Lymphatic System Research Articles

Safety profiles of IDH inhibitors: a pharmacovigilance analysis of the FDA Adverse Event Reporting System (FAERS) database

Abstract Background With the increased use of isocitrate dehydrogenase (IDH) inhibitors in acute myeloid leukemia (AML) and cholangiocarcinoma, the toxicity of these drugs is a growing concern. This study aimed to evaluate the adverse events (AEs) of IDH inhibitors based on the Food and Drug Administration Adverse Event Reporting System (FAERS) database. Methods AE reports for IDH inhibitors (enasidenib, ivosidenib, and olutasidenib) were collected and analyzed from the time of launch through the first quarter of 2024. Only IDH inhibitors reported as the target drug and coded as the primary suspect (PS) were included in the analysis. AEs were standardized and classified according to the preferred term (PT) and system organ classification (SOC) in the Medical Dictionary for Regulatory Activities (MedDRA) version 26.0. Disproportionality analyses including the reporting odds ratio and the Bayesian confidence propagation neural network were performed in data mining to assess IDH inhibitor-relatedAEs. Differentiation syndrome was the AE of special interest. Results The reports number of enasidenib, ivosidenib, and olutasidenib was 11 616 357, 10 067 250, and 2 563 464, respectively. A total of 80 enasidenib-related signals involving 15 SOCs, 78 ivosidenib-related signals involving 17 SOCs, and 7 olutasidenib-related signals involving 4 SOCs were obtained. The most signals reported were “blood and lymphatic system disorders,” “infections and infestations,” and “nervous system disorders” in enasidenib. For signals of ivosidenib, the most frequently reported were “gastrointestinal disorders,” “general disorders and administration site conditions,” and “injury, poisoning and procedural complications.” Ivosidenib was the only IDH inhibitor with signals in “cardiac disorders.” Differentiation syndrome events were reported in 89, 40, and 2 cases for enasidenib, ivosidenib, and olutasidenib, respectively. The median time to onset was 26–31 days for ivosidenib and enasidenib. AML was the most common indication in the differentiation syndrome reports. Conclusions Our study identifies potential AE signals associated with IDH inhibitors and provides a broader understanding of the safety. The safety profiles highlight the need for long-term safety monitoring of IDH inhibitor recipients. Promptly monitoring and intervention in specific organ systems depending on the type of IDH inhibitor may improve the overall survival or enhance the quality of life. In the future, it will be necessary to validate our findings in prospective large-scale studies and to investigate the underlying mechanisms.

Analysis of ADR reports of cetuximab based on the FDA adverse event reporting system database

This study aims to monitor and identify adverse events (AEs) associated with cetuximab, a drug used to treat various late-stage (metastatic) tumors, to improve patient safety and guide drug use. This study retrospectively analyzed the cases reported in the FDA adverse event reporting system (FAERS) related to the application of cetuximab from 2013 Q1 to 2022 Q4. Disproportionality analyses, including the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN), and the empirical Bayesian geometric mean (EBGM) algorithms, were employed to quantify the signals of cetuximab-associated AEs. A total of 8364225 reports were contained in the FAERS database, of which 5186 reports of cetuximab were identified as ‘primary suspected (PS)’ AEs. The application of cetuximab resulted in AEs in 22 system organ classes (SOCs), which preserved 176 significant disproportionality preferred terms (PTs) through the computation of four algorithms. The main SOCs (Skin and subcutaneous tissue disorders, investigations, metabolism and nutrition disorders, and blood and lymphatic system disorders) accounted for 58.63%. Some AEs were not on the drug label: speech disorder, intervertebral discitis, glomerulonephritis rapidly progressive and disseminated intravascular coagulation. This study identified new signals of adverse drug reactions (ADRs) other than those mentioned in the specification associated with cetuximab, providing valuable insights into the relationship between ADRs and cetuximab use. The findings highlight the importance of continuous surveillance to detect and manage AEs effectively, ultimately improving patient safety during treatment with cetuximab.

A 13-years pharmacovigilance analysis of novel hormonal agents in prostate cancer using the FDA adverse event reporting system database

ABSTRACT Background Novel hormonal agents (NHAs), such as abiraterone, apalutamide, enzalutamide, and darolutamide, play a pivotal role in prostate cancer treatment. However, the toxicity spectrum of NHAs in the real-world has not been fully investigated. This study aims to analyze the adverse events (AEs) linked to NHAs. Methods The safety profiles of NHAs were evaluated by using the United States FDA Adverse Event Reporting System (FAERS) database. Disproportionality analysis methods were applied to compare the safety signals of AEs associated with NHAs. Results Our research has identified significant safety signals for all NHAs in vascular disorders, particularly noting elevated risk in the combined treatment involving docetaxel or poly ADP-ribose polymerase (PARP) inhibitors, specifically in blood and lymphatic system. Apalutamide, enzalutamide, and darolutamide displayed notable safety signals related to nervous system disorders, whereas abiraterone did not. Apalutamide exhibited specific AEs primarily linked to skin and subcutaneous tissue disorders, with severe AEs (SAEs) also concentrated in this category. Enzalutamide’s specific AEs were predominantly associated with gastrointestinal disorders. Meanwhile, abiraterone’s SAEs were mainly related to cardiac and hepatobiliary disorders. Conclusion Our study offers a comprehensive overview of safety signals associated with NHAs, providing a valuable reference for drug selection and future prospective research.

Higher Rates of Visualization for Axillary Reverse Mapping Using Indocyanine Green Fluorescence Compared With Blue Dye.

Successful axillary reverse mapping (ARM) during lymph node surgery for breast cancer has the potential to reduce risk of lymphedema. Standard of care uses blue dye for ARM; however, recent imaging advances with near-infrared indocyanine green (ICG) fluorescence has demonstrated potential to improve intraoperative ARM imaging. The objective was to determine the feasibility of using ICG fluorescence through the OnLume Avata System for ARM. Breast cancer patients undergoing axillary lymph node dissection and were to undergo ARM were enrolled. Lymphatic structures were visualized using ICG fluorescence and blue dye. Real-time fluorescence images were acquired with the OnLume Avata System preincision, intraoperatively, and post dissection during the ARM. Preincision images were quantitatively analyzed for lymphatic fluorescence signal in terms of contrast-to-noise ratio. Imaging data were evaluated in terms of binary visualization rates and signal-to-background ratio. Lymph nodes, lymphatic vessels, and lymph pooling were observed with fluorescence more frequently than blue dye. For seven out of eight cases, at least one vessel was visualized near the axilla preincision. In all eight cases, ICG fluorescence was noted during the procedure with five cases visualizing intact lymphatics at the end of the procedure. The ambient-light compatibility of the imager allowed the surgeon to operate with image guidance throughout the ARM procedure. The Avata demonstrated superior identification and visualization with ICG when compared to blue dye for visualizing lymphatic structures in real time with minimal disruption to the clinical workflow.

The Role of Lymphatic System Transfer (LYST) for Treatment of Lymphedema: A Long-Term Outcome Study of SCIP Flap Incorporating the Lymph Nodes and the Afferent Lymphatic Vessels

Vascularized lymph node transfer (VLNT) is traditionally performed in patients with advanced-stage lymphedema. To enhance and promote the physiological effects of VLNT, lymphatic system transfer (LYST) was developed. In this technique, lymph nodes and a portion of their corresponding afferent lymphatic vessels are transferred to stimulate lymphangiogenesis. This study presented our experience, pearls, and pitfalls of using superficial circumflex iliac artery perforator LYST. A retrospective review of patients treated with LYST for lymphedema treatment from July 2018 to March 2022 was included. Patient characteristics, perioperative data, and long-term outcomes were analyzed. Eight patients with unilateral lower-extremity lymphedema underwent LYST. The mean follow-up duration was 39.0 (24.0-60.0) months. The mean improvement in the excess volume percentage compared to the unaffected limb was 11.2% (100% improvement to 0% worsening) at the last follow-up, with statistical significance (p < 0.001). The incidence of cellulitis decreased with statistical significance (p = 0.025). A long-term study on using LYST flaps in lymphedema treatment has not been previously performed. This study showed that the LYST procedure provides reliable and effective long-term outcomes in treating patients with advanced-stage lymphedema.

New perspectives on the glymphatic system and the relationship between glymphatic system and neurodegenerative diseases.

Neurodegenerative diseases (ND) are characterized by the accumulation of aggregated proteins. The glymphatic system, through its rapid exchange mechanisms between cerebrospinal fluid (CSF) and interstitial fluid (ISF), facilitates the movement of metabolic substances within the brain, serving functions akin to those of the peripheral lymphatic system. This emerging waste clearance mechanism offers a novel perspective on the removal of pathological substances in ND. This article elucidates recent discoveries regarding the glymphatic system and updates relevant concepts within its model. It discusses the potential roles of the glymphatic system in ND, including Alzheimer's disease (AD), Parkinson's disease (PD), and multiple system atrophy (MSA), and proposes the glymphatic system as a novel therapeutic target for these conditions.

A real-world pharmacovigilance analysis for Demethylation drug: findings from the FDA adverse event reporting database.

The real-world safety profiles of the demethylating agents Azacitidine and Decitabine remain inadequately characterized despite their widespread clinical use. Both drugs are extensively employed for the treatment of hematologic malignancies such as myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). This study aims to evaluate their adverse event (AE) profiles by leveraging data from the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database. All adverse drug event (ADE) data related to Azacitidine and Decitabine were collected from the FAERS database from its inception through the second quarter of 2024 (Q2). After standardizing the data, four disproportionality methods were applied to evaluate the association between Azacitidine, Decitabine, and ADEs. The Weibull shape parameter (WSP) was used to analyze the time-to-onset curves. Among the 15,538 ADEs where Azacitidine was the primary suspect drug, a total of 439 preferred terms (PTs) and two system organ classes (SOCs) showed significant disproportionality across all four algorithms. These SOCs included INFECTIONS AND INFESTATIONS (n=7328, ROR 3.78) and BLOOD AND LYMPHATIC SYSTEM DISORDERS (n=5613, ROR 8.92). Compared with the Azacitidine label, 52 previously unreported ADEs were identified at the PT level. Among the 3,064 ADEs where Decitabine was the primary suspect drug, a total of 200 PTs and two SOCs exhibited significant disproportionality across all four algorithms. These SOCs included BLOOD AND LYMPHATIC SYSTEM DISORDERS (n=1284, ROR 6.53) and SURGICAL AND MEDICAL PROCEDURES (n=571, ROR 3.41). Compared with the Decitabine label, 29 previously unreported ADEs were identified at the PT level. Furthermore, the Bayesian Confidence Propagation Neural Network (BCPNN) algorithm revealed that the highest IC025 values for both Azacitidine and Decitabine were concentrated in SOCs related to benign, malignant, and unspecified tumors. In summary, using the FAERS database, we compared the real-world safety profiles of two demethylating agents, Azacitidine and Decitabine. The results indicate that adverse drug reactions (ADRs) related to these two agents are concentrated in the hematologic, respiratory, circulatory, and digestive systems, as well as in neoplasms of unspecified nature, warranting close clinical attention.

From blood vessels to brain cells: Connecting the circulatory system and Parkinson's disease

Parkinson's disease (PD) is traditionally recognized as a neurodegenerative disorder characterized by motor dysfunction and α-synuclein protein accumulation in the brain. However, recent research suggests that the circulatory system may also contribute to PD pathogenesis through the spread of α-synuclein beyond the brain. The blood-brain barrier (BBB), a key regulator of molecular exchange between the bloodstream and the brain, may become compromised in PD, allowing harmful substances, including pathogenic forms of α-synuclein, to infiltrate the brain and promote neurodegeneration. Transport mechanisms such as P-glycoprotein and the low-density lipoprotein (LDL) receptor-related protein (LRP-1) further modulate the movement of α-synuclein across the BBB, influencing disease progression. Additionally, extracellular vesicles are emerging as crucial mediators in the dissemination of α-synuclein between the brain and peripheral tissues, facilitating its spread and accumulation. The lymphatic system, responsible for clearing α-synuclein, may also contribute to PD pathology when impaired. This review highlights the growing evidence for a circulatory axis in the initiation and progression of PD. We propose that future research should explore the hypothesis that the circulatory system contributes to the pathogenesis of PD by aiding the distribution of α-synuclein throughout the body.

Tuberculosis and Cardiovascular Complications

Tuberculosis is one of the major life-taking diseases all over the world, with most of the victims from low- and middle-income countries. The etiology of this disease is primarily a bacterium called Mycobacterium tuberculosis (MTB). Although it normally affects the lungs, dissemination can occur in the lymphatic system, the central nervous system (CNS), the gastrointestinal system, and the cardiovascular system. Though the leading cause of death globally, cardiovascular diseases tend to be especially lethal as TB-related heart complications in these regions; hence, understanding and management of cardiovascular issues in TB patients are even more critical. TB can cause various cardiovascular complications, ranging from the more common pericarditis (inflammation of the lining around the heart) to rarer conditions such as myocarditis (inflammation of the heart muscle), coronary artery disease, and aortitis (inflammation of the aorta). These complications have a potential for the significant deterioration of the prognosis of TB patients; however, being mostly underdiagnosed or missed, requires a high degree of clinical awareness. This discussion addresses the complex interaction of TB and cardiovascular health.

A single-cell atlas of normal and KRASG12D-malformed lymphatic vessels.

Somatic activating mutations in KRAS can cause complex lymphatic anomalies (CLAs). However, the specific processes that drive KRAS-mediated CLAs have yet to be fully elucidated. Here, we used single-cell RNA sequencing to construct an atlas of normal and KrasG12D-malformed lymphatic vessels. We identified six subtypes of lymphatic endothelial cells (LECs) in the lungs of adult wild-type mice (Ptx3, capillary, collecting, valve, mixed, and proliferating). To determine when the LEC subtypes were specified during development, we integrated our data with data from four stages of development. We found that proliferating and Ptx3 LECs were prevalent during early lymphatic development and that collecting and valve LECs emerged later in development. Additionally, we discovered that the proportion of Ptx3 LECs decreased as the lymphatic network matured but remained high in KrasG12D mice. We also observed that the proportion of collecting and valve LECs was lower in KrasG12D mice than in wild-type mice. Last, we found that immature lymphatic vessels in young mice were more sensitive to the pathologic effects of KrasG12D than mature lymphatic vessels in older mice. Together, our results expand the current model for the development of the lymphatic system and suggest that KRAS mutations impair the maturation of lymphatic vessels.

Lymphatic vessel network injury reduces local tumor control despite preservation of the tumor-draining lymph node

The lymphatic system plays complex, often contradictory, roles in many cancers, including melanoma; these roles include contributions to tumor cell metastasis and immunosuppression in the tumor microenvironment as well as generation of antitumor immunity. Advancing our understanding of lymphatic vessel involvement in regulating tumor growth and immune response may provide new therapeutic targets or treatment plans to enhance the efficacy of existing therapies. We utilized a syngeneic murine melanoma model in which we surgically disrupted the lymphatic vessel network draining from the tumor to the tumor-draining lymph node (TDLN) while leaving the TDLN intact. Although transport of lymphatic-specific molecular weight tracers to the TDLN remains present after surgery, disruption of the tumor-draining lymphatic vessels results in decreased local tumor control, as reflected in an increase in the rate of tumor growth and reduction in effector-like T cell infiltration into the tumor. Our findings suggest that preservation of the functional tumor-draining lymphatic network may be essential in promoting a robust antitumor immune response.

Important Anatomy in Lymphatic Interventions: A Practical Review

AbstractNew understanding of the lymphatic system as well as increasing recognition of its importance in various pathologies have increased the opportunity to perform lymphatic interventions. Advancement in our understanding of the lymphatic system anatomy, including variations, combined with improved imaging has renewed interest in both surgical and interventional management of a wide range of complex lymphatic pathologies. It is important for the proceduralist to recognize the anatomy, variability, and physiology of the lymphatic system, including lower extremity lymphatic drainage, cisterna chyli location, and thoracic duct drainage. The purpose of this study is to convey the practical aspects of performing lymphatic interventions in an effort to improve the speed and reliability of these procedures.

Predictors of the Efficacy of Lymphedema Decongestive Therapy

Lymphedema is a chronic condition characterized by the accumulation of lymphatic fluid in the tissues, causing swelling primarily in the limbs, though other body parts can also be affected. It commonly develops after lymph node removal, or radiation therapy, or due to congenital lymphatic system defects. Effective management is essential due to its significant impact on physical function and quality of life. Complete Decongestive Therapy (CDT) is the primary treatment for lymphedema. This comprehensive approach combines manual lymphatic drainage (MLD), compression bandaging, skincare, and exercise. An early diagnosis and initiation of CDT are critical to preventing irreversible damage to the lymphatic system and worsening symptoms. Successful outcomes depend on timely treatment, patient adherence, and the consistent use of all CDT components, with compression therapy and exercise playing particularly vital roles. Recent research highlights how skin and fat tissue characteristics, such as increased skin thickness and adipose tissue accumulation, complicate lymphedema management, especially in advanced stages. In these cases, where fibrosis and fat deposition are more prominent, traditional CDT may need to be supplemented with advanced treatments like liposuction or enhanced compression techniques. This study explores the factors influencing the success of decongestive therapy, including the stage of lymphedema at the diagnosis, treatment protocols, and individual patient characteristics like skin and fat tissue properties.

Complex lymphatic anomalies.

Complex lymphatic anomalies are unique diseases marked by abnormal lymphatic vessel development and growth. Imaging is crucial in the evaluation and management of complex lymphatic anomalies, with dynamic contrast-enhanced MR lymphangiography emerging as a valuable modality for visualizing abnormal lymphatic structures and informing treatment decisions. This article gives an overview of complex lymphatic anomalies and their management strategies, focusing specifically on generalized lymphatic anomaly, Gorham-Stout disease, Kaposiform lymphangiomatosis, and central conducting lymphatic anomalies. Simple lymphatic diseases are beyond the scope of this review.

Overview of historical occupational exposure to trichloroethylene in China.

Trichloroethylene (TCE) is a carcinogen that has been causally linked to kidney cancer and possibly other cancer sites including the liver and lymphatic system. Its use in China has increased since the early 1990s due to the growing metal and electronic industries. We aimed to summarize the major sources of occupational exposure to TCE over time in China. Occupational TCE exposure assessments were extracted from both the Chinese and English scientific literature, as well as from industrial hygiene surveys performed in Guangdong, Tianjin, and Hong Kong. Weighted mean concentrations were summarized by occupation and industry. We extracted over 12,412 measurements from 55 industries and 35 occupations across China since 1976, of which at least 201 were from case reports. More than half of the measurements were derived from 4 industries, including "manufacture of footwear" (29%), "manufacture of electronic components and boards" (17%), "manufacture of games and toys" (14%), and "manufacture of fabricated metal products, except machinery and equipment" (13%). Several occupations, including "electronic-equipment assemblers," "metal-, rubber-, and plastic-products assemblers," "metal finishing-, plating-, and coating-machine operators," "precision-instrument makers and repairers," "printing-machine operators," and "ore and metal furnace operators" were identified as having high risks of TCE exposure, with either pooled weighted mean task-based or full-shift concentrations over 150mg/m3 over the years. TCE exposure levels varied across different occupations and changed over time. In 1990 and earlier, 1991 to 2000, the exposure levels were at their highest with pooled weighted mean task-based concentrations of 202.8 and 242.9mg/m3, respectively. Subsequently, the level decreased to 118.7mg/m3 from 2001 to 2010 before increasing again to 216.0mg/m3 from 2011 onwards. This overall trend was also observed for "electronic-equipment assemblers" and "metal finishing-, plating-, and coating-machine operators." However, for "precision-instrument makers and repairers," the exposure levels consistently declined over the years. Over the past few decades, degreasing-related occupations, such as "electronic-equipment assemblers" and "metal finishing-, plating-, and coating-machine operators" have been consistently identified as being at high risk of significant TCE exposure and continued to warrant attention. Identifying high-risk industries and occupations can inform the development of targeted interventions and regulations to mitigate TCE exposure. Furthermore, enhancing the quality and coverage of exposure measurement data in occupational settings will advance epidemiological investigations in occupational health.

Association of Influenza Vaccination During Pregnancy with Health Outcomes in Mothers and Children: A Population-Based Cohort Study.

Immunization rates of maternal influenza vaccination during pregnancy remain suboptimal, with concerns about potential harm to the mothers and their offspring. We conducted a population-based cohort study, using mother-child linked database in Korea: (a) maternal cohort between December 2019, and March 2022; (b) neonatal cohort between September 2020, and June 2021. Exposure was defined as influenza vaccination during pregnancy. Study outcomes included gestational outcomes, vaccine-related adverse events, and other health outcomes in mothers and childbirth and immune-related health outcomes in children. After 1-to-1 propensity score matching using diverse potential confounders, effect estimates with 95% confidence intervals were estimated using the log-binomial model for cumulative outcomes and the Cox proportional model for time-to-event outcomes. After 1-to-1 propensity score matching, we identified 174,008 and 53,344 pairs for the maternal and neonatal cohorts, respectively. In the maternal cohort, influenza vaccination during pregnancy was not associated with preeclampsia, antenatal bleeding, and various adverse outcomes, including neurological, vascular, blood, and lymphatic system disorders, except for marginally elevated risks of gestational diabetes mellitus (effect estimate 1.06, 95% confidence interval 1.05 to 1.08) and postpartum hemorrhage (1.05, 1.01 to 1.08). In the neonatal cohort, maternal influenza vaccination did not increase risks of childbirth (e.g., preterm/low birth weight, congenital malformations, mortality) and immune-related outcomes, except for a slightly increased risk of lower respiratory tract infection (1.06, 1.007 to 1.12). In this population-based cohort study, influenza vaccination during pregnancy was not associated with an increased risk of a range of adverse outcomes in mothers and their offspring.

Cardiac Lymph Flow Features and New Opportunities for Their Experimental Visualization.

The aim of this study was to describe the features of myocardial lymph flow using a new combined method of visualization of the lymphatic system. The study was performed on pig hearts harvested from a local slaughterhouse. The original dye, consisting of lipid-soluble chlorophyll and lipiodol, was injected stepwise into the lymphatic vessels. After sufficient optical identification of the lymphatic vessels, continuous injection of air into the coronary arteries was performed and CT scans were done. In this way, both optical and radiologic visibility of the cardiac lymphatic system was achieved. It was shown that lymph flow of the left and most part of the right ventricle is carried out through lymphatic collectors of the anterior wall of the heart, including retrogradely with respect to the right coronary artery, which complements the previously known facts about the structure of the lymphatic system of the heart.

Synergistic effects of mTOR inhibitors with VEGFR3 inhibitors on the interaction between TSC2-mutated cells and lymphatic endothelial cells.

Lymphangioleiomyomatosis (LAM) is a rare neoplastic disease affecting the lung, kidney, and lymphatic system with a molecular mechanism of tuberous sclerosis complex 2 (TSC2) mutations. Vascular endothelial growth factor D (VEGF-D), a ligand for vascular endothelial growth factor receptor 3 (VEGFR3), is a diagnostic biomarker of LAM and is associated with lymphatic circulation abnormalities. This study explored the interaction between LAM cells and lymphatic endothelial cells (LECs) and the effects of rapamycin on this interaction, which may help to identify new targets for LAM treatment. This study used direct and indirect cocultures of TSC2-null cells and LECs. The xenograft model was applied to explore the therapeutic feasibility. Single-cell sequencing revealed increased LECs in the lungs of LAM patients through activation of pathways involved in lymphangiogenesis. TSC2-null cells attracted LECs and promoted tube formation. VEGF-D/VEGFR3 was a key mediator of the above interaction. Rapamycin can directly inhibit recruitment but not the tube formation of LECs in vitro. The combination of rapamycin with VEGFR3 inhibitors not only enhanced the effect of rapamycin but also inhibited lymphatic related manifestations including the tube formation and the lymphatic metastasis. Our findings demonstrated that LAM cells recruit LECs and promote tube formation via VEGF-D/VEGFR3. Rapamycin only partially blocked this interaction. The synergistic effects of rapamycin and VEGFR3 inhibitors suggest a novel strategy for the treatment of LAM and other TSC2-mutated diseases.

Understanding the Lymphatic System: Tissue-on-Chip Modeling.

The lymphatic vasculature plays critical roles in maintaining fluid homeostasis, transporting lipid, and facilitating immune surveillance. A growing body of work has identified lymphatic dysfunction as contributing to the severity of myriad diseases and to systemic inflammation, as well as modulating drug responses. Here, we review efforts to reconstruct lymphatic vessels in vitro toward establishing humanized, functional models to advance understanding of lymphatic biology and pathophysiology. We first review lymphatic endothelial cell biology and the biophysical lymphatic microenvironment, with a focus on features that are unique to the lymphatics and that have been used as design parameters for lymphatic-on-chip devices. We then discuss the state of the art for recapitulating lymphatic function in vitro, and we acknowledge limitations and challenges to current approaches. Finally, we discuss opportunities and the need for further development of microphysiological lymphatic systems to bridge the gap in model systems between lymphatic cell culture and animal physiology.

Evaluation of the safety profile of amivantamab based on real-world evidence: a call to vigilance

ABSTRACT Background Amivantamab has been approved for EGFR exon 20 insertion-mutated non-small-cell lung cancer. The aim of this study was to perform an in-depth analysis of its safety profile. Research design and methods Safety reports were collected from the database of the Food and Drug Administration Adverse Event Reporting System from April 2021 to September 2023, and the reporting odds ratio (ROR) method was used to detect potential safety signals. Mobocertinib, an agent with similar properties to amivantamab, served as a control for comparison. Results A total of 88 safety signals were detected, most of which were novel. In comparison with mobocertinib, amivantamab appeared to cause more injury, poisoning, and procedural complications (ROR = 15.54, 95% CI 10.25–23.58); respiratory, thoracic, and mediastinal disorders (ROR = 1.92, 95% CI 1.57–2.34); infections and infestations (ROR = 1.39, 95% CI 1.09–1.76); blood and lymphatic system disorders (ROR = 9.57, 95% CI 6.17–14.84); and immune system disorders (ROR = 6.41, 95% CI 3.14–13.12). Moreover, amivantamab was associated with higher risks of thrombosis events, bone marrow suppression, skin and soft tissue infection, deterioration of respiratory symptoms, and noninfectious pneumonitis. Conclusion The safety profile of amivantamab requires attention; particularly, monitoring of the adverse drug events described above is necessary during its administration.