Hypoxia Preconditioned Serum (HPS)-Hydrogel Can Accelerate Dermal Wound Healing in Mice—An In Vivo Pilot Study

The ability to use the body’s resources to promote wound repair is increasingly becoming an interesting area of regenerative medicine research. Here, we tested the effect of topical application of blood-derived hypoxia preconditioned serum (HPS) on wound healing in a murine wound model. Alginate hydrogels loaded with two different HPS concentrations (10 and 40%) were applied topically on full-thickness wounds created on the back of immunocompromised mice. We achieved a significant dose-dependent wound area reduction after 5 days in HPS-treated groups compared with no treatment (NT). On average, both HPS-10% and HPS-40% -treated wounds healed 1.4 days faster than NT. Healed tissue samples were investigated on post-operative day 15 (POD 15) by immunohistology and showed an increase in lymphatic vessels (LYVE-1) up to 45% with HPS-40% application, while at this stage, vascularization (CD31) was comparable in the HPS-treated and NT groups. Furthermore, the expression of proliferation marker Ki67 was greater on POD 15 in the NT-group compared to HPS-treated groups, in accordance with the earlier completion of wound healing observed in the latter. Collagen deposition was similar in all groups, indicating lack of scar tissue hypertrophy as a result of HPS-hydrogel treatment. These findings show that topical HPS application is safe and can accelerate dermal wound healing in mice.

Bleb-Independent Glaucoma Surgery to Activate the Uveolymphatic Route of Non-Trabecular Aqueous Humor Outflow: Short-Term Clinical and OCT Results

The deep sclerectomy technique was modified to enhance aqueous humor (AH) outflow via the non-trabecular pathway. A pilot study was carried out to assess its safety and effectiveness. Thirty-eight patients were under observation. After superficial scleral flap (4 × 4 mm), deep scleral layers were divided into three parts by three parallel-to-limbus incisions. Deep sclerectomy without creating a window in the Descemetes’ membrane was carried out in the distal part. A collagen implant was placed under the sclera of the remaining two parts with one end in the intrascleral pool. The third proximal part was excised to expose the uvea and implant. A Nd:YAG laser trabeculotomy at the surgery site was made on postoperative days 7–10. Outcome measures were IOP change, use of hypotensive medication(s), complications, and the need for a second surgery. At six months, the mean IOP decreased from 29.1 ± 9.2 mm Hg to 14.0 ± 4.3 mm Hg (p = 1.4 × 10−9); hypotensive medication use reduced from 2.9 ± 0.9 to 0.6 ± 1.0 (p = 1.3 × 10−10); complete success was achieved in 68.4% of cases and partial success was achieved in 31.6% of cases. Intraoperative and postoperative complications were rare and manageable. The OCT of the surgery site revealed the absence of bleb in all cases. Lymphatic vessels with characteristic bicuspid valves in their lumen were detected in conjunctiva near the operation site and over it in 32 patients. IOP decrease in the proposed technique was achieved by activation of the uveolymphatic route of AH outflow.

Non-invasive MR imaging of human brain lymphatic networks with connections to cervical lymph nodes

Meningeal lymphatic vessels have been described in animal studies, but limited comparable data is available in human studies. Here we show dural lymphatic structures along the dural venous sinuses in dorsal regions and along cranial nerves in the ventral regions in the human brain. 3D T2-Fluid Attenuated Inversion Recovery magnetic resonance imaging relies on internal signals of protein rich lymphatic fluid rather than contrast media and is used in the present study to visualize the major human dural lymphatic structures. Moreover we detect direct connections between lymphatic fluid channels along the cranial nerves and vascular structures and the cervical lymph nodes. We also identify age-related cervical lymph node atrophy and thickening of lymphatics channels in both dorsal and ventral regions, findings which reflect the reduced lymphatic output of the aged brain.

Radiofrequency Irradiation Mitigated UV-B-Induced Skin Pigmentation by Increasing Lymphangiogenesis

Dermal macrophages containing melanin increase skin pigmentation since dermal melanin removal is slower than epidermal melanin removal. Lymphatic vessels are also involved in melanin clearance. We evaluated whether radiofrequency (RF) irradiation induced an increase in HSP90, which promotes lymphangiogenesis by activating the BRAF/MEK/ERK pathway and decreasing tyrosinase activity, in the UV-B exposed animal model. The HSP90/BRAF/MEK/ERK pathway was upregulated by RF. Tyrosinase activity and the VEGF-C/VEGFR 3/PI3K/pAKT1/2/pERK1/2 pathway, which increase lymphangiogenesis, as well as the expression of the lymphatic endothelial marker LYVE-1, were increased by RF. Additionally, the number of melanin-containing dermal macrophages, the melanin content in the lymph nodes, and melanin deposition in the skin were decreased by RF. In conclusion, RF increased HSP90/BRAF/MEK/ERK expression, which decreased tyrosinase activity and increased lymphangiogenesis to eventually promote the clearance of dermal melanin-containing macrophages, thereby decreasing skin pigmentation.

Cryotherapy Treatment of Cutaneous Kaposi Sarcoma in a Patient With B-Cell Chronic Lymphocytic Leukemia: A Case Report and Short Review of the Literature

Introduction. Kaposi sarcoma (KS) is a low-grade mesenchymal tumor involving the blood and the lymphatic vessels that primarily effaces the skin and is mediated by human herpesvirus-8 (HHV-8) in more than 90% of patients. There are 4 distinct types of KS. Compared with the classic and AIDS-related variants, chronic lymphocytic leukemia (CLL) associated with KS is a relatively rare clinical condition; thus, only a few cases have been reported. Case Report. This report presents a case study of an 87-year-old patient with B-cell CLL and cutaneous KS managed with cryotherapy, along with a short review of the literature. Conclusions. Considering that the method is relatively simple and with few adverse effects, cryotherapy may represent a simple and safe treatment method for cutaneous KS. However, more studies should be conducted to further evaluate the effectiveness of cryotherapy as a promising treatment for cutaneous KS.

Advances in Drugs Targeting Lymphangiogenesis for Preventing Tumor Progression and Metastasis

Metastasis of cancer cells from the primary tumor to other organs and tissues in the body is the leading cause of death in patients with malignancies. One of the principal ways cancer cells travel is through lymphatic vessels, and tumor invasion into the regional lymph nodes is a hallmark of early metastasis; thus, the formation of especially peritumoral lymphatic vessels is essential for tumor transportation that gives rise to further progression. In the past few decades, tumor-induced lymphangiogenesis has been testified to its tight correlation with lymphatic metastasis and poor clinical outcomes in multiple types of human malignancies, which warrants novel potential therapeutic targets for cancer treatment. As the understanding of underlying molecular mechanisms has grown tremendously over the years, an inexorable march of anti-lymphangiogenic therapy also aroused terrific interest. As a result, a great number of drugs have entered clinical trials, and some of them exhibited predominant contributions in cancer management. Herein, this review provides an updated summary of the current advances in therapies preventing lymphatic metastasis and discusses the validity of different applications.

IL-1β Impacts Vascular Integrity and Lymphatic Function in the Embryonic Omentum

Background: The chromatin remodeling enzyme Brahma Related Gene 1 (BRG1) regulates gene expression in a variety of rapidly differentiating cells during embryonic development. However, the critical genes that BRG1 regulates during lymphatic vascular development are unknown. Methods: We used genetic and imaging techniques to define the role of BRG1 in murine embryonic lymphatic development, although this approach inadvertently expanded our study to multiple interacting cell types. Results: We found that omental macrophages fine-tune an unexpected developmental process by which erythrocytes escaping from naturally discontinuous omental blood vessels are collected by nearby lymphatic vessels. Our data indicate that circulating fibrin(ogen) leaking from gaps in omental blood vessels can trigger inflammasome-mediated interleukin 1 beta (IL-1β) production and secretion from nearby macrophages. IL-1β destabilizes adherens junctions in omental blood and lymphatic vessels, contributing to both extravasation of erythrocytes and their uptake by lymphatics. BRG1 regulates IL-1β production in omental macrophages by transcriptionally suppressing the inflammasome trigger Receptor Interacting Protein Kinase 3 (RIPK3). Conclusions: Genetic deletion of Brg1 in embryonic macrophages leads to excessive IL-1β production, erythrocyte leakage from blood vessels, and blood-filled lymphatics in the developing omentum. Altogether, these results highlight a novel context for epigenetically-regulated crosstalk between macrophages, blood vessels, and lymphatics.

Lymph Node Involvement in Early-Stage Cervical Cancer: Is Lymphangiogenesis a Risk Factor? Results from the MICROCOL Study

Background: In patients with cervical cancer, the presence of tumoral lymph-vascular space invasion (LVSI) is the main risk factor for pelvic lymph node metastasis (PLNM). The objective of this study was to evaluate the presence of several markers of lymphangiogenesis in early-stage cervical cancer and their correlation with PLNM and tumoral recurrence. Materials and Methods: Seventy-five patients with early-stage cervical carcinoma underwent sentinel lymph node (SLN) sampling in association with complete pelvic lymph node dissection. Primary tumors were stained with the following markers: Ki67, D2-40, CD31 and VEGF-C. A 3-year follow-up was performed to evaluate the disease-free survival. Results: Overall, 14 patients (18.6%) had PLNM. Positive LVSI was seen in 29 patients (38.6%). There was a significant correlation between LVSI evidenced by H/E staining and PLNM (p < 0.001). There was no correlation between high Ki67, CD31, D2-40, and VEGF-C staining with PLNM or tumor recurrence. Conclusions: Our data support that lymphatic spread does not require the proliferation of new lymphatic endothelial cells in early-stage cervical cancer. These results emphasize the importance of pre-existing peritumoral lymphatic vessels in the metastatic process in early cervical cancer. None of the markers of lymphangiogenesis and proliferation assessed in this study were predictive of PLNM or recurrence.

Computed tomography lymphangiography via intrametatarsal pad injection is feasible in cats with chylothorax

OBJECTIVE To evaluate the feasibility of CT lymphangiography via intrametatarsal pad injection in cats with chylothorax. ANIMALS 7 client-owned cats. PROCEDURES This was a multicenter, retrospective, descriptive study. Medical records and imaging data from 4 veterinary hospitals were reviewed to identify cats with chylothorax that had undergone intrametatarsal pad injection via CT lymphangiography. In total, 7 client-owned cats were included in the study. Signalment, history, image findings, and follow-up data were recorded. Descriptive statistics were used to analyze the success rate of thoracic duct (TD) enhancement and describe relevant clinical findings. RESULTS Enhancement of TDs was successful in 6 of the 7 cats within 5 to 15 minutes after initiating intrametatarsal pad injection under general anesthesia. Successful migration of contrast medium into the lymphatic vessels cranial to the popliteal lymph nodes was observed in all cats within 5 minutes after injection. The recommended dose of contrast medium to achieve TD enhancement was 1 mL/kg (0.5 mL/kg/pad; concentration, 350 mg of iodine/kg). Only 1 cat had mild swelling of the paws after the procedure, and it recovered quickly without pain medication; no cats experienced lameness. Similar to dogs and unlike in previously published reports, 72% of TD branches were located in the right hemithorax. CLINICAL RELEVANCE CT lymphangiography via intrametatarsal pad injection is a feasible and safe procedure for cats with chylothorax. This technique provides detailed information regarding the unique TD anatomy and cisterna chyli location. It also contributes to surgical planning.