Treatment of Brain Arteriovenous Malformations.

Brain arteriovenous malformations (AVMs) are a rare entity of vascular anomalies, characteristic of anatomical shunting where arterial blood directly flows into the venous circulation. The main aim of the active treatment policy of brain AVMs is the prevention of haemorrhage. There are well-established treatment strategies that continually improve in their safety and efficacy, primarily due to the advances in imaging modalities, targeted and novel techniques, the development of alternative treatment approaches, and even better experience with the disease itself. There are interesting imaging novelties that may be prospectively applicable in the decision-making and planning of the most effective treatment approach for individual patients with intracranial AVM. Surgery is often considered the first-line treatment; however, each patient should be evaluated individually, and the risks of the active treatment policy should not overcome the benefits of the spontaneous natural history of the disease. All treatment modalities, i.e., surgery, radiosurgery, endovascular embolization, and observation, are justified but need to be meticulously selected for each individual patient in order to deliver the best treatment outcome. This chapter deals with historical and currently applied dogmas, followed by introductions of advances in each available treatment modality of AVM management.

Molecular Profiling of Axial Spondyloarthritis Patients Reveals an Association between Innate and Adaptive Cell Populations and Therapeutic Response to Tumor Necrosis Factor Inhibitors.

This study aims at identifying molecular biomarkers differentiating responders and non-responders to treatment with Tumor Necrosis Factor inhibitors (TNFi) among patients with axial spondyloarthritis (axSpA). Whole blood mRNA and plasma proteins were measured in a cohort of biologic-naïve axSpA patients (n = 35), pre and post (14 weeks) TNFi treatment with adalimumab. Differential expression analysis was used to identify the most enriched pathways and in predictive models to distinguish responses to TNFi. A treatment-associated signature suggests a reduction in inflammatory activity. We found transcripts and proteins robustly differentially expressed between baseline and week 14 in responders. C-reactive protein (CRP) and Haptoglobin (HP) proteins showed strong and early decrease in the plasma of axSpA patients, while a cluster of apolipoproteins (APOD, APOA2, APOA1) showed increased expression at week 14. Responders to TNFi treatment present higher levels of markers of innate immunity at baseline, and lower levels of adaptive immunity markers, particularly B-cells. A logistic regression model incorporating ASDAS-CRP, gender, and AFF3, the top differentially expressed gene at baseline, enabled an accurate prediction of response to adalimumab in our cohort (AUC = 0.97). In conclusion, innate and adaptive immune cell type composition at baseline may be a major contributor to response to adalimumab in axSpA patients. A model including clinical and gene expression variables should also be considered.

Clinical and molecular study of radiation-induced gliomas.

In this study, we provide a comprehensive clinical and molecular biological characterization of radiation-induced gliomas (RIG), including a risk assessment for developing gliomas. A cohort of 12 patients who developed RIG 9.5 years (3-31 years) after previous cranial radiotherapy for brain tumors or T-cell acute lymphoblastic leukemia was established. The derived risk of RIG development based on our consecutive cohort of 371 irradiated patients was 1.6% at 10 years and 3.02% at 15 years. Patients with RIG glioma had a dismal prognosis with a median survival of 7.3 months. We described radiology features that might indicate the suspicion of RIG rather than the primary tumor recurrence. Typical molecular features identified by molecular biology examination included the absence of Histon3 mutation, methylation profile of pedHGG-RTK1 and the presence of recurrent PDGFRA amplification and CDKN2A/B deletion. Of the two long-term surviving patients, one had gliomatosis cerebri, and the other had pleomorphic xanthoastrocytoma with BRAF V600E mutation. In summary, our experience highlights the need for tissue diagnostics to allow detailed molecular biological characterization of the tumor, differentiation of the secondary tumor from the recurrence of the primary disease and potentially finding a therapeutic target.

Stability of gut microbiome after COVID-19 vaccination in healthy and immuno-compromised individuals.

Bidirectional interactions between the immune system and the gut microbiota are key contributors to various physiological functions. Immune-associated diseases such as cancer and autoimmunity, and efficacy of immunomodulatory therapies, have been linked to microbiome variation. Although COVID-19 infection has been shown to cause microbial dysbiosis, it remains understudied whether the inflammatory response associated with vaccination also impacts the microbiota. Here, we investigate the temporal impact of COVID-19 vaccination on the gut microbiome in healthy and immuno-compromised individuals; the latter included patients with primary immunodeficiency and cancer patients on immunomodulating therapies. We find that the gut microbiome remained remarkably stable post-vaccination irrespective of diverse immune status, vaccine response, and microbial composition spanned by the cohort. The stability is evident at all evaluated levels including diversity, phylum, species, and functional capacity. Our results indicate the resilience of the gut microbiome to host immune changes triggered by COVID-19 vaccination and suggest minimal, if any, impact on microbiome-mediated processes. These findings encourage vaccine acceptance, particularly when contrasted with the significant microbiome shifts observed during COVID-19 infection.

Non-apoptotic FAS signaling controls mTOR activation and extrafollicular maturation in human B cells.

Defective FAS (CD95/Apo-1/TNFRSF6) signaling causes autoimmune lymphoproliferative syndrome (ALPS). Hypergammaglobulinemia is a common feature in ALPS with FAS mutations (ALPS-FAS), but paradoxically, fewer conventional memory cells differentiate from FAS-expressing germinal center (GC) B cells. Resistance to FAS-induced apoptosis does not explain this phenotype. We tested the hypothesis that defective non-apoptotic FAS signaling may contribute to impaired B cell differentiation in ALPS. We analyzed secondary lymphoid organs of patients with ALPS-FAS and found low numbers of memory B cells, fewer GC B cells, and an expanded extrafollicular (EF) B cell response. Enhanced mTOR activity has been shown to favor EF versus GC fate decision, and we found enhanced PI3K/mTOR and BCR signaling in ALPS-FAS splenic B cells. Modeling initial T-dependent B cell activation with CD40L in vitro, we showed that FAS competent cells with transient FAS ligation showed specifically decreased mTOR axis activation without apoptosis. Mechanistically, transient FAS engagement with involvement of caspase-8 induced nuclear exclusion of PTEN, leading to mTOR inhibition. In addition, FASL-dependent PTEN nuclear exclusion and mTOR modulation were defective in patients with ALPS-FAS. In the early phase of activation, FAS stimulation promoted expression of genes related to GC initiation at the expense of processes related to the EF response. Hence, our data suggest that non-apoptotic FAS signaling acts as molecular switch between EF versus GC fate decisions via regulation of the mTOR axis and transcription. The defect of this modulatory circuit may explain the observed hypergammaglobulinemia and low memory B cell numbers in ALPS.

Utility of texture analysis for objective quantitative ex vivo assessment of meningioma consistency: method proposal and validation.

BACKGROUND: Tumor consistency is considered to be a critical factor for the surgical removal of meningiomas and its preoperative assessment is intensively studied. A significant drawback in the research of predictive methods is the lack of a clear shared definition of tumor consistency, with most authors resorting to subjective binary classification labeling the samples as "soft" and "hard." This classification is highly observer-dependent and its discrete nature fails to capture the fine nuances in tumor consistency. To compensate for these shortcomings, we examined the utility of texture analysis to provide an objective observer-independent continuous measure of meningioma consistency. METHODS: A total of 169 texturometric measurements were conducted using the Brookfield CT3 Texture Analyzer on meningioma samples from five patients immediately after the removal and on the first, second, and seventh postoperative day. The relationship between measured stiffness and time from sample extraction, subjectively assessed consistency grade and histopathological features (amount of collagen and reticulin fibers, presence of psammoma bodies, predominant microscopic morphology) was analyzed. RESULTS: The stiffness measurements exhibited significantly lower variance within a sample than among samples (p = 0.0225) and significant increase with a higher objectively assessed consistency grade (p = 0.0161, p = 0.0055). A significant negative correlation was found between the measured stiffness and the time from sample extraction (p < 0.01). A significant monotonic relationship was revealed between stiffness values and amount of collagen I and reticulin fibers; there were no statistically significant differences between histological phenotypes in regard to presence of psammoma bodies and predominant microscopic morphology. CONCLUSIONS: We conclude that the values yielded by texture analysis are highly representative of an intrinsic consistency-related quality of the sample despite the influence of intra-sample heterogeneity and that our proposed method can be used to conduct quantitative studies on the role of meningioma consistency.

RNA-sequencing based first choice of treatment and determination of risk in multiple myeloma.

Background: Immunotherapeutic targets in multiple myeloma (MM) have variable expression height and are partly expressed in subfractions of patients only. With increasing numbers of available compounds, strategies for appropriate choice of targets (combinations) are warranted. Simultaneously, risk assessment is advisable as patient's life expectancy varies between months and decades. Methods: We first assess feasibility of RNA-sequencing in a multicenter trial (GMMG-MM5, n=604 patients). Next, we use a clinical routine cohort of untreated symptomatic myeloma patients undergoing autologous stem cell transplantation (n=535, median follow-up (FU) 64 months) to perform RNA-sequencing, gene expression profiling (GEP), and iFISH by ten-probe panel on CD138-purified malignant plasma cells. We subsequently compare target expression to plasma cell precursors, MGUS (n=59), asymptomatic (n=142) and relapsed (n=69) myeloma patients, myeloma cell lines (n=26), and between longitudinal samples (MM vs. relapsed MM). Data are validated using the independent MMRF CoMMpass-cohort (n=767, FU 31 months). Results: RNA-sequencing is feasible in 90.8% of patients (GMMG-MM5). Actionable immune-oncological targets (n=19) can be divided in those expressed in all normal and >99% of MM-patients (CD38, SLAMF7, BCMA, GPRC5D, FCRH5, TACI, CD74, CD44, CD37, CD79B), those with expression loss in subfractions of MM-patients (BAFF-R [81.3%], CD19 [57.9%], CD20 [82.8%], CD22 [28.4%]), aberrantly expressed in MM (NY-ESO1/2 [12%], MUC1 [12.7%], CD30 [4.9%], mutated BRAF V600E/K [2.1%]), and resistance-conveying target-mutations e.g., against part but not all BCMA-directed treatments. Risk is assessable regarding proliferation, translated GEP- (UAMS70-, SKY92-, RS-score) and de novo (LfM-HRS) defined risk scores. LfM-HRS delineates three groups of 40%, 38%, and 22% of patients with 5-year and 12-year survival rates of 84% (49%), 67% (18%), and 32% (0%). R-ISS and RNA-sequencing identify partially overlapping patient populations, with R-ISS missing, e.g., 30% (22/72) of highly proliferative myeloma. Conclusion: RNA-sequencing based assessment of risk and targets for first choice treatment is possible in clinical routine.

Predictors of postoperative complications and functional outcomes in pediatric patients with surgically treated fourth ventricle tumors.

BACKGROUND: Tumors of the fourth ventricle are frequently treated pathologies in pediatric neurosurgery. Data regarding predictors for permanent neurological deficits, long-term functional outcomes, cerebellar mutism (CM), the extent of resection (EOR), and oncological outcomes are scarce. We attempt to contribute to this topic with an analysis of our institutional cohort. METHODS: A retrospective single-center study of patients aged ≤ 19 years who underwent primary surgical resection of a fourth ventricular tumor over a 15-year period (2006-2021). Predictors analyzed included age, gender, surgical approach, anatomical pattern, tumor grade, EOR, tumor volume, and others as appropriate. RESULTS: One hundred six patients were included (64 males, mean age 7.3 years). The rate of permanent neurological deficit was 24.2%; lateral tumor extension (p = 0.036) and tumor volume greater than 38 cm3 (p = 0.020) were significant predictors. The presence of a deficit was the only significant predictor of reduced (less than 90) Lansky score (p = 0.005). CM occurred in 20.8% of patients and was influenced by medulloblastoma histology (p = 0.011), lateral tumor extension (p = 0.017), and male gender (p = 0.021). No significant difference between the transvermian and telovelar approach in the development of CM was detected (p = 0.478). No significant predictor was found for the EOR. EOR was not found to be a significant predictor of overall survival for both low-grade and high-grade tumors; however, gross total resection (GTR) was protective against tumor recurrence compared to near-total or subtotal resection (p < 0.001). In addition, survival was found to be better in older patients (≥ 7.0 years, p = 0.019). CONCLUSION: The overall rate of postoperative complications remains high due to the eloquent localization. Older patients (> 7 years) have been found to have better outcomes and prognosis. Achieving GTR whenever feasible and safe has been shown to be critical for tumor recurrence. CM was more common in patients with medulloblastoma and in patients with tumors extending through the foramen of Luschka. The telovelar approach uses a safe and anatomically sparing corridor; however, it has not been associated with a lower incidence of CM and neurological sequelae in our series, showing that each case should be assessed on an individual basis.

Diffusion tensor imaging helps identify shunt-responsive normal pressure hydrocephalus patients among probable iNPH cohort.

The aim of this study was to investigate whether white matter changes as measured by diffusion tensor imaging (DTI) can help differentiate shunt-responsive idiopathic normal pressure hydrocephalus (iNPH) patients from patients with other causes of gait disturbances and/or cognitive decline with ventriculomegaly whose clinical symptoms do not improve significantly after cerebrospinal fluid derivation (non-iNPH). Between 2017 and 2022, 85 patients with probable iNPH underwent prospective preoperative magnetic resonance imaging (MRI) and comprehensive clinical workup. Patients with clinical symptoms of iNPH, positive result on lumbar infusion test, and gait improvement after 120-h lumbar drainage were diagnosed with iNPH and underwent shunt-placement surgery. Fractional anisotropy (FA) and mean diffusivity (MD) values for individual regions of interest were extracted from preoperative MRI, using the TBSS pipeline of FSL toolkit. These FA and MD values were then compared to results of clinical workup and established diagnosis of iNPH. An identical MRI protocol was performed on 13 age- and sex-matched healthy volunteers. Statistically significant differences in FA values of several white matter structures were found not only between iNPH patients and healthy controls but also between iNPH and non-iNPH patients. ROI that showed best diagnostic ability when differentiating iNPH among probable iNPH cohort was uncinate fasciculus, with AUC of 0.74 (p < 0.001). DTI methods of white matter analysis using standardised methods of ROI extraction can help in differentiation of iNPH patients not only from healthy patients but also from patients with other causes of gait disturbances with cognitive decline and ventriculomegaly.

Spinal fusion for single-level SPECT/CT positive lumbar degenerative disc disease: the SPINUS I study.

INTRODUCTION AND PURPOSE: With current imaging modalities and diagnostic tests, identifying pain generators in patients with non-specific chronic low back pain (CLBP) is difficult. There is growing evidence of the effectiveness of SPECT/CT examination in diagnosing the source of pain in the spine. The study aims to investigate the effect of posterior interbody fusion on a single-level SPECT/CT positive lumbar degenerative disc disease (DDD). MATERIAL AND METHODS: This is a prospective study of patients with chronic low back pain (CLBP) operated on for a single-level SPECT/CT positive DDD. Primary outcomes were changes in visual analogue scale (VAS) scores and the Oswestry Disability Index (ODI). Secondary outcomes were complications, return to work, satisfaction and willingness to re-undergo surgery. RESULTS: During a 3-year period, 38 patients underwent single-level fusion surgery. The mean preoperative VAS score of 8.4 (± 1.1) decreased to 3.2 (± 2.5, p < 0.001) and the mean preoperative ODI of 51.5 (± 7.3) improved to 20.7 (± 14.68, p < 0.001) at a 2-year follow-up. A minimum clinically important difference (30% reduction in VAS and ODI) was achieved in 84.2% of patients. Some 71% of patients were satisfied with the surgery results and 89.4% would undergo surgery again. There were four complications, and two patients underwent revision surgery. Some 82.9% of patients returned to work. CONCLUSION: Fusion for one-level SPECT/CT positive lumbar DDD resulted in substantial clinical improvement and satisfaction with surgical treatment. Therefore, SPECT/CT imaging could be useful in assessing patients with CLBP, especially those with unclear MRI findings. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04876586.

Role of risk factors, scoring systems, and prognostic models in predicting the functional outcome in meningioma surgery: multicentric study of 552 skull base meningiomas.

Despite the importance of functional outcome, only a few scoring systems exist to predict neurologic outcome in meningioma surgery. Therefore, our study aims to identify preoperative risk factors and develop the receiver operating characteristics (ROC) models estimating the risk of a new postoperative neurologic deficit and a decrease in Karnofsky performance status (KPS). A multicentric study was conducted in a cohort of 552 consecutive patients with skull base meningiomas who underwent surgical resection from 2014 to 2019. Data were gathered from clinical, surgical, and pathology records as well as radiological diagnostics. The preoperative predictive factors of functional outcome (neurologic deficit, decrease in KPS) were analyzed in univariate and multivariate stepwise selection analyses. Permanent neurologic deficits were present in 73 (13.2%) patients and a postoperative decrease in KPS in 84 (15.2%). Surgery-related mortality was 1.3%. A ROC model was developed to estimate the probability of a new neurologic deficit (area 0.74; SE 0.0284; 95% Wald confidence limits (0.69; 0.80)) based on meningioma location and diameter. Consequently, a ROC model was developed to predict the probability of a postoperative decrease in KPS (area 0.80; SE 0.0289; 95% Wald confidence limits (0.74; 0.85)) based on the patient's age, meningioma location, diameter, presence of hyperostosis, and dural tail. To ensure an evidence-based therapeutic approach, treatment should be founded on known risk factors, scoring systems, and predictive models. We propose ROC models predicting the functional outcome of skull base meningioma resection based on the age of the patient, meningioma size, and location and the presence of hyperostosis and dural tail.

Clonally resolved single-cell multi-omics identifies routes of cellular differentiation in acute myeloid leukemia.

Inter-patient variability and the similarity of healthy and leukemic stem cells (LSCs) have impeded the characterization of LSCs in acute myeloid leukemia (AML) and their differentiation landscape. Here, we introduce CloneTracer, a novel method that adds clonal resolution to single-cell RNA-seq datasets. Applied to samples from 19 AML patients, CloneTracer revealed routes of leukemic differentiation. Although residual healthy and preleukemic cells dominated the dormant stem cell compartment, active LSCs resembled their healthy counterpart and retained erythroid capacity. By contrast, downstream myeloid progenitors constituted a highly aberrant, disease-defining compartment: their gene expression and differentiation state affected both the chemotherapy response and leukemia's ability to differentiate into transcriptomically normal monocytes. Finally, we demonstrated the potential of CloneTracer to identify surface markers misregulated specifically in leukemic cells. Taken together, CloneTracer reveals a differentiation landscape that mimics its healthy counterpart and may determine biology and therapy response in AML.

Increased macrophage M2/M1 ratio is associated with intracranial aneurysm rupture.

PURPOSE: Intracranial aneurysm (IA) rupture results in one of the most severe forms of stroke, with severe neurological sequelae. Inflammation appears to drive aneurysm formation and progression with macrophages playing a key role in this process. However, less is known about their involvement in aneurysm rupture. This study is aimed at demonstrating how relationship between the M1 (pro-inflammatory) and M2 (reparative) macrophage subtypes affect an aneurysm's structure resulting in its rupture. METHODS: Forty-one saccular aneurysm wall samples were collected during surgery including 13 ruptured and 28 unruptured aneurysm sacs. Structural changes were evaluated using histological staining. Macrophages in the aneurysm wall were quantified and defined as M1 and M2 using HLA-DR and CD163 antibodies. Aneurysm samples were divided into four groups according to the structural changes and the M2/1 ratio. Data were analyzed using the Mann-Whitney U test. RESULTS: This study has demonstrated an association between the severity of structural changes of an aneurysm with inflammatory cell infiltration within its wall and subsequent aneurysm rupture. More severe morphological changes and a significantly higher number of inflammatory cells were observed in ruptured IAs (p < 0.001). There was a prevalence of M2 macrophage subtypes within the wall of ruptured aneurysms (p < 0.001). A subgroup of unruptured IAs with morphological and inflammatory changes similar to ruptured IAs was observed. The common feature of this subgroup was the presence of an intraluminal thrombus. CONCLUSIONS: The degree of inflammatory cell infiltration associated with a shift in macrophage phenotype towards M2 macrophages could play an important role in structural changes of the aneurysm wall leading to its rupture.

Evaluation of the growth rates and related prognostic factors in radiation-induced meningiomas.

PURPOSE: Literature dedicated to growth patterns and growth rate influencing factors of radiation-induced meningiomas (RIMs) is limited. To deliver new insights into the topic, a volumetric growth analysis of RIMs was performed. METHODS: This single-center, retrospective cohort study included patients diagnosed with intracranial meningioma who received radiation treatment at least > 5 years before the RIM diagnosis. Volumetric analysis of individual RIMs was performed using 3D volumetry at the time of RIM diagnosis and during follow-up. RIM growth was determined by calculating absolute (AGR), and relative (RGR) growth rates. Prognostic factors associated with RIM growth were evaluated. RESULTS: A total of 26 patients with 33 meningiomas were enrolled in the study and radiologically/clinically followed up during a median duration of 5.6 years (IQR 3.9-8.8 years). Median AGR was 0.19 cm3 per year and the median RGR was 34.5% per year. Surgically managed RIMs were more likely fast-growing compared to observed ones based on the AGR (p < 0.002). The recurrence rate after total resection was 14.3%. Younger age at RIM diagnosis was associated with higher tumor growth (RGR ≥ 30%, p = 0.040). A significant correlation was found between the length of latency period and the RGR (p = 0.005). CONCLUSION: To diagnose RIM as early as possible comprehensive MRI surveillance is required. Younger patients with shorter latency periods may profit from shortened MRI intervals, with further management being dependent on the growth rate and eventual symptomatology.

Current management in the treatment of intramedullary ependymomas in children.

PURPOSE: Current management of pediatric intramedullary ependymoma is extrapolated from adult series since large studies in children are unavailable. This has led us to share our experience with this rare tumor and compare it to the literature and to review and highlight important aspects of current management and point out inconsistencies. METHODS: This is a retrospective analysis of patients with intramedullary ependymoma managed at our institution between 2004 and 2021. RESULTS: During the study period, 5 patients were treated for intramedullary ependymoma. Cases of myxopapillary ependymoma were excluded. The mean age of our cohort was 11.2 years. We identified 4 cases of grade II ependymoma and 1 case of grade III ependymoma. Gross tumor removal (GTR) was achieved in two patients (40%) of patients. One patient was treated with radiotherapy for recurrence and two patients received chemotherapy. There were no cases of recurrence among patients treated with GTR, but in all patients treated with STR. Eighty percent of patients either improved or stayed stable neurologically. During follow-up (mean 73 months), 2 patients died of disease. CONCLUSION: GTR and tumor grade remain the key prognostic factor of long-term tumor-free survival. Many questions prevail regarding outcomes, correct use of adjuvant therapy, and prognostic factors.

Targeted parallel DNA sequencing detects circulating tumor-associated variants of the mitochondrial and nuclear genomes in patients with neuroblastoma.

BACKGROUND: The utility for liquid biopsy of tumor-associated circulating single-nucleotide variants, as opposed to mutations, of the mitochondrial (mt) and nuclear genomes in neuroblastoma (NB) is unknown. PROCEDURE: Variants of the mt and nuclear genomes from tumor, blood cells, and consecutive plasma samples of five patients with metastatic NB that relapsed or progressed were analyzed. Targeted parallel sequencing results of the mt genome, and of the coding region of 139 nuclear genes and 22 miRNAs implicated in NB, were correlated with clinical imaging and laboratory data. RESULTS: All tumors harbored multiple somatic mt and nuclear single nucleotide variants with low allelic frequency, most of them not detected in the circulation. In one patient a tumor-associated mt somatic variant was detected in the plasma before and during progressive disease. In a second patient a circulating nuclear tumor-associated DNA variant heralded clinical relapse. In all patients somatic mt and nuclear variants not evident in the tumor biopsy at time of diagnosis were found circulating at varying timepoints. This suggests either tumor heterogeneity, evolution of tumor variants or a confounding contribution of normal tissues to somatic variants in patient plasma. The number and allelic frequency of the circulating variants did not reflect the clinical course of the tumors. Mutational signatures of mt and nuclear somatic variants differed. They varied between patients and were detected in the circulation without mirroring the patients' course. CONCLUSIONS: In this limited cohort of NB patients clinically informative tumor-associated mt and nuclear circulating variants were detected by targeted parallel sequencing in a minority of patients.

DNA damage independent inhibition of NF-κB transcription by anthracyclines.

Anthracyclines are among the most used and effective anticancer drugs. Their activity has been attributed to DNA double-strand breaks resulting from topoisomerase II poisoning and to eviction of histones from select sites in the genome. Here, we show that the extensively used anthracyclines Doxorubicin, Daunorubicin, and Epirubicin decrease the transcription of nuclear factor kappa B (NF-κB)-dependent gene targets, but not interferon-responsive genes in primary mouse (Mus musculus) macrophages. Using an NMR-based structural approach, we demonstrate that anthracyclines disturb the complexes formed between the NF-κB subunit RelA and its DNA-binding sites. The anthracycline variants Aclarubicin, Doxorubicinone, and the newly developed Dimethyl-doxorubicin, which share anticancer properties with the other anthracyclines but do not induce DNA damage, also suppressed inflammation, thus uncoupling DNA damage from the effects on inflammation. These findings have implications for anticancer therapy and for the development of novel anti-inflammatory drugs with limited side effects for life-threatening conditions such as sepsis.

What is the most effective method to treat indirect carotid-cavernous fistula?

To review the most relevant treatment options for indirect carotid-cavernous fistulas (iCCF), cohorts of 20 patients or more published after 2000 were analyzed. Clinical and radiological outcomes, as well as embolization techniques and material, had to be clarified in the study to be considered. Statistical analysis was based on calculating the relative percentage of therapeutic methods or embolic material, followed by calculating parametric and nonparametric correlations. Some 22 studies and 1550 patients were included. Transvenous embolization (TVE) was used in 53% of the patients and was strongly associated with coiling (rw = 0.66, p = 0.0.0012; rs = 0.53, p = 0.0138), transarterial embolization (TAE) was preferred in 11% of the patients and was strongly linked to liquid embolics (rw = 0.44, p = 0.0434;rs = 0.64, p = 0.0018). A combination of TAE and TVE treatment was used in 7% and a combination of embolic materials in 13% of the patients. None of the endovascular techniques or embolization materials showed significant superiority over the others in clinical outcome and obliteration rate. Radiosurgery in 22% and mechanical compression in 5% of patients showed a lower obliteration rate (rw = - 0.48, p = 0.0254; rs = - 0.45, p = 0.0371). The clinical outcomes were comparable to endovascular treatment (EVT). The remaining 2% of the patients were treated by open surgery or a combination of EVT and radiosurgery. Transvenous coiling is the preferred EVT method for iCCF. However, comparable results may be accomplished with TAE using liquid. Radiosurgery may achieve a lower percentage of fistula occlusion, but the clinical results are equal to EVT.

Integrated genomic analysis reveals actionable targets in pediatric spinal cord low-grade gliomas.

Gliomas are the most common central nervous tumors in children and adolescents. However, spinal cord low-grade gliomas (sLGGs) are rare, with scarce information on tumor genomics and epigenomics. To define the molecular landscape of sLGGs, we integrated clinical data, histology, and multi-level genetic and epigenetic analyses on a consecutive cohort of 26 pediatric patients. Driver molecular alteration was found in 92% of patients (24/26). A novel variant of KIAA1549:BRAF fusion (ex10:ex9) was identified using RNA-seq in four cases. Importantly, only one-third of oncogenic drivers could be revealed using standard diagnostic methods, and two-thirds of pediatric patients with sLGGs required extensive molecular examination. The majority (23/24) of detected alterations were potentially druggable targets. Four patients in our cohort received targeted therapy with MEK or NTRK inhibitors. Three of those exhibited clinical improvement (two with trametinib, one with larotrectinib), and two patients achieved partial response. Methylation profiling was implemented to further refine the diagnosis and revealed intertumoral heterogeneity in sLGGs. Although 55% of tumors clustered with pilocytic astrocytoma, other rare entities were identified in this patient population. In particular, diffuse leptomeningeal glioneuronal tumors (n = 3) and high-grade astrocytoma with piloid features (n = 1) and pleomorphic xanthoastrocytoma (n = 1) were present. A proportion of tumors (14%) had no match with the current version of the classifier. Complex molecular genetic sLGGs characterization was invaluable to refine diagnosis, which has proven to be essential in such a rare tumor entity. Moreover, identifying a high proportion of drugable targets in sLGGs opened an opportunity for new treatment modalities.