Search Results (173)

Breast cancer-related lymphedema (BCRL) is a debilitating complication in breast cancer survivors, with axillary lymph node dissection (ALND) as the greatest independent risk factor. Beyond non-surgical therapies such as complete decongestive and compression therapy, there has been increased interest in immediate microsurgical reconstruction via immediate lymphatic reconstruction (ILR) anastomosing transected lymphatic vessels to a local venous recipient at the time of ALND to mitigate the risks of BCRL. This work provides a scoping review of the landscape surrounding ILR, spanning the updated literature investigating patient outcomes, current accepted best practices, and critical components of surgical techniques for a successful multidisciplinary approach. While limited by heterogeneity in the methods of lymphedema detection, a growing body of work demonstrates the protective effects of ILR. From the pioneering work by Boccardo et al. in 2009 and his introduction of Lymphatic Microsurgical Preventive Healing Approach (LYMPHA) using an intussusception-type end-to-end microanastmosis, to the first randomized control trial by Coriddi in 2023, which importantly employed relative upper extremity volume change as an outcome measure to circumvent the confounding effects of body size and BMI, the current literature supports ILR following ALND in the prevention of BCRL. Collaboration between the oncologic breast surgeon and reconstructive microsurgeon are central to the success of ILR. Critical components for operative success include preoperative and intraoperative lymphatic mapping, preservation of suitable venous targets, availability of supermicrosurgical instruments and sutures, as well as aptitude with a variety of microsurgical anastomotic techniques. Full article

Background and Clinical Significance: Kaposi sarcoma (KS) is a rare angio-proliferative mesenchymal tumor that predominantly affects the skin and mucous membranes but may involve lymph nodes and visceral organs. Clinically, it manifests as red-purple-brown papules, nodules, or plaques, either painless or painful, often with disfiguring potential. The diagnosis is traditionally based on clinical and histopathological evaluation, although non-invasive imaging techniques are increasingly used to support diagnosis and treatment monitoring. We report a case of HHV-8-negative Kaposi sarcoma evaluated with multiple non-invasive imaging modalities to highlight their diagnostic utility. Case Presentation: An 83-year-old man presented with multiple painful, violaceous papulo-nodular lesions, some ulcerated, on the lateral aspect of his left foot. Dermoscopy revealed the characteristic rainbow pattern. Dynamic Optical Coherence Tomography (D-OCT) allowed real-time visualization of microvascular abnormalities, identifying large serpentine and branching vessels with clearly delineated capsules. Line-field Optical Coherence Tomography (LC-OCT) showed irregular dermal collagen, vascular lacunae, and the presence of spindle cells and slit-like vessels. Histological analysis confirmed the diagnosis of Kaposi sarcoma, revealing a proliferation of spindle-shaped endothelial cells forming angulated vascular spaces, with red blood cell extravasation and a mixed inflammatory infiltrate. Conclusions: Non-invasive imaging tools, including dermoscopy, D-OCT, and LC-OCT, have emerged as valuable adjuncts in the diagnosis and monitoring of KS. These techniques enable in vivo assessment of vascular architecture and tissue morphology, enhancing clinical decision-making while reducing the need for immediate biopsy. Dermoscopy reveals polychromatic vascular features, such as the rainbow pattern, while D-OCT and LC-OCT provide high-resolution insights into vascular proliferation, tissue heterogeneity, and cellular morphology. Dermoscopy, dynamic OCT, and LC-OCT represent promising non-invasive diagnostic tools for the assessment of Kaposi sarcoma. These technologies provide detailed morphological and vascular information, enabling earlier diagnosis and more personalized management. While histopathology remains the gold standard, non-invasive imaging offers a valuable complementary approach for diagnosis and follow-up, particularly in complex or atypical presentations. Ongoing research and technological refinement are essential to improve accessibility and clinical applicability. Full article

Cancer metastasis often accounts for the primary cause of cancer-related mortality, with the lymphatic system playing a pivotal role in the dissemination of malignant cells. While hematogenous vessel spread is commonly associated with distant organ metastasis, the lymphatic system serves as an early conduit for tumor cell invasion and dissemination. The process of lymphatic metastasis is a highly coordinated sequence of events that involves cancer cell invasion, intravasation into lymphatic vessels, survival, transport, and colonization of regional lymph nodes (LNs). Cancerous cells then establish micro-metastases at the colonized sites and expand in the new microenvironment, ultimately resulting in the generation of secondary tumors. Tumor-secreted factors, such as vascular endothelial growth factors (VEGF-C and VEGF-D), contribute to metastasis through lymphangiogenesis, the formation of new lymphatic vessels. In addition, cancer cells utilize pre-existing chemokine signaling pathways by expressing chemokine receptors, such as CCR7, which bind to chemokine ligands, such as CCL19 and CCL21, to facilitate targeted migration into the lymphatic vessels. LNs are often the initial sites for metastasis and therefore are indicators of distant organ involvement. It is well established that the location and extent of LN involvement provides significant prognostic information, although the optimal treatment approach for LN metastases remains a subject of debate. Understanding the mechanisms of lymphatic metastasis offers potential therapeutic targets to mitigate cancer progression. Full article

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. Full article

This study investigates long-term volume reduction after microsurgical autologous lymphatic vessel transplantation (LVT) in patients with chronic lymphoedema. Lymphoedema is caused by inadequate lymphatic drainage and leads to swelling, pain, and a reduced quality of life. Conservative treatments often show only limited success, which is why surgical procedures such as LVT are increasingly gaining in importance. In a retrospective long-term analysis, patients who underwent LVT between 1988 and 2010 were examined on average 21.7 years after surgery. The examination included pre- and post-operative volume measurements, which were supplemented by modern 3D body scanner analyses and lymphoscintigraphy. The results show a significant volume reduction both in the short term (p < 0.01) and at the follow-up examination (p = 0.04). There was no significant difference between manual volumetry with circumferential measurements and 3D volumetry (p = 0.775). The improvement in lymph transport capacity was considerable (p = 0.078). This study provides valuable insights for the further development of lymphatic surgery. While preferred surgical methods change over time, this study demonstrates that LVT can make a decisive contribution to improving the quality of life of lymphedema patients. Full article

Background: Bone marrow (BM)-derived myeloid–lymphatic endothelial cell progenitors (M-LECPs) promote formation of tumor lymphatics that are responsible for metastasis to lymph nodes. The regenerative capacity of BM progenitors to other lineages is mediated through cell fusion, a process that delivers a pro-mitotic message directly to division-restricted cells. This suggested that M-LECPs might use a similar mechanism to induce division of lymphatic endothelial cells (LECs). Methods: To test this hypothesis, we determined expression of fusogenic markers in M-LECP produced in vitro and recruited to human or mouse tumors in vivo as well as quantified their fusion with LECs in both settings. Fusion in vivo was determined in female chimera mice grafted with male BM that have been implanted with MDA-MB-231 or EMT6 breast tumors. Co-staining for Y-chromosome and LEC-specific markers allowed us to quantify tumor lymphatic vessels fused with BM progenitors. Results: We found that both tumor-recruited and in-vitro-produced M-LECPs expressed multiple fusogenic regulators and possessed a significant fusogenic activity towards cultured and vessel-lining LECs. Y-chromosomes, a marker of fusion, were detected in nearly half of tumor lymphatics and were associated with mitotic division, vessel formation, and node metastasis. Both in vitro and in vivo assays showed dependency of fusion on Th2 and Toll-like receptor-4 (TLR4) pathways. Conclusions: This novel mechanism of tumor lymphatic formation triggered by fusion with BM myeloid–lymphatic progenitors suggests a variety of new targets for inhibition of metastatic spread. Full article

The lymphatic system, a complex and dynamic network comprising lymphatic vessels, lymph nodes (LNs), and associated lymphoid tissues, plays a pivotal role in regulating interstitial fluid balance and providing immune surveillance across the body. In cancer, however, the lymphatic system often transforms into a pathway for malignant cell dissemination, leading to lymphatic metastasis—a significant step in tumor progression associated with worse patient prognoses. Mechanistically, tumor cells exploit lymphangiogenic pathways to facilitate their entry and spread within the lymphatic network. Key mechanisms in this process include the upregulation of vascular endothelial growth factors C and D (VEGF-C/D), which promote lymphatic endothelial proliferation, vessel dilation, and increased permeability. This review seeks to provide an in-depth examination of the biological mechanisms underpinning lymphatic metastasis, explore its impact on cancer progression, and highlight current and emerging strategies aimed at managing metastatic disease. Full article

Cannabidiol (CBD) and tetrahydrocurcumin (THC) have demonstrated anti-inflammatory activity as well as generating new lymph vessels. We present the formulations and evaluations of CBD and THC loaded in hydrogels for the treatment of lymphedema to promote angiogenesis of lymph vessels and an anti-inflammatory response. Six CBD-THC hydrogel formulations were prepared and evaluated. The hydrodynamic particle sizes were 302.0–545.1 nm and the zeta potentials were from −58.80 to −33.63 mV. The hydrogel pHs were 6.43–6.54. The hydrogel formulations were non-toxic for both CBD (<25 µg/mL) and THC (<12.5 µg/mL). It was observed that high-molecular-weight hyaluronic acid in hydrogel affected collagen production. Hydrogel formulations at 2 µg/mL of CBD and 1 µg/mL of THC induced human dermal lymphatic endothelial cell tube formation. CBD-THC hydrogel formulations showed a notable ability to induce angiogenesis, which suggested its potential effectiveness in promoting new lymphatic vessel formation. Moreover, CBD-THC hydrogels showed anti-inflammatory properties. Further research is needed to ensure these treatments effectively enhance lymphatic repair. 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

The impaired repair of lymphatic vessels after tissue damage is an etiological hallmark of lymphedema. Previously, we demonstrated that lymphatic recanalization after the popliteal lymph node extirpation was delayed in Gata2 heterozygous mice. This impaired lymphatic vessel recanalization in Gata2 heterozygous mice was mitigated by administrating atelocollagen or crossing with heterozygous Gata3 deletion mice. To clarify the potential involvement of Gata3 heterozygosity in collagen gene expression within subdermal tissue, we conducted an RNAseq analysis and found 273 genes with up and 522 genes with down expression in Gata3 heterozygous mice, and these genes were categorized as collagen and extracellular matrix-related genes by GO analysis. We also found that Col6a1, a2, and a3, which compose type VI collagen, underwent a transient but significant upregulation during the lymphatic recanalization process. Histological analysis revealed that the collagen structure in the subdermal tissue exhibited thinner collagen fiber in Gata3 heterozygous deficient mice. These findings suggest that the altered collagen pattern in Gata3 heterozygous mice contributed to the enhanced lymphatic vessel recanalization in Gata2 heterozygous mice. The altered collagen expression pattern might play a role in shaping and maintaining the subcutaneous microenvironment. Full article

Many viruses induce viremia (virus in the blood) and disseminate throughout the body via the bloodstream from the initial infection site. However, viruses must often pass through the lymphatic system to reach the blood. The lymphatic system comprises a network of vessels distinct from blood vessels, along with interconnected lymph nodes (LNs). The complex network has become increasingly appreciated as a crucial host factor that contributes to both the spread and control of viral infections. Viruses can enter the lymphatics as free virions or along with migratory cells. Once virions arrive in the LN, sinus-resident macrophages remove infectious virus from the lymph. Depending on the virus, macrophages can eliminate infection or propagate the virus. A virus released from an LN is eventually deposited into the blood. This unique pathway highlights LNs as targets for viral infection control and for modulation of antiviral response development. Here, we review the lymphatic system and viruses that disseminate through this network. We discuss infection of the LN, the generation of adaptive antiviral immunity, and current knowledge of protection within the infected node. We conclude by sharing insights from ongoing efforts to optimize lymphatic targeting by vaccines and pharmaceuticals. Understanding the lymphatic system’s role during viral infection enhances our knowledge of antiviral immunity and virus–host interactions and reveals potential targets for next-generation therapies. Full article

Background: Diagnosis of nevoid melanoma (NeM) is often difficult because NeM closely resembles a common nevus clinically and histologically. Methods: A retrospective study was conducted on 110 patients diagnosed with and/or treated for primary nevoid melanoma at the Veneto Institute of Oncology and at the University Hospital of Padua from August 1999. Results: Mean Breslow thickness was of 1.4 mm. Sentinel lymph node biopsy was conducted in nearly half of the patients, and positivity was detected in 16.7% of them. Twenty-four clinical and 23 dermoscopic pictures were collected. Papular and macular lesions prevailed over nodular and plaque-type lesions. Different hues of brown, pink, and red color were most represented. Twenty nevus-like NeMs and four multicomponent-pattern NeMs were observed. The Most frequent dermoscopic patterns for nevus-like NeM were atypical pigmented reticulum, irregular globules and dots, and hyperpigmented blotches. Atypical vessels, asymmetric peripheric striae, blue-white veil, and areas of regression were less frequent and prevailed in multicomponent pattern NeM. A structureless pattern was also featured. Many patients in the series had multiple melanomas. However, none of them had numerous multiple nevoid melanomas. Conclusions: NeM should not be regarded as a separate biological entity from classical melanoma, and the same histological and clinical prognostic factors apply to NeM. Clinically and dermoscopically, it often resembles benign nevi, although some clues such as evolution and some dermoscopic patterns could suggest malignancy. Clinical suspicion might prove crucial to further pathological analysis and recognition. Full article

Lymphoma growth, progression, and dissemination require tumor cell interaction with supporting vessels and are facilitated through tumor-promoted angiogenesis, lymphangiogenesis, and/or lymphoma vessel co-option. Vessel co-option has been shown to be responsible for tumor initiation, metastasis, and resistance to anti-angiogenic treatment but is largely uncharacterized in the setting of lymphoma. We developed an in vitro model to study lymphoma–vessel interactions and found that mantle cell lymphoma (MCL) cells co-cultured on Matrigel with human umbilical vein (HUVEC) or human lymphatic (HLEC) endothelial cells migrate to and anneal with newly formed capillary-like (CLS) or lymphatic-like (LLS) structures, consistent with lymphoma–vessel co-option. To inhibit this interaction, we constructed an antibody fusion protein, αCD20-EndoP125A, linking mutant anti-angiogenic endostatin (EndoP125A) to an αCD20-IgG1-targeting antibody. αCD20-EndoP125A inhibited both CLS and LLS formation, as well as MCL migration and vessel co-option. Lymphoma vessel co-option requires cell migration, which is regulated by chemokine–chemokine receptor interactions. CXCL12 and its receptor, CXCR4, are highly expressed by both endothelial cells forming CLS and by MCL cells during vessel co-option. αCD20-EndoP125A suppressed expression of both CXCL12 and CXCR4, which were required to facilitate CLS assembly and vessel co-option. We also tested αCD20-EndoP125A effects in vivo using an aggressive murine B cell lymphoma model, 38c13-hCD20, which demonstrated rapid growth and dissemination to tumor-draining lymph nodes (TDLNs) and the spleen, lung, and brain. The pattern of lymphoma distribution and growth within the lung was consistent with vessel co-option. As predicted by our in vitro model, αCD20-EndoP125A treatment inhibited primary tumor growth, angiogenesis, and lymphangiogenesis, and markedly reduced the number of circulating tumor cells and lymphoma dissemination to TDLNs and the lungs, spleen, and brain. αCD20-EndoP125A inhibited lymphoma vessel co-option within the lung. Marked inhibition of MCL primary tumor growth and dissemination were also seen using an MCL xenograft model. The ability of αCD20-EndoP125A to inhibit angiogenesis, lymphangiogenesis, and lymphoma vessel co-option provides a novel therapeutic approach for inhibition of lymphoma progression and dissemination. Full article

Osteoarthritis (OA), a common and disabling degenerative joint disease, affects millions of people worldwide and imposes a considerable burden on patients and society due to its high prevalence and economic costs. The pathogenesis of OA is closely related to the progressive degradation of articular cartilage and the accompany inflammation; however, articular cartilage itself cannot heal and modulate the inflammation due to the lack of nerves, blood vessels, and lymph-vessels. Therefore, reliable and effective methods to treat OA remain highly desired. Local administration of drugs or bioactive materials by intra-articular injection of the delivery system represents a promising approach to treat OA, especially considering the prolonged joint retention, cartilage or chondrocytes targeting, and stimuli-responsive release to achieve precision OA therapy. This article summarizes and discusses the advances in the currently used delivery systems (nanoparticle, hydrogel, liposome, and microsphere) and then focuses on their applications in OA treatment from the perspective of endogenous stimulus (redox reactions, pH, enzymes, and temperature) and exogenous stimulus (near-infrared, magnetic, and ultrasound)-responsive release. Finally, the challenges and potential future directions for the development of nano-delivery systems are summarized. Full article