Therapeutic Choice Research Articles

Anti-PD1 therapies induce an early expansion of Ki67+CD8+ T cells in metastatic non-oncogene addicted NSCLC patients

Pembrolizumab (an anti-PD1 antibody) alone or combined with chemotherapy represented the standard of care for advanced non-oncogene addicted non-small cell lung cancer (NSCLC) patients. These therapies induced early modifications of the immune response impacting the clinical outcome. Identifying early changes in the immune system was critical to directing the therapeutic choice and improving the clinical outcome. In this study, we aim to analyze the activating and inhibiting immune cells of NSCLC patients before and during therapy to identify patients who will benefit from immunotherapies. Forty-eight NSCLC patients were analyzed before (T0) and after the first cycle of immunotherapy (T1), evaluating several activating (CD137+and PD1+), proliferating (Ki67+) and immunosuppressing immune subsets (Tregs: total, active, resting, and non-suppressive; MDSCs: PMN(Lox1+)-MDSC and M-MDSCs) by cytofluorimetry. Concurrently, 14 soluble immune checkpoints were analyzed by Luminex assay. Immunotherapy significantly increased the levels of Ki67+(total and CD8+) T cells, PMN(Lox1+)-MDSCs, non-suppressive Tregs (nsTregs), and soluble PD1 from T0 to T1 in the entire NSCLC population, while decreased active Tregs. These changes were partially attributed to responding patients who showed an increase of Ki67+ and CD8+T cells and nsTregs at T1. CD137+(total, CD8+, and CD4+) T cells and soluble LAG3 were predictor factors at T0 and T1. A low ratio of Tregs/CD137+ T cells and high levels of Ki67+CD137+ T cells positively correlated with response to therapy at T0 and T1, respectively. Results highlighted that immunotherapy improved the immunological fitness of those patients who benefited from immunotherapy, changing the immunological balance towards immune activation.

Precision Medicine in Prostate Cancer: Integrating Genomics, AI, and Big Data for Personalized Treatment

Prostate cancer (PCa) remains one of the most prevalent cancers among men worldwide, exhibiting significant heterogeneity in its molecular profile and clinical course. Traditional approaches to treatment have often been generalized, leading to variable outcomes and, at times, unnecessary overtreatment. Precision medicine promises to transform PCa management by leveraging genomics, artificial intelligence (AI), and big data to tailor treatments to each patient’s molecular profile. This review examines how genomics has enhanced our understanding of PCa, identifying critical genetic mutations and molecular subtypes that influence disease progression. Additionally, the application of AI and machine learning in analyzing complex datasets has proven instrumental in discovering novel biomarkers, optimizing therapeutic choices, and predicting patient responses. The integration of big data from multiple platforms, including genomics, imaging, and electronic health records (EHRs), offers an unprecedented level of insight into the nuances of PCa. We discuss key genomic biomarkers, emerging AI-based predictive models, and the role of big data in advancing PCa precision medicine. Finally, we explore the challenges of clinical implementation, including data privacy, ethical concerns, and the need for interdisciplinary collaboration. The insights from this review underscore the transformative potential of precision medicine in enhancing prostate cancer treatment outcomes and the necessity for further research to overcome existing limitations. Keywords: Prostate cancer, precision medicine, genomics, artificial intelligence, big data, personalized treatment, biomarkers, molecular subtypes, machine learning.

Cancer-associated fibroblasts regulate mitochondrial metabolism and inhibit chemosensitivity via ANGPTL4-IQGAP1 axis in prostate cancer.

Cancer-associated fibroblasts (CAFs) are a critical component of the tumor microenvironment, being implicated in enhancing tumor growth and fostering drug resistance. Nonetheless, the mechanisms underlying their function in prostate cancer (PCa) remain incompletely understood, which is essential for devising effective therapeutic strategies. The main objective of this study was to explore the mechanisms by which CAFs mediate PCa growth and chemoresistance. We validated through data analysis and experimentation that CAFs significantly impact PCa cell proliferation and chemoresistance. Subsequently, we conducted a comprehensive proteomic analysis of the conditioned media from CAFs and PCa cells and identified angiopoietin-like protein 4 (ANGPTL4) as a key factor. We employed ELISA and multiplex immunofluorescence assays, all of which indicated that ANGPTL4 was primarily secreted by CAFs.Next, we conducted metabolomics analysis, GST pull-down assays, Co-IP, and other experiments to explore the specific molecular mechanisms of ANGPTL4 and its precise effects on PCa cells. Through drug screening, we identified Quercetin 3-O-(6'-galactopyranosyl)-β-D-galactopyranoside (QGGP) as an effective inhibitor of CAFs function. Finally, we thoroughly assessed the therapeutic potential of QGGP both as a monotherapy and in combination with docetaxel in PCa cells RESULTS: We discovered that the extracrine factor ANGPTL4 is primarily expressed in CAFs in PCa. When ANGPTL4 binds to IQ motif-containing GTPase-activating protein 1 (IQGAP1) on the PCa cell membrane, it activates the Raf-MEK-ERK-PGC1α axis, promoting mitochondrial biogenesis and OXPHOS metabolism, and thereby facilitating PCa growth and chemoresistance. Furthermore, virtual and functional screening strategies identified QGGP as a specific inhibitor of IQGAP1 that promotes its degradation. Combined with docetaxel treatment, QGGP can reverse the effects of CAFs and improve the responsiveness of PCa to chemotherapy. This study uncovers a paracrine mechanism of chemoresistance in PCa and proposes that targeting the stroma could be a therapeutic choice.

Underutilized edible Himalayan herb, Viola canescens Wall.; chemical composition, antioxidant and antimicrobial activity against respiratory tract pathogens

Understanding the intricacies of herbs and foods against bacterial infections is paramount for informed therapeutic choices. Delving into this domain, current study was focused to assess antimicrobial properties of Viola canescens organ specific extracts against prevalent respiratory tract pathogens (Klebsiella pneumoniae, Staphylococcus aureus, and Streptococcus pneumonia). Our methodology entailed proximate composition, TPC, TFC, Total condensed tannins and comprehensive chemical profiling by GC-MS, UPLC-PDA, and UPLC-MS/MS. Further, in-vitro, antioxidant potential through ABTS ֹ+ and DPPH ֹ radical scavenging assays was assessed. The root showed higher amount of proximate composition than its counterparts. Further, ethanol extract showed highest TPC (32.15±0.92mg GAE/g), TFC (125.61±2.28mg RE/g), and comparable TCT with methanol extract (34±0.19mg CE/g). UPLC analysis showed that p-coumaric acid was most predominant followed by rutin and luteolin among the V. canescens parts. In GC/MS analysis, methyl linoleate emerged as a major component as 10.70%, 17.62%, and 35.90% in flowers, leaves, and roots, respectively. Further, UHPLC- MS/MS data-based METLIN search revealed the presence of flavonoids, coumarins, terpenoids, and fatty acid derivatives etc. Chemo-metric analysis also showed variations of metabolites in different parts. All samples showed significant antioxidant activity with highest in methanol and ethanol flower extracts (0.037±0.001, 0.071±0.001 DPPHֹ and ABTS ֹ + IC50 mg/mL). The study suggested aerial parts can be a promising source of antioxidant and antimicrobial agents that may protect against respiratory tract pathogens similar to azithromycin. This substantiates the potential of V. canescens as a foundational ingredient for novel therapeutics.

Overprescription of antibiotics in Brazilian dental clinics: an evaluation of current practices

The use of antibiotics by dentist surgeons faces a lack of consensus among professionals and researchers, whether in relation to prophylaxis, or at least regarding the real need for their use. Recent studies increasingly question the use of prophylactic antibiotic therapy in healthy patients. This study aimed to evaluate the knowledge of dentist surgeons working in offices across Brazil regarding antibiotic use protocols and antibiotic resistance. A questionnaire was made via Google Forms and sent by email. The results showed that most dentists prescribe antibiotics for all surgical procedures performed in their office, regardless of the complexity and the patient. Furthermore, low scientific basis was observed among some of the professionals interviewed regarding the best therapeutic choice and the role of antibiotics in the surgical procedure. The present study highlights the urgent need to improve the knowledge of these professionals in Brazil, to reduce the impact on antibiotic resistance.

Epidemiological characteristics of myxopapillary ependymoma and factors affecting overall survival: a SEER-based analysis.

Myxopapillary ependymoma (MPE) is a rare tumor. Most studies have discussed the clinical symptoms and treatment of individual cases, but limited data are provided on overall survival and its influencing factors. Consequently, we aimed to further explore the epidemiological features of MPE and factors influencing overall survival. The cohort study extracted information about all patients diagnosed with intracranial MPE from the Surveillance, Epidemiology, and End Results (SEER) 2004-2015. Epidemiological characteristics and prognostic factors after adjustment for different variables were analyzed. Outcomes were 5- and 10-year overall survival. Univariate and multivariate analyses were conducted using the Cox proportional hazards model, with hazard ratios (HRs) and 95% confidence intervals (CIs). A total of 1,026 cases were identified in the SEER database. No significant difference was found between the incidence of total MPE and the incidence of non-malignant MPE from 2004 to 2015, and there was no incidence trend. The incidence of MPE was higher among people aged 30-34 and 45-49 years old. In 2005, 2007 and 2011, the incidence of men was greater than that of women (P<0.001). Blacks had a lower incidence than whites in years other than 2007, 2010, and 2013. The older age (older vs. younger: HR =1.081, 95% CI: 1.055-1.107), widowed status (widowed vs. single/unmarried: HR =3.058, 95% CI: 1.282-7.296), no surgery (surgery vs. no surgery: HR =0.283, 95% CI: 0.126-0.635), and radiotherapy (radiotherapy vs. no radiotherapy: HR =4.355, 95% CI: 2.211-8.578) were significantly adverse prognostic factors. Age, marital status, surgery and radiotherapy are factors influencing the overall survival of MPE patients. Surgery is still the main therapeutic choice, while radiotherapy plays a negative role in the management of MPE. Therefore, prospective research is required to verify and complement our findings for MPE control.

Immunotherapy in Non-Small-Cell Lung Cancer: A Modified Delphi Survey Consensus on First Line Treatment, Special Populations and Rechallenge

Background: The treatment landscape for non-small cell lung cancer (NSCLC) has evolved significantly with the advent of immunotherapy. Nonetheless, uncertainty regarding optimal first-line treatments, special populations, and the feasibility of rechallenge remains. This study aims to investigate Italian oncologists’ opinions on these aspects through a Delphi Survey. Methods: A steering committee (SC) of six oncologists identified three topics of interest, namely NSCLC (first line) therapeutic choice, NSCLC special populations, and NSCLC immunotherapy rechallenge), and drafted several topic-related statements to be voted in the Delphi Survey by the 61 oncologists forming the Delphi Panel. The survey included two rounds, wherein the experts rated their agreement/disagreement with the statements on a 5-point Likert scale. Consensus was defined as agreement/disagreement by at least 75% of the panel. Results: The SC drafted 69 statements for the first round, of which 16 (23.2%) met the agreement threshold, 5 (7.2%) met the disagreement threshold, and 48 (69.6%) did not reach consensus. The SC revised the latter statements and drafted 37 for the second round. Overall, 5 (13.5%) statements met the agreement threshold, 1 (2.7%) met the disagreement threshold, and 31 (83.8%) did not reach consensus in the second round. Conclusions: The survey showed agreement on the necessity of molecular characterization, mutations, smoke, the role of steroid therapy, and immunotherapy rechallenge, and revealed several areas of uncertainty among Italian oncologists on the use of immunotherapy in NSCLC. Statements—where consensus was not met—can be used to guide future clinical research in resolving the issues.

Hesperidin Suppressed Colorectal Cancer through Inhibition of Glycolysis.

To explore the role of the natural compound hesperidin in glycolysis, the key ratelimiting enzyme, in colorectal cancer (CRC) cell lines. In vitro, HCT116 and SW620 were treated with different doses of hesperidin (0-500 µmol/L), cell counting kit-8 and colone formation assays were utilized to detected inhibition effect of hesperidin on CRC cell lines. Transwell and wound healing assays were performed to detect the ability of hesperidin (0, 25, 50 and 75 µmol/L) to migrate CRC cells. To confirm the apoptotic-inducing effect of hesperidin, apoptosis and cycle assays were employed. Western blot, glucose uptake, and lactate production determination measurements were applied to determine inhibitory effects of hesperidin (0, 25 and 50 µmol/L) on glycolysis. In vivo, according to the random number table method, nude mice with successful tumor loading were randomly divided into vehicle, low-dose hesperidin (20 mg/kg) and high-dose hesperidin (60 mg/kg) groups, with 6 mice in each group. The body weights and tumor volumes of mice were recorded during 4-week treatment. The expression of key glycolysis rate-limiting enzymes was determined using Western blot, and glucose uptake and lactate production were assessed. Finally, protein interactions were probed with DirectDIA Quantitative Proteomics, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Hesperidin could inhibit CRC cell line growth (P<0.05 or P<0.01). Moreover, hesperidin presented an inhibitory effect on the migrating abilities of CRC cells. Hesperidin also promoted apoptosis and cell cycle alterations (P<0.05). The immunoblotting results manifested that hesperidin decreased the levels of hexokinase 2, glucose transporter protein 1 (GLUT1), GLUT3, L-lactate dehydrogenase A, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 2 (PFKFB2), PFKFB3, and pyruvate kinase isozymes M2 (P<0.01). It remarkably suppressed tumor xenograft growth in nude mice. GO and KEGG analyses showed that hesperidin treatment altered metabolic function. Hesperidin inhibits glycolysis and is a potential therapeutic choice for CRC treatment.

The POD24 challenge: where do we go from here for early progressors?

Follicular lymphoma is the most common indolent lymphoma, with a favorable prognosis and survival measured in decades. However, approximately 15% to 20% of patients encounter early disease progression, termed POD24, within 24 months from diagnosis or treatment initiation. Recognizing the correlation between POD24 and a heightened risk of lymphoma-related death has sparked intensive investigations into the clinical and biological determinants of POD24 and the development of innovative treatment strategies targeting this group. Research is also ongoing to understand the varying impact of POD24 based on different clinical contexts and the implications of early histologic transformation on POD24 prognosis. Recent investigations have uncovered potential new predictors of POD24, including genetic and nongenetic alterations as well as some conflicting F-fludeoxyglucose-positron emission tomography characteristics such as maximum standardized uptake value and total metabolic tumor volume. These developments, together with clinical predictors, have led to the emergence of several clinicopathologic tools to help identify at diagnosis patients who may be at higher risk for POD24. As these models are not routinely used, more work is needed to develop new risk-stratification strategies integrating clinical and molecular risk profiling that can be easily implemented in clinical practice to drive therapeutic choice. This review aims to delineate the modest but incremental progress achieved in our understanding of POD24, both clinically and biologically. Furthermore, we offer insights into the best practices to approach POD24 in the current era, aspiring to chart a new path forward to optimize patient outcomes.

THE CHALLENGE IN TEACHING MEDICAL PRESCRIPTION SKILLS, PROPOSAL OF ACTIVE LEARNING MODELS

Introduction: The adoption of active methodologies in undergraduate courses requires that teachers adopt a creative approach and seek out diverse tools that enhance meaningful learning. Teaching medical prescription is a challenge and undergraduates consider it a deficient practical area, requiring better applied learning. A medication display was developed as an active methodology tool to aid learning and overcome the theoretical-practical dissociation. Objective: To report the experience of students in using the medication display as a facilitator in the development of medical prescription skills in stages V and VI of the course. Experience report: In the pediatric skills clinic, students perform a complete anamnesis and physical examination, proposing a diagnostic hypothesis and conduct that will be discussed with the preceptor. Given the students' difficulty in choosing the medication, performing calculations and structuring the prescription, the medications were fixed on a 60/60 cm MDF board, so that students could view the bottles during their prescription practice. The display is assembled with empty medication bottles provided by the Popular Pharmacy Program or with other formulations obtained through free samples, related to the pathologies studied in the stage according to the pedagogical project of the course. There is no conflict of interest on the part of the institution, professor or student. Through problematization, the students practiced therapeutic choices, learned about the various presentations of the same active ingredient, performed calculations and structured prescriptions for internal and external use. Discussion: The students reported security, a feeling of scientific empowerment, increased professional responsibility and social maturity in the application of comprehensive patient care. The proximity of theory to the practice of prescription reinforced the perception that an effective prescription depends on assertive clinical reasoning. This evidences the stimulus to scientific study and responsibility in reducing prescription errors. Conclusion: It is considered that the early initiation of medical prescription guidelines in medical school, through the application of the medication display as a teaching-learning tool, was positive in the process of fixing concepts.

Spontaneous Postoperative Reduction of Ulnar Aneurism by Simple Decompression of Guyon’s Canal in a Patient with Hypothenar Hammer Syndrome: A Case Report

Background: Guyon’s canal syndrome is a pathological condition caused by compression of the ulnar nerve at the level of the wrist. It is less frequent than other compression syndromes of the upper limb (cubital and carpal tunnel), and different causative agents, including vascular lesions, are described. Among these, aneurysm of the ulnar artery is described in the literature as an infrequent aetiology. Case Presentation: We report the case of a 25-year-old young man with Guyon’s canal syndrome caused by an aneurysm of the ulnar artery, who underwent surgical decompression of the Guyon’s canal without intervening on the aneurysm. The postoperative course was free of complications, and the patient reported satisfaction, with reduced symptoms. Clinical examination and ultrasound imaging showed mass reduction of the aneurysm in the postoperative period, which appears to be an evolution hitherto undocumented in the literature. Conclusions: Many treatments are available for Guyon’s canal syndrome. Past medical and surgical treatments, duration and severity of symptoms, causes, and pathogenesis are important for therapeutic choice. Surgical treatment based on ligament section and lysis of the Guyon’s canal downstream, without any action on the aneurysm and with ulnar artery preservation, determined a reduction in terms of volume, relief of the symptoms, and patient satisfaction. With this case we describe a surgical therapeutic option for the treatment of Guyon’s canal syndrome caused by an aneurysm of the ulnar artery, in which surgery is limited to canal decompression and consequential aneurism mass reduction with concomitant relief of symptoms.

Subcutaneous Insulin Infusion Versus Multiple Administrations of Insulin Analogs: Is Either Method Associated with Better Quality of Life in Pediatric Patients with Type 1 Diabetes Mellitus?

Objectives − Type 1 Diabetes Mellitus (DM1) requires demanding treatment in order to achieve good metabolic control. Our aim was to assess whether either method of insulin administration (multiple daily administrations of insulin analogues (MDIA) or continuous subcutaneous insulin infusion (CSII)) is associated with better health-related quality of life (HRQoL).Methods − We conducted a cross-sectional study. Patients aged 10-18 years with a disease duration of at least six months were included. HRQoL was assessed by having patients and their caregivers complete the DISABKIDS-37 questionnaire.Results − Of the 40 patients included, 22 (55%) had CSII. There were no statistically significant differences between subscale scores and overall HRQoL between patients or between parents of patients with CSII or MDIA. CSII patients and parents scored better on all subscales and on the total scale, although without statistically significant differences. There were no statistically significant differences in the subscale scores and overall HRQoL reported by the patients and their parents, but there was a strong correlation between the children’s and parents’ scores (R=0.770; P&lt;0.01), which was similar in patients with CSII or MDIA (R=0.735 vs R=0.790).Conclusion − Although we did not identify statistically significant differences, there was a trend towards a better HRQoL associated with the use of CSII, both from the perspective of the adolescents and their parents. This could influence therapeutic choice. Consistency between the assessments of adolescents and their carers was observed. The choice between MDIA and CSII should be based on individual preferences in order to optimize the HRQoL of adolescents with DM1.

Different regimens for eradication of Helicobacter pylori infection in children: a randomized controlled trial

Eradication of Helicobacter pylori (H. pylori) infection in children is challenging due to increased antibiotic resistance and decreased effectiveness of the current therapeutic choices, especially in developing countries. The purpose of this study is to compare the efficacy and safety of triple therapy (TT), sequential therapy (ST), hybrid therapy (HT), concomitant therapy (CT), and ciprofloxacin-based triple therapy (CTT) as an empirical therapy for H. pylori eradication in children. In this randomized controlled trial, 200 children (aged between 3 and 16 years) with both positive rapid urease test and histopathology for H. pylori infection were included. Patients were randomly assigned to receive either TT, ST, HT, CT, or CTT. The eradication status was evaluated using a stool antigen test (SAT) 4 weeks after stoppage of antibiotic therapy and 2 weeks after stoppage of proton pump inhibitors. SAT was performed using an ELISA monoclonal antibody-based kit. The most common presenting symptom was epigastric pain (79%). The most common endoscopic findings were gastric antral erythema (98%) and antral nodularity (54.5%). All gastric biopsies showed superficial lamina propria infiltration with plasma cells and lymphocytes. Active gastritis with neutrophils infiltration was seen in 75% of the cases. Gastric atrophy and intestinal metaplasia were uncommon histopathological findings (8.5% and 1%, respectively). The eradication rates for TT, ST, HT, CT, and CTT were 70%, 77.5%, 80%, 85%, and 90%, respectively, with the latter achieving a statistically significant difference when compared with TT (p = 0.025). The rate of occurrence of adverse effects among different regimens was not statistically different. Conclusion: As an empirical treatment for children with H. pylori infection, CTT is safe and provides the highest eradication rate. HT, ST, and CT might not be superior to TT.Trial registration: This study was registered at the Pan African Clinical Trials Registry, Cochrane South Africa, under the identifier PACTR202201686010590. Date of registration: 04 January 2022.What is Known:• Triple therapy has been the standard eradication regimen for pediatric H. pylori infection. The efficacy of triple therapy has decreased in many countries due to increased antibiotic resistance.What is New:• This randomized controlled trial is the first to compare triple therapy, sequential therapy, hybrid therapy, concomitant therapy, and ciprofloxacin-based triple therapy for the eradication of pediatric H. pylori infection. Triple therapy exhibited the lowest eradication rate among the studied regimens, suggesting it may not be an adequate therapeutic option for infected children. Ciprofloxacin-based triple therapy appears to be a safe and effective therapeutic choice for pediatric H. pylori infection. Additionally, this study provides the first reported eradication rate of hybrid therapy in pediatric H. pylori infection.

USP1 deubiquitinates PARP1 to regulate its trapping and PARylation activity.

PARP inhibitors (PARPi) represent a game-changing treatment for patients with ovarian cancer with tumors deficient for the homologous recombination (HR) pathway treated with platinum (Pt)-based therapy. PARPi exert their cytotoxic effect by both trapping PARP1 on the damaged DNA and by restraining its enzymatic activity (PARylation). How PARP1 is recruited and trapped at the DNA damage sites and how resistance to PARPi could be overcome are still matters of investigation. Here, we described PARP1 as a substrate of the deubiquitinase USP1. At molecular level, USP1 binds PARP1 to remove its K63-linked polyubiquitination and controls PARP1 chromatin trapping and PARylation activity, regulating sensitivity to PARPi. In both Pt/PARPi-sensitive and -resistant cells, USP1/PARP1 combined blockade enhances replicative stress, DNA damage, and cell death. Our work dissected the biological interaction between USP1 and PARP1 and recommended this axis as a promising and powerful therapeutic choice for not only sensitive but also chemoresistant patients with ovarian cancer irrespective of their HR status.

A multicenter, cross-sectional analysis to assess the safety and usage pattern of brivaracetam in the management of partial-onset seizure with BAEs-BREEZE study: A post-hoc analysis.

Brivaracetam (BRV), a third-generation anti-seizure medication (ASM) offers strong conformational receptor domain binding, faster blood brain barrier (BBB) permeability and better tolerability making it potential therapeutic option as an initial line or initial line add-on strategy for focal onset seizure (FoS). The following study was planned to further understand the role and relevance of BRV in the real world settings of India. This was a multicentric, cross-sectional, and non-interventional study conducted in patients with FoS across India. The study was approved by central independent ethics committee. Descriptive and analytical statistics employed using SPSS version 29.0.1.0. Per protocol (PP) analysis included 8479 eligible patients from 1069 sites, gender; 5771 (68.06%) male and 2708 (31.94%) female with mean age 41.21 ± 12.74 years. Total 8019 (94.57%) patients had FoS and 460 (5.43%) patients had focal to bilateral tonic-clonic seizures (FBTCs). In FoS, 4105 (51.19%) patients switched from LEV to BRV whereas 3914 (48.81%) switched from other ASMs to BRV. BAEs accounted for 2059 (50.16%) patients in LEV to BRV switch versus 133 (3.39%) in other ASM to BRV switch. Post switch, LEV-associated BAEs reduced irrespective of being used as monotherapy 85.65% (p < 0.001) or as an adjuvant therapy 83.71% (p < 0.001) at BRV dosage of 50 to 100 mg BID. This RWE showed the utility of BRV as mono component as an initial add-on strategy in FoS cases. BRV remains a pertinent therapeutic choice for FoS for the treatment naïve and/or BAE cases. Exposure of LEV leads to considerable BAEs compared to patients without LEV exposure. Patients who switched to BRV due to LEV-induced BAEs significantly improved tolerability with BRV irrespective being used as monotherapy or as adjuvant therapy. Current study was planned to understand the clinical role and relevance of third-generation anti-seizure medication (ASM), brivaracetam (BRV) in the real world settings of India. Outcome of the study highlighted that BRV is an emerging, potential and safe ASM treatment option for epilepsy in Indian context. Many patients with epilepsy who are not able to tolerate the other ASM including levetiracetam (LEV) primarily due to behavioral side effects improves tolerability post switch to BRV, additionally results are consistent either BRV being used as an adjuvant therapy or as monotherapy therapy.

Abstract IA024: Validation of liquid biopsy approaches for the care of children with cancer

Abstract Pediatric cancers are driven by a unique set of mutations, destinct from the variants that typically drive adult cancers. Therefore, widely available liquid biopsy assays are often not relevant for detection, quantificaiton, or profiling of circulating tumor DNA in childhood cancer. Custom liquid biopsy approaches have been developed by the Crompton lab and others and these assays demonstrate that ctDNA levels provide valuable prognostic information and can guide some therapeutic choices in pediatrics. Implementation of liquid biopsies into national phase 3 trials for children with cancer will require translation of these approaches into a clinical molecular laboratory environment. Citation Format: Brian Crompton. Validation of liquid biopsy approaches for the care of children with cancer [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr IA024.

Saturation profiling of drug-resistant genetic variants using prime editing.

Methods to characterize the functional effects of genetic variants of uncertain significance (VUSs) have been limited by incomplete coverage of the mutational space. In clinical oncology, drug resistance arising from VUSs can prevent optimal treatment. Here we introduce PEER-seq, a high-throughput method based on prime editing that can evaluate the functional effects of single-nucleotide variants (SNVs). PEER-seq introduces both intended SNVs and synonymous marker mutations using prime editing and deep sequences the endogenous target regions to identify the introduced SNVs. We generate and functionally evaluate 2,476 SNVs in the epidermal growth factor receptor gene (EGFR), including 99% of all possible variants in the canonical tyrosine kinase domain. We determined resistance profiles of 95% of all possible EGFR protein variants encoded in the whole tyrosine kinase domain against the common tyrosine kinase inhibitors afatinib, osimertinib and osimertinib in the presence of the co-occurring substitution T790M, in PC-9 cells. Our study has the potential to substantially improve the precision of therapeutic choices in clinical settings.

Triple Negative Breast Cancer: Experience of the Obstetrics and Gynecology Department 2 Over A Period of 3 Years about 105 Cases at the Hassan II University Hospital in Fes

Introduction: Breast cancer is the second leading cause of death worldwide and the leading cancer in women. It is both the most common and the leading cause of death in women from cancer, thus posing a real public health problem. It presents tumor heterogeneity on the histological and molecular levels, explaining the diversity of presentations, responses to treatments, and prognosis. Triple-negative breast cancer is defined by the absence of expression of hormone receptors: estrogen receptors (ER), progesterone receptors (PR) and by the absence of overexpression or amplification of genes encoding HER2 receptors (Human epidermal growth factor receptor 2) and representing only a minority of breast cancers (10-20%). The therapeutic choices for this type of breast cancer are limited because patients do not benefit from hormonal therapy or targeted therapies, which poses a real problem in therapeutic management. Our objective is to describe the epidemiological, clinical, anatomo-pathological characteristics, as well as the evolutionary profile after adequate management of triple-negative breast cancer through the analysis of a series of cases of triple-negative breast cancer collected at the gynecology-obstetrics department 2 at the Hassan II University Hospital in Fez. Method: This is a retrospective study of a series of triple negative breast cancer cases collected in the gynecology-obstetrics department II at the Hassan II University Hospital in Fez during the period between January 2020 and December 2023. Inclusion criteria: Histologically confirmed triple negative infiltrating breast cancer treated in the gynecology-obstetrics department 2 of the Hassan II University Hospital in Fez. IHC = ER = 0% RP = 0% HER2 negative Exclusion criteria: male sex and presence of distant metastases. Results: On the epidemio-clinical level: a peak in frequency between 31 and 42 years old, and 45.7% of patients still in genital activity. On the anatomo-pathological level: ...

Ex Vivo Tools and Models in MASLD Research.

Metabolic dysfunction-associated fatty liver disease (MASLD) presents a growing global health challenge with limited therapeutic choices. This review delves into the array of ex vivo tools and models utilized in MASLD research, encompassing liver-on-a-chip (LoC) systems, organoid-derived tissue-like structures, and human precision-cut liver slice (PCLS) systems. Given the urgent need to comprehend MASLD pathophysiology and identify novel therapeutic targets, this paper aims to shed light on the pivotal role of advanced ex vivo models in enhancing disease understanding and facilitating the development of potential therapies. Despite challenges posed by the elusive disease mechanism, these innovative methodologies offer promise in reducing the utilization of in vivo models for MASLD research while accelerating drug discovery and biomarker identification, thereby addressing critical unmet clinical needs.

Careers of chloroquine and hydroxychloroquine as “miraculous” anti-Covid-19 drugs

In early January 2024, a widely publicized article in the journal Biomedicine and Pharmacology estimated that approximately 17,000 COVID-19 patients in France, Italy, Spain, Turkey, and the US died as a result of hydroxychloroquine treatment. The publication of this article is a fitting closure to nearly three years of controversy about the possible use of chloroquine and hydroxychloroquine to treat COVID-19. Repurposed in early 2020 as miracle answers to the COVID-19 pandemic, they had a brief moment of worldwide celebrity, despite the doubts expressed by many experts. Hydroxychloroquine’s career ended in September 2020, when a series of clinical trials showed not only inefficacy to treat COVID-19 but also safety concerns. However, the use of chloroquine and hydroxychloroquine continued in Brazil, where the government continued to promote their use as the first therapeutic choice against COVID-19. Our study outlines the employ of these drugs in France and Brazil. Grounded in the methodology developed by social studies of science, our article reconstructs the trajectories of hydroxychloroquine in France and Brazil. It aims to elucidate the reasons for the Brazilian exception, illuminating the disastrous consequences of the exercise of a monolithic political power and of anti-democratic practices on drug regulation and proposes new reflections on a topic that has been visible in the media and widely discussed in society, but attracted much less attention in the academic sphere.