Winter 2024

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Original Articles

Novel Long Non-Coding RNA Biomarker Candidates in Pediatric High-Grade Glioma and ATRT

Assaf Freed [1,2], and Ruty Mehrian-Shai PhD [3] 6-15

Background: Despite advancements in treatment and management, pediatric brain tumors remain the leading cause of cancer-related deaths among children. The identification of novel biomarkers and therapeutic targets is crucial for improving patient outcomes. In recent years, there is great interest in long non-coding RNAs (lncRNAs) as potential biomarkers and therapeutic targets in cancer.

Objectives: This study aimed to identify dysregulated lncRNAs in pediatric brain tumors by assessing the expression levels of 41 specific lncRNAs in cellular models of pediatric high-grade gliomas (HGG) and atypical teratoid/rhabdoid tumors (ATRT).

Methods: We employed RNA sequencing data to analyze the expression of 41 lncRNAs in 117 cell lines established from pediatric brain tumor patients, categorized into three groups: pediatric HGG (n=74), ATRT (n=19), and non-malignant central nervous system (CNS) controls (n=24). The control group was derived from the tissue surrounding the tumor and was validated as non-malignant through whole genome sequencing (WGS) or short tandem repeat (STR) profiling. These 41 lncRNAs were selected based on our prior observation of their dysregulation in medulloblastoma tumors, using an in-house machine learning algorithm.

Results: Our analysis revealed significant dysregulation in the expression levels of 29 lncRNAs in HGG and ATRT cell lines compared to the control group of non-malignant CNS cell lines. This suggests their possible involvement in various tumorigenic mechanisms specific to these cancers.

Conclusions: These findings add to the growing body of evidence regarding possible involvement of lncRNAs in brain tumor biology, highlighting potential novel biomarkers and therapeutic targets for pediatric brain tumors. These lncRNAs may provide new avenues for inhibiting tumor growth and improving patient survival. Further research is warranted to investigate the roles of these lncRNAs, as well as to develop targeted therapeutic approaches and assess their efficacy in preclinical models.

Brain Tumor Localization and Classification Using a Focal Loss Object Detector

Snir Shalom B.Sc[1,2,3], Moshe Yerachmiel M.Sc[[1,2,4], Dafna Ben Bashat Ph.D[1,4,5] and Moran Artzi Ph.D[1,4,5] 16-24

Full Article Abstract

Background: Differentiating between high-grade glioma (HGG) and brain metastasis is of great importance since the medical treatment strategies for each diagnosis are different. While MRI is the modality of choice for the assessment of patients with brain tumors, differentiation between HGG and solitary brain metastasis is highly challenging due to their similar appearance on conventional MRI.

Objectives: This paper proposes an automatic detection and classification method for brain lesions, focusing on improving clinical diagnosis through advanced MRI-based analysis.

Methods: The proposed method employs a focal loss object detector (RetinaNet) with multi-channel MRI input (T1-weighted images + contrast agent and FLAIR images). Detection is performed using 2D RetinaNet architecture, followed by a post-processing phase to utilize 3D spatial information and improve detection results. We also propose a bounding box application tool for 3D lesion labeling which was developed to enable visualization and fast 3D-based delimitation of lesion areas, serving as ground truth for network training. We evaluated our method on data from 417 patients with newly diagnosed brain tumors.

Results: The best detection results were obtained using two-channel input data and by applying the 2D RetinaNet model followed by 3D post-processing phase, achieving a mean average precision (mAP) of 81% (92% for the HGG and 71% for the brain metastasis) for the validation dataset and 76% (83% for the HGG and 69% for the brain metastasis) for the test dataset.

Conclusions: These results demonstrate the feasibility of automatic object detection of brain tumors based on MRI. The proposed method provides an end-to-end solution for tumor detection, adjusted for clinical practice. The system receives raw MRI images and extracts tumor location (if any), classification and the probability score for the detection.

Assessment of Intraocular Pressure Changes Following Intravitreal Injections of Three Anti-VEGF Agents

Amit Hibsh*, Adiel Barak* MD, Efrat Fleissig MD, Michael Regenbogen MD and Ainat Klein MD 26-34

Full Article Abstract

Background: The advent of anti-vascular endothelial growth factor (anti-VEGF) agents, such as bevacizumab (Avastin), ranibizumab (Lucentis), and aflibercept (Eyelea), has transformed the management of neovascular ocular diseases. While effective, intravitreal injections pose risks of adverse effects, including ocular discomfort, hemorrhage, retinal tear and/or detachment and intraocular inflammation. Notably, these injections can cause a transient increase in intraocular pressure (IOP), which varies with drug properties and molecular structures. Understanding these variations is crucial for optimizing treatment strategies and mitigating potential risks.

Objectives: Intravitreal injection (IVI) of anti-VEGF agents has emerged as the primary treatment for prevalent retinal diseases. Despite its efficacy, IVI may induce intraocular pressure elevation due to vitreous fluid shifts. This study aims to compare the effects of three distinct anti-VEGF agents on IOP elevation within a single clinical setting.

Methods: This single-center prospective study included patients receiving three different anti-VEGF medications; bevacizumab, aflibercept, and ranibizumab. IOP was measured pre and post-injection using an iCare Pro tonometer. Demographic parameters and ocular characteristics were collected.

Results: The study included 195 patients (average age 76.13 years; 100 males, 95 females). The medications administered were aflibercept (N=70, 35%), bevacizumab (N=73, 37.4%), and ranibizumab (N=52, 26.7%). In patients with a normal baseline IOP, no significant variance was observed in the post-injection versus pre-injection pressure change (delta) across medications. Conversely, in patients with high IOP pressure (>20 mmHg), aflibercept resulted in a more substantial increase than bevacizumab or ranibizumab. No correlation emerged between the pressure rise and age or lens status.

Conclusions: No significant difference was found in the increase of IOP following injection among different medications in patients with low-normal intraocular pressure. However, for patients prone to higher baseline pressure, caution is recommended with aflibercept due to a more pronounced increase. Further research is essential to understand the factors influencing IOP increase and the associated clinical implications.

T. Gondii Seroprevalence Among Women of Childbearing age – an Epidemiological Study in Israel

Amit Ifrah B.Med.Sc[1], Rachel Michaelson-Cohen MD MPH[2], Yonit Wiener-Well MD[3], Assaf Ben Shoham MD PhD[4] 35-42

Full Article Abstract

Background: Toxoplasma gondii is a parasite with teratogenic potential. The epidemiology of T. gondii varies widely around the world and research is scarce in Israel. Congenital toxoplasmosis can lead to severe adverse effects in the fetus. Hence, serology screening tests are performed during pregnancy and treatment is offered when acute infection is suspected. The cost-effectiveness of this screening varies in correlation with the epidemiology of toxoplasmosis.

Objectives: Describing updated, localized T. gondii epidemiology in order to aid in the determination of relevant policies.

Methods: This study includes over 43,000 women, aged 18-44, who were pregnant at least once between 2013-2018 and had serology tests for T. gondii. The serology test results between 2010-2019 were examined. For each woman demographic information and all T. gondii serology tests were extracted from medical files. Correlation between demographic variables and exposure to T. gondii was examined, using χ2 tests.

Results: Overall, 11.79% of the study population had positive T. gondii serology, and only 0.31% had suspected acute infections when first tested during the study period. The most significant positive predictors for T. gondii positive serology in this study were Arab subpopulation with OR of 1.91 (95% CI 1.79-2.04, P<0.01) in reference to the general subpopulation, and African WHO birth region, maternal origin and paternal origin, with OR of 4.98 (95% CI 4.57-5.42, P<0.01), 2.23 (95% CI 2.01-2.49, P<0.01) and 2.34 (95% CI 2.11-2.59, P<0.01) respectively. The most significant negative predictors were ultra-orthodox subpopulation, with OR of 0.71 (95% CI 0.65-0.77, P<0.01) in reference to the general subpopulation, and WHO American birth region, maternal origin and paternal origin, with OR of 0.50 (95% CI 0.42-0.61, P<0.01), 0.31 (95% CI 0.26-0.38, P<0.01) and 0.41 (95% CI 0.35-0.49, P<0.01) respectively.

Conclusions: Targeted screening of pregnant women from high-risk populations, such as the Arab subpopulation, WHO Eastern Mediterranean Region or African Region birth region, may be advised.

Review Articles

Endo’ What?!

Anne Krinsky B.Med.Sc[1]* , and Shir Shahar B.Sc[2]* 44-50

Full Article Abstract

Background: Endometriosis, affecting 10-12% of women worldwide, involves abnormal endometrial tissue growth outside the uterus, leading to symptoms such as dysmenorrhea and pelvic pain, and to infertility. Despite its prevalence and impact on quality of life, its exact cause remains unclear. Diagnostic challenges contribute to underdiagnosis, prolonging patient suffering. The economic burden is also significant, encompassing direct medical costs and indirect expenses due to productivity loss. Improved understanding and awareness are crucial for timely diagnosis and management. Endometriosis represents a complex and debilitating condition that requires enhanced research efforts and the development of comprehensive care strategies to alleviate its burden on affected individuals and healthcare systems.

Objectives: This review aims to provide an overview of endometriosis, focusing on its epidemiology, symptoms, diagnostic challenges, and management options.

Methods: Information for this review was gathered from published literature, including articles and surveys, focusing on the epidemiology, symptomatology, diagnostic approaches, and management strategies related to endometriosis.

Results: Endometriosis presents a significant health burden, with symptoms ranging from chronic pelvic pain to fertility issues. Diagnosis often involves a delay due to varied symptomatology and limited awareness among healthcare professionals. Treatment modalities include pain management, hormonal therapy, and surgical interventions, with complementary medicine also showing promise for symptom alleviation.

Conclusions: Despite the challenges posed by endometriosis, early intervention and comprehensive care can significantly improve patients’ quality of life. Continued research and improved awareness are crucial for enhancing diagnostic methods and treatment options, to offer hope for individuals affected by this complex condition.