Differential Glial Chitotriosidase 1 and Chitinase 3-like Protein 1 Expression in the Human Primary Visual Cortex and Cerebellum after Global Hypoxia-Ischemia.

Here, we studied the neuroinflammation- and ischemia-related glial markers chitotriosidase 1 (CHIT1) and chitinase-3-like protein 1 (CHI3L1, alias YKL-40) in the human striate cortex and cerebellum at different time points after global hypoxic-ischemic brain injury (HIBI). Both regions differ considerably in their glial cell population but are supplied by the posterior circulation. CHIT1 and CHI3L1 expression was compared to changes in microglial (IBA1, CD68), astrocytic (GFAP, S100ß), and neuronal markers (H&E, neurofilament heavy chain, NfH; calretinin, CALR) using immunohistochemistry and multiple-label immunofluorescence. Initial striatal cortical and cerebellar Purkinje cell damage, detectable already 1/2 d after HIBI, led to delayed neuronal death, whereas loss of cerebellar NfH-positive stellate and CALR-positive granule cells was variable. During the first week post-HIBI, a transient reduction of IBA1-positive microglia was observed in both regions, and fragmented/clasmatodendritic cerebellar Bergmann glia appeared. In long-term survivors, both brain regions displayed high densities of activated IBA1-positive cells and CD68-positive macrophages, which showed CHIT1 co-localization in the striate cortex. Furthermore, enlarged GFAP- and S100ß-positive astroglia emerged in both regions around 9-10 d post-HIBI, i.e., along with clearance of dead neurons from the neuropil, although GFAP-/S100ß-positive gemistocytic astrocytes that co-expressed CHI3L1 were found only in the striate cortex. Thus, only GFAP-/S100ß-positive astrocytes in the striate cortex, but not cerebellar Bergmann glia, differentiated into CHI3L1-positive gemistocytes. CHIT1 was co-expressed almost entirely in macrophages in the striate cortex and not cerebellum of long-term survivors, thereby indicating that CHIT1 and CHI3L1 could be valuable biomarkers for monitoring the outcome of global HIBI.

The effect of targeted hyperoxemia in a randomized controlled trial employing a long-term resuscitated, model of combined acute subdural hematoma and hemorrhagic shock in swine with coronary artery disease: An exploratory, hypothesis-generating study.

Controversial evidence is available regarding suitable targets for the arterial O2 tension (PaO2) after traumatic brain injury and/or hemorrhagic shock (HS). We previously demonstrated that hyperoxia during resuscitation from hemorrhagic shock attenuated cardiac injury and renal dysfunction in swine with coronary artery disease. Therefore, this study investigated the impact of targeted hyperoxemia in a long-term, resuscitated model of combined acute subdural hematoma (ASDH)-induced brain injury and HS. The prospective randomized, controlled, resuscitated animal investigation consisted of 15 adult pigs. Combined ASDH plus HS was induced by injection of 0.1 ml/kg autologous blood into the subdural space followed by controlled passive removal of blood. Two hours later, resuscitation was initiated comprising re-transfusion of shed blood, fluids, continuous i.v. noradrenaline, and either hyperoxemia (target PaO2 200 - 250 mmHg) or normoxemia (target PaO2 80 - 120 mmHg) during the first 24 h of the total of 54 h of intensive care. Systemic hemodynamics, intracranial and cerebral perfusion pressures, parameters of brain microdialysis and blood biomarkers of brain injury did not significantly differ between the two groups. According to the experimental protocol, PaO2 was significantly higher in the hyperoxemia group at the end of the intervention period, i.e., at 24 h of resuscitation, which coincided with a higher brain tissue PO2. The latter persisted until the end of observation period. While neurological function as assessed using the veterinary Modified Glasgow Coma Score progressively deteriorated in the control group, it remained unaffected in the hyperoxemia animals, however, without significant intergroup difference. Survival times did not significantly differ in the hyperoxemia and control groups either. Despite being associated with higher brain tissue PO2 levels, which were sustained beyond the intervention period, targeted hyperoxemia exerted neither significantly beneficial nor deleterious effects after combined ASDH and HS in swine with pre-existing coronary artery disease. The unavailability of a power calculation and, thus, the limited number of animals included, are the limitations of the study.

Brain Histology and Immunohistochemistry After Resuscitation From Hemorrhagic Shock in Swine With Pre-Existing Atherosclerosis and Sodium Thiosulfate (Na2S2O3) Treatment.

Background: The hydrogen sulfide (H2S) and the oxytocin/oxytocin receptor (OT/OTR) systems interact in the central nervous and cardiovascular system. As a consequence of osmotic balance stress, H2S stimulates OT release from the paraventricular nuclei (PVN) in the hypothalamic regulation of blood volume and pressure. Hemorrhagic shock (HS) represents one of the most pronounced acute changes in blood volume, which, moreover, may cause at least transient brain tissue hypoxia. Atherosclerosis is associated with reduced vascular expression of the main endogenous H2S producing enzyme cystathionine-γ-lyase (CSE), and, hence, exogenous H2S administration could be beneficial in these patients, in particular after HS. However, so far cerebral effects of systemic H2S administration are poorly understood. Having previously shown lung-protective effects of therapeutic Na2S2O3 administration in a clinically relevant, long-term, porcine model of HS and resuscitation we evaluated if these protective effects were extended to the brain. Methods: In this study, available unanalyzed paraffin embedded brain sections (Na2S2O3 N = 8 or vehicle N = 5) of our recently published HS study were analyzed via neuro-histopathology and immunohistochemistry for the endogenous H2S producing enzymes, OT, OTR, and markers for brain injury and oxidative stress (glial fibrillary acidic protein (GFAP) and nitrotyrosine). Results: Neuro-histopathological analysis revealed uninjured brain tissue with minor white matter edema. Protein quantification in the hypothalamic PVN showed no significant inter-group differences between vehicle or Na2S2O3 treatment. Conclusions: The endogenous H2S enzymes, OT/OTR co-localized in magnocellular neurons in the hypothalamus, which may reflect their interaction in response to HS-induced hypovolemia. The preserved blood brain barrier (BBB) may have resulted in impermeability for Na2S2O3 and no inter-group differences in the PVN. Nonetheless, our results do not preclude that Na2S2O3 could have a therapeutic benefit in the brain in an injury that disrupts the BBB, e.g., traumatic brain injury (TBI) or acute subdural hematoma (ASDH).

Bcl-XL but Not Bcl-2 Is a Potential Target in Medulloblastoma Therapy.

Medulloblastoma (MB) is the most common solid tumour in children and, despite current treatment with a rather aggressive combination therapy, accounts for 10% of all deaths associated with paediatric cancer. Breaking the tumour cells' intrinsic resistance to therapy-induced cell death should lead to less aggressive and more effective treatment options. In other tumour entities, this has been achieved by modulating the balance between the various pro- and anti-apoptotic members of the Bcl-2 family with small molecule inhibitors. To evaluate the therapeutic benefits of ABT-199 (Venetoclax), a Bcl-2 inhibitor, and ABT-263 (Navitoclax), a dual Bcl-XL/Bcl-2 inhibitor, increasingly more relevant model systems were investigated. Starting from established MB cell lines, progressing to primary patient-derived material and finally an experimental tumour system imbedded in an organic environment were chosen. Assessment of the metabolic activity (a surrogate readout for population viability), the induction of DNA fragmentation (apoptosis) and changes in cell number (the combined effect of alterations in proliferation and cell death induction) revealed that ABT-263, but not ABT-199, is a promising candidate for combination therapy, synergizing with cell death-inducing stimuli. Interestingly, in the experimental tumour setting, the sensitizing effect of ABT-263 seems to be predominantly mediated via an anti-proliferative and not a pro-apoptotic effect, opening a future line of investigation. Our data show that modulation of specific members of the Bcl-2 family might be a promising therapeutic addition for the treatment of MB.

Perineurioma: A Rare Entity of Peripheral Nerve Sheath Tumors.

OBJECTIVE: Intraneural perineurioma is a rare tumor entity. It is a benign, very slow growing peripheral nerve sheath tumor that typically occurs in children and young adults. Motor deficits and muscle atrophy are classic presenting symptoms, while sensory deficits are rare at the onset of the disease. Recommended treatment strategies are lacking. We have evaluated the clinical follow-up and our experience with treatment of this rare entity. METHODS: A total of 30 patients with intraneural perineuriomas were assessed retrospectively. Demographic data, clinical symptoms, diagnostic examinations, therapy strategies, and clinical outcome were analyzed. Descriptive statistical methods were used for evaluation. RESULTS: The mean age was 22 years. Eleven women and 19 men were affected. The lesion occurred in the area of the upper extremity in 16 patients and in the area of the lower extremity in 14 patients. The most frequently affected nerve was the sciatic nerve, followed by the radial nerve. All patients showed a motor deficit to some extent. Seventy percent (n = 21) revealed atrophy, 43.3% (n = 13) had sensitive deficits, and 17% (n = 5) suffered of pain. Fascicle biopsies were performed in 26 patients (87%). In four patients (13%), the tumor was completely resected and then reconstructed via nerve grafts. Seventy percent of the patients (n = 21) received a magnetic resonance imaging (MRI) within 5 years postoperatively, in which no progress was shown. CONCLUSIONS: To diagnose perineurioma, it is essential to take a biopsy of an enlarged, nonfunctional fascicle. Furthermore, a long-distance epineuriotomy to decompress the hypertrophic fascicle is reasonable. To preserve the nerves' residual function, a complete resection is not recommended. Results after grafting are poor. One reason for this might be residual tumor cells along the nerve that cannot be visualized. Malignant transformation is not yet reported and tumor growth is stable for years.

A phase Ib/IIa trial of 9 repurposed drugs combined with temozolomide for the treatment of recurrent glioblastoma: CUSP9v3.

BACKGROUND: The dismal prognosis of glioblastoma (GBM) may be related to the ability of GBM cells to develop mechanisms of treatment resistance. We designed a protocol called Coordinated Undermining of Survival Paths combining 9 repurposed non-oncological drugs with metronomic temozolomide-version 3-(CUSP9v3) to address this issue. The aim of this phase Ib/IIa trial was to assess the safety of CUSP9v3. METHODS: Ten adults with histologically confirmed GBM and recurrent or progressive disease were included. Treatment consisted of aprepitant, auranofin, celecoxib, captopril, disulfiram, itraconazole, minocycline, ritonavir, and sertraline added to metronomic low-dose temozolomide. Treatment was continued until toxicity or progression. Primary endpoint was dose-limiting toxicity defined as either any unmanageable grade 3-4 toxicity or inability to receive at least 7 of the 10 drugs at ≥ 50% of the per-protocol doses at the end of the second treatment cycle. RESULTS: One patient was not evaluable for the primary endpoint (safety). All 9 evaluable patients met the primary endpoint. Ritonavir, temozolomide, captopril, and itraconazole were the drugs most frequently requiring dose modification or pausing. The most common adverse events were nausea, headache, fatigue, diarrhea, and ataxia. Progression-free survival at 12 months was 50%. CONCLUSIONS: CUSP9v3 can be safely administered in patients with recurrent GBM under careful monitoring. A randomized phase II trial is in preparation to assess the efficacy of the CUSP9v3 regimen in GBM.

Sequence of proteome profiles in preclinical and symptomatic Alzheimer's disease.

Proteome profile changes in Alzheimer's disease (AD) brains have been reported. However, it is unclear whether they represent a continuous process, or whether there is a sequential involvement of distinct proteins. To address this question, we used mass spectrometry. We analyzed soluble, dispersible, sodium dodecyl sulfate, and formic acid fractions of neocortex homogenates (mainly Brodmann area 17-19) from 18 pathologically diagnosed preclinical AD, 17 symptomatic AD, and 18 cases without signs of neurodegeneration. By doing so, we identified four groups of AD-related proteins being changed in levels in preclinical and symptomatic AD cases: early-responding, late-responding, gradually-changing, and fraction-shifting proteins. Gene ontology analysis of these proteins and all known AD-risk/causative genes identified vesicle endocytosis and the secretory pathway-related processes as an early-involved AD component. In conclusion, our findings suggest that subtle changes involving the secretory pathway and endocytosis precede severe proteome changes in symptomatic AD as part of the preclinical phase of AD. The respective early-responding proteins may also contribute to synaptic vesicle cycle alterations in symptomatic AD.

Localization of the hydrogen sulfide and oxytocin systems at the depth of the sulci in a porcine model of acute subdural hematoma.

In the porcine model discussed in this review, the acute subdural hematoma was induced by subdural injection of autologous blood over the left parietal cortex, which led to a transient elevation of the intracerebral pressure, measured by bilateral neuromonitoring. The hematoma-induced brain injury was associated with albumin extravasation, oxidative stress, reactive astrogliosis and microglial activation in the ipsilateral hemisphere. Further proteins and injury markers were validated to be used for immunohistochemistry of porcine brain tissue. The cerebral expression patterns of oxytocin, oxytocin receptor, cystathionine-γ-lyase and cystathionine-ß-synthase were particularly interesting: these four proteins all co-localized at the base of the sulci, where pressure-induced brain injury elicits maximum stress. In this context, the pig is a very relevant translational model in contrast to the rodent brain. The structure of the porcine brain is very similar to the human: the presence of gyri and sulci (gyrencephalic brain), white matter to grey matter proportion and tentorium cerebelli. Thus, pressure-induced injury in the porcine brain, unlike in the rodent brain, is reflective of the human pathophysiology.

Impaired Glucocorticoid Receptor Signaling Aggravates Lung Injury after Hemorrhagic Shock.

We previously showed that attenuated lung injury after hemorrhagic shock (HS) coincided with enhanced levels of the glucocorticoid (GC) receptor (GR) in lung tissue of swine. Here, we investigated the effects of impaired GR signaling on the lung during resuscitated HS using a dysfunctional GR mouse model (GRdim/dim). In a mouse intensive care unit, HS led to impaired lung mechanics and aggravated lung inflammation in GRdim/dim mice compared to wildtype mice (GR+/+). After HS, high levels of the pro-inflammatory and pro-apoptotic transcription factor STAT1/pSTAT1 were found in lung samples from GRdim/dim mice. Lungs of GRdim/dim mice revealed apoptosis, most likely as consequence of reduced expression of the lung-protective Angpt1 compared to GR+/+ after HS. RNA-sequencing revealed increased expression of pro-apoptotic and cytokine-signaling associated genes in lung tissue of GRdim/dim mice. Furthermore, high levels of pro-inflammatory cytokines and iNOS were found in lungs of GRdim/dim mice. Our results indicate impaired repression of STAT1/pSTAT1 due to dysfunctional GR signaling in GRdim/dim mice, which leads to increased inflammation and apoptosis in the lungs. These data highlight the crucial role of functional GR signaling to attenuate HS-induced lung damage.

Cerebral Immunohistochemical Characterization of the H2S and the Oxytocin Systems in a Porcine Model of Acute Subdural Hematoma.

The hydrogen sulfide (H2S) and the oxytocin/oxytocin receptor (OT/OTR) systems interact in trauma and are implicated in vascular protection and regulation of fluid homeostasis. Acute brain injury is associated with pressure-induced edema formation, blood brain barrier disruption, and neuro-inflammation. The similarities in brain anatomy: size, gyrencephalic organization, skull structure, may render the pig a highly relevant model for translational medicine. Cerebral biomarkers for pigs for pathophysiological changes and neuro-inflammation are limited. The current study aims to characterize the localization of OT/OTR and the endogenous H2S producing enzymes together with relevant neuro-inflammatory markers on available porcine brain tissue from an acute subdural hematoma (ASDH) model. In a recent pilot study, anesthetized pigs underwent ASDH by injection of 20 mL of autologous blood above the left parietal cortex and were resuscitated with neuro-intensive care measures. After 54 h of intensive care, the animals were sacrificed, the brain was removed and analyzed via immunohistochemistry. The endogenous H2S producing enzymes cystathionine-ɤ-lyase (CSE) and cystathionine-ß-synthase (CBS), the OTR, and OT were localized in neurons, vasculature and parenchyma at the base of sulci, where pressure-induced injury leads to maximal stress in the gyrencephalic brain. The pathophysiological changes in response to brain injury in humans and pigs, we show here, are comparable. We additionally identified modulators of brain injury to further characterize the pathophysiology of ASDH and which may indicate future therapeutic approaches.

Histological correlates of postmortem ultra-high-resolution single-section MRI in cortical cerebral microinfarcts.

The identification of cerebral microinfarctions with magnetic resonance imaging (MRI) and histological methods remains challenging in aging and dementia. Here, we matched pathological changes in the microvasculature of cortical cerebral microinfarcts to MRI signals using single 100 µm-thick histological sections scanned with ultra-high-resolution 11.7 T MRI. Histologically, microinfarcts were located in superficial or deep cortical layers or transcortically, compatible with the pattern of layer-specific arteriolar blood supply of the cerebral cortex. Contrary to acute microinfarcts, at chronic stages the core region of microinfarcts showed pallor with extracellular accumulation of lipofuscin and depletion of neurons, a dense meshwork of collagen 4-positive microvessels with numerous string vessels, CD68-positive macrophages and glial fibrillary acidic protein (GFAP)-positive astrocytes. In MRI scans, cortical microinfarcts at chronic stages, called chronic cortical microinfarcts here, gave hypointense signals in T1-weighted and hyperintense signals in T2-weighted images when thinning of the tissue and cavitation and/or prominent iron accumulation were present. Iron accumulation in chronic microinfarcts, histologically verified with Prussian blue staining, also produced strong hypointense T2*-weighted signals. In summary, the microinfarct core was occupied by a dense microvascular meshwork with string vessels, which was invaded by macrophages and astroglia and contained various degrees of iron accumulation. While postmortem ultra-high-resolution single-section imaging improved MRI-histological matching and the structural characterization of chronic cortical cerebral microinfarcts, miniscule microinfarcts without thinning or iron accumulation could not be detected with certainty in the MRI scans. Moreover, string vessels at the infarct margin indicate disturbances in the microcirculation in and around microinfarcts, which might be exploitable in the diagnostics of cortical cerebral microinfarcts with MRI in vivo.

Sodium Fluorescein as Intraoperative Visualization Tool During Peripheral Nerve Biopsies.

OBJECTIVE: Owing to technical development of specific fluorophore filters, the neurosurgical application of sodium fluorescein (SF) has regained value in brain tumor surgery. The aim of this study was to determine the usefulness of SF during nerve biopsies. METHODS: This single-center study included 5 cases of nerve biopsies performed under microscope-based fluorescence with SF performed between March 2016 and February 2017. SF was applied intravenously (1 mg/kg body weight). After microsurgical dissection of the involved nerve segment, fluorescence-guided fascicular biopsy was performed. Selection of target fascicles was at the surgeon's discretion and took into account nerve stimulation for preservation of motor function and fluorescence intensity. Correlation to histopathologic examination was examined. Video analysis of intraoperative images comparing target fascicles with intense fluorescent response to adjacent fascicles of the same nerve segment was performed using ImageJ. RESULTS: All patients had motor or sensory deficits. Magnetic resonance imaging findings were similar, depicting long segments of gadolinium enhancement (minimum 11.7 cm). Each biopsy sample was positive resulting in diverse histopathologic results. Digital image analysis revealed a statistically significant difference of the complementary color green (P = 0.0473). CONCLUSIONS: Magnetic resonance imaging is the gold standard in diagnostic work-up of peripheral nerve disorders. Longitudinal nerve thickening with positive contrast enhancement is an unspecific magnetic resonance imaging finding. Various pathologies, such as tumors and inflammatory lesions, may cause this morphologic phenomenon. Nerve biopsies may be needed for diagnostic work-up. Intraoperative SF may help to depict the most affected fascicles and identify target fascicles for biopsy and increase diagnostic certainty of nerve biopsies.

Rare Case of Sporadic Malignant Optic Pathway Glioma in 71-Year-Old Woman.

A 71-year-old woman presented to our institution with a 2-week history of concentric bilateral left accentuated visual field loss. Examination of her eyes including funduscopy was normal. A gadolinium-enhanced magnetic resonance tomography showed contrast enhancement of the optic pathway in the T1-weighted sequence that included both optic nerves, the optic chiasm, and the left optic tract. Differential diagnoses of this kind of lesion extending along the optic nerves include neurosarcoidosis, lymphoma, and glioma. The patient was treated with high-dose corticosteroids under the suspicion of neurosarcoidosis. During that time her vision deteriorated, resulting in amaurosis on her left eye and marginal peripheral vision on the right. A biopsy of the left optic nerve revealed a pilocytic astrocytoma, which to some extent contrasted the observed clinical course. After discussing the treatment options including radiotherapy and chemotherapy, the patient opted for supportive care and died 3 months later.

Quantitative Analysis of Superb Microvascular Imaging versus Color-Coded Doppler Sonography for Preoperative Evaluation of Vascularization of Schwannomas.

PURPOSE: Comparison of vascularization of schwannomas, benign peripheral nerve sheath tumors, using color-coded Doppler sonography (CCDS) and the Toshiba monochrome Superb Microvascular Imaging (mSMI) (Minato, Tokyo, Japan) technique. METHODS: In a retrospective single-center analysis, 16 patients were identified with histologically confirmed schwannomas. Between March and June 2018, all of them underwent ultrasonography using mSMI and CCDS before surgery. Schwannoma vascularization was quantitatively measured using ImageJ, an open platform for scientific image analysis. As the diagnostic gold standard, magnetic resonance imaging was mandatory. RESULTS: The mSMI and CCDS vascularization showed a moderate agreement between the techniques (κ = 0.5556; p = 0.0066). The quantitative visual assessment of the vascularization revealed no difference (25.3 ± 8.2 vs. 18.2 ± 3.8; p = 0.0532). Significant differences were found for the quantitative assessment of CCDS with ImageJ (26.8 ± 8.8 vs. 19.3 ± 2.8; p = 0.0368). However, in a subanalysis of highly vascularized schwannomas, mSMI revealed significant differences to slightly vascularized schwannomas (32.0 ± 8.2 vs. 21.3 ± 6.1; p = 0.0065) but not between moderately and slightly vascularized types (p = not significant). CONCLUSION: The mSMI mode is qualitatively superior to conventional CCDS; however, quantitative analysis of the vascularization of schwannomas revealed no significant quantitative advantage for mSMI. Nevertheless, the mean ImageJ values showed a positive trend toward a better representation of the vascularization degree of schwannomas with mSMI.

In-depth characterization of a long-term, resuscitated model of acute subdural hematoma-induced brain injury.

OBJECTIVE: Acute subdural hematoma (ASDH) is a leading entity in brain injury. Rodent models mostly lack standard intensive care, while large animal models frequently are only short term. Therefore, the authors developed a long-term, resuscitated porcine model of ASDH-induced brain injury and report their findings. METHODS: Anesthetized, mechanically ventilated, and instrumented pigs with human-like coagulation underwent subdural injection of 20 mL of autologous blood and subsequent observation for 54 hours. Continuous bilateral multimodal brain monitoring (intracranial pressure [ICP], cerebral perfusion pressure [CPP], partial pressure of oxygen in brain tissue [PbtO2], and brain temperature) was combined with intermittent neurological assessment (veterinary modified Glasgow Coma Scale [MGCS]), microdialysis, and measurement of plasma protein S100ß, GFAP, neuron-specific enolase [NSE], nitrite+nitrate, and isoprostanes. Fluid resuscitation and continuous intravenous norepinephrine were targeted to maintain CPP at pre-ASDH levels. Immediately postmortem, the brains were taken for macroscopic and histological evaluation, immunohistochemical analysis for nitrotyrosine formation, albumin extravasation, NADPH oxidase 2 (NOX2) and GFAP expression, and quantification of tissue mitochondrial respiration. RESULTS: Nine of 11 pigs survived the complete observation period. While ICP significantly increased after ASDH induction, CPP, PbtO2, and the MGCS score remained unaffected. Blood S100ß levels significantly fell over time, whereas GFAP, NSE, nitrite+nitrate, and isoprostane concentrations were unaltered. Immunohistochemistry showed nitrotyrosine formation, albumin extravasation, NOX2 expression, fibrillary astrogliosis, and microglial activation. CONCLUSIONS: The authors describe a clinically relevant, long-term, resuscitated porcine model of ASDH-induced brain injury. Despite the morphological injury, maintaining CPP and PbtO2 prevented serious neurological dysfunction. This model is suitable for studying therapeutic interventions during hemorrhage-induced acute brain injury with standard brain-targeted intensive care.

To treat or not to treat? A retrospective multicenter assessment of survival in patients with IDH-mutant low-grade glioma based on adjuvant treatment.

OBJECTIVE: The level of evidence for adjuvant treatment of diffuse WHO grade II glioma (low-grade glioma, LGG) is low. In so-called "high-risk" patients most centers currently apply an early aggressive adjuvant treatment after surgery. The aim of this assessment was to compare progression-free survival (PFS) and overall survival (OS) in patients receiving radiation therapy (RT) alone, chemotherapy (CT) alone, or a combined/consecutive RT+CT, with patients receiving no primary adjuvant treatment after surgery. METHODS: Based on a retrospective multicenter cohort of 288 patients (≥ 18 years old) with diffuse WHO grade II gliomas, a subgroup analysis of patients with a confirmed isocitrate dehydrogenase (IDH) mutation was performed. The influence of primary adjuvant treatment after surgery on PFS and OS was assessed using Kaplan-Meier estimates and multivariate Cox regression models, including age (≥ 40 years), complete tumor resection (CTR), recurrent surgery, and astrocytoma versus oligodendroglioma. RESULTS: One hundred forty-four patients matched the inclusion criteria. Forty patients (27.8%) received adjuvant treatment. The median follow-up duration was 6 years (95% confidence interval 4.8-6.3 years). The median overall PFS was 3.9 years and OS 16.1 years. PFS and OS were significantly longer without adjuvant treatment (p = 0.003). A significant difference in favor of no adjuvant therapy was observed even in high-risk patients (age ≥ 40 years or residual tumor, 3.9 vs 3.1 years, p = 0.025). In the multivariate model (controlled for age, CTR, oligodendroglial diagnosis, and recurrent surgery), patients who received no adjuvant therapy showed a significantly positive influence on PFS (p = 0.030) and OS (p = 0.009) compared to any other adjuvant treatment regimen. This effect was most pronounced if RT+CT was applied (p = 0.004, hazard ratio [HR] 2.7 for PFS, and p = 0.001, HR 20.2 for OS). CTR was independently associated with longer PFS (p = 0.019). Age ≥ 40 years, histopathological diagnosis, and recurrence did not achieve statistical significance. CONCLUSIONS: In this series of IDH-mutated LGGs, adjuvant treatment with RT, CT with temozolomide (TMZ), or the combination of both showed no significant advantage in terms of PFS and OS. Even in high-risk patients, the authors observed a similar significantly negative impact of adjuvant treatment on PFS and OS. These results underscore the importance of a CTR in LGG. Whether patients ≥ 40 years old should receive adjuvant treatment despite a CTR should be a matter of debate. A potential tumor dedifferentiation by administration of early TMZ, RT, or RT+CT in IDH-mutated LGG should be considered. However, these data are limited by the retrospective study design and the potentially heterogeneous indication for adjuvant treatment.

The Mitochondria-Targeted H2S-Donor AP39 in a Murine Model of Combined Hemorrhagic Shock and Blunt Chest Trauma.

Hemorrhagic shock (HS) accounts for 30% to 40% of trauma-induced mortality, which is due to multi-organ-failure subsequent to systemic hyper-inflammation, triggered by hypoxemia and tissue ischemia. The slow-releasing, mitochondria-targeted H2S donor AP39 exerted beneficial effects in several models of ischemia-reperfusion injury and acute inflammation. Therefore, we tested the effects of AP39-treatment in a murine model of combined blunt chest trauma (TxT) and HS with subsequent resuscitation. METHODS: After blast wave-induced TxT or sham procedure, anesthetized and instrumented mice underwent 1 h of hemorrhage followed by 4 h of resuscitation comprising an i.v. bolus injection of 100 or 10 nmol kg AP39 or vehicle, retransfusion of shed blood, fluid resuscitation, and norepinephrine. Lung mechanics and gas exchange were assessed together with hemodynamics, metabolism, and acid-base status. Blood and tissue samples were analyzed for cytokine and chemokine levels, western blot, immunohistochemistry, mitochondrial oxygen consumption (JO2), and histological changes. RESULTS: High dose AP39 attenuated systemic inflammation and reduced the expression of inducible nitric oxide synthase (iNOS) and IκBα expression in lung tissue. In the combined trauma group (TxT + HS), animals treated with high dose AP39 presented with the lowest mean arterial pressure and thus highest norepinephrine requirements and higher mortality. Low dose AP39 had no effects on hemodynamics, leading to unchanged norepinephrine requirements and mortality rates. CONCLUSION: AP39 is a systemic anti-inflammatory agent. In our model of trauma with HS, there may be a narrow dosing and timing window due to its potent vasodilatory properties, which might result in or contribute to aggravation of circulatory shock-related hypotension.

Diagnostic accuracy of intraoperative perfusion-weighted MRI and 5-aminolevulinic acid in relation to contrast-enhanced intraoperative MRI and 11C-methionine positron emission tomography in resection of glioblastoma: a prospective study.

The aim of our study was to compare depicted pre-, intra-, and postoperative tumor volume of met-PET, perfusion-weighed MRI (PWI), and Gd-DTPA MRI. Further, to assess their sensitivity and specificity in correlation with histopathological specimen. Inclusion criteria of the prospective study were histological confirmed glioblastoma (GB), age > 18, and eligible for gross total resection (GTR). Met-PET was performed before and after surgery. Gd-DTPA MRI and PWI were performed before, during, and after surgery. A combined 5-aminolevulinic acid (5-ALA) and iMRI-guided surgery was performed. Volumetric analysis was evaluated for all imaging modalities except for 5-ALA. A total of 59 navigated biopsies were taken. Sensitivity and specificity were calculated for Gd-DTPA MRI, PWI, met-PET, and 5-ALA according to the histology of specimen. Met-PET depicted significantly larger tumor volume before surgery (p = 0.01) compared to PWI and Gd-DTPI MRI. We found no significant difference in tumor volume between met-PET and PWI after surgery (p = 0.059). Both PWI and met-PET showed significantly larger tumor volume after surgery when compared to Gd-DTPA (p = 0.018 and p = 0.003, respectively). Intraoperative PWI reading was impaired in 33.3% due to artifacts. Met-PET showed the highest sensitivity for detection of GB with 95%. The lowest sensitivity was found with Gd-DTPA MRI (50%), while 5-ALA and intraoperative PWI showed similar results (69 and 67%). Met-Pet is the imaging modality with the highest sensitivity to detect a residual tumor in GB. Intraoperative PWI seems to have a synergistic effect to Gd-DTPA and 5-ALA. However, its value may be limited by artifacts. Both pre- and intraoperative PWI cannot substitute met-PET in tumor detection.