A Systematic Review of Neuropsychological Studies Confirms that Adequate Folinic Acid Rescue Prevents Post Methotrexate Neurotoxicity

A comprehensive literature search was performed of all databases of the Web of Science Citation Index, during 1990-2020, for the terms: neuropsychological, neurocognitive, cognitive, acute lymphoblastic (and lymphocytic) leukemia, and osteogenic sarcoma, to see if there was evidence of a correlation between folinic acid (FA) rescue inadequacy and long-term cognitive damage. All English language, peer-reviewed articles of neuropsychological assessments of children who had been treated with high-dose methotrexate without irradiation, and which included details of methotrexate and FA schedules, were selected. Four groups of studies were found and analyzed, Those with no evidence of cognitive deterioration, Those with evidence of cognitive deterioration, studies with more than one protocol grouped together, preventing separate analysis of any protocols, and those with significant serious methodical problems. In all studies, protocols without evidence of cognitive deterioration reported adequate FA rescue, and those with evidence of cognitive deterioration reported inadequate FA rescue.

Assessment of the effectiveness of the use of tumoroids for personalized drug therapies for solid tumors

The approach to the management of cancerous neoplasms, which aims to define the effective curative strategies in each patient, defines the requirement for the elaboration and use of modelling systems that replicate the structures and the biology of human solitary tumors. Three-dimensional cultures of spheroids/tumoroids, which are multi-cell aggregates of malignized cells, can create the intercellular connections of interest, gradients of the nutrients and oxygen, and cell polarity, all of which are absent in the conventional two-dimensional single-layer system. The present work is dedicated to a comparison study of in vitro viability and invasiveness of solid tumor cells of patients under the effect of chemopreparations and their combinations in view of evaluating the efficacy of the 3D-cell modelling system in the translational personalized medicine context. Cell cultures of patients who were treated at the N.N. Petrov National Medicine Research Center of oncology were used as a basis for the development of 3D-cell models. N.N. Petrov NMRC in 2015-2021. Tumor tissue pieces were acquired intraoperatively: 1 - leiomyosarcoma (LMS), 1 - rhabdomyosarcoma (RMS), 1 - synovial sarcoma (SS), 2 - myxofibrosarcoma (MFS), 2 - osteogenic sarcoma (OS), 1 - skin melanoma (MC), 1 - breast cancer (BC) (n=9). Our individual comparison of the effectiveness of in vitro chemotherapeutic agents against tumor cells of various origins cultivated in 2D and 3D model systems with real clinically relevant cases confirmed that the monolayer culture as the test system was less adequate for selecting and personalizing the treatment of malignant tumor patients: the 3D cell system proved itself in 77.7% of cases, and the monolayer culture - in 44.4% of cases. The combination of doxorubicin/iforsfamide and paclitaxel significantly suppressed the motility in the matrigel of spheroid cells, but did not affect tumor cell viability, which was seen in all but OS #921 and MK #929 cases. The cultivation of tumor cells in form of spheroids/tumoroids allows to utilize them as more adequate pre-clinical model as individual predictive test-system, enabling the personalized selection of therapy.

Early Onset Colorectal Cancer: An Emerging Cancer Risk in Patients with Diamond Blackfan Anemia

Diamond Blackfan anemia (DBA) is a rare inherited bone marrow failure syndrome, the founding member of a class of disorders known as ribosomopathies. Most cases result from loss of function mutations or deletions in 1 of 23 genes encoding either a small or large subunit-associated ribosomal protein (RP), resulting in RP haploinsufficiency. DBA is characterized by red cell hypoplasia or aplasia, poor linear growth and congenital anomalies. Small case series and case reports demonstrate DBA to be a cancer predisposition syndrome. Recent analyses from the Diamond Blackfan Anemia Registry of North America (DBAR) have quantified the cancer risk in DBA. These studies reveal the most prevalent solid tumor, presenting in young adults and in children and adolescents, to be colorectal cancer (CRC) and osteogenic sarcoma, respectively. Of concern is that these cancers are typically detected at an advanced stage in patients who, because of their constitutional bone marrow failure, may not tolerate full-dose chemotherapy. Thus, the inability to provide optimal therapy contributes to poor outcomes. CRC screening in individuals over the age of 50 years, and now 45 years, has led to early detection and significant improvements in outcomes for non-DBA patients with CRC. These screening and surveillance strategies have been adapted to detect familial early onset CRC. With the recognition of DBA as a moderately penetrant cancer risk syndrome a rational screening and surveillance strategy will be implemented. The downstream molecular events, resulting from RP haploinsufficiency and leading to cancer, are the subject of significant scientific inquiry.

CircDOCK1 promotes the tumorigenesis and cisplatin resistance of osteogenic sarcoma via the miR-339-3p/IGF1R axis

Background Circular RNAs (circRNAs), a class of noncoding RNAs (ncRNAs), may modulate gene expression by binding to miRNAs. Additionally, recent studies show that circRNAs participate in some pathological processes. However, there is a large gap in the knowledge about circDOCK1 expression and its biological functions in osteogenic sarcoma (OS). Methods Differentially expressed circRNAs in OS cell lines and tissues were identified by circRNA microarray analysis and quantitative real-time PCR (qRT–PCR). To explore the actions of circDOCK1 in vivo and in vitro, circDOCK1 was knocked down or overexpressed. To assess the binding and regulatory associations among miR-339-3p, circDOCK1 and IGF1R, we performed rescue experiments, RNA immunoprecipitation (RIP), RNA pulldown assays and dual-luciferase assays. Moreover, we performed apoptosis assays to reveal the regulatory effects of the circDOCK1/miR-339-3p/IGF1R axis on cisplatin sensitivity. Results CircDOCK1 expression remained stable in the cytoplasm and was higher in OS tissues and cells than in the corresponding controls. Overexpression of circDOCK1 increased oncogenicity in vivo and malignant transformation in vitro. In the U2OS and MG63 cell lines, circDOCK1 modulated tumor progression by regulating IGF1R through sponging of miR-339-3p. Additionally, in the U2OS/DDP and MG63/DDP cell lines, cisplatin sensitivity was regulated by circDOCK1 via the miR-339-3p/IGF1R axis. Conclusions CircDOCK1 can promote progression and regulate cisplatin sensitivity in OS via the miR-339-3p/IGF1R axis. Thus, the circDOCK1/miR-339-3p/IGF1R axis may be a key mechanism and therapeutic target in OS.

Role of Diffusion Weighted MRI in Assessment of Treatment Response to Chemotherapy in Patients with Osteogenic Sarcoma

Background Osteosarcoma (OS) is the most common malignant bone tumor in children and adolescents. Currently, 10-year overall survival rates are 60% to 70% for all patients and only approximately 20% for patients with metastatic disease. Aim of the Work To investigate whether diffusion-weighted imaging (DWI) is useful for monitoring the therapeutic response after chemotherapy in osteosarcoma by comparing the ADC values pre and post chemotherapeutic treatment. Patients and Methods This is a retrospective study included 30 patients (18 females & 12 males), their ages range from 7 to 36 years. Mean age 14.8 years. The study was perfotmed Radiology Depaflment at Ain-Shams University Hospitals between September 2018 & Dec 2019. Resillts Most of cases about 50 % show partial response according to RECIST criteria. Conclusion Chemotheraphy is effective in reducing size, increase tissue breakdown and improvement of cases of osteosarcomas according to results of this study.

Impact of Locus of Care on Outcomes in Adolescents and Young Adults with Osteogenic sarcoma and Ewing Sarcoma treated at Pediatric versus Adult Cancer Centers: An IMPACT Cohort Study

Background: Location of cancer care (LOC: pediatric versus adult center) impacts outcomes in adolescents and young adults (AYA) with some cancer types. Data on impact of LOC on survival in AYA with osteogenic sarcoma (OGS) and Ewing sarcoma (EWS) are limited. Objectives: To compare differences in demographics, disease/treatment characteristics, and survival in a population-based cohort of AYA with OGS or EWS treated at pediatric versus adult centers Methods: The IMPACT Cohort captured demographic, disease, and treatment data for all AYA (15-21 years old) diagnosed with OGS and EWS in Ontario, Canada between 1992-2012. Patients were linked to provincial administrative healthcare databases. Outcomes were compared between patients treated in pediatric versus adult centers using appropriate statistical methods. Results: 137 AYA were diagnosed with OGS (LOC: 47 pediatric, 90 adult) and 84 with EWS (LOC: 38 pediatric, 46 adult). AYA treated at pediatric centers were more likely to be enrolled in a clinical trial (OGS 55% vs 1%, [p<0.001]; EWS 53% vs 2%, [p<0.001]) and received higher cumulative chemotherapy doses. Five-year event-free survival (EFS ± Standard Error) in OGS and EWS were 47% ± 4 and 43% ± 5, respectively. In multivariable analysis, the impact of LOC (pediatric vs adult center) on EFS in OGS (adjusted hazard ratio [HR] 1.15, 95% CI 0.58-2.27, P=0.69) and EWS (adjusted HR 1.82, 95% CI 0.97-3.43, P=0.06) were not statistically significant. Conclusion: Outcomes did not differ by LOC suggesting that AYA with bone tumors can be treated at either pediatric or adult centers.

Circulating Long Non-Coding RNAs as Novel Potential Biomarkers for Osteogenic Sarcoma

Circulating cell-free nucleic acids recently became attractive targets to develop non-invasive diagnostic tools for cancer detection. Along with DNA and mRNAs, transcripts lacking coding potential (non-coding RNAs, ncRNAs) directly involved in the process of tumor pathogenesis have been recently detected in liquid biopsies. Interestingly, circulating ncRNAs exhibit specific expression patterns associated with cancer and suggest their role as novel biomarkers. However, the potential of circulating long ncRNAs (c-lncRNAs) to be markers in osteosarcoma (OS) is still elusive. In this study we performed a systematic review to identify thirteen c-lncRNAs whose altered expression in blood associate with OS. We herein discuss the potential impact that these c-lncRNAs may have on clinical decision-making in the management of OS. Overall, we aimed to provide novel insights that can contribute to the development of future precision medicine in oncology.

Biocompatibility and Antibiofilm Properties of Calcium Silicate-Based Cements: An In Vitro Evaluation and Report of Two Clinical Cases

Calcium silicate-based cements have reached excellent levels of performance in endodontics, providing predictable and successful results. To better assess the properties of these bioactive materials, the present study aimed to compare the biocompatibility and antibiofilm properties of ProRoot MTA and Biodentine. Human osteogenic sarcoma (Saos-2) cells were cultured on ProRoot MTA and Biodentine samples or in the presence of both cement extracts. Cell viability assay, measurement of reactive oxygen species (ROS), immunofluorescence analysis, as well as morphological evaluations were conducted. Moreover, Streptococcus mutans was used to assess the biofilm forming ability on ProRoot MTA and Biodentine disks. Finally, both cements were applied in vivo to treat immature permanent teeth affected by reversible pulpitis. Results: Cell viability assay demonstrated that Saos-2 cells had a dose- and time-dependent cytotoxicity to both analyzed cements, although cells exposed to ProRoot MTA showed a better cell vitality than those exposed to Biodentine (p < 0.001). Both cements demonstrated ROS production while this was greater in the case of Biodentine than ProRoot MTA (p < 0.001). Immunofluorescence images of the cytoskeleton and focal adhesions showed no differences in Saos-2 cells grown in the presence of ProRoot MTA eluate; whereas in the Biodentine groups, cells showed a morphology and focal adhesions more similar to that of the control sample, as the eluate concentration decreased. Morphological analysis revealed that Saos-2 cells were more flattened and exhibited better spreading when attached to ProRoot MTA disks than to Biodentine ones. The antibiofilm properties showed a time-dependent powerful inhibition of S. mutans superficial colonization and an antibiofilm effect of both cements. Clinically, complete root formation of the treated elements was achieved using the two studied cements, showing stable results over time. ProRoot MTA and Biodentine was demonstrated to be biocompatible and to possess antibiofilm properties. Their clinical application in vital pulp therapy provided successful outcomes after 2 years of follow-up.