bluuebunny/crossref_metadata_2025_split huggingface dataset:
Grade 3 Meningiomas Following 2021 WHO Guidelines—A Dual Center Retrospective Study on Clinical Characteristics and Outcomes
Authors: English Collin , Pugazenthi Sangami , Leidig Will , MgGeehan Kyle , Khan Basit , Gadot Ron , Kim Albert H. , Patel Akash J. 
Published: March 2024

INTRODUCTION:
In their updated 2021 guidelines, the World Health Organization (WHO) for the first time included molecular markers in the classification of Grade 3 meningiomas (G3Ms). Now, homozygous deletion of CDKN2A/B or TERT Promoter (TERTp) mutations independently qualify a meningioma as Grade 3 [1].

METHODS:
We performed a dual-center retrospective review from 2005 to 2021 on primary G3Ms. To adhere to guidelines, tumors were regraded when RNA sequencing, methylation profiling, or DNA microarray was available. Tumor recurrence was the outcome metric.

RESULTS:
A total of 1358 patients were reviewed with 31 (2.3%) primary tumors meeting criteria for Grade 3 and 4/31 (13%) meeting only molecular criteria. Among the 31 patients, 16 (52%) were female with a median age of 65. Upon regrading, 25 (81%) met only histological criteria, 3 (9.7%) had only TERTp mutations, 1 (3.1%) had only CDKN2A deletion, 1 (3.1%) met histological criteria and had TERT mutation, and 1 (3.1%) met histological criteria and had CDKN2A deletion. Molecular profiling of 18 G3Ms demonstrated chromosomal deletions in 1p (16/18, 89%), 14q (10/18, 56%), and 22q (16/18, 89%). Common locations were frontal (11/31, 35%) and parietal convexity (6/31, 23%). Histological findings included necrosis (24/31, 77%), hypercellularity (23/31, 74%), and prominent nucleoli (21/31, 68%). Tumors recurred in 9/31 (29%) and 8/31 (26%) recurred multiple times.

CONCLUSIONS:
Here we present the first description of G3Ms following the updated 2021 WHO guidelines.
Where Do Surgical Resection and Radiosurgery Fall Short for Large Metastatic Brain Lesions?
Authors: Mishra Akash , Koffler Daniel , Calugaru Emel , Viswanatha Sirisha Devi , Rowe Niara , Bajaj Vikram , Goenka Anuj , Schulder Michael 
Published: March 2024

INTRODUCTION:
Stereotactic radiosurgery is established as the optimal treatment modality for metastatic disease of the brain, but there is ongoing debate about the optimal treatment for larger brain metastases. There have been few studies identifying and quantifying lesion characteristics where efficacy and local control of these lesions suffer.

METHODS:
We retrospectively identified patients who received surgical resection and/or hypofractionated Gamma Knife radiosurgery (HF-GKRS) between 2017 and 2022 for the treatment of metastatic brain tumors greater than 10cc. Clinical, treatment, and radiological data was collected. Local failure (LF) events were examined, and independent factors associated with subsequent local failure were identified.

RESULTS:
105 lesions greater than 10cc (in 97 patients) were treated and the median patient follow-up was 10.1 months. The median gross tumor volume was 15.8cc (range 10.1-62.4). Prior surgical resection was performed on 49 lesions (54%). Tumor volume larger than 33.5cc (p = 0.029, 12-month LF rate 38%) and radioresistant histology (p=0.047, 12-month LF rate 54%) were associated with increased risk of LF (p=0.018) whereas surgical resection did not correlate with increased LC (p = 0.642, 12-month LF rate 19%).

CONCLUSIONS:
Patients with brain metastases that are greater than 4cm in diameter or are of radioresistant histology (primary origin of gastrointestinal adenocarcinoma, melanoma, or renal cell carcinoma) are especially prone to local failure despite aggressive surgical resection, stereotactic radiosurgery, and systemic chemotherapy. In these cases, the optimal management needs to be further elucidated and may involve preoperative stereotactic radiosurgery or intraoperative brachytherapy.
Reliability and Predictors of Intraoperative Neuromonitoring Changes During Intramedullary Tumor Resection: A Multicenter Experience
Authors: Otamendi-Lopez Andrea , Akinduro Oluwaseun O. , de Macedo Filho Leonardo , Goyal Anshit , De Biase Gaetano , Ghaith Abdul Karim , McKevitt Chase , Kalani Maziyar A. , Meyer Fredric B. , Marsh W. Richard , Clarke Michelle J. , Krauss William E. , Bydon Mohamad , Quinones-Hinojosa Alfredo 
Published: March 2024

INTRODUCTION:
Intraoperative neuromonitoring (IONM) is used in real-time to alert neurosurgeons of potential neurological changes when resecting intramedullary spinal cord tumors (IMSCTs). Previous studies have reported variable reliability of IONM.

METHODS:
A multicenter retrospective study was performed on patients undergoing IMSCTs surgery with neuromonitoring at the three Mayo Clinic sites between 2005 to 2022. Demographics, SSEP, MEP changes and postoperative outcomes were recorded. Specificity, sensitivity, positive predictive value (PPV), and negative predictive value (NPV) were calculated. Variables found significant on univariate analysis (p < 0.05) were applied to a multivariate model to identify predictors for IONM SSEP and MEP changes.

RESULTS:
135 patients underwent surgical resection for IMSCTs using IONM. The mean age at diagnosis was 45 ± 17.9 years. Laminectomy was the most frequent index operation (96.3%). A total of 8.9% of patients presented with short-term improvement, while 70.4% presented long-term improvement on their baseline McCormick Scale. Sensitivity, specificity, PPV, NPV, accounted for 86.2%, 51%, 5.2%, 99.2% for MEP; 77.8%, 48.2%, 4.4%, 98.6% for SSEP. We found predictors of IONM changes: poorly defined MEP baseline (OR 3.004, 95% CI 1.22-7.397, p = 0.017), WHO grade II tumors (OR 2.334, 95% CI 1.043-5.223, p = 0.039), cervicomedullary junction location (OR 0.103, 95% CI 0.011-0.983, p = 0.048). Only WHO grade II tumors (OR 2.85, 95% CI 1.208-6.727, p = 0.017) was a predictor for SSEP changes.

CONCLUSIONS:
Our study represents the largest cohort describing sensitivity, specificity, and predictive factors for intraoperative changes and postoperative outcomes of resection of IMSCTs. A poorly defined baseline and cervicomedullary tumor location were predictors of IONM MEP changes, whiIe WHO grade II tumors were a predictor for both IONM SSEP and MEP changes.
Blood-Brain Barrier Opening with Ultrasound Augments Doxorubicin and Anti-PD-1 Therapy Efficacy, Intracranial Immune Activation, and Prolongs Survival in Preclinical Glioma Models
Authors: Arrieta Victor Andrés , Gould Andrew , Kim Kwang-Soo , Habashy Karl , Dmello Crismita , Amidei Christina , Gómez Cristal G. , Zhang Daniel , Saganty Ruth , Chen Li , Pandey Surya , Cholak Meghan E. , McCord Matthew , McCortney Kathleen , Castro Brandyn , Ward Rachel , Muzzio Miguel , Bouchoux Guillaume , Desseaux Carole , Carpentier Alexandre C. , Zhang Bin , Miska Jason , Horbinski Craig , Lukas Rimas Vincas , Stupp Roger , Chang Catalina Lee , Sonabend Adam M. 
Published: March 2024

INTRODUCTION:
The limited drug penetration across the blood-brain barrier (BBB) represents a challenge for the treatment of glioblastoma patients. A novel drug delivery technology based on low-intensity pulsed ultrasound combined with intravenous microbubbles (LIPU/MB) overcomes this challenge by opening the BBB. In this study, we hypothesize that LIPU/MB enhances the therapeutic effect of both liposomal doxorubicin and anti-PD-1 therapy in gliomas by eliciting local immune responses.

METHODS:
We utilized LIPU/MB to deliver doxorubicin and anti-PD-1 blocking antibodies to murine models and evaluated drug concentrations in the brain. Flow cytometry evaluated IFN-g production by glioma-associated microglia and macrophages in murine gliomas treated with doxorubicin and anti-PD-1 therapy delivered by LIPU/MB. Furthermore, we assessed the efficacy of this drug combination delivered by LIPU/MB in glioma-bearing mice.

RESULTS:
LIPU/MB induced a 4-fold increase in doxorubicin concentrations in sonicated brains compared to those not sonicated (p = 0.003). In addition, doxorubicin delivered with LIPU/MB elicited an IFN-g phenotype (p < 0.0001) as well as MHC I and PD-L1 expression in glioma-associated microglia and macrophages (p < 0.05). Increased brain concentrations of doxorubicin led to long-term survivors in the majority of glioma-bearing mice. On the other hand, LIPU/MB-mediated BBB opening increased brain concentrations of anti-PD-1 therapy in mice (6.3-fold increase, p < 0.01). The combination of doxorubicin and anti-PD-1 therapy delivered with LIPU/MB resulted in long-term survival (p < 0.0001). This effect was abrogated in CD8-/- mice suggesting that T cells are important for the efficacy of doxorubicin and anti-PD-1 therapy delivered with LIPU/MB.

CONCLUSIONS:
This preclinical study demonstrates the immense potential of LIPU/MB technology in enhancing intracranial immune responses and drug delivery for glioblastoma treatment using doxorubicin and anti-PD-1 therapy, paving the way for more effective treatment strategies for this brain cancer.
Safety and Feasibility of JAK Inhibitor Ruxolitinib in Newly-Diagnosed High-Grade Gliomas (CRUX): Final Trial Report
Authors: Ozair Ahmad , Khosla Atulya , Rauf Yasmeen , Wei Wei (Auston) , Murphy Erin , Chao Samuel T. , Suh John H. , Stevens Glen , Peereboom David M. , Ahluwalia Manmeet 
Published: March 2024

INTRODUCTION:
Dysregulation of the JAK/STAT pathway in newly-diagnosed high-grade gliomas (nHGG) is linked to enhanced survival and proliferation of tumor cells. Ruxolitinib, a small molecule inhibitor of JAK1, JAK2, and JAK3, limits glioma growth in preclinical models.

METHODS:
This non-randomized prospective study included 60 WHO Grade 3-4 nHGG patients who received standard of care (SOC) therapy along with ruxolitinib in a 3 + 3 dose-escalation design; level 1 of 10 mg BID, level 2 of 15 mg BID, level 3 of 20 mg BID, level -1 of 5 mg BID. Primary study objective was determination of maximum tolerated dose (MTD) of ruxolitinib in combination with chemoradiation. Secondary objective was the determination of safety as assessed using NIH CTCAE scale, overall survival (OS), and progression-free survival (PFS). Exploratory aims were to investigate relationships between clinical outcomes and genomic signatures.

RESULTS:
60 patients were enrolled, with median age 60.5 years (range 22-78), 23 (38%) female, and 37 (62%) were male. Amongst 59 evaluable patients, 29 (49%) were MGMT unmethylated and received ruxolitinib with 60Gy radiation over 6 weeks, while 30 (51%) patients were MGMT methylated and received ruxolitinib with 75mg/m2 of temozolomide (TMZ) with 60Gy radiation over 6 weeks. MTD for both cohorts was 20 mg BID. No dose-limiting toxicities were observed. Toxicities attributable to study medications included four grade 4 AEs including seizure, respiratory distress, somnolence, and thromboembolic event along with 14 grade 3 adverse events (AEs), including respiratory distress, seizure, gait disturbance, weakness, thrombocytopenia, cognitive disturbance, urinary retention, and meningitis. Median follow-up of patients alive was 34.2 months (range 18-52.2) with outcomes.

CONCLUSIONS:
Ruxolitinib therapy is safe and therapeutically feasible in combination with TMZ and radiation. A randomized phase 2 trial is planned.
Transcranial Agonism of CD40 and ICOS Promotes Meningeal Immunity and Control of Glioblastoma
Authors: Walsh Lisa , Monaghan Kelly , Ampie Leonel , Ghabdan-Zanluqui Nagela , Heiss John D. , McGavern Dorian 
Published: March 2024

INTRODUCTION:
Glioblastomas generate an immunosuppressive microenvironment that limits antitumor immune responses.

METHODS:
We used the SB28 model of glioblastoma in C57BL/6J (B6) mice, which is a poorly immunogenic tumor with a lower mutational load than other many glioblastoma cell lines used in rodents. We stereotactically injected 7,000 SB28 cells at a depth of 1 mm into the neocortex of 8- to 10-week-old mice. At day 7, a carboxymethylcellulose gel containing 100 µg of agonistic anti-ICOS and 200 µg anti-CD40 were injected transcranially (i.e., under the scalp) of mice. Control mice received corresponding isotype control antibodies. Meningeal whole mounts were then stained using immunohistochemistry and imaged by confocal microscopy.

RESULTS:
Transcranial agonism of CD40 and ICOS generated a markedly enhanced and more localized meningeal immune response against SB28 tumors than intravenous agonism. Specifically, transcranial treatment promoted formation of CD4 T cell and B cell clusters in the meninges as well as increased production of class-switched immunoglobulins. These clusters were also associated with reduced tumor size at day 14.

CONCLUSIONS:
Our results demonstrate that transcranial delivery of antibodies against CD40 and ICOS can drive a local humoral immune response against an immunologically silent SB28 glioblastoma. We postulate that application of these agonistic antibodies in combination with a tumor neoantigen will further enhance tumor control and may offer a possible treatment modality in human glioblastoma patients.
Extent of Resection Thresholds in Molecular Subgroups of IDH-Wildtype Glioblastoma
Authors: Dono Ostorga Antonio Gabriel , Zhu Ping , Takayasu Takeshi , Arevalo Octavio , Tandon Nitin , Ballester Leomar , Esquenazi Yoshua 
Published: March 2024

INTRODUCTION:
Maximizing the extent of resection (EOR) improves outcomes in glioblastoma (GBM). However, prior GBM studies have not addressed the impact of EOR in molecular subgroups of GBM beyond IDH1/IDH2 status. Therefore, it remains unclear whether EOR confers a benefit in all GBM subtypes or only in particular molecular subgroups.

METHODS:
Patients with newly diagnosed GBM IDH-wildtype undergoing resection were prospectively included in a database (n=138). EOR and RTV were quantified with semi-automated software. Formalin-fixed paraffin-embedded tumor tissues were analyzed by targeted next-generation sequencing. The association between recurrent genomic alterations and EOR/RTV was evaluated using a recursive partitioning analysis (RPA) to identify thresholds of EOR or RTV that may predict survival. The Kaplan-Meier methods and multivariable Cox proportional hazards regression methods were applied for survival analysis.

RESULTS:
Patients with EOR = 95.9% and younger than 67.5 years experienced improved survival compared to older patients with EOR <95.9% (Hazard ratio [HR] 5.85, p < 0.002). Patients with alterations in the TP53 pathway and EOR <88.72% showed reduced OS (mOS: 10.5 vs. 18.8 months; HR: 2.78, p = 0.013). However, EOR/RTV was not associated with OS in patients without alterations in the TP53 pathway. Among patients with EOR <87.69%, PTEN altered had significantly worse overall survival than PTEN wildtype (9.5 vs. 15.4 months; HR: 4.53, p < 0.001).

CONCLUSIONS:
Our results suggest that a subset of molecularly defined GBMs IDH-wildtype may benefit more from aggressive resections. Re-resections to optimize EOR might be beneficial in a subset of molecularly defined GBMs. Molecular alterations should be taken into consideration for surgical treatment decisions in GBM IDH-wildtype.
Murine Models of Laser Interstitial Thermal Therapy for Immuno-Oncology
Authors: Haskell-Mendoza Aden Pepe , Wachsmuth Lucas , Tyc Richard , Fecci Peter Edward 
Published: March 2024

INTRODUCTION:
Cytoreductive surgery is a cornerstone of management for intracranial tumors. However, such treatment may remove an important source of neoantigen. In the case of laser interstital thermal therapy (LITT), thermally-ablated tumor remans in situ, allowing for a potential anti-tumor immune response.

METHODS:
Brain tumor cell lines (CT-2A) were stereotactically implanted into C57BL/6 mice. A 1064 nm Nd:YAG laser (Neuroblate, Monteris Medical) was used to ablate normal brain and tumor tissue.

RESULTS:
To establish anatomical boundaries for our ablation, we characterized our CT-2A model on T2 MRI, selecting 10 days post-implantation for LITT based on lesion size. We simultaneously implanted a 400 μm laser fiber and thermocouple probe into the center and edge of the target volume, respectively, for simultaneous ablation and temperature monitoring. To characterize the laser's effects, we first performed a dose titration of laser power/time in normal mouse brains, finding that doses above 2 W for 30 s produced cavitary lesions with charring that resulted in death at 24 h post-LITT. We therefore selected 1 W for 60 s as a safe laser power dose in our tumor model. Ablations at this setting rapidly heated the lesion edge to a peak temperature of mean 43.79 ± 2.993 °C, sparing the surrounding brain. MRI imaging at 1, 3, and 7 days post-LITT revealed an expansile T2 hyperintense lesion, with hemmorhage and necrosis on H&E. LITT increased survival to 28 from 25.5 days (vs sham, p = 0.0172).

CONCLUSIONS:
Using a clinical laser system, we were able to model the essential clinicopathological effects of LITT in mice: a cytoreductive survival benefit; lesion expansion on MRI; and focal necrosis with hemorrhagic vasculature on H&E. This model allows for detailed immunological studies of LITT and use with existing brain metastasis cell lines.
Spreadsheet Modeling and Wrangling with Python
Authors: Isken Mark W. 
Published: March 2024

A staple of many spreadsheet-based management science courses is the use of Excel for activities such as model building, sensitivity analysis, goal seeking, and Monte-Carlo simulation. What might those things look like if carried out using Python? We describe a teaching module in which Python is used to do typical Excel-based modeling and data-wrangling tasks. In addition, students are exposed to basic software engineering principles, including project folder structures, version control, object-oriented programming, and other more advanced Python skills, creating deployable packages and documentation. The module is supported with Jupyter notebooks, Python scripts, course web pages that include numerous screencasts, and a few GitHub repositories. All of the supporting materials are permissively licensed and freely accessible. Supplemental Material: The supplemental files are available at https://doi.org/10.1287/ited.2023.0047 .
An evaluation of driveline dressing protocols and infection rates for left ventricular assist devices across UK transplant centres
Authors: Woods Andrew , Tovey Sian , McGurk Jennifer , Kore Shishir , Synowiec Ewa , Mulhern Justin , Smith Sophie , Sequeira Joao , Fernandez Oscar , McDiarmid Adam , Shah Asif , Scheuler Stephan , MacGowan Guy 
Published: March 2024

Background/Aims Left ventricular assist devices are used to improve the quality of life of people waiting for heart transplantation. Driveline infections are a significant complication of these devices, occurring in 30–40% of cases, which could lead to life threatening sepsis. This study aimed to review UK driveline dressing protocols and infection rates to determine if national standardisation is possible. Methods Six UK heart transplant centres were asked to share their driveline dressing protocols for comparison. National driveline infection data were obtained from the NHS Blood and Transplant database. Infection rates, patient demographics and device types were compared using Chi squared tests, with a P value of <0.05 indicating statistical significance. Results The study found 38 driveline infections over a 3-year period, with an average infection rate was 4.4% per year. There were no significant difference in infection rates between device types. Dressing protocols varied between centres, but all centres followed international guidance. The timepoint where the highest number of infections were diagnosed was 12 months post implantations, accounting for 23.7% of infections. There were no significant differences in infection rates between centres in 2019–20 or 2021–22, but a significant difference was observed for 2020–21 (P=0.013). Conclusions UK driveline infection rates are below the average reported in the literature. Despite some differences in dressing protocols, all centres examined in this study maintained a level of infection comparable to reported rates. The feasibility of national standardisation remains uncertain, and further research is needed to determine the most effective dressing protocols for preventing driveline infections.
Lifetime cost-effectiveness analysis osseointegrated transfemoral versus socket prosthesis using Markov modelling
Authors: Voigt Jeffrey D. , Potter Benjamin K. , Souza Jason , Forsberg Jonathan , Melton Danielle , Hsu Joseph R. , Wilke Benjamin 
Published: March 2024

AimsPrior cost-effectiveness analyses on osseointegrated prosthesis for transfemoral unilateral amputees have analyzed outcomes in non-USA countries using generic quality of life instruments, which may not be appropriate when evaluating disease-specific quality of life. These prior analyses have also focused only on patients who had failed a socket-based prosthesis. The aim of the current study is to use a disease-specific quality of life instrument, which can more accurately reflect a patient’s quality of life with this condition in order to evaluate cost-effectiveness, examining both treatment-naïve and socket refractory patients.MethodsLifetime Markov models were developed evaluating active healthy middle-aged male amputees. Costs of the prostheses, associated complications, use/non-use, and annual costs of arthroplasty parts and service for both a socket and osseointegrated (OPRA) prosthesis were included. Effectiveness was evaluated using the questionnaire for persons with a transfemoral amputation (Q-TFA) until death. All costs and Q-TFA were discounted at 3% annually. Sensitivity analyses on those cost variables which affected a change in treatment (OPRA to socket, or socket to OPRA) were evaluated to determine threshold values. Incremental cost-effectiveness ratios (ICERs) were calculated.ResultsFor treatment-naïve patients, the lifetime ICER for OPRA was $279/quality-adjusted life-year (QALY). For treatment-refractory patients the ICER was $273/QALY. In sensitivity analysis, the variable thresholds that would affect a change in the course of treatment based on cost (from socket to OPRA), included the following for the treatment-naïve group: yearly replacement components for socket > $8,511; cost yearly replacement parts OPRA < $1,758; and for treatment-refractory group: yearly replacement component for socket of > $12,467.ConclusionThe use of the OPRA prosthesis in physically active transfemoral amputees should be considered as a cost-effective alternative in both treatment-naïve and treatment-refractory socket prosthesis patients. Disease-specific quality of life assessments such as Q-TFA are more sensitive when evaluating cost-effectiveness.Cite this article: Bone Jt Open 2024;5(3):218–226.
Laser-pump-resistive-probe technique to study nanosecond-scale relaxation processes
Authors: Blumenau Mark I. , Kuntsevich Aleksander Yu. 
Published: March 2024

Standard optical pump-probe methods analyze a system’s temporal
response to a laser pulse within sub-femtoseconds to several
nanoseconds, constrained by the optical delay line’s length. While
resistance is a sensitive detector in various fields, its measurements
are typically slow (>µs) due to stabilization requirements.
We suggest here a time-resolved pump-probe technique that combines an
optical pump pulse and a rectangular electrical probe pulse through
the sample, measuring transmission in a 50 ohm matched circuit
with a digital oscilloscope. This allows electrically driven delays
from nanoseconds to seconds. Demonstrations include studying
heat-induced changes in a thin amorphous VO
x
film and carrier relaxation in a CdS
photoresistor, showcasing potential applications in heat transfer,
biochemical reactions, and gradual electronic transformations.