bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chronic kidney disease: the missing concept in the 2019 EULAR/ERA-EDTA recommendations for lupus nephritis
Authors: Rojas-Rivera Jorge E , Bakkaloglu Sevcan A , Bolignano Davide , Nistor Ionut , Sarafidis Pantelis A , Stoumpos Sokratis , Cozzolino Mario Gennaro , Ortiz Alberto 
Published: July 2023

ABSTRACT
Chronic kidney disease (CKD) is diagnosed when glomerular filtration rate (GFR) falls below 60 ml/min/1.73 m2 or urinary albumin:creatinine ratio (UACR) reaches ≥30 mg/g, as these two thresholds indicate a higher risk of adverse health outcomes, including cardiovascular mortality. CKD is classified as mild, moderate or severe, based on GFR and UACR values, and the latter two classifications convey a high or very high cardiovascular risk, respectively. Additionally, CKD can be diagnosed based on abnormalities detected by histology or imaging. Lupus nephritis (LN) is a cause of CKD. Despite the high cardiovascular mortality of patients with LN, neither albuminuria nor CKD are discussed in the 2019 European League Against Rheumatism (EULAR)/European Renal Association–European Dialysis and Transplant Association recommendations for the management of LN or the more recent 2022 EULAR recommendations for cardiovascular risk management in rheumatic and musculoskeletal diseases. Indeed, the proteinuria target values discussed in the recommendations may be present in patients with severe CKD and a very high cardiovascular risk who may benefit from guidance detailed in the 2021 European Society of Cardiology guidelines on cardiovascular disease prevention in clinical practice. We propose that the recommendations should move from a conceptual framework of LN as an entity separate from CKD to a framework in which LN is considered a cause of CKD and evidence generated from large CKD trials applies unless demonstrated otherwise.
Interpretation of GFR slope in untreated and treated adult Fabry patients
Authors: Pisani Antonio , Pieruzzi Federico , Cirami Calogero Lino , Riccio Eleonora , Mignani Renzo 
Published: July 2023

ABSTRACT
Nephropathy is one of the main features of Fabry disease (FD) that leads, in untreated patients with classical mutations, to end-stage renal disease (ESRD) from the third to the fifth decade of life. The availability of a specific treatment modified the natural history of FD; in particular, it was widely reported that enzyme replacement therapy (ERT) is able to slow the progression of the disease. Regarding Fabry nephropathy, several reports have documented an elevated estimated glomerular filtration rate (eGFR) slope in untreated patients as expression of a rapid disease progression towards ESRD. Otherwise, the prompt start of treatment may be beneficial in stabilizing renal function or slowing its decline. Therefore, based on data in the literature about the effects of ERT on eGFR decline and on the evidence supporting the role of eGFR slope as a surrogate endpoint for chronic kidney disease progression, we suggest, in this ‘Expert Opinion’, that a treatment should be defined effective when eGFR decline is &lt;1 ml/min/1.73 m2/year and not effective when eGFR loss remains ≥3 ml/min/1.73 m2/year (≥2.5 ml/min/1.73 m2/year in females). Moreover, practical clinical recommendations and guidance for Fabry patients suggests that a change in treatment may be appropriate if individualized therapeutic goals are not achieved. Since a dose-dependent efficacy has been demonstrated for ERT, we suggest considering a switch to a higher dose of ERT in symptomatic adult Fabry patients (ages 18–60 years) with an eGFR of 45–90 ml/min/1.73 m2 and treated with a stable dose of ERT for at least 1 year, in which a linear negative slope of eGFR of 3 ml/min/1.73 m2/year for males (2.5 ml/min/1.73 m2/year for females) was observed.
Novel SOX10 indel mutations drive schwannomas through impaired transactivation of myelination gene programs
Authors: Williams Erik A , Ravindranathan Ajay , Gupta Rohit , Stevers Nicholas O , Suwala Abigail K , Hong Chibo , Kim Somang , Yuan Jimmy Bo , Wu Jasper , Barreto Jairo , Lucas Calixto-Hope G , Chan Emily , Pekmezci Melike , LeBoit Philip E , Mully Thaddeus , Perry Arie , Bollen Andrew , Van Ziffle Jessica , Devine W Patrick , Reddy Alyssa T , Gupta Nalin , Basnet Kristen M , Macaulay Robert J B , Malafronte Patrick , Lee Han , Yong William H , Williams Kevin Jon , Juratli Tareq A , Mata Douglas A , Huang Richard S P , Hiemenz Matthew C , Pavlick Dean C , Frampton Garrett M , Janovitz Tyler , Ross Jeffrey S , Chang Susan M , Berger Mitchel S , Jacques Line , Song Jun S , Costello Joseph F , Solomon David A 
Published: July 2023

Abstract

Background
Schwannomas are common peripheral nerve sheath tumors that can cause severe morbidity given their stereotypic intracranial and paraspinal locations. Similar to many solid tumors, schwannomas and other nerve sheath tumors are primarily thought to arise due to aberrant hyperactivation of the RAS growth factor signaling pathway. Here, we sought to further define the molecular pathogenesis of schwannomas.

Methods
We performed comprehensive genomic profiling on a cohort of 96 human schwannomas, as well as DNA methylation profiling on a subset. Functional studies including RNA sequencing, chromatin immunoprecipitation-DNA sequencing, electrophoretic mobility shift assay, and luciferase reporter assays were performed in a fetal glial cell model following transduction with wildtype and tumor-derived mutant isoforms of SOX10.

Results
We identified that nearly one-third of sporadic schwannomas lack alterations in known nerve sheath tumor genes and instead harbor novel recurrent in-frame insertion/deletion mutations in SOX10, which encodes a transcription factor responsible for controlling Schwann cell differentiation and myelination. SOX10 indel mutations were highly enriched in schwannomas arising from nonvestibular cranial nerves (eg facial, trigeminal, vagus) and were absent from vestibular nerve schwannomas driven by NF2 mutation. Functional studies revealed these SOX10 indel mutations have retained DNA binding capacity but impaired transactivation of glial differentiation and myelination gene programs.

Conclusions
We thus speculate that SOX10 indel mutations drive a unique subtype of schwannomas by impeding proper differentiation of immature Schwann cells.
COMPARING THE EFFICIENCY OF A REAL-TIME ARTIFICIAL INTELLIGENCE INSTRUCTOR TO HUMAN EXPERT INSTRUCTORS IN SIMULATED SURGICAL TECHNICAL SKILLS TRAINING– A RANDOMIZED CONTROLLED TRIAL
Authors: Yilmaz Recai , Bakhaidar Mohamad , Alsayegh Ahmad , Hamdan Nour Abou , Fazlollahi Ali M , Agu Chinyelum , Pachchigar Puja , Del Maestro Rolando 
Published: July 2023

Abstract
BTFC travel award recipient
Artificial intelligence systems provide risk-free training on realistically simulated patient cases and objective assessment of surgical technical skills. This randomized controlled study compared a real-time intelligent tutoring system in technical skills learning with human expert instructor-mediated training.
METHODS: Ninety-eight medical students performed six simulated brain tumor resections. Participants were randomly allocated into (1)no-real-time feedback, (2)real-time intelligent instruction, and (3)in- person human instruction. All students performed the first repetition without receiving feedback (baseline). Group-1 received visual feedback only after each procedure based on expert benchmarks. Group-2 was instructed by the intelligent system in real-time. After each task, the students were shown their error-video clips generated by this system alongside expert-level demonstrations on how to improve. Group-3 was instructed by human instructors during the tasks. After each task, instructors summarized the areas of improvement and demonstrated correction techniques. Participant performance was scored by the intelligent system and also by blinded experts using OSATS scores. The performance score was compared within groups and between groups to compare learning. RESULTS: Compared to baseline performance, Group-2 and Group-3 significantly improved in the performance score by the third and second repetition, respectively (p&lt;0.01, p=0.01). The between-groups comparison demonstrated that Group-2 scored significantly higher than Group-3 in the fifth repetition (p&lt;0.01). Group-2 achieved significantly higher OSATS scores than Group-1 in the sixth task. CONCLUSIONS: Artificial intelligence may facilitate trainee learning by providing equally or more efficient learning when compared to human instruction. These systems may aid in developing competency-based standardized curricula in surgical training.
AUTOLOGOUS PATIENT-DERIVED CAR-TS SHOW FUNCTIONAL DEFICITS AGAINST HUMAN GLIOBLASTOMA
Authors: Salim Sabra K , Shaikh Vaseem , Maich William T , Anand Alisha , Brakel Benjamin , Wei Jeffrey , Subapanditha Minomi K , Alizada Zahra , Suk Yujin , Singh Manoj , Dimitrov Vassil , Tabunshchyk Zoya , Chen Katie , Vora Parvez , Venugopal Chitra , Moffat Jason , Singh Sheila K 
Published: July 2023

Abstract
Glioblastoma (GBM) is the most common malignant brain tumor in adults, with a poor prognosis despite aggressive standard of care. Chimeric antigen receptor T-cell (CAR-T) therapy has shown promising results in liquid malignancies, but clinical trials in GBM targeting various tumor antigens have not shown durable clinical benefit. While this may be attributable to various tumor-intrinsic immune evasion strategies characteristic of GBM, little work has assessed whether the issue is due to the quality of the CAR-T treatment itself. Currently, CAR-Ts for GBMs and liquid malignancies are manufactured in an autologous setting in which T-cells are extracted from patients, engineered ex-vivo, and subsequently reinfused back. However, peripheral T-cells taken from untreated GBM patients have demonstrated qualitative and functional deficits, which may contribute to suboptimal treatment outcomes. Thus, we aimed to establish whether CAR-Ts generated from GBM patients would show reduced efficacy in comparison to healthy donors using our previously validated CD133 CAR-T. In this work, we show pre-treatment exhaustion and reduced survival advantage in autologous, patient-derived CD133-targeting CAR-T cell products using an orthotopic xenograft model of human GBM. To overcome the functional and logistical considerations of autologous therapy, we additionally aimed to generate an “off-the-shelf” allogeneic CD133 CAR-T. Using CRISPR gene editing technology, we generated TCR-knockout CAR-T cells with comparable pre- clinical efficacy to our autologous models. Ultimately, this work highlights the need to reassess autologous CAR-T therapy for GBM, and consider allogeneic approaches as biologically-informed therapeutic alternatives.
RE-IRRADIATION FOR RECURRENT HIGH-GRADE GLIOMA: AN ANALYSIS OF PROGNOSTIC FACTORS FOR SURVIVAL AND PREDICTORS OF RADIATION NECROSIS
Authors: Moore-Palhares Daniel , Chen Hanbo , Keith Julia , Wang Michael , Myrehaug Sten , Tseng Chia-Lin , Detsky Jay , Perry James , Lim-Fat Mary Jane , Heyn Chris , Maralani Pejman , Lipsman Nir , Das Sunit , Sahgal Arjun , Soliman Hany 
Published: July 2023

Abstract
Recurrent high-grade glioma (rHGG) is a heterogeneous population, and the ideal patient selection for reirradiation (re-RT) has yet to be established. This study aims to identify prognostic factors for rHGG patients treated with re-RT.
METHODS: We retrospectively reviewed consecutive adults with rHGG who underwent re-RT from 2009-2020 from our institutional database. The primary objective was overall survival (OS). The secondary outcomes included prognostic factors for early death (&lt;6 months after re-RT) and predictors of radiation necrosis (RN). RESULTS: For the 79 patients identified, the median OS after re-RT was 9.9 months (95% CI 8.3-11.6). On multivariate analyses (MVA), re-resection at progression (HR=0.56, p=0.027), interval from primary treatment to first progression ≥16.3 months (HR=0.61, p=0.034), interval from primary treatment to re-RT ≥23.9 months (HR=0.35, p&lt;0.001), and re-RT PTV volume &lt;112 cc (HR=0.27, p&lt;0.001) were prognostic for improved OS. Patients who had unmethylated-MGMT tumours (OR=12.4, p=0.034), ≥3 prior systemic treatment lines (OR=29.1, p=0.22), interval to re-RT &lt;23.9 months (OR=9.0, p=0.039), and re-RT PTV volume ≥112 cc (OR=17.8, p=0.003) were more likely to survive &lt;6 months. The cumulative incidence of RN was 11.4% (95% CI 4.3-18.5) at 12 months. Concurrent bevacizumab use (HR&lt;0.001, p&lt;0.001) and cumulative equivalent dose in 2 Gy fractions (cEQD2, a/b=2) &lt;99 Gy2 (HR&lt;0.001, p&lt;0.001) were independent protective factors against RN. CONCLUSIONS: We observe favorable OS rates following re-RT and identified prognostic factors, including methylation status, that can assist in patient selection and clinical trial design. Concurrent use of bevacizumab and cEQD2 &lt;99 Gy2 mitigates the risk of RN.
SHH PATHWAY ACTIVATION IN DEDIFFERENTIATION DURING TUMOR PROGRESSION IN MPNST
Authors: Yakubov R Y , Bunda S B , Zadeh G Z 
Published: July 2023

Abstract
Malignant peripheral nerve sheath tumours (MPNST) are highly aggressive sarcomas with little progress on outcomes and treatment strategies. Previous work conducted in our lab used unsupervised analyses of methylome and transcriptome profiles of 108 peripheral nerve sheath tumours to uncover two subgroups of MPNSTs that predict progression-free survival, MPNST-G1 (characterized by SHH pathway activation) and MPNST-G2 (characterized by WNT/ß-catenin/CCND1 pathway activation). Further, single nuclear RNA-sequencing revealed that MPNST-G1 and MPNST-G2 cells resemble neural crest-like and Schwann cell precursor-like cells, respectively. Purpose & Hypothesis: To examine the expression of transcription factors (TWIST1, SOX9, SNAI2, OTX2, PAX3, and PAX6) known to play canonical roles in the early neural crest cell specification in MPNST-G1 cells. We speculate that MPNST-G1 cells will display overexpression of these transcription factors compared to MPNST-G2 cells and that Sonidegib (SMO inhibitor) will revert dedifferentiation by decreasing activation of the SHH pathway.
METHODS: Dedifferentiation transcription factor expression and the effects of SMO activation and inhibition in MPNST-G1 and MPNST-G2 cells were analyzed using RT-PCR and western blotting. Alamar blue and Trypan blue assays were used to determine the effect of SMO inhibition on proliferation. RESULTS: Compared to MPNST-G2 cells, MPNST-G1 cells displayed elevated expression of dedifferentiation transcription factors, SMO inhibition was able to reverse these effects. Conversely SMO activation induced the expression of these factors and induced an increase in proliferation. CONCLUSIONS: The SHH pathway activation promotes the expression of important transcription factors in dedifferentiation. This finding provides insights into the transformation process of MPNST and novel therapeutic options for these lethal cancers.
UPAR AS A NOVEL IMMUNOTHERAPEUTIC TARGET IN RECURRENT GLIOBLASTOMA
Authors: Maich William , Shaikh Vaseem , Puri Anish , Anand Alisha , Rosotti Martin , Savage Neil , Chokshi Chirayu , Suk Yujin , Savage Neil , Gwynne Will , Seyfrid Mathieu , Venugopal Chitra , Henry Kevin , Singh Sheila 
Published: July 2023

Abstract
Glioblastoma (GBM) is the common malignant brain tumor in adults, accounting for approximately 15% of all CNS tumors, and 48.6% of malignant brain tumors, with a median survival of approximately 15 months, and minimal clinical progress having been made in the past two decades. GBM is characterized by extensive inter- and intra-tumoral heterogeneity as well as an extremely immunosuppressive tumor microenvironment. Following Standard-of-Care (SoC) surgical resection and chemoradiotherapy at primary diagnosis, few therapeutic avenues exist at recurrence, owing in part due to a lack of clinically relevant targets. Data from our multi-institutional target pipeline suggests that the extracellular urokinase plasminogen activator receptor (uPAR) is significantly upregulated at recurrence on putative GBM brain tumor initiating cells (BTICs), which are believed to drive de novo tumor formation, tumor recurrence, and therapeutic resistance. uPAR plays an important role in the plasminogen activation system, and in the context of cancer, has been implicated in numerous pro-tumorigenic processes such as invasion, proliferation, epithelial-to-mesenchymal transition, and therapy resistance. In vitro, knockout of uPAR expression in recurrent GBM cells significantly reduces proliferation and sphere formation capacity, two stem-like traits associated with BTICs. Additionally, uPAR knockout cells display increased sensitivity to standard-of-care chemoradiotherapy, implicating uPAR expression in therapy resistance, as seen in recurrent disease. From these initial studies, we believe uPAR to be a clinically relevant target in recurrent GBM, and further investigation into therapeutic strategies to target uPAR-positive GBMs should be investigated further.
LONGITUDINAL NEUROLOGICAL ASSESSMENTS IN BRAIN TUMOR PATIENTS: CORRELATION BETWEEN NANO DOMAINS AND PERFORMANCE STATUS
Authors: Machado M , Roberto K , Melhem J , Theriault A , Chan A , Granovskaya I , Perry J , Chen H , Lim-Fat M J 
Published: July 2023

Abstract
The Karnofsky Performance Status (KPS) and Eastern Cooperative Oncology Group (ECOG) performance status are clinician-reported outcomes critical in guiding management and prognostication in patients with primary brain tumors as they can reflect longitudinal functional changes. However, they are subjective. The Neurologic Assessment in Neuro-Oncology (NANO) scale is a metric with specific neurological domains that was subsequently developed to provide an objective standardized measure of the neurologic functional status of patients, but how longitudinal changes in NANO scale relate to KPS or ECOG scores is unknown.
METHODS: A linear mixed model analysis involving 111 patients with primary brain tumors was performed. RESULTS: Statistically significant associations were identified between changes in specific NANO domains and KPS or ECOG scores. After controlling for time course both in univariable and multivariable analyses, worsening scores in gait, language and behavior domains showed significant association with decreased KPS. Gait and behavior were demonstrated to be significantly associated with ECOG both in univariable and multivariable analyses. CONCLUSIONS: The neurologic status of patients with a primary brain tumor is closely related to their performance status. In particular, the patient’s cognitive status and mobility have the greatest impact on their functional status and therefore their prognosis. Interventions and supportive care targeting these domains of function may help improve the outcomes of patients with brain tumors.
SURVEY OF CANADIAN NEURO-ONCOLOGY CLINICIANS ABOUT THE TREATMENT OF ADULT MEDULLOBLASTOMA
Authors: Cacciotti Chantel , Roberto Katrina , Climans Seth , Lim-Fat Mary Jane 
Published: July 2023

Abstract
Given the rarity of adult medulloblastoma, the optimal chemotherapy strategy is unknown and its management is thought to vary from institution to institution. Guidelines often omit suggestions for specific chemotherapy regimens, reflecting the lack of high-quality evidence in this population. We sought to understand Canadian adult medulloblastoma practice patterns, hoping to inform future quality metrics and guidelines.
METHODS: In March 2022, a 30-question survey was sent out to 71 adult neuro-oncology clinicians on the Canadian Adolescent and Young Adult national rounds mailing list. Snowball sampling was permitted. RESULTS: The response rate was 35%. Radiation oncologists (11), neuro-oncologists (8), medical oncologists (4), and neurosurgeons (2) responded from 6/10 Canadian provinces. They each treated on average 1.6 medulloblastoma patients per year. Most (61%) said that molecular subgrouping was always done at their centre. Half indicated that cerebrospinal fluid testing was always done at diagnosis. The most common (64%) radiation regimen was 36 Gy (in 20 fractions) craniospinal irradiation + 18 Gy (in 10 fractions) boost. Concomitant chemotherapy was rarely given while adjuvant chemotherapy was frequently administered. The most common adjuvant chemotherapy was Cisplatin/Lomustine/Vincristine (57%), but other regimens included Cisplatin/ Lomustine/ Vincristine alternating with Cyclophosphamide/ Vincristine (21%), Cisplatin/ Cyclophosphamide/ Vincristine (14%), and carboplatin-based regimens (14%). Respondents noted challenges prescribing chemotherapy in this population: drug toxicities, limited resources, and clinical uncertainty. There was support for standard-of-care adult medulloblastoma guidelines in 92%. CONCLUSIONS: There is significant practice variation among Canadian neuro-oncology centres treating adult medulloblastoma. This variation can serve as an opportunity for quality improvement and clinical research.
NEURO-CRITICAL CARE UNIT OR POST-ANESTHESIA CARE UNIT RECOVERY? ANALYSIS OF 24-HOUR OUTCOMES FOLLOWING 1078 ADULT BRAIN TUMOR SURGERIES
Authors: Yang Angela , Almansouri Abdulrahman , Djedid Anissa , Emara Ashraf , Nadaf Javad , Petrecca Kevin 
Published: July 2023

Abstract
Post-craniotomy recovery in a neuro-critical care unit (NCCU) has been routine for most patients. There is no evidence to support this practice. To address this, we assessed the development of post-operative adverse events in brain tumor resection patients surveilled in the NCCU or the post-anesthesia care unit (PACU).
METHODS: All brain tumor craniotomies performed between 2016-2021 (KP) were reviewed. Inclusion criteria were: age &gt;18; craniotomy for biopsy or resection of intracerebral or extracerebral tumors. Cohorts were divided into two groups based on recovery destination: NCCU or PACU. Past medical history, pre- and post-operative neuroradiological imaging, surgical resection features, and neuropathology results were reviewed for both groups. RESULTS: There were 681 patients in NCCU group and 397 in the PACU group. Mean ages were 55.6 (NCCU) and 59.7 (PACU) (p &lt;0.001). The American Society of Anesthesiologists (ASA) class was not significantly different between groups (p=0.89). Median recovery time in the NCCU group was 19 hours, and 4 hours in the PACU group. The incidence of adverse events within 24 hours post- surgery was 0.04 in NCCU group and 0.03 in PACU group (p=0.46). Post-operative hospital stay was 9.5 days in the NCCU group and 8.5 days in PACU group (p &lt;0.001). CONCLUSION: The incidence of adverse events within 24 hours post brain tumor surgery is not different between patients being surveilled for a long period in a NCCU, or a short period in a PACU.