Therapeutic Challenge Research Articles

Diagnostic and Therapeutic Challenges of Focal Cortical Dysplasia in Mali: A Case Report

Focal Cortical Dysplasias (FCDs) are a common cause of pharmaco-resistant epilepsy. FCDs are rare conditions, and their pathogenesis remains poorly understood. We report a 12-year-old patient seen in our clinic for focal onset epileptic seizures. Neurological examination and brain CT-scan were nearly normal. However, an electroencephalogram (EEG) revealed a slightly slow background rhythm with slow spikes in the medial and right parietal regions and a brain magnetic resonance imaging (MRI) showed a focal cortical thickening in the right parietal lobe with FLAIR hypersignal, indicating a focal cortical dysplasia. Ongoing seizures marked the disease course under antiepileptic polytherapy after 15 months of treatment. Keywords: Focal cortical dysplasia, pharmaco-resistant epilepsy, Mali, Africa.

DEALING WITH TWO SYNCHRONOUS LESIONS

Introduction Multiple synchronous intracranial lesions present a significant diagnostic and therapeutic challenge, in most cases appearing as metastatic tumors or same-cell type tumors. Case Report We report the case of a 73-year-old patient admitted in our department with light left hemiparesis (MRC MMT 4/5), light left hypoesthesia and transitory and remitted state of temporo-spatial confusion that debuted around six weeks prior to presentation. The neurological exam confirmed the sensorimotor deficit and displayed the existence of left neglect syndrome. The patient’s MRI revealed a giant temporo-parieto-occipital mass almost 7 cm in diameter that appeared to have an intraventricular starting point and showed a relatively homogeneous contrast enhancement with significant mass effect. A concomitant superficial parieto-temporal lesion was also noted. Both lesions were excised in a successive manner from superficial to deep, using a right parieto-temporal craniotomy. While the giant mass had a yellowish color and an extremely hard consistency, the superficial one was easily suctionable and had a grey-reddish color and was extremely well vascularized, raising the suspicion of concomitant brain lesions of different histology. Postoperatively the patient underwent a routine thoracic CT scan in the context of a position related soft tissue injury that revealed the existence of two pulmonary lesions, further deepening our suspicion of concomitant brain lesions of different histology. Conclusions Although extremely rare, the appearance of two histologically distinct brain lesions in patients with no evidence of a genetic condition should be taken into consideration especially in the context of intraoperative differences in order to successfully guide the patients’ follow-up treatment.

Novel Biomarkers as Potential Predictors of Decompensated Advanced Chronic Heart Failure-Single Center Study.

Background/Objectives: Heart failure (HF) remains a major therapeutic and diagnostic challenge nowadays. Albeit, acute decompensated HF is associated with several clinical signs such as dyspnea or edema, it remains a challenge to use easy accessible and suitable tools, such as biomarkers, to distinguish between patients at risk for an acute decompensation of their heart failure and compensated, stable HF patients. Existing biomarkers, such as natriuretic peptides or troponin, are not specific and can be elevated due to several other disease conditions, such as myocardial infarction, atrial fibrillation, or valve diseases. Therefore, the aim of this study was to analyze the predictive potential of four novel cardiovascular biomarkers-the soluble urokinase-type plasminogen activator receptor (suPAR), heart-type fatty acid binding protein (H-FABP), vascular cell adhesion molecule 1 (VCAM-1), and growth/differentiation factor 15 (GDF-15) for the detection of cardiac decompensation in patients with HF. Methods: In this study, 146 patients were prospectively enrolled and the serum biomarker concentrations were analyzed using Enzyme Linked Immunosorbent Assay (ELISA). We correlated the biomarker concentrations with clinical and biochemical parameters of all patients and the predictive value for detection of cardiac decompensation was assessed. Results: A significant increase in the levels of suPAR (1.6-fold-change, p < 0.0001), H-FABP (2.2-fold-change, p = 0.0458), VCAM-1 (1.6-fold-change, p < 0.0001), and GDF-15 (1.7-fold-change, p = 0.0009) was detected in all patients with acute decompensated HF in comparison to patients with compensated HF. Univariate logistic regression analysis revealed a significant association of biomarker plasma concentration with the risk for a cardiac decompensation (suPAR: p < 0.0001; VCAM-1: p < 0.0001, H-FABP: p = 0.0458; GDF-15: p = 0.0009). Conclusions: In conclusion, the investigated novel cardiovascular biomarkers suPAR, GDF-15, VCAM-1, and H-FABP could be a valuable tool to facilitate therapeutic decisions in patients with heart failure and suspicion of a cardiac decompensation. Parameters such as renal function should be taken into account. Further studies on novel biomarkers are required to find reliable, sensitive, and specific tools that will enable the early detection of patients with acute decompensation.

Decoding Acute Myeloid Leukemia: A Clinician's Guide to Functional Profiling.

Acute myeloid leukemia (AML) is a complex clonal disorder characterized by clinical, genetic, metabolomic, and epigenetic heterogeneity resulting in the uncontrolled proliferation of aberrant blood-forming precursor cells. Despite advancements in the understanding of the genetic, metabolic, and epigenetic landscape of AML, it remains a significant therapeutic challenge. Functional profiling techniques, such as BH3 profiling (BP), gene expression profiling (GEP), proteomics, metabolomics, drug sensitivity/resistance testing (DSRT), CRISPR/Cas9, and RNAi screens offer valuable insights into the functional behavior of leukemia cells. BP evaluates the mitochondrial response to pro-apoptotic BH3 peptides, determining a cell's apoptotic threshold and its reliance on specific anti-apoptotic proteins. This knowledge can pinpoint vulnerabilities in the mitochondria-mediated apoptotic pathway in leukemia cells, potentially informing treatment strategies and predicting therapeutic responses. GEP, particularly RNA sequencing, evaluates the transcriptomic landscape and identifies gene expression alterations specific to AML subtypes. Proteomics and metabolomics, utilizing mass spectrometry and nuclear magnetic resonance (NMR), provide a detailed view of the active proteins and metabolic pathways in leukemia cells. DSRT involves exposing leukemia cells to a panel of chemotherapeutic and targeted agents to assess their sensitivity or resistance profiles and potentially guide personalized treatment strategies. CRISPR/Cas9 and RNAi screens enable systematic disruption of genes to ascertain their roles in leukemia cell survival and proliferation. These techniques facilitate precise disease subtyping, uncover novel biomarkers and therapeutic targets, and provide a deeper understanding of drug-resistance mechanisms. Recent studies utilizing functional profiling have identified specific mutations and gene signatures associated with aggressive AML subtypes, aberrant signaling pathways, and potential opportunities for drug repurposing. The integration of multi-omics approaches, advances in single-cell sequencing, and artificial intelligence is expected to refine the precision of functional profiling and ultimately improve patient outcomes in AML. This review highlights the diverse landscape of functional profiling methods and emphasizes their respective advantages and limitations. It highlights select successes in how these methods have further advanced our understanding of AML biology, identifies druggable targets that have improved outcomes, delineates challenges associated with these techniques, and provides a prospective view of the future where these techniques are likely to be increasingly incorporated into the routine care of patients with AML.

BN SO62 - Laparoscopic technique for right sided paraduodenal hernia repair: A clinical study and surgical insights

Abstract Background Paraduodenal hernias can present significant diagnostic and therapeutic challenges, with up to 50% potentially leading to bowel obstruction. A minimally invasive approach to repairing these defects offers reduced morbidity and quicker recovery. This report highlights the feasibility and safety of laparoscopic repair of a right-sided paraduodenal hernia. Method A 19-year-old female presented with persistent postprandial bilious vomiting and a long history of forceful regurgitation 10-30 minutes after eating. The preoperative evaluation, surgical technique and operative outcomes are detailed. Results Preoperative evaluation included magnetic resonance imaging, computed tomography and a barium swallow, revealing an incidental finding of the duodenojejunal flexure and most jejunal loops on the right side of the abdomen. A right paraduodenal hernia was diagnosed during laparoscopy. After delineating and reducing the hernia laparoscopically, the sac was obliterated by opening up the posterior aspect over the inferior vena cava. The repair was completed by suturing the hernia orifice and plicating the duodenum. The patient's symptoms resolved postoperatively, with no intraoperative or immediate postoperative adverse outcomes reported. Scheduled outpatient follow-up showed satisfactory resolution of symptoms. Conclusion The laparoscopic repair of the right paraduodenal hernia was successfully performed, leading to the resolution of the patient's symptoms. This case underscores the importance of considering laparoscopic approaches for managing complex and rare hernias, especially when cross-sectional imaging modalities do not clearly identify the cause of symptoms. The laparoscopic technique offers significant advantages, including reduced pain and faster recovery.

Combined micro-needling with topical metformin versus micro-needling with topical placebo in the treatment of melasma: a concurrent split-face study.

Melasma is an acquired dysfunction of melanogenesis, that poses a major therapeutic challenge and tends to recur after therapy. Several combination therapies are being tested nowadays for the treatment of melasma, with promising results. Metformin, an anti-diabetic medication, seems to inhibit melanogenesis by different mechanisms. In addition, there has been a long-term improvement in melasma after microneedle therapy. To evaluate the potential therapeutic role of topical metformin combined with micro-needling for the treatment of melasma. Eighteen patients with melasma received treatment in split-face manner, right side with micro-needling and topical metformin, while the left side was treated with micro-needling and topical placebo for four sessions at 2-week intervals. Hemi-mMASI score was used for the final evaluation of results. ThevariabilitypatterninHemi-mMASI score between both sides revealed significant reduction in the right side (micro-needling + metformin), as compared to the left side (micro-needling + placebo) (2.39 ± 1.42 vs 4.72 ± 1.27, p = 0.001). The effectiveness of topical metformin in the management of melasma could be significantly improved by pretreatment with micro-needling as a combined therapy, without any apparent side effects.

CCL2-scavenging nanodecoy hydrogel multi-step remodel monocytes recruitment and macrophages polarization for periodontitis treatment

Periodontitis is a chronic inflammatory disease caused by pathogenic biofilms and over-activated host immune response, leading to sustained damage to periodontal supporting tissue and even tooth loss. A key therapeutic challenge in recurrence of periodontitis is persistent existence of infiltrating monocytes and macrophages in periodontal tissues. Particularly, C-C motif ligand 2 (CCL2) is vital for monocyte recruitment and macrophage polarization in periodontitis. In this study, we developed biomimetic caffeic acid phenethyl ester-loaded nanoparticles (M−CNPs) as nanodecoys by macrophage membrane encapsulation to block CCL2-mediated inflammatory response and tissue damage. M−CNPs were distributed in the thermosensitive gel matrix (M−CNPs@Gel) to improve the retention time and sustained-release in the periodontal pocket. Our study demonstrated that M−CNPs@Gel exhibited a significant nanodecoy effect by competitively binding to CCL2 in periodontium, which inhibited monocyte/macrophages recruitment. Additionally, biomimetic nanodecoy system could reprogram macrophages phenotype through multi-step blocking CCL-CCR2-PI3K pathway and ROS elimination. M−CNPs@Gel effectively reduced the infiltration of monocytes and macrophages, and promote alveolar bone regeneration by regulating the ratio of M1/M2 macrophages in vivo. This study develops a novel CCL2-scavenging biomimetic nanodecoy hydrogel that remodel monocytes recruitment and macrophages polarization for effective periodontitis treatment.

BN SO55 - Rare case of Ectopic pancreatitis in stomach and its Surgical Management

Abstract Background This presentation covers the case of Mr. D, a 38-year-old male who presented with upper abdominal pain and vomiting, initially treated as gastritis but later developing more complex symptoms. This case highlights the diagnostic challenges and management of ectopic pancreatitis, a rare condition characterized by pancreatic tissue located outside its usual anatomical position.Mr. D, a personal trainer with a history of asthma and Meckel's diverticulum excision, experienced recurring epigastric pain, bloating, and early satiety. His pain was particularly related to eating, fasting and often disrupted his sleep. Despite treatment with proton pump inhibitors (PPIs), his symptoms persisted, prompting further investigation Method Initial investigations including ultrasound, chest X-ray, and ECG showed no significant abnormalities. However, subsequent gastroscopy and CT scans suggested a gastrointestinal stromal tumor (GIST), leading to referral for endoscopic ultrasound (EUS) and biopsy. The findings indicated a highly vascular, mixed echogenic lesion in the submucosa, likely a GIST, but initial biopsies were inconclusive Results Following conservative treatment, Mr. D's inflammation significantly reduced, though he experienced recurrent pain necessitating surgical intervention. Diagnostic laparoscopy and gastroscopy revealed extensive adhesions and an inflammatory mass. The patient underwent a pyloric-preserving sleeve gastrectomy, with histology confirming pancreatic heterotopia with inflammation and cystic degeneration. Post-operatively, Mr. D initially struggled with dietary intake but improved over time, tolerating a solid diet by the last follow-up. Conclusion This case underscores the complexity of diagnosing and managing rare conditions like ectopic pancreatitis. It highlights the importance of a multidisciplinary approach and the potential need for surgical intervention when conservative management fails. The presentation aims to provide valuable insights into the diagnostic process, the role of MDT discussions, and the therapeutic challenges associated with ectopic pancreatitis.

Abstract 4120805: Comparison of Thermodilution and Doppler Flow Velocity Derived Indexes of Coronary Physiology using Intracoronary Adenosine in Patients with Angina and Unobstructed Coronary Arteries (ANOCA)

Introduction: Patients with angina but unobstructed coronaries (ANOCA) represent a diagnostic and therapeutic challenge. Current Guidelines recommend invasive testing using acetylcholine and adenosine for evaluation of coronary vasomotor disorders. However, there is a broad variability among the different measurement techniques. Purpose: To assess the differences of bolus thermodilution versus Doppler flow velocity derived indexes of coronary physiology using intracoronary adenosine in patients with ANOCA. Methods: A total of 162 patients (61.1% women, mean age 63±28 years) with ANOCA (no epicardial stenosis &gt;50%, FFR &gt;0.80) were enrolled between 2018 and 2023. All patients underwent wire-based assessment of coronary flow reserve (CFR) and microvascular resistance (MR) using adenosine in the left anterior descending artery. The bolus thermodilution technique was applied in 46 patients (CFR/IMR, CFRThermo) and the Doppler technique in another 116 patients (CFR/HMR, CFRDoppler). All measurements were performed according to a standardised protocol. The commonly applied cut-offs for CFR (&lt;2.5), HMR (&gt;2.5) and IMR (&gt;25) were used. Results: The study population was characterized by the following risk factors: arterial hypertension (63%), hypercholesterolemia (62%), positive family history for cardiovascular disease (36%), diabetes (16%) and smoking (10%). The frequency of an abnormal CFR &lt;2.5 was 36%. There was a significant difference between the frequency of an abnormal CFR among patients with CFRThermo (8/46, 17.4%) and patients with CFRDoppler (50/116, 43.1%, p=0.002). Moreover, the median CFR was higher in the CFRThermo group compared to the CFRDoppler group (3.5 [IQR2.8] vs. 2.6 [IQR 0.9], p&lt;0.0005) with a much larger interquartile range in the former (Figure 1). Assessment of MR revealed an abnormal result in 20% of cases which was more often observed with the thermodilution (IMR &gt;25 in 39.1%, median 22.5 [IQR 17.0]) compared to the Doppler technique (HMR &gt;2.5 in 12.1%, median 1.7 [IQR 0.7], p&lt;0.0005). Multivariable analysis revealed arterial hypertension (OR 4.04, CI 1.88 – 8.77, p&lt;0.0005) and female sex (2.12, 1.04 - 4.34, p=0.04) as independent predictors for an abnormal CFR. Conclusion: Comparison of thermodilution and Doppler derived indexes of coronary physiology in patients with ANOCA reveals marked differences among the different measurement techniques. The results are important for the endotype classification and subsequent patient management.

The Critical Role of Host and Bacterial Extracellular Vesicles in Endometriosis.

Endometriosis is a chronic, inflammatory, oestrogen-dependent disorder that is defined by the presence of endometrium-like tissue in the extra-uterine environment. It is estimated to affect approximately 10% of women of reproductive age, and the cause is still largely unknown. The heterogenous nature and complex pathophysiology of the disease results in diagnostic and therapeutic challenges. This review examines the emerging role of host extracellular vesicles (EVs) in endometriosis development and progression, with a particular focus on bacterial extracellular vesicles (BEVs). EVs are nano-sized membrane-bound particles that can transport bioactive molecules such as nucleic acids, proteins, and lipids, and therefore play an essential role in intercellular communication. Due to their unique cargo composition, EVs can play a dual role, both in the disease pathogenesis and as biomarkers. Both host and bacterial EVs (HEVs and BEVs) have been implicated in endometriosis, by modulating inflammatory responses, angiogenesis, tissue remodelling, and cellular proliferation within the peritoneal microenvironment. Understanding the intricate mechanisms underlying EVs in endometriosis pathophysiology and modulation of the lesion microenvironment may lead to novel diagnostic tools and therapeutic targets. Future research should focus on uncovering the specific cargo, the inter-kingdom cell-to-cell interactions, and the anti-inflammatory and anti-microbial mechanisms of both HEVs and BEVs in endometriosis in the hope of discovering translational findings that could improve the diagnosis and treatment of the disease.

Abstract 4118959: Pulmonary Artery-Targeted Metformin-Loaded Nanocapsules Enhance Treatment of Pulmonary Arterial Hypertension

Background: Pulmonary arterial hypertension (PAH) remains a therapeutic challenge despite the availability of various medications. Metformin can be able to treat PAH but is associated with significant side effects. This study aims to enhance the efficacy and safety of metformin through a novel drug delivery system using low-dose metformin encapsulated in pulmonary artery-targeted nanocapsules. Methods: Metformin-loaded lung-targeted nanocapsules (MET nanocapsules) were synthesized using a specific lipid composition, including cationic lipids. The uptake and effects on cell viability were assessed in human pulmonary arterial smooth muscle cells (hPASMCs) from both healthy individuals and PAH patients. The therapeutic efficacy of MET nanocapsules was evaluated in a rat model of PAH. Safety was confirmed via serum biochemical tests in rats. Results: MET nanocapsules were successfully synthesized and demonstrated significant inhibition of PASMC proliferation. In the PAH rat model, MET nanocapsule treatment led to improved hemodynamic parameters, reduced right ventricular hypertrophy, and decreased pulmonary arterial medial thickening. Importantly, MET nanocapsules showed effective accumulation in the lungs of PAH rats. Conclusions: Intravenous administration of MET nanocapsules represents a safe and innovative therapeutic approach for PAH. This targeted delivery system has the potential to improve treatment outcomes while minimizing side effects and may have broader applications for other forms of pulmonary hypertension.

Leiomyosarcoma of the inferior vena cava: case report

Introduction and Importance: Leiomyosarcomas of the inferior vena cava are exceedingly rare tumors, presenting diagnostic dilemmas due to their nonspecific clinical features. This case report aims to shed light on the challenges associated with diagnosing and managing such tumors, emphasizing the importance of a multidisciplinary approach. This article uses SCARE2023 criteria as a framework to sort out a case report in order[1]. Case Presentation: We present a case of leiomyosarcoma of the inferior vena cava in a patient presenting with abdominal pain. Initial clinical signs, supported by computed tomography (CT) and magnetic resonance imaging (MRI), led to the suspicion of the tumor. Histological analysis confirmed the diagnosis, prompting surgical intervention. Clinical Discussion: The diagnosis of tumors within the inferior vena cava is often challenging due to their nonspecific presentation. Imaging modalities such as CT and MRI play an important role in describing the extent of the tumor and guiding surgical planning. Histological analysis remains supreme for definitive diagnosis. Surgical resection, aimed at complete excision, is the keystone of treatment to minimize the risk of recurrence. Conclusion: Leiomyosarcomas of the inferior vena cava pose diagnostic and therapeutic challenges due to their rarity and nonspecific clinical presentation. A comprehensive approach integrating clinical assessment, imaging, and histological analysis is essential for accurate diagnosis and optimal management. Multidisciplinary collaboration is key for navigating the complexities associated with these rare vascular neoplasms, ensuring positive patient outcomes.

PATH-68. THE CLINICAL AND PROTEOMIC CLASSIFICATION FOR THE PRECISION TREATMENT STRATEGY OF CHORDOMA

Abstract Chordoma is a rare and heterogeneous mesenchymal malignancy, with distinct clinical and biological behaviors. Till now, its comprehensive clinical-molecular characteristics and accurate molecular classification remain obscure, leading to numerous diagnostic and therapeutic challenges. In this research, we enroll a large cohort of chordoma (102 patients) and describe their clinical, imageological and histopathological features. Through tandem mass tag-based proteomic analysis and nonnegative matrix factorization clustering, we classify chordoma into the following three molecular subtypes: bone microenvironment dominant, mesenchymal derived, and mesenchymal to epithelial transition mediated pattern. The three subtypes exhibit discrete clinical prognosis and distinct biological attributes of osteoclastogenesis and immunogenicity, oxidative phosphorylation, and receptor tyrosine kinase activation, suggesting targeted therapeutic strategies of Denosumab, S-Gboxin and Anlotinib, respectively. Notably, these approaches demonstrate positive treatment outcomes for each subtype in vivo and in vitro, as well as in patient-derived xenograft models. Altogether, this work sheds light on the clinical-proteomic characteristics of chordoma that deepens our understanding of this rare disease and provides candidate precision treatment strategy for chordoma according to molecular classification, underscoring their potential for clinical application.

SURG-47. SUPRAMAXIMAL RESECTION IMPROVES OVERALL SURVIVAL IN PATIENTS WITH MGMT-UNMETHYLATED GLIOBLASTOMA

Abstract INTRODUCTION Glioblastoma is highly resistant to radio- and chemotherapy and its heterogeneity is a therapeutic challenge. O6-methylguanine–DNA methyltransferase (MGMT) promotor methylation is an established biomarker for favorable effect of chemotherapy. Supramaximal resection has proven predict the best overall survival (OS), but whether this benefit applies equally to patients with different MGMT-promotor methylation status is still to be debated. MATERIAL AND METHODS Population based retrospective study that examined all adult patients in South-Eastern Norway that underwent resection for IDH wildtype glioblastoma between January 2019 and December 2021. Extent of resection (EOR) was classified according to RANO resect classification and MGMT-promotor methylation status by pyrosequencing-qPCR. RESULTS The study included 281 patients. MGMT-promotor methylated patients (MGMT+) had a median OS of 18.4 months compared to 13.1 months in MGMT-unmethylated (MGMT-) patients (p&amp;lt;0.0001). Patients with supramaximal resection had a median OS of 20.4 months compared to 14.9 months (p&amp;lt;0.01) with maximal resection. For patients with supramaximal resection we found no significant difference in median OS (25.5 vs. 18.3 months (p=0.24)) dependent on MGMT-status. Separated analysis between MGMT-status and EOR showed a median survival of 18.3, 13.4 (p&amp;lt;0.001), and 8.5 (p&amp;lt;0.001) months for MGMT-, and 25.5, 18.4 (p=.99), and 9.0 (p&amp;lt;0.001) months for MGMT+ in patients where supramaximal-, maximal-, and submaximal resection was achieved, respectively. CONCLUSIONS Patients with supramaximal resection and MGMT+ have a 50% 2-years survival probability. In patients where supramaximal resection was achieved, survival benefit was not dependent on MGMT-status. There was a significant improved survival in MGMT- patients between supramaximal and maximal resection, that was not present for MGMT+ patients. Intraoperative molecular diagnosis has the potential to guide the surgical strategy dependent on MGMT-promotor methylation status, especially in tumors where supramaximal resection has a higher risk of new neurological deficits.

Diagnostic and therapeutic challenges in implementing hypertension management after kidney transplantation.

Evidence for blood pressure (BP) measurement and hypertension management in kidney transplant recipients (KTR) remains lacking. Accurate BP measurement technique is a critical component of hypertension management, and 24-h ambulatory BP monitoring remains the gold standard for diagnosis of hypertension in KTR. BP target at different periods posttransplant is uncertain, but likely higher than that in nontransplant patients given factors related to long-standing uremic milieu and kidney transplantation such as vascular calcification altering transplant renal hemodynamic and allograft perfusion and immunosuppression. Dividing BP target into immediate, early, and late posttransplant periods can guide differential diagnoses of hypertension and BP control with a target SBP less than 160 mmHg in general and BP 115-135/65-85 mmHg for adult KTR receiving pediatric kidneys during the immediate posttransplant period, 130/80 mmHg during early and late posttransplant periods. Calcium channel blockers were shown to have favorable graft outcomes. Novel antihypertensive medications for resistant and refractory hypertension and device-based therapies are limited due to KTR's ineligibility for participating in clinical trials. In KTR, BP measurement and monitoring practice should follow the standard clinical practice guideline for nontransplant patients by considering posttransplant factors and immunosuppressive state. Novel treatment options required further studies.

Adrenocortical Carcinoma about One Case and Literature Review

Introduction: Adrenocortical carcinoma (ACC) is a rare malignant tumor that develops in the layers of the adrenal cortex with an incidence of 0.5–2 per million per year. Case report: A 40-year-old female patient, admitted for left flank heaviness, evaluation was in favour of a suspicious left adrenal tumour, the non-functional caracater was retained after a negative secretory workup. The patient was operated on with a histological appearance of metastatic ACC. Discussion and conclusion: The prognosis for these tumors is poor, since at the time of diagnosis the majority of cases are already metastatic, especially when the tumour is non-functional. The management of ACC is complex, representing a real diagnostic and therapeutic challenge.

IMMU-35. TARGETING THE AHR IMMUNOMETABOLIC HUB DURING VIROIMMUNOTHERAPY OF GLIOMAS

Abstract Glioblastoma (GBM) poses a significant therapeutic challenge in oncology. Recent clinical trials have shown the feasibility of virotherapy to treat patients with GBM. Our laboratory developed an oncolytic adenovirus termed Delta-24-RGD that has been tested in clinical trials for recurrent GBM patients with encouraging results (NCT00805376, NCT02798406). These clinical studies, together with preclinical data, showed that the efficacy of Delta-24-RGD was due to direct tumor cell oncolysis and indirect activation of anti-tumor immune response. To further leverage this immune component, our group generated Delta-24-RGDOX, an armed version of Delta-24-RGD expressing the T-cell activator OX40-L, which exhibits a superior anti-cancer effect. In this project, we aim to further boost the effectiveness of Delta-24-RGDOX by targeting factors that maintain the immunosuppressive characteristic of gliomas. Specifically, we identified the environmental sensor and transcription factor Aryl Hydrocarbon Receptor (AhR) as one of the immunosuppressive factors. We show that AhR is overexpressed in GBM surgical specimens compared to healthy brain tissue, and high AhR expression correlates with poorer survival in glioma patients. Immunofluorescence staining of glioma cells treated with Delta-24-RGDOX demonstrated that AhR translocates to the nucleus, and qPCR showed that translocation resulted in the enhanced transcription of AhR-responsive elements. Additionally, bulk RNA-seq reveals that in vivo glioma models treated with Delta-24-RGDOX exhibit activation of the AhR pathway network. This unexpected and paradoxical activation may be responsible for immune suppression mechanisms, which might hinder the effect of Delta-24-RGDOX. Based on these data, we combined two innovative strategies, the oncolytic virus Delta-24-RGDOX and AhR inhibitors. Survival analysis in immunocompetent models of gliomas treated with this combined therapy showed the greatest therapeutic benefit compared to monotherapy controls. These findings highlight the critical role of AhR activation triggered by Delta-24-RGDOX and position AhR as a potential therapeutic target for enhancing the efficacy of oncolytic adenovirus therapy in GBM.

RADT-23. MOLECULAR PROFILING OF GLIOMAS: INSIGHTS INTO RADIONECROSIS AND PSEUDOPROGRESSION THROUGH NEXT-GENERATION SEQUENCING

Abstract BACKGROUND Gliomas, the most common primary tumors of the CNS, presenting diagnostic and therapeutic challenges due to their heterogeneity. Next-generation sequencing (NGS) enhances diagnostic precision by identifying genetic alterations, guiding accurate diagnosis and personalized treatment strategies. Post-treatment complications such as radionecrosis and pseudoprogression present additional diagnostic difficulties, often mimicking tumor recurrence. This study aimed to evaluate the association between genetic alterations detected by NGS and treatment-related complications. METHODS This retrospective study analyzed data from electronic medical records at a Brazilian Radiation Therapy Department (2018-2023). The study included patients with gliomas who underwent surgical resection followed by adjuvant radiochemotherapy and subsequently developed complications such as radionecrosis and pseudoprogression. Genetic alterations detected by the HSL 500 (NGS) test were evaluated for their association with these complications using Fisher’s Exact Test. RESULTS Out of 192 patients treated for glioma, 46 (23.96%) experienced treatment-related complications, with 20 patients having available NGS test results. Among these, eight cases were identified as pseudoprogression, fifteen as radionecrosis, with three patients presenting both conditions. All 20 patients with NGS results were diagnosed with high-grade gliomas, eight of whom underwent reirradiation, resulting in two cases of radionecrosis post-reirradiation. Although no statistically significant association was found between genetic alterations and radionecrosis or pseudoprogression, specific mutations were prevalent in each group. In radionecrosis cases, the most common mutations were TERT promoter (c.1-124C&amp;gt;T) (n=9, p=0.613) and EGFR amplification (n=8, p=1.0). In pseudoprogression, frequent mutations included TERT promoter (c.1-124C&amp;gt;T) (n=6, p=0.642), EGFR (n=5, p=0.67), PTEN (n=4, p=1.0), NF1 (n=2, p=0.537), and P53 (n=2, p=0.197). CONCLUSION Molecular testing for glioma characterization is crucial for diagnosis and prognosis, aiding in understanding treatment-related complications. Strategies to avoid radionecrosis and pseudoprogression are vital to improve patient quality of life, especially in high-grade gliomas. Further studies are needed to confirm these trends and explore clinical relevance of mutations.

NCOG-39. EXPLORING THE POTENTIAL OF STEREOTACTIC RADIOSURGERY IN THE MANAGEMENT OF MENINGIOMAS

Abstract INTRODUCTION Meningiomas present complex therapeutic challenges due to their potential impact on neurological function and quality of life. While the standard of care involves observation and surgical resection, stereotactic radiosurgery (SRS) is an alternative treatment modality. This study aimed to compare the relative efficacy of SRS and surgical resection in the management of meningiomas to inform evidence-based decision-making in this clinical context. METHODS A retrospective cohort study was conducted using the TriNetX database, comparing patients undergoing treatment for meningiomas with either stereotactic radiosurgery (SRS) or surgical resection. Cohorts were matched on comorbidities. Rates of mortality and malignant neoplasms of the brain within 5-years of treatment with either modality were compared. In addition, short-term outcomes were assessed at 3 months post-treatment. RESULTS After matching, there were 1,898 patients in each cohort. Patients receiving SRS exhibited a significantly lower risk of mortality (95% CI: 0.76-1.07) and a decreased risk of developing malignant neoplasms of the brain (RR: 0.68, 95% CI: 0.54-0.85) over 5 years, compared to surgical resection. At 3-months post treatment, patients treated with SRS demonstrated significantly lower relative risks for several outcomes, including cerebral infarction (RR: 0.27, 95% CI: 0.18-0.39), hydrocephalus (RR: 0.19, 95% CI: 0.11-0.32), cerebral edema (RR: 0.13, 95% CI: 0.10-0.18), seizures (RR: 0.27, 95% CI: 0.21-0.34), neurological deficits (RR: 0.19, 95% CI: 0.13-0.28), and post-procedural infection (RR: 0.14, 95% CI: 0.07-0.28). CONCLUSION This retrospective cohort study suggests that in the management of meningiomas, SRS may be associated with lower mortality rates, decreased risks of malignant neoplasms of the brain, and improved short-term outcomes compared to surgical resection. Further research is warranted to validate these results and explore long-term outcomes and potential adverse effects.

RBIO-08. INVESTIGATING THE EFFICACY AND MECHANISMS OF TUMOR TREATING FIELDS IN RADIATION-RESISTANT GLIOBLASTOMA MODELS

Abstract Glioblastoma (GBM) is an aggressive malignant brain tumor with poor prognosis despite current treatment regimens involving surgical resection, radiation, temozolomide, and the newly approved use of Tumor Treating Fields (TTFields; a noninvasive, transdermal, administration of alternating low-intensity, intermediate-frequency electrical fields). Acquired radiation resistance, thought to be partially driven by brain tumor-initiating cells (BTICs), underscores therapeutic challenges in GBM. While clinical evidence supports the therapeutic benefit of TTFields, its precise mechanisms of action are poorly understood, and TTFields impact on radiation-resistant GBM is unknown. To better understand the effect and mechanism of TTFields in radiation-resistant GBM, we utilized patient-derived xenolines (PDX) and their acquired radio-resistant pairs to assess changes in viability and molecular signaling. PDX were previously developed by subcutaneous implantation of patient GBM cells into immunodeficient (nu/nu) mice. Acquired radiation-resistant PDX were generated through serial in vivo radiation. TTFields were administered with the Novocure inovitroTM device in a cooling incubator to maintain 37oC sample temperature in the ceramic well plates of the device. PDX were cultured on geltrex-coated coverslips under serum-free conditions. Cytotoxicity was quantified 72h post TTFields with crystal violet. Molecular signaling was captured with PamChip peptide-based kinase activity arrays and RayBiotech proteomic arrays. We found that TTFields inhibit cell growth in both parental and acquired radiation-resistant PDX. Differences in molecular signatures between the PDX lines suggest molecular mechanisms of TTFields sensitivity signatures and interactions with acquired radio-resistant PDX. We are currently trying to generate TTFields-resistant PDX lines through serial treatment with plans to examine BTIC populations relative to TTFields efficacy. We also plan to explore targetable TTFields-induced alterations in the future.