Breast cancer-related lymphedema results in impaired epidermal differentiation and tight junction dysfunction.

Breast cancer-related lymphedema (BCRL) is characterized by skin changes, swelling, fibrosis, and recurrent skin infections. Clinical studies have suggested that lymphedema results in skin barrier defects; however, the underlying cellular mechanisms and the effects of bacterial contamination on skin barrier function remain unknown. In matched biopsies from patients with unilateral BCRL, we observed decreased expression of filaggrin and the tight junction protein zona occludens-1 (ZO-1) in skin affected by moderate lymphedema, or by subclinical lymphedema in which dermal backflow of lymph was identified by indocyanine green lymphography, relative to controls (areas without backflow and from the unaffected arm). In vitro stimulation of keratinocytes with lymph fluid obtained from patients undergoing lymphedema surgery led to the same changes, as well as increased expression of keratin 14, a marker of immature keratinocytes. Finally, using mouse models of lymphedema, we showed that like the clinical scenario, the expression of skin barrier proteins was decreased relative to normal skin and that colonization with S. epidermidis bacteria amplified this effect, as well as lymphedema severity. Taken together, our findings suggest that lymphatic fluid stasis contributes to skin barrier dysfunction in lymphedema.

Permanent Compared With Absorbable Suture in Apical Prolapse Surgery: A Systematic Review and Meta-analysis.

OBJECTIVE: To explore how permanent compared with absorbable suture affects anatomic success in native tissue vaginal suspension (uterosacral ligament suspension and sacrospinous ligament suspension) and sacrocolpopexy with mesh. DATA SOURCES: MEDLINE, EMBASE, and ClinicalTrials.gov were searched through March 29, 2022. METHODS OF STUDY SELECTION: Our population included women undergoing apical prolapse surgery (uterosacral ligament suspension and sacrospinous ligament suspension and abdominal sacrocolpopexy). Our intervention was permanent suture for apical prolapse surgery, and our comparator was absorbable suture. We determined a single anatomic success proportion per study. Adverse events collected included suture and mesh exposure, surgery for suture and mesh complication, dyspareunia, and granulation tissue. Abstracts were doubly screened, full-text articles were doubly screened, and accepted articles were doubly extracted. Quality of studies was assessed using GRADE (Grading of Recommendations Assessment, Development and Evaluation) criteria. In single-arm studies using either permanent or absorbable suture, random effects meta-analyses of pooled proportions were used to assess anatomic success. In comparative studies investigating both suture types, random effects meta-analyses of pooled risk ratios were used. TABULATION, INTEGRATION, AND RESULTS: Of 4,658 abstracts screened, 398 full-text articles were assessed and 63 studies were included (24 vaginal suspension [13 uterosacral ligament suspension and 11 sacrospinous ligament suspension] and 39 sacrocolpopexy). At 2-year follow-up, there was no difference in permanent compared with absorbable suture in uterosacral ligament suspension and sacrospinous ligament suspension (proportional anatomic success rate 88% [95% CI 0.81-0.93] vs 88% [95% CI 0.82-0.92]). Similarly, at 18-month follow-up, there was no difference in permanent compared with absorbable suture in sacrocolpopexy (proportional anatomic success rate 92% [95% CI 0.88-0.95] vs 96% [95% CI 0.92-0.99]). On meta-analysis, there was no difference in relative risk (RR) of success for permanent compared with absorbable suture for uterosacral ligament suspension and sacrospinous ligament suspension (RR 1.11, 95% CI 0.93-1.33) or sacrocolpopexy (RR 1.00, 95% CI0.98-1.03). CONCLUSION: Success rates were similarly high for absorbable and permanent suture after uterosacral ligament suspension, sacrospinous ligament suspension, and sacrocolpopexy, with medium-term follow-up. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42021265848.

Dysregulation of Lymphatic Endothelial VEGFR3 Signaling in Disease.

Vascular endothelial growth factor (VEGF) receptor 3 (VEGFR3), a receptor tyrosine kinase encoded by the FLT4 gene, plays a significant role in the morphogenesis and maintenance of lymphatic vessels. Under both normal and pathologic conditions, VEGF-C and VEGF-D bind VEGFR3 on the surface of lymphatic endothelial cells (LECs) and induce lymphatic proliferation, migration, and survival by activating intracellular PI3K-Akt and MAPK-ERK signaling pathways. Impaired lymphatic function and VEGFR3 signaling has been linked with a myriad of commonly encountered clinical conditions. This review provides a brief overview of intracellular VEGFR3 signaling in LECs and explores examples of dysregulated VEGFR3 signaling in various disease states, including (1) lymphedema, (2) tumor growth and metastasis, (3) obesity and metabolic syndrome, (4) organ transplant rejection, and (5) autoimmune disorders. A more complete understanding of the molecular mechanisms underlying the lymphatic pathology of each disease will allow for the development of novel strategies to treat these chronic and often debilitating illnesses.