55-Year Follow-Up of the First Adult Patient With Craniopharyngioma Treated With Gamma Knife Radiosurgery.

In May 1968, Lars Leksell and Erik-Olof Backlund achieved a pioneering breakthrough by performing the first Gamma Knife radiosurgery (GKRS) on a craniopharyngioma (CP). Today, more than 50 years later, this patient remains under continuous monitoring, providing the longest documented follow-up of a GKRS-treated CP. This case report provides a complete record of the patient's preoperative presentation, surgical assessment, GKRS, and an extensive long-term follow-up with multiple interventions. The investigation involved analysis of archived and digitalized patient records and radiological images. The patient was a 21-year-old female who presented with amenorrhea and low levels of gonadotropins. Pneumoencephalography showed a calcified 2 × 2.5 cm mass located in the suprasellar region, indicative of a CP. Subsequent stereotactic puncture confirmed a predominantly solid nature of the CP. Given the size and composition of the tumor, the surgical team opted for GKRS. Dose planning was performed manually, with coordinates determined using Leksell's stereotactic frame. The tumor was targeted with a total dose of 50 Gy using 179 beams of 60Co. Over the subsequent 55 years, the patient underwent radiological and clinical follow-ups. Throughout this period, 4 cystic tumor recurrences occurred and were managed by stereotactic puncture and Yttrium-90 instillation radiotherapy. The solid component remained stable without repeated GKRS. The patient suffered lateral quadrant anopsia and endocrinological deficits, necessitating pharmaceutical intervention. Despite these challenges, the patient is still living an active life at age 76 years. This case stands as historic evidence of long-term safety and efficacy of GKRS for CPs.

Longitudinal molecular profiling elucidates immunometabolism dynamics in breast cancer.

Although metabolic reprogramming within tumor cells and tumor microenvironment (TME) is well described in breast cancer, little is known about how the interplay of immune state and cancer metabolism evolves during treatment. Here, we characterize the immunometabolic profiles of tumor tissue samples longitudinally collected from individuals with breast cancer before, during and after neoadjuvant chemotherapy (NAC) using proteomics, genomics and histopathology. We show that the pre-, on-treatment and dynamic changes of the immune state, tumor metabolic proteins and tumor cell gene expression profiling-based metabolic phenotype are associated with treatment response. Single-cell/nucleus RNA sequencing revealed distinct tumor and immune cell states in metabolism between cold and hot tumors. Potential drivers of NAC based on above analyses were validated in vitro. In summary, the study shows that the interaction of tumor-intrinsic metabolic states and TME is associated with treatment outcome, supporting the concept of targeting tumor metabolism for immunoregulation.

The prevalence of imposter syndrome among neurosurgeons in Europe: An EANS YNC survey.

Introduction: Imposter syndrome (IS), characterized by persistent doubts about one's abilities and fear of exposure as a fraud, is a prevalent psychological condition, particularly impacting physicians. In neurosurgery, known for its competitiveness and demands, the prevalence of IS remains high. Research question: Recognizing the limited literature on IS within the neurosurgical community, this European survey aimed to determine its prevalence among young neurosurgeons and identify associated factors. Material and methods: The survey, conducted by the Young Neurosurgeon Committee of the European Association of Neurosurgical Societies, gathered responses from 232 participants. The survey included demographics, the Clance Imposter Phenomenon Survey (CIPS), and an analysis of potential compensatory mechanisms. Results: Nearly 94% of respondents exhibited signs of IS, with the majority experiencing moderate (36.21%) or frequent (40.52%) symptoms. Analyses revealed associations between IS and factors such as level of experience, sex, and board-certification. Discussion and conclusion: The findings suggest a significant prevalence of IS among young neurosurgeons, with notable associations with sex and level of experience. Compensatory mechanisms, such as working hours, article reading, and participation in events, did not show significant correlations with IS. Notably, male sex emerged as an independent protective factor against frequent/intense IS, while reading more than five articles per week was identified as a risk factor. The identification of protective and risk factors, particularly the influence of gender and reading habits, contributes valuable insights for developing targeted interventions to mitigate IS and improve the well-being of neurosurgeons.

The nexus of nuclear envelope dynamics, circular economy and cancer cell pathophysiology.

The nuclear envelope (NE) is a critical component in maintaining the function and structure of the eukaryotic nucleus. The NE and lamina are disassembled during each cell cycle to enable an open mitosis. Nuclear architecture construction and deconstruction is a prime example of a circular economy, as it fulfills a highly efficient recycling program bound to continuous assessment of the quality and functionality of the building blocks. Alterations in the nuclear dynamics and lamina structure have emerged as important contributors to both oncogenic transformation and cancer progression. However, the knowledge of the NE breakdown and reassembly is still limited to a fraction of participating proteins and complexes. As cancer cells contain highly diverse nuclei in terms of DNA content, but also in terms of nuclear number, size, and shape, it is of great interest to understand the intricate relationship between these nuclear features in cancer cell pathophysiology. In this review, we provide insights into how those NE dynamics are regulated, and how lamina destabilization processes may alter the NE circular economy. Moreover, we expand the knowledge of the lamina-associated domain region by using strategic algorithms, including Artificial Intelligence, to infer protein associations, assess their function and location, and predict cancer-type specificity with implications for the future of cancer diagnosis, prognosis and treatment. Using this approach we identified NUP98 and MECP2 as potential proteins that exhibit upregulation in Acute Myeloid Leukemia (LAML) patients with implications for early diagnosis.

Modulator of TMB-associated immune infiltration (MOTIF) predicts immunotherapy response and guides combination therapy.

Patients with high tumor mutational burden (TMB) levels do not consistently respond to immune checkpoint inhibitors (ICIs), possibly because a high TMB level does not necessarily result in adequate infiltration of CD8+ T cells. Using bulk ribonucleic acid sequencing (RNA-seq) data from 9311 tumor samples across 30 cancer types, we developed a novel tool called the modulator of TMB-associated immune infiltration (MOTIF), which comprises genes that can determine the extent of CD8+ T cell infiltration prompted by a certain TMB level. We confirmed that MOTIF can accurately reflect the integrity and defects of the cancer-immunity cycle. By analyzing 84 human single-cell RNA-seq datasets from 32 types of solid tumors, we revealed that MOTIF can provide insights into the diverse roles of various cell types in the modulation of CD8+ T cell infiltration. Using pretreatment RNA-seq data from 13 ICI-treated cohorts, we validated the use of MOTIF in predicting CD8+ T cell infiltration and ICI efficacy. Among the components of MOTIF, we identified EMC3 as a negative regulator of CD8+ T cell infiltration, which was validated via in vivo studies. Additionally, MOTIF provided guidance for the potential combinations of programmed death 1 blockade with certain immunostimulatory drugs to facilitate CD8+ T cell infiltration and improve ICI efficacy.

Chromatin damage generated by DNA intercalators leads to degradation of RNA Polymerase II.

In cancer therapy, DNA intercalators are mainly known for their capacity to kill cells by inducing DNA damage. Recently, several DNA intercalators have attracted much interest given their ability to inhibit RNA Polymerase I transcription (BMH-21), evict histones (Aclarubicin) or induce chromatin trapping of FACT (Curaxin CBL0137). Interestingly, these DNA intercalators lack the capacity to induce DNA damage while still retaining cytotoxic effects and stabilize p53. Herein, we report that these DNA intercalators impact chromatin biology by interfering with the chromatin stability of RNA polymerases I, II and III. These three compounds have the capacity to induce degradation of RNA polymerase II and they simultaneously enable the trapping of Topoisomerases TOP2A and TOP2B on the chromatin. In addition, BMH-21 also acts as a catalytic inhibitor of Topoisomerase II, resembling Aclarubicin. Moreover, BMH-21 induces chromatin trapping of the histone chaperone FACT and propels accumulation of Z-DNA and histone eviction, similarly to Aclarubicin and CBL0137. These DNA intercalators have a cumulative impact on general transcription machinery by inducing accumulation of topological defects and impacting nuclear chromatin. Therefore, their cytotoxic capabilities may be the result of compounding deleterious effects on chromatin homeostasis.

Increased Incidence and Mortality of Civilian Penetrating Traumatic Brain Injury in Sweden: A Single-Center Registry-Based Study.

BACKGROUND: Penetrating trauma to the head and neck has increased during the past decade in Sweden. The aim of this study was to characterize these injuries and evaluate the outcomes for patients treated at a tertiary trauma center. METHODS: Swedish trauma registry data were extracted on patients with head and neck injuries admitted to Karolinska University Hospital (Stockholm, Sweden) between 2011 and 2019. Outcome information was extracted from hospital records, with the primary endpoints focusing on the physiological outcome measures and the secondary endpoints on the surgical and radiological outcomes. RESULTS: Of 1436 patients with penetrating trauma, 329 with penetrating head and neck injuries were identified. Of the 329 patients, 66 (20%) had suffered a gunshot wound (GSW), 240 (73%) a stab wound (SW), and 23 (7%) an injury from other trauma mechanisms (OTMs). The median age for the corresponding 3 groups of patients was 25, 33, and 21 years, respectively. Assault was the primary intent, with 54 patients experiencing GSWs (81.8%) and 158 SWs (65.8%). Patients with GSWs had more severe injuries, worse admission Glasgow coma scale, motor, scores, and a higher intubation rate at the injury site. Most GSW patients underwent major surgery (59.1%) as the initial procedure and were more likely to have intracranial hemorrhage (21.2%). The 30-day mortality was 45.5% (n = 30) for GSWs, 5.4% (n = 13) for SWs, and 0% (n = 0) for OTMs. There was an annual increase in the incidence and mortality for GSWs and SWs. CONCLUSIONS: Between 2011 and 2019, an increasing annual trend was found in the incidence and mortality from penetrating head and neck trauma in Stockholm, Sweden. GSW patients experienced more severe injuries and intracranial hemorrhage and underwent more surgical interventions compared with patients with SWs and OTMs.

APOBEC3 as a driver of genetic intratumor heterogeneity.

Our recent study revealed that APOBEC3B is upregulated during the preinvasive stages of non-small cell lung cancer and breast cancer. In addition to its role in mediating single nucleotide variants, we propose that APOBEC3 promotes copy number intratumor heterogeneity prior to invasion, providing a substrate for cancer evolution.

NAD+ regulates nucleotide metabolism and genomic DNA replication.

The intricate orchestration of enzymatic activities involving nicotinamide adenine dinucleotide (NAD+) is essential for maintaining metabolic homeostasis and preserving genomic integrity. As a co-enzyme, NAD+ plays a key role in regulating metabolic pathways, such as glycolysis and Kreb's cycle. ADP-ribosyltransferases (PARPs) and sirtuins rely on NAD+ to mediate post-translational modifications of target proteins. The activation of PARP1 in response to DNA breaks leads to rapid depletion of cellular NAD+ compromising cell viability. Therefore, the levels of NAD+ must be tightly regulated. Here we show that exogenous NAD+, but not its precursors, has a direct effect on mitochondrial activity. Short-term incubation with NAD+ boosts Kreb's cycle and the electron transport chain and enhances pyrimidine biosynthesis. Extended incubation with NAD+ results in depletion of pyrimidines, accumulation of purines, activation of the replication stress response and cell cycle arrest. Moreover, a combination of NAD+ and 5-fluorouridine selectively kills cancer cells that rely on de novo pyrimidine synthesis. We propose an integrated model of how NAD+ regulates nucleotide metabolism, with relevance to healthspan, ageing and cancer therapy.

The use of advanced technology for preoperative planning in cranial surgery - A survey by the EANS Young Neurosurgeons Committee.

Introduction: Technological advancements provided several preoperative tools allowing for precise preoperative planning in cranial neurosurgery, aiming to increase the efficacy and safety of surgery. However, little data are available regarding if and how young neurosurgeons are trained in using such technologies, how often they use them in clinical practice, and how valuable they consider these technologies. Research question: How frequently these technologies are used during training and clinical practice as well as to how their perceived value can be qualitatively assessed. Materials and methods: The Young Neurosurgeons' Committee (YNC) of the European Association of Neurosurgical Societies (EANS) distributed a 14-items survey among young neurosurgeons between June 1st and August 31st, 2022. Results: A total of 441 responses were collected. Most responders (42.34%) received "formal" training during their residency. Planning techniques were used mainly in neuro-oncology (90.86%), and 3D visualization of patients' DICOM dataset using open-source software was the most frequently used (>20 times/month, 20.34% of responders). Software for 3D visualization of patients' DICOM dataset was the most valuable technology, especially for planning surgical approach (42.03%). Conversely, simulation based on augmented/mixed/virtual reality was considered the less valuable tool, being rated below sufficiency by 39.7% of responders. Discussion and conclusion: Training for using preoperative planning technologies in cranial neurosurgery is provided by neurosurgical residency programs. Software for 3D visualization of DICOM datasets is the most valuable and used tool, especially in neuro-oncology. Interestingly, simulation tools based on augmented/virtual/mixed reality are considered less valuable and, therefore, less used than other technologies.

Autophagy-mediated control of ribosome homeostasis in oncogene-induced senescence.

Oncogene-induced senescence (OIS) is a persistent anti-proliferative response that acts as a barrier against malignant transformation. During OIS, cells undergo dynamic remodeling, which involves alterations in protein and organelle homeostasis through autophagy. Here, we show that ribosomes are selectively targeted for degradation by autophagy during OIS. By characterizing senescence-dependent alterations in the ribosomal interactome, we find that the deubiquitinase USP10 dissociates from the ribosome during the transition to OIS. This release of USP10 leads to an enhanced ribosome ubiquitination, particularly of small subunit proteins, including lysine 275 on RPS2. Both reinforcement of the USP10-ribosome interaction and mutation of RPS2 K275 abrogate ribosomal delivery to lysosomes without affecting bulk autophagy. We show that the selective recruitment of ubiquitinated ribosomes to autophagosomes is mediated by the p62 receptor. While ribophagy is not required for the establishment of senescence per se, it contributes to senescence-related metabolome alterations and facilitates the senescence-associated secretory phenotype.

A fluorophore-conjugated reagent enabling rapid detection, isolation and live tracking of senescent cells.

Cellular senescence is a stress-response mechanism implicated in various physiological processes, diseases, and aging. Current detection approaches have partially addressed the issue of senescent cell identification in clinical specimens. Effective methodologies enabling precise isolation or live tracking of senescent cells are still lacking. In-depth analysis of truly senescent cells is, therefore, an extremely challenging task. We report (1) the synthesis and validation of a fluorophore-conjugated, Sudan Black-B analog (GLF16), suitable for in vivo and in vitro analysis of senescence by fluorescence microscopy and flow cytometry and (2) the development and application of a GLF16-carrying micelle vector facilitating GLF16 uptake by living senescent cells in vivo and in vitro. The compound and the applied methodology render isolation of senescent cells an easy, rapid, and precise process. Straightforward nanocarrier-mediated GLF16 delivery in live senescent cells comprises a unique tool for characterization of senescence at an unprecedented depth.

[Treatment of intracerebral hemorrhage - An overview]. / Modern handläggning av intracerebralt hematom.

Intracerebral hemorrhage (ICH) carries the highest mortality and morbidity of all stroke types. Although small vessel disease accounts for the majority of ICH, there is a broad spectrum of other etiologies. Modern imaging techniques are a cornerstone of the work-up process. The goals of acute management are to prevent hematoma expansion, stabilize and prevent failure of vital functions, and establish the cause of ICH. ICH expansion can be alleviated by rapid correction of any contributing coagulopathy and antihypertensive treatment. Early prognostication within 24 hours after onset is imprecise. For this reason, international guidelines recommend postponing decision-making on withdrawal or limitation of care until at least the second full day of hospitalization. Indications for intensive care differ from those for neurosurgical treatment and should be assessed separately. Neurosurgical treatment is commonly recommended to reduce mortality in the presence of hydrocephalus or infratentorial hematomas with significant mass effect. In deteriorating patients with supratentorial ICH, surgical treatment can be considered as a life-saving treatment on an individual basis, with consideration given to anatomical location, level of consciousness and medical history.

Long-term follow up of patients with WHO grade 2 oligodendroglioma.

PURPOSE: Since the introduction of the molecular definition of oligodendrogliomas based on isocitrate dehydrogenase (IDH)-status and the 1p19q-codeletion, it has become increasingly evident how this glioma entity differs much from other diffuse lower grade gliomas and stands out with longer survival and often better responsiveness to adjuvant therapy. Therefore, apart from using a molecular oligodendroglioma definition, an extended follow-up time is necessary to understand the nature of this slow growing, yet malignant condition. The aim of this study was to describe the long-term course of the oligodendroglioma disease in a population-based setting and to determine which factors affect outcome in terms of survival. METHODS: All adults with WHO-grade 2 oligodendrogliomas with known 1p19q-codeletion from five Scandinavian neurosurgical centers and with a follow-up time exceeding 5 years, were analyzed regarding survival and factors potentially affecting survival. RESULTS: 126 patients diagnosed between 1998 and 2016 were identified. The median follow-up was 12.0 years, and the median survival was 17.8 years (95% CI 16.0-19.6). Factors associated with shorter survival in multivariable analysis were age (HR 1.05 per year; CI 1.02-1.08, p < 0.001), tumor diameter (HR 1.05 per millimeter; CI 1.02-1.08, p < 0.001) and poor preoperative functional status (KPS < 80) (HR 4.47; CI 1.70-11.78, p = 0.002). In our material, surgical strategy was not associated with survival. CONCLUSION: Individuals with molecularly defined oligodendrogliomas demonstrate long survival, also in a population-based setting. This is important to consider for optimal timing of therapies that may cause long-term side effects. Advanced age, large tumors and poor function before surgery are predictors of shorter survival.

Increased risk for ex-vacuo ventriculomegaly with leukoencephalopathy (EVL) in whole brain radiation therapy and repeat radiosurgery treated brain metastasis patients.

INTRODUCTION: Cerebral atrophy with leukoencephalopathy is a known morbidity after whole brain radiation therapy (WBRT), resulting in ex-vacuo ventriculomegaly with leukoencephalopathy (EVL). Here we studied the correlation between WBRT, stereotactic radiosurgery (SRS), and risk for EVL in brain metastases patients. METHODS: In a retrospective study, we identified 195 patients (with 1,018 BM) who underwent SRS for BM (2007-2017) and had > 3 months of MRI follow-up. All patients who underwent ventriculoperitoneal shunting were excluded. Cerebral atrophy was measured by ex-vacuo-ventriculomegaly, defined based on Evans' criteria. Demographic and clinical variables were analyzed using logistic regression models. RESULTS: Ex-vacuo ventriculomegaly was observed on pre-radiosurgery imaging in 29.7% (58/195) of the study cohort. On multivariate analysis, older age was the only variable associated with pre-radiosurgery ventriculomegaly. Of the 137 patients with normal ventricular size before radiosurgery, 27 (19.7 %) developed ex-vacuo ventriculomegaly and leukoencephalopathy (EVL) post-SRS. In univariate analysis, previous whole brain radiation therapy was the main factor associated with increased risk for developing EVL (OR = 5.08, p < 0.001). In bivariate models that included prior receipt of WBRT, both the number of SRS treatments (OR = 1.499, p = 0.025) and WBRT (OR = 11.321, p = 0.003 were independently associated with increased EVL risk. CONCLUSIONS: While repeat radiosurgery contributes to the risk of EVL in BM patients, this risk is ∼20-fold lower than that associated with WBRT.

High-resolution bioenergetics correlates the length of continuous protonatable diaminoethane motif of four-armed oligo(ethanamino)amide transfectants to cytotoxicity.

Recent clinical success with Onpattro and cationic ionizable lipid nanoparticle-based mRNA vaccines has rejuvenated research in the design and engineering of broader synthetic cationic vectors for nucleic acid compaction and transfection. However, perturbation of metabolic processes and cytotoxicity are still of concern with synthetic cationic vectors. Here, through an integrated bioenergetic and biomembrane integrity probing in three different human cell lines we reveal the dynamic effect of a library of sequence-defined four-arm oligo(ethanamino)amide transfectant on cell homeostasis, and identify metabolically safe building units over wide concentration ranges. The results show differential effects of the oligo(ethanamino)amide structure of comparable molecular weight on cell energetics. The severity of polycation effect on bioenergetic crisis follows with the length of continuous protonatable diaminoethane motif in the ascending order of glutaryl-triethylene tetramine, succinyl-tetraethylene pentamine and succinyl-pentaethylene hexamine. We further identify oligomeric structures that do not induce bioenergetic crisis even at high concentrations. Finally, transfection studies with a library of polyplexes carrying a reporter gene show no correlation between transfection efficiency and cytotoxicity. These observations demonstrate the usefulness of integrated high-resolution respirometry and plasma membrane integrity probing as a highly sensitive medium-throughput screening strategy for identification and selection of safe building units for transfectant engineering.

Higher Human Cytomegalovirus (HCMV) Specific IgG Antibody Levels in Plasma Samples from Patients with Metastatic Brain Tumors Are Associated with Longer Survival.

Background: Human cytomegalovirus (HCMV) has been detected in tissue samples from patients with glioblastoma but little is known about the systemic immunological response to HCMV in these patients. Objectives: To investigate the presence and clinical significance of HCMV antibodies levels in plasma samples obtained from patients with brain tumors. Materials and Methods: HCMV-specific IgG and IgM antibody levels were determined in 59 plasma samples collected from brain tumor patients included in a prospective study and in 114 healthy individuals. We examined if the levels of HCMV specific antibodies varied in patients with different brain tumor diagnoses compared to healthy individuals, and if antibody levels were predictive for survival time. Results: HCMV specific IgG antibodies were detected by ELISA in 80% and 89% of patients with GBM and astrocytoma grades II-III, respectively, in all samples (100%) from patients with secondary GBM and brain metastases, as well as in 80% of healthy donors (n = 114). All plasma samples were negative for HCMV-IgM. Patients with brain metastases who had higher plasma HCMV-IgG titers had longer survival times (p = 0.03). Conclusions: HCMV specific IgG titers were higher among all brain tumor patient groups compared with healthy donors, except for patients with secondary GBM. Higher HCMV specific IgG levels in patients with brain metastases but not in patients with primary brain tumors were associated with prolonged survival time.

Preoperative Prognostic Index for Patients with Brain Metastases-A Population-Based Multi-Centre Study.

BACKGROUND: Brain metastases (BM) are common in cancer patients and are associated with high morbidity and mortality. Surgery is an option, but the optimal selection of patients for surgery is challenging and controversial. Current prognostication tools are not ideal for preoperative prognostication. By using a reference population (derivation data set) and two external populations (validation data set) of patients who underwent surgery for BM, we aimed to create and validate a preoperative prognostic index. METHODS: The derivation data set consists of 590 patients who underwent surgery for BM (2011-2018) at Oslo University Hospital. We identified variables associated with survival and created a preoperative prognostic index with four prognostic groups, which was validated on patients who underwent surgery for BM at Karolinska University Hospital and St. Olavs University Hospital during the same time period. To reduce over-fitting, we adjusted the index in accordance with our findings. RESULTS: 438 patients were included in the validation data set. The preoperative prognostic index correctly divided patients into four true prognostic groups. The two prognostic groups with the poorest survival outcomes overlapped, and these were merged to create the adjusted preoperative prognostic index. CONCLUSION: We created a prognostic index for patients with BM that predicts overall survival preoperatively. This index might be valuable in supporting informed choice when considering surgery for BM.