Favorable Adverse Effect Profile Research Articles

Enhancement of Glutamate Uptake as Novel Antiseizure Approach: Preclinical Proof of Concept.

Excitotoxicity is a common hallmark of epilepsy and other neurological diseases associated with elevated extracellular glutamate levels. Thus, here, we studied the protective effects of (R)-AS-1, a positive allosteric modulator (PAM) of glutamate uptake in epilepsy models. (R)-AS-1 was evaluated in a range of acute and chronic seizure models, while its adverse effect profile was assessed in a panel of standard tests in rodents. The effect of (R)-AS-1 on glutamate uptake was assessed in COS-7 cells expressing the transporter. WAY 213613, a selective competitive EAAT2 inhibitor, was used to probe the reversal of the enhanced glutamate uptake in the same transporter expression system. Confocal microscopy and Western blotting analyses were used to study a potential influence of (R)-AS-1 on GLT-1 expression in mice. (R)-AS-1 showed robust protection in a panel of animal models of seizures and epilepsy, including the maximal electroshock- and 6 Hz-induced seizures, corneal kindling, mesial temporal lobe epilepsy, lamotrigine-resistant amygdala kindling, as well as seizures induced by pilocarpine or Theiler's murine encephalomyelitis virus. Importantly, (R)-AS-1 displayed a favorable adverse effect profile in the rotarod, the minimal motor impairment, and the Irwin tests. (R)-AS-1 enhanced glutamate uptake in vitro and this effect was abolished by WAY 213613, while no influence on GLT-1 expression in vivo was observed after repeated treatment. Collectively, our results show that (R)-AS-1 has favorable tolerability and provides robust preclinical efficacy against seizures. Thus, allosteric enhancement of EAAT2 function could offer a novel therapeutic strategy for treatment of epilepsy and potentially other neurological disorders associated with glutamate excitotoxicity. ANN NEUROL 2024.

Emerging applications of hypomethylating agents in the treatment of glioblastoma (Review).

DNA hypomethylating agents (HMAs) such as decitabine and 5-azacytidine have established roles in the treatment paradigms for myelodysplastic syndrome and acute myelogenous leukemia, where they are considered to exert their anticancer effects by restoring the expression of tumor suppressor genes. Due to their relatively favorable adverse effect profile and known ability to pass through the blood-brain barrier, applications in the treatment of glioblastoma (GBM) and other central nervous system malignancies are under active investigation. The present review examines the types of HMAs currently available, their known and less-understood antineoplastic mechanisms, and the evidence to date of their preclinical and clinical efficacy in glioblastoma and other solid malignancies. The present review discusses the potential synergies HMAs may have with established and emerging GBM treatments, including temozolomide, immune checkpoint inhibitors and cancer vaccines. Recent successes and setbacks in clinical trials for newly diagnosed and recurrent GBM are summarized in order to highlight opportunities for HMAs to improve therapeutic responses. Challenges for future clinical trials are also assessed.

Outcomes of Different Surgical Interventions for Treating Trigeminal Neuralgia: A Review.

Trigeminal neuralgia (TN) is a debilitating condition characterized by severe facial pain. Various surgical interventions are employed to manage this condition, including microvascular decompression (MVD), percutaneous radiofrequency rhizotomy (PRR), glycerol rhizotomy, percutaneous balloon compression (PBC), and stereotactic radiosurgery such as Gamma Knife radiosurgery (GKRS). This review synthesizes the outcomes of these interventions to provide an understanding of their efficacy and associated risks. MVD, known for its high initial relief rates, shows substantial long-term effectiveness, with recurrence rates varying based on patient demographics and comorbidities. GKRS offers significant pain relief with a favorable adverse event profile; however, recurrence rates increase over time, necessitating repeat procedures for sustained efficacy. PBC demonstrates high initial success, but pain recurrence is common, especially in patients with atypical TN. PRR provides immediate relief with a manageable recurrence rate and is particularly suitable for elderly patients and those with comorbidities. Glycerol rhizotomy, a cost-effective procedure, yields comparable outcomes to other interventions but requires careful patient selection. This review highlights the importance of tailored treatment approaches based on individual patient profiles, emphasizing the need for precise diagnostic criteria and careful patient selection to optimize outcomes. Long-term follow-up and the potential for repeat interventions are critical considerations in managing TN surgically.

Epidural methadone and morphine pharmacokinetics and clinical effects in healthy volunteers: A randomized, crossover-design trial.

Epidural opioids can provide effective analgesia for acute postoperative pain. Due to its unique physicochemical properties and long systemic elimination half-life, epidural methadone may provide lasting analgesia with minimal adverse effects; however, human studies are lacking. The aim of the study was to test the hypothesis that epidural methadone would exhibit greater segmental analgesia (analgesia at the dermatome of injection vs. distant dermatomes) than epidural morphine. In a prospective, randomized, double-blinded, crossover study, thirteen healthy volunteers received a 4-mg epidural bolus of methadone or morphine at L3-L4 and underwent repeated assessment of dermatomal heat pain tolerance and pressure pain threshold at lumbar (L3) and trigeminal (V2) dermatomes, pupil diameter, respiratory parameters and venous opioid concentration for 24 h. The primary outcome was selective (lumbar vs. trigeminal) segmental analgesia for heat pain, as a marker of a spinal analgesic mechanism. The degree of segmental analgesia to heat pain tolerance was not different between morphine and methadone (P =.09), although morphine (P =.0009) but not methadone (P =.81) produced significant analgesia to heat pain at the lumbar vs. trigeminal dermatome over 0-12 h. Morphine overall provided longer lasting analgesia to heat pain vs. methadone (24 vs. 2 h, respectively). Morphine elicited greater systemic effects, including miosis (P =.009) and opioid-related adverse effects (P =.002). These results suggest that, with equal epidural doses, both methadone and morphine produced analgesia and methadone did not produce greater segmental effects than morphine. Epidural methadone provided a more favourable adverse effect profile.

Major Psychiatric Disorders, Substance Use Behaviors, and Longevity

Observational studies suggest that major psychiatric disorders and substance use behaviors reduce longevity, making it difficult to disentangle their relationships with aging-related outcomes. To evaluate the associations between the genetic liabilities for major psychiatric disorders, substance use behaviors (smoking and alcohol consumption), and longevity. This 2-sample mendelian randomization (MR) study assessed associations between psychiatric disorders, substance use behaviors, and longevity using single-variable and multivariable models. Multiomics analyses were performed elucidating transcriptomic underpinnings of the MR associations and identifying potential proteomic therapeutic targets. This study sourced summary-level genome-wide association study (GWAS) data, gene expression, and proteomic data from cohorts of European ancestry. Analyses were performed from May 2022 to November 2023. Genetic susceptibility for major depression (n = 500 199), bipolar disorder (n = 413 466), schizophrenia (n = 127 906), problematic alcohol use (n = 435 563), weekly alcohol consumption (n = 666 978), and lifetime smoking index (n = 462 690). The main outcome encompassed aspects of health span, lifespan, and exceptional longevity. Additional outcomes were epigenetic age acceleration (EAA) clocks. Findings from multivariable MR models simultaneously assessing psychiatric disorders and substance use behaviorsm suggest a negative association between smoking and longevity in cohorts of European ancestry (n = 709 709; 431 503 [60.8%] female; β, -0.33; 95% CI, -0.38 to -0.28; P = 4.59 × 10-34) and with increased EAA (n = 34 449; 18 017 [52.3%] female; eg, PhenoAge: β, 1.76; 95% CI, 0.72 to 2.79; P = 8.83 × 10-4). Transcriptomic imputation and colocalization identified 249 genes associated with smoking, including 36 novel genes not captured by the original smoking GWAS. Enriched pathways included chromatin remodeling and telomere assembly and maintenance. The transcriptome-wide signature of smoking was inversely associated with longevity, and estimates of individual smoking-associated genes, eg, XRCC3 and PRMT6, aligned with the smoking-longevity MR analyses, suggesting underlying transcriptomic mediators. Cis-instrument MR prioritized brain proteins associated with smoking behavior, including LY6H (β, 0.02; 95% CI, 0.01 to 0.03; P = 2.37 × 10-6) and RIT2 (β, 0.02; 95% CI, 0.01 to 0.03; P = 1.05 × 10-5), which had favorable adverse-effect profiles across 367 traits evaluated in phenome-wide MR. The findings suggest that the genetic liability of smoking, but not of psychiatric disorders, is associated with longevity. Transcriptomic associations offer insights into smoking-related pathways, and identified proteomic targets may inform therapeutic development for smoking cessation strategies.

Real-World Experience with Isavuconazole in Allogeneic Stem Cell Transplantation in Spain

Invasive fungal infections (IFI) pose a significant complication after hematopoietic stem cell transplantation (HSCT). Isavuconazole (ISV) is a new generation azole with a favourable adverse effect and interaction profile approved for the treatment of invasive aspergillosis and mucormycosis. We analyzed the indications, effectiveness, adverse event profile and drug interaction management of ISV in the real-world setting in adults who received allogeneic-HSCT (allo-HSCT) within the Spanish Group of HSCT and Cell Therapy (GETH-TC). We conducted a multicenter retrospective study of all consecutive adult allo-HSCT recipients (≥18 years) who received ISV either for IFI treatment or prophylaxis, from December 2017 to August 2021, in 20 centers within the Spanish Group of Hematopoietic Stem Cell Transplantation and Cell Therapy (GETH-TC). A total of 166 adult allografted patients who received ISV from 2017 to 2021 were included. Median age was 48 years with 43% females. In 81 (49%) patients, ISV was used for treatment of IFI, and in 85 (51%) for prophylaxis. Median duration of ISV administration for IFI treatment was 57 days (range 31-126) and 86 days (range 33-196) for prophylaxis. Most frequent indication for treatment was invasive aspergillosis (78%), followed by mucormycosis (6%). Therapeutic success (45%) was the most frequent reason for ISV withdrawal. In the prophylaxis group, the resolution of IFI risk factors was the most frequent reason for withdrawal (62%). Six (7%) breakthrough IFI were reported. The majority of patients (80%) presented pharmacologic interactions. Twenty-one patients (13%) reported adverse events related to ISV, mainly liver biochemistry abnormalities, which led to ISV withdrawal in 7 patients (4%). ISV was effective and well tolerated for IFI treatment and prophylaxis, with a manageable interaction profile.

Inflammation and cancer: friend or foe?

Chronic inflammation plays a crucial role in the onset and progression of pathologies like neurodegenerative and cardiovascular diseases, diabetes, and cancer, since tumor development and chronic inflammation are linked, sharing common signaling pathways. At least 20% of breast and colorectal cancers are associated with chronic inflammation triggered by infections, irritants, or autoimmune diseases. Obesity, chronic inflammation, and cancer interconnection underscore the importance of population-based interventions in maintaining healthy body weight, to disrupt this axis. Given that the dietary inflammatory index is correlated with an increased risk of cancer, adopting an anti-inflammatory diet supplemented with nutraceuticals may be useful for cancer prevention. Natural products and their derivatives offer promising antitumor activity with favorable adverse effect profiles; however, the development of natural bioactive drugs is challenging due to their variability and complexity, requiring rigorous research processes. It has been shown that combining anti-inflammatory products, such as non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and statins, with plant-derived products demonstrate clinical utility as accessible adjuvants to traditional therapeutic approaches, with known safety profiles. Pharmacological approaches targeting multiple proteins involved in inflammation and cancer pathogenesis emerge as a particularly promising option. Given the systemic and multifactorial nature of inflammation, comprehensive strategies are essential for long term success in cancer therapy. To gain insights into carcinogenic phenomena and discover diagnostic or clinically relevant biomarkers, is pivotal to understand genetic variability, environmental exposure, dietary habits, and TME composition, to establish therapeutic approaches based on molecular and genetic analysis. Furthermore, the use of endocannabinoid, cannabinoid, and prostamide-type compounds as potential therapeutic targets or biomarkers requires further investigation. This review aims to elucidate the role of specific etiological agents and mediators contributing to persistent inflammatory reactions in tumor development. It explores potential therapeutic strategies for cancer treatment, emphasizing the urgent need for cost-effective approaches to address cancer-associated inflammation.

Abstract PO3-26-06: A self-replicating RNA Precision Immunotherapeutic for Overcoming Resistance to Endocrine Therapy in Estrogen Receptor Positive Breast Cancer (ER+BC)

Abstract Advanced or metastatic ER+HER2- breast cancer (ER+BC) is an incurable disease. Standard 1L therapy (SOC) utilizes endocrine blockade with a nonsteroidal aromatase inhibitor (NSAI) combined with a CDK4/6 inhibitor (CDK4/6i). While most patients respond and disease remains controlled for over 2 years (mPFS ~25-28 months), virtually all patients progress over time, requiring more toxic therapies with decreasing periods of disease control. Prolonging the time that the tumor remains under endocrine control is therefore of significant medical value. The most common molecular drivers of endocrine resistance are well characterized and include mutations in ESR1 and bypass mechanisms in select signaling pathways. RBI-1000 is a self-replicating RNA (srRNA) precision immunotherapeutic to generate robust immunity directed against acquired resistance mutations that develop in ER+ BC in response to endocrine blockade by NSAI. RBI-1000 includes 6 on-target mutations within the estrogen receptor ligand binding domain, and bypass mutations either in the form of activating mutations in PI3K kinase or amplifications of HER2/HER3. Precision immunotherapy (PIO), combined with SOC targeted therapy, educates the patient’s immune system to eliminate tumor cells that express acquired resistance mutations. Thus, the tumor is in a lose-lose situation where it is either eliminated by the targeted therapy, or if it develops acquired resistance mutations to the targeted therapy, it is killed by the PIO. Specifically for endocrine resistance, RBI-1000 PIO offers an attractive therapeutic approach to prevent/delay endocrine resistance specifically, by generating an effective immune response against those tumor cells that express the resistance-associated molecules that arise while on NSAI+CDK4/6i. The ability to encode multiple targets in a single therapeutic srRNA molecule, alongside the prolonged expression of srRNA in host cells (>49 days) creates a versatile and powerful cancer drug development platform. srRNA precision immunotherapeutics are delivered intramuscularly (i.e. a jab in the non-dominant deltoid) and generate an effective immune response via the same pathways and mechanisms as a traditional vaccine. We have demonstrated that this srRNA encapsulated in a lipid nanoparticle primes polyfunctional CD4 and CD8 T cells and antibody responses, leading to tumor growth inhibition and improved survival in a mouse model expressing the targeted acquired resistance mutations. Priming of T cells against acquired mutations is also confirmed in human HLA-transgenic mice. The immune cell-mediated elimination of clones expressing the acquired resistance mutations is predicted to prolong endocrine control of ER+BC, in an analogous manner to small molecule or monoclonal antibody targeted therapies, but with a more favorable dosing and adverse event profile due to precise immunologic targeting and no DDI. RBI-1000 is anticipated to enter clinical studies in the first half of 2024. Citation Format: Zelanna Goldberg, Christian Maine, Gabrielle Dailey, Christine Domingo, Gaelle Picarda, Hunter Little, Annie Chou, Jessica Sparks, Darina Spasova, Shiegeki Miyake-Stoner, Zachary C Hartman, Christopher Rabiola, Erika Crosby, Herbert Lyerly, Nathaniel Wang, Parinaz Aliahmad. A self-replicating RNA Precision Immunotherapeutic for Overcoming Resistance to Endocrine Therapy in Estrogen Receptor Positive Breast Cancer (ER+BC) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-26-06.

Abstract PO1-22-08: Ductal Lavage versus Oral Corticosteroids in Patients with Idiopathic Granulomatous Mastitis: A Multicenter, Open-label, Randomized, Controlled, Non-inferiority Study

Abstract Background: Idiopathic granulomatous mastitis (IGM) is an inflammatory breast disease characterized by the presence of mass, erythema and fistula. Various treatments have been proposed, including steroids, surgery, immunosuppressants, and observation alone. However, most of the reported studies are single-center, retrospective, single-arm with limited sample sizes, leaving the optimal treatment strategy unknown. In a previous single-arm study, we reported the efficacy and safety of ductal lavage as a novel treatment. This presentation presents the results of a multicenter, open-label, randomized controlled, non-inferiority trial that compares the efficacy and safety of ductal lavage with oral corticosteroids as the first-line treatment for IGM patients. Methods: Eligible IGM patients were randomized 1:1 to receive either ductal lavage or oral corticosteroids, stratified by M-score status. The M-score quantitatively evaluates IGM symptom severity as reported in our previous studies. Ductal lavage involved the intraductal infusion of lidocaine, triamcinolone acetonide, and ceftriaxone with saline, a total 5 times within 2 weeks. Oral corticosteroids were administered using prednisone or methylprednisolone at an initial dose of 20-40mg per day, decreased by 5mg every 2 weeks, and then maintained at 20mg per day for at least 1 month. The primary outcome was the rate of complete Clinical Response (cCR), which was defined as achieving M-score≤1 during any follow-up visit. Secondary outcomes included median time to first cCR, treatment failure, relapse, adverse events, and protocol compliance rate. If the lower limit of 95%CI of the absolute difference between ductal lavage and oral corticosteroids was greater than -15%, the non-inferiority was met. This trial was approved by the ethical committee of Sun Yat-sen Memorial Hospital and registered with ClinicalTrials.gov (NCT03724903). Results: Recruitment for this trial began in March 2019 and follow-up ended in May 2023 at 3 hospitals in China. In the intention-to-treat set (N=140), 69 patients were randomly assigned to the ductal lavage group and 71 patients to the oral corticosteroids group. The cCR rates after treatment were 85.51% (95% CI 77.20 ~ 93.81%) and 87.32% (95% CI 79.59 ~ 95.06%) in the ductal lavage and oral corticosteroids groups, respectively. The rate difference was -1.82% (95% CI -13.17 ~ 9.54%), not exceeding the non-inferiority margin (Non-inferiority P=0.011). In the per-protocol set (N=111), the cCR rate difference was -5.32%(ductal lavage: 92.86% vs. oral corticosteroids: 98.18%),with a 95%CI of -12.94% to 2.29%,also not exceeding the non-inferiority margin(Non-inferiority P=0.006).No significant differences were observed between groups in median time to first cCR (34.0 vs. 32.5 days, P= 0.878), treatment failure rate (14.49% vs. 11.27%, P=0.569), or relapse rate (10.14% vs. 4.23%, P=0.302).In the safety analysis set (N=129), the most frequently reported adverse events ( >15%) in the ductal lavage group were irregular menstruation (46.27%), while in the oral corticosteroids group, they were Cushingoid (79.03%), epigastric pain (17.74%), and arthralgia (16.13%). Conclusions: Ductal lavage demonstrates non-inferiority to oral corticosteroids in terms of efficacy as a first-line treatment for IGM patients. Furthermore, ductal lavage exhibits a significantly favorable adverse events profile. Primary endpoint in ITT and PP set *P value for non-inferiority comparison. Secondary endpoint in PP set §P value calculated by chi-square test. Adverse event in safety set No adverse event exceeding Grade3 have been recorded. Citation Format: Kai Chen, Xiaolin Chen, Shunrong Li, Liling Zhu, Jian Zhang, Tingting Hu, Hui Huang, Heng Huang, Lili Chen, Qiaozhen Xiao, Linhong Su. Ductal Lavage versus Oral Corticosteroids in Patients with Idiopathic Granulomatous Mastitis: A Multicenter, Open-label, Randomized, Controlled, Non-inferiority Study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-22-08.

Use of Calcitonin Gene-Related Peptide Monoclonal Antibodies for the Treatment of Migraines in Individuals With Multiple Sclerosis.

Migraines are a common comorbidity and source of disability in patients with chronic inflammatory diseases like multiple sclerosis (MS). Recently, therapeutic agents for episodic and chronic migraine known as calcitonin gene-related peptide (CGRP) inhibitors have shown to effectively control migraine attacks and improve quality of life in the general population. This study explored the use of these novel agents in individuals with comorbid MS. This was a retrospective, population-based cohort study at the University of South Florida's neurology clinic; it evaluated individuals with both MS and migraine. A total of 27 individuals with MS and chronic or episodic migraine who received treatment with a CGRP monoclonal antibody were identified. Of these, 63% reported a reduction in their migraine frequency of greater than 75%. Concurrent use of a disease-modifying therapy (DMT) for MS occurred in 82% of patients, and in 37% of these, the DMT used was also a monoclonal antibody. Adverse effects from CGRP monoclonal antibodies were mild and occurred in only 11% of patients, and no patient experienced worsening of their MS symptoms during cotreatment over the duration of the study. Our study showed a significant reduction in migraine frequency and a favorable adverse event profile for individuals with comorbid MS who took CGRP monoclonal antibodies and experienced no worsening of MS symptoms. In individuals with MS, CGRP monoclonal antibodies seem to be a safe and effective therapy for episodic or chronic migraine.

Applications of SGLT2 inhibitors beyond glycaemic control.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors were initially developed for their glucose-lowering effects and have shown a modest glycaemic benefit in people with type 2 diabetes mellitus (T2DM). In the past decade, a series of large, robust clinical trials of these therapies have demonstrated striking beneficial effects for various care goals, transforming the chronic disease therapeutic landscape. Cardiovascular safety studies in people with T2DM demonstrated that SGLT2 inhibitors reduce cardiovascular death and hospitalization for heart failure. Subsequent trials in participants with heart failure with reduced or preserved left ventricular ejection fraction demonstrated that SGLT2 inhibitors have beneficial effects on heart failure outcomes. In dedicated kidney outcome studies, SGLT2 inhibitors reduced the incidence of kidney failure among participants with or without diabetes. Post hoc analyses have suggested a range of other benefits of these drugs in conditions as diverse as metabolic dysfunction-associated steatotic liver disease, kidney stone prevention and anaemia. SGLT2 inhibitors have a generally favourable adverse effect profile, although patient selection and medication counselling remain important. Concerted efforts are needed to better integrate these agents into routine care and support long-term medication adherence to close the gap between clinical trial outcomes and those achieved in the real world.

Non-opioid analgesic combinations following total hip arthroplasty (RECIPE): a randomised, placebo-controlled, blinded, multicentre trial

Multimodal postoperative analgesia following total hip arthroplasty is recommended, but the optimal combination of drugs remains uncertain. The aim of the RECIPE trial was to investigate the relative benefit and harm of the different combinations of paracetamol, ibuprofen, and the analgesic adjuvant dexamethasone for treatment of postoperative pain following total hip arthroplasty. The RECIPE trial was a randomised, blinded, placebo-controlled trial conducted at nine Danish hospitals. Adults scheduled for total hip arthroplasty were randomly assigned (1:1:1:1) using a computer-generated list with stratification by site to receive combinations of oral paracetamol 1000 mg every 6 h, oral ibuprofen 400 mg every 6 h, or a single-dose of intravenous dexamethasone 24 mg in the following groups: paracetamol plus ibuprofen, ibuprofen plus dexamethasone, paracetamol plus dexamethasone, and paracetamol plus ibuprofen plus dexamethasone. The primary outcome was 24 h intravenous morphine consumption, analysed in a modified intention-to-treat population, defined as all randomly assigned participants who underwent total hip arthroplasty. The predefined minimal important difference was 8 mg. Safety outcomes included serious and non-serious adverse events within 90 days and 24 h. The trial was registered with ClinicalTrials.gov, NCT04123873. Between March 5, 2020, and Nov 15, 2022, we randomly assigned 1060 participants, of whom 1043 (589 [56%] women and 454 [44%] men) were included in the modified intention-to-treat population. 261 were assigned to paracetamol plus ibuprofen, 262 to ibuprofen plus dexamethasone, 262 to paracetamol plus dexamethasone, and 258 to paracetamol plus ibuprofen plus dexamethasone. Median 24 h morphine consumption was 24 mg (IQR 12-38) in the paracetamol plus ibuprofen group, 20 mg (12-32) in the paracetamol plus dexamethasone group, 16 mg (10-30) in the ibuprofen plus dexamethasone group, and 15 mg (8-26) in the paracetamol plus ibuprofen plus dexamethasone group. The paracetamol plus ibuprofen plus dexamethasone group had a significantly reduced 24 h morphine consumption compared with paracetamol plus ibuprofen (Hodges-Lehmann median difference -6 mg [99% CI -10 to -3]; p<0·0001) and paracetamol plus dexamethasone (-4 mg [-8 to -1]; p=0·0013), however, none of the comparisons showed differences reaching the minimal important threshold of 8 mg. 91 (35%) of 258 participants in the paracetamol plus ibuprofen plus dexamethasone group had one or more adverse events, compared with 99 (38%) of 262 in the ibuprofen plus dexamethasone group, 103 (39%) of 262 in the paracetamol plus dexamethasone group, and 165 (63%) of 261 in the paracetamol plus ibuprofen group. In adults undergoing total hip arthroplasty, a combination of paracetamol, ibuprofen, and dexamethasone had the lowest morphine consumption within 24 h following surgery and the most favourable adverse event profile, with a lower incidence of serious and non-serious adverse events (primarily driven by differences in nausea, vomiting, and dizziness) compared with paracetamol plus ibuprofen. The Novo Nordisk Foundation and Næstved-Slagelse-Ringsted Hospitals' Research Fund.

Modafinil Therapy and Mental Status Following Aneurysmal Subarachnoid Hemorrhage: Comprehensive Stroke Center Analysis

Disorders of consciousness impair early recovery after aneurysmal subarachnoid hemorrhage (aSAH). Modafinil, a wakefulness-promoting agent, is efficacious for treating fatigue in stroke survivors, but data pertaining to its use in the acute setting are scarce. This study sought to assess the effects of modafinil use on mental status after aSAH. Modafinil timing and dosage, neurological examination, intubation status, and physical and occupational therapy participation were documented. Repeated-measures paired tests were used for a before-after analysis of modafinil recipients. Propensity score matching (1:1 nearest neighbor) for modafinil and no-modafinil cohorts was used to compare outcomes. Modafinil (100-200mg/day) was administered to 21% (88/422) of aSAH patients for a median (IQR) duration of 10.5 (4-16) days and initiated 14 (7-17) days after aSAH. Improvement in mentation (alertness, orientation, or Glasgow Coma Scale score) was documented in 87.5% (77/88) of modafinil recipients within 72hours and 86.4% (76/88) at discharge. Of 37 intubated patients, 10 (27%) were extubated within 72hours after modafinil initiation. Physical and occupational therapy teams noted increased alertness or participation in 47 of 56 modafinil patients (83.9%). After propensity score matching for baseline covariates, the modafinil cohort had a greater mean (SD) change in Glasgow Coma Scale score than the no-modafinil cohort at discharge (2.2 [4.0] vs.-0.2 [6.32], P= 0.003). A temporal relationship with improvement in mental status was noted for most patients administered modafinil after aSAH. These findings, a favorable adverse-effect profile, and implications for goals-of-care decisions favor a low threshold for modafinil initiation in aSAH patients in the acute-care setting.

High-intensity focused ultrasound in adenomyosis treatment: Insights on safety, efficacy, and reproductive prospects.

The management of adenomyosis has undergone significant evolution, moving from traditional surgical interventions like hysterectomy to more conservative methods aimed at preserving fertility. Essential roles have been played by uterine-sparing surgeries and uterine artery embolization. Despite these advancements, there is a growing interest in less invasive alternatives. This review delves into the potential of high-intensity focused ultrasound (HIFU). HIFU employs focused ultrasound waves for precise ablation of adenomyotic lesions. The review conducts a thorough analysis of HIFU principles, safety, efficacy, and its possible synergies with other therapies. HIFU seems to be effective for adenomyosis treatment, demonstrating a favorable adverse effect profile and suitability for fertility preservation. Combining HIFU with hormonal treatment appears to enhance long-term symptom control, presenting a promising and comprehensive approach for managing adenomyosis. The goal of this article is to develop a comprehensive understanding of HIFU's role in contemporary adenomyosis management and to explore areas requiring further research.

Use of venetoclax in t(11;14) positive relapsed/refractory multiple myeloma: A systematic review.

The plasma cell malignancy, multiple myeloma (MM), remains incurable despite advanced treatment protocols. Overexpression of Bcl-2 (an anti-apoptotic protein), in MM harboring the translocation (11;14), contributes to resistance to prior therapy. Venetoclax, a selective oral inhibitor of BCL-2 is a novel agent that shows promise as a therapeutic agent. The objective of this systematic review is to address how the use of venetoclax, alone or as a combination regimen, contributed to the treatment of patients with t(11:14) positive relapsed/refractory multiple myeloma (RRMM). This systematic review was conducted in accordance to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and was done on 5th June 2022. A literature search was conducted on PubMed and Scopus, 145 articles were screened and 10 studies were included. Risk of bias assessment was performed using the Methodological Index for Non-Randomized Studies (MINORS) criteria. Across the studies reviewed, a total of 311 patients were identified with t(11;14) positive RRMM. The overall response rate achieved ranged between 33% and 95.5%. Furthermore, the use of venetoclax has exhibited a favorable adverse effect profile. Side effects included hematological side effects, nausea, vomiting, and diarrhea. Venetoclax demonstrates promising results. When given with drugs like dexamethasone, daratumumab and carfilzomib, a synergistic effect is seen in treating translocation (11:14) positive relapsed/refractory MM. The use of venetoclax in clinical practice can potentially improve outcomes and quality of life in RRMM patients, and future research should continue to explore this promising treatment option.

Fostemsavir: A Novel CD4 Attachment Inhibitor for Heavily Treated HIV-1 Patient

Abstract: Despite the evident success of antiretroviral therapy in recent years, many patients undergoing intense treatment still struggle to find a cure for their disease due to drug resistance or treatment failure. To solve this problem, new antiretroviral drug alternatives are required. The HIV-1 antiretroviral drug fostemsavir (GSK3684394, previously BMS-663068) is a first-in-class HIV-1 attachment inhibitor with a novel mechanism. After oral administration, fostemsavir gets converted into temsavir in the gastrointestinal lumen, which then attaches to the glycoprotein 120 surface subunit on HIV-1 and produces a conformational change that prevents it from adhering to CD4+ T cells of the host immune system, thereby preventing the virus from infecting other cells. Fostemsavir is indicated in heavily treated (HTE) patients with an ideal antiretroviral (ARV) regimen. The drug has shown significant tolerability, and no hepatic or renal dose adjustments were required. Fostemsavir can be used as an effective alternative in salvage therapy because of its favourable adverse effect profile and few drug interactions.

Avatrombopag in Combination with Immunosuppressive Therapy for Hepatitis-Associated Aplastic Anemia

Hepatitis-associated aplastic anemia (HAAA) is an uncommon but distinct variant of aplastic anemia (AA), in which an episode of seronegative acute hepatitis precedes the onset of pancytopenia. Previous studies indicated that about only 20% of HAAA patients can get their hematologic partially restored after 3 months treatment with standard immunosuppressive therapy (IST). Recent studies have shown that adding thrombopoietin receptor agonist (TPO-RA) eltrombopag to standard IST can lead to a more, faster, and better hematologic responses. Nevertheless, eltrombopag is often associated with hepatic adverse effects, i.e., elevated transaminases and bilirubin, which maybe limit its use in patients with HAAA who have just experienced severe liver damage. Avatrombopag is also a TPO-RA, which was approved for the treatment of thrombocytopenia in patients with chronic liver disease (CLD) and patients with chronic immune thrombocytopenia (ITP) by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA). The pre-clinical studies indicated that avatrombopag can promote the hematopoietic and megakaryocyte progenitor cells proliferation and differentiation by the dose-dependence. These in vitro effects are similar to those of other TPO-RAs, including Eltrombopag. Theoretically, on the basis of adequate IST, avatrombopag can also promote hematopoietic recovery in patients with aplastic anemia just as Eltrombopag works. If this is true, then avatrombopag should be particularly suitable for HAAA due to its favorable hepatic adverse effect profile. Nevertheless, avatrombopag added to standard IST as first-line treatment for aplastic anemia could increase the rapidity and strength of hematologic response is still unknown. Herein, we retrospectively reviewed 8 consecutive cases of patients with hepatitis-associated aplastic anemia who were treated with avatrombopag plus IST regimen. From September 2021 to December 2022, eight patients with hepatitis-associated aplastic anemia treated with avatrombopag in combination with standard IST were enrolled in this study. Among them, seven patients were diagnosed as VSAA and one SAA. The median age was 17 (9-20) years old and the median absolute neutrophil count was 0.09 (0.02-0.39) ×10 9/L. The median time from onset of hepatitis to hematopoietic failure was 2 (0.5-5.5) months, and at the time of beginning of IST all the eight patients had their liver biochemical testing returns to normal. The karyocytes were normal in all patients. One patient presented positive PNH clone at the diagnosis of HAAA, with PNH clone size of 4.7%. Avatrombopag was incorporated into day 1 of standard immunosuppressive therapy with p-ATG and cyclosporine for all the eight HAAA patients. The dose of avatrombopag was 40 mg/d at least 6 months. Dosage adjusting of avatrombopag was according to patient's platelet counts and adverse events. Encouragingly, four of the eight patients (50.0%) achieved hematologic response (HR) with two (20.0%) getting complete response (CR) at 3 months after IST and avatrombopag. Between 3 and 6 months after IST, the other two patient entered their hematologic responded. Then, six of eight (75.0%) patients got HR at 6 months, including 3 CR, 2 good partial hematologic response (GPR), and 1 partial response (PR). Unfortunately, one patient who was diagnosed as very severe HAAA, was without getting hematologic response and died at 118 days after treatment due to gastrointestinal infection. We evaluate the side effects of avatrombopag and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. No hepatic adverse events were observed in all the eight patients, that indicated avatrombopag may not increase the hepatic burden and is safe for HAAA. The median follow-up time was 371(118-665) days. Except for one patient who died within 6 months, six cases achieved hematologic response, with 4 CR and 2 GPR. There is no clonal evolution, i.e., MDS, AML, and PNH, was observed. In conclusion, avatrombopag may be used as a safe and effective TPO-RA, added to IST for the treatment of hepatitis-associated aplastic anemia, which maybe improve the efficacy and the strength of hematologic response in HAAA.

Pain Management and Opioid Use with Long-Acting Peripheral Nerve Blocks for Hand Surgery: A Descriptive Study.

Peripheral nerve blocks (PNBs) are used in multiple surgical fields to provide a high level of regional pain relief with a favorable adverse effect profile. Peripheral nerve blocks aim to decrease overall perioperative pain and lower systemic analgesic requirements. Short-acting anesthetic agents are commonly given as single-injection PNBs for pain relief, typically lasting less than 24 hours. Liposomal bupivacaine is a newer anesthetic formulation lasting up to 72 hours as a single-injection PNB and may allow patients to recover postoperatively with a lower need for opioid analgesics. This study investigates peri- and postoperative pain and opioid use in patients receiving a long-acting brachial plexus PNB for hand surgery. A retrospective review of patients who underwent a long-acting PNB using liposomal bupivacaine in the brachial plexus for minor hand operations was performed between July 2020 and May 2023 in Florida, USA. Patients were administered a ten-question survey regarding perioperative pain levels, post-operative symptoms, patient satisfaction, postoperative opioid use, and postoperative non-opioid analgesics. One hundred three patients, including 21 males and 82 females with an average age of 68.3 ± 15.8 years, completed a survey (34.2% response rate). Patients reported a considerable reduction in pain from 7.9 ± 2.2 out of ten before the PNB to 1.6 ± 1.8 in the perioperative period, 4.3 ± 2.7 in postoperative days zero to three, and 3.8 ± 2.4 in postoperative days four and five. Nerve block effects lasted a mean of 2.2 ± 2.0 days and patients reported a high level of satisfaction regarding their pain management plan with a score of 9.4 ± 1.4 out of ten. 20.4% of patients were prescribed opioids and 41.7% used NSAIDs postoperatively. Liposomal bupivacaine PNBs effectively reduced peri- and postoperative pain with pain relief lasting 2.2 ± 2.0 days. Patients were highly satisfied with their pain management and there was a low rate of postoperative opioid prescription. Given these results, long-acting PNBs have the potential to significantly improve patient satisfaction, reduce anesthesia use, and reduce postoperative opioid prescription.

THU277 Deletion Or inhibition Of Ornithine Decarboxylase Protects Islet β-cell Health And Is Associated With Preserved Residual C-peptide In Persons With Recent Onset Type 1 Diabetes

Abstract Disclosure: B. Hammoud: None. L.A. DiMeglio: None. A. Kulkarni: None. A. Hull: None. S. Woerner: None. S. Cabrera: None. L.D. Mastrandrea: None. F. Ouyang: None. S.N. Perkins: None. C. Evans-Molina: None. T.L. Mastracci: None. S.A. Tersey: None. S. Sarkar: None. E. Nakayasu: None. B. Webb-Robertson: None. E. Gerner: None. R.G. Mirmira: None. E.K. Sims: None. Inhibition of polyamine biosynthesis using α-difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase, reduces β cell stress and type 1 diabetes (T1D) incidence in preclinical animal models. However, the cellular and molecular mechanisms by which polyamines promote β-cell stress and the tolerability and effectiveness of their depletion by DFMO in humans with T1D remain unknown. We hypothesized that β-cell protection from stress occurs via cell-autonomous effects of polyamine depletion. To test this hypothesis, we generated β-cell specific knockout of ornithine decarboxylase in mice, performed comprehensive proteomics and transcriptomics on human islets treated with DFMO under inflammatory conditions in vitro, and performed a clinical study of DFMO tolerability, safety, and efficacy in persons with new-onset T1D. β-cell-specific deletion of the gene encoding ornithine decarboxylase in mice demonstrated protection of these animals against toxin (streptozotocin)-induced β-cell loss and hyperglycemia, implicating a cell-autonomous role for ornithine decarboxylase in β-cell stress. RNA sequencing and proteomics analyses of human islets exposed to a cytokine mix (1000 U/mL IFNγ + 50 U/mL IL-1β) +/- 5 mM DFMO identified 130 differentially regulated transcripts and 701 differentially regulated proteins. Pathway analysis implicated endosomal transport, vesicle organization and regulation of exocytosis, mRNA processing, and antigen cross presentation as mechanisms underlying DFMO effects on the islet response. To test DFMO in humans, we performed a 3-site randomized, placebo-controlled, double masked dose-ranging study of 3 months daily oral DFMO in persons with recent-onset T1D (&amp;lt;100 days). Dosing at 125, 250, 500, 750 or 1000 mg/m2/day was tested in 41 persons (12-34 y/o, 59% male, mean HbA1c 7.3%), with 6-10 participants/dosing group. Only mild and moderate adverse effects (AEs) were noted. Possible drug-related AEs included mild-moderate gastrointestinal symptoms, headache, upper respiratory infections, a pump site infection, and anemia. Urinary levels of the ODC product putrescine were decreased (p=0.05) in the 1000 mg/m2 dosing group. Compared to placebo, individuals receiving 750 and 1000 mg/m2 doses had significantly higher mixed-meal C-peptide area under the curve values at the 6-month post-randomization visit (p&amp;lt;0.05 vs. placebo). In conclusion, β-cell ODC inhibition protects β-cell health and function in the context of the proinflammatory T1D milieu. A 3-month course of oral DFMO was well tolerated with a favorable AE profile in persons with recent-onset T1D. Higher doses were associated with greater β-function compared to placebo. DFMO may have utility as a β-cell preservation therapy in recent-onset T1D. Presentation: Thursday, June 15, 2023

Comparison of trans-gastric vs trans-enteric (trans-duodenal or trans-jejunal) endoscopic ultrasound guided gallbladder drainage using lumen apposing metal stents.

Endoscopic ultrasound guided gallbladder drainage (EUS-GBD) is being increasingly used in practice (either as a bridge to cholecystectomy in high-risk patients or as destination therapy in non-surgical patients). Stents are used to create a conduit between the lumen of the gallbladder (GB) and the intestinal lumen through the gastric or enteric routes. Among the various types of stents used, cautery-enhanced lumen apposing metallic stents (LAMS) may be associated with fewer adverse events (AEs). To compare the clinical success, technical success, and rate of AEs between transgastric (TG) and trans-enteric [transduodenal (TD)/transjejunal (TJ)] approach to GB drainage. Further, we analyzed whether using cautery enhanced stents during EUS-GBD impacts the above parameters. Study was registered in PROSPERO (CRD42022319019) and comprehensive literature review was conducted. Manuscripts were reviewed for the data collection: Rate of AEs, clinical success, and technical success. Random effects model was utilized for the analysis. No statistically significant difference in clinical and technical success between the TD/TJ and TG approaches (P > 0.05) were noted. There was no statistically significant difference in the rate of AEs when comparing two-arm studies only. However, when all studies were included in the analysis difference was almost significant favoring the TD/TJ approach. When comparing cautery-enhanced LAMS with non-cautery enhanced LAMS, a statistically significant difference in the rate of AEs was observed when all the studies were included, with the rate being higher in non-cautery enhanced stents (14.0% vs 37.8%; P < 0.01). As per our study results, TD/TJ approach appears to be associated with lower rate of adverse events and comparable efficacy when compared to the TG approach for the EUS-GBD. Additionally, use of cautery-enhanced LAMS for EUS-GBD is associated with a more favorable adverse event profile compared to cold LAMS. Though the approach chosen depends on several patient and physician factors, the above findings could help in deciding the ideal drainage route when both TG and TD/TJ approaches are feasible.