Diffuse Leptomeningeal Glioneuronal Tumors: A Case Series of Five Patients with Parenchymal Forms and an Analysis of the Diagnostic Challenges, Treatment Options and Outcomes.

BACKGROUND: Diffuse leptomeningeal glioneuronal tumors (DL-GNT) are rare glioneuronal neoplasms with oligodendroglioma-like cells. These tumors can present as a dominant intracranial mass or as a solitary spinal cord mass without leptomeningeal involvement. In this study, we aimed to determine the magnetic resonance imaging and histopathological features, treatment modalities, and clinical outcomes of the parenchymal forms of DL-GNTs. METHODS: This is a retrospective three-center case series study of 5 patients with a confirmed parenchymal form of DLGTs, out of which 4 patients were adults. Brain and spinal cord MR imaging were performed in all patients at either 1.5 or 3T. The patients' age ranged from 5 years to 50 years with a mean age of 27.6 years at presentation. RESULTS: Four of the tumors were located in the frontal lobe, and one in the tectum. They were usually solid-cystic enhancing tumors as the other mixed neuronal-glial tumors. All of the tumors had an extension to the superficial surface of a cerebral hemisphere. One had systemic bone metastases. The clinical signs and symptoms of the parenchymal form varied based on the location of the mass, in contrast to the leptomeningeal form associated with hydrocephalus. In one case, the tumor's initial grade was defined as intermediate. The initial histopathology of the two cases was low-grade and no upgrade occurred in the follow-up period. In two cases, although the tumors were low grade initially, they progressed to an anaplastic form in the follow-up period. CONCLUSION: The parenchymal form of DL-GNTs is common in adults. Extension to the superficial surface of a cerebral hemisphere is a distinctive imaging feature. Systemic osseous metastasis may occur. Due to the presence of common histopathological features, including the biphasic composition of glial and neuronal cell elements and oligodendroglioma-like cells, a proposed classification approach might be more beneficial for the histopathological and imaging description, and management of the glioneuronal tumors with oligodendroglioma-like features.

A Successful Model for an Introductory Oncology Teaching Conference and Its Impact on Preclinical and Clinical Medical Students.

PURPOSE: Oncology education at medical schools is often fragmented, under-represented, and nonstandardized. Medical students lack essential knowledge, skills, and attitudes necessary for them to provide optimal primary care to patients with cancer upon graduation. METHODS: In this study, we designed and assessed the impact of a compact oncology teaching conference on medical students. The conference covered topics in cancer biology, public health, diagnosis, patient management, treatment, and communication skills. Medical students completed voluntary presurveys and postsurveys regarding their perceived knowledge, attitudes, and perspectives. The event was promoted by student groups, particularly our ASCO Oncology Student Interest Group, and took place online. RESULTS: A total of 228 responses from medical students representing 50 universities were analyzed. We revealed significant baseline confidence and perceived knowledge deficits especially in diagnosis and patient management, and treatment modalities. Our conference positively affected self-assessed knowledge acquisition among students, with the most pronounced differences seen in diagnosis and patient management (2.51 ± 1 v 3.87 ± 0.81) and treatment modalities (2.54 ± 0.96 v 3.79 ± 0.88), P < .001. Students believed the program was beneficial, felt more confident in applying their knowledge in the clinic and in delivering bad news, and were more interested in pursuing oncology-related fields, P < .001. CONCLUSION: We demonstrated that a compact teaching conference resulted in significant improvements in students' confidence and perceived knowledge about oncology. Our successful teaching model can be adapted and implemented at medical schools globally. Development and evaluation of teaching programs are important to urgently reform undergraduate medical education in oncology.

Transcription factor NF-κB as target for SARS-CoV-2 drug discovery efforts using inflammation-based QSAR screening model.

NF-κB is a central regulator of immunity and inflammation. It is suggested that the inflammatory response mediated by SARS-CoV-2 is predominated by NF-κB activation. Thus, NF-κB inhibition is considered a potential therapeutic strategy for COVID-19. The aim of this study was to identify potential anti-inflammation lead molecules that target NF-κB using a quantitative structure-activity relationships (QSAR) model of currently used and investigated anti-inflammatory drugs as the basis for screening. We applied an integrated approach by starting with the inflammation-based QSAR model to screen three libraries containing more than 220,000 drug-like molecules for the purpose of finding potential drugs that target the NF-κB/IκBα p50/p65 (RelA) complex. We also used QSAR models to rule out molecules that were predicted to be toxic. Among screening libraries, 382 molecules were selected as potentially nontoxic and were analyzed further by short and long molecular dynamics (MD) simulations and free energy calculations. We have discovered five hit ligands with highly predicted anti-inflammation activity and nearly no predicted toxicities which had strongly favorable protein-ligand interactions and conformational stability at the binding pocket compared to a known NF-κB inhibitor (procyanidin B2). We propose these hit molecules as potential NF-κB inhibitors which can be further investigated in pre-clinical studies against SARS-CoV-2 and may be used as a scaffold for chemical optimization and drug development efforts.

Magnetic resonance imaging criteria for prediction of isocitrate dehydrogenase (IDH) mutation status in patients with grade II-III astrocytoma and oligodendroglioma.

BACKGROUND: IDH mutation status is an important prognostic marker for glial tumors, which is detected immunohistochemically after surgery. Since this method is invasive, easy and noninvasive magnetic resonance imaging (MRI) methods have recently been used in predicting the IDH mutation status. However, there is currently no standard MRI technique to predict IDH mutation. We analyzed the value of conventional MRI to predict IDH mutation and its effect on survival among grade II-III astrocytoma and oligodendroglioma patients. MATERIAL AND METHODS: We included WHO grade II-III astrocytoma and oligodendroglioma patients who underwent surgery at Bahcesehir University Goztepe Medical Park Hospital. All patients were analyzed according to their immunohistochemical IDH mutation status. Preoperative conventional MRI studies with respect to their location, diffusion restriction, contrast enhancement, calcification and hemorrhage on susceptibility-weighted image (SWI) or T2*- weighted imaging (T2*WI), and T2 -FLAIR mismatch properties were retrospectively assessed by a neuroradiologist. The relation between MRI characteristics and IDH mutation was analyzed using a chi-square test. The sensitivity and specificity of radiological IDH mutation were determined by ROC analysis. The impact of IDH mutation on survival was also analyzed by Kaplan-Meier tests. RESULTS: IDH mutation was found to be positive in 82.5% of tumors histopathologically and 54.4% radiologically. The sensitivity and specificity were 63.8% and 90%, respectively (Area under the curve/AUC = 0.369, p = 0.08). IDH wild gliomas were predominantly diffusion-restricted tumors. IDH mutant tumors were less likely to have contrast enhancement and had lower grades compared to the IDH wild tumors. The median survival time could not be reached and the overall survival was not related to any tumor characteristics or IDH mutation. CONCLUSIONS: Conventional MRI predicts IDH-mutation status in Grade II-III astrocytoma and oligodendroglioma. Contrast-enhancement and restricted diffusion were strongly associated with grade III astrocytoma and oligodendroglioma, IDH-wild type. Location, T2-FLAIR mismatch, and SWI did not contribute to making a decision on the IDH mutation status. There was no significant difference between the survival times of patients and their IDH status.

An Integrated in silico Approach and in†vitro Study for the Discovery of Small-Molecule USP7 Inhibitors as Potential Cancer Therapies.

The ubiquitin-specific protease 7 (USP7) is a highly promising well-validated target for a variety of malignancies. USP7 is critical in regulating the tumor suppressor p53 along with numerous epigenetic modifiers and transcription factors. Previous studies showed that USP7 inhibitors led to increased levels of p53 and anti-proliferative effects in hematological and solid tumor cell lines. Thus, this study aimed to identify potent and safe USP7 hit inhibitors as potential anti-cancer therapeutics via an integrated computational approach that combines pharmacophore modeling, molecular docking, molecular dynamics (MD) simulations and post-MD free energy calculations. In this study, the crystal structure of USP7 has been extensively investigated using a combination of three different chemical pharmacophore modeling approaches. We then screened ∼220.000 drug-like small molecule library and the hit ligands predicted to be nontoxic were evaluated further. The identified hits from each pharmacophore modeling study were further examined by 1-ns short MD simulations and MM/GBSA free energy analysis. In total, we ran 1 ns MD simulations for 1137 selected on small compounds. Based on their average MM/GBSA scores, 18 ligands were selected for 50 ns MD simulations along with one highly potent USP7 inhibitor used as a positive control. The in vitro enzymatic inhibition assay testing of our lead 18 molecules confirmed that 7 of these molecules were successful in USP7 inhibition. Screening results showed that within the used screening approaches, the most successful one was structure-based pharmacophore modeling with the success rate of 75 %. The identification of potent and safe USP7 small molecules as potential inhibitors is a step closer to finding appropriate effective therapies for cancer. Our lead ligands can be used as a scaffold for further structural optimization and development, enabling further research in this promising field.

Targeting the NF-κB/IκBα complex via fragment-based E-Pharmacophore virtual screening and binary QSAR models.

Nuclear factor-κB (NF-κB) transcription factors represent a conserved family of proteins that regulate not only immune cells, but also heart cells, glial cells and neurons, playing a fundamental role in various cellular processes. Due to its dysregulation in certain cancer types as well as in chronic inflammation and autoimmune diseases, it has recently been appreciated as an important therapeutic target. The aim of this study was to investigate the binding pocket of NF-κB (p50/p65) heterodimer complex in association with NF-κB inhibitor IκBα to identify potent ligands via fragment-based e-pharmacophore screening. The ZINC Clean Fragments (∼2 million) and the Schrodinger's medically relevant Glide fragments library (∼670) were used to create the e-pharmacophore models at the potential binding site which was validated by site mapping. Glide/HTVS docking was conducted followed by re-docking of the top 20% fragments by Glide/SP and Glide/XP protocols. The top-85000 Glide XP-docked fragments were used to generate the e-pharmacophore hypotheses. The Otava small molecule library (∼260000 drug-like molecules) and 85 known NF-κB inhibitors were additionally screened against the derived e-pharmacophore models. The top-1000 high-scored molecules, which were well aligned to the e-pharmacophore models, from the Otava small molecule library, were then docked into the binding pocket. Finally, the selected 88 hit molecules and the 85 known inhibitors were analyzed by the MetaCore/MetaDrug™ platform, which uses developed binary QSAR models for therapeutic activity prediction as well as pharmacokinetic and toxicity profile predictions of screening molecules. Ligand selection criteria led to the refinement of 3 potent hit molecules using molecular dynamics (MD) simulations to better investigate their structural and dynamical profiles. The selected hit molecules had a low toxicity and a significant therapeutic potential for heart failure, antiviral activity, asthma and depression, all conditions in which NF-κB plays a critical role. These hit ligands were also structurally stable at the NF-κB/IκBα complex as per the MD simulations and MM/GBSA analysis. Two of these ligands (Otava IDs: 1426436 and 6248112) showed stronger binding and therefore are hypothesized to be more potent. The identification of new potent NF-κB/IκBα inhibitors may thus present a novel therapy for inflammation-mediated conditions as well as cancer, facilitating more efficient research, and leading the way to future drug development efforts.