Search Results (1,913)

Background/Objectives: Human epidermal growth factor receptor 2 (HER2) inhibitors have markedly improved outcomes in patients with HER2-positive breast cancer. Clinical treatment often involves the sequential or combined use of multiple HER2 inhibitors, making it essential to clarify their distinct adverse event (AE) profiles. However, AE trends remain insufficiently understood. This study aimed to comprehensively analyze characteristic AEs associated with HER2 inhibitors. Methods: Using the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS, January 2004–September 2024), we conducted disproportionality analyses of AEs associated with HER2 inhibitors approved for breast cancer. Based on the natural logarithm of the reporting odds ratio (lnROR), hierarchical cluster analysis and principal component analysis (PCA) were performed. Results: Disproportionality analysis treating HER2 inhibitors as a single group identified several signals, with hair disorder (ROR 39.93 [95% CI: 37.68–42.32]) as a representative example. Hierarchical clustering showed that monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs) diverged early in the dendrogram, and clusters broadly corresponded to pharmacological classes. The cluster of hair-related AEs closely corresponded to mAbs. PCA indicated that the first component reflected AE occurrence risk (R² = 0.655, p < 0.0001), the second component distinguished mAbs from TKIs (tucatinib: r = 0.667; trastuzumab: r = −0.567), and the third component separated molecular targeted agents from antibody–drug conjugates (neratinib: r = 0.521; T-DXd: r = −0.440). Conclusions: FAERS-based analyses enabled visualization of the distinct AE profiles of HER2 inhibitors. These findings may support safe drug selection, risk stratification, and improved AE management strategies. Full article

Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive non-Hodgkin lymphoma (NHL) worldwide. Currently, approximately sixty percent of patients are cured with R-CHOP as frontline treatment, while the remaining patients experience primary refractory or relapsed (R/R) disease. Recently, the introduction of Pola-R-CHP as front-line therapy has represented a major advance in the management of DLBCL, resulting in improved outcomes. Prognosis of R/R DLBCL patients is poor, particularly for those eligible neither for chimeric antigen receptor (CAR) T-cell therapy nor autologous stem cell transplantation (ASCT), representing a significant unmet clinical need. The advent of bispecific monoclonal antibodies (BsAbs), such as bispecific T-cell engagers (BiTEs), dual affinity retargeting (DART) molecules and IgG-like bispecific antibodies, offers a novel promising therapeutic approach in the treatment of DLBCL, both as frontline treatment and in the R/R setting. BsAbs simultaneously engage two different antigens, a tumor-associated antigen and an immune cell antigen, redirecting T-cells against malignant cells and enhancing the immune response. Most BsAbs developed for the treatment of NHLs engage T-cells via CD3 and malignant B-cells via CD20, a surface antigen expressed on most lymphomatous cells. Engagement of malignant B-cells by BsAbs activates T-cells, leading to the release of multiple cytokines and potentially to two characteristic adverse events: cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The most extensively studied BsAbs, in both the frontline and relapsed/refractory (R/R) settings, include epcoritamab, glofitamab, mosunetuzumab, and odronextamab. Epcoritamab and glofitamab have received FDA and EMA approval for R/R DLBCL after two or more systemic line of therapies. EMA has also approved glofitamab in combination with gemcitabine and oxaliplatin (GemOx) for patients with R/R DLBCL ineligible for ASCT, whereas this indication has not been approved by FDA. Odronextamab is approved by EMA for R/R DLBCL and FL in patients who have received at least two prior lines of therapy, but it has not been approved by FDA. Mosunetuzumab is approved by both agencies—but only for R/R follicular lymphoma (FL). BsAbs represent a breakthrough therapy in the treatment of DLBCL, especially in R/R diseases. The purpose of this article is to review the landscape of BsAbs in DLBCL. Full article

Background: Pulmonary hypertension (PH) is a frequent complication in patients with interstitial lung disease (ILD); its occurrence results in significant morbidity and mortality. Currently approved treatment options for PH-ILD include inhaled prostacyclin therapy, although this approach may be insufficient in patients who have developed simultaneous right ventricular failure. Moreover, there is no available treatment algorithm regarding the optimal therapy and timing of lung transplant referral for PH-ILD patients based on disease severity. Design/Methods: In this study, we created such a tool to guide PH-specific therapy in PH-ILD patients, especially as further treatment strategies are developed. We developed a 4-point PH-ILD Severity score that integrated both subjective and objective information (WHO FC, CI, TAPSE, PVR) from retrospective analysis of 57 PH-ILD patients. Results: A score of 3 or greater in the PH-ILD Severity score yielded an AUC of 0.831 (p < 0.001) for the composite endpoint of clinical worsening (hospitalization due to a cardiopulmonary indication; decrease in 6 min walk distance by >15% at 2 consecutive visits; all-cause mortality; lung transplantation). Conclusions: Further confirmation and evolution of this PH-ILD Severity score will assist in the development of optimal treatment plans in ILD patients diagnosed with concomitant PH. Full article

Background: Antibody-drug conjugates (ADCs) have ushered in a new era of precision oncology by combining the targeting specificity of monoclonal antibodies with the potent cytotoxicity of chemotherapeutic drugs. However, the cellular and molecular mechanisms underlying their dose-limiting ocular toxicity remain unclear. Elahere™, the first FDA-approved ADC targeting folate receptor α (FRα), demonstrates remarkable efficacy in platinum-resistant ovarian cancer but causes keratitis and other ocular toxicities in some patients. Notably, FRα is not expressed in the corneal epithelium—the primary site of damage—highlighting the urgent need to elucidate its underlying mechanisms. The aim of this study was to identify the cell-type-specific molecular mechanisms underlying Elahere-induced ocular toxicity. Methods: Sprague-Dawley rats were treated with intravenous Elahere (20 mg/kg) or vehicle weekly for five weeks. Ocular toxicity was determined by clinical examination and histopathology. Corneal single-cell suspensions were analyzed using the BD Rhapsody single-cell RNA sequencing (scRNA-seq) platform. Bioinformatic analyses to characterize changes in corneal cell populations, gene expression, and signaling pathways included cell clustering, differential gene expression, pseudotime trajectory inference, and cell-cell interaction modeling. Results: scRNA-seq profiling of 47,606 corneal cells revealed significant damage to the ocular surface and corneal epithelia in the Elahere group. Twenty distinct cell types were identified. Elahere depleted myeloid immune cells; in particular, homeostatic gene expression was suppressed in phagocytic macrophages. Progenitor populations (limbal stem cells and basal cells) accumulated (e.g., a ~2.6-fold expansion of limbal stem cells), while terminally differentiated cells decreased in corneal epithelium, indicating differentiation blockade. Endothelial cells exhibited signs of injury and inflammation, including reduced angiogenic subtypes and heightened stress responses. Folate receptor alpha, the target of Elahere, was expressed in endothelial and stromal cells, potentially driving stromal cells toward a pro-fibrotic phenotype. Fc receptor genes were predominantly expressed in myeloid cells, suggesting a potential mechanism underlying their depletion. Conclusions: Elahere induces complex, multi-compartmental ocular toxicity characterized by initial perturbations in vascular endothelial and immune cell populations followed by the arrest of epithelial differentiation and stromal remodeling. These findings reveal a cascade of cellular disruptions and provide mechanistic insights into mitigating Elahere-associated ocular side effects. Full article

Non-communicable diseases (NCDs) are the leading global cause of death, causing over 43 million deaths in 2021, including 18 million premature deaths, disproportionately affecting low- and middle-income countries. NCDs also incur significant economic losses, estimated at USD 7 trillion from 2011 to 2025, despite low prevention costs. This study evaluated body mapping indicators: body mass index (BMI), waist circumference, and waist-to-hip ratio—for predicting NCD risk, including hypertension, diabetes, and cardiovascular diseases, using data from a nationally representative survey in Ghana. The study sampled 5775 participants via multistage stratified sampling, ensuring proportional representation by region, urban/rural residency, age, and gender. Ethical approval and informed consent were obtained. Anthropometric and biochemical data, including height, weight, waist and hip circumferences, blood pressure, fasting glucose, and lipid profiles, were collected using standardized protocols. Data analysis was conducted with STATA 17.0, accounting for complex survey design. Significant sex-based differences were observed: men were taller and lighter, while women had higher BMI and waist/hip circumferences. NCD prevalence increased with age, peaking at 60–69 years, and was higher in females. Lower education and marital status (widowed, divorced, separated) correlated with higher NCD prevalence. Obesity and high waist circumference strongly predicted NCD risk, but individual anthropometric measures lacked screening accuracy. Integrated screening and tailored interventions are recommended for improved NCD detection and management in resource-limited settings. Full article

RNA-targeting techniques have emerged as powerful tools in cancer research and therapeutics, offering precise and programmable control over gene expression at the post-transcriptional level. Once viewed as passive intermediates in the central dogma, RNA molecules are now recognized as dynamic regulators of cellular function, capable of influencing transcription, translation, and epigenetic regulation. Advances in high-throughput sequencing technologies, transcriptomics, and structural RNA biology have uncovered a diverse landscape of coding and non-coding RNAs involved in oncogenesis, drug resistance, and tumor progression. In response, several RNA-targeting strategies have been developed to modulate these transcripts, including antisense oligonucleotides (ASOs), RNA interference (RNAi), CRISPR-Cas13 systems, small molecules, and aptamers. This review provides a comparative analysis of these technologies, highlighting their molecular mechanisms, therapeutic potential, and current limitations. Emphasis is placed on the translational progress of RNA-targeting agents, including recent FDA approvals and ongoing clinical trials for cancer indications. Through a critical comparison of these strategies, this review underscores the growing significance of RNA-targeting technologies as a foundation for next-generation cancer therapeutics and precision oncology. Full article

Cannabidiol (CBD) is a chemical produced by the cannabis plant that acts as an allosteric modulator of cannabinoid receptors resulting in non-competitive receptor antagonism in the central nervous system. This mechanism of action leads to anti-convulsant, anti-anxiety, and analgesic properties with minimal psycho-activity, which has led to significant interest in the use of CBD as a medication. Legislation around cannabis has changed in recent years, with many states permitting the use of CBD-based products as “medication” without approval from the Federal Drug Administration. This has led to a proliferation of products with associated marketing claims that are often unsubstantiated. This review summarizes the evidence for cannabidiol as a medical treatment, focusing on epilepsy, mental health, behavioral and substance use disorders occurring in pediatric and adolescent populations for which information is available. CBD preparations have been approved by the FDA to treat epilepsy in childhood; no other indications currently exist, and the literature remains inconclusive. Few adverse effects related to CBD use have been reported. However, endogenous cannabinoids play an important role in guiding brain development, and the long-term impact of modulating the endocannabinoid system during periods of brain growth during childhood and adolescence is unknown. While there is excitement about the potential for the development of CBD medications, currently, there is very limited information about the long-term safety of CBD, especially in children and adolescents, and caution is recommended regarding the use of unregulated, unapproved CBD preparations that are currently available over the counter. Full article

First-line options for chronic lymphocytic leukemia (CLL) are evolving, recently returning to a fixed-duration (FD) approach incorporating regimens such as venetoclax + obinutuzumab, ibrutinib + venetoclax, and soon acalabrutinib + venetoclax ± obinutuzumab. Five Canadian hematologists convened to share perspectives regarding the attributes of these options and considerations for clinically appropriate integration within Canada’s publicly funded healthcare system. The hematologists underscored the importance of shared decision-making with patients, family members, and caregivers involving careful consideration of disease profile and patient characteristics, preferences, and values. They indicated that although a role persists for continuous therapy with approved covalent Bruton’s tyrosine kinase inhibitors (typically in high-risk disease), newer FD regimens offer multiple benefits related to the treatment-free period, quality of life, safety, re-treatment, healthcare resource utilization, and costs. The hematologists highlighted the appeal of all-oral FD combinations given their convenience and impact on treatment equity, factors especially compelling given Canada’s vast geography and large segment of rural populations. In closing, they emphasized the quickly evolving therapeutic setting of CLL in the 1L and beyond, underscoring the need for ongoing patient involvement in decision-making to support optimal treatment selection based on patient goals and within the confines of provincial funding. Full article

Tyrosine kinase 2 (TYK2) mediates the signaling pathways of proinflammatory cytokines such as interleukin (IL)-12, IL-23, and type I interferons (IFNs) and plays a pivotal role in the pathogenesis of psoriasis and various other immune-mediated diseases. Deucravacitinib, a selective oral TYK2 inhibitor, has been approved for the treatment of psoriasis and demonstrated high efficacy and a favorable safety profile. This review summarizes the potential for expanding deucravacitinib indications based on case reports, clinical trials, and preclinical studies. Diseases in which TYK2 pathway has been demonstrated to be involved and for which clinical benefit of deucravacitinib has been reported include discoid lupus erythematosus, systemic lupus erythematosus, alopecia areata, lichen planus, palmoplantar pustulosis, psoriatic arthritis, systemic sclerosis, interstitial pneumonia, inflammatory bowel disease, and chronic recurrent multifocal osteomyelitis. Furthermore, emerging research suggests potential therapeutic applications in neurodegenerative diseases such as Alzheimer’s disease, and malignancies such as type 1 diabetes, vascular calcification in chronic kidney disease, T-cell acute lymphoblastic leukemia, and multiple sclerosis. Deucravacitinib may exert therapeutic effects by broadly suppressing cytokine signaling in a diverse range of inflammatory disorders. Ongoing clinical trials and mechanistic studies are required to clarify the efficacy and support its future indications. Full article

Polydeoxyribonucleotides (PDRN), highly purified DNA-derived polymers, were approved by the Italian Medicines Agency (AIFA) in 1994 to treat superficial wounds, skin ulcers, and dystrophic connective tissue disorders. Since then, PDRN have gained considerable attention as regenerative biomaterials. Beyond their established role in wound healing, they have also been approved as dermal fillers in several countries, with growing clinical evidence supporting their benefits for facial skin health. Recent clinical and preclinical studies suggest that PDRN may improve various skin conditions, including wrinkles, dryness, hyperpigmentation, hair loss, and barrier dysfunction. These findings have generated interest in their broader dermatological applications beyond traditional indications. This review aims to explore the therapeutic potential of PDRN for the treatment of skin disorders. We examine the efficacy and safety of PDRN-based drugs and medical devices in dermatology, with a focus on their clinical applications, pharmacological effects, and underlying molecular mechanisms. Given that PDRN consists of over 90% purified DNA, we further examine the biological functions of extracellular DNA (exDNA) and propose potential mechanisms by which PDRN may function as exDNA, beyond its classical action via the A2A receptor pathway. Collectively, current evidence highlights PDRN as safe and effective biopolymers with promising potential as DNA-based therapeutics in dermatology. Full article

Acute kidney injury (AKI) is a frequent and severe complication in trauma patients, affecting up to 28% of intensive care unit (ICU) admissions and contributing significantly to morbidity, mortality, and long-term renal impairment. Trauma-related AKI (TRAKI) arises from diverse mechanisms, including hemorrhagic shock, ischemia–reperfusion injury, systemic inflammation, rhabdomyolysis, nephrotoxicity, and complex organ crosstalk involving the brain, lungs, and abdomen. Pathophysiologically, TRAKI involves early disruption of the glomerular filtration barrier, tubular epithelial injury, and renal microvascular dysfunction. Inflammatory cascades, oxidative stress, immune thrombosis, and maladaptive repair mechanisms mediate these injuries. Trauma-related rhabdomyolysis and exposure to contrast agents or nephrotoxic drugs further exacerbate renal stress, particularly in patients with pre-existing comorbidities. Traditional markers such as serum creatinine (sCr) are late indicators of kidney damage and lack specificity. Emerging structural and stress response biomarkers—such as neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule 1 (KIM-1), liver-type fatty acid-binding protein (L-FABP), interleukin-18 (IL-18), C-C motif chemokine ligand 14 (CCL14), Dickkopf-3 (DKK3), and the U.S. Food and Drug Administration (FDA)-approved tissue inhibitor of metalloproteinases-2 × insulin-like growth factor-binding protein 7 (TIMP-2 × IGFBP-7)—allow earlier detection of subclinical AKI and better predict progression and the need for renal replacement therapy. Together, functional indices like urinary sodium and fractional potassium excretion reflect early microcirculatory stress and add clinical value. In parallel, risk stratification tools, including the Renal Angina Index (RAI), the McMahon score, and the Haines model, enable the early identification of high-risk patients and help tailor nephroprotective strategies. Together, these biomarkers and risk models shift from passive AKI recognition to proactive, personalized management. A new paradigm that integrates biomarker-guided diagnostics and dynamic clinical scoring into trauma care promises to reduce AKI burden and improve renal outcomes in this critically ill population. Full article

Personalized medicine has gained an important relevance over the years with the development of targeted therapies, especially in cancer, adapted to the individual molecular tumour profiles. Accordingly, drug repurposing arises as a powerful strategy to identify and use drugs already approved for other conditions, offering advantages in terms of cost, development time, and safety. Src and Abl tyrosine kinases have been investigated as potential targets in oncology, being frequently implicated in tumour development and progression by promoting cell proliferation, migration, and angiogenesis. This review aims to provide a comprehensive overview of five tyrosine kinase inhibitors—saracatinib, imatinib, PP2, nilotinib and, tirbanibulin—that act on Src and/or Abl. Their mechanisms of action, original therapeutic indications, and potential for repurposing in other diseases, such as lung cancer, will be discussed. Although clinical data for these drugs in lung cancer remain limited, preclinical and clinical studies suggest promising therapeutic potential, particularly in specific molecular subtypes. Overall, this review highlights the therapeutic potential of Src and Abl inhibitors beyond their original contexts and supports their possible role in lung cancer therapy, considering the disease’s high heterogeneity and the growing applicability of personalized medicine. Full article

Background: Patients with symptomatic abdominal tissue excess following massive weight loss (MWL) often experience skin affections associated with hygiene challenges, functional impairments, and psychological distress, all of which significantly impact their quality of life (QoL). Abdominoplasty effectively addresses these issues when conservative treatments prove ineffective. However, health insurance companies (HICs) in Switzerland frequently deny reimbursement. This study aimed to evaluate HIC’s reimbursement policies for abdominoplasty, quantifying time delays and additional costs generated by reconsideration due to initial rejections while assessing postoperative QoL of patients. Methods: A retrospective cohort study was conducted including patients undergoing abdominoplasty for symptomatic abdominal tissue excess after MWL between July 2019 and December 2023. Eligibility required HIC approval, informed consent, and legal age. Primary outcomes measured the number of reimbursement requests needed per patient, duration until approval, and additional diagnostic and therapeutic interventions following rejection. Secondary outcomes focused on additional consequent costs, differences in baseline characteristics and symptomatology, as well as QoL improvements using a non-validated, study-specific questionnaire. Results: Of 52 patients included, 33 received cost approval after a single request, whereas 19 required multiple submissions. The mean duration until approval was 15 weeks, with a 26-week delay for the multiple-request group, generating additional costs of CHF 715 per patient. Moreover, abdominoplasty significantly improved QoL in all patients, with no differences between groups. Conclusions: Initial reimbursement denials caused treatment delays, prolonged symptomatology, and increased healthcare costs, despite clear surgical indications. However, future studies involving larger cohorts are needed to support these findings. Full article

Background: Longitudinal genomic profiling through serial circulating tumor DNA (ctDNA) testing offers a noninvasive method to monitor clonal evolution in advanced prostate cancer. This study evaluated the frequency and nature of newly emergent and potentially actionable genomic alterations detected through serial testing in a real-world setting. Methods: We conducted a retrospective analysis of advanced prostate cancer patients who underwent multiple Guardant360 ctDNA tests between October 2020 and March 2023. The study focused on identifying new genomic alterations absent in the initial test, with particular attention to alterations relevant for on-label therapies, therapies approved in other oncologic indications (i.e., off-label), or a clinical trial. Results: Among 479 patients with at least two ctDNA tests, the median interval between the first and second evaluable tests was 207 days. New and potentially actionable alterations emerged in 57.8% of patients, including potential targets for on-label therapies (16.7%), off-label therapies (16.5%), and clinical trials (55.7%). Tumor mutational burden (TMB) increased from “low” to “high” in 11% of patients, although none had microsatellite instability or mismatch repair deficiency. In a Mayo Clinic subset, ten patients received olaparib based on treatment-emergent alterations, but none achieved a prostate-specific antigen (PSA) response. Two patients who transitioned from low to high TMB received pembrolizumab, both with progressive disease as best response. Conclusions: In a large real-world cohort, serial ctDNA testing frequently identified new alterations that were not detected at baseline and are potentially actionable therapeutic targets, highlighting the value of serial genomic profiling for capturing clonal dynamics. Additional research is needed to better establish a framework for retesting and to clarify how these results should influence subsequent treatment decisions. Full article

Pesticides are used in agriculture to protect crops from disease. Among these, the herbicide glyphosate, the insecticide deltamethrin, and the fungicides propamocarb and tebuconazole are approved for use in Europe. These pesticides, along with their metabolites, have been detected in the environment including in food and water sources. Human biomonitoring studies have confirmed the presence of these compounds in biological samples, indicating persistent exposure even among the general population, unrelated to agricultural occupations. Consequently, numerous studies have investigated the health effects of these four pesticides and their metabolites. This review focuses on their impacts on gut health primarily the gut microbiota, inflammation, metabolism, cancer and gut–brain axis. Epidemiological studies were included to assess health risks among various groups including adults, children and pregnant women. Animal and in vitro models have been employed to explore in a more controlled and targeted way the physiological and biochemical effects observed in epidemiological studies. Despite some controversy, pesticides and their metabolites have been linked to gut dysbiosis, inflammatory bowel disease (IBD), metabolic disorders, cancer and neurodevelopmental disorders. Mechanistically, these pesticides influence gut microbiome composition, sugar and lipid metabolism, oxidative stress, inflammatory pathways, cell death, oncogenic signalling pathways, endocrine disruption, and epigenetics. However, further studies are needed to confirm these risks and health impacts, particularly concerning low-dose, long-term exposure as experienced by the general population. A comprehensive investigation of these effects is essential, incorporating dietary factors, age, sex, health status, and the cumulative impact of multiple pesticides, to develop a thorough risk assessment. Full article