Effects of Long-Term Temozolomide Treatment on Glioblastoma and Astrocytoma WHO Grade 4 Stem-like Cells.

Glioblastoma leads to a fatal course within two years in more than two thirds of patients. An essential cornerstone of therapy is chemotherapy with temozolomide (TMZ). The effect of TMZ is counteracted by the cellular repair enzyme O6-methylguanine-DNA methyltransferase (MGMT). The MGMT promoter methylation, the main regulator of MGMT expression, can change from primary tumor to recurrence, and TMZ may play a significant role in this process. To identify the potential mechanisms involved, three primary stem-like cell lines (one astrocytoma with the mutation of the isocitrate dehydrogenase (IDH), CNS WHO grade 4 (HGA)), and two glioblastoma (IDH-wildtype, CNS WHO grade 4) were treated with TMZ. The MGMT promoter methylation, migration, proliferation, and TMZ-response of the tumor cells were examined at different time points. The strong effects of TMZ treatment on the MGMT methylated cells were observed. Furthermore, TMZ led to a loss of the MGMT promoter hypermethylation and induced migratory rather than proliferative behavior. Cells with the unmethylated MGMT promoter showed more aggressive behavior after treatment, while HGA cells reacted heterogenously. Our study provides further evidence to consider the potential adverse effects of TMZ chemotherapy and a rationale for investigating potential relationships between TMZ treatment and change in the MGMT promoter methylation during relapse.

Protocadherin Gamma C3 (PCDHGC3) Is Strongly Expressed in Glioblastoma and Its High Expression Is Associated with Longer Progression-Free Survival of Patients.

Protocadherins (PCDHs) belong to the cadherin superfamily and represent the largest subgroup of calcium-dependent adhesion molecules. In the genome, most PCDHs are arranged in three clusters, α, ß, and γ on chromosome 5q31. PCDHs are highly expressed in the central nervous system (CNS). Several PCDHs have tumor suppressor functions, but their individual role in primary brain tumors has not yet been elucidated. Here, we examined the mRNA expression of PCDHGC3, a member of the PCDHγ cluster, in non-cancerous brain tissue and in gliomas of different World Health Organization (WHO) grades and correlated it with the clinical data of the patients. We generated a PCDHGC3 knockout U343 cell line and examined its growth rate and migration in a wound healing assay. We showed that PCDHGC3 mRNA and protein were significantly overexpressed in glioma tissue compared to a non-cancerous brain specimen. This could be confirmed in glioma cell lines. High PCDHGC3 mRNA expression correlated with longer progression-free survival (PFS) in glioma patients. PCDHGC3 knockout in U343 resulted in a slower growth rate but a significantly faster migration rate in the wound healing assay and decreased the expression of several genes involved in WNT signaling. PCDHGC3 expression should therefore be further investigated as a PFS-marker in gliomas. However, more studies are needed to elucidate the molecular mechanisms underlying the PCDHGC3 effects.

Hospital preparedness for mass critical care during SARS-CoV-2 pandemic.

Mass critical care caused by the severe acute respiratory syndrome corona virus 2 pandemic poses an extreme challenge to hospitals. The primary goal of hospital disaster preparedness and response is to maintain conventional or contingency care for as long as possible. Crisis care must be delayed as long as possible by appropriate measures. Increasing the intensive care unit (ICU) capacities is essential. In order to adjust surge capacity, the reduction of planned, elective patient care is an adequate response. However, this involves numerous problems that must be solved with a sense of proportion. This paper summarises preparedness and response measures recommended to acute care hospitals.

Primary brain amyloidoma, both a neoplastic and a neurodegenerative disease: a case report.

BACKGROUND: Scattered extracellular deposits of amyloid within the brain parenchyma can be found in a heterogeneous group of diseases. Its condensed accumulation in the white matter without evidence for systemic amyloidosis is known as primary brain amyloidoma (PBA). Although originally considered as a tumor-like lesion by its space-occupying effect, this condition displays also common hallmarks of a neurodegenerative disorder. CASE PRESENTATION: A 50-year-old woman presented with a mild cognitive decline and seizures with a right temporal, irregular and contrast-enhancing mass on magnetic resonance imaging. Suspecting a high-grade glioma, the firm tumor was subtotally resected. Neuropathological examination showed no glioma, but distinct features of a neurodegenerative disorder. The lesion was composed of amyloid AL λ aggregating within the brain parenchyma as well as the adjacent vessels, partially obstructing the vascular lumina. Immunostaining confirmed a distinct perivascular inflammatory reaction. After removal of the PBA, mnestic impairments improved considerably, the clinical course and MRI-results are stable in the 8-year follow-up. CONCLUSION: Based on our histopathological findings, we propose to regard the clinicopathological entity of PBA as an overlap between a neoplastic and neurodegenerative disorder. Since the lesions are locally restricted, they might be amenable to surgery with the prospect of a definite cure.

High-grade glioma associated immunosuppression does not prevent immune responses induced by therapeutic vaccines in combination with Treg depletion.

High-grade gliomas (HGG) exert systemic immunosuppression, which is of particular importance as immunotherapeutic strategies such as therapeutic vaccines are increasingly used to treat HGGs. In a first cohort of 61 HGG patients we evaluated a panel of 30 hematological and 34 plasma biomarkers. Then, we investigated in a second cohort of 11 relapsed HGG patients receiving immunomodulation with metronomic cyclophosphamide upfront to a DC-based vaccine whether immune abnormalities persisted and whether they hampered induction of IFNγ+ T-cell responses. HGG patients from the first cohort showed increased numbers of leukocytes, neutrophils and MDSCs and in parallel reduced numbers of CD4+/CD8+ T-cells, plasmacytoid and conventional DC2s. MDSCs and T-cell alterations were more profound in WHO IV° glioma patients. Moreover, levels of MDSCs and epidermal growth factor were negatively associated with survival. Serum levels of IL-2, IL-4, IL-5 and IL-10 were altered in HGG patients, however, without any impact on clinical outcome. In the immunotherapy cohort, 6-month overall survival was 100%. Metronomic cyclophosphamide led to > 40% reduction of regulatory T cells (Treg). In parallel to Treg-depletion, MDSCs and DC subsets became indistinguishable from healthy controls, whereas T-lymphopenia persisted. Despite low T-cells, IFNγ-responses could be induced in 9/10 analyzed cases. Importantly, frequency of CD8+VLA-4+ T-cells with CNS-homing properties, but not of CD4+ VLA-4+ T-cells, increased during vaccination. Our study identifies several features of systemic immunosuppression in HGGs. Metronomic cyclophosphamide in combination with an active immunization alleviates the latter and the combined treatment allows induction of a high rate of anti-glioma immune responses.

Screening for symptom burden and supportive needs of patients with glioblastoma and brain metastases and their caregivers in relation to their use of specialized palliative care.

PURPOSE: Patients with brain tumors have a high symptom burden and multiple supportive needs. Needs of caregivers are often unattended. This study aims to determine screening-based symptom burden and supportive needs of patients and caregivers with regard to the use of specialized palliative care (SPC). METHODS: Seventy-nine patients with glioblastoma and brain metastases and 46 caregivers were screened with standardized questionnaires following diagnosis and 2 months later. The screening assessed symptom burden, quality of life (QoL), distress, and supportive needs. RESULTS: The most relevant symptoms were drowsiness, tiredness, and low well-being (53-58%). The most prevalent patient supportive needs were the need for information about available resources, the illness, and possible lifestyle changes (50-56%). The most prevalent caregiver needs were information about the illness, lifestyle changes, and about available resources (56-74%). Patients who received SCP and their caregivers had higher symptom burden and supportive needs than those without SPC. They reported moderate improvement in pain, distress, and QoL, while patients without SPC also improved their QoL, but had small to moderate deteriorations in pain, drowsiness, nauseas, well-being, and other problems. Distress of caregivers with SPC improved with moderate to large effect sizes but still was on a high level and remained stable for those without SPC. CONCLUSIONS: Symptom burden and supportive needs were high, but even more caregivers than patients expressed high distress and supportive needs. SPC appears to reach the target group, both patients and caregivers with elevated symptom burden. Targeted interventions are needed to improve tiredness and drowsiness.

3D rotational fluoroscopy for intraoperative clip control in patients with intracranial aneurysms--assessment of feasibility and image quality.

BACKGROUND: Mobile 3D fluoroscopes have become increasingly available in neurosurgical operating rooms. In this series, the image quality and value of intraoperative 3D fluoroscopy with intravenous contrast agent for the evaluation of aneurysm occlusion and vessel patency after clip placement was assessed in patients who underwent surgery for intracranial aneurysms. MATERIALS AND METHODS: Twelve patients were included in this retrospective analysis. Prior to surgery, a 360° rotational fluoroscopy scan was performed without contrast agent followed by another scan with 50 ml of intravenous iodine contrast agent. The image files of both scans were transferred to an Apple PowerMac® workstation, subtracted and reconstructed using OsiriX® free software. The procedure was repeated after clip placement. Both image sets were compared for assessment of aneurysm occlusion and vessel patency. RESULTS: Image acquisition and contrast administration caused no adverse effects. Image quality was sufficient to follow the patency of the vessels distal to the clip. Metal artifacts reduce the assessability of the immediate vicinity of the clip. Precise image subtraction and post-processing can reduce metal artifacts and make the clip-site assessable and depict larger neck-remnants. CONCLUSION: This technique quickly supplies images at adequate quality to evaluate distal vessel patency after aneurysm clipping. Significant aneurysm remnants may be depicted as well. As it does not require visual control of all vessels that are supposed to be evaluated intraoperatively, this technique may be complementary to other intraoperative tools like indocyanine green videoangiography and micro-Doppler, especially for the assessment of larger aneurysms. At the momentary state of this technology, it cannot replace postoperative conventional angiography. However, 3D fluoroscopy and image post-processing are young technologies. Further technical developments are likely to result in improved image quality.

Perception of children's faces with unilateral coronal synostosis--an eye-tracking investigation.

PURPOSE: Premature unilateral coronal craniosynostosis results in distinctive cranial and facial abnormalities of varying severity, including orbital dystopia and an abnormal head shape. As the face is affected, these children may encounter stigmatization. To avoid this scenario, many parents elect for their child to undergo surgical correction. Laypeople's perception of children with either untreated or treated unilateral coronal craniosynostosis (UCS) has not yet been objectively evaluated. METHODS: This study introduces eye tracking as an objective instrument in order to evaluate the perception of 14 children with coronal synostosis, both pre- and postoperatively. Age-matched healthy children served as a control group. Using standardized photos, the involuntary eye movements and the fixations of 30 unaffected laypeople were evaluated. RESULTS: In the untreated children, whose faces were characterized by striking orbital dystopia, the eyes drew more attention than those of the healthy children. The results of our study demonstrate that the operative correction of unilateral coronal synostosis results in the normalization of the asymmetry of the fronto-orbital region, whereas the C-shaped deformity of the midface, which is not addressed via surgery, subsequently attracts more attention. CONCLUSION: Eye tracking objectively evaluates both the perception of craniofacial abnormalities and the extent of the approximation of normality after surgical correction. We introduce eye tracking as an objective measurement tool for craniofacial abnormalities for the first time.

Gout tophus on an intradural fascicle: a case description.

STUDY DESIGN: Case report and review of literature. OBJECTIVE: Detailed description of case and review of literature to determine its uniqueness with special regard to intradural gout tophus formation without any boney attachment or underlying systemic gout. Gout tophi commonly involve the peripheral joints of the upper and lower extremities. Rarely, gout tophi are located within the spinal cord, especially without any underlying hyperuricemia. METHODS: We report the case of a 64-year-old patient presenting with radiculopathy along the right L2-dermatome and bladder dysfunction and review literature for further discussion. RESULTS: Imaging studies showed a partly calcified round intradural lesion at the level L2 without contrast enhancement. The lesion was removed via a hemilaminectomy L2. It was adherent to a dorsal sensory fascicle exiting with the L2 nerve root. The neuropathological examination showed a gout tophus. Serologic testing revealed no signs of hyperuricemia. CONCLUSION: To the best of our knowledge, this is the first report of a gout tophus originating from an intradural fascicle and without any boney attachment or underlying systemic gout. The literature is reviewed and possible pathophysiological mechanisms are discussed.

Controlled Hypercapnia Enhances Cerebral Blood Flow and Brain Tissue Oxygenation After Aneurysmal Subarachnoid Hemorrhage: Results of a Phase 1 Study.

BACKGROUND: This study investigated if cerebral blood flow (CBF) regulation by changes of the arterial partial pressure of carbon dioxide (PaCO2) can be used therapeutically to increase CBF and improve neurological outcome after subarachnoid hemorrhage (SAH). METHODS: In 12 mechanically ventilated poor-grade SAH-patients, a daily trial intervention was performed between day 4 and 14. During this intervention, PaCO2 was decreased to 30 mmHg and then gradually increased to 40, 50, and 60 mmHg in 15-min intervals by modifications of the respiratory minute volume. CBF and brain tissue oxygen saturation (StiO2) were the primary and secondary endpoints. Intracranial pressure was controlled by an external ventricular drainage. RESULTS: CBF reproducibly decreased during hyperventilation and increased to a maximum of 141 ± 53 % of baseline during hypercapnia (PaCO2 60 mmHg) on all days between day 4 and 14 after SAH. Similarly, StiO2 increased during hypercapnia. CBF remained elevated within the first hour after resetting ventilation to baseline parameters and no rebound effect was observed within this time-span. PaCO2-reactivities of CBF and StiO2 were highest between 30 and 50 mmHg and slightly decreased at higher levels. CONCLUSION: CBF and StiO2 reproducibly increased by controlled hypercapnia of up to 60 mmHg even during the period of the maximum expected vasospasm. The absence of a rebound effect within the first hour after hypercapnia indicates that an improvement of the protocol is possible. The intervention may yield a therapeutic potential to prevent ischemic deficits after aneurysmal SAH.

Diagnostic features of prematurely fused cranial sutures on plain skull X-rays.

PURPOSE: The characteristic features of prematurely fused craniosynostosis in plain radiographs have already been described in literature, but there is no clinical trial investigating the individual features of every single form of craniosynostosis. We described suture-specific characteristics as well as its frequency of appearance in plain radiographs in every different form of craniosynostosis. Intraoperative findings served as control to confirm the diagnosis. METHODS: One hundred twenty-seven children with prematurely fused cranial sutures who underwent a skull X-ray from 2008 to 2012 were investigated in the present study. In detail, 34 children with frontal, 60 with sagittal, 13 with unilateral and 14 with bilateral coronal synostosis and 3 with unilateral lambdoid craniosynostosis as well as 3 children with a bilateral lambdoid synostosis were included. RESULTS: Typical radiological characteristics in craniosynostosis exist. These features as well as its frequency in craniosynostosis in plain skull radiographs are presented. In all cases, these typical features enabled a correct diagnosis, which was confirmed by intraoperative findings. CONCLUSION: The frequency of the appearance of typical features is listed and may serve as a "mental internal check list" in the radiological approach to craniosynostosis. The study points out the value of plain skull X-rays as it enabled proper diagnosis in all investigated 127 cases.

Trauma- and distress-associated mental illness symptoms in close relatives of patients with severe traumatic brain injury and high-grade subarachnoid hemorrhage.

BACKGROUND: Close relatives (CR) of patients with severe traumatic brain injury (TBI) and high-grade subarachnoid hemorrhage (SAH) suffer extraordinary distress during the treatment: Distress may lead to persisting mental illness symptoms within the spectrum of post-traumatic stress disorder (PTSD), anxiety disorders, and depression. The primary goal of this study was to determine the prevalence and severity of these symptoms in CR. The secondary goal was identification of associated factors. METHOD: Standardized interviews were conducted with 53 CR (mean age of 57.7 ± 11.4 years) of patients with TBI °III (n = 27) and high-grade SAH H&H °III-V (n = 26) between 5 and 15 months after the event. The interviews contained a battery of surveys to quantify symptoms of PTSD, anxiety disorders, and depression, i.e., Impact of Event Scale (IES-R), 36-item Short-Form General Health Survey (SF-36), and Hospital Anxiety and Depression Scale (HADS). Fixed and modifiable possibly influencing factors were correlated. RESULTS: Twenty-eight CR (53 %) showed IES-R scores indicating a probable diagnosis of PTSD. Twenty-five CR (47 %) showed an increased anxiety score and 18 (34 %) an increased depression score using HADS. Mean physical component summary of SF-36 was not abnormal (49.1 ± 9.1), whereas mean mental component summary was under average (41.0 ± 13.2), indicating a decreased quality of life caused by mental effects. Perception of the interaction quality with the medical staff and involvement into medical decisions correlated negatively with severity of mental illness symptoms. Evasive coping strategies were highly significantly associated with symptoms. CONCLUSIONS: This study quantifies an extraordinarily high prevalence of mental illness symptoms in CR of patients with critical acquired brain injury due to SAH and TBI. Modifiable factors were associated with severity of mental illness symptoms. Prospective studies testing efficiency of early psychotherapeutic interventions are needed.

Intraoperative 3D rotational angiography: an emergency tool for the diagnosis of intracranial aneurysms.

It was the objective of this report to present a case of recurrent aneurysmal subarachnoid hemorrhage (SAH) and intracerebral hemorrhage (ICH) in which an MCA aneurysm was detected by 3D rotational fluoroscopy in an emergency situation. A 44-year-old woman was admitted from an external department after repeated SAH and temporal ICH. Due to progressive anisocoria and cardiocirculatory instability, she was transferred to the operating room without angiography. After a 3D rotational fluoroscopy baseline scan, another scan with 50 ml of iodine contrast agent was performed. The Digital Imaging and Communications in Medicine (DICOM) data sets were subtracted and reconstructed using the OsiriX® free imaging software. No adverse effect was observed during and after the administration of the contrast agent. The entire procedure from positioning of the fluoroscope to the production of utilizable 3D images was completely integrated into the surgical workflow with an image acquisition time of 2 × 24 s. The configuration of the aneurysm, the aneurysm-carrying vessel, and the distal vessel anatomy were well assessable. This technique quickly supplies images at adequate quality to assess the configuration of an intracranial aneurysm and is a useful diagnostic tool if the patient's critical condition prohibits aneurysm diagnostics by angiography or CT angiography.

Value of transcranial Doppler, perfusion-CT and neurological evaluation to forecast secondary ischemia after aneurysmal SAH.

INTRODUCTION: This study was conducted to prospectively evaluate the diagnostic value of detailed neurological evaluation, transcranial Doppler sonography (TCD) and Perfusion-CT (PCT) to predict delayed vasospasm (DV) and delayed cerebral infarction (DCI) within the following 3 days in patients with aneurysmal subarachnoid hemorrhage (SAH). METHODS: A total of 61 patients with aneurysmal SAH were included in the study. All patients were amenable for neurological evaluation throughout the critical phase to develop secondary ischemia after SAH. The neurological status was assessed three times a day according to a detailed examination protocol. Mean flow velocities (MFV) in intracranial vessel trunks were measured daily by TCD. Native CT and PCT were routinely acquired at 3-day intervals and, in addition, whenever it was thought to be of diagnostic relevance. The predictive values of abnormal PCT and accelerations in TCD (MFV > 140 cm/s) to detect angiographic DV and DCI within the following 2 days were calculated and compared to the predictive value of delayed ischemic neurological deficits (DIND). RESULTS: The accuracy of TCD and PCT to predict DV or DCI was 0.65 and 0.63, respectively. In comparison, DIND predicted DV or DCI with an accuracy of 0.96. Pathological PCT findings had a higher sensitivity (0.93) and negative predictive value (0.98) than TCD (0.81 and 0.96). CONCLUSION: Neurological assessment at close intervals is the most accurate parameter to detect DV and DCI in the following 3 days. However, DIND may not be reversible. The routine acquisition of PCT in addition to daily TCD examinations seems reasonable, particularly in patients who are not amenable to a detailed neurological examination since it has a higher sensitivity and negative predictive value than TCD and leaves a lower number of undetected cases of vasospasm and infarction.

Vertebral body replacement with PEEK-cages after anterior corpectomy in multilevel cervical spinal stenosis: a clinical and radiological evaluation.

INTRODUCTION: A growing number of industrially manufactured implants have been developed in the last years for vertebral replacement in anterior cervical corpectomy and fusion (ACCF). Polyetheretherketone (PEEK)-cages are used in many centers, but outcome reports are scarce. This study assesses the clinical and radiological outcome after one- or two-level ACCF by the use of a PEEK-cage augmented by a plate-screw osteosynthesis. METHODS: A total of 21 patients received one-level (18 patients) or two-level (3 patients) ACCF by a PEEK-cage and plate-screw osteosynthesis for multilevel degenerative stenosis. The Visual Analogue Scale, Nurick Score, Neck Disability Index and European Myelopathy Score were used for clinical assessment. Radiological outcome-osseous fusion and loss of height-was evaluated by CT. RESULTS: The mean follow-up was 28 ± 12 months. In 19 patients, bony fusion was achieved after the primary operation. Graft failure that required surgical revision occurred in two patients. In these patients, osseous fusion was achieved after the second operation. Myelopathy improved significantly. The loss of height was 2.2 ± 2.3 and 5.3 ± 2.1 mm after one- and two-level ACCF, respectively. CONCLUSION: Anterior corpectomy and fusion by a PEEK-cage and plate-screw osteosynthesis resulted in clinical improvement in all patients. Bony fusion was achieved in all patients in the long run. PEEK cages are allegedly less rigid than other xenografts. Similar to those, however, their use bears the risk of early cage-dislocation and subsidence. A comparison of industrial xenografts and autologous bone implants is required to challenge the different fusion techniques.

Cultivating Ex Vivo Patient-Derived Glioma Organoids Using a Tissue Chopper.

Glioblastoma, IDH-wild type, CNS WHO grade 4 (GBM) is a primary brain tumor associated with poor patient survival despite aggressive treatment. Developing realistic ex vivo models remain challenging. Patient-derived 3-dimensional organoid (PDO) models offer innovative platforms that capture the phenotypic and molecular heterogeneity of GBM, while preserving key characteristics of the original tumors. However, manual dissection for PDO generation is time-consuming, expensive and can result in a number of irregular and unevenly sized PDOs. This study presents an innovative method for PDO production using an automated tissue chopper. Tumor samples from four GBM and one astrocytoma, IDH-mutant, CNS WHO grade 2 patients were processed manually as well as using the tissue chopper. In the manual approach, the tumor material was dissected using scalpels under microscopic control, while the tissue chopper was employed at three different angles. Following culture on an orbital shaker at 37 °C, morphological changes were evaluated using bright field microscopy, while proliferation (Ki67) and apoptosis (CC3) were assessed by immunofluorescence after 6 weeks. The tissue chopper method reduced almost 70% of the manufacturing time and resulted in a significantly higher PDOs mean count compared to the manually processed tissue from the second week onwards (week 2: 801 vs. 601, P = 0.018; week 3: 1105 vs. 771, P = 0.032; and week 4:1195 vs. 784, P < 0.01). Quality assessment revealed similar rates of tumor-cell apoptosis and proliferation for both manufacturing methods. Therefore, the automated tissue chopper method offers a more efficient approach in terms of time and PDO yield. This method holds promise for drug- or immunotherapy-screening of GBM patients.

Development of a vestibular schwannoma tumor slice model for pharmacological testing.

BACKGROUND: Our goal was to develop a 3D tumor slice model, replicating the individual tumor microenvironment and for individual pharmaceutical testing in vestibular schwannomas with and without relation to NF2. METHODS: Tissue samples from 16 VS patients (14 sporadic, 2 NF2-related) were prospectively analyzed. Slices of 350 µm thickness were cultured in vitro, and the 3D tumor slice model underwent thorough evaluation for culturing time, microenvironment characteristics, morphology, apoptosis, and proliferation rates. Common drugs - Lapatinib (10 µM), Nilotinib (20 µM), and Bevacizumab (10 µg/ml) - known for their responses in VS were used for treatment. Treatment responses were assessed using CC3 as an apoptosis marker and Ki67 as a proliferation marker. Standard 2D cell culture models of the same tumors served as controls. RESULTS: The 3D tumor slice model accurately mimicked VS ex vivo, maintaining stability for three months. Cell count within the model was approximately tenfold higher than in standard cell culture, and the tumor microenvironment remained stable for 46 days. Pharmacological testing was feasible for up to three weeks, revealing interindividual differences in treatment response to Lapatinib and intraindividual variability in response to Lapatinib and Nilotinib. The observed effects were less pronounced in tumor slices than in standard cell culture, indicating the model's proximity to in vivo tumor biology and enhanced realism. Bevacizumab had limited impact in both models. CONCLUSION: This study introduces a 3D tumor slice model for sporadic and NF2-related VS, demonstrating stability for up to 3 months, replication of the schwannoma microenvironment, and utility for individualized pharmacological testing.

Analysis of tumor microenvironment composition in vestibular schwannomas: insights into NF2-associated and sporadic variations and their clinical correlations.

Objective: Vestibular schwannomas (VS), benign tumors stemming from the eighth cranial nerve's Schwann cells, are associated with Merlin gene mutations, inflammation, and the tumor microenvironment (TME), influencing tumor initiation, maintenance, and potential neural dysfunction. Understanding TME composition holds promise for systemic therapeutic interventions, particularly for NF2-related schwannomatosis. Methodology: A retrospective analysis of paraffin-embedded tissue from 40 patients (2013-2020), evenly divided by neurofibromatosis type 2 status, with further stratification based on magnetic resonance imaging (MRI) progression and hearing function. Immunohistochemistry assessed TME components, including T-cell markers (CD4, CD8, CD25), NK cells (CD7), and macrophages (CD14, CD68, CD163, CCR2). Fiji software facilitated image analysis. Results: T-cell markers (CD4, CD8, CD7) exhibited low expression in VS, with no significant NF2-associated vs. sporadic distinctions. Macrophage-related markers (CD14, CD68, CD163, CCR2) showed significantly higher expression (CD14: p = 0.0187, CD68: p < 0.0001, CD163: p = 0.0006, CCR2: p < 0.0001). CCR2 and CD163 significantly differed between NF2-associated and sporadic VS. iNOS, an M1-macrophage marker, was downregulated. CD25, a regulatory T-cell marker, correlated significantly with tumor growth dynamics (p = 0.016). Discussion: Immune cells, notably monocytes and macrophages, crucially contribute to VS pathogenesis in both NF2-associated and sporadic cases. Significant differences in CCR2 and CD163 expression suggest distinct immune responses. Regulatory T-cells may serve as growth dynamic markers. These findings highlight immune cells as potential biomarkers and therapeutic targets for managing VS.

Three-dimensional analysis of positional plagiocephaly before and after molding helmet therapy in comparison to normal head growth.

OBJECTIVE: Stereophotogrammetry enables a simple and radiation free longitudinal analysis of skull asymmetries: in a three-dimensional coordinate system various distances (length, breadth, cephalic index, oblique diameters, ear shift, head circumference) can be analyzed. We also defined separate volume sections in order to further quantify the degree of asymmetry in the posterior and anterior components of both sides of the head. PATIENTS AND METHODS: In 51 infants (mean age, 6 months; SD 0.97) with positional plagiocephaly, we determined these parameters at the beginning as well as at the end of molding helmet therapy (mean therapy time 4.9 months). Thirty-seven infants without positional deformity (mean age, 6.4 months; SD 0.3) served as control group and provided data about what appears to be normal and how these parameters change during growth over a comparable period of time. RESULTS: Compared with the control group, the plagiocephalic heads were more brachycephalic, but closely approximated the normal shape under molding therapy. The striking volume difference between the left and right posterior sections in the plagiocephalic children (the mean volume of the flattened side being 21% smaller than the one on the contralateral side) improved as well (to a residual difference of mean 8%) and ended up with a value close to the control group (mean 6%). CONCLUSION: There is a broad clinical application area for stereophotogrammetry analyzing skull morphology: In plagiocephalic infants we demonstrate impressive changes of head shape under molding therapy; in normal-looking infants we describe the extent of unperceived asymmetry.