Mass Spectrometry Imaging Reveals Abnormalities in Cardiolipin Composition and Distribution in Astrocytoma Tumor Tissues.

Cardiolipin (CL) is a mitochondrial lipid with diverse roles in cellular respiration, signaling, and organelle membrane structure. CL content and composition are essential for proper mitochondrial function. Deranged mitochondrial energy production and signaling are key components of glial cell cancers and altered CL molecular species have been observed in mouse brain glial cell xenograft tumors. The objective of this study was to describe CL structural diversity trends in human astrocytoma tumors of varying grades and correlate these trends with histological regions within the heterogeneous astrocytoma microenvironment. To this aim, we applied desorption electrospray ionization coupled with high field asymmetric ion mobility mass spectrometry (DESI-FAIMS-MS) to map CL molecular species in human normal cortex (N = 29), lower-grade astrocytoma (N = 19), and glioblastoma (N = 28) tissues. With this platform, we detected 46 CL species and 12 monolysocardiolipin species from normal cortex samples. CL profiles detected from glioblastoma tissues lacked diversity and abundance of longer chain polyunsaturated fatty acid containing CL species when compared to CL detected from normal and lower-grade tumors. CL profiles correlated with trends in tumor viability and tumor infiltration. Structural characterization of the CL species by tandem MS experiments revealed differences in fatty acid and double bond isomer composition among astrocytoma tissues compared with normal cortex and glioblastoma tissues. The GlioVis platform was used to analyze astrocytoma gene expression data from the CGGA dataset. Decreased expression of several mitochondrial respiratory enzyme encoding-genes was observed for higher-grade versus lower-grade tumors, however no significant difference was observed for cardiolipin synthesis enzyme CRLS1.

Varied histomorphology and clinical outcomes of FGFR3-TACC3 fusion gliomas.

Targeted therapies for driver gene fusions in cancers have yielded substantial improvements in care. Here, the authors outline a case series of 6 patients with FGFR3-TACC3 fusion in primary brain tumors ranging from polymorphous low-grade neuroepithelial tumor of the young to papillary glioneuronal tumors and glioblastoma (GBM). Previous studies indicated the FGFR3-TACC3 fusion provides survival benefit to GBM patients. Consistent with this, 2 patients with GBM had unexpectedly good outcomes and survived for 5 and 7 years, respectively. In contrast, 2 patients with initially lower graded tumors survived only 3 years and 1 year, respectively. One patient received erdafitinib, a targeted FGFR inhibitor, for 3 months at late disease recurrence and no response was seen. There were varied histomorphological features, including many cases that lacked the characteristic FGFR3-TACC3 pathology. The findings of this cohort suggest that molecular testing is justified, even for glioma cases lacking classic histopathological signatures. Currently, FGFR3-TACC3 fusion gliomas are often classified on the basis of histopathological features. However, further research is needed to examine whether IDH1/2-wild-type tumors with FGFR3-TACC3 fusion should be classified as a subtype on the basis of this molecular fusion. Because patients with IDH1/2-wild-type GBM with FGFR3-TACC3 fusion have improved survival, routine molecular testing for this mutation in patients enrolled in clinical trials and subsequent stratification may be warranted.

Recurrent liponeurocytoma: A case report and systematic review of the literature.

Background: Liponeurocytomas are rare neurocytic neoplasms that most often arise in the posterior fossa and affect individuals in the third and fifth decades of life. Most reported cases of this unique tumor in the literature have described a favorable clinical prognosis without recurrence. However, increasing reports of recurrent cases prompted the World Health Organization, in 2016, to recategorize the tumor from Grade I to the less favorable Grade II classification. We conducted a systematic review to identify recurrent cases of this unique tumor and to summarize differences between the primary and recurrent cases of liponeurocytoma. Methods: A systematic review exploring recurrent liponeurocytoma cases was conducted by searching the PubMed, Google Scholar, and Scopus databases for articles in English. Abstracts from articles were read and selected for full-text review according to a priori criteria. Relevant full-text articles were analyzed for symptoms, imaging, location, histological, pathological, treatment, and recurrence-free time between the primary and recurrent cases. Results: Of 4392 articles, 15 articles accounting for 18 patients were included (level of evidence: IV) in the study. Recurrence-free time decreased from an average of 82 months between the primary tumor resection to first recurrence to 31.3 months between the first and second recurrence. Recurrent tumors demonstrated increased pleomorphic neural cells, necrosis, vascular proliferation, and MIB-1 index when compared to the primary tumor. Several cases also demonstrated decreased lipidizing components when compared to the primary tumor, further indicating increased dedifferentiation. The primary treatment for this tumor was surgical resection with occasional adjunctive radiotherapy. Conclusion: Recurrent cases of liponeurocytoma have features of increased malignant proliferation compared to the primary cases. The standard treatment for these primary and recurrent tumors is gross total resection. The role of adjunctive radiotherapy remains a matter of debate.

Molecular profiling predicts meningioma recurrence and reveals loss of DREAM complex repression in aggressive tumors.

Meningiomas account for one-third of all primary brain tumors. Although typically benign, about 20% of meningiomas are aggressive, and despite the rigor of the current histopathological classification system there remains considerable uncertainty in predicting tumor behavior. Here, we analyzed 160 tumors from all 3 World Health Organization (WHO) grades (I through III) using clinical, gene expression, and sequencing data. Unsupervised clustering analysis identified 3 molecular types (A, B, and C) that reliably predicted recurrence. These groups did not directly correlate with the WHO grading system, which classifies more than half of the tumors in the most aggressive molecular type as benign. Transcriptional and biochemical analyses revealed that aggressive meningiomas involve loss of the repressor function of the DREAM complex, which results in cell-cycle activation; only tumors in this category tend to recur after full resection. These findings should improve our ability to predict recurrence and develop targeted treatments for these clinically challenging tumors.

Recurrent Papillary Glioneuronal Tumor.

BACKGROUND: Papillary glioneuronal tumors (PGNTs) are rare World Health Organization grade I neoplasms that are characterized by a benign course and excellent response to surgical resection. A few reports exist of tumors with more aggressive clinical and histologic features. In this report we detail the case of an unusually aggressive PGNT in a 67-year-old woman. CASE DESCRIPTION: The patient had a 3-year history of seizures and was diagnosed with a frontoparietal mass on imaging. She underwent subtotal resection with a histologic diagnosis of PGNT. Less than a year after surgery, the patient experienced recurrence of disease and underwent reresection and adjuvant radiation treatment. The patient's disease continued to progress despite radiation treatment, so adjuvant temozolomide was initiated. Molecular testing was performed and revealed a TERT promotor mutation, an FGFR3-TACC3 oncogenic fusion, and a copy number loss in CDKN2A/CDKN2B. CONCLUSIONS: PGNTs, while typically benign, can rarely recur after surgery. Molecular testing should be performed on all PGNTs to help possibly identify more aggressive tumors and potentially reveal novel treatment options.

Functional and Structural Improvement with a Catalytic Carbon Nano-Antioxidant in Experimental Traumatic Brain Injury Complicated by Hypotension and Resuscitation.

Hypotension worsens outcome after all severities of traumatic brain injury (TBI), with loss of cerebral autoregulation being a potential contributor. Previously, we demonstrated that intravenous injection of a high capacity catalytic antioxidant, poly(ethylene)glycol conjugated hydrophilic carbon clusters (PEG-HCCs) rapidly restored cerebral perfusion and acutely restored brain oxidative balance in a TBI model complicated by hemorrhagic hypotension without evidence of toxicity. Here, we tested whether these acute effects translated into behavioral and structural benefit. TBI was generated by a cortical contusion impactor in 38 Long Evans rats, followed by blood withdrawal to a target mean arterial pressure of 40 mm Hg. PEG-HCC (2 mg/kg) or diluent was injected intravenously 80 min later at the onset of blood resuscitation followed by another injection 2 h later (doses determined in prior studies). Performance on beam walking (performed on days 1-5) and Morris water maze (MWM) (performed on days 11-15) was tested, and lesion size was determined at the termination. PEG-HCC treatment nearly completely prevented motor dysfunction (p < 0.001 vs. diluent), improved MWM performance (p < 0.001; treatment vs. time interaction) and reduced lesion size by 61% (p = 0.054). Here we show that treatment with PEG-HCCs at a clinically realistic time point (onset of resuscitation) prevented a major portion of the neurological dysfunction induced in this TBI model, and that PEG-HCCs are candidates for additional study as a potential therapeutic agent.

IMPACT probability of poor outcome and plasma cytokine concentrations are associated with multiple organ dysfunction syndrome following traumatic brain injury.

OBJECTIVE: Traumatic brain injury (TBI) is a major cause of morbidity and mortality. Multiple organ dysfunction syndrome (MODS) occurs frequently after TBI and independently worsens outcome. The present study aimed to identify potential admission characteristics associated with post-TBI MODS. METHODS: The authors performed a secondary analysis of a recent randomized clinical trial studying the effects of erythropoietin and blood transfusion threshold on neurological recovery after TBI. Admission clinical, demographic, laboratory, and imaging parameters were used in a multivariable Cox regression analysis to identify independent risk factors for MODS following TBI, defined as maximum total Sequential Organ Failure Assessment (SOFA) score > 7 within 10 days of TBI. RESULTS: Two hundred patients were initially recruited and 166 were included in the final analysis. Respiratory dysfunction was the most common nonneurological organ system dysfunction, occurring in 62% of the patients. International Mission for Prognosis and Analysis of Clinical Trials (IMPACT) probability of poor outcome at admission was significantly associated with MODS following TBI (odds ratio [OR] 8.88, 95% confidence interval [CI] 1.94-42.68, p < 0.05). However, more commonly used measures of TBI severity, such as the Glasgow Coma Scale, Injury Severity Scale, and Marshall classification, were not associated with post-TBI MODS. In addition, initial plasma concentrations of interleukin (IL)-6, IL-8, and IL-10 were significantly associated with the development of MODS (OR 1.47, 95% CI 1.20-1.80, p < 0.001 for IL-6; OR 1.26, 95% CI 1.01-1.58, p = 0.042 for IL-8; OR 1.77, 95% CI 1.24-2.53, p = 0.002 for IL-10) as well as individual organ dysfunction (SOFA component score ≥ 1). Finally, MODS following TBI was significantly associated with mortality (OR 5.95, 95% CI 2.18-19.14, p = 0.001), and SOFA score was significantly associated with poor outcome at 6 months (Glasgow Outcome Scale score < 4) when analyzed as a continuous variable (OR 1.21, 95% CI 1.06-1.40, p = 0.006). CONCLUSIONS: Admission IMPACT probability of poor outcome and initial plasma concentrations of IL-6, IL-8, and IL-10 were associated with MODS following TBI.

Intracranial Erdheim-Chester Disease Mimicking Parafalcine Meningioma: Report of Two Cases and Review of the Literature.

BACKGROUND: Erdheim-Chester disease (ECD) is a rare, non-Langerhans cell histiocytosis that typically occurs in middle-aged patients. It is usually characterized by multifocal osteosclerotic lesions of the long-bones, however many cases have extraskeletal involvement. Central nervous system (CNS) involvement is common, but isolated CNS involvement at presentation has rarely been reported. CASE DESCRIPTION: Here we report two cases of dural-based ECD mimicking meningioma on imaging with no other identified sites of disease. CONCLUSION: ECD is a rare disease, with isolated CNS involvement reported only a few times in the literature. The significance of this presentation requires additional study and long-term follow up.

Consensus statement from the 2014 International Microdialysis Forum.

Microdialysis enables the chemistry of the extracellular interstitial space to be monitored. Use of this technique in patients with acute brain injury has increased our understanding of the pathophysiology of several acute neurological disorders. In 2004, a consensus document on the clinical application of cerebral microdialysis was published. Since then, there have been significant advances in the clinical use of microdialysis in neurocritical care. The objective of this review is to report on the International Microdialysis Forum held in Cambridge, UK, in April 2014 and to produce a revised and updated consensus statement about its clinical use including technique, data interpretation, relationship with outcome, role in guiding therapy in neurocritical care and research applications.

Malignant peripheral nerve sheath tumor of the cauda equina with craniospinal metastasis.

Intradural spinal malignant peripheral nerve sheath tumors (MPNST) are extremely rare, with only 20 adult patients reported to our knowledge, and only four primary tumors arising from the cauda equina. A 49-year-old man presented with back pain, constipation, and lower extremity weakness and was found to have a large intradural lesion involving the cauda equina. Imaging of the rest of his neuraxis revealed additional small left temporal lobe, cervical, and thoracic lesions. The patient underwent laminectomy for tumor debulking and biopsy, as gross total resection was not possible due to envelopment of the cauda equina. Histopathology revealed a MPNST with high cellularity, elevated proliferative indices, and nerve fascicle invasion. After the debulking, the patient reported improvement in his symptoms. However, 6 weeks later, the patient began having severe headaches, and his left temporal lobe lesion was found to have increased significantly in size, requiring craniotomy for palliative resection. The authors report the first adult patient with sporadic spinal MPNST with craniospinal metastasis to our knowledge. Imaging of the entire neuraxis is recommended for initial workup of these lesions, which are capable of intradural spread. The best treatment approach is unclear, but total surgical resection should be attempted, barring infiltration and engulfment of the nerve roots or widespread dissemination.

Effect of erythropoietin and transfusion threshold on neurological recovery after traumatic brain injury: a randomized clinical trial.

IMPORTANCE: There is limited information about the effect of erythropoietin or a high hemoglobin transfusion threshold after a traumatic brain injury. OBJECTIVE: To compare the effects of erythropoietin and 2 hemoglobin transfusion thresholds (7 and 10 g/dL) on neurological recovery after traumatic brain injury. DESIGN, SETTING, AND PARTICIPANTS: Randomized clinical trial of 200 patients (erythropoietin, n = 102; placebo, n = 98) with closed head injury who were unable to follow commands and were enrolled within 6 hours of injury at neurosurgical intensive care units in 2 US level I trauma centers between May 2006 and August 2012. The study used a factorial design to test whether erythropoietin would fail to improve favorable outcomes by 20% and whether a hemoglobin transfusion threshold of greater than 10 g/dL would increase favorable outcomes without increasing complications. Erythropoietin or placebo was initially dosed daily for 3 days and then weekly for 2 more weeks (n = 74) and then the 24- and 48-hour doses were stopped for the remainder of the patients (n = 126). There were 99 patients assigned to a hemoglobin transfusion threshold of 7 g/dL and 101 patients assigned to 10 g/dL. INTERVENTIONS: Intravenous erythropoietin (500 IU/kg per dose) or saline. Transfusion threshold maintained with packed red blood cells. MAIN OUTCOMES AND MEASURES: Glasgow Outcome Scale score dichotomized as favorable (good recovery and moderate disability) or unfavorable (severe disability, vegetative, or dead) at 6 months postinjury. RESULTS: There was no interaction between erythropoietin and hemoglobin transfusion threshold. Compared with placebo (favorable outcome rate: 34/89 [38.2%; 95% CI, 28.1% to 49.1%]), both erythropoietin groups were futile (first dosing regimen: 17/35 [48.6%; 95% CI, 31.4% to 66.0%], P = .13; second dosing regimen: 17/57 [29.8%; 95% CI, 18.4% to 43.4%], P < .001). Favorable outcome rates were 37/87 (42.5%) for the hemoglobin transfusion threshold of 7 g/dL and 31/94 (33.0%) for 10 g/dL (95% CI for the difference, -0.06 to 0.25, P = .28). There was a higher incidence of thromboembolic events for the transfusion threshold of 10 g/dL (22/101 [21.8%] vs 8/99 [8.1%] for the threshold of 7 g/dL, odds ratio, 0.32 [95% CI, 0.12 to 0.79], P = .009). CONCLUSIONS AND RELEVANCE: In patients with closed head injury, neither the administration of erythropoietin nor maintaining hemoglobin concentration of greater than 10 g/dL resulted in improved neurological outcome at 6 months. The transfusion threshold of 10 g/dL was associated with a higher incidence of adverse events. These findings do not support either approach in this setting. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00313716.

Pediatric and adult malignant peripheral nerve sheath tumors: an analysis of data from the surveillance, epidemiology, and end results program.

Malignant peripheral nerve sheath tumors (MPNSTs) are rare soft tissue sarcomas that arise predominantly from Schwann cells. Despite the fact that MPNSTs have high local recurrence rates and are generally associated with poor prognosis, little is known about prognostic factors or effective clinical management for this tumor type. The purpose of this study was to describe the distributions of patient and tumor characteristics and to identify predictors of cause-specific survival among MPNST cases reported to SEER between 1973 and 2008. Patient and tumor characteristics were compared between pediatric and adult MPNST cases. Cox regression and tree-based survival analysis were used to examine factors associated with MPNST-related mortality separately among adults and children. A total of 1,315 MPNST cases were isolated from the 1973-2008 SEER dataset. Among pediatric cases, sex, race, and radiation therapy predicted MPNST survival, whereas among adults, tumor site, tumor grade, number of primary tumors, and tumor size were significant predictors. As tumor size at diagnosis/resection may be the only somewhat "modifiable" prognostic factor, future studies should aim to identify biological and social attributes associated with tumor size at diagnosis, separately among individuals with and without NF-1, in order to help identify earlier opportunities for clinical intervention.

Paradoxical immune reconstitution inflammatory syndrome due to toxoplasmic encephalitis: two cases and review of initiation of antiretroviral timing in toxoplasmic encephalitis IRIS.

Toxoplasma encephalitis immune reconstitution inflammatory syndrome (TE-IRIS) is rare and usually occurs in an unmasking, rather than paradoxical form. To the best of our knowledge, only two cases of paradoxical TE-IRIS and nine cases of unmasking TE-IRIS have been previously described. We present two additional cases of histopathology-consistent paradoxical TE-IRIS, after early initiation of antiretroviral therapy (ART), and review the literature on TE-IRIS. Three of the four reported cases of paradoxical TE-IRIS were associated with early (within one week) initiation of ART, an issue that was not addressed in the 2009 US Department of Health and Human Services guidelines for the treatment of opportunistic infections.

Disseminated germinoma in the brain and cervical spinal cord 10 years after radiographic resolution of pineal germinoma.

Intracranial germinoma, a radiosensitive tumor, is seldom recurrent following initial treatment. When it does recur, it is usually soon after initial treatment and secondary to inadequate radiation field coverage of the tumor. Rarely, there have been case reports of late recurrence many years after initial therapy. Patients with recurrent germinoma in the spine have a less favorable prognosis in terms of treatment response compared to the initial lesion. Thus, careful consideration of the initial lesion, its treatment, and serial imaging of the neural axis with close follow-up is important. We report a patient with a rare delayed recurrence in the brain and cervical spinal cord despite close follow-up with clinical examination and serial imaging.

Absence of IDH1-R132H mutation predicts rapid progression of nonenhancing diffuse glioma in older adults.

Advanced age and contrast enhancement portend a poor prognosis in diffuse glioma (DG). Diffuse glioma may present as nonenhancing tumors that rapidly progress in weeks to months to a pattern of ring enhancement, characteristic of glioblastoma (GBM). Mutations involving isocitrate dehydrogenase 1 (IDH1) have recently emerged as important diagnostic and prognostic markers in DG. R132H is the most common mutation, expressed in more than 80% of DG and secondary GBM but in less than 10% of primary GBM. Adults older than 50 years with nonenhancing, rapidly progressing DG were identified. A comparison group comprised randomly selected, age-matched patients with nonenhancing, nonprogressing DG. Isocitrate dehydrogenase 1 status was evaluated using anti-IDH1-R132H antibodies (Dianova, Hamburg, Germany). The results were correlated with the clinical outcomes. We identified 4 patients who presented with nonenhancing DG that rapidly progressed to ring-enhancing lesions that were subsequently diagnosed on surgical resection as GBM. This group showed absent IDH1-R132H expression, which is characteristic of primary GBM. The comparison group of 5 patients presented with nonenhancing, nonprogressing DG, and all 5 tumors showed IDH1-R132H expression. In conclusion, negative IDH1-R132H mutation status in nonenhancing DG of older adults is a poor prognostic factor associated with rapid progression to ring-enhancing GBM. The shorter interval of progression and negative IDH1-R132H mutation status suggest a similar molecular pathway as seen in primary GBM.

Clinical microdialysis in neuro-oncology: principles and applications.

Clinical microdialysis allows a discrete volume of the brain to be sampled for neurochemical analysis of neurotransmitters, metabolites, biomarkers, and drugs. The technique can be safely used in humans intraoperatively, in the intensive care unit, and in ambulatory settings. Microdialysis probes, micropumps, and analytical equipment are commercially available and have been used extensively for neurochemical monitoring in traumatic brain injury, stroke, and subarachnoid hemorrhage. There has been very limited use of microdialysis in neuro-oncology, but this technique has great promise in the study of the basic neurochemistry of brain tumors, alterations in neurochemistry in response to therapy, and the pharmacokinetics of chemotherapeutic agents. Microdialysis probes may also be used to deliver drugs while simultaneously permitting monitoring of neurochemical changes induced by this therapy.