Top advances of the year: Neuro-oncology.

Management of brain tumors has been challenging given the limited therapeutic options and disabling morbidities associated with central nervous system (CNS) dysfunction. This review focuses on recent developments in the field, with an emphasis on clinical management. The growing clinical trials landscape reflects advanced insights into cancer immunology and genomics and the need to address molecular and clinical heterogeneity. Recent phase 3 trials investigating anti-PD-1 immunotherapies, particularly nivolumab, have failed to demonstrate improved survival in glioblastoma, underscoring the need to better understand the complexity of CNS immunologic surveillance. Conversely, targeted therapies have accounted for several US Food and Drug Administration approvals extended to brain tumors, particularly therapies directed to BRAF V600E mutations and TRAK fusions, underscoring a need to routinely screen patients for these rare molecular abnormalities. In primary CNS lymphoma, attention has turned to long-term outcomes of consolidation therapies, and recent studies have highlighted the excellent disease control afforded by high-dose chemotherapy and stem cell transplantation. Meningiomas remain a focus of investigations, with preliminary promising results observed with octreotide combined with mTOR inhibition, and immunotherapy with single-agent pembrolizumab. Finally, proton radiotherapy has emerged as a novel alternative for leptomeningeal metastases from solid tumors, which can now be treated more safely with craniospinal irradiation and monitored by the enumeration of circulating tumor cells in the cerebrospinal fluid as a biomarker. Taken together, these incremental advances have improved outcomes in select brain tumor patient populations, whereas ongoing clinical trials hold the promise of meaningful advances and breakthroughs for larger proportions of patients with brain tumors.

Postcardiac Arrest Neuroprognostication Practices: A Survey of Brazilian Physicians.

End-of-life care and decisions on withdrawal of life-sustaining therapies vary across countries, which may affect the feasibility of future multicenter cardiac arrest trials. In Brazil, withdrawal of life-sustaining therapy is reportedly uncommon, allowing the natural history of postcardiac arrest hypoxic-ischemic brain injury to present itself. We aimed to characterize approaches to neuroprognostication of cardiac arrest survivors among physicians in Brazil. DESIGN: Cross-sectional study. SETTING: Between August 2, 2019, and July 31, 2020, we distributed a web-based survey to physicians practicing in Brazil. SUBJECTS: Physicians practicing in Brazil and members of the Brazilian Association of Neurointensive Care, who care for patients resuscitated following cardiac arrest. INTERVENTIONS: Not applicable. MEASUREMENTS AND MAIN RESULTS: Responses from 185 physicians were obtained. Pupillary reflexes, corneal reflexes, and motor responses were considered critical to prognostication, whereas neuroimaging and electroencephalography were also regarded as important. For patients without targeted temperature management, absent pupillary and corneal reflexes at 24 hours postarrest were considered strongly predictive of poor neurologic outcome by 31.8% and 33.0%, respectively. For targeted temperature management-treated patients, absent pupillary and corneal reflexes at 24-hour postrewarming were considered prognostic by 22.9% and 20.0%, respectively. Physicians felt comfortable making definitive prognostic recommendations at day 6 postarrest or later (34.2%) for nontargeted temperature management-treated patients, and at day 6 postrewarming (20.4%) for targeted temperature management-treated patients. Over 90% believed that improving neuroprognostic accuracy would affect end-of-life decision-making. CONCLUSIONS: There is significant variability in neuroprognostic approaches to postcardiac arrest patients and timing of prognostic studies among Brazilian physicians, with practices frequently deviating from current guidelines, underscoring a need for greater neuroprognostic accuracy. Nearly all physicians believed that improving neuroprognostication will impact end-of-life decision-making. Given the tendency to delay prognostic recommendations while using similar neuroprognostic tools, Brazil offers a unique cohort in which to examine the natural history of hypoxic-ischemic brain injury in future studies.

Neuroprognostication Practices in Postcardiac Arrest Patients: An International Survey of Critical Care Providers.

OBJECTIVES: To characterize approaches to neurologic outcome prediction by practitioners who assess prognosis in unconscious cardiac arrest individuals, and assess compliance to available guidelines. DESIGN: International cross-sectional study. SETTING: We administered a web-based survey to members of Neurocritical Care Society, Society of Critical Care Medicine, and American Academy of Neurology who manage unconscious cardiac arrest patients to characterize practitioner demographics and current neuroprognostic practice patterns. SUBJECTS: Physicians that are members of aforementioned societies who care for successfully resuscitated cardiac arrest individuals. INTERVENTIONS: Not applicable. MEASUREMENTS AND MAIN RESULTS: A total of 762 physicians from 22 countries responses were obtained. A significant proportion of respondents used absent corneal reflexes (33.5%) and absent pupillary reflexes (36.2%) at 24 hours, which is earlier than the recommended 72 hours in the standard guidelines. Certain components of the neurologic examination may be overvalued, such as absent motor response or extensor posturing, which 87% of respondents considered being very or critically important prognostic indicators. Respondents continue to rely on myoclonic status epilepticus and neuroimaging, which were favored over median nerve somatosensory evoked potentials for prognostication, although the latter has been demonstrated to have a higher predictive value. Regarding definitive recommendations based on poor neurologic prognosis, most physicians seem to wait until the postarrest timepoints proposed by current guidelines, but up to 25% use premature time windows. CONCLUSIONS: Neuroprognostic approaches to hypoxic-ischemic encephalopathy vary among physicians and are often not consistent with current guidelines. The overall inconsistency in approaches and deviation from evidence-based recommendations are concerning in this disease state where mortality is so integrally related to outcome prediction.

Corneal Reflex Testing in the Evaluation of a Comatose Patient: An Ode to Precise Semiology and Examination Skills.

BACKGROUND/OBJECTIVE: The corneal reflex assesses the integrity of the trigeminal and facial cranial nerves. This brainstem reflex is fundamental in neuroprognostication after cardiac arrest and in brain death determination. We sought to investigate corneal reflex testing methods among neurologists and general critical care providers in the context of neuroprognostication following cardiac arrest. METHODS: This is an international cross-sectional study disseminated to members of the Neurocritical Care Society, Society of Critical Care Medicine, and American Academy of Neurology. We utilized an open Web-based survey (Qualtrics®, Provo, UT, USA) to disseminate 26 questions regarding neuroprognostication practices following cardiac arrest, in which 3 questions pertained to corneal reflex testing. Descriptive statistical measures were used, and subgroup analyses performed between neurologists and non-neurologists. Questions were not mandatory; therefore, the percentages were relative to the number of respondents for each question. RESULTS: There were 959 respondents in total. Physicians comprised 85.1% of practitioners (762 out of 895), of which 55% (419) identified themselves as non-neurologists and 45% (343) as neurologists. Among physicians, 85.9% (608 out of 708) deemed corneal reflex relevant for prognostication following cardiac arrest (neurologists 84.4% versus non-neurologists 87.0%). A variety of techniques were employed for corneal reflex testing, the most common being "light cotton touch" (59.2%), followed by "cotton-tipped applicator with pressure" (23.9%), "saline or water squirt" (15.9%), and "puff of air" (1.0%). There were no significant differences in the methods for testing between neurologists and non-neurologists (p = 0.52). The location of stimulus application was variable, and 26.1% of physicians (148/567) apply the stimulus on the temporal conjunctiva rather than on the cornea itself. CONCLUSIONS: Corneal reflex testing remains a cornerstone of the coma exam and is commonly used in neuroprognostication of unconscious cardiac arrest survivors and in brain death determination. A wide variability of techniques is noted among practitioners, including some that may provide suboptimal stimulation of corneal nerve endings. Imprecise testing in this setting may lead to inaccuracies in critical settings, which carries significant consequences such as guiding decisions of care limitations, misdiagnosis of brain death, and loss of public trust.

Differential outcomes following successful resuscitation in cardiac arrest due to drug overdose.

BACKGROUND: Data pertaining to clinical characteristics and outcomes of cardiac arrest (CA) due to drug overdose (ODCA) are limited. We hypothesized that patients with ODCA would have binary outcomes (brain death or functional recovery) compared to patients in whom CA was due to another etiology. METHODS: We performed a retrospective analysis of CA cases from a single academic institution from 2012 to 2017. ODCA cases were ascertained by admission notes strongly suggestive of OD or positive toxicology screens not explained by medication administration. Clinical characteristics and outcomes were extracted from medical records, and regression modeling was used to compare ODCA and non-ODCA patients. RESULTS: Of the 300 CA cases in this analysis, 28 (9%) were attributed to drug overdose, with opioids accounting for 54%. ODCA patients were younger, had fewer comorbidities, were less likely to have witnessed arrests or bystander cardiopulmonary resuscitation, and had longer downtimes. Inpatient mortality did not differ between cohorts (79% ODCA, 73% non-ODCA, p = 0.66), but ODCA was associated with higher rates of brain death (43%, 6%, p < 0.001). Of patients who survived to discharge, there was no difference in the likelihood of favorable neurological recovery, defined as Cerebral Performance Category score of 1-2 (7%, 7%, p = 1.00) or modified Rankin Scale score of 0-3 (7%, 9%, p = 1.00). CONCLUSIONS: Despite similar neurological recovery and survival rates to hospital discharge, ODCA patients were more likely than non-ODCA patients to progress to brain death. Larger prospective studies analyzing ODCA are needed to better understand potential treatment options and prognostic tools in this cohort.

Probing the extended lipid anchorage with cytochrome c and liposomes containing diacylphosphatidylglycerol lipids.

Experiments investigating the adsorption and desorption of cytochrome c onto and from liposomes containing 50 mol% 1,2-diacylphosphatidylglycerol lipids [10:0, 12:0, 14:0, 16:0, 18:1(Δ9 cis)] with 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC) in pH 7.4 buffered solutions of low to moderate ionic strength are reported. Fluorescence experiments show that cytochrome c has a similar adsorption affinity for the five labeled 50 mol% PG liposome systems investigated. Fluorescence recovery experiments reveal the extent of cytochrome c desorption upon the addition of >10× excess of unlabeled 100% 1,2-dioleoyl-sn-glycero-3-phosphatidylglycerol (DOPG) liposomes is dependent on the lipid's acyl chain length. The extent of desorption is also shown to be independent of temperature, albeit over a narrow range. The differences in the extent of cytochrome c desorption from liposomes containing PG lipids with different acyl chain lengths is attributed to the varying contribution of the binding motif involving the extended lipid anchorage in response to lipid packing stress.

Neurologic Recovery After Cardiac Arrest: a Multifaceted Puzzle Requiring Comprehensive Coordinated Care.

OPINION STATEMENT: Surviving cardiac arrest (CA) requires a longitudinal approach with multiple levels of responsibility, including fostering a culture of action by increasing public awareness and training, optimization of resuscitation measures including frequent updates of guidelines and their timely implementation into practice, and optimization of post-CA care. This clearly goes beyond resuscitation and targeted temperature management. Brain-directed physiologic goals should dictate the post-CA management, as accumulating evidence suggests that the degree of hypoxic brain injury is the main determinant of survival, regardless of the etiology of arrest. Early assessment of the need for further hemodynamic and electrophysiologic cardiac interventions, adjusting ventilator settings to avoid hyperoxia/hypoxia while targeting high-normal to mildly elevated PaCO2, maintaining mean arterial blood pressures >65 mmHg, evaluating for and treating seizures, maintaining euglycemia, and aggressively pursuing normothermia are key steps in reducing the bioenergetic failure that underlies secondary brain injury. Accurate neuroprognostication requires a multimodal approach with standardized assessments accounting for confounders while recognizing the importance of a delayed prognostication when there is any uncertainty regarding outcome. The concept of a highly specialized post-CA team with expertise in the management of post-CA syndrome (mindful of the brain-directed physiologic goals during the early post-resuscitation phase), TTM, and neuroprognostication, guiding the comprehensive care to the CA survivor, is likely cost-effective and should be explored by institutions that frequently care for these patients. Finally, providing tailored rehabilitation care with systematic reassessment of the needs and overall goals is key for increasing independence and improving quality-of-life in survivors, thereby also alleviating the burden on families. Emerging evidence from multicenter collaborations advances the field of resuscitation at an incredible pace, challenging previously well-established paradigms. There is no more room for "conventional wisdom" in saving the survivors of cardiac arrest.