Adaption of neurosurgical resection patterns for pediatric low-grade glioma spanning two decades-Report from the German LGG-studies 1996-2018.

INTRODUCTION: Neurosurgery is considered the mainstay of treatment for pediatric low-grade glioma (LGG); the extent of resection determines subsequent stratification in current treatment protocols. Yet, surgical radicality must be balanced against the risks of complications that may affect long-term quality of life. We investigated whether this consideration impacted surgical resection patterns over time for patients of the German LGG studies. PATIENTS AND METHODS: Four thousand two hundred and seventy pediatric patients from three successive LGG studies (median age at diagnosis 7.6 years, neurofibromatosis (NF1) 14.7%) were grouped into 5 consecutive time intervals (TI1-5) for date of diagnosis and analyzed for timing and extent of first surgery with respect to tumor site, histology, NF1-status, sex, and age. RESULTS: The fraction of radiological LGG diagnoses increased over time (TI1 12.6%; TI5 21.7%), while the extent of the first neurosurgical intervention (3440/4270) showed a reduced fraction of complete/subtotal and an increase of partial resections from TI1 to TI5. Binary logistic regression analysis for the first intervention within the first year following diagnosis confirmed the temporal trends (p < 0.001) and the link with tumor site for each extent of resection (p < 0.001). Higher age is related to more complete resections in the cerebellum and cerebral hemispheres. CONCLUSIONS: The declining extent of surgical resections over time was unrelated to patient characteristics. It paralleled the evolution of comprehensive treatment algorithms; thus, it may reflect alignment of surgical practice to recommendations in respect to age, tumor site, and NF1-status integrated as such into current treatment guidelines. Further investigations are needed to understand how planning, performance, or tumor characteristics impact achieving surgical goals.

A multi-institutional series of a novel, recurrent TRIM24::MET fusion-driven infant-type hemispheric glioma reveals significant clinico-pathological heterogeneity.

Within the past decade, incremental integration of molecular characteristics into the classification of central nervous system neoplasms increasingly facilitated precise diagnosis and advanced stratification, beyond potentially providing the foundation for advanced targeted therapies. We report a series of three cases of infant-type hemispheric glioma (IHG) involving three infants diagnosed with neuroepithelial tumors of the cerebral hemispheres harboring a novel, recurrent TRIM24::MET fusion. Histopathology showed glial tumors with either low-grade or high-grade characteristics, while molecular characterization found an additional homozygous CDKN2A/B deletion in two cases. Two patients showed leptomeningeal dissemination, while multiple supra- and infratentorial tumor manifestations were found in one case. Following subtotal resection (two cases) and biopsy (one case), treatment intensity of adjuvant chemotherapy regimens did not reflect in the progression patterns within the reported cases. Two patients showed progression after first-line treatment, of which one patient died not responding to tyrosine kinase inhibitor cabozantinib. As the detection of a recurrent TRIM24::MET fusion expands the spectrum of renowned driving fusion genes in IHG, this comparative illustration may indicate a distinct clinico-pathological heterogeneity of tumors bearing this driver alteration. Upfront clinical trials of IHG promoting further characterization and the implementation of individualized therapies involving receptor tyrosine kinase inhibition are required.

Surgical options of chiasmatic hypothalamic glioma-a relevant part of therapy in an interdisciplinary approach for tumor control.

OBJECTIVE: The extent of resection of pediatric low-grade glioma mostly improves progression-free survival. In chiasmatic hypothalamic glioma (CHG), complete resections are limited due to the relevantly high risk of associated neurological and endocrinological deficits. Still, surgery might have its role in the framework of a multidisciplinary team (MDT) approach. We report our retrospective experience from two centers on surgical options and their impact on long-term outcomes. METHODS: Medical records of surgically treated pediatric CHG patients between 2004 and 2022 were analyzed. Patient characteristics, surgical interventions, histology, and non-surgical therapy were retrieved together with outcome measures such as visual acuity, endocrine function, and survival. RESULTS: A total of 63 patients (33 female, NF-1, n = 8) were included. Age at first diagnosis was 4.6 years (range 0.2-16.9) and cohort follow-up was 108 ± 72 months. Twenty patients were surgically treated with a biopsy and 43 patients with debulking at a median age of 6.5 years (range 0.16-16.9). Patients received a median of 2 tumor surgeries (range 1-5). Cyst drainage was accomplished in 15 patients, and 27 patients had ventriculoperitoneal shunt implantation. Non-surgical therapy was given in 69.8%. At the end of follow-up, 74.6% of patients had stable disease. The cohort had a median Karnofsky score of 90 (range 0-100). Four patients died. Hormone substitution was necessary in 30.2%, and visual acuity was impaired in 66% of patients. CONCLUSION: Pediatric CHG is a chronic disease due to overall high survival with multiple progressions. Surgical therapy remains a key treatment option offering biopsy, limited tumor-debulking, cyst fenestration, and hydrocephalus management in the framework of MDT decision-making. Team experience contributes to reducing possible deficits in this challenging cohort.

Juvenile survival of little owls decreases with snow cover.

Global environmental changes are associated with warmer average temperatures and more extreme weather events, potentially affecting wildlife population dynamics by altering demographic processes. Extreme weather events can reduce food resources and survival in all seasons of the year. Estimates of season-specific survival probabilities are therefore crucial to understand the moderating effect of extreme events on annual mortality. Here, we analysed survival probabilities of 307 radio-tracked juvenile little owls (Athene noctua) over two-week periods from fledging to their first breeding attempt in the following spring to assess the contribution of extreme weather events. Survival probabilities were typically lowest during the first weeks after fledging in summer but were moderated by seasonal extremes in winter. The duration of snow cover in winter had a strong negative effect on survival probability, while being food supplemented during the nestling stage increased survival during the first weeks after fledging in summer and ultimately led to a larger proportion of birds surviving the first year. Overall annual survival probability over the first year varied by 34.3% between 0.117 (95% credible interval 0.052-0.223) and 0.178 (0.097-0.293) depending on the severity of the winter, and was as high as 0.233 (0.127-0.373) for food-supplemented fledglings. In years with mild winters, the season with the lowest survival was the summer post-fledging period (0.508; 0.428-0.594), but in years with extensive snow cover the winter was the season with the lowest survival (0.481; 0.337-0.626). We therefore show that extreme weather events occurring in a particular season reduced the proportion of first-year survivors. Increasing extreme weather events can moderate seasonal survival probability through altering food supply of juvenile little owls either during the nestling period or in winter, with similarly large effects on annual survival and the viability of populations.

BCOR::CREBBP fusion in malignant neuroepithelial tumor of CNS expands the spectrum of methylation class CNS tumor with BCOR/BCOR(L1)-fusion.

Methylation class "CNS tumor with BCOR/BCOR(L1)-fusion" was recently defined based on methylation profiling and tSNE analysis of a series of 21 neuroepithelial tumors with predominant presence of a BCOR fusion and/or characteristic CNV breakpoints at chromosome 22q12.31 and chromosome Xp11.4. Clear diagnostic criteria are still missing for this tumor type, specially that BCOR/BCOR(L1)-fusion is not a consistent finding in these tumors despite being frequent and that none of the Heidelberger classifier versions is able to clearly identify these cases, in particular tumors with alternative fusions other than those involving BCOR, BCORL1, EP300 and CREBBP. In this study, we introduce a BCOR::CREBBP fusion in an adult patient with a right temporomediobasal tumor, for the first time in association with methylation class "CNS tumor with BCOR/BCOR(L1)-fusion" in addition to 35 cases of CNS neuroepithelial tumors with molecular and histopathological characteristics compatible with "CNS tumor with BCOR/BCOR(L1)-fusion" based on a comprehensive literature review and data mining in the repository of 23 published studies on neuroepithelial brain Tumors including 7207 samples of 6761 patients. Based on our index case and the 35 cases found in the literature, we suggest the archetypical histological and molecular features of "CNS tumor with BCOR/BCOR(L1)-fusion". We also present four adult diffuse glioma cases including GBM, IDH-Wildtype and Astrocytoma, IDH-Mutant with CREBBP fusions and describe the necessity of complementary molecular analysis in "CNS tumor with BCOR/BCOR(L1)-alterations for securing a final diagnosis.

Prognostic utility and characteristics of MIB-1 labeling index as a proliferative activity marker in childhood low-grade glioma: a retrospective observational study.

PURPOSE: The prognostic utility of MIB-1 labeling index (LI) in pediatric low-grade glioma (PLGG) has not yet conclusively been described. We assess the correlation of MIB-1 LI and tumor growth velocity (TGV), aiming to contribute to the understanding of clinical implications and the predictive value of MIB-1 LI as an indicator of proliferative activity and progression-free survival (PFS) in PLGG. METHODS: MIB-1 LI of a cohort of 172 nonependymal PLGGs were comprehensively characterized. Correlation to TGV, assessed by sequential MRI-based three-dimensional volumetry, and PFS was analyzed. RESULTS: Mean MIB-1 LI accounted for 2.7% (range: < 1-10) and showed a significant decrease to 1.5% at secondary surgery (p = .0013). A significant difference of MIB-1 LI in different histopathological types and a correlation to tumor volume at diagnosis could be shown. Linear regression analysis showed a correlation between MIB-1 LI and preoperative TGV (R2 = .55, p < .0001), while correlation to TGV remarkably decreased after incomplete resection (R2 = .08, p = .013). Log-rank test showed no association of MIB-1 LI and 5-year PFS after incomplete (MIB-1 LI > 1 vs ≤ 1%: 48 vs 46%, p = .73) and gross-total resection (MIB-1 LI > 1 vs ≤ 1%: 89 vs 95%, p = .75). CONCLUSION: These data confirm a correlation of MIB-1 LI and radiologically detectable TGV in PLGG for the first time. Compared with preoperative TGV, a crucially decreasing correlation of MIB-1 LI and TGV after surgery may result in limited prognostic capability of MIB-1 LI in PLGG.

Fitting individual-based models of spatial population dynamics to long-term monitoring data.

Generating spatial predictions of species distribution is a central task for research and policy. Currently, correlative species distribution models (cSDMs) are among the most widely used tools for this purpose. However, a fundamental assumption of cSDMs, that species distributions are in equilibrium with their environment, is rarely fulfilled in real data and limits the applicability of cSDMs for dynamic projections. Process-based, dynamic SDMs (dSDMs) promise to overcome these limitations as they explicitly represent transient dynamics and enhance spatiotemporal transferability. Software tools for implementing dSDMs are becoming increasingly available, but their parameter estimation can be complex. Here, we test the feasibility of calibrating and validating a dSDM using long-term monitoring data of Swiss red kites (Milvus milvus). This population has shown strong increases in abundance and a progressive range expansion over the last decades, indicating a nonequilibrium situation. We construct an individual-based model using the RangeShiftR modeling platform and use Bayesian inference for model calibration. This allows the integration of heterogeneous data sources, such as parameter estimates from published literature and observational data from monitoring schemes, with a coherent assessment of parameter uncertainty. Our monitoring data encompass counts of breeding pairs at 267 sites across Switzerland over 22 years. We validate our model using a spatial-block cross-validation scheme and assess predictive performance with a rank-correlation coefficient. Our model showed very good predictive accuracy of spatial projections and represented well the observed population dynamics over the last two decades. Results suggest that reproductive success was a key factor driving the observed range expansion. According to our model, the Swiss red kite population fills large parts of its current range but has potential for further increases in density. We demonstrate the practicality of data integration and validation for dSDMs using RangeShiftR. This approach can improve predictive performance compared to cSDMs. The workflow presented here can be adopted for any population for which some prior knowledge on demographic and dispersal parameters as well as spatiotemporal observations of abundance or presence/absence are available. The fitted model provides improved quantitative insights into the ecology of a species, which can greatly aid conservation and management efforts.

Case report: Solitary mass of the sciatic nerve confirmed as a primary extranodal manifestation of diffuse large B-cell lymphoma in a geriatric patient.

Background: Neoplastic lesions affecting peripheral nerves are rare in the general population and, most often, are benign peripheral nerve sheath tumors. However, a minority of lesions represent high-grade malignancies associated with a poor prognosis, such as malignant peripheral nerve sheath tumors (MPNSTs). Very rarely, these tumors represent peripheral non-nerve sheath tumors (PNNSTs), such as hematological neoplasms that impair nerve function. These can be hard to distinguish from MPNSTs and other lesions arising from the nerve itself. In the present case report, we describe a rare case of direct infiltration of nerves by tumor cells of a hematological neoplasm. Methods: We report the case of a 90-year-old woman with acute onset of right-sided foot palsy, sensory loss, and pain, caused by an extensive solitary mass of the sciatic nerve in the thigh. We present and discuss the clinical presentation, multimodal diagnostic procedures, and treatment. Results: MRI of the right thigh and the caudal pelvis revealed a contrast-enhancing lesion infiltrating the sciatic nerve. Additionally performed staging imaging was non-revealing. After multidisciplinary discussion in the neuro-oncology tumor board, a MPNST was suspected and the patient underwent radical tumor resection. However, final histopathology revealed a diffuse large B-cell lymphoma (DLBCL). The patient received adjuvant palliative local radiotherapy which led to acceptable symptom control. Conclusion: Rare PNNSTs, including extranodal manifestations of DLBCL can have similar clinical and radiological diagnostical features as PNSTs. Comprehensive diagnostic workup of contrast-enhancing lesions affecting peripheral nerves including MRI and metabolic imaging are recommended. Discussion in interdisciplinary tumor boards facilitates finding individual treatment approaches.

High Temperature Electron Diffraction on Organic Crystals: In Situ Crystal Structure Determination of Pigment Orange 34.

Small molecule structures and their applications rely on good knowledge of their atomic arrangements. However, the crystal structures of these compounds and materials, which are often composed of fine crystalline domains, cannot be determined with single-crystal X-ray diffraction. Three-dimensional electron diffraction (3D ED) is already becoming a reliable method for the structure analysis of submicrometer-sized organic materials. The reduction of electron beam damage is essential for successful structure determination and often prevents the analysis of organic materials at room temperature, not to mention high temperature studies. In this work, we apply advanced 3D ED methods at different temperatures enabling the accurate structure determination of two phases of Pigment Orange 34 (C34H28N8O2Cl2), a biphenyl pyrazolone pigment that has been industrially produced for more than 80 years and used for plastics application. The crystal structure of the high-temperature phase, which can be formed during plastic coloration, was determined at 220 °C. For the first time, we were able to observe a reversible phase transition in an industrial organic pigment in the solid state, even with atomic resolution, despite crystallites being submicrometer in size. By localizing hydrogen atoms, we were even able to detect the tautomeric state of the molecules at different temperatures. This demonstrates that precise, fast, and low-dose 3D ED measurements enable high-temperature studies the door for general in situ studies of nanocrystalline materials at the atomic level.

Intraoperative High-Resolution Color-Coded Ultrasound to Identify the Posterior Median Sulcus for Midline Myelotomy in Intramedullary Spinal Cord Surgery.

A 14-year-old boy presented with a 2-year history of slowly increasing weakness and atrophy in the right forearm and leg. Magnetic resonance imaging (MRI) revealed an intramedullary diffusely infiltrating lateralized tumor at C3-7. An extended biopsy was planned. After laminotomy and durotomy, the swollen spinal cord was noted to be rotated by 45° with the right dorsal root entry zone being in the midline. A 15 MHz linear ultrasound probe was used to identify the midline by visualizing the dorsal median sulcal vein within the midline raphe. A myelotomy was made in that zone without deterioration of somatosensory evoked potentials (SEPs) and an extended biopsy was performed. Histological examination revealed a pilocytic astrocytoma. Modern intraoperative high-resolution color-coded ultrasound enables the identification of the midline in intramedullary spinal cord lesions even when the spinal cord anatomy is distorted.

Natal legacies cause social and spatial marginalization during dispersal.

Early-life experiences can drive subsequent variation in social behaviours, but how differences among individuals emerge remains unknown. We combined experimental manipulations with GPS-tracking to investigate the pathways through which developmental conditions affect social network position during the early dispersal of wild red kites (Milvus milvus). Across 211 juveniles from 140 broods, last-hatched chicks-the least competitive-had the fewest number of peer encounters after fledging. However, when food supplemented, they had more encounters than all others. Using 4425 bird-days of GPS data, we revealed that this was driven by differential responses to competition, with less competitive individuals naturally spreading out into marginal areas, and clustering in central foraging areas when food supplemented. Our results suggest that early-life adversities can cause significant natal legacies on individual behaviour beyond independence, with potentially far-reaching consequences on the social and spatial structure of animal populations.

Trap-Door Thoracotomy and Clamshell Thoracotomy as Surgical Approaches for Neuroblastoma and Other Thoracic Tumors in Children.

Solid tumors of the cervicothoracic junction, the posterior mediastinum, or bilateral dorsal thoracic tumors represent a challenge in pediatric surgical oncology. The aim of this study was to evaluate trap-door thoracotomy and clamshell thoracotomy as surgical approaches. A single-center retrospective study of children with solid tumors in these specific localizations was performed. From 2015 to 2023, 26 children (17 girls; 9 boys) were treated at a median age of 54 months (range 8-229). Tumor resection was performed for neuroblastoma (n = 11); metastatic disease (n = 7); malignant rhabdoid tumor (n = 4); Ewing sarcoma (n = 1); inflammatory myofibroblastic tumor (n = 1); rhabdomyosarcoma (n = 1); and neurofibroma (n = 1). The surgical goal of macroscopic complete excision was achieved in all of the 14 children who underwent trap-door thoracotomy and in 11 of the 12 children who underwent clamshell thoracotomy. There were no major complications. At a median follow-up of 8 months (range 0-60), the disease was under local control or in complete remission in 66.7% of the children. In conclusion, surgical resection of solid tumors of the cervicothoracic junction in children can be performed safely and successfully with trap-door thoracotomy and with clamshell thoracotomy for posterior mediastinal or bilateral dorsal thoracic tumors.

Sex and size shape the ontogeny of partial migration.

The arrival-time hypothesis of partial seasonal migration proposes that over-winter residence is driven by reproductive benefits of early presence on the breeding grounds. Thus, it predicts increased occurrence of residence at reproductive age. In contrast, the body size hypothesis proposes age-independent benefits of residence for large individuals, who should exhibit greater winter tolerance. Despite different expectations in age patterns for the two hypotheses in long-lived partially migrant species, there is little empirical work investigating the ontogeny of migratory phenotypic expression, that is the expression of residence or migration. We investigated the influence of age, sex and body size on migratory phenotype throughout ontogeny (from first year to early adulthood) in a long-lived partially migrant species, the red kite Milvus milvus. We GPS-tracked 311 individuals tagged as juveniles and 70 individuals tagged as adults over multiple years, yielding 881 observed annual cycles. From this data, we estimated age-dependent probabilities of the transition to residence and of survival in migrants and residents using a Bayesian multistate capture-recapture model, as well as the probability of resuming migration once resident. We then calculated the resulting proportion of residents per age class. In both sexes, almost all juveniles migrated in their first winter, after which the probability of becoming resident gradually increased with age class to approximately 0.3 in adults (>3 calendar years). A size effect in third calendar year females suggests that large females adopt residence earlier in life than small females. The transition from residence back to migration only occurred with a probability of 0.15 across all resident individuals. In addition, survival was notably reduced in adult male migrants compared to adult male residents. These results are largely consistent with the arrival-time and body size hypotheses, simultaneously. Our results reveal a plastic, yet primarily directional within-individual change in migratory phenotype towards more residence with increasing age, varying between sexes and between individuals of different size. This study highlights that different individual characteristics can jointly shape the ontogeny of migratory behaviour and result in complex within-population patterns and persistence of migratory phenotypes.

The effect of intraoperative cerebral oxygen desaturations on postoperative cerebral oxygen metabolism in neonates and infants a pilot study.

INTRODUCTION: Cerebral oxygen desaturation during pediatric surgery has been associated with adverse perioperative outcomes. The aim of this pilot study was to analyze the frequency and severity of intraoperative cerebral oxygen desaturations and their impact on postoperative cerebral oxygen metabolism in neonates and infants undergoing pediatric surgery. METHODS: In a prospective pilot study, intra- and postoperative regional cerebral oxygen saturation and blood flow were measured noninvasively using a device combining laser Doppler flowmetry and white-light-spectrometry. Thirty-seven consecutive neonates and infants undergoing noncardiac surgery under general anesthesia for more than 30 min and necessity for invasive arterial blood pressure monitoring were included. Patients with pre-known congenital structural heart disease or cerebral disease were excluded. Continuously brain monitor recording was started in sedated patients before induction of anesthesia (preoperative baseline) and was completed 1 h postoperatively in the PICU in sedated, intubated, and mechanically ventilated states at the PICU (postoperative state). Baseline and postoperative state for cerebral fractional tissue oxygen extraction and approximated cerebral metabolic rate of oxygen were calculated. RESULTS: Seventeen (46%) of the 37 studied neonates and infants suffered from intraoperative periods of regional cerebral oxygen desaturation below 20% of the baseline (event group). Severity of cerebral desaturations was median 4.0%min/h [range 0.1-58.7; interquartile range [IQR] 0.99-21.29]. In the event group, the duration of surgery was significantly longer (median 135 min [range 11-260; IQR 113.5-167.0] vs median 46.5 min [range 11-180; IQR 30.5-159.3]; difference of -62.94; 95% confidence interval [CI] -105.17 to -20.71; p = .021). In the event group, cerebral fractional tissue oxygen extraction (median 0.41 [range 0.20-0.55; IQR 0.26-0.44] vs. median 0.27 [range 0.11-0.41; IQR 0.20-0.31]; difference of -0.11; 95% CI -0.17 to -0.05; p = .001) and approximated cerebral metabolic rate of oxygen (median 6.15 arbitrary unit [range 2.69-12.07; IQR 5.12-7.21] vs. median 4.14 arbitrary unit [range 1.78-7.86; IQR 3.82-6.31]; difference of -1.76; 95% CI -3.03 to -0.49; p = .009) were significantly higher and the cerebral regional oxygen saturation (median 58.99% [range 44.87-79.1; IQR 54.26-72.61] vs median 70.94% [range 57.9-86.13; IQR 67.07-76.59]; difference of 10.01; 95% CI 4.13-15.90; p = .002) significantly lower after surgery compared to the nonevent group. DISCUSSION: The increase of approximated cerebral metabolic rate of oxygen could indicate an elevated oxidative energy metabolism in the "stressed" brain, due to repair processes. The increased cerebral fractional tissue oxygen extraction fits with the decreased NIRS cerebral oxygenation. Our data suggest that an increase in cerebral oxygen metabolism was the cause. CONCLUSION: Cerebral oxygen desaturation during major surgery in neonates and infants is associated with early postoperative increased cerebral oxygen extraction and possibly increased cerebral oxygen metabolism.

Retrospective longitudinal assessment of optic nerve sheath diameter in patients with malignant glioma.

INTRODUCTION: Glioblastoma (GBM) is a tumor with rapid growth and a possible relationship to elevated intracranial pressure (ICP). High ICP may not always be associated with clinical signs. A non-invasive technique for assessment of ICP is measuring the optic nerve sheath diameter (ONSD). Identifying patients who need immediate intervention is of importance in neuro-oncological care. The goal of this study is to assess the available magnetic resonance imaging (MRI) of patients with GBM with respect to pre- and postoperative ONSD. METHODS AND MATERIALS: Retrospective data analysis was performed on all patients operated for GBM at a tertiary care center between 2010 and 2020. Two pre and one postoperative MRI had to be available. Clinical data and ONSD at multiple time points were analyzed and correlated, as well as preoperative volumetrics. RESULTS: Sixty-seven patients met the inclusion criteria. Clinical signs of elevated ICP were seen in 25.4% (n = 17), while significant perifocal edema was present in 67.2% (n = 45) of patients. Clinical signs of preoperatively elevated ICP were associated with significantly elevated ONSD at diagnosis (p < 0.001) as well as preoperative tumor volume (p < 0.001). Significant perifocal edema at the time of diagnosis was associated with elevated ONSD (p = 0.029) and higher tumor volume (p = 0.003). In patients with significant edema, ONSD increased significantly between preoperative MRIs (p = 0.003/005). In patients with clinical signs of raised ICP, ONSD also increased, whereas it was stable in asymptomatic patients (yes: 5.01+/-4.17 to 5.83+/-0.55 mm, p = 0.010, no: 5.17+/-0.46 mm to 5.38+/-0.41 mm, p = 0.81). A significant increase of ONSD from diagnosis to preoperative MRI and a significant decrease until 3 months postoperatively were observed (p < 0.001). CONCLUSIONS: ONSD might help identify high ICP in patients with GBM. In this first-of-its kind study, we observed a significant increase of ONSD preoperatively, likely associated with edema. Postoperatively, ONSD decreased significantly until 3 months after surgery and increased again at 12 months. Further prospective data collection is warranted.

Generation of patient-derived pediatric pilocytic astrocytoma in-vitro models using SV40 large T: evaluation of a modeling workflow.

PURPOSE: Although pediatric low-grade gliomas (pLGG) are the most common pediatric brain tumors, patient-derived cell lines reflecting pLGG biology in culture are scarce. This also applies to the most common pLGG subtype pilocytic astrocytoma (PA). Conventional cell culture approaches adapted from higher-grade tumors fail in PA due to oncogene-induced senescence (OIS) driving tumor cells into arrest. Here, we describe a PA modeling workflow using the Simian Virus large T antigen (SV40-TAg) to circumvent OIS. METHODS: 18 pLGG tissue samples (17 (94%) histological and/or molecular diagnosis PA) were mechanically dissociated. Tumor cell positive-selection using A2B5 was perfomed in 8/18 (44%) cases. All primary cell suspensions were seeded in Neural Stem Cell Medium (NSM) and Astrocyte Basal Medium (ABM). Resulting short-term cultures were infected with SV40-TAg lentivirus. Detection of tumor specific alterations (BRAF-duplication and BRAF V600E-mutation) by digital droplet PCR (ddPCR) at defined time points allowed for determination of tumor cell fraction (TCF) and evaluation of the workflow. DNA-methylation profiling and gene-panel sequencing were used for molecular profiling of primary samples. RESULTS: Primary cell suspensions had a mean TCF of 55% (+/- 23% (SD)). No sample in NSM (0/18) and ten samples in ABM (10/18) were successfully transduced. Three of these ten (30%) converted into long-term pLGG cell lines (TCF 100%), while TCF declined to 0% (outgrowth of microenvironmental cells) in 7/10 (70%) cultures. Young patient age was associated with successful model establishment. CONCLUSION: A subset of primary PA cultures can be converted into long-term cell lines using SV40-TAg depending on sample intrinsic (patient age) and extrinsic workflow-related (e.g. type of medium, successful transduction) parameters. Careful monitoring of sample-intrinsic and extrinsic factors optimizes the process.

[Interdisciplinary networks in diseases of peripheral nerves-Exemplified by the Tübingen nerve team]. / Interdisziplinäre Netzwerke bei Erkrankungen der peripheren Nerven ­ am Beispiel des Tübinger Nerve Teams.

BACKGROUND: Nerve damage can be autoimmune inflammatory, metabolic or traumatic, among others, and can be difficult to differentiate. OBJECTIVE: What are the advantages of interdisciplinary networks and how do they work? MATERIAL AND METHOD: Field report with case presentation from the University Hospital Tübingen in cooperation with the BG Accident Clinic Tübingen. CONCLUSION: Interdisciplinary networks improve the care of our patients and also serve as regular multidisciplinary continuing education.

Multimodal Therapy with Consolidating Haploidentical Stem Cell Transplantation and Dinutuximab Beta for Patients with High-Risk Neuroblastoma and Central Nervous System Relapse.

Despite highly intensive multimodality treatment regimens, the prognosis of patients with high-risk neuroblastoma (HRNB) and central nervous system (CNS) relapse remains poor. We retrospectively reviewed data from 13 patients with HRNB and CNS relapse who received multimodal therapy with consolidating haploidentical stem cell transplantation (haplo-SCT) followed by dinutuximab beta ± subcutaneous interleukin-2 (scIL-2). Following individual relapse treatment, patients aged 1-21 years underwent haplo-SCT with T/B-cell-depleted grafts followed by dinutuximab beta 20 mg/m2/day × 5 days for 5-6 cycles. If a response was demonstrated after cycle 5 or 6, patients received up to nine treatment cycles. After haplo-SCT, eight patients had a complete response, four had a partial response, and one had a stable disease. All 13 patients received ≥3 cycles of immunotherapy. At the end of the follow-up, 9/13 patients (66.7%) demonstrated complete response. As of July 2023, all nine patients remain disease-free, with a median follow-up time of 5.1 years since relapse. Estimated 5-year event-free and overall survival rates were 55.5% and 65.27%, respectively. Dinutuximab beta ± scIL-2 following haplo-SCT is a promising treatment option with a generally well-tolerated safety profile for patients with HRNB and CNS relapse.

Turning tables: food availability shapes dynamic aggressive behaviour among asynchronously hatching siblings in red kites Milvus milvus.

Aggression represents the backbone of dominance acquisition in several animal societies, where the decision to interact is dictated by its relative cost. Among siblings, such costs are weighted in the light of inclusive fitness, but how this translates to aggression patterns in response to changing external and internal conditions remains unclear. Using a null-model-based approach, we investigate how day-to-day changes in food provisioning affect aggression networks and food allocation in growing red kite (Milvus milvus) nestlings, whose dominance rank is largely dictated by age. We show that older siblings, irrespective of age, change from targeting only close-aged peers (close-competitor pattern) when food provisioning is low, to uniformly attacking all other peers (downward heuristic pattern) as food conditions improve. While food allocation was generally skewed towards the older siblings, the youngest sibling in the nest increased its probability of accessing food as more was provisioned and as downward heuristic patterns became more prominent, suggesting that different aggression patterns allow for catch-up growth after periods of low food. Our results indicate that dynamic aggression patterns within the nest modulate environmental effects on juvenile development by influencing the process of dominance acquisition and potentially impacting the fledging body condition, with far-reaching fitness consequences.