Search Results (57)

We report a rare case of pulmonary tumor thrombotic microangiopathy (PTTM) in a patient with metastatic neurotrophic tropomyosin receptor kinase (NTRK) fusion-positive transverse colon cancer who exhibited a marked radiologic and biochemical response to entrectinib. Despite significant tumor shrinkage, progressive dyspnea and hypoxemia developed approximately four weeks after therapy initiation. Chest CT revealed diffuse interstitial infiltrates, initially interpreted as drug-induced pneumonitis or infection. Entrectinib was discontinued, but respiratory failure progressed, and the patient died shortly thereafter. Autopsy revealed widespread pulmonary microangiopathy with fibrocellular intimal proliferation and tumor emboli in small pulmonary arteries, consistent with PTTM. Notably, no hematogenous metastases were identified; instead, tumor spread appeared to occur via an atypical lymphatic route through the thoracic duct. The tumor exhibited microsatellite stability and a modest mutation burden, suggesting that lymphatic dissemination and microvascular pathology may progress independently of these genomic features. This case underscores a critical dissociation between oncologic response and vascular complications, indicating that tropomyosin receptor kinase (TRK) inhibitor monotherapy may be insufficient to prevent PTTM. Comprehensive management may require concurrent strategies targeting the pulmonary microvasculature, including antiangiogenic therapy and modulation of cytokine and growth factor signaling. Full article

Introduction: Indocyanine green (ICG) dye is used in a myriad of medical and surgical applications and complications related to its use are exceedingly rare. ICG fluorescence can be detected in unique locations depending on route, dosage, and timing. Although ICG fluorescence is used more commonly in the adult population, its adoption in pediatric surgery has been increasing more frequently. This comprehensive review aims to elucidate the myriad of ICG surgical applications within the pediatric population and important clinical considerations for administration. Methods: PubMed was queried for pediatric surgical applications of indocyanine green. Surgical application, route of administration, dosage, ICG-related complications, and surgical impact of ICG fluorescence were analyzed. Results: In the pediatric population, ICG is used in a multitude of hepatobiliary, gastrointestinal, cardiothoracic, lymphatic, urologic, gynecologic, plastic, ENT, ophthalmologic, and neurosurgical procedures. Applications range from oncologic resections to benign and congenital reconstructions. Administration can be intravenous, intralesional, subcutaneous, inhaled, or enteric. Timing, dosage, and route of administration are dependent on the pathology of interest. Conclusions: ICG is a safe and useful adjunct for a wide variety of pediatric surgical applications. This comprehensive review aims to highlight administration considerations and the efficacy of ICG fluorescence in various surgical subspecialty pathologies. Future studies should continue to focus on how to integrate pathology-specific ICG fluorescence into intraoperative decision-making. Full article

Background and Clinical Significance: Breast cancer-related lymphedema (BCRL) is a chronic condition affecting up to 20% of breast cancer survivors. Manual lymphatic drainage (MLD) has traditionally included techniques to redirect lymph flow toward alternative pathways when axillary drainage is impaired. However, emerging imaging techniques suggest that most lymph continues to drain toward the ipsilateral axilla, and this has led to the widespread uptake of treatment protocols that exclude traditional redirecting movements, even in cases where personalized imaging is unavailable. Case Presentation: This case report describes a woman with BCRL affecting the right arm and hand who underwent 3 years of conservative lymphedema therapy, including MLD and self-massage techniques that incorporated traditional redirection strategies. Pre-operative indocyanine green (ICG) lymphography, performed after prolonged conservative treatment, confirmed the presence of an open alternative drainage pathway bypassing the axilla and demonstrated dermal flow along the redirected pathways towards a previously described “radial” pathway. These findings suggest that targeted manual therapy may have reinforced or optimized this compensatory route. Conclusions: This case highlights the potential risk of relying on a single form of assessment and generalized cohort imaging studies to guide individualized MLD protocols. In the absence of personal imaging, prematurely abandoning traditional redirection techniques may limit opportunities to establish functional alternative pathways, particularly in early edema in patients who have this anatomical variation. ICG lymphography provides valuable insight into compensatory lymphatic drainage. However, until imaging protocols are standardized and individual imaging is widely accessible, retaining traditional MLD techniques for newly diagnosed BCRL may be crucial for optimizing treatment outcomes. Future research should explore the long-term impact of manual therapy on alternative pathway development and function. Full article

The inner ear is a relatively isolated organ, protected by the blood-labyrinth barrier (BLB). This barrier creates a unique lymphatic fluid environment within the inner ear, maintaining a stable physiological state essential for the mechano-electrical transduction process in the inner ear hair cells while simultaneously restricting most drugs from entering the lymphatic fluid. Under pathological conditions, dysfunction of the stria vascularis and disruption in barrier structure can lead to temporary or permanent hearing impairment. This review describes the structure and function of the BLB, along with recent advancements in modeling and protective studies related to the BLB. The review emphasizes some newly developed non-invasive inner ear drug delivery strategies, including ultrasound therapy assisted by microbubbles, inner ear-targeting peptides, sound therapy, and the route of administration of the cerebrospinal fluid conduit. We argue that some intrinsic properties of the BLB can be strategically utilized for effective inner ear drug delivery. Full article

Tumor-associated macrophages (TAMs) are known to induce epithelial–mesenchymal transition (EMT) and angiogenesis in areas with a high density of accumulation in the submucosal (SM) layer. However, lymphatic vessels, which are important routes for lymph node metastasis, have rarely been analyzed, and their relationship to TAM accumulation is unknown. In this study, paraffin-embedded sections from 11 cases of human early-stage colorectal cancer (SM invasive carcinoma) were stained with CD34 antibody for vascular endothelium and podoplanin antibody for lymphatic endothelium at the deepest, central, and marginal sites of tumor invasion. Tumor blood vessels increased in the deepest invasive areas, and a positive correlation was observed between the number of TAMs and tumor blood vessels. Interestingly, lymphatic vessels with CD34-positive endothelial cells (CD34-positive lymphatic vessels) were observed within the tumor. The number of CD34-positive lymphatic vessels was significantly higher in the metastasis-positive group. These results suggest that abnormalities in the vascular and lymphatic systems are observed from the early stage of colorectal cancer development and that VEGF-A derived from TAMs is important for tumor angiogenesis. In addition, CD34-positive lymphatic vessels observed in the deepest areas of tumor invasion have not been reported in Japan, with initial reports indicating that they are neoplastic lymphatic vessels. Full article

Background: The parenteral administration of antivenoms is the mainstay in snakebite envenoming therapy. The standardized protocol does not exist, but it is agreed that the intravenous (i.v.) route is more effective than the others, especially the intramuscular (i.m.) route, based on the monitoring of venom/antivenom pharmacokinetics in the systemic circulation. Recent evidence suggests that the lymphatic system may be crucial in abolishing venom action. Methods: A preclinical study was performed to determine the optimal administration route with emphasis on venom/antivenom interplay in both the blood and lymph of experimentally envenomed sheep. Timed level measurements were used to compare the antivenom effect on the decrement of venom quantities in both relevant body compartments. Hematological and coagulation parameters, as well as proportions of developed anti-antivenom IgGs, were evaluated. Results: The i.m. antivenom resulted in faster and greater lymphatic absorption and complete neutralization of the venom, whereas the i.v. antivenom only slowed its absorption. The total amount of venom reaching the lymph (AUC_0-t) was two times lower after i.m. administration. In the systemic circulation, i.m. antivenom had a lower peak concentration (c_max) and a longer time to reach it (t_max). However, the total venom exposure was three times lower than with i.v. antivenom. Irrespective of the treatment approach, both groups showed improvement in blood disorders with no significant difference in humoral response against equine F(ab’)₂ fragments. Conclusions: I.m. administration proved to be a viable option for the snakebite management. Full article

A primary purpose of sleep for humans is to remove toxins and metabolic wastes from the brain (e.g., Aβ, tau, lactate) that would otherwise build up and compromise brain functionality. There are currently no drugs or devices that have been clinically shown in humans to enhance brain toxin removal, either during sleep or wakefulness. This perspective article focuses on a recently (re)discovered major route of toxin drainage from the human brain through meningeal lymphatic vessels (mLVs) and the primary enhancer of their flow—the cytokine Vascular Endothelial Growth Factor (VEGF). The purpose of this perspective article is to present pre-clinical and clinical evidence relevant to a new bioengineered technology (Transcranial Radiofrequency Treatment; TRFT) that appears to enhance mLV flow to increase brain toxin cleansing in humans during wakefulness. In being both safe and non-invasive, TRFT is administered in-home, presently through a device called “MemorEM”. Two months of daily TRFT during wakefulness increased the typically low plasma/brain levels of VEGF in Alzheimer’s Disease (AD) subjects, which was associated with increased Aβ and tau toxin removal from their brains during wakefulness—ostensibly through VEGF-increased mLV flow. Even irrespective of baseline VEGF levels, brain toxin cleansing was increased by TRFT in AD subjects, who also experienced a notable reversal of their cognitive impairment after TRFT. Additional clinical studies are nonetheless required to firmly establish TRFT’s brain cleansing abilities during wakefulness. In performing a major duty of sleep, TRFT during wakefulness is proposed as a viable intervention to counter the decline in nighttime brain toxin cleansing that occurs with aging and in multiple brain diseases, most notably Alzheimer’s Disease. The implications of TRFT for insomnia and for sleep deprivation are also discussed, as is the potential for TRFT to extend healthy human longevity. Full article

Tumor growth and progression require molecular interactions between malignant and host cells. In recent years, extracellular vesicles (EVs) emerged as an important pillar of such interactions, carrying molecular information from their donor cells to distant recipient cells. Thereby, the phenotype and function of the recipient cells are altered, which may facilitate tumor immune escape and tumor metastasis to other organs through the formation of pre-metastatic niches. A prerequisite for these effects of tumor cell-derived EVs is an efficient transport system from the site of origin to the body periphery. Here, we highlight the role of the lymphatic vascular system in the distribution and progression-promoting functions of tumor cell-derived EVs. Importantly, the lymphatic vascular system is the primary drainage system for interstitial fluid and its soluble, particulate, and cellular contents, and therefore represents the principal route for regional (i.e., to tumor-draining lymph nodes) and systemic distribution of EVs derived from solid tumors. Furthermore, recent studies highlighted the tumor-draining lymph node as a crucial site where tumor-derived EVs exert their effects. A deeper mechanistic understanding of how EVs gain access to the lymphatic vasculature, how they interact with their recipient cells in tumor-draining lymph nodes and beyond, and how they induce phenotypic and functional maladaptation will be instrumental to identify new molecular targets and conceive innovative approaches for cancer therapy. Full article

High levels of vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF)-2 and angiopoietin (ANG)-2 are found in tissues from oral squamous cell carcinoma (OSCC) and oral potentially malignant disorders (OPMDs). As might be expected, VEGF, FGF-2, and ANG-2 overexpression parallels the development of new blood and lymphatic vessels that nourish the growing OPMDs or OSCCs and provide the latter with metastatic routes. Notably, VEGF, FGF-2, and ANG-2 are also linked to the epithelial-to-mesenchymal transition (EMT), a trans-differentiation process that respectively promotes or exasperates the invasiveness of normal and neoplastic oral epithelial cells. Here, we have summarized published work regarding the impact that the interplay among VEGF, FGF-2, ANG-2, vessel generation, and EMT has on oral carcinogenesis. Results from the reviewed studies indicate that VEGF, FGF-2, and ANG-2 spark either protein kinase B (AKT) or mitogen-activated protein kinases (MAPK), two signaling pathways that can promote both EMT and new vessels’ formation in OPMDs and OSCCs. Since EMT and vessel generation are key to the onset and progression of OSCC, as well as to its radio- and chemo-resistance, these data encourage including AKT or MAPK inhibitors and/or antiangiogenic drugs in the treatment of this malignancy. Full article

Plastic bronchitis (PB) constitutes a life-threatening pulmonary disorder, predominantly attributed to Mycoplasma pneumoniae (MP) infection. The pathogenic mechanisms involved remain largely unexplored, leading to the absence of reliable approaches for early diagnosis and clear treatment. Thus, the present investigation aimed to develop an MP-induced mouse model of PB, thereby enhancing our understanding of this complex condition. In the first stage, healthy BALB/c mice were utilized to investigate the optimal methods for establishing PB. This involved the application of nebulization (15–20 min) and intratracheal administration (6–50 μL) with 2-chloroethyl ethyl sulfide (CEES) concentrations ranging from 4.5% to 7.5%. Subsequently, the MP model was induced by administering an MP solution (2 mL/kg/day, 10⁸ CFU/50 μL) via the intranasal route for a duration of five consecutive days. Ultimately, suitable techniques were employed to induce plastic bronchitis in the MP model. Pathological changes in lung tissue were analyzed, and immunohistochemistry was employed to ascertain the expression levels of vascular endothelial growth factor receptor 3 (VEGFR-3) and the PI3K/AKT/mTOR signaling pathway. The administration of 4.5% CEES via a 6 µL trachea was the optimal approach to establishing a PB model. This method primarily induced neutrophilic inflammation and fibrinous exudate. The MP-infected group manifested symptoms indicative of respiratory infection, including erect hair, oral and nasal secretions, and a decrease in body weight. Furthermore, the pathological score of the MP+CEES group surpassed that of the groups treated with MP or CEES independently. Notably, the MP+CEES group demonstrated significant activation of the VEGFR-3 and PI3K/AKT/mTOR signaling pathways, implying a substantial involvement of lymphatic vessel impairment in this pathology. This study successfully established a mouse model of PB induced by MP using a two-step method. Lymphatic vessel impairment is a pivotal element in the pathogenetic mechanisms underlying this disease entity. This accomplishment will aid in further research into treatment methods for patients with PB caused by MP. Full article

One of the characteristic features of ovarian cancer is its early dissemination. Metastasis and the invasiveness of ovarian cancer are strongly dependent on the phenotypical and molecular determinants of cancer cells. Invasive cancer cells, circulating tumor cells, and cancer stem cells, which are responsible for the metastatic process, may all undergo different modes of transition, giving rise to mesenchymal, amoeboid, and redifferentiated epithelial cells. Such variability is the result of the changing needs of cancer cells, which strive to survive and colonize new organs. This would not be possible if not for the variety of migration modes adopted by the transformed cells. The most common type of metastasis in ovarian cancer is dissemination through the transcoelomic route, but transitions in ovarian cancer cells contribute greatly to hematogenous and lymphatic dissemination. This review aims to outline the transition modes of ovarian cancer cells and discuss the migratory capabilities of those cells in light of the known ovarian cancer metastasis routes. Full article

Tumor diseases become a huge problem when they embark on a path that advances to malignancy, such as the process of metastasis. Cancer metastasis has been thoroughly investigated from a biological perspective in the past, whereas it has still been less explored from a physical perspective. Until now, the intraluminal pathway of cancer metastasis has received the most attention, while the interaction of cancer cells with macrophages has received little attention. Apart from the biochemical characteristics, tumor treatments also rely on the tumor microenvironment, which is recognized to be immunosuppressive and, as has recently been found, mechanically stimulates cancer cells and thus alters their functions. The review article highlights the interaction of cancer cells with other cells in the vascular metastatic route and discusses the impact of this intercellular interplay on the mechanical characteristics and subsequently on the functionality of cancer cells. For instance, macrophages can guide cancer cells on their intravascular route of cancer metastasis, whereby they can help to circumvent the adverse conditions within blood or lymphatic vessels. Macrophages induce microchannel tunneling that can possibly avoid mechanical forces during extra- and intravasation and reduce the forces within the vascular lumen due to vascular flow. The review article highlights the vascular route of cancer metastasis and discusses the key players in this traditional route. Moreover, the effects of flows during the process of metastasis are presented, and the effects of the microenvironment, such as mechanical influences, are characterized. Finally, the increased knowledge of cancer metastasis opens up new perspectives for cancer treatment. Full article

The lymphatic vascular system plays a key role in cancer progression. Indeed, the activation of lymphatic endothelial cells (LECs) through the lymphangiogenic process allows for the formation of new lymphatic vessels (LVs) that represent the major route for the dissemination of solid tumors. This process is governed by a plethora of cancer-derived and microevironmental mediators that strictly activate and control specific molecular pathways in LECs. In this work we used an in vitro model of LEC activation to trigger lymphangiogenesis using a mix of recombinant pro-lymphangiogenic factors (VFS) and a co-culture system with human melanoma cells. Both systems efficiently activated LECs, and under these experimental conditions, RNA sequencing was exploited to unveil the transcriptional profile of activated LECs. Our data demonstrate that both recombinant and tumor cell-mediated activation trigger significant molecular pathways associated with endothelial activation, morphogenesis, and cytokine-mediated signaling. In addition, this system provides information on new genes to be further investigated in the lymphangiogenesis process and open the possibility for further exploitation in other tumor contexts where lymphatic dissemination plays a relevant role. Full article

The lymphatic system plays a crucial role in the absorption of lipophilic drugs, making it an important route for drug delivery. In this study, an in vitro model using Intralipid^® was developed to investigate the lymphatic uptake of drugs. The model was validated using cannabidiol, halofantrine, quercetin, and rifampicin. Remarkably, the uptake of these drugs closely mirrored what would transpire in vivo. Furthermore, adding peanut oil to the model system significantly increased the lymphatic uptake of rifampicin, consistent with meals containing fat stimulating lymphatic drug uptake. Conversely, the inclusion of pluronic L-81 was observed to inhibit the lymphatic uptake of rifampicin in the model. This in vitro model emerges as a valuable tool for investigating and predicting drug uptake via the lymphatic system. It marks the first phase in developing a physiologically based predictive tool that can be refined further to enhance the precision of drug interaction predictions with chylomicrons and their subsequent transport via the lymphatic system. Moreover, it can be employed to explore innovative drug formulations and excipients that either enhance or hinder lymphatic drug uptake. The insights gained from this study have significant implications for advancing drug delivery through the lymphatic system. Full article

Inoculation routes may significantly affect vaccine performance due to the local microenvironment, antigen localization and presentation, and, therefore, final immune responses. In this study, we conducted a head-to-head comparison of immune response and safety of inactivated rabies vaccine inoculated via intraperitoneal (IP), intramuscular (IM), subcutaneous (SC) and needle-free injection technology-based intradermal (ID) routes in ICR mice. Immune response was assessed in terms of antigen-specific antibodies, antibody subtypes and neutralizing antibodies for up to 28 weeks. A live rabies virus challenge was also carried out to evaluate vaccine potency. The dynamics of inflammatory cell infiltration at the skin and muscle levels were determined via histopathological examination. The kinetics and distribution of a model antigen were also determined by using in vivo fluorescence imaging. Evidence is presented that the vaccine inoculated via the ID route resulted in the highest antigen-specific antibody and neutralizing antibody titers among all administration routes, while IP and IM routes were comparable, followed by the SC route. Antibody subtype analysis shows that the IP route elicited a Th1-biased immune response, while SC and IM administration elicited a prominent Th2-type immune response. Unexpectedly, the ID route leads to a balanced Th1 and Th2 immune response. In addition, the ID route conferred effective protection against lethal challenge with 40 LD50 of the rabies CVS strain, which was followed by IP and IM routes. Moreover, a one-third dose of the vaccine inoculated via the ID route provided comparable or higher efficacy to a full dose of the vaccine via the other three routes. The superior performance of ID inoculation over other routes is related to longer local retention at injection sites and higher lymphatic drainage. Histopathology examination reveals a transient inflammatory cell infiltration at ID and IM injection sites which peaked at 48 h and 24 h, respectively, after immunization, with all side effects disappearing within one week. These results suggest that needle-free injection technology-based ID inoculation is a promising strategy for rabies vaccination in regard to safety and efficacy. Full article