bluuebunny/crossref_metadata_2025 huggingface dataset:
Burnout among public sector pharmacy staff two years into the COVID-19 pandemic
Authors: Kho Boon Phiaw , Chua Wan Ching Wendy , Liu Wei Tiing Emily , Lim Siau Choon , Leong Hui Hui Lynn , Chai Yeehui Aleen
Published: July 2023

Objectives

This study aimed to determine the prevalence and factors contributing to burnout among public sector pharmacy staff in Sarawak, Malaysia, two years into the COVID-19 pandemic. Impact of burnout on their lives and their coping strategies were also examined.

Methods

A cross-sectional online survey was carried out among all pharmacy staff in public healthcare facilities throughout Sarawak. Burnout was measured using the Copenhagen Burnout Inventory. Multiple logistic regression analysed demographic and work characteristics associated with burnout. Open-ended replies on burnout causes, impact, coping strategies and employer’s role were coded and thematically analysed.

Key findings

A total of 329 responses were received. The prevalence of personal, work and patient-related burnout was 54.7, 47.1 and 35.3%, respectively. Respondents facing problems with child support were 8.26 and 3.62 times more likely to suffer from personal and work-related burnout. Working in areas with potential exposure to COVID-19 patients increased the odds of patient and work-related burnout by 2.80 and 1.86 times, respectively. Burnout symptoms affected their quality of life; nevertheless, self-reported coping strategies were mostly positive. Respondents emphasised the need for organisational interventions, including increased resource allocation, better workload distribution and promotion of work–life balance, to mitigate burnout.

Conclusions

A significant percentage of public sector pharmacy staff continue to experience burnout two years into the pandemic. Regular well-being assessments and supportive policies are recommended to help them cope with increased stress. Additional training for supervisors may be necessary to effectively manage staff and workload during a pandemic.
Evaluating Clinic-Based Interventions to Reduce Racial Differences in Mortality Among People With Human Immunodeficiency Virus in the United States
Authors: Zalla Lauren C , Cole Stephen R , Eron Joseph J , Adimora Adaora A , Vines Anissa I , Althoff Keri N , Marconi Vincent C , Gill M John , Horberg Michael A , Silverberg Michael J , Rebeiro Peter F , Lang Raynell , Kasaie Parastu , Moore Richard D , Edwards Jessie K
Published: July 2023

Background

Mortality remains elevated among Black versus White adults receiving human immunodeficiency virus (HIV) care in the United States. We evaluated the effects of hypothetical clinic-based interventions on this mortality gap.

Methods

We computed 3-year mortality under observed treatment patterns among >40 000 Black and >30 000 White adults entering HIV care in the United States from 1996 to 2019. We then used inverse probability weights to impose hypothetical interventions, including immediate treatment and guideline-based follow-up. We considered 2 scenarios: “universal” delivery of interventions to all patients and “focused” delivery of interventions to Black patients while White patients continued to follow observed treatment patterns.

Results

Under observed treatment patterns, 3-year mortality was 8% among White patients and 9% among Black patients, for a difference of 1 percentage point (95% confidence interval [CI], .5–1.4). The difference was reduced to 0.5% under universal immediate treatment (95% CI, −.4% to 1.3%) and to 0.2% under universal immediate treatment combined with guideline-based follow-up (95% CI, −1.0% to 1.4%). Under the focused delivery of both interventions to Black patients, the Black–White difference in 3-year mortality was −1.4% (95% CI, −2.3% to −.4%).

Conclusions

Clinical interventions, particularly those focused on enhancing the care of Black patients, could have significantly reduced the mortality gap between Black and White patients entering HIV care from 1996 to 2019.
Sexual and mating system inThor hainanensis(Decapoda: Natantia: Thoridae) from the Lakshadweep Archipelago, India
Authors: Jose Sheena , Prakash Sanjeevi , Ajith Kumar Thipramalai Thangappan , Sarkar Uttam Kumar
Published: July 2023

We tested the hypothesis that the Hainan’s squat shrimp Thor hainanensisXu & Li, 2014 undergoes a sex change and displays protandric hermaphroditism, a well-known feature from other congeners (T. dicaprioAnker & Baeza, 2021 and T. amboinensis (De Man, 1888)). We used morphological traits indicative of male function to categorize shrimp as prehensile males, non-prehensile males, and females. The linear relationship among the different morphological characters and the sexual morphs revealed that T. hainanensis has a sexual system of partial protandric hermaphroditism, where 50% of the population stays as active males and the rest of the population changes to female. Observations on the social and mating behaviour suggest that T. hainanensis exhibits a ‘search and defend’ mating system unlike other tropical caridean shrimps featuring protandrous hermaphroditism.
Adaptive neural network ensemble using prediction frequency
Authors: Lee Ungki , Kang Namwoo
Published: July 2023

Neural network (NN) ensembles can reduce large prediction variance of NN and improve prediction accuracy. For highly non-linear problems with insufficient data set, the prediction accuracy of NN models becomes unstable, resulting in a decrease in the accuracy of ensembles. Therefore, this study proposes a prediction frequency-based ensemble that identifies core prediction values, which are core prediction members to be used in the ensemble and are expected to be concentrated near the true response. The prediction frequency-based ensemble classifies core prediction values ​​supported by multiple NN models ​​by conducting statistical analysis with a frequency distribution, which is a collection of prediction values ​​obtained from various NN models for a given prediction point. The prediction frequency-based ensemble searches for a range of prediction values that contains prediction values above a certain frequency, and thus the predictive performance can be improved by excluding prediction values with low accuracy ​​and coping with the uncertainty of the most frequent value. An adaptive sampling strategy that sequentially adds samples based on the core prediction variance calculated as the variance of the core prediction values is proposed to improve the predictive performance of the prediction frequency-based ensemble efficiently. Results of various case studies show that the prediction accuracy of the prediction frequency-based ensemble is higher than that of Kriging and other existing ensemble methods. In addition, the proposed adaptive sampling strategy effectively improves the predictive performance of the prediction frequency-based ensemble compared with the previously developed space-filling and prediction variance-based strategies.
Enhancing prestack seismic data by sparse radon transform and dynamic waveform matching
Authors: Ma Fangzheng , Wu Chengliang , Sheng Shen
Published: July 2023

In the field of complex underground geological structures and irregular topography, prestack seismic data often have a low signal-to-noise ratio (SNR), in which weakly reflected signals are buried beneath strong incoherent, and scattered noise. Stacking, such as beamforming along the moveout surfaces of coherent local events, can significantly improve seismic data quality. Accurate and efficient estimation of the moveout for an irregular acquisition geometry and uneven illumination is important in a complex environment. In this paper, a new optimal stacking approach for enhancing weak prestack reflection signals is presented. The proposed method mainly includes regional division and moveout estimation. Optimal stacking should be implemented within local time and space domains. Based on beam-ray theory, we designed a reasonable regional division of the common-shot (CS), common-receiver (CR) and common-middle-point (CMP) domains. Then, we proposed using the sparse radon transform and dynamic waveform matching method to estimate the moveout surfaces of local reflection events. The sparse radon transform was applied to obtain the linear moveout to ensure the correctness of the reflection wave direction. The residual nonlinear disturbance was estimated using the dynamic waveform matching method. Tests on synthetic and field data demonstrated the effectiveness of the proposed method, which can effectively improve the SNR of prestack seismic data and attenuate incoherent noise.
Adjuvant endocrine therapy uptake, toxicity, quality of life, and prediction of early discontinuation
Authors: Balazard Félix , Bertaut Aurélie , Bordet Élise , Mulard Stéphane , Blanc Julie , Briot Nathalie , Paux Gautier , Dhaini Merimeche Asma , Rigal Olivier , Coutant Charles , Fournier Marion , Jouannaud Christelle , Soulie Patrick , Lerebours Florence , Cottu Paul-Henri , Tredan Olivier , Vanlemmens Laurence , Levy Christelle , Mouret-Reynier Marie-Ange , Campone Mario , Brady Keri J S , Sasane Medha , Rice Megan , Coulouvrat Catherine , Martin Anne-Laure , Jacquet Alexandra , Vaz-Luis Ines , Herold Christina , Pistilli Barbara
Published: July 2023

Background

Many patients receiving adjuvant endocrine therapy (ET) for breast cancer experience side effects and reduced quality of life (QoL) and discontinue ET. We sought to describe these issues and develop a prediction model of early discontinuation of ET.

Methods

Among patients with hormone receptor–positive and HER2-negative stage I-III breast cancer of the Cancer Toxicities cohort (NCT01993498) who were prescribed adjuvant ET between 2012 and 2017, upon stratification by menopausal status, we evaluated adjuvant ET patterns including treatment change and patient-reported discontinuation and ET-associated toxicities and impact on QoL. Independent variables included clinical and demographic features, toxicities, and patient-reported outcomes. A machine-learning model to predict time to early discontinuation was trained and evaluated on a held-out validation set.

Results

Patient-reported discontinuation rate of the first prescribed ET at 4 years was 30% and 35% in 4122 postmenopausal and 2087 premenopausal patients, respectively. Switching to a new ET was associated with higher symptom burden, poorer QoL, and higher discontinuation rate. Early discontinuation rate of adjuvant ET before treatment completion was 13% in postmenopausal and 15% in premenopausal patients. The early discontinuation model obtained a C index of 0.62 in the held-out validation set. Many aspects of QoL, most importantly fatigue and insomnia (European Organization for Research and Treatment of Cancer QoL questionnaire 30), were associated with early discontinuation.

Conclusion

Tolerability and adherence to ET remains a challenge for patients who switch to a second ET. An early discontinuation model using patient-reported outcomes identifies patients likely to discontinue their adjuvant ET. Improved management of toxicities and novel more tolerable adjuvant ETs are needed for maintaining patients on treatment.
Gastrojejunocolic fistula: a rare complication of peptic ulcer surgery
Authors: Azouz Sarra Ben , Hassine Hajer , Debbabi Habiba , Yacoub Haythem , Cherif Dhouha , Elkhouni Balkis , Boukriba Seif , Kchir Hela , Maamouri Nadia
Published: July 2023

Gastrojejunocolic fistula (GJF) is a very rare complication of peptic ulcer surgery. Patients with this condition often present with diarrhea, fecal vomiting as well as weight loss. Here, we report a case of 62-year-old male with a GJF complicating upper gastrointestinal surgery.
Haemorrhagic cholecystitis treated with endovascular embolization
Authors: Morrow Joseph , Garvey Christopher , Ryan J Mark
Published: July 2023

Haemorrhagic cholecystitis is a rare complication of acute cholecystitis. Traditionally, treatment has been with emergency cholecystectomy. Endovascular management of haemorrhage allows the patient to be optimized for surgery at a later date. Our case presents a 52-year-old woman with haemorrhagic cholecystitis who underwent endovascular coil embolization of the cystic artery in interventional radiology. Further complications later ensued including a haematoma in the gallbladder fossa and a bile leak into the peritoneal cavity. As a result, the patient had an endoscopic retrograde cholangiopancreatography (ERCP) with placement of a covered stent into the extrahepatic bile ducts. The patient later developed abscess formation in the gallbladder fossa, which was managed with a percutaneous pigtail drain. Following clinical and radiological improvement, the patient was discharged with the gallbladder fossa drain and biliary stent in situ to await elective cholecystectomy. Endovascular embolization is a useful alternative, in the acute setting, to emergency surgical cholecystectomy.
Redox regulation, thioredoxins, and glutaredoxins in retrograde signalling and gene transcription
Authors: Sevilla Francisca , Martí Maria Carmen , De Brasi-Velasco Sabrina , Jiménez Ana
Published: July 2023

Integration of reactive oxygen species (ROS)-mediated signal transduction pathways via redox sensors and the thiol-dependent signalling network is of increasing interest in cell biology for their implications in plant growth and productivity. Redox regulation is an important point of control in protein structure, interactions, cellular location, and function, with thioredoxins (TRXs) and glutaredoxins (GRXs) being key players in the maintenance of cellular redox homeostasis. The crosstalk between second messengers, ROS, thiol redox signalling, and redox homeostasis-related genes controls almost every aspect of plant development and stress response. We review the emerging roles of TRXs and GRXs in redox-regulated processes interacting with other cell signalling systems such as organellar retrograde communication and gene expression, especially in plants during their development and under stressful environments. This approach will cast light on the specific role of these proteins as redox signalling components, and their importance in different developmental processes during abiotic stress.
The Influence of Advanced Hyperbaric Medical Training on Arterial Gas Embolism Treatment
Authors: Franco Michael A , Ng Peter , Tuft Michael J , Keuski Brian M
Published: July 2023

3d Reconnaissance Battalion, a forward-deployed Marine Corps unit in Okinawa, Japan, frequently performs diving operations. Often throughout the year, several reconnaissance teams are diving simultaneously in different locations for training. We present a case of an otherwise healthy 30-year-old-male Reconnaissance Marine who surfaced from a dive with abnormal symptoms and received prompt care from exercise participants who were nonmedical personnel. Studies have demonstrated improved morbidity outcomes in decompression illness patients with shorter times to hyperbaric treatment following the onset of symptoms. High-risk military exercises with diving components have a mandatory safety structure that includes recompression chamber support. All United States Marine Corps Reconnaissance, Marine Corps Special Operations Command, and U.S. Navy dive operations are required to have at least one diving supervisor. To expand the diving capabilities of the unit, Marines are encouraged to attend training and qualify as diving supervisors. This case study demonstrates the efficacy and importance of training Recon Marines to recognize decompression illness as diving supervisors.
Mass-stream trajectories with non-synchronously rotating donors
Authors: Hendriks D D , Izzard R G
Published: July 2023

Mass-transfer interactions in binary stars can lead to accretion disc formation, mass-loss from the system, and spin-up of the accretor. To determine the trajectory of the mass-transfer stream, and whether it directly impacts the accretor, or forms an accretion disc, requires numerical simulations. The mass-transfer stream is approximately ballistic, and analytic approximations based on such trajectories are used in many binary population synthesis codes as well as in detailed stellar evolution codes. We use binary population synthesis to explore the conditions under which mass transfer takes place. We then solve the reduced three-body equations to compute the trajectory of a particle in the stream for systems with varying system mass ratio, donor synchronicity, and initial stream velocity. Our results show that, on average, both more mass and more time are spent during mass transfer from a sub-synchronous donor than from a synchronous donor. Moreover, we find that at low initial stream velocity, the asynchronous rotation of the donor leads to self-accretion over a large range of mass ratios, especially for supersynchronous donors. The stream (self-)intersects in a narrow region of parameter space where it transitions between accreting on to the donor or the accretor. Increasing the initial stream velocity leads to larger areas of the parameter space where the stream accretes on to the accretor, but also more (self-)intersection. The radii of closest approach generally increase, but the range of specific angular momenta that these trajectories carry at the radius of closest approach gets broader. Our results are made publicly available.
Efficacy and safety of tocilizumab in Japanese patients with systemic sclerosis and associated interstitial lung disease: A subgroup analysis of a global, randomised, controlled Phase 3 trial
Authors: Kuwana Masataka , Takehara Kazuhiko , Tanaka Yoshiya , Yamashita Katsuhisa , Katsumata Kyoko , Takata Mai , Shima Yoshihito
Published: July 2023

Objectives

The aim of this article is to investigate the efficacy and safety of tocilizumab in Japanese patients with systemic sclerosis.

Methods

Post hoc subgroup analysis of a global, randomised, controlled trial in patients treated with weekly tocilizumab 162 mg or placebo subcutaneously in a 48-week double-blind period (tocilizumab and placebo groups) followed by tocilizumab for 48 weeks in an open-label extension (continuous-tocilizumab and placebo-tocilizumab groups).

Results

Among 20 patients, 12 were randomised to tocilizumab (all had interstitial lung disease) and eight were randomised to placebo (six had interstitial lung disease). The modified Rodnan skin score improved in both treatment groups. The mean change in percent-predicted forced vital capacity was 3.3% [95% confidence interval (CI), −2.5 to 9.0] for tocilizumab and −3.8% (95% CI, −9.9 to 2.2) for placebo in the double-blind period and 2.0% (95% CI, −0.7 to 4.6) for continuous-tocilizumab and −1.4% (95% CI, −6.7 to 4.0) for placebo-tocilizumab in the open-label extension. Rates of serious adverse events per 100 patient-years were 19.3 for tocilizumab and 26.8 for placebo in the double-blind period and 0.0 for continuous-tocilizumab and 13.6 for placebo-tocilizumab in the open-label period.

Conclusions

The efficacy and safety of tocilizumab in patients with systemic sclerosis were consistent between the Japanese subpopulation and the global trial population.
A low-coverage 3′ RNA-seq to detect homeolog expression in polyploid wheat
Authors: Sun Jianqiang , Okada Moeko , Tameshige Toshiaki , Shimizu-Inatsugi Rie , Akiyama Reiko , Nagano Atsushi J , Sese Jun , Shimizu Kentaro K
Published: July 2023

Although allopolyploid species are common among natural and crop species, it is not easy to distinguish duplicated genes, known as homeologs, during their genomic analysis. Yet, cost-efficient RNA sequencing (RNA-seq) is to be developed for large-scale transcriptomic studies such as time-series analysis and genome-wide association studies in allopolyploids. In this study, we employed a 3′ RNA-seq utilizing 3′ untranslated regions (UTRs) containing frequent mutations among homeologous genes, compared to coding sequence. Among the 3′ RNA-seq protocols, we examined a low-cost method Lasy-Seq using an allohexaploid bread wheat, Triticum aestivum. HISAT2 showed the best performance for 3′ RNA-seq with the least mapping errors and quick computational time. The number of detected homeologs was further improved by extending 1 kb of the 3′ UTR annotation. Differentially expressed genes in response to mild cold treatment detected by the 3′ RNA-seq were verified with high-coverage conventional RNA-seq, although the latter detected more differentially expressed genes. Finally, downsampling showed that even a 2 million sequencing depth can still detect more than half of expressed homeologs identifiable by the conventional 32 million reads. These data demonstrate that this low-cost 3′ RNA-seq facilitates large-scale transcriptomic studies of allohexaploid wheat and indicate the potential application to other allopolyploid species.
GENETIC SCREENING REVEALS DEPENDENCY ON FEN1 TO RESIST TEMOZOLOMIDE IN TREATMENT-RESISTANT GLIOBLASTOMA STEM CELLS
Authors: Brakel Benjamin , Saleh Ali , Saleh Melissa , Miletic Petar , Salim Sabra , Maich William , Brown Kevin R , Tieu David , Venugopal Chitra , Moffat Jason , Katyal Sachin , Singh Sheila K , Chokshi Chirayu R
Published: July 2023

BTFC travel award recipient

Glioblastoma (GBM) is a lethal brain tumor. Despite intensive standard of care (SoC) consisting of surgical resection followed by radiation therapy (RT) and chemotherapy with temozolomide (TMZ), tumor relapse is inevitable with a median overall survival of 14.6 months. Therapeutic failure is attributable to the presence of GBM stem-like cells (GSCs), which are highly resistant to genotoxic therapies, self-renew and differentiate to perpetuate intra-tumoral heterogeneity, and seed tumor recurrence. However, no clinical advances have been made in overcoming resistance to therapy in GSCs, and the mechanisms underlying this resistance remain largely unknown. With the advent of CRISPR-Cas9 technology, functional genetic screens have been used to identify genes that regulate survival and sensitivity to TMZ in GSCs. However, they have not been applied to SoC and a comprehensive set of modulators governing resistance to combination treatment has yet to be determined. Here, we perform genome-wide CRISPR-Cas9 screening in patient-derived treatment-sensitive and treatment-resistant GSC models under normal growth conditions or while exposed to in vitro chemoradiotherapy. By integrating genetic dependencies and treatment-based conditional genetic interactions modulating sensitivity to SoC, we identify flap endonuclease 1 (FEN1) as a driver of GSC survival and therapy resistance in treatment-resistant GBM. Functionally, FEN1 inhibition demonstrates specific killing and synergy with TMZ in treatment-resistant GSCs while sparing healthy neural stem cells (NSCs) and treatment-sensitive GSCs. At the molecular level, FEN1 inhibition induces DNA damage and repair specifically in treatment-resistant GBM, posing FEN1 as an attractive therapeutic target in this population of GBM patients which SoC currently fails.
THE CLINICAL AND MOLECULAR LANDSCAPE OF GLIOMAS IN ADOLESCENTS AND YOUNG ADULTS
Authors: Bennett J , Nobre L , Sheth J , Ryall S , Fang K , Johnson M , Negm L , Chung J , Komosa M , Nunes N , Lim Fat M J , Perry J , Sahgal A , Detsky J , Bouffet E , Naz-Hazrati L , Dirks P , Ertl-Wagner B , Kongkham P , Zadeh G , Mason W , Cusimano M , Das S , Gao A , Tsang D , Nguyen L , Laperriere N , Keith J , Munoz D , Tabori U , Hawkins C
Published: July 2023

Molecular alterations in gliomas in adolescents and young adults (AYA) have not been comprehensively described to date. To determine the impact of mutation, we performed a population based study of gliomas in AYA.

METHODS: Patients diagnosed from 2000-2019 with glioma between 15-39.9 years were eligible. Comprehensive molecular analysis was performed. Therapeutic and outcome data was collected. For comparison, analysis included patients aged 0-39.9 years. RESULTS: A total of 876 AYA gliomas were included. Genetic alterations were found in 95% of available tumours. Pediatric-type mutations were found in 33% of AYA tumours. The most common paediatric alterations included BRAF p.V600E (11%) and FGFR alterations (7%) while BRAF fusions (4%), H3 p.K27M (4%) and H3.3 p.G34R (1%) were rare. IDH mutation was found in 57% of tumours. Molecular GBM accounted for 7%. Paediatric-type alterations had different outcomes in AYA than children. Ten-year OS of 100%, 90% and 95% was seen for BRAF fused, BRAF-V600E and FGFR-altered AYA low grade glioma (LGG), compared to 14% and 25% for BRAF- V600E and FGFR-altered high grade glioma (HGG) respectively. BRAF and FGFR mutant tumours had higher proportion of HGG versus LGG in AYA compared to children (OR 2.6, 95% CI 1.2-5.6) while outcome was improved in LGG in AYA compared to children with a 10 year PFS of 76.8% vs 51.6% respectively (p=0.0009) suggesting a transition phase occurring during adolescence and early adulthood. CONCLUSIONS: AYA gliomas are enriched for paediatric-type alterations with distinct outcomes. Routine analysis is required given the role for targeted inhibitors.
ROBO1 CAR-T CELL THERAPY FOR TREATMENT REFRACTORY BRAIN CANCER
Authors: Shaikh Muhammad Vaseem , Chokshi Chirayu R , Brakel Benjamin , Anand Alisha , Maich William Thomas , Suk Yujin , Kieliszek Agata , Subapanditha Minomi , Alizada Zahra , Venugopal Chitra , Rossotti Martin A , Moffat Jason , Henry Kevin A , Kislinger Thomas , Singh Sheila K
Published: July 2023

BTFC travel award recipient

Glioblastoma (GBM) is the most common malignant adult brain tumor, with a dismal prognosis. Despite the multimodal treatment regimen, tumor recurrence is inevitable, and no standardized treatment exists for recurrent glioblastoma (rGBM). Neurodevelopment signaling pathways are often hijacked during tumor progression. Roundabout guidance receptor 1 (ROBO1) protein is involved in axonal guidance during neurodevelopment. Our preliminary findings implicated aberrant ROBO1 signaling axis to be associated with higher tumorigenecity in GBM, making it a functionally relevant therapeutic target. Moreover, ROBO1 was highly expressed on the surface of malignant and treatment-refractory brain tumor initiating cells (BTICs) in rGBM, brain metastasis (BM) and medulloblastoma (MB), prompting the development of an anti-ROBO1 CAR-T cell therapy. Here we report the development and validation of second-generation CAR-T cells using a single-domain antibody targeting ROBO1 expressing BTICs across three different brain tumors. We validated anti-ROBO1 CAR-T cells in-vitro and in-vivo using our established patient derived tumor models. In-vitro studies demonstrated upregulation of activation markers, enhanced cytokine release, markedly increased proliferation, and induction of potent and specific tumor cell death with ROBO1 CAR-T cells as compared to untransduced cells (UT) in all the three cancers. These findings were further validated in-vivo using 3 different BTIC lines one each from rGBM, MB and BM. ROBO1 CAR-T showed significant reduction in tumor burden and significant increase in survival of the mice treated with ROBO1 CAR-T cells in all the three cohorts. Thus, targeting ROBO1 could be a therapeutically tractable strategy for treating rGBM as well as other brain malignancies.
THE USE OF 5-AMINOLEVULINIC ACID (5-ALA) IN HIGH-GRADE GLIOMA SURGERY, A SINGLE CANADIAN CENTER EXPERIENCE
Authors: LeBlanc Félix , Boone Lyndon , Noble Timothy , Burns Jane , Fawaz Charbel , Charest Dhany , El Helou Antonios
Published: July 2023

5-Aminolevulinic acid (5-ALA) is a prodrug used to selectively illuminate high-grade glioma (HGG) tissue intra-operatively, shown to nearly double complete resection rates in a 2006 multicentre, phase III clinical trial. Here, we review the history of the 2020 approval of 5-ALA in Canada and present some of the first preliminary results on resection rates, survival analysis, and adverse effects from a single Canadian center.

METHODS: We enrolled 76 patients (median age 61 years, 42 male) with suspected HGG amenable to surgical resection to undergo 5-ALA fluorescence-guided surgery between June 2020 and January 2023. Gross total resection was defined by the absence of enhancing l esions on postoperative MRI. We compared the survival distributions of confirmed HGG cases with complete vs. incomplete resection using a log-rank test and Kaplan-Meier statistics. RESULTS: 52 patients were confirmed as having a HGG (grade III or IV) based on a pathological diagnosis. In 32 of these patients (60.3%) a gross total resection was achieved. 46 patients of the initial cohort had their surgery done for more than 180 days. 47.8% had a survival of 600 or more days. CONCLUSIONS: 5-ALA fluorescence-guided surgery resulted in high complete resection rates, comparable to literature with no notable adverse side effects.
ACQUIRED PTEN LOSS MAY MEDIATE DABRAFENIB AND TRAMETINIB RESISTANCE IN BRAF V600E–MUTATED EPITHELIOID GLIOBLASTOMA: A CASE REPORT
Authors: Ahmed Abrar , Nobre Liana , Mason Warren , Bennett Julie , Tabori Uri , Hawkins Cynthia , Climans Seth
Published: July 2023

Epithelioid glioblastoma is a rare variant of glioblastoma that primarily affects children and young adults. This commonly has a BRAF V600E mutation and can be treated with BRAF and MEK inhibitors.

CASE DESCRIPTION: An 18-year-old woman was diagnosed with an epithelioid glioblastoma. She received temozolomide chemoradiotherapy. Upon progression she had redo surgery and received dabrafenib and trametinib. The patient developed a drop metastasis to the cervical spine, and consequently received focal radiotherapy, 20 Gy in five fractions. Treatments were halted six months after her second resection due to further disease progression. She developed uncal herniation, requiring her to have a third resection approximately six months after her second resection. She passed away after this, 12 months following her initial diagnosis. Retrospective genetic analysis of three tumor specimens showed a novel PTEN mutation that arose after her first surgery. We suspect that the acquired PTEN mutation conferred resistance to dabrafenib and trametinib. DISCUSSION: This case offers teaching points and research questions. Firstly, early treatment with BRAF and MEK inhibitors in high grade BRAF V600E–mutated gliomas may be optimal as the patient may have stabilized with earlier treatment on dabrafenib and trametinib. Secondly, further studies are required to investigate whether the addition of PTEN mutation to BRAF V600E leads to aggressive tumor behavior. Lastly, there is a need for investigation into potential benefits of treating similar patients by co-targeting the BRAF and PI3K/AKT pathways.
PREOPERATIVE DETERMINATION OF IDH STATUS AND GRADE IN GLIOMAS USING MRS
Authors: Nguyen Thanh Binh
Published: July 2023

PURPOSE

To evaluate the diagnostic accuracy of preoperative MRS in the determination of the IDH status and grade in patients with newly diagnosed gliomas.

METHODS

MRS was performed using a regular PRESS sequence and a spectral editing sequence (MEGA-PRESS). Concentration of 2-HG was estimated from the subtracted spectra from the edited MRS sequence while NAA, choline and creatinine concentrations were obtained from the regular PRESS sequence. IDH mutation status was assessed by immunohistochemistry for all patients and additional next generation sequencing for all grade 2 and 3 gliomas. Differences in metabolite concentrations between IHD-mutant and wild-type gliomas and between gliomas of various grades were assessed using non parametric tests. TAreas under-the ROC curve (AUC) for different metabolites were calculated with IDH mutation status or glioma grade as the outcome.

RESULTS

There were 29 IDH-mutant gliomas and 52 wild-type gliomas. There was a significant difference in the NAA/Choline ratio among various glioma grades (P<0.05). The AUC for 2HG was 0.74 in the differentiation between IDH-mutant vs wild type gliomas. Using a 2-HG cut-off of >0.96 I.U., sensitivity was 59% and specificity was 90% for the identification of IDH-mutant gliomas. The AUC for the NAA/Choline ratio was 0.74 in the differentiation of high vs low grade gliomas. Using a NAA/Choline cut-off ≤0.53, sensitivity was 45% and specificity was 100% for identification of high grade gliomas.

CONCLUSION

Preoperative MRS can identify IDH-mutant gliomas and high grade gliomas with high specificity.
HIGH-DIMENSIONAL HISTOPATHOLOGIC EVALUATION OF THE HYPOXIC MICROENVIRONMENT IN GLIOBLASTOMA
Authors: Mansouri Sheila , Zaidi Mark , Singh Olivia , Karimi Shirin , Lombard Phoebe , Dvorkin-Gheva Anna , Velasquez Carlos , Ali Hafsah , Devaraja Kaviya , Sosa Julio , Patil Vikas , Wei QingXia , Wu Ronald , Li Mira , Cheung May , Voisin Mathew , Gao Andrew , Hedley David , Aldape Kenneth , Wouters Bradly , Zadeh Gelareh
Published: July 2023

Rapidly growing solid tumors such as glioblastoma (GBM) are characteristically hypoxic, displaying large areas of necrosis surrounded by hyperproliferative pseudopalisading cells. Intra-tumoral hypoxia develops over time in the three-dimensional space and the degree of tissue oxygenation is a dynamic process that varies continuously. Combined with the extensive inter- and intra-tumoral heterogeneity associated with GBM at the bulk and single cell level, hypoxia contributes to a gradient of molecular alterations that are specific to the different cell populations that make up the bulk of the tumor and reside in specific niches. To date, high dimensional histopathologic analyses of the hypoxic regions within GBM tissue have not been performed. Here, we took a combined spatial and single-cell proteomic profiling approach to investigate the histopathologic features of hypoxia by leveraging a unique clinical study where the exogenous hypoxia marker pimonidazole (PIMO) is administered to patients with GBM prior to surgery. Tissue specimens were subjected to imaging mass cytometry and serial immunohistochemistry using a panel of 27 markers associated with cellular hallmarks of hypoxia, metabolism, proliferation, stemness, angiogenesis, and immune cell types. We took high-resolution imaging and statistical approaches to explore the interplay of the different markers within hypoxic regions of primary and recurrent GBMs, in addition to IDH-mutant gliomas. Our findings elucidate the expression pattern of key biological markers relative to one another, altered composition of different cell types, along with differential proliferative, transcriptional, and translational activation states associated with each cell type within the hypoxic regions of GBM.
STEREOTACTIC BODY RADIOTHERAPY (SBRT) FOR SACRAL METASTASES: DEVIATION FROM RECOMMENDED TARGET VOLUME DELINEATION PREDICTS HIGHER RISK OF LOCAL FAILURE
Authors: Moore-Palhares Daniel , Zeng Kang Liang , Myrehaug Sten , Tseng Chia-Lin (Eric) , Soliman Hany , Chen Hanbo , Maralani Pejman , Larouche Jeremie , Wilson Jeff , Ruschin Mark , Zhang Beibei , Atenafu Eshetu G , Sahgal Arjun , Detsky Jay
Published: July 2023

Report outcomes after sacrum SBRT, focusing on the impact of contouring deviation on local failure (LF) risk, with an aim to validate the contouring consensus guidelines.

METHODS/MATERIALS: Patients who underwent sacral SBRT from 2010- 2021 were identified from a prospectively maintained institutional database. Primary outcomes were magnetic resonance-based LF and vertebral compression fracture (VCF). RESULTS: A total of 215 treated sacral segments in 112 patients were reviewed. Most segments were treated with 30 Gy/4 fractions (51%), 24 Gy/2 fractions (31%), or 30 Gy/5 fractions (10%). Thirty-one percent of segments were of radioresistant histology (gastrointestinal, kidney, melanoma, sarcoma, or thyroid primary), and 51% had extraosseous disease. Sixteen percent of segments were under-contoured per consensus guidelines. The cumulative incidence of LF was 18.4% (95% CI 13.5-24.0) at 12-months and 23.1% (95% CI 17.6-29.0) at 24-months. On multivariate analysis (MVA), under- contouring (HR 2.4, 95% CI 1.3-4.7, p=0.008), radioresistant histology (HR 2.4, 95% CI 1,4-4.1, p=0.001), and extraosseous extension (HR 2.5, 95% CI 1.3-4.7, p=0.005) were predictors of increased risk of LF. The LF rates at 12/24-months were 15.1%/18.8% for segments contoured per guideline versus 31.4%/40.0% for those under-contoured. The cumulative incidence of VCF was 7.1% (95% CI 4.1-11.1) at 12-months and 12.3% (95% CI 8.2-17.2) at 24-months. On MVA, female gender predicted increased VCF risk (HR 2.3, 95% CI 1.1-5.2, p=0.04). CONCLUSIONS: Sacral SBRT is associated with high rates of efficacy and an acceptable VCF risk. Adherence to target volume delineation consensus guidelines reduces the risk of LF.
THE ROLE OF ICAM1 IN TUMOR ASSOCIATED MACROPHAGES IN GLIOBLASTOMA TUMORIGENESIS
Authors: Devaraja Kaviya , Mansouri Sheila , Singh Olivia , Ali Hafsah , Patil Vikas , Karimi Shirin , Sosa Julio , Wu Ronald , Wei Qinxqia , Li Mira , Wouters Bradley , Zadeh Gelareh
Published: July 2023

Glioblastoma (GBM) is a fatal brain cancer in adults with ineffective treatment methods. Cell adhesion molecules (CAMs) are proteins that are expressed on the surface of cells and enable them to interact with one another and the surrounding microenvironment. Intracellular adhesion molecule 1 (ICAM-1) is a cell adhesion molecule expressed by various cell types. Preliminary data showed that ICAM-1 is associated with poorer overall and progression free survival in patients and ICAM-1 expression levels increase in recurrent tumors. TAMs enhance GBM tumor growth. The aim of this study was to determine if ICAM-1 expression on TAMs contributes to GBM tumorigenesis, specifically within the hypoxic tumor microenvironment. We hypothesized that ICAM1 facilitates TAM migration, proliferation, cell adhesion and phagocytosis, thus enhancing tumor growth. We found that upon incubation of human and mouse primary macrophages in hypoxia, ICAM-1 expression levels increased and were further exasperated upon culturing with tumor cell-conditioned medium. The migration, cell adhesion and phagocytosis of ICAM-1 deficient macrophages was lower than wild type macrophages, and effects were further exasperated upon culturing with tumor conditioned media and incubation in hypoxia. Intracranial injection of tumor cells into ICAM-1 deficient and wild type mice revealed that ICAM1 deficient mice survived longer with lower overall tumor volume than wild type mice, with survival and volume differences being rescued upon ICAM1 bone marrow reconstitution. In conclusion, the expression of ICAM1 in TAMs likely promotes GBM tumorigenesis and hypoxia further enhances the expression of ICAM-1 in macrophages which is associated with more aggressive GBM.
CORRELATION OF CLINICAL FEATURES TO DNA METHYLATION-BASED PROGNOSTIC SUBTYPES IN CHORODOMA PATIENTS
Authors: Ajisebutu Andrew , Zuccato Jeffrey A , Patil Vikas , Sosa Julio , Zadeh Gelareh
Published: July 2023

Chordomas are rare aggressive primary bone cancers affecting the skull-base and spine. We have previously identified robust DNA methylation-based prognostic groups, immune infiltrated and cellular subtypes. Here we further characterize these prognostic subtypes with an extensively annotated clinical database to identify factors that correlate with subtype, and investigate methylation patterns between existing clinical scoring systems groups.

METHODS: 68 patients from a multi-institutional 20-year series were identified. These patients’ tumor samples had undergone whole genome DNA methylation profiling on the Illumina EPIC array. Baseline clinical features, including clinical features, treatment details, outcomes parameters and imaging were analyzed using chi-squared or kruskal-wallis test, and differential methylation patterns were examined between clinically distinct groups based on the Sekhar scoring system. RESULTS: Of all the variables tested, age of onset (p-value 0.012), location (skull base vs spine vs sacral: p-value 0.0365) and histological subtype (classical vs chondroid: p-value 0.0132) were the only significant predictors of subgroup placement; older age, spinal location, and classical histological typing were predictors of immune infiltrated chordoma subtype, which has a poorer clinical performance. As expected, death from chordoma was significantly different between subtypes (p-value 0.0056). Patients survival stratified based on Shakur grading, and clustered together on unsupervised hierarchical analysis on methylation. CONCLUSION: Overall, there are limited variables that correlate with methylation subtype, meaning that the epigenetic chordoma subtypes cannot be reliably identified using clinical or imaging features in the absence of molecular data. However clinical grading systems remain a valuable tool for prognostication, and display distinct methylation patterns.
PREDICTORS OF TUMOR DYNAMICS DURING A COURSE OF 30-FRACTION RADIOTHERAPY FOR GLIOBLASTOMA
Authors: Ong W L , Stewart J , Sahgal A , Soliman H , Tseng C L , Detsky J , Ho L , Das S , Maralani P , Lipsman N , Stanisz G , Perry J , Chen H , Atenafu E , Lau A , Ruschin M , Myrehaug S
Published: July 2023

We aim to identify predictors of tumor dynamics during radiotherapy for glioblastoma.

METHODS: This is a prospective serial MRI study in patients with glioblastoma. MRIs were obtained at radiotherapy planning (F0), fraction-10 (F10), and fraction-20 (F20). The tumor dynamics metrics (relative to F0) assessed included: relative gross tumor volume (GTV) changes (Vrel) and migration distance (dM). RESULTS: 129 patients were included in this study. Median GTV was 20.9cc at F0, 17.6cc at F10 (Vrel 0.85), and 16.1cc at F20 (Vrel 0.78). Patients with no corpus-callosum involvement (CCI) (vs with CCI) had more marked GTV volume reduction: Vrel 0.82 vs 1.02 at F10 (P=0.05), and Vrel 0.77 vs 0.88 at F20 (P=0.03). Patients with gross total resection (GTR) had more marked GTV volume reduction (vs subtotal resection (STR) vs biopsy (Bx)): Vrel 0.78, 0.85 and 1.07 at F10 (P=0.001), and Vrel 0.69, 0.80, 1.04 at F20 (P=0.001). The median dM were 4.7mm at both F10 and F20. Patients with CCI had larger dM (vs no CCI): 41% vs 12% had dM>10mm at F10 (P=0.01), and 45% vs 9% had dM>10mm at F20 (P<0.001). At F20, 0%, 25% and 19% of patients with GTR, STR and Bx had dM>10mm (P=0.002). Age, sex, MGMT methylation and IDH-mutation status were not associated with tumor dynamics during treatment. CONCLUSION: CCI and extent of surgery predict for tumor dynamics, which may allow us to better select patients who benefit the most from re-planning/ treatment adaptation during radiotherapy.
A RADIATION ONCOLOGIST’S EXPERIENCE TREATING MALIGNANT GLIOMA WITH TUMOR TREATING FIELDS IN CANADA
Authors: Roberge David , Labelle Denys
Published: July 2023

The FDA approved tumor treating fields (TTFields) in 2011. Through Health Canada special access, a limited number of treatments were provided prior to regulatory approval. This work describes a single physician’s experience with TTFields. With ethics approval, charts were retrospectively reviewed. Access provided as an extension of prior research was excluded. Kaplan-Meier estimates were used for survival and time on treatment. From 2013-2022, 62 cases were identified. 65% from Quebec, 21% from Ontario and the rest from either Alberta or British Colombia. TTFields were prescribed as an adjuvant following chemo-radiation in 41 cases and for recurrent disease in 21. Median age was 49 (range 16-75). 76% of patients were male. Median KPS was 75%. 95% of tumors were classified as glioblastoma by the criteria used at the time of diagnosis (IDH positive in 4). Where known, 40% had MGMT promoter methylation. Adjuvant treatment started a median of 1.0 months following radiotherapy. Recurrent patients had had a median of 2 prior lines of treatment (range 1-9). Two young adults discontinued treatment after less than one week but otherwise patients tolerated the device until treatment was recommended to be discontinued. Median OS for adjuvant patients was 15.4 months, 5.3 months for recurrent patients. For adjuvant patients, median estimated time on treatment was 7 months. It was possible to offer TTFields over a wide geographic area with support from device specialists. Treatment may be more easily integrated into care with the development of a larger network of prescribers.
REPURPOSING OF FDA APPROVED COMPOUNDS TO INHIBIT OSM/OSMR SIGNALING IN GLIOBLASTOMA
Authors: Lotfipour Farzaneh , Jahani-Asl Arezu
Published: July 2023

Repurposing of FDA approved compounds to inhibit OSM/OSMR signaling in glioblastoma OSM/OSMR signalling is important in glioblastoma, yet specific inhibitors to suppress this signaling pathway remain to be explored. Here we conducted HTS screening of FDA approved compounds to identify lead compounds that can suppress OSM signalling via OSMR to inhibit STAT3 phosphorylation. The strategy of drug repurposing that have already been approved by FDA, with known pharmacological and safety profiles, offers several advantages including bypassing development costs and rapid and effective translation into phase 2 clinical trials. Importantly, 99% of newly developed drugs fail in clinical trials, further highlighting the significance of drug repurposing. Our HTS screen revealed 456 compounds with > 40% potency. We analyzed the compounds based on their mode of action and physicochemical properties. Our HTS discovered 63 G-protein coupled receptor modulators including 5-Hydroxy tryptamine (5-HT) and Dopamine receptor D2 (DRD2) modulators as OSM/OSMR inhibitors. Following a counter-screen we focused on compounds with highest potency as well as their potential to cross BBB using physicochemical attributes and the safety profiles previously established in human patients. These analyses revealed 7 lead compounds which are presently being tested in vivo in combination with present standards of care of glioblastoma patients.
DETERMINING THE ROLE OF GALECTIN1/HOXA5 INTERACTION AND REGULATION IN GLIOBLASTOMA DEVELOPMENT
Authors: Qu Dianbo , Popatia Alyanna , Jahani-Asl Arezu
Published: July 2023

LGALS1 is directly transcribed by STAT3, which promotes glioblastoma tumorigenesis via its interaction with HOXA5. However, the underling molecular mechanism of this interaction remains uninvestigated. In this study, we predicted the interacting mode between galectin1 and HOXA5 using a protein-protein docking method. Our analysis suggests that the interaction between Galectin1 monomer and the homeobox domain of HOXA5 impedes the interaction between the homeobox domain of HOXA5 and DNA. In contrast, the interaction of Galectin1 homodimer and the N-terminal region of HOXA5 facilitates or stabilizes the homeobox domain of HOXA5 to bind DNA. Based on this predicted binding mode, we hypothesized that HOXA5 transcriptional activity is regulated by phosphorylated HOXA5, which may impact the interaction by attenuating the binding of HOXA5 to negatively charged DNA. To validate this model, we generated a mutant Galectin1 that cannot form dimers by substituting Cys at position 2 with Ser and Val at position 5 with Asp. We also generated functional domain deletion mutants of HOXA5 to confirm the interaction of the N- terminal region of HOXA5 with Galectin1, according to the prediction on functional domains in HOXA5 by Pfam. Using wild type (dimer) and mutant (monomer) recombinant galectin1 proteins and deletion-mutant proteins of HOXA5, we are conducting a binding assay to validate this model. Next, we employed knock-in lines to explore the role of HOXA5 phosphorylation in tumorigenesis using a glioblastoma mouse model. The proposed models will help uncover the underlying regulatory mechanisms of HOXA5/Galectin1 on BTSC self-renewal and glioblastoma tumorigenesis.