Citations

Abstract The ability of breast cancer cells to transiently transition between epithelial and mesenchymal states contributes to their metastatic potential. Therefore, driving tumor cells into a stable mesenchymal state, as opposed to complete tumor cell eradication, presents an opportunity to pharmacologically limit disease progression by promoting an asymptomatic state of dormancy. Here, we compare a reversible model of epithelial–mesenchymal transition (EMT) induced by TGFβ to a stable mesenchymal phenotype induced by chronic exposure to the ErbB kinase inhibitor lapatinib. Only cells capable of returning to an epithelial phenotype resulted in skeletal metastasis. Gene expression analyses of the two mesenchymal states indicated similar transition expression profiles. A potently downregulated gene in both datasets was spleen tyrosine kinase (SYK). In contrast to this similar diminution in mRNA, kinome analyses using a peptide array and DNA-conjugated peptide substrates showed a robust increase in SYK activity upon TGFβ-induced EMT only. SYK was present in cytoplasmic RNA processing depots known as P-bodies formed during the onset of EMT, and SYK activity was required for autophagy-mediated clearance of P-bodies during mesenchymal–epithelial transition (MET). Genetic knockout of autophagy-related 7 (ATG7) or pharmacologic inhibition of SYK activity with fostamatinib, a clinically approved inhibitor of SYK, prevented P-body clearance and MET, inhibiting metastatic tumor outgrowth. Overall, this study suggests assessment of SYK activity as a biomarker for metastatic disease and the use of fostamatinib as a means to stabilize the latency of disseminated tumor cells. Significance: These findings present inhibition of spleen tyrosine kinase as a therapeutic option to limit breast cancer metastasis by promoting systemic tumor dormancy. See related commentary by Farrington and Narla, p. 1756

BackgroundEnd‐stage lower extremity lymphedema (LEL) poses a particularly formidable challenge to surgeons as multiple pathological processes are at work. Because single modality treatment is often unsuccessful, we devised a comprehensive multimodal surgical treatment. The aim of this study is to share the technical considerations and examine the clinical outcomes of this combined approach.MethodsBetween 2013 and 2017, patients with International Society of Lymphology stage III, who underwent the combination treatment of Charles,’ Homan’s procedure with toe management and vascularized lymph node transfer (CHAHOVA), were included in this retrospective study. Outcomes evaluated were limb size, number of infectious episodes, compression garment usage, and rate of complications.ResultsA total of 68 patients were included. With a mean follow‐up of 29 months, the overall circumference reduction rate for the upper thigh and the rest of the extremity was 67.4% (48.2‐88.2%) and 98.1% (88‐100%), respectively. During the follow‐ups, 2 (2.9%) patients experienced episodes of cellulitis and the average number of yearly infections decreased from 4.2 to 1.2 episodes per person. All patients were able to discontinue compression therapy without recurrence of lymphedema. Nine (13.2%) patients reported minor complications.ConclusionThe combine CHAHOVA in a single‐stage procedure is an effective and safe approach in the end‐stage LEL.

BackgroundTreatment of advanced lymphedema requires not only restoration of physiological lymph drainage, but also excision of fibrotic tissue and excess skin. The aim of this study is to show how the combination of double vascularized lymph node transfers (VLNTs) and a modified radical reduction with preservation of perforators (RRPP) can accomplish both of these treatment goals.MethodsBetween 2010 and 2016, 16 patients (15 female and one male) with extremity lymphedema underwent a combined double gastroepiploic VLNTs and modified RRPP. Demographics, outcomes including circumference reduction rates, preoperative and postoperative lymphoscintigraphy, complications, and responses to the Lymphedema Quality of Life (LYMQOL) questionnaire were analyzed.ResultsAll flaps survived. The mean follow‐up period was 14.2 months (range, 12‐19). The mean circumference reduction rate was 74.5% ± 6.9% for the upper limb and 68.0% ± 4.2% for the lower limb. There were no major complications. Minor complications, including numbness and hyperesthesia, were treated conservatively. LYMQOL showed a 2.7‐fold quality‐of‐life improvement (P < 0.01). Postoperative lymphoscintigraphy showed improved lymphatic drainage in all cases.ConclusionCombined double VLNTs and modified RRPP safely and effectively improves lymphatic drainage, reduces fibrotic tissue and excess skin, decreases episodes of infections, and improves patients’ quality of life in the advanced stages of lymphedema.