Early vs Late Fixation of Extremity Fractures Among Adults With Traumatic Brain Injury.

Importance: The optimal timing for fixation of extremity fractures after traumatic brain injury (TBI) remains controversial. Objective: To investigate whether patients who underwent extremity fixation within 24 hours of TBI experienced worse outcomes than those who had the procedure 24 hours or more after TBI. Design, Setting, and Participants: This cohort study used data from the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. Patients 16 years or older with TBI who underwent internal extremity fixation met inclusion criteria. To compare outcomes, patients who underwent the procedure within 24 hours were propensity score matched with those who underwent it 24 hours or later. Patients were treated from December 9, 2014, to December 17, 2017. Data analysis was conducted between August 1, 2022, and December 25, 2023. Main Outcomes and Measures: The primary outcome was an unfavorable functional status at 6 months (Glasgow Outcome Scale-Extended [GOSE] score ≤4). Results: A total of 253 patients were included in this study. The median age was 41 (IQR, 27-57) years, and 184 patients (72.7%) were male. The median Injury Severity Score (ISS) was 41 (IQR, 27-49). Approximately half of the patients (122 [48.2%]) had a mild TBI while 120 (47.4%) had moderate to severe TBI. Seventy-four patients (29.2%) underwent an internal extremity fixation within 24 hours, while 179 (70.8%) had the procedure 24 hours or later. At 6 months, 86 patients (34.0%) had an unfavorable functional outcome. After propensity score matching, there were no statistically significant differences in unfavorable functional outcomes at 6 months (odds ratio [OR], 1.12 [95% CI, 0.51-1.99]; P = .77) in patients with TBI of any severity. Similar results were observed in patients with mild TBI (OR, 0.71 [95% CI, 0.22-2.29]; P = .56) and moderate to severe TBI (OR, 1.08 [95% CI, 0.32-3.70]; P = .90). Conclusions and Relevance: The outcomes of extremity fracture fixation performed within 24 hours after TBI appear not to be worse than those of procedures performed 24 hours or later. This finding suggests that early fixation after TBI could be considered in patients with mild head injuries.

Repeat surgery of recurrent glioma for molecularly informed treatment in the age of precision oncology: A risk-benefit analysis.

PURPOSE: Surgery for recurrent glioma provides cytoreduction and tissue for molecularly informed treatment. With mostly heavily pretreated patients involved, it is unclear whether the benefits of repeat surgery outweigh its potential risks. METHODS: Patients receiving surgery for recurrent glioma WHO grade 2-4 with the goal of tissue sampling for targeted therapies were analyzed retrospectively. Complication rates (surgical, neurological) were compared to our institutional glioma surgery cohort. Tissue molecular diagnostic yield, targeted therapies and post-surgical survival rates were analyzed. RESULTS: Between 2017 and 2022, tumor board recommendation for targeted therapy through molecular diagnostics was made for 180 patients. Of these, 70 patients (38%) underwent repeat surgery. IDH-wildtype glioblastoma was diagnosed in 48 patients (69%), followed by IDH-mutant astrocytoma (n = 13; 19%) and oligodendroglioma (n = 9; 13%). Gross total resection (GTR) was achieved in 50 patients (71%). Tissue was processed for next-generation sequencing in 64 cases (91%), and for DNA methylation analysis in 58 cases (83%), while immunohistochemistry for mTOR phosphorylation was performed in 24 cases (34%). Targeted therapy was recommended in 35 (50%) and commenced in 21 (30%) cases. Postoperatively, 7 patients (11%) required revision surgery, compared to 7% (p = 0.519) and 6% (p = 0.359) of our reference cohorts of patients undergoing first and second craniotomy, respectively. Non-resolving neurological deterioration was documented in 6 cases (10% vs. 8%, p = 0.612, after first and 4%, p = 0.519, after second craniotomy). Median survival after repeat surgery was 399 days in all patients and 348 days in GBM patients after repeat GTR. CONCLUSION: Surgery for recurrent glioma provides relevant molecular diagnostic information with a direct consequence for targeted therapy under a reasonable risk of postoperative complications. With satisfactory postoperative survival it can therefore complement a multi-modal glioma therapy approach.

Association of early surgery and absence of ataxia with full recovery after spinal intramedullary ependymoma resection.

OBJECTIVE: Spinal intramedullary ependymomas (IEs) represent a well-defined tumor entity usually warranting resection. Factors that determine full long-term neurological recovery after resection are seldomly reported on in larger clinical series. In this study, the authors aimed to highlight the neurological outcome of patients with IEs after resection, with a focus on full neurological recovery, and to explore possible risk factors for the absence of neurological amelioration to an optimal function after surgical treatment. METHODS: A single-center retrospective analysis of all patients undergoing surgery for IEs between 2007 and 2021 was performed. Data collection included patient demographics, symptoms, clinical findings, histopathological diagnosis, surgical procedures, complications, and neurological outcome. Patients harboring a favorable outcome (modified McCormick Scale [mMS] grade of I) were compared with patients with a less favorable outcome (mMS grade ≥ II) at the final follow-up. RESULTS: In total, 72 patients with a histologically diagnosed IE were included. IEs in those patients (41 males, 31 females; median age 51 [IQR 40-59] years) mostly occurred in the cervical (n = 40, 56%) or thoracic (n = 23, 32%) spine. Upon admission, motor deficits or gait deficits (mMS grade ≥ II) were present in 29 patients (40%), with a median mMS grade of II (IQR I-II). Gross-total resection was achieved in 60 patients (90%), and the rate of surgical complications was 7%. Histopathologically, 67 tumors (93%) were classified as WHO grade 2 ependymomas, 3 (4%) as WHO grade 1 subependymomas, and 2 (3%) as WHO grade 3 anaplastic ependymomas. After a mean follow-up of 863 ± 479 days, 37 patients (51%) had a fully preserved neurological function and 62 patients (86%) demonstrated an mMS grade of I or II. Comparison of favorable with unfavorable outcomes revealed an association of early surgery (within a year after symptom onset), the absence of ataxia or gait disorders, and a low mMS grade with full neurological recovery at the final follow-up. A subgroup of patients (n = 15, 21%) had nonresolving deterioration at the final follow-up, with no significant differences in relevant variables compared with the rest of the cohort. CONCLUSIONS: The data presented solidify the role of early surgery in the management of spinal IEs, especially in patients with mild neurological deficits. Furthermore, the presence of gait disturbance or ataxia confers a higher risk of incomplete long-term recovery after spinal ependymoma resection. Because a distinct subgroup of patients had nonresolving deterioration, even when presenting with an uneventful history, further analyses into this subgroup of patients are required.

The Single-Dose Application of Interleukin-4 Ameliorates Secondary Brain Damage in the Early Phase after Moderate Experimental Traumatic Brain Injury in Mice.

Activation of the interleukin-4 (IL-4) pathway ameliorates secondary injury mechanisms after experimental traumatic brain injury (TBI); therefore, we assessed the effect of a therapeutic IL-4 administration on secondary brain damage after experimental TBI. We subjected 100 C57/Bl6 wildtype mice to controlled cortical impact (CCI) and administered IL-4 or a placebo control subcutaneously 15 min thereafter. Contusion volume (Nissl staining), neurological function (hole board, video open field, and CatWalkXT®), and the immune response (immunofluorescent staining) were analyzed up to 28 days post injury (dpi). Contusion volumes were significantly reduced after IL-4 treatment up to 14 dpi (e.g., 6.47 ± 0.41 mm3 vs. 3.80 ± 0.85 mm3, p = 0.011 3 dpi). Macrophage invasion and microglial response were significantly attenuated in the IL-4 group in the acute phase after CCI (e.g., 1.79 ± 0.15 Iba-1+/CD86+ cells/sROI vs. 1.06 ± 0.21 Iba-1/CD86+ cells/sROI, p = 0.030 in the penumbra 3 dpi), whereas we observed an increased neuroinflammation thereafter (e.g., mean GFAP intensity of 3296.04 ± 354.21 U vs. 6408.65 ± 999.54 U, p = 0.026 in the ipsilateral hippocampus 7 dpi). In terms of functional outcome, several gait parameters were improved in the acute phase following IL-4 treatment (e.g., a difference in max intensity of -7.58 ± 2.00 U vs. -2.71 ± 2.44 U, p = 0.041 3 dpi). In conclusion, the early single-dose administration of IL-4 significantly reduces secondary brain damage in the acute phase after experimental TBI in mice, which seems to be mediated by attenuation of macrophage and microglial invasion.

The molecular diagnostic yield of frame-based stereotactic biopsies in the age of precision neuro-oncology: a cross-sectional study.

PURPOSE: With the increasing role of molecular genetics in the diagnostics of intracranial tumors, delivering sufficient representative tissue for such analyses is of paramount importance. This study explored the rate of successful diagnosis after frame-based stereotactic biopsies of intracranial lesions. METHODS: Consecutive patients undergoing frame-based stereotactic biopsies in 2020 and 2021 were included in this retrospective analysis. Cases were classified into three groups: conclusive, diagnosis with missing molecular genetics (MG) data, and inconclusive neuropathological diagnosis. RESULTS: Of 145 patients, a conclusive diagnosis was possible in n = 137 cases (94.5%). For 3 cases (2.0%), diagnosis was established with missing MG data. In 5 cases (3.5%), an inconclusive (tumor) diagnosis was met. Diagnoses comprised mainly WHO 4 glioblastomas (n = 73, 56%), CNS lymphomas (n = 23, 16%), inflammatory diseases (n = 14, 10%), and metastases (n = 5, 3%). Methylomics were applied in 49% (n = 44) of tumor cases (panel sequencing in n = 28, 30% of tumors). The average number of specimens used for MG diagnostics was 5, while the average number of specimens provided was 15. In a univariate analysis, insufficient DNA was associated with an inconclusive diagnosis or a diagnosis with missing MG data (p < 0.001). Analyses of planned and implemented trajectories of cases with diagnosis with missing MG data or inconclusive diagnosis (n = 8) revealed that regions of interest were reached in almost all cases (n = 7). CONCLUSION: Although stereotactic frame-based biopsies deliver a limited amount of tissue, they bear high histopathological and molecular genetic diagnostic yields. Given the proven surgical precision of the planned biopsy trajectories, optimizing surveyed lesion regions could help improve the rate of conclusive diagnoses.

Reappraisal of Intracerebral Hemorrhages and Intracerebral Hemorrhage Grading Scale Score in Surgically and Medically Managed Cerebellar Intracerebral Hemorrhage.

BACKGROUND: As compared with supratentorial intracerebral hemorrhages (ICH), bleeds that occur within the cerebellum require special consideration given the nature of the posterior fossa. OBJECTIVE: To validate ICH and ICH grading scale (ICH-GS) scores in patients with cerebellar hemorrhage and examine the outcomes of patients managed surgically as compared with those who underwent conservative treatment. METHODS: This observational multicenter study included 475 patients with cerebellar hemorrhage from 9 different neurosurgical departments in Germany between 2005 and 2021. The prognostic accuracy of ICH and ICH-GS scores were calculated by the area under the curve of the receiver operating characteristic curves. Analyzed outcomes were the in-hospital mortality, mortality at 6 months, in-hospital outcome, and outcome at 6 months. RESULTS: Of 403 patients, 252 patients (62.5%) underwent surgical treatment and 151 patients (37.5%) conservative treatment. Both ICH and ICH-GS scores demonstrated good prognostic accuracy regarding both overall mortality and functional outcomes. In those patients presenting with severe cerebellar hemorrhages, ie, ICH score >3 and ICH-GS score >11, overall mortality was significantly lower in surgically treated patients. Mortality was significantly higher in those patients managed surgically who presented with ICH scores 3; in such patients, improved outcomes were noted when the hematoma was treated conservatively. CONCLUSION: ICH and ICH scores are useful tools for prediction of survival and outcome in patients with cerebellar ICH. Surgical management may be beneficial for those who present with severe cerebellar ICH as reflected by ICH scores >3, while conservative management seems reasonable in patients with lower ICH scores.

Concomitant spine trauma in patients with traumatic brain injury: Patient characteristics and outcomes.

Objective: Spine injury is highly prevalent in patients with poly-trauma, but data on the co-occurrence of spine trauma in patients with traumatic brain injury (TBI) are scarce. In this study, we used the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) database to assess the prevalence, characteristics, and outcomes of patients with TBI and a concurrent traumatic spinal injury (TSI). Methods: Data from the European multi-center CENTER-TBI study were analyzed. Adult patients with TBI (≥18 years) presenting with a concomitant, isolated TSI of at least serious severity (Abbreviated Injury Scale; AIS ≥3) were included. For outcome analysis, comparison groups of TBI patients with TSI and systemic injuries (non-isolated TSI) and without TSI were created using propensity score matching. Rates of mortality, unfavorable outcomes (Glasgow Outcome Scale Extended; GOSe < 5), and full recovery (GOSe 7-8) of all patients and separately for patients with only mild TBI (mTBI) were compared between groups at 6-month follow-up. Results: A total of 164 (4%) of the 4,254 CENTER-TBI core study patients suffered from a concomitant isolated TSI. The median age was 53 [interquartile range (IQR): 37-66] years and 71% of patients were men. mTBI was documented in 62% of cases, followed by severe TBI (26%), and spine injuries were mostly cervical (63%) or thoracic (31%). Surgical spine stabilization was performed in 19% of cases and 57% of patients were admitted to the ICU. Mortality at 6 months was 11% and only 36% of patients regained full recovery. There were no significant differences in the 6-month rates of mortality, unfavorable outcomes, or full recovery between TBI patients with and without concomitant isolated TSI. However, concomitant non-isolated TSI was associated with an unfavorable outcome and a higher mortality. In patients with mTBI, a negative association with full recovery could be observed for both concomitant isolated and non-isolated TSI. Conclusion: Rates of mortality, unfavorable outcomes, and full recovery in TBI patients with and without concomitant, isolated TSIs were comparable after 6 months. However, in patients with mTBI, concomitant TSI was a negative predictor for a full recovery. These findings might indicate that patients with moderate to severe TBI do not necessarily exhibit worse outcomes when having a concomitant TSI, whereas patients with mTBI might be more affected.

Site-Specific Considerations on Engineered T Cells for Malignant Gliomas.

Immunotherapy has revolutionized cancer treatment. Despite the recent advances in immunotherapeutic approaches for several tumor entities, limited response has been observed in malignant gliomas, including glioblastoma (GBM). Conversely, one of the emerging immunotherapeutic modalities is chimeric antigen receptors (CAR) T cell therapy, which demonstrated promising clinical responses in other solid tumors. Current pre-clinical and interventional clinical studies suggest improved efficacy when CAR-T cells are delivered locoregionally, rather than intravenously. In this review, we summarize possible CAR-T cell administration routes including locoregional therapy, systemic administration with and without focused ultrasound, direct intra-arterial drug delivery and nanoparticle-enhanced delivery in glioma. Moreover, we discuss published as well as ongoing and planned clinical trials involving CAR-T cell therapy in malignant glioma. With increasing neoadjuvant and/or adjuvant combinatorial immunotherapeutic concepts and modalities with specific modes of action for malignant glioma, selection of administration routes becomes increasingly important.

Spinal oncologic paraparesis: Analysis of neurological and surgical outcomes in patients with intramedullary, extramedullary, and extradural tumors.

Objectives: Paraparesis due to oncologic lesions of the spine warrants swift neurosurgical intervention to prevent permanent disability and hence maintain independence of affected patients. Clinical parameters that predict a favorable outcome after surgical intervention could aid decision-making in emergency situations. Methods: Patients who underwent surgical intervention for paraparesis (grade of muscle strength <5 according to the British Medical Research Council grading system) secondary to spinal neoplasms between 2006 and 2020 were included in a single-center retrospective analysis. Pre- and postoperative clinical data were collected. The neurological status was assessed using the modified McCormick Disability Scale (mMcC) Score. In a univariate analysis, patients with favorable (discharge mMcC improved or stable at <3) and non-favorable outcome (discharge mMcC deteriorated or stable at >2) and different tumor anatomical compartments were statistically compared. Results: 117 patients with oncologic paraparesis pertaining to intramedullary lesions (n=17, 15%), intradural extramedullary (n=24, 21%) and extradural lesions (n=76, 65%) with a mean age of 65.3 ± 14.6 years were included in the analysis. Thoracic tumors were the most common (77%), followed by lumbar and cervical tumors (13% and 12%, respectively). Surgery was performed within a mean of 36±60 hours of admission across all tumors and included decompression over a median of 2 segments (IQR:1-3) and mostly subtotal tumor resection (n=83, 71%). Surgical and medical complications were documented in 9% (n=11) and 7% (n=8) of cases, respectively. The median hospital length-of-stay was 9 (7-13) days. Upon discharge, the median mMcC score had improved from 3 to 2 (p<0.0001). At last follow-up (median 180; IQR 51-1080 days), patients showed an improvement in their mean Karnofsky Performance Score (KPS) from 51.7±18.8% to 65.3±20.4% (p<0.001). Localization in the intramedullary compartment, a high preoperative mMcC score, in addition to bladder and bowel dysfunction were associated with a non-favorable outcome (p<0.001). Conclusion: The data presented on patients with spinal oncologic paraparesis provide a risk-benefit narrative that favors surgical intervention across all etiologies. At the same time, they outline clinical factors that confer a less-favorable outcome like intramedullary tumor localization, a high McCormick score and/or bladder and bowel abnormalities at admission.

A novel patient stratification strategy to enhance the therapeutic efficacy of dasatinib in glioblastoma.

BACKGROUND: Glioblastoma is the most common primary malignancy of the central nervous system with a dismal prognosis. Genomic signatures classify isocitrate dehydrogenase 1 (IDH)-wildtype glioblastoma into three subtypes: proneural, mesenchymal, and classical. Dasatinib, an inhibitor of proto-oncogene kinase Src (SRC), is one of many therapeutics which, despite promising preclinical results, have failed to improve overall survival in glioblastoma patients in clinical trials. We examined whether glioblastoma subtypes differ in their response to dasatinib and could hence be evaluated for patient enrichment strategies in clinical trials. METHODS: We carried out in silico analyses on glioblastoma gene expression (TCGA) and single-cell RNA-Seq data. In addition, in vitro experiments using glioblastoma stem-like cells (GSCs) derived from primary patient tumors were performed, with complementary gene expression profiling and immunohistochemistry analysis of tumor samples. RESULTS: Patients with the mesenchymal subtype of glioblastoma showed higher SRC pathway activation based on gene expression profiling. Accordingly, mesenchymal GSCs were more sensitive to SRC inhibition by dasatinib compared to proneural and classical GSCs. Notably, SRC phosphorylation status did not predict response to dasatinib treatment. Furthermore, serpin peptidase inhibitor clade H member 1 (SERPINH1), a collagen-related heat-shock protein associated with cancer progression, was shown to correlate with dasatinib response and with the mesenchymal subtype. CONCLUSION: This work highlights further molecular-based patient selection strategies in clinical trials and suggests the mesenchymal subtype as well as SERPINH1 to be associated with response to dasatinib. Our findings indicate that stratification based on gene expression subtyping should be considered in future dasatinib trials.

Subjective and objective appearance of head and neck cancer patients following microsurgical reconstruction and associated quality of life─A cross-sectional study.

PURPOSE: Depending on the site and size of head and neck cancer, the disease affects patients' appearance and subsequently their quality of life. The aim of this study was to correlate subjective and objective evaluation of facial appearance and associated quality of life following ablative tumor surgery and microsurgical reconstruction. MATERIAL AND METHODS: A total of 99 patients with combined ablative and reconstructive microsurgical procedure for head and neck malignancy and seven patients with non-malignant disease were examined by three-dimensional (3D) (photogrammetry at least 6 months post-surgery and were evaluated by two-dimensional (2D) and 3D means for symmetry and facial proportions. Measurements were correlated with subjective reporting from the University of Washington Quality of Life Questionnaire and observer ratings. RESULTS: Of the 106 patients, three patients scored themselves as significantly disfigured (2.8%), 19 were bothered by their appearance (17.9%), 27 (25.5%) reported no change, and 57 (53.8%) reported minor changes in their appearance. On 2D evaluation, 10 patients (9.4%) showed severely abnormal facial proportions. On 3D analysis, 17 patients showed major asymmetry. There was a high correlation (0.67) between patient and observer subjective rating (p < 0.05). While 2D evaluation alone showed no significant correlation with subjective rating, 3D evaluation showed a moderate correlation (0.37; p < 0.05). The best results were achieved by combining 2D and 3D measurements (0.5; p < 0.05). Young female patients were most critical about their appearance. CONCLUSION: Following combined ablative and microsurgical reconstructive procedures, patients have a realistic perception of their appearance compared with observer ratings and a combination of 2D and 3D objective evaluation.

Symposium "International Medical Students - Support Programs in Practical Application": Networking, best-practice examples and local representation.

The new project "International Medical Students" within the German Medical Students' Association (bvmd) aims at connecting local support programs for international medical students as well as the representation of their interests within the bvmd. Within the frame of this project, the first symposium "International Medical Students - Support Programs in Practical Application" took place from the 12th to the 14th of May 2017 at the Hannover Medical School (MHH). Through partaking in different workshops, 31 participants discussed the framework conditions of local work (i.e. curricula, tutorials, social offers, cooperation between faculty members and student body, legal aspects), common problems (i.e. addressing the target group, funding of support programs) and possible solutions (i.e. targeted advertisement, application for public funds). This report constitutes a summary of the results of these discussions. The feedback from the participants on the need for such a regular exchange and the format of the symposium was positive. However, there were requests for further thematic specification. Based on this feedback the next symposium is planned for 2018.

Interactive peer-guided examination preparation course for second-year international full-time medical students: quantitative and qualitative evaluation.

Background: It has been documented that international students face diverse challenges due to language and cultural barriers. International medical students suffer from personal distress, a lack of support and perform poorer than local fellow-students in clinical examinations. It has been documented that international medical students benefit from peer-led tutorials in their first year. We investigated the effectiveness of a tutorial offered for international medical students in their second year. Methods: A peer-guided examination preparation course with interactive elements for second year international medical students was designed, learning objectives were defined. Two evaluations were undertaken: In a quantitative assessment, students were asked to fill out five multiple-choice-questions at the beginning of every session of the tutorial (pre-test) as well as to participate in a post-test at the end of the semester in which all former multiple-choice-questions were re-used. Using a qualitative approach, participants were asked for their thoughts and comments in a semi-structured interview at the end of the semester. Results: International students (N=12) showed significantly better results in the post- than in the pre-test (t(11)=-8.48, p<.001, d=1.95). Within the interviews, international students (N=10) reported to have benefited from technical and didactic, as well as social learning experiences. The individual lectures students were asked to contribute were discussed controversially. Conclusion: Our peer-guided tutorial for second year international medical students is an effective and well accepted possibility to prepare these students for examinations.

On center field or at the sidelines? - A plea for a multimodal approach between medical schools and medical student communities while integrating international medical students.

An increasing number of medical schools offer support services for international students. Their frequent focus on linguistic and academic support often reflects a rather deficit-oriented perception of international medical students. Therefore, this comment advocates a stronger focus on the integration into the local medical student communities. This happens both against the background of the expected academic benefits and the added value of intercultural learning at medical schools.