Intolerable Side Effects Research Articles

Remote Collaborative Specialist Panel Deployment to Address Health Disparities in the RICH LIFE Project.

Individuals with low income or from minoritized racial or ethnic groups experience a high burden of hypertension and other chronic conditions (eg, diabetes, chronic kidney disease, and mental health conditions) and often lack access to specialist care when compared to their more socially advantaged counterparts. We used a mixed-methods approach to describe the deployment of a Remote Collaborative Specialist Panel intervention aimed at the comprehensive and coordinated management of patients with hypertension and comorbid conditions to address health disparities. Participants of the collaborative care/stepped care arm of the Reducing Inequities in Care of Hypertension: Lifestyle Improvement for Everyone (RICH LIFE) Project, a cluster-randomized trial comparing the effectiveness of enhanced standard of care to a multilevel intervention (collaborative care/stepped care) for improving blood pressure control and reducing disparities, were included. Participants were eligible for referral by their care manager to the Specialist Panel if they continued to have poorly controlled hypertension or had uncontrolled comorbid conditions (eg, diabetes, hyperlipidemia, depression) after 3months in the RICH LIFE trial. Referred participant cases were discussed remotely with a panel of specialists in internal medicine, cardiology, nephrology, endocrinology, and psychiatry. Qualitative data on the Specialist Panel recommendations and interviews with care managers to understand barriers and facilitators to the intervention were collected. We used available components of the RE-AIM (Reach, Effectiveness, Adoption, Implementation, and Maintenance) framework to examine the impact of the intervention. Of 302 participants in the relevant RICH LIFE arm who were potentially eligible for the Specialist Panel, 19 (6.3%) were referred. The majority were women (53%) and of Black race (84%). Referral reasons included uncontrolled blood pressure, diabetes, and other concerns (eg, chronic kidney disease, life-stressors, medication side effects, and medication nonadherence). Panel recommendations centered on guideline-recommended diagnostic and management algorithms, minimizing intolerable medication side effects and costs, and recommendations for additional referrals. Panel utilization was limited. Barriers reported by care managers were lack of perceived need by clinicians due to redundant specialists, a cumbersome referral process, the remote nature of the panel, and the sensitivity of relaying recommendations back to the primary care physician. Care managers who made panel referrals reported it was overwhelmingly valuable. The use of a Remote Collaborative Specialist Panel was limited but well-received by referring clinicians. With modifications to enhance uptake, the Remote Collaborative Specialist Panel may be a practical care model for addressing some disparities in hypertension and multi-morbidity care.

Risk of early etonogestrel and levonorgestrel implant discontinuation in adolescents and adults

BackgroundEtonogestrel and levonorgestrel implants are effective for 3 and 5 years of contraception, respectively. The removal of contraceptive implants before the due date, also known as implant early discontinuation, contributes to unplanned pregnancies, which can lead to unfavourable reproductive health outcomes, especially in adolescents. We aimed to assess the magnitude of early implant discontinuation among those who initiated the method at our hospital, and to compare this rate between adolescents and adults.MethodsThis retrospective cohort study reviewed the medical records of participants who initiated contraceptive implants from January 2014 to December 2019 at King Chulalongkorn Memorial Hospital. Early discontinuation was defined as the removal of implants prior to the due date. Cox proportional hazard regression analysis was performed to identify factors associated with early discontinuation.ResultsOur analysis included 1,435 participants, 409 of whom were adolescents. Levonorgestrel implants were used by 53.3% of the participants(68.7% and 47.1% of adolescents and adults, respectively); the remainder used etonogestrel implants. The total early discontinuation rate was 19.3%, which was comparable between the two implant types. The most common reason for discontinuation was intolerance of side effects, with abnormal bleeding being the most frequent. Adolescents were less likely to discontinue implants early (HR 0.72, 95% CI = 0.55–0.95). Factors significantly associated with decreased early discontinuation were: free-of-charge implants (HR 0.75, 95% CI = 0.58–0.95), continuous users of implants (HR 0.56, 95% CI = 0.36–0.86), postpartum status during implant initiation (HR 0.77, 95% CI = 0.60–0.98), and participants with children (HR 0.77, 95% CI = 0.60–0.99).ConclusionCompared with adults, adolescents were less likely to discontinue contraceptive implants before the due date. Participants who received free implants, continuous users who had previously used implants, postpartum insertion, and having children were associated with less early discontinuation. Our findings supports continued government funding for free implants in Thailand.

12339 Rotating Insulin Injection Sites Isn't Enough: A Challenging Case Of Insulin-Induced Lipoatrophic Panniculitis

Abstract Disclosure: J. Hand: None. S. Nemiroff: None. C. Zmijewski: None. C.J. Levy: None. Introduction: Insulin-induced localized lipoatrophy is a rare phenomenon that involves the loss of subcutaneous adipose tissue around sites of insulin injections, and it often presents as a deep, retracted scar on the skin. Its prevalence has dropped significantly given improvements in recombinant and purified insulin and its analogs, from 55% to more recently 1-2%. Lipoatrophy can cause erratic absorption of insulin, leading to suboptimal glycemic control and hypoglycemia. The pathophysiology is not completely understood but is thought to be immune-mediated. Treatment options are limited and often focus on rotating injection sites or changing the type of insulin, though some case reports alternatively describe using corticosteroid injections. Here, we report an unusual case where a patient developed a form of early, localized lipoatrophy called lipoatrophic panniculitis due to insulin. Clinical Case: A 28-year-old male with a 13-year history of type 1 diabetes presented for insulin optimization. The patient was using multiple daily injection (MDI) insulin therapy and later an insulin pump, with careful infusion site rotation. Seven years later, he experienced issues with his pump sites, developing nodules and bruises that became painful and caused labile glycemic control. He underwent dermatologic, rheumatologic, and allergic workup with two biopsies confirming insulin-induced lipoatrophic panniculitis. Immunosuppressive and varying insulin regimens were unsuccessful. Hydroxychloroquine and methotrexate showed limited improvement with intolerable gastrointestinal side effects. Trials of hydrocortisone in his insulin infusion or topical clobetasol with tacrolimus provided no benefit. Various MDI regimens with different concentrations of lispro, aspart, faster aspart, glargine, detemir, and degludec were tried; all elicited varying degrees of pain with suboptimal glycemic response. A supervised trial of inhaled insulin was associated with bronchospasms. An implantable insulin pump was sought through clinical trials but was not feasible due to eligibility. Ultimately, he was successfully referred for pancreas transplantation due to his labile and complicated diabetes, but the procedure was complicated by allograft thrombosis and failure. He is currently awaiting a second transplant. Clinical Lesson: There are few reports of patients with insulin-induced lipoatrophic panniculitis in the literature. It is an important differential to consider for a patient that is having unexpected glycemic excursions, and it is equally as challenging to select an adequate management regimen. Treatment is limited and a broad range of options need to be considered. When these patients fail mainstay immunosuppressive, corticosteroid, and insulin-based management, pancreas transplantation may be considered as an alternative feasible treatment. Presentation: 6/1/2024

12553 Severe Hyperglycemia After Initiation Of Bictegravir Antiretroviral Therapy With Resolution Upon Discontinuation

Abstract Disclosure: S. Hudson: None. J. Aurora: None. K. Grossman: None. L. Kogelman: None. A.G. Pittas: None. Background: Antiretroviral therapy (ART) containing bictegravir (BIC), a second-generation integrase strand transfer inhibitor (INSTI), is a first-line treatment for HIV. There are mixed reports of INSTIs causing adverse metabolic effects, such as weight gain and hyperglycemia. There are cases of BIC causing hyperglycemia and diabetic ketoacidosis (DKA) within weeks to months following initiation; however, this has not been reported in clinical trials (1). It is unclear whether discontinuing BIC resolves hyperglycemia. We report a case of a patient with prediabetes who developed severe hyperglycemia after switching to a BIC-containing ART. The discontinuation of BIC resulted in significant improvement in glycemia, leading to the de-escalation of diabetes pharmacotherapy. Clinical Case: A 36-year-old woman with obesity was diagnosed with HIV during pregnancy, which was complicated by gestational diabetes mellitus. After pregnancy, she had prediabetes. Her initial ART was darunavir/cobicistat/emtricitabine/tenofovir alafenamide. Due to intolerable GI side effects, six years later, she was switched to bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF). Laboratory tests four months before starting BIC/FTC/TAF were consistent with prediabetes (HbA1c 6.4%, non-fasting blood glucose of 118 mg/dL). After one month, she was started on metformin when her HbA1c increased to 9.1% with a non-fasting blood glucose of 332 mg/dL. Another month later, HbA1c increased to 12.8% with a non-fasting blood glucose of 685 mg/dL without DKA. She was hospitalized for diabetes management. There were no significant changes in weight, viral load, or CD4 count. A search for secondary causes of hyperglycemia (diabetogenic medications, hypercortisolism, and autoimmune diabetes) was not revealing. She was discharged on metformin and insulin glargine. Her HIV regimen was switched to FTC/TAF and doravirine due to suspicion of BIC-induced hyperglycemia. After five months, she developed symptoms of hypoglycemia, and her estimated HbA1c by continuous glucose monitoring was 6.3%. Insulin glargine was discontinued. While on metformin, HbA1c three months later was 6.3%. Two years later on metformin and linagliptin: HbA1c was 6.1% and beta-cell function did not reveal insulin deficiency or resistance (non-fasting blood glucose 96 mg/dL, insulin 13.5 uIU/mL [RR 2.6-24.9 mIU/mL], C-peptide 3.7 ng/mL [RR 1.1-4.4 ng/mL]). Conclusion: Patients with HIV and a history of obesity and/or dysglycemia who are switched to a BIC-containing ART regimen should be educated and monitored for acute hyperglycemia. This may be due to impaired beta-cell function and/or insulin resistance; however, further research is needed to understand the mechanism. An alternative ART regimen should be considered if hyperglycemia develops. Reference: 1. Nolan NS, et al. Open Forum Infect Dis. 2021;16;8(5): ofab077. Presentation: 6/3/2024

Dual Kv7.2/3-TRPV1 modulators inhibit nociceptor hyperexcitability and alleviate pain without target-related side effects.

Persistent or chronic pain is the primary reason people seek medical care, yet current therapies are either limited in efficacy or cause intolerable side effects. Diverse mechanisms contribute to the basic phenomena of nociceptor hyperexcitability that initiates and maintains pain. Two prominent players in the modulation of nociceptor hyperexcitability are the transient receptor potential vanilloid type 1 (TRPV1) ligand-gated ion channel and the voltage-gated potassium channel, Kv7.2/3, that reciprocally regulate neuronal excitability. Across many drug development programs targeting either TRPV1 or Kv7.2/3, significant evidence has been accumulated to support these as highly relevant targets; however, side effects that are poorly separated from efficacy have limited the successful clinical translation of numerous Kv7.2/3 and TRPV1 drug development programs. We report here the pharmacological profile of 3 structurally related small molecule analogues that demonstrate a novel mechanism of action (MOA) of dual modulation of Kv7.2/3 and TRPV1. Specifically, these compounds simultaneously activate Kv7.2/3 and enable unexpected specific and potent inhibition of TRPV1. This in vitro potency translated to significant analgesia in vivo in several animal models of acute and chronic pain. Importantly, this specific MOA is not associated with any previously described Kv7.2/3 or TRPV1 class-specific side effects. We suggest that the therapeutic potential of this MOA is derived from the selective and specific targeting of a subpopulation of nociceptors found in rodents and humans. This efficacy and safety profile supports the advancement of dual TRPV1-Kv7.2/3 modulating compounds into preclinical and clinical development for the treatment of chronic pain.

A Review for Clinical Practice in the Treatment and Prevention of Recurrent Urinary Tract Infections in Women over Age 65.

Urinary tract infection (UTI) is a pervasive, costly, and dangerous cause of morbidity and mortality worldwide, which can lead to further complications if they become recurrent or progress to urosepsis. Recurrent UTI is a particular concern among postmenopausal females because of increased risk factors and decreased estrogen levels, leading to changes in the urogenital epithelium and subsequently causing alterations in the urogenital microbiome. Prevention strategies for recurrent UTIs are often incorporated into patient-centered care plans, but finding the right management can be difficult for older women since many of the common treatment options have contraindications and adverse side effects. This review aims to describe the diagnosis, treatment, and special considerations for the treatment and prevention of recurrent UTIs in women over 65. Current prevention strategies include both antibiotic and nonantibiotic options. The antibiotic choice for older women presents a few unique challenges, including frequent allergy or intolerance of side effects, renal or liver dysfunction, and polypharmacy or drug interactions. Nonantibiotic options range from readily accessible drugstore remedies to experimental vaccines, which all are accompanied by certain advantages and disadvantages. Appropriate management plans can help to reduce symptoms and poor outcomes among older females. In addition, we hope future studies continue to investigate the proper dosing and routes for optimal management in this aging female population.

Calcium channel blockers and beta blockers in pediatric supraventricular tachycardia.

Supraventricular tachycardia (SVT) is a common pediatric arrhythmia. Beta blockers (BBs) and calcium channel blockers (CCBs) are used for treatment despite little data examining their use. We describe the prescriptive tendencies, efficacy, and tolerability of BBs and CCBs used in the treatment of pediatric SVT. This is a multicenter retrospective cohort study from three academic children's hospitals. Individuals aged 1-21 years at time of SVT diagnosis initiated on a BB or a CCB between 01/01/2010 and 12/31/2020 were included. Exclusion criteria were pre-excitation, ectopic atrial tachycardia, and hemodynamically significant heart disease. Demographic, comorbidity, symptomatology, and medication data were collected. Treatment success was defined using a composite data abstraction tool. Of 164 patients, 151 received a BB and 13 received a CCB. The success rate on the initial dosage was 46% for both BB and CCB; the success rate following dosage adjustments was also comparable for BBs (98/151, 65%) and CCBs (9/13, 69%). While 27 (18%) BB patients experienced intolerable side effects, no CCB patient did. Treatment with a BB or CCB was successful in half of patients. BBs were prescribed more frequently than CCBs but were associated with more side effects.

Recent Advancements in Cell-Based Therapies in Melanoma.

Malignant melanoma outcomes have drastically changed in recent years due to the introduction of immune checkpoint inhibitors (ICIs). However, many patients still experience intolerable side effects, therapy resistance, and disease progression on ICI therapy. Therefore, there remains a need for novel therapeutics that address this gap in treatment options. Cell-based therapies have gained wide attention as a therapeutic option that could address this gap in treatment options for advanced melanoma. These therapies work by extracting certain cell types produced in the human body such as T-cells, modifying them based on a specific target, and transfusing them back into the patient. In the realm of cancer therapy, cell-based therapies utilize immune cells to target tumor cells while sparing healthy cells. Recently, the Food and Drug Administration (FDA) has approved the usage of lifileucel, a tumor-infiltrating lymphocyte (TIL) therapy, in advanced melanoma. This came following recent results from the C-144-01 study (NCT02360579), which demonstrated the efficacy and safety of TILs in metastatic melanoma patients who otherwise failed on standard ICI/targeted therapy. Thus, the results of this trial as well as the recent FDA approval have proven the viability of utilizing cell-based therapies to fill the gap in treatment options for patients with advanced melanoma. This review aims to provide a comprehensive overview of major cell-based therapies that have been utilized in melanoma by delineating results of the most recent multi-center phase II/ III clinical trials that evaluate the efficacy and safety of major cell-based therapies in melanoma. Additionally, we provide a summary of current limitations in each cell-based therapeutic option as well as a future direction of how to further extrapolate these cell-based therapies in advanced melanoma.

Potential therapeutic effects of topical recombinant human erythropoietin on burn wound healing: A preliminary randomized double-blind controlled clinical trial

BackgroundBurn injuries can cause significant mortality and morbidity. This study aimed to evaluate the efficiency of topical recombinant human erythropoietin (rhEPO) on enhancing burn wound healing. MethodsIn this randomized double-blind controlled clinical trial, we enrolled 40 participants aged 18 years and older who were referred to a burn center during the first 24 h of burning. The participants with no concurrent comorbidities had superficial and deep second-degree burns, no respiratory burns, no face and perineum burns, no keloid formation, or a healed, fully epithelialized, hypertrophic burn scar. Topical rhEPO or nitrofurazone/Vitamin A was administered every other day, and the patients were scheduled for follow-up visits to receive wound cleansing, debridement, and dressing changes. Burn wound healing response to treatment was measured as the study main outcome. ResultsAt the second follow-up visit, all parameters were significantly lower in the rhEPO group compared with the control group except for itchiness. The results of the next two follow-up sessions were also the same. The total value of the modified Vancouver Scar Scale (VSS) at days 5, 7, and 14 was significantly lower in the rhEPO group compared with the routine of care group.Trial Registry Date: 2022–03-02, Trial Registry number: IRCT20190810044500N23 ConclusionsThe results of the present study suggested that topical rhEPO is a potential option in burn wounds and patient satisfaction, without causing intolerable side effects.

Efficacy and safety of anlotinib as maintenance therapy in patients with advanced non-small cell lung cancer achieving SD post first-line chemotherapy combined with immunotherapy.

Advanced non-small cell lung cancer (NSCLC) remains a significant clinical challenge, particularly in patients who exhibit stable disease (SD) following first-line chemotherapy combined with immunotherapy. This study aims to evaluate the efficacy and safety of Anlotinib, a novel multitarget tyrosine kinase inhibitor, as maintenance therapy in this patient cohort. This retrospective, single-center study enrolled patients with advanced NSCLC who showed SD after receiving a combination of first-line chemo-immunotherapy for 4 cycles, then add anlotinib to subsequent standard maintenance therapy, continuing treatment until disease progression or the occurrence of intolerable toxic side effects. The primary endpoint was progression-free survival (P FS), overall survival (OS), objective response rate (ORR), disease control rate (DCR) and safety profile. A total of 52 patients were enrolled, the median P FS and OS was 5.0m and 10.0m, respectively. The ORR and DCR was 28.85% and 67.31%. subgroup analysis indicated that its efficacy correlate with certain Adverse Effects (AEs, such as hypertension, proteinuria, and hand-foot syndrome). Further mechanistic analysis suggests that this regimen may likely reduce immune suppression by depleting Tregs, thereby further activating the immune system to exert synergistic anti-tumor effects. Besides promising efficacy, the toxicity can be tolerated. Anlotinib demonstrates promising efficacy as a maintenance therapy in patients with advanced NSCLC who have achieved SD following first-line chemotherapy combined with immunotherapy. The manageable safety profile and the observed extension in P FS and OS suggest that Anlotinib could be a valuable therapeutic option for this challenging patient population. Further large-scale randomized controlled trials are warranted to confirm these findings and to optimize patient selection and management strategies.

Brain targeting for focused ultrasound essential tremor ablation: proceedings from the 2023 Focused Ultrasound Foundation workshop.

Essential tremor (ET) is the most common movement disorder globally and has negative impacts on quality of life. While medical treatments exist, approximately 50% of patients have tremor that is refractory to medication or experience intolerable medication side effects. Magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy is an option for these patients and while incisionless, it is still invasive, although less so than other surgical treatments such as deep brain stimulation and radiofrequency thalamotomy. Despite MRgFUS being FDA-approved since 2016, there is still no current consensus on the best approaches for targeting, imaging, and outcome measurement. A 2-day workshop held by the Focused Ultrasound Foundation in September of 2023 convened experts and critical stakeholders in the field to share their knowledge and experiences. The goals of the workshop were to determine the optimal target location within the thalamus and compare best practices for localizing the target and tracking patient outcomes. This paper summarizes the current landscape, important questions, and discussions that will help direct future treatments to improve patient care and outcomes.

Co-amorphous systems of sulfasalazine with matrine-type alkaloids: Enhanced solubility behaviors and synergistic therapeutic potential

Sulfasalazine (SULF), a sulfonamide antibiotic, has been utilized in the treatment of rheumatoid arthritis (RA) and inflammatory bowel disease (IBD) since its discovery. However, its poor water solubility causes the high daily doses (1–––3 g) for patients, which may lead to the intolerable toxic and side effects for their lifelong treatment for RA and IBD. In this work, two water-soluble natural anti-inflammatory alkaloids, matrine (MAR) and sophoridine (SPD), were employed to construct the co-amorphous systems of SULF for addressing its solubility issue. These newly obtained co-amorphous forms of SULF were comprehensively characterized by powder X-ray diffraction (PXRD), temperature-modulated differential scanning calorimetry (mDSC), Fourier-transform infrared spectroscopy (FTIR), and X-ray photoelectron spectroscopy (XPS). We also investigated their dissolution behavior, including powder dissolution, in vitro release, and intrinsic dissolution rate. Both co-amorphous systems exhibited superior dissolution performance compared to crystalline SULF. The underlying mechanism responsible for the enhanced dissolution behaviors in co-amorphous systems were also elucidated. These mechanisms include the inhibition of nucleation, complexation, increased hydrophilicity, and robust intermolecular interactions in aqueous solutions. Importantly, these co-amorphous systems demonstrated satisfactory physical stability under various storage conditions. Network pharmacological analysis was utilized to investigate the potential therapeutic targets of both co-amorphous systems against RA, revealing similar yet distinct multi-target synergistic therapeutic mechanisms in the treatment of this condition. Our study suggests these drug-drug co-amorphous systems hold promise for optimizing SULF dosage in the future and providing a potential drug combination strategy.

Frequency of Topical Immunomodulatory and Immunosuppressive Therapies for Ocular Chronic Graft-versus-Host Disease.

Introduction: The purpose of the study was to evaluate the frequency of topical immunomodulatory and immunosuppressive therapies in patients with ocular chronic graft-versus-host disease (cGVHD) in consideration of inflammatory activity and systemic immunosuppressive therapies in a tertiary care university hospital setting. Methods: We included 95 adult patients (48 male, 47 female) with ocular chronic graft-versus-host disease (cGVHD) after alloHSCT (median age 49.5 years). Clinical ophthalmological findings and the grade of ocular cGVHD according to the NIH eye score and the German-Austrian-Swiss Consensus (GAS) Grading were analyzed. Systemic GVHD manifestations as well as the prevalence of topical and systemic (immunomodulatory) therapies were assessed. Results: A total of 74 of 95 patients (77.8%) had manifestations of systemic chronic graft-versus-host disease other than ocular GVHD. 68.42% (65/95) of patients were under systemic immunosuppressive therapy with at least one immunosuppressive medication. All patients (95/95) received lid-margin hygiene and phosphate- and preservative-free lubricating eye drops. Twenty-five percent of the cohort (24/95) were treated with autologous serum eye drops (ASEDs). In total, 80% (76/95) of patients required topical steroid therapy to treat acute exacerbation of inflammation at least once; continuous topical steroid therapy was only necessary for a minor part (12%) with refractory chronic inflammation. A total of 92.63% (88/95) were primarily treated with ciclosporin A 0.1% as Ikervis®, of whom at least one third did not continue the therapy because of intolerable side effects during follow-up and received alternative topical formulations. Conclusions: Our data show that patients with ocular cGVHD mostly need topical therapy including anti-inflammatory agents despite systemic immunosuppressive therapy. In our cohort, 80% of patients received topical steroids, and more than 90% received topical ciclosporin A eye drops, which were tolerated by only two thirds of patients due to side effects.

Nanoliposomal in situ gel of fluoxetine and embelin as a potent intervention for depression via the intranasal route in CUMS animal model

Due to the intricate mechanism of depression, slow therapeutic effect, and intolerable side effects, fluoxetine does not treat its many symptoms. To address monotherapy's limitations, novel and synergistic therapies are needed. This study delves into the potential of thermosensitive nanoliposomal gel loaded with fluoxetine and embelin (FXT-EMB NLs in situ gel) to manage depression via the intranasal route in a chronic unpredictable mild stress (CUMS) animal model. FXT-EMB NLs were prepared using thin-film hydration, optimized by a central composite design, and loaded into an in situ gel containing Poloxamer-407 and HPMC polymers. The optimized NLs had satisfactory vesicle size (92.6 ± 1.3 nm), TEM, SEM, PDI (0.22 ± 0.01), zeta potential (35.1 ± 0.2 mV), and entrapment efficiency (87.09 and 73.26 % for FXT and EMB) results. DSC, FTIR, and XRD confirmed the purity of APIs, compatibility, and loading efficiency of the in situ gel. The in vitro release showed sustained release, whereas the ex vivo permeation and CLSM studies demonstrated enhanced permeation across goat nasal mucosa (19.351 and 19.6 μg/cm2/h). DPPH assay confirmed the antioxidant potential of the NLs and was non-irritant according to the nasal toxicity and HET-CAM studies. The N2a neuroblastoma cell line revealed cell viability and the synergistic effect of the drug combination (CI < 1). The in vivo study found that NLs significantly enhanced SOD and CAT levels in Wistar rats, and reduced IL-6, TNF-α levels, and immobility time in the CUMS model of depression (p < 0.001). The combination and synergistic antioxidant action of FXT and EMB-loaded NLs in situ gel could be beneficial for effectively treating depression.

The use of biologics in patients suffering from chronic rhinosinusitis with nasal polyps - a 4-year real life observation.

Antibody therapy for chronic rhinosinusitis with nasal polyps (CRSwNP) has been established in Germany since 2019. With limited long-term data on biologic treatment for CRSwNP, we conducted a comprehensive evaluation of our 4-year data. This monocentric study aims to assess the real-world effects of this treatment on clinical course, quality of life, treatment adherence, biologic switching, dual therapy, and comorbidities. We retrospectively analysed biologic therapy data in patients with severe chronic rhinosinusitis with nasal polyps. 191 patients with CRSwNP treated with Dupilumab, Mepolizumab, or Omalizumab were observed for up to 4 years in a real-life setting. We observed clear symptom improvements with few side effects. No loss of efficacy or tolerability was noted during the 4-year period. Patients reported high satisfaction compared to previous therapies, with overall improved quality of life. Revision surgery or oral steroid use during biologic therapy was rare. Some patients prolonged injection intervals or discontinued steroid nasal spray. Biologic switching occurred infrequently due to side effects or inadequate response and was generally well tolerated. Many patients reported additional positive effects such as asthma or allergy symptom improvement and reduced medication intake. In summary, this study confirms the potency and tolerability of biologics for CRSwNP treatment, with sustained efficacy over 4 years. Biologic switching is a viable option for inadequate response or intolerable side effects. Therapy positively impacts Th2 comorbidities, corticosteroid requirements, surgery need, and overall compliance remains high. Project No.: 22-0802. Registry name: Biologika bei Patient*innen mit chronischer Sinusitis mit Nasenpolypen.

Pyrotinib and trastuzumab plus palbociclib and fulvestrant in HR+/HER2+ breast cancer patients with brain metastasis

Human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC) patients are at a high risk of developing metastases in the brain. However, research focusing on treatment strategies for hormonal receptor positive (HR+), HER2+ BC patients with brain metastases (BM) remains limited. Thus, a multi-center, prospective trial was conducted in China. Women over the age of 18 who were naive to whole brain radiotherapy and had estrogen receptor (ER)/progesterone-receptor (PgR) positive, HER2+ BM were treated with palbociclib, fulvestrant, trastuzumab and pyrotinib, until disease progression or the development of intolerable side effects. The primary endpoint was objective response rate (ORR) in the central nervous system (CNS). This ongoing study is still recruiting participants and is registered with ClinicalTrials.gov (NCT04334330). This report presents the findings from an interim analysis. From December 4, 2020, to November 2, 2022, 15 patients were enrolled. Among the 14 patients who were evaluable for clinical response, the ORR was 35.7% (95% CI: 12.8–64.9%), with a CNS–ORR of 28.6% (95% CI: 8.4–58.1%). The median follow-up period was 6.3 months (range, 2.1–14.3 months), during which the median progression-free survival (PFS) was 10.6 months (95% CI: 4.3–16.9 months), and the median time to CNS progression was 8.5 months (95% CI: 5.9–11.1 months). The most common adverse event was diarrhea (93%), with 33% having grade 3 and 6.7% having grade 4. The study suggests that the combination of palbociclib, trastuzumab, pyrotinib and fulvestrant offers a promising chemo-free treatment strategy for HR+, HER2+ BC patients with BM.

Phase 3 randomized study for evaluation of physician choice Rx versus best supportive care as second-line or beyond therapy in head and neck cancer with poor performance status.

LBA6019 Background: Relapsed-recurrent head and neck squamous cell carcinoma (HNSCC) cancers have limited treatment options in the second line and beyond setting. Many of these patients have poor performance status (PS) and are subject to best supportive care (BSC). There is a lack of any level 1 evidence about the benefit of systemic therapy in HNSCC with poor PS. Methods: This was a randomized phase 3 superiority open-label multicentric study. Adult patients (age&gt;=18 years) with relapsed-recurrent HNSCC, qualified to receive 2nd line or beyond systemic palliative therapy and had ECOG PS 2-3 were eligible. Such patients underwent central stratified random assignment 2:1 to either physician choice therapy either triple metronomic chemotherapy (tablet erlotinib 150 mg [fixed-dose] OD, capsule celecoxib 200 mg [fixed-dose] BD, and oral weekly methotrexate 9 mg/m2 orally or intravenous docetaxel [75 mg/m2 3 weekly]) or BSC. The chemotherapy was continued either till the progression of the disease or till the development of intolerable side effects. The primary endpoint was 6 month-overall survival (OS). The OS in the 2 arms was estimated using the Kaplan-Meier method and by log-rank test. A p-value of 0.05 was considered significant. Sample size: The 6-month OS assumed based on our previous data was 20%, we had assumed that it would increase to 50% in the intervention arm with a type 1 error of 5%, type 2 error of 20%, 2:1 allocation (1- BSC and 2- intervention) and 10% lost to follow up rate. The sample size required was 66. The events required for analysis were 47. Results: The study recruited 66 patients between 1st September 2022 to 27th December 2022 with 44 patients in physician choice therapy (PCT) and 22 in the BSC arm. The data was censored for analysis on 1st March 2024. The median age was 50 years (Range 25-75) with a predominantly male population (n=53;85%). The ECOG PS was PS 2 in 56 (84.8%) and PS 3 in 10 (15.2%) patients. The predominant site of primary was the oral cavity with 52 patients (78.8%). The previous number of systemic lines of therapy received were 1 in 41 (62.1%), 2 in 22 (33.3%), and &gt;2 in 3 (4.5%) patients. Except for 2, all patients had a platinum refractory status (64;97%). The PCT was triple metronomic chemotherapy in 41 patients (93.2%; n=44) and docetaxel in 3 patients (6.8%; n=44). The 6-month OS was 9.09% (95% CI 1.56-25.1) in the BSC versus 53.8% (95% CI 37.9-67.2) in the PCT arm (P&lt;0.0001). The median overall survival in PCT was 223.0 days (95% CI 129-283) versus 77.5 days (95%CI 58 -110) in the BSC arm. The corresponding hazard ratio was 0.333 (95%CI 0.187-0.593; P&lt;0.0001). The data regarding adverse events will be presented at the conference. Conclusions: In this first-ever randomized study on poor PS HNSCC patients, warranting second-line and beyond therapy, the administration of systemic therapy led to a substantial improvement in OS. Clinical trial information: CTRI/2022/08/044733 .

VAMANA: A phase 2 study of low-dose bevacizumab plus CCNU in relapsed/recurrent glioblastoma.

LBA2064 Background: There are limited systemic therapy options for recurrent glioblastomas (rGBM). CCNU and/or Bevacizumab are often used to treat rGBM not amenable to local therapy. The addition of Bevacizumab (10 mg/kg) to CCNU failed to improve overall survival in the EORTC 26101 study. The question is whether the failure was due to the high dose of Bevacizumab used in the study. High doses of Bevacizumab may lead to excessive pruning &amp; destruction of blood vessels, hampering the delivery of CCNU. In vitro &amp; in vivo studies showed that a lower dose of Bevacizumab (1-1.5 mg/kg) has the potential to normalize tumor vasculature leading to improved drug delivery &amp; outcomes. To test this hypothesis, we conducted this study to evaluate the efficacy of low-dose Bevacizumab in combination with CCNU in rGBM. Methods: This was a phase 2 open-label, single-arm trial that included adults with rGBM with an ECOG PS 0-2 and adequate organ &amp; marrow function. The participants received CCNU 110 mg/m2 PO once a day, on day 1 of a 42-day cycle (max. 8 cycles) with Bevacizumab 1.5 mg/kg intravenously every 3 weeks (max.16 cycles). Appropriate anti-emetic prophylaxis was given. Treatment continued until disease progression, clinical deterioration, or development of intolerable side effects. Response assessment was done with MRI Brain +/- spine at 2 monthly intervals till disease progression. The modified RANO criteria were used for response assessment. Safety assessments were done on day 8 of cycle 1, &amp; days 21 &amp; 42 of each cycle. The primary end-point of this study was overall survival (OS) and secondary end-points were progression-free survival (PFS) &amp; safety. A 6-month OS ≥ 40% was the signal to explore this regimen further and if the 6-month OS &lt;20% it would be considered futile. Descriptive statistics were performed and the Kaplan-Meier method was used for time-to-event analysis. Results: Forty-six patients were enrolled in this study. The median age was 42 years (IQR 33-52.75) and 78.3% (36/46) were males. Most patients (76.1%, 35/46) had an ECOG PS of 1. The median follow-up duration was 15.27 months (95% CI 13.47-17.06). The median number of doses of Bevacizumab and CCNU were 4 and 2 respectively. Three (6.5%) patients completed all planned doses of Bevacizumab and CCNU. The objective response rate (ORR) was 15.2 % (7/46). The median OS was 6.133 months (95% CI 5.474-6.793). The 6-month OS was 57.1%. The median PFS was 3.267 months (95% CI 0.850-5.684). The most frequent grade 3 or higher toxicities seen were neutropenia (7/46, 15.2%), thrombocytopenia (5/46,10.8%), elevated ALT levels (3/46, 6.5%), anemia (2/46, 4.3%) and hyponatremia (2/46, 4.3%). Conclusions: This study demonstrates the efficacy of low-dose Bevacizumab in combination with CCNU in rGBM (the median OS exceeded the preplanned cut-off of 40%) with an acceptable toxicity profile and no new safety signals. This combination should be explored further in a phase III randomized study. Clinical trial information: CTRI/2020/07/026696 .

Long term results of phase 3 randomized study evaluating the addition of low dose nivolumab to palliative chemotherapy in head and neck cancer.

LBA6054 Background: The addition of low-dose nivolumab to metronomic chemotherapy (MC) improved 1-year overall survival in relapsed and refractory head and neck squamous cell carcinoma (HNSCC). However, sustained benefit over the long term is an important aspect of immunotherapy and it has never been studied in a prospective randomized study for low-dose nivolumab. Methods: This was an open-label randomized phase 3 superiority study. Adult patients (age= or &gt;18 years), ECOG PS (0-1), relapsed -recurrent or newly diagnosed advanced HNSCC, and normal organ functions were eligible. Patients were randomly assigned 1:1 to oral metronomic chemotherapy consisting of methotrexate 9 mg/m2 weekly, celecoxib 200 mg twice daily, and erlotinib 150 mg daily, with (TMC-I) or without (TMC) with intravenous nivolumab 20 mg flat dose once-every-3-weeks. Systemic therapy was continued till the development of intolerable side effects or progression of disease. The primary endpoint was overall survival (OS). Landmark analysis was performed to compare OS between 2 arms. Results: The median follow-up was 32.5 months (95% CI 29.6-32.7). The 1 year, 2 year and 2.5 year OS were 20% (95%CI 11.9-29.7) versus 35.5% (95%CI 25-46.2) {Hazard ratio (HR)= 0.6534, 95%CI 0.4473 -0.956: P=0.028}, 5.3% (95%CI 1.7-12.3) versus 18.4 %(95%CI 10.7-27.8) {HR= 0.6318, 95%CI 0.4476 -0.8919: P=0.009} and 5.3% (95%CI 1.7-12.3) versus 17.1 % (95%CI 9.66.-26.3) {HR= 0.6379, 95%CI 0.4524 -0.8993: P=0.01} in the TMC and the TMC-I arms respectively. The benefit of the addition of nivolumab was independent of other factors like age, gender, ECOG PS, Site of malignancy, time to failure, PDL1 score, and previous exposure to platinum (Table). Conclusions: The addition of low-dose nivolumab to triple metronomic chemotherapy leads to a tripling of OS thus suggesting that even low-dose nivolumab has sustainable benefits. The benefit observed is irrespective of known prognostic factors in HNSCC. Clinical trial information: CTRI/2020/11/028953 . [Table: see text]

Overall survival of adebrelimab plus chemotherapy and sequential thoracic radiotherapy as first-line treatment for extensive-stage small cell lung cancer.

8014 Background: The phase 3 trial (CAPSTONE-1) showed that adebrelimab (PD-L1 antibody) combined with first-line chemotherapy could prolong overall survival (OS) in patients (pts) with extensive-stage small cell lung cancer (ES-SCLC). Previous studies have shown that radiotherapy can enhance the immunogenicity of tumors, indicating the great potential of combining radiotherapy with immunotherapy. The purpose of this study was to explore the efficacy and safety of adebrelimab combined with chemotherapy and sequential thoracic radiotherapy (TRT) as first-line therapy for ES-SCLC. Methods: Key inclusion factors were 18-75 years old, histologically or cytologically confirmed ES-SCLC, ECOG performance status 0-1, no previous systematic treatment. Pts received 4~6 cycles of adebrelimab (20mg/kg, D1, q3w) combined with EP/EC (etoposide, 100mg/m2, D1-3, q3w and cisplatin, 75mg/m², D1, q3w or carboplatin, AUC = 5, D1, q3w). Pts with response sequentially received adebrelimab combined with consolidate TRT (≥30 Gy in 10 fractions or ≥50 Gy in 25 fractions, involved-field irradiation). Pts then entered the maintenance treatment stage with adebrelimab until disease progression or intolerable side effects. The primary endpoint was OS. The secondary endpoints included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and safety. Results: From October 2020 to April 2023, 67 pts with ES-SCLC were enrolled. Most patients were male (83.6%), current or former smokers (65.7%) with an ECOG performance status of 1 (95.5%). 22 (32.8%) patients were diagnosed with brain metastasis and 21 (31.3%) patients had liver metastasis at baseline. 45 patients received sequential TRT as planned. All patients were included in the safety and efficacy analysis population. At data cutoff (December 22, 2023), the median follow-up duration was 17.7 months. The median OS was 21.4 months (95% CI: 17.2–not reached months). 1-year and 2-year OS rate were 74.1% (95% CI: 63.6-86.4%) and 39.7% (95% CI: 25.5-61.9%). The median PFS was 10.1 months (95% CI: 6.9–15.5 months). The confirmed ORR was 71.6% (95% CI: 59.3-82.0%) and DCR was 89.6% (95% CI: 79.7-95.7%). The most common grade 3 or higher treatment-related adverse events included neutrophil count decreased (41.8%), white blood cell count decreased (19.4%) and lymphocyte count decreased (13.4%). No unexpected adverse events were observed. Conclusions: Adebrelimab plus chemotherapy and sequential TRT as first-line therapy for ES-SCLC showed promising efficacy and acceptable safety. Clinical trial information: NCT04562337 .