412–8. ©2016 AACR.

Red Blood Cell Transfusions Following Resection of Skull Base Meningiomas: Risk Factors and Clinical Outcomes

Abstract Objective This article identifies risk factors for and investigates clinical outcomes of postoperative red blood cell transfusion in patients with skull base meningiomas. Design Retrospective cohort study. Setting Single academic medical center. Participants The transfusion group included patients who had skull base meningiomas and who received packed red blood cell (RBC) transfusion within 7 days of surgery. The no transfusion group included patients who had skull base meningiomas but who did not have RBCs transfused within 7 days of surgery. Main Outcome Measures In‐hospital complication rate, length of stay (LOS), and discharge disposition. Results One hundred and ninety‐six patients had a craniotomy for resection of a meningioma at our institution from March 2013 to January 2017. Seven patients had skull base meningiomas and received RBC transfusion within 7 days of surgery (the transfusion group). The skull base was an independent risk factor for transfusion after we controlled for the effect of meningioma size (OR 3.89, 95% CI 1.34, 11.25). Operative time greater than 10 hours was an independent risk factor for prolonged hospital stay (OR 8.84, 95% CI 1.08, 72.10) once we controlled for the effect of transfusion. In contrast, transfusion did not independently impact LOS or discharge disposition once we controlled for the effect of operative time. Conclusions The skull base is an independent predictor of RBC transfusion. However, RBC transfusion alone cannot predict LOS or discharge disposition in patients who undergo surgical resection of a skull base meningioma.

Next Generation Case Report: Supraorbital Craniotomy for Anterior Communicating Artery Aneurysm Clipping in Annotated Virtual Reality Environment

BACKGROUND AND IMPORTANCE Recent years have seen significant advancements in virtual reality. Implementation of this technology in combination with traditional learning methods is a powerful tool for medical teaching. CLINICAL PRESENTATION This is a 60-yr-old woman who presented with a history of headaches and was found to have an unruptured 4-mm anterior communicating artery aneurysm. After discussion, the patient elected to have the aneurysm treated by surgical clipping. The aneurysm was completely occluded through a supraorbital craniotomy with a single clip. The patient was discharged home in good condition on postoperative day 2. This case was imported into a virtual reality environment with annotated slides and operative video for resident teaching. CONCLUSION As virtual reality technology continues to grow, library of interactive case reports could revolutionize neurosurgical education.

Survival Outcomes After Intracranial Hemorrhage in Liver Disease

BACKGROUND Survival outcomes for patients with liver disease who suffer an intracranial hemorrhage (ICH) have not been thoroughly investigated. OBJECTIVE To understand survival outcomes for 3 groups: (1) patients with an admission diagnosis of liver disease (end-stage liver disease [ESLD] or non-ESLD) who developed an ICH in the hospital, (2) patients with ESLD who undergo either operative vs nonoperative management, and (3) patients with ESLD on the liver transplant waitlist who developed an ICH in the hospital. METHODS We retrospectively reviewed hospital charts from March 2006 through February 2017 of patients with liver disease and an ICH evaluated by the neurosurgery service at a single academic medical center. The primary outcome was survival. RESULTS We included a total of 53 patients in this study. The overall survival for patients with an admission diagnosis of liver disease who developed an ICH (n = 29, 55%) in the hospital was 22%. Of those patients with an admission diagnosis of liver disease, 27 patients also had ESLD. Kaplan-Meier analysis found no significant difference in survival for ESLD patients (n = 33, 62%) according to operative status. There were 11 ESLD patients on the liver transplant waitlist. The overall survival for patients with ESLD on the liver transplant waitlist who suffered an in-hospital ICH (n = 7, 13%) was 14%. CONCLUSION ICH in the setting of liver disease carries a grave prognosis. Also, a survival advantage for surgical hematoma evacuation in ESLD patients is not clear.