[Research progress of combined surgical treatment of lymphedema based on vascularized lymph node transfer].

Objective: To summarize the research progress of combined surgical treatment of lymphedema based on vascularized lymph node transfer (VLNT), and to provide systematic information for combined surgical treatment of lymphedema. Methods: Literature on VLNT in recent years was extensively reviewed, and the history, treatment mechanism, and clinical application of VLNT were summarized, with emphasis on the research progress of VLNT combined with other surgical methods. Results: VLNT is a physiological operation to restore lymphatic drainage. Multiple lymph node donor sites have been developed clinically, and two hypotheses have been proposed to explain its mechanism for the treatment of lymphedema. But it has some inadequacies such as slow effect and limb volume reduction rate less than 60%. To address these inadequacies, VLNT combined with other surgical methods for lymphedema has become a trend. VLNT can be used in combination with lymphovenous anastomosis (LVA), liposuction, debulking operation, breast reconstruction, and tissue engineered material, which have been shown to reduce the volume of affected limbs, reduce the incidence of cellulitis, and improve patients' quality of life. Conclusion: Current evidence shows that VLNT is safe and feasible in combination with LVA, liposuction, debulking operation, breast reconstruction, and tissue engineered material. However, many issues need to be solved, including the sequence of two surgeries, the interval between two surgeries, and the effectiveness compared with surgery alone. Rigorous standardized clinical studies need to be designed to confirm the efficacy of VLNT alone or in combination, and to further discuss the subsistent issues in the use of combination therapy.

Retrograde Manual Lymphatic Drainage following Vascularized Lymph Node Transfer to Distal Recipient Sites for Extremity Lymphedema: A Retrospective Study and Literature Review.

BACKGROUND: Vascularized lymph node transfer is an efficacious treatment for extremity lymphedema. This study investigated the outcome of retrograde manual lymphatic drainage for vascularized lymph node transfer to distal recipient sites. METHODS: Lymphedema patients who underwent either complete decongestive therapy or vascularized lymph node transfer between 2013 and 2018 were retrospectively included. Retrograde manual lymphatic drainage was started with intermittent manual compression and the assistance of a sphygmomanometer and proximal-to-distal massage of the limb 1 month postoperatively. Outcomes evaluations used the circumferential reduction rate and the Lymphedema-Specific Quality-of-Life Questionnaire. Outcomes of vascularized lymph node transfer to proximal versus distal recipient sites in the literature between 2006 and 2018 were also compared. RESULTS: One hundred thirty-eight unilateral extremity lymphedema patients, including 68 patients in the complete decongestive therapy group and 70 patients in the vascularized lymph node transfer group, were included. The mean circumferential reduction rate of 38.9 ± 2.5 percent in the vascularized lymph node transfer group was statistically greater than the 13.2 ± 10.1 percent rate in the complete decongestive therapy group (p = 0.01). At a mean follow-up of 36 months, the improvement of overall Lymphedema-Specific Quality-of-Life Questionnaire score from 3.8 ± 0.3 to 7.5 ± 1.8 in the vascularized lymph node transfer group was statistically greater than that in the complete decongestive therapy group (from 4.7 ± 0.9 to 5.0 ± 1.9; p < 0.01). In total, 536 lymphedema patients who underwent 548 vascularized lymph node transfers in 23 published articles were reviewed; the distal recipient-site group was found to have more efficacious results than the proximal recipient-site group. CONCLUSION: Vascularized lymph node transfer to a distal recipient site with standard retrograde manual lymphatic drainage significantly improved circumferential reduction rates and Lymphedema-Specific Quality-of-Life Questionnaire scores. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Surgical treatment of Milroy disease.

BACKGROUND AND OBJECTIVES: Milroy disease is a form of congenital primary lymphedema affecting the lower limbs. When conservative management is ineffective, surgical treatment becomes necessary. The purpose of this study was to investigate the efficacy of vascularized lymph node transfer (VLNT) associated with extensive therapeutic lipectomy in the treatment of these patients. METHODS: In China Medical University Hospital, four patients have been diagnosed with Milroy disease and treated over an 8 year-period time. All patients presented with hereditary bilateral legs swelling since birth. All patients were treated with VLNT from the gastroepiploic region bilaterally associated with extensive therapeutic lipectomy. RESULTS: All procedures have been executed bilaterally and have been successful, without complications. The average follow-up of the patients was 20.2 ± 2.8 months. The limbs treated presented an average circumference reduction of a 4.0 ± 2.1 cm and patients did not experience cellulitis during follow-up. Patients expressed satisfaction with the procedure. CONCLUSIONS: VLNT together with therapeutic lipectomy proved to be a reliable technique in moderate cases of Milroy disease, providing an alternative path for lymph drainage, and reducing the lymph load and the excess of subcutaneous adipose tissues, thus improving patients' quality of life.

Observation of a Flowing Duct in the Abdominal Wall by Using Nanoparticles.

The primo vascular system (PVS) is being established as a circulatory system that corresponds to acupuncture meridians. There have been two critical questions in making the PVS accepted as a novel liquid flowing system. The first one was directly to show the flow of liquid in PVS and the second one was to explain why it was not observed in the conventional histological study of animal tissues. Flow in the PVS in the abdominal cavity was previously verified by injecting Alcian blue into a primo node. However, the tracing of the dye to other subsystems of the PVS has not been done. In the current work we injected fluorescent nanoparticles (FNPs) into a primo node and traced them along a primo vessel which was inside a fat tissue in the abdominal wall. Linea alba is a white middle line in the abdominal skin of a mammal and a band of fat tissue is located in parallel to the linea alba in the parietal side of the abdominal wall of a rat. In this fat band a primo vessel runs parallel to the prominent blood vessels in the fat band and is located just inside the parietal peritoneum. About the second question on the reason why the PVS was not in conventional histological study the current work provided the answer. Histological analysis with hematoxyline and eosine, Masson's trichrome, and Toluidine blue could not discriminate the primo vessel even when we knew the location of the PVS by the trace of the FNPs. This clearly explains why the PVS is hard to observe in conventional histology: it is not a matter of resolution but the contrast. The PVS has very similar structure to the connective tissues that surround the PVS. In the current work we propose a method to find the PVS: Observation of mast cell distribution with toluidine blue staining and the PN has a high density of mast cells, while the lymph node has low density.

Quantity of lymph nodes correlates with improvement in lymphatic drainage in treatment of hind limb lymphedema with lymph node flap transfer in rats.

PURPOSE: This study was conducted to investigate the correlation between the number of vascularized lymph nodes (LN) transferred and resolution of hind limb lymphedema in a rat model. METHODS: Unilateral hind limb lymphedema was created in 18 male Sprague-Dawley rats following inguinal and popliteal LN resection and radiation. A para-aortic LN flap based on the celiac artery was subsequently transferred to the affected groin. The three study groups consisted of Group A (no LN transfer), Group B (transfer of a single vascularized LN), and Group C (transfer of three vascularized LNs). Volumetric analysis of bilateral hind limbs was performed using micro-CT imaging at 1, 2, and 3 months postoperatively. Lymphatic drainage was assessed with Tc(99) lymphoscintigraphy preoperatively and at 3 months postoperatively. RESULTS: A statistically significant volume reduction was seen in Groups B and C compared to Group A at all time points. Volume reduction of Group A vs.Group B at 1 month (8.6% ± 2.0% vs. 2.7% ± 2.6%, P < 0.05), 2 months (9.3% ± 2.2% vs. -4.3% ± 2.7%, P < 0.05), and 3 months (7.6% ± 3.3% vs. -8.9% ± 5.2%, P < 0.05). Volume reduction of Group A vs. Group C at 1 month (8.6% ± 2.0% vs. -6.6% ± 3.1%, P < 0.05), 2 months (9.3% ± 2.2% vs. -10.2% ± 4.6%, P < 0.05), and 3 months (7.6% ± 3.3% vs. -9.1% ± 3.1%, P < 0.05). Of note, comparison of Groups B and C demonstrated greater volume reduction in Group C at 1 (P < 0.02) and 2 (P = 0.07) months postoperatively. CONCLUSIONS: LN flap transfer is an effective procedure for the treatment of lymphedema. The number of vascularized LNs transferred correlates positively with the degree of volume reduction.

Primo vascular system floating in lymph ducts of rats.

An epoch-making development in the gross anatomy of the lymph system has emerged: the observation of the primo vascular system (PVS), which is a threadlike structure floating in lymph ducts. The PVS, which was proposed as the conduit for the acupuncture Qi, is a complex network distributed throughout an animal's body. The lymph-PVS, which is a subsystem of the PVS, is one of the most convincing visual demonstrations of the PVS. Because its existence is not easily demonstrated, even with a microscope, due to its transparency, in current anatomy its existence is largely unknown despite its potential significance in physiology and medicine. The lymph-PVS has been observed in rabbits, rats, and mice by several independent teams. Because the involved techniques are rather complicated, we provide detailed protocols for surgery, for injection of the staining dye, and for detection, extraction, and identification of the PVS in a rat.

Inhibition of lymphangiogenesis and lymphatic drainage via vascular endothelial growth factor receptor 3 blockade increases the severity of inflammation in a mouse model of chronic inflammatory arthritis.

OBJECTIVE: This study was undertaken to investigate the effect of lymphatic inhibition on joint and draining lymph node (LN) pathology during the course of arthritis progression in mice. METHODS: Tumor necrosis factor (TNF)-transgenic mice were used as a model of chronic inflammatory arthritis. Mice were subjected to contrast-enhanced magnetic resonance imaging to obtain ankle and knee joint synovial volumes and draining popliteal LN volumes before and after 8 weeks of treatment with vascular endothelial growth factor receptor 3 (VEGFR-3) neutralizing antibody, VEGFR-2 neutralizing antibody, or isotype IgG. Animals were subjected to near-infrared lymphatic imaging to determine the effect of VEGFR-3 neutralization on lymph transport from paws to draining popliteal LNs. Histologic, immunohistochemical, and reverse transcriptase-polymerase chain reaction analyses were used to examine lymphatic vessel formation and the morphology of joints and popliteal LNs. RESULTS: Compared with IgG treatment, VEGFR-3 neutralizing antibody treatment significantly decreased the size of popliteal LNs, the number of lymphatic vessels in joints and popliteal LNs, lymphatic drainage from paws to popliteal LNs, and the number of VEGF-C-expressing CD11b+ myeloid cells in popliteal LNs. However, it increased the synovial volume and area of inflammation in ankle and knee joints. VEGFR-2 neutralizing antibody, in contrast, inhibited both lymphangiogenesis and joint inflammation. CONCLUSION: These findings indicate that lymphangiogenesis and lymphatic drainage are reciprocally related to the severity of joint lesions during the development of chronic arthritis. Lymphatic drainage plays a beneficial role in controlling the progression of chronic inflammation.

Localized deep hyperthermia increases the traffic of lymphocytes through peripheral lymph nodes of sheep in vivo.

The production of localized deep hyperthermia by the radio frequency wave magnetic-loop induction method has been utilized to study the effects of deep hyperthermia on lymphocyte traffic in sheep in vivo. Deep hyperthermia has been applied both to primary peripheral lymph node drainage areas alone (popliteal and prefemoral) and directly over the study lymph node (popliteal). Deep tissue core temperatures were monitored in all studies and the findings were correlated with alterations in the levels of lymphocyte outputs into study node efferent lymph and the volume of efferent lymph flow. In all of 32 studies, there was a prompt and sharp increase in the output of lymphocytes into efferent lymph at 40-43 degrees C. Efferent lymph flow also was increased promptly but to a lesser degree than the output of lymphocytes. The two were not closely correlated. High deep temperature in the nodal area (45 degrees C) appeared to cause delayed nodal malfunction, which depressed lymphocyte output but did not affect lymph flow. Localized deep hyperthermia is an effective and noninvasive means for the local increase of lymphocyte traffic and lymph flow and may prove to be a useful means for the evaluation of the immunological consequences of altering both deep tissue temperature and lymphocyte traffic.

Afferent lymph and lymph borne cells: their influence on lymph node function.

In AO rats the afferent lymphatics to the right cervical lymph nodes (LN) were interrupted and the LN were encased in silicone rubber tubes to prevent reunion of the lymphatics. At regular intervals over the next 12 weeks the following were measured in comparison with the intact contralateral LN - LN weight, influx of lymphocytes from the blood, blood flow, the incorporation of 125IUdR and the incorporation of 35S-sulphate into high endothelial venules (HEV). Systematic histological observations are also reported. One day after deafferentization lymphocyte influx was significantly reduced although blood flow was unchanged and a temporary increase in LN weight was associated with crowding of the lymphatic sinuses with small lymphocytes. The subsequent decline in lymphocyte influx was biphasic and quicker than the decline of other parameters--being undetectable by 6 weeks. Flattening of HEV and diminished secretion of 35S-sulphate was noted at 1 week and progressive degeneration and eventual disappearance of the HEV network was seen by 6-12 weeks. Doubtlessly because of lack of antigenic stimulation 125IUdR incorporation, and numbers of lymphoblasts, plasma cells and finally germinal centres were progressively reduced. The numbers of macrophages and interdigitating cells (IDC) were greatly reduced by 3 weeks and very few were present at 6 weeks probably because most or all arrive in afferent lymph and have a limited life span in the LN. At 12 weeks the LN was difficult to recognize as such since only stromal cells and occasional small lymphocytes remained. In supplementary experiments u.v. irradiation of the LN at the time of deafferentization reduced lymphocyte influx without affecting blood flow suggesting that a u.v. sensitive cell like the IDC may influence lymphocyte influx. In conclusion the involution of the deafferentized LN is partly due to the lack of antigen but progression to the complete loss of specialized structure and function is probably due to lack of other factors including non-lymphoid cells that normally arrive in afferent lymph.