Lymphatics最新文献

The World Health Organization (WHO) and International Consensus Classification (ICC) systems have classified EBV-positive NK/T-cell neoplasms in adults and EBV-positive T/NK-cell lymphoid lymphoproliferative disorders (LPD) in children. Recent molecular profiling techniques have revealed the pathogenesis of these disorders, showing interactions among EBV-encoded proteins, host immune responses, and genetic alterations. Extranodal NK/T-cell lymphoma (ENKTL) shows molecular diversity, with various subtypes (TSIM, MB, and HEA) identified through a multiomics approach. Aggressive NK-cell leukemia (ANKL) has mutations in JAK/STAT, epigenetic regulators, and TP53 pathways. EBV-positive nodal T- and NK-cell lymphoma (ENTNKL) is a new entity, distinguished by primary nodal presentation and a unique molecular profile. Severe mosquito bite allergy (SMBA), hydroa vacciniforme lymphoproliferative disorder (HVLPD), and systemic chronic active EBV disease (CAEBV) are rare childhood EBV-driven LPDs defined by clinico-pathologic criteria, with largely unexplored genomic landscapes. Studies of CAEBV samples have found ENKTL-like driver mutations, including DDX3X and KMT2D, in EBV-infected NK/T cells, while KMT2D and chromatin modifier mutations were common in HVLPD. Comprehensive molecular sequencing of SMBA and Systemic EBV-positive T-cell lymphoma of childhood remains lacking. These findings suggest all EBV+ NK/T-cell LPDs exist on a biological continuum of viral oncogenesis. The integration of clinical, pathological, and molecular information aims to create a more accurate classification system, enabling better risk evaluation and tailored treatment strategies for patients with these complex disorders.

Breast cancer-related lymphedema (BCRL) is the most common cause of secondary lymphedema in the Western world and occurs in up to one-third of breast cancer survivors following axillary lymph node dissection (ALND). Compression of the affected limb is a mainstay of therapy. Surgical management of BCRL involves excision of excess fibroadipose tissue and physiologic procedures to improve fluid retention in the limb. Once lymphedema is established, the inflammatory cascade and fibrosis render the disease hard to reverse. The purpose of this review is to elucidate existing management strategies for prevention of breast cancer-related lymphedema. A literature search was conducted using PubMed, Ovid, Embase, and Scopus. Articles that included management strategies for prevention of BCRL were selected for review. Immediate lymphatic reconstruction (ILR) is a microsurgical technique that connects disrupted axillary lymphatic vessels to nearby veins by lymphovenous anastomoses at the time of ALND and has been shown to reduce rates of lymphedema from 30% to 4-12%. BCRL remains incurable. Immediate lymphatic reconstruction has emerged as a preventative strategy to reduce rates of lymphedema in breast cancer patients.

Lymphoid neoplasms (LN), a diverse group of malignancies arising from lymphocytes, exhibit a striking increase in incidence with chronological age, suggesting a deep connection with the aging process. While chronological age remains a primary risk factor, the concept of biological age, reflecting an individual's physiological state and susceptibility to age-related diseases, offers a more nuanced understanding of this relationship. Aging clocks, particularly epigenetic clocks based on DNA methylation, provide quantitative measures of biological age and have revealed associations between accelerated aging and increased cancer risk, including LN. Immunosenescence, the age-related decline in immune function characterized by thymic involution, altered lymphocyte populations, and chronic inflammation (inflammaging), appears to be a key mechanistic link between aging and LN development, potentially providing a more accurate predictor of cancer risk than mutation accumulation alone. Accelerated biological aging, measured by various clocks, correlates with LN risk and progression (e.g., in chronic lymphocytic leukemia), and may influence treatment tolerance and outcomes, particularly in older adults who are often burdened by frailty and comorbidities like sarcopenia. Integrating biological age assessments into clinical practice holds promise for refining diagnosis, prognosis, and personalizing treatment strategies (including guiding intensity and considering anti-aging interventions), and improving outcomes for patients with LN. This review synthesizes the current understanding of the intricate relationship between LN, immunosenescence, biological age, and aging clocks, highlighting clinical implications and key future research directions aimed at translating these insights into better patient care.

Inflammatory breast cancer (IBC) is characterized by numerous tumor emboli within lymphatics. In a recent study, we observed tumor embolic budding both in vitro and in vivo within lymphovascular spaces and proposed this to account for the plethora of tumor emboli seen in IBC. These observations did not address, however, how lymphovascular invasion is initiated or the mechanisms involved. In the present study, using the well-characterized patient-derived xenograft (PDX), Mary-X, which exhibited florid lymphovascular invasion (LVI) in athymic mice (LVI) as defined by E-cadherin-positive tumor emboli within lymphatic channels distinguished by podoplanin and LYVE1 membrane and Prox1 nuclear immunoreactivities and spontaneous spheroidgenesis in vitro and human cases of IBC which showed similar LVI, we compared laser-captured microdissected emboli from Mary-X and from the cases of human IBC to non-embolic areas. Mary-X and IBC emboli expressed high levels of E-cadherin and no evidence of epithelial-mesenchymal transition (EMT). Mary-X spheroids expressed high levels of VEGF, especially VEGF-C, and stimulated both vascular and lymphatic endothelial haptotaxis. We then transplanted Mary-X serially into green, cyano, red, and nestin-green fluorescing protein (GFP-, CFP-, RFP-, and nestin-GFP) transgenic reporter mice in various combinations. Multicolor murine imaging studies indicated that reporter-labeled stroma initially encircled clumps of tumor cells and then served as a scaffold that supported nestin-GFP-labeled endothelial haptotaxis resulting in encircling lymphangiogenesis, confirmed by dual LYVE1 immunofluorescence. The present studies demonstrate a possible mechanism of a critical step of the tumor emboli formation of IBC.

Despite chronic fibrosis occurring in many pathological conditions, few in vitro studies examine how fibrosis impacts lymphatic endothelial cell (LEC) behavior. This study examined stiffening profiles of PhotoCol^®-commercially available methacrylated type I collagen-photo-crosslinked with the photoinitiators: Lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP), Irgacure 2959 (IRG), and Ruthenium/Sodium Persulfate (Ru/SPS) prior to evaluating PhotoCol^® permeability and LEC response to PhotoCol^® at stiffnesses representing normal and fibrotic tissues. Ru/SPS produced the highest stiffness (~6 kilopascal (kPa)) for photo-crosslinked PhotoCol^®, but stiffness did not change with burst light exposures (30 and 90 s). The collagen fibril area fraction increased, and dextran permeability (40 kilodalton (kDa)) decreased with photo-crosslinking, showing the impact of photo-crosslinking on microstructure and molecular transport. Human dermal LECs on softer, uncrosslinked PhotoCol^® (~0.5 kPa) appeared smaller with less prominent vascular endothelial (VE)-cadherin (cell-cell junction) expression compared to LECs on stiffer PhotoCol^® (~6 kPa), which had increased cell size, border irregularity, and VE-cadherin thickness (junction zippering) that is consistent with LEC morphology in fibrotic tissues. Our quantitative morphological analysis demonstrates our ability to produce LECs with a fibrotic phenotype, and the overall study shows that PhotoCol^® with Ru/SPS provides the necessary physical properties to systematically study LEC responses related to capillary growth and function under fibrotic conditions.

Radiotherapy and/or chemotherapy have been used for nearly 100 years to treat lymphoma. Recently, immunotherapy has been incorporated into the treatment of lymphomas. Here, we will review both the role of immunotherapy in lymphoma as well as the feasibility of incorporating immunotherapies with conventional lymphoma treatments, especially radiotherapy. Immunotherapy agents include checkpoint inhibitors that target the PD-1/PD-L1 axis, CTLA-4, or CD47. In addition, other immunotherapy agents such as bi-specific antibodies and CD19 CAR-T cell therapy are being implemented in various non-Hodgkin's lymphomas. Extrapolating from observations in other disease sites and incorporating immunotherapy with conventional treatments of lymphoma, including radiotherapy, may have opposing effects. Radiotherapy may stimulate anti-tumor immune responses that synergize with immunotherapies. In contrast, radiotherapy, as well as chemotherapy, may also induce local and systemic immune dysfunction which reduces the efficacy of immunotherapies. With newer radiation treatment techniques and limited radiation fields, it is likely that the efficacy of immunotherapy can be maintained when included with conventional treatments. Therefore, there remains an unmet need to better understand the role of immunotherapy alone and in combination with current treatments in lymphoma patients.