Evaluation of surgical treatment strategies and outcome for cerebral arachnoid cysts in children and adults.

OBJECTIVE: The best treatment strategies for cerebral arachnoid cysts (CAC) are still up for debate. In this study, we present CAC management, outcome data, and risk factors for recurrence after surgical treatment, focusing on microscopic/endoscopic approaches as compared to minimally invasive stereotactic procedures in children and adults. METHODS: In our single-institution retrospective database, we identified all patients treated surgically for newly diagnosed CAC between 2000 and 2022. Microscopic/endoscopic surgery (ME) aimed for safe cyst wall fenestration. Stereotactic implantation of an internal shunt catheter (STX) to drain CAC into the ventricles and/or cisterns was used as an alternative procedure in patients aged ≥ 3 years. Treatment decisions in favor of ME vs. STX were made by interdisciplinary consensus. The primary study endpoint was time to CAC recurrence (TTR). Secondary endpoints were outcome metrics including clinical symptoms and MR-morphological analyses. Data analysis included subdivision of the total cohort into three distinct age groups (AG1, < 6 years; AG2, 6-18 years; AG3, ≥ 18 years). RESULTS: Sixty-two patients (median age 26.5 years, range 0-82 years) were analyzed. AG1 included 15, AG2 10, and AG3 37 patients, respectively. The main presenting symptoms were headache and vertigo. In AG1 hygromas, an increase in head circumference and thinning of cranial calvaria were most frequent. Thirty-five patients underwent ME and 27 STX, respectively; frequency did not differ between AGs. There were two (22.2%) periprocedural venous complications in infants (4- and 10-month-old) during an attempt at prepontine fenestration of a complex CAC, one with fatal outcome in a 10-month-old boy. Other complications included postoperative bleeding (2, 22.2%), CSF leaks (4, 44.4%), and meningitis (1, 11.1%). Overall, clinical improvement and significant volume reduction (p = 0.008) were seen in all other patients; this did not differ between AGs. Median follow-up for all patients was 25.4 months (range, 3.1-87.1 months). Recurrent cysts were seen in 16.1%, independent of surgical procedure used (p = 0.7). In cases of recurrence, TTR was 7.9 ± 12.7 months. Preoperative ventricular expansion (p = 0.03), paresis (p = 0.008), and age under 6 years (p = 0.03) were significant risk factors for CAC recurrence in multivariate analysis. CONCLUSIONS: In patients suffering from CAC, both ME and STX can improve clinical symptoms at low procedural risk, with equal extent of CAC volume reduction. However, in infants and young children, CAC are more often associated with severe clinical symptoms, stereotactic procedures have limited use, and microsurgery in the posterior fossa may bear the risk of severe venous bleeding.

Strong Association of Depression and Anxiety With the Presence of Back Pain While Impact of Spinal Imaging Findings is Limited: Analysis of an MRI Cohort Study.

Development of back pain is multifactorial, and it is not well understood which factors are the main drivers of the disease. We therefore applied a machine-learning approach to an existing large cohort study data set and sought to identify and rank the most important contributors to the presence of back pain amongst the documented parameters of the cohort. Data from 399 participants in the KORA-MRI (Cooperative health research in the region Augsburg-magnetic resonance imaging) (Cooperative Health Research in the Region Augsburg) study was analyzed. The data set included MRI images of the whole body, including the spine, metabolic, sociodemographic, anthropometric, and cardiovascular data. The presence of back pain was one of the documented items in this data set. Applying a machine-learning approach to this preexisting data set, we sought to identify the variables that were most strongly associated with back pain. Mediation analysis was performed to evaluate the underlying mechanisms of the identified associations. We found that depression and anxiety were the 2 most selected predictors for back pain in our model. Additionally, body mass index, spinal canal width and disc generation, medium and heavy physical work as well as cardiovascular factors were among the top 10 most selected predictors. Using mediation analysis, we found that the effects of anxiety and depression on the presence of back pain were mainly direct effects that were not mediated by spinal imaging. In summary, we found that psychological factors were the most important predictors of back pain in our cohort. This supports the notion that back pain should be treated in a personalized multidimensional framework. PERSPECTIVE: This article presents a wholistic approach to the problem of back pain. We found that depression and anxiety were the top predictors of back pain in our cohort. This strengthens the case for a multidimensional treatment approach to back pain, possibly with a special emphasis on psychological factors.

Functional connectivity MRI provides an imaging correlate for chimeric antigen receptor T-cell-associated neurotoxicity.

Background: Treatment of hematological malignancies with chimeric antigen receptor modified T cells (CART) is highly efficient, but often limited by an immune effector cell-associated neurotoxicity syndrome (ICANS). As conventional MRI is often unremarkable during ICANS, we aimed to examine whether resting-state functional MRI (rsfMRI) is suitable to depict and quantify brain network alterations underlying ICANS in the individual patient. Methods: The dysconnectivity index (DCI) based on rsfMRI was longitudinally assessed in systemic lymphoma patients and 1 melanoma patient during ICANS and before or after clinical resolution of ICANS. Results: Seven lymphoma patients and 1 melanoma patient (19-77 years; 2 female) were included. DCI was significantly increased during ICANS with normalization after recovery (P = .0039). Higher ICANS grades were significantly correlated with increased DCI scores (r = 0.7807; P = .0222). DCI increase was most prominent in the inferior frontal gyrus and the frontal operculum (ie, Broca's area) and in the posterior parts of the superior temporal gyrus and the temporoparietal junction (ie, Wernicke's area) of the language-dominant hemisphere, thus reflecting the major clinical symptoms of nonfluent dysphasia and dyspraxia. Conclusions: RsfMRI-based DCI might be suitable to directly quantify the severity of ICANS in individual patients undergoing CAR T-transfusion. Besides ICANS, DCI seems a promising diagnostic tool to quantify functional brain network alterations during encephalopathies of different etiologies, in general.

Significance of molecular diagnostics for therapeutic decision-making in recurrent glioma.

Background: Targeted therapies have substantially improved survival in cancer patients with malignancies outside the brain. Whether in-depth analysis for molecular alterations may also offer therapeutic avenues in primary brain tumors remains unclear. We herein present our institutional experience for glioma patients discussed in our interdisciplinary molecular tumor board (MTB) implemented at the Comprehensive Cancer Center Munich (LMU). Methods: We retrospectively searched the database of the MTB for all recurrent glioma patients after previous therapy. Recommendations were based on next-generation sequencing results of individual patient's tumor tissue. Clinical and molecular information, previous therapy regimens, and outcome parameters were collected. Results: Overall, 73 consecutive recurrent glioma patients were identified. In the median, advanced molecular testing was initiated with the third tumor recurrence. The median turnaround time between initiation of molecular profiling and MTB case discussion was 48 ± 75 days (range: 32-536 days). Targetable mutations were found for 50 recurrent glioma patients (68.5%). IDH1 mutation (27/73; 37%), epidermal growth factor receptor amplification (19/73; 26%), and NF1 mutation (8/73; 11%) were the most detected alterations and a molecular-based treatment recommendation could be made for all of them. Therapeutic recommendations were implemented in 12 cases (24%) and one-third of these heavily pretreated patients experienced clinical benefit with at least disease stabilization. Conclusions: In-depth molecular analysis of tumor tissue may guide targeted therapy also in brain tumor patients and considerable antitumor effects might be observed in selected cases. However, future studies to corroborate our results are needed.

Treatment benefit in patients aged 80 years or older with biopsy-proven and non-resected glioblastoma is dependent on MGMT promoter methylation status.

PURPOSE: Glioblastoma is associated with especially poor outcome in the elderly. It is unclear if patients aged ≥80 years benefit from tumor-specific therapy as opposed to receiving best supportive care (BSC) only. METHODS: Patients with IDH-wildtype glioblastoma (WHO 2021), aged ≥80 years, and diagnosed by biopsy between 2010 and 2022 were included. Patient characteristics and clinical parameters were assessed. Uni- and multivariate analyses were performed. RESULTS: 76 patients with a median age of 82 (range 80-89) and a median initial KPS of 80 (range 50-90) were included. Tumor-specific therapy was initiated in 52 patients (68%). 22 patients (29%) received temozolomide monotherapy, 23 patients (30%) were treated with radiotherapy (RT) alone and 7 patients (9%) received combination therapies. In 24 patients (32%), tumor-specific therapy was omitted in lieu of BSC. Overall survival (OS) was longer in patients receiving tumor-specific therapy (5.4 vs. 3.3 months, p < 0.001). Molecular stratification showed that the survival benefit was owed to patients with MGMT promoter methylation (MGMTpos) who received tumor-specific therapy as opposed to BSC (6.2 vs. 2.6 months, p < 0.001), especially to those with better clinical status and no initial polypharmacy. Patients with unmethylated MGMT promoter (MGMTneg) did not benefit from tumor-specific therapy (3.6 vs. 3.7 months, p = 0.18). In multivariate analyses, better clinical status and MGMT promoter methylation were associated with prolonged survival (p < 0.01 and p = 0.01). CONCLUSION: Benefit from tumor-specific treatment in patients with newly diagnosed glioblastoma aged ≥80 years might be restricted to MGMTpos patients, especially to those with good clinical status and no polypharmacy.

Subventricular zone involvement is associated with worse outcome in glioma WHO grade 2 depending on molecular markers.

Neural stem cells within the subventricular zone were identified as cells of origin driving growth of high-grade gliomas, and anatomical involvement of the subventricular zone has been associated with an inferior clinical outcome. Whether the association between poor outcome and subventricular zone involvement also applies to glioma of lower grades is unclear. We therefore analysed a retrospective cohort of 182 patients with glioma grade 2 (according to the WHO 2016 classification) including 78 individuals (43%) with subventricular zone involvement. Patients with and without subventricular zone involvement did not differ in regard to demographics, histopathology, and molecular markers. Notably, subventricular zone involvement was a negative prognostic marker for malignant progression and overall survival on uni- and multivariate analysis. When patients were stratified according to the cIMPACT-NOW update 6, subventricular zone involvement was negatively associated with outcome in IDH-wildtype astrocytomas and 1p19q-codeleted oligodendrogliomas but not in IDH-mutant astrocytomas. Collectively, subventricular zone involvement may represent a risk factor for worse outcome in glioma WHO grade 2 depending on the molecular tumor signature. The present data confirm the relevance of molecular glioma classifications as proposed by the cIMPACT-NOW update 6. These findings warrant evaluation in prospective cohorts.

Extended stereotactic brain biopsy in suspected primary central nervous system angiitis: good diagnostic accuracy and high safety.

OBJECTIVE: To evaluate the diagnostic accuracy and safety of extended stereotactic brain biopsy (ESBB) in a single center cohort with suspected primary angiitis of the central nervous system (PACNS). METHODS: A standardized stereotactic biopsy targeting MRI-positive lesions and collecting samples from the meninges and the cortex as well as from the white matter was performed in 23 patients with clinically suspected PACNS between 2010 and 2017. The relationship between biopsy yield and clinical characteristics, cerebrospinal fluid parameters, MR-imaging, time point of biopsy and exact localization of biopsy as well as number of tissue samples were examined. RESULTS: PACNS was confirmed in 7 of 23 patients (30.4%). Alternative diagnoses were identified in 7 patients (30%). A shorter time period between the onset or worsening of symptoms (p = 0.018) and ESBB significantly increased the diagnostic yield. We observed only minor and transient postoperative complications in 3 patients (13.0%). ESBB led to a direct change of the therapeutic regime in 13 of 23 patients (56.5%). Careful neuropathological analysis furthermore revealed that cortical samples were crucial in obtaining a diagnosis. CONCLUSION: ESBB is a safe approach with good feasibility, even in critically ill patients, and high diagnostic accuracy in patients with suspected PACNS changing future therapies in 13 of 23 patients (56.5%). Early biopsy after symptom onset/worsening is crucial and (sub)acute MRI-lesions should be targeted with a particular need for biopsy samples from the cortical layer.

Resting-state fMRI detects alterations in whole brain connectivity related to tumor biology in glioma patients.

BACKGROUND: Systemic infiltration of the brain by tumor cells is a hallmark of glioma pathogenesis which may cause disturbances in functional connectivity. We hypothesized that aggressive high-grade tumors cause more damage to functional connectivity than low-grade tumors. METHODS: We designed an imaging tool based on resting-state functional (f)MRI to individually quantify abnormality of functional connectivity and tested it in a prospective cohort of patients with newly diagnosed glioma. RESULTS: Thirty-four patients were analyzed (World Health Organization [WHO] grade II, n = 13; grade III, n = 6; grade IV, n = 15; mean age, 48.7 y). Connectivity abnormality could be observed not only in the lesioned brain area but also in the contralateral hemisphere with a close correlation between connectivity abnormality and aggressiveness of the tumor as indicated by WHO grade. Isocitrate dehydrogenase 1 (IDH1) mutation status was also associated with abnormal connectivity, with more alterations in IDH1 wildtype tumors independent of tumor size. Finally, deficits in neuropsychological performance were correlated with connectivity abnormality. CONCLUSION: Here, we suggested an individually applicable resting-state fMRI marker in glioma patients. Analysis of the functional connectome using this marker revealed that abnormalities of functional connectivity could be detected not only adjacent to the visible lesion but also in distant brain tissue, even in the contralesional hemisphere. These changes were associated with tumor biology and cognitive function. The ability of our novel method to capture tumor effects in nonlesional brain suggests a potential clinical value for both individualizing and monitoring glioma therapy.

Introduction of intraoperative neuromonitoring does not necessarily improve overall long-term outcome in elective aneurysm clipping.

OBJECTIVE: Intraoperative neuromonitoring (IOM), particularly of somatosensory-evoked potentials (SSEPs) and motor-evoked potentials (MEPs), evolved as standard of care in a variety of neurosurgical procedures. Case series report a positive impact of IOM for elective microsurgical clipping of unruptured intracranial aneurysms (ECUIA), whereas systematic evaluation of its predictive value is lacking. Therefore, the authors analyzed the neurological outcome of patients undergoing ECUIA before and after IOM introduction to this procedure. METHODS: The dates of inclusion in the study were 2007-2014. In this period, ECUIA procedures before (n = 136, NIOM-group; 2007-2010) and after introduction of IOM (n = 138, IOM-group; 2011-2014) were included. The cutoff value for SSEP/MEP abnormality was chosen as an amplitude reduction ≥ 50%. SSEP/MEP changes were correlated with neurological outcome. IOM-undetectable deficits (bulbar, vision, ataxia) were not included in risk stratification. RESULTS: There was no significant difference in sex distribution, follow-up period, subarachnoid hemorrhage risk factors, aneurysm diameter, complexity, and location. Age was higher in the IOM-group (57 vs 54 years, p = 0.012). In the IOM group, there were 18 new postoperative deficits (13.0%, 5.8% permanent), 9 hemisyndromes, 2 comas, 4 bulbar symptoms, and 3 visual deficits. In the NIOM group there were 18 new deficits (13.2%; 7.3% permanent, including 7 hemisyndromes). The groups did not significantly differ in the number or nature of postoperative deficits, nor in their recovery rate. In the IOM group, SSEPs and MEPs were available in 99% of cases. Significant changes were noted in 18 cases, 4 of which exhibited postoperative hemisyndrome, and 1 suffered from prolonged comatose state (5 true-positive cases). Twelve patients showed no new detectable deficits (false positives), however 2 of these cases showed asymptomatic infarction. Five patients with new hemisyndrome and 1 comatose patient did not show significant SSEP/MEP alterations (false negatives). Overall sensitivity of SSEP/MEP monitoring was 45.5%, specificity 89.8%, positive predictive value 27.8%, and negative predictive value 95.0%. CONCLUSIONS: The assumed positive impact of introducing SSEP/MEP monitoring on overall neurological outcome in ECUIA did not reach significance. This study suggests that from a medicolegal point of view, IOM is not stringently required in all neurovascular procedures. However, future studies should carefully address high-risk patients with complex procedures who might benefit more clearly from IOM than others.

Targeting APLN/APLNR Improves Antiangiogenic Efficiency and Blunts Proinvasive Side Effects of VEGFA/VEGFR2 Blockade in Glioblastoma.

Antiangiogenic therapy of glioblastoma (GBM) with bevacizumab, a VEGFA-blocking antibody, may accelerate tumor cell invasion and induce alternative angiogenic pathways. Here we investigate the roles of the proangiogenic apelin receptor APLNR and its cognate ligand apelin in VEGFA/VEGFR2 antiangiogenic therapy against distinct subtypes of GBM. In proneural GBM, apelin levels were downregulated by VEGFA or VEGFR2 blockade. A central role for apelin/APLNR in controlling GBM vascularization was corroborated in a serial implantation model of the angiogenic switch that occurs in human GBM. Apelin and APLNR are broadly expressed in human GBM, and knockdown or knockout of APLN in orthotopic models of proneural or classical GBM subtypes significantly reduced GBM vascularization compared with controls. However, reduction in apelin expression led to accelerated GBM cell invasion. Analysis of stereotactic GBM biopsies from patients as well as from in vitro and in vivo experiments revealed increased dissemination of APLNR-positive tumor cells when apelin levels were reduced. Application of apelin-F13A, a mutant APLNR ligand, blocked tumor angiogenesis and GBM cell invasion. Furthermore, cotargeting VEGFR2 and APLNR synergistically improved survival of mice bearing proneural GBM. In summary, we show that apelin/APLNR signaling controls GBM angiogenesis and invasion and that both pathologic features are blunted by apelin-F13A. We suggest that apelin-F13A can improve the efficiency and reduce the side effects of established antiangiogenic treatments for distinct GBM subtypes. SIGNIFICANCE: Pharmacologic targeting of the APLNR acts synergistically with established antiangiogenic treatments in glioblastoma and blunts therapy resistance to current strategies for antiangiogenesis.See related commentary by Amoozgar et al., p. 2104.

Long-Term Functional Outcome of Symptomatic Unruptured Intracranial Aneurysms in an Interdisciplinary Treatment Concept.

OBJECTIVE: In symptomatic unruptured intracranial aneurysms (UIAs), data on long-term functional outcome are sparse in the literature, even in the light of modern interdisciplinary treatment decisions. We therefore analyzed our in-house database for prognostic factors and long-term outcome of neurologic symptoms after microsurgical/endovascular treatment. METHODS: Patients treated between 2000 and 2016 after interdisciplinary vascular board decision were included. UIAs were categorized as symptomatic in cases of cranial nerve or brainstem compression. Symptoms were categorized as mild/severe. Long-term development of symptoms after treatment was assessed in a standardized and independent fashion. RESULTS: Of 98 symptomatic UIAs (microsurgery/endovascular 43/55), 84 patients presented with cranial nerve (NII-VI) compression and 14 patients with brainstem compression symptoms. Permanent morbidity occurred in 9% of patients. Of 119 symptoms (mild/severe 71/48), 60.4% recovered (full/partial 22%/39%) and 29% stabilized by the time of last follow-up; median follow-up was 19.5 months. Symptom recovery was higher in the long-term compared with that at discharge (P = 0.002). Optic nerve compression symptoms were less likely to improve compared with abducens nerve palsies and brainstem compression. Prognostic factors for recovery were duration and severity of symptoms, treatment modality (microsurgery) and absence of ischemia in the multivariate analysis. CONCLUSIONS: This recent study presents for the first time a detailed analysis of relevant prognostic factors for long-term recovery of cranial nerve/brainstem compression symptoms in an interdisciplinary treatment concept, which was excellent in most patients, with lowest recovery rates in optic nerve compression. Symptom recovery was remarkably higher in the long-term compared with recovery at discharge.

Somatostatin receptor-targeted radionuclide therapy for progressive meningioma: benefit linked to 68Ga-DOTATATE/-TOC uptake.

BACKGROUND: The prognosis of patients with progressive meningioma after failure of surgery and radiotherapy is poor. METHODS: We retrospectively evaluated the safety and efficacy of somatostatin-receptor (SSTR)-targeted radionuclide therapy (177Lu-DOTATATE [n = 16], 90Y-DOTATOC [n = 3], or both [n = 1]) in patients with progressive, treatment-refractory meningiomas (5 World Health Organization [WHO] grade I, 7 WHO grade II, 8 WHO grade III) and in part multifocal disease (17 of 20 patients). RESULTS: SSTR radionuclide treatment (median of 3 treatment cycles, median administered dose/cycle 7400 MBq) led to a disease stabilization in 10 of 20 patients for a median time of 17 months. Stratification according to WHO grade showed a median progression-free survival (PFS) of 32.2 months for grade I tumors, 7.2 for grade II, and 2.1 for grade III. PFS at 6 months was 100% for grade I, 57% for grade II, and 0% for grade III. Median overall survival was 17.2 months in WHO grade III patients and not reached for WHO I and II at a median follow-up of 20 months. In the analysis of single meningioma lesions, maximal and mean standardized uptake values in pretherapeutic 68Ga-DOTATOC/-TATE PET/CT were significantly higher in those lesions with radiographic stability after 6 months. In line with this, high expression of SSTR via immunohistochemistry was associated with PFS >6 months. CONCLUSIONS: SSTR-targeted radionuclide treatment has activity in a subset of patients with meningioma. Expression of SSTR via immunohistochemistry or radionuclide uptake might serve as a predictive biomarker for outcome to facilitate individualized treatment optimization in patients with uni- and multifocal meningiomas.

Optional real-time display of intraoperative neurophysiological monitoring in the microscopic field of view: avoiding communication failures in the operating room.

BACKGROUND: The use of intraoperative neurophysiological monitoring (IONM) in neurosurgery has improved patient safety and outcomes. However, a pitfall in the use of IONM remains unsolved. Currently, there is no feasible way for surgeons to interpret IONM waves themselves during operations. Instead, they have to rely on verbal feedback from a neurophysiologist. This method is prone to communication failures, which can lead to delayed or false interpretation of the data. Direct visualization of IONM waves is a way to alleviate this problem and make IONM more effective. METHODS: Microscope-integrated IONM (MI-IONM) was used in 163 cranial and spinal cases. We evaluated the feasibility, system stability and how well the system integrated into the surgical workflow. We used an IONM system that was connected to a surgical microscope. All IONM modalities used at our institution could be visualized as required, superimposed on the surgical field in the eyepiece of the microscope without obstructing the surgeon's field of vision. RESULTS: Use of MI-IONM was safe and reliable. It furthermore provided valuable intraoperative information. The system merely required a short learning curve. Only minor system problems without impact on surgical workflow occurred. MI-IONM proved to be especially useful in surgical cases where careful monitoring of nerve function is required, e.g., cerebellopontine angle surgery. Here, direct assessment of surgical action and IONM wave change was provided to the surgeon, if necessary (on-off control). CONCLUSION: MI-IONM is a useful extension of conventional IONM that provides optional real-time functional information to the surgeon on demand.

Increased 68Ga-DOTATATE uptake in PET imaging discriminates meningioma and tumor-free tissue.

UNLABELLED: Meningiomas are known to express somatostatin receptor 2 (SSTR2). PET using the SSTR2 analog (68)Ga-DOTATATE has recently been introduced for imaging of meningiomas. However, a systematic correlation between (68)Ga-DOTATATE uptake, SSTR2 expression, and histology (including tumor-free scar tissue) is still lacking. For elucidation, we conducted this prospective study. METHODS: Twenty-one adult patients with primary (n = 12) or recurrent (n = 9) meningiomas were prospectively enrolled. Preoperative MR imaging and (68)Ga-DOTATATE PET scans were fused and used for a spatially precise neuronavigated tissue-sampling procedure during tumor resection. Histopathologic diagnosis included immunohistochemical determination of SSTR2 expression. At each individual sampling site, the maximum standardized uptake value (SUVmax) of (68)Ga-DOTATATE was correlated with MR imaging findings, histology, and semiquantitative SSTR2 expression. RESULTS: One hundred fifteen samples (81 tumor, 34 tumor-free) were obtained. There was a significant positive correlation between SUVmax and SSTR2 expression. Receiver-operating characteristic analysis revealed a threshold of 2.3 for SUVmax to discriminate between tumor and nontumoral tissue. Regarding the detection of tumor tissue, PET imaging showed a higher sensitivity (90% vs. 79%; P = 0.049), with specificity and positive predictive values similar to MR imaging, for both de novo and recurrent tumors. CONCLUSION: (68)Ga-DOTATATE uptake correlates with SSTR2 expression and offers high diagnostic accuracy to delineate meningioma from tumor-free tissue even in recurrent tumors after previous therapy. Our findings substantiate an important role for (68)Ga-DOTATATE PET in meningioma management.

Radiation exposure induces inflammasome pathway activation in immune cells.

Radiation exposure induces cell and tissue damage, causing local and systemic inflammatory responses. Because the inflammasome pathway is triggered by cell death and danger-associated molecular patterns, we hypothesized that the inflammasome may signal acute and chronic immune responses to radiation. Using a mouse radiation model, we show that radiation induces a dose-dependent increase in inflammasome activation in macrophages, dendritic cells, NK cells, T cells, and B cells as judged by cleaved caspase-1 detection in cells. Time course analysis showed the appearance of cleaved caspase-1 in cells by day 1 and sustained expression until day 7 after radiation. Also, cells showing inflammasome activation coexpressed the cell surface apoptosis marker annexin V. The role of caspase-1 as a trigger for hematopoietic cell losses after radiation was studied in caspase-1(-/-) mice. We found less radiation-induced cell apoptosis and immune cell loss in caspase-1(-/-) mice than in control mice. Next, we tested whether uric acid might mediate inflammasome activation in cells by treating mice with allopurinol and discovered that allopurinol treatment completely blocked caspase-1 activation in cells. Finally, we demonstrate that radiation-induced caspase-1 activation occurs by a Nod-like receptor family protein 3-independent mechanism because radiation-exposed Nlrp3(-/-) mice showed caspase-1 activation profiles that were indistinguishable from those of wild-type mice. In summary, our data demonstrate that inflammasome activation occurs in many immune cell types following radiation exposure and that allopurinol prevented radiation-induced inflammasome activation. These results suggest that targeting the inflammasome may help control radiation-induced inflammation.

Subject-specific increases in serum S-100B distinguish sports-related concussion from sports-related exertion.

BACKGROUND: The on-field diagnosis of sports-related concussion (SRC) is complicated by the lack of an accurate and objective marker of brain injury. PURPOSE: To compare subject-specific changes in the astroglial protein, S100B, before and after SRC among collegiate and semi-professional contact sport athletes, and compare these changes to differences in S100B before and after non-contact exertion. STUDY DESIGN: Longitudinal cohort study. METHODS: From 2009-2011, we performed a prospective study of athletes from Munich, Germany, and Rochester, New York, USA. Serum S100B was measured in all SRC athletes at pre-season baseline, within 3 hours of injury, and at days 2, 3 and 7 post-SRC. Among a subset of athletes, S100B was measured after non-contact exertion but before injury. All samples were collected identically and analyzed using an automated electrochemiluminescent assay to quantify serum S100B levels. RESULTS: Forty-six athletes (30 Munich, 16 Rochester) underwent baseline testing. Thirty underwent additional post-exertion S100B testing. Twenty-two athletes (16 Rochester, 6 Munich) sustained a SRC, and 17 had S100B testing within 3 hours post-injury. The mean 3-hour post-SRC S100B was significantly higher than pre-season baseline (0.099±0.008 µg/L vs. 0.058±0.006 µg/L, p = 0.0002). Mean post-exertion S100B was not significantly different than the preseason baseline. S100B levels at post-injury days 2, 3 and 7 were significantly lower than the 3-hour level, and not different than baseline. Both the absolute change and proportional increase in S100B 3-hour post-injury were accurate discriminators of SRC from non-contact exertion without SRC (AUC 0.772 and 0.904, respectively). A 3-hour post-concussion S100B >0.122 µg/L and a proportional S100B increase of >45.9% over baseline were both 96.7% specific for SRC. CONCLUSIONS: Relative and absolute increases in serum S100B can accurately distinguish SRC from sports-related exertion, and may be a useful adjunct to the diagnosis of SRC.

Increased activation of the transcription factor c-Jun by MAP kinases in monocytes of multiple trauma patients is associated with adverse outcome and mass transfusion.

BACKGROUND: Post-traumatic dysfunction of the immune system is a major source of morbidity and mortality in patients with multiple trauma. The underlying intracellular mechanisms are still incompletely understood. Previous mRNA expression studies in monocytes suggested an involvement of the MAP kinases p38 and JNK and of the transcription factor c-Jun. Therefore, it was the aim of this study to elucidate whether alterations in the protein expression p38 MAPK, JNK, and c-Jun could be linked to PRBC substitution and survival. MATERIALS AND METHODS: Thirty-seven patients with blunt multiple injuries and an ISS > 16 points were enrolled in our study. Blood was drawn on admission and 6, 12, 24, 48, and 72 h after the traumatic event. Monocytes were isolated immediately after sample collection and nuclear protein was extracted and phosphoprotein concentrations were measured. The resulting data were statistically analyzed. RESULTS: An increased activation of MAP kinases and c-Jun could be shown in patients who died from their injuries. Additionally, patients who received PRBC substitution ≥10 units exhibited increased expression of activated MAP kinases and c-Jun. CONCLUSIONS: We present a serial, sequential investigation in human monocytes of major trauma patients evaluating the activation of p38 MAPK, JNK and c-Jun in the post-traumatic period. We show that death after trauma and massive PRBC substitution are associated with activation of this pathway. The p38 MAPK, JNK, and c-Jun have well established proinflammatory properties. Therefore, it appears likely that this pathway is involved in the systemic hyperinflammatory states seen after massive PRBC transfusion and multiple trauma.

Trauma equals danger--damage control by the immune system.

Traumatic injuries induce a complex host response that disrupts immune system homeostasis and predisposes patients to opportunistic infections and inflammatory complications. The response to injuries varies considerably by type and severity, as well as by individual variables, such as age, sex, and genetics. These variables make studying the impact of trauma on the immune system challenging. Nevertheless, advances have been made in understanding how injuries influence immune system function as well as the immune cells and pathways involved in regulating the response to injuries. This review provides an overview of current knowledge about how traumatic injuries affect immune system phenotype and function. We discuss the current ideas that traumatic injuries induce a unique type of a response that may be triggered by a combination of endogenous danger signals, including alarmins, DAMPs, self-antigens, and cytokines. Additionally, we review and propose strategies for redirecting injury responses to help restore immune system homeostasis.

A protective role for inflammasome activation following injury.

The inflammasome is activated in response to pathogen or endogenous danger signals and acts as an initiator and mediator of inflammatory reactions. In this study, we wished to identify whether the inflammasome is activated in vivo by injury. And if so, we wanted to characterize the kinetics, the immune cell distribution, and the functional impact of inflammasome activation on the injury response. Because caspase-1 activation is the final product of the inflammasome pathway, we used cleaved caspase-1 p10 and p20 as a measure for inflammasome activation in cells. We first developed a procedure to stain for caspase-1 p10 and p20 by flow cytometry (FACS) in lipopolysaccharide + adenosine triphosphate-stimulated spleen cells. This method for measuring caspase-1 activation was validated using FLICA (fluorochrome inhibitor of caspase), a fluorescently tagged specific binding reagent for activated caspase-1. Once validated by in vitro studies, we measured caspase-1 activation by FACS in immune cell subsets prepared from the lymph nodes and spleens of sham- or burn-injured mice at different time points. Lastly, the functional significance of inflammasome activation following burn injury was tested in mice treated with the specific caspase-1 inhibitor, AC-YVAD-CMK. The results of in vitro studies indicated that adenosine triphosphate and lipopolysaccharide stimulation induced significant caspase-1 activation in dendritic cells, macrophages, and natural killer (NK) cells. This approach also revealed caspase-1 activation in CD4 and CD8 T cells as well as B cells. We then measured caspase-1 activation in cells prepared from the lymph nodes and spleens of sham- or burn-injured mice. Significant caspase-1 activation was detected in macrophages and dendritic cells by 4 h after injury and peaked by day 1 after injury. FLICA staining confirmed that caspase-1 activation occurred in these cells at 1 day after injury. We also found significant injury-induced caspase-1 activation in NK cells, CD4 T cells, and B cells, but CD8 T cells did not demonstrate caspase-1 activation. Surprisingly, we found that blocking caspase-1 activation with AC-YVAD-CMK in vivo caused significantly higher mortality in burn-injured mice (P < 0.01). Taken together, these findings document that injury induces inflammasome activation in many immune cell subsets, but primarily in macrophages, and that inflammasome activation plays a protective role in the host response to severe injury.