Prevention of Secondary Lymphedema after Complete Lymph Node Dissection in Melanoma Patients: The Role of Preventive Multiple Lymphatic–Venous Anastomosis in Observational Era

Background and Objectives: Current guidelines have limited the performance of complete lymph node dissection (CLND) for patients with clinically detectable lymphatic metastases. Despite the limitations of this surgical procedure, secondary lymphedema (SL) is an unsolved problem that affects approximately 20% of patients undergoing CLND. Preventive lymphatic–venous micro-anastomoses (PMLVA) has already demonstrated its efficacy in the prevention of SL in melanoma patients with a positive sentinel lymph node biopsy (SLNB), but the efficacy of this procedure is not demonstrated in patients with clinically detectable lymphatic metastases. Materials and Methods: This retrospective cohort study, was performed in two observation periods. Until March 2018, CLND was proposed to all subjects with positive-SLNB andPMLVA was performed in a subgroup of patients with risk factors for SL (Group 1). From April 2018, according to the modification of melanoma guidelines, all patients with detectable metastatic lymph nodes underwent PMLVA during CLND (Group 2). The frequency of lymphedema in subjects undergoing PMLVA was compared with the control group. Results: Database evaluation revealed 172 patients with melanoma of the trunk with follow-up information for at least 6 mounts. Twenty-three patients underwent PMLVA during CLND until March 2018, 29 from April 2018, and 120 subjects underwent CLND without any preventive surgery (control Group). The frequency of SL was significantly lower in both Group 1 (4.3% vs. 24.2%, p = 0.03) and Group 2 (3.5%, p = 0.01). Patients undergoing PMLVA showed a similar recurrence-free periods and overall survival when compared to the control group. Conclusions: PMLVA significantly reduces the frequency of SL both in immediate and delayed CLND. This procedure is safe and does not lead to an increase in length of hospitalization.

Pharmacokinetics of a retrograde infusion of Paclitaxel into the thoracic duct in a porcine model

Gastrointestinal cancer with massive nodal metastases is a lethal disease. In this study, using a porcine model, we attempted to infuse the anti-cancer drug, Paclitaxel (PTX), into the thoracic duct to examine the efficiency of drug delivery to intra-abdominal lymph nodes. We established a technical method to catheterize the thoracic duct in the necks of pigs. Serum, liver, and spleen concentrations of PTX were significantly lower after thoracic duct (IT) infusion than after intravenous (IV) administration. Approximately 12–24 h after infusion, PTX concentrations in abdominal lymph nodes tended to be higher with IT than with IV infusion; however, increased levels of PTX were much lower than expected. Unexpectedly, concentrations of PTX in urine were much higher after IT administration than after IV administration, demonstrating that most PTX administered via the thoracic duct was promptly excreted from the kidneys. These findings suggest that infusion of anti-cancer drugs into the thoracic duct will not produce clinical benefits for patients with extensive lymphatic metastases in abdominal malignancies.

Long non-coding RNA Lnc-408 promotes invasion and metastasis of breast cancer cell by regulating LIMK1

Invasion and metastasis are the leading causes of death in patients with breast cancer (BC), and epithelial-mesenchymal transformation (EMT) plays an essential role in this process. Here, we found that Lnc-408, a novel long noncoding RNA (lncRNA), is significantly upregulated in BC cells undergoing EMT and in BC tumor with lymphatic metastases compared with those without lymphatic metastases. Lnc-408 can enhance BC invasion and metastasis by regulating the expression of LIMK1. Mechanistically, Lnc-408 serves as a sponge for miR-654-5p to relieve the suppression of miR-654-5p on its target LIMK1. Knockdown or knockout of Lnc-408 in invasive BC cells clearly decreased LIMK1 levels, and ectopic Lnc-408 in MCF-7 cells increased LIMK1 expression to promote cell invasion. Lnc-408-mediated enhancement of LIMK1 plays a key role in cytoskeletal stability and promotes invadopodium formation in BC cells via p-cofilin/F-actin. In addition, the increased LIMK1 also facilitates the expression of MMP2, ITGB1, and COL1A1 by phosphorylating CREB. In conclusion, our findings reveal that Lnc-408 promotes BC invasion and metastasis via the Lnc-408/miR-654-5p/LIMK1 axis, highlighting a novel promising target for the diagnosis and treatment of BC.

Lymphatic metastases have more diverse roots than distant metastases

Both lymphatic and distant metastases arise through cancer cell migration and colonization of ectopic sites. Nonetheless, the two metastasis types are associated with significantly different clinical outcomes, suggesting that distinct biological mechanisms may drive their formation. Here we show fundamental differences in the seeding patterns of lymphatic and distant metastases. Analyzing the reconstructed phylogenies of human colorectal cancers, we find that distant metastases typically are monophyletic, originating from one common ancestor. Lymphatic metastases, in contrast, are almost exclusively polyphyletic and can be seeded from many primary tumor regions. We develop a rigorous mathematical framework for quantifying the phylogenetic diversity of metastases while accounting for differential lesion sampling among patients. Our results indicate that a smaller fraction of primary tumor cells gives rise to distant metastases than lymphatic metastases. Thus, the two metastasis types exhibit profoundly distinct phylogenetic traits, indicating that different evolutionary mechanisms may drive their formation and influence their clinical behavior.