Management of irradiated post-mastectomy wound dehiscence with synthetic electrospun fiber matrix: a case report.

Breast-conserving surgery (BCS) is a well-established standard treatment option alternative to mastectomy for patients with early breast cancer that consists of a lumpectomy followed by adjuvant radiotherapy. However, irradiated tissues are at an increased risk of wound healing complications when post-treatment surgical management is required. The management of an irradiated wound dehiscence can be challenging, as it often requires a multimodal treatment approach that includes more invasive interventions when compared to a traditional surgical wound dehiscence. We present a 64 year old female patient with a remote history of right BCS with radiation therapy for early breast cancer 12 years ago, who recently required a simple mastectomy due to ipsilateral breast cancer recurrence. The post-operative course was complicated by dehiscence of the mastectomy wound. After standard wound care therapies failed, her surgical wound successfully healed after treatment with a synthetic electrospun fiber matrix application. Patients with additional comorbidities often do not qualify for invasive reconstructive options; therefore, effective local management options are warranted. This is the first reported case documenting synthetic electrospun fiber matrix efficacy and safety in healing a dehisced surgical wound within a previously irradiated fibrotic area, without the need for further invasive surgical intervention. Larger scale research, such as a prospective cohort study or randomized control trial, is needed to investigate its novel use in irradiated wounds.

Impact of intra-abdominal insufflation pressure on gas leakage occurring during laparoscopy.

INTRODUCTION: The advent of the COVID-19 pandemic led to recommendations aimed at minimizing the risk of gas leaks at laparoscopy. As this has continuing relevance including regarding operating room pollution, we empirically quantified carbon dioxide (CO2) leak jet velocity (important for particle propulsion) occurring with different instruments inserted into differing trocars repeated across a range of intra-abdominal pressures (IAPs) and modern insufflators in an experimental model. METHOD: Laparoscopic gas plume leak velocity (metres/second) was computationally enumerated from schlieren optical flow videography on a porcine cadaveric laparoscopic model with IAPs of 4-5, 7-8, 12-15 and 24-25 mmHg (repeated with 5 different insufflators) during simulated operative use of laparoscopic clip appliers, scissors, energy device, camera and staplers as well as Veres needle (positive control) and trocar obturator (negative control) in fresh 5 mm and 12 mm ports. RESULTS: Close-fitting solid instruments (i.e. cameras and obturators) demonstrated slower gas leak velocities in both the 5 mm and 12 mm ports (p = 0.02 and less than 0.001) when compared to slimmer instruments, however, hollow instrument designs were seen to defy this pattern with the endoscopic linear stapler visibly inducing multiple rapid jests even when compared to similarly sized clip appliers (p = 0.03). However, on a per device basis the operating instrumentation displayed plume speeds which did not vary significantly when challenged with varying post size, IAP and a range of insufflators. CONCLUSION: In general, surgeon's selection of instrument, port or pressure does not usefully mitigate trocar CO2 leak velocity. Instead better trocar design is needed, helped by a fuller understanding of trocar valve mechanics via computational fluid dynamics informed by relevant surgical modelling.

A gain-of-functional screen identifies the Hippo pathway as a central mediator of receptor tyrosine kinases during tumorigenesis.

The Hippo pathway has emerged as a key signaling pathway that regulates various biological functions. Dysregulation of the Hippo pathway has been implicated in a broad range of human cancer types. While a number of stimuli affecting the Hippo pathway have been reported, its upstream kinase and extracellular regulators remain largely unknown. Here we performed the first comprehensive gain-of-functional screen for receptor tyrosine kinases (RTKs) regulating the Hippo pathway using an RTK overexpression library and a Hippo signaling activity biosensor. Surprisingly, we found that the majority of RTKs could regulate the Hippo signaling activity. We further characterized several of these novel relationships [TAM family members (TYRO3, AXL, METRK), RET, and FGFR family members (FGFR1 and FGFR2)] and found that the Hippo effectors YAP/TAZ are central mediators of the tumorigenic phenotypes (e.g., increased cell proliferation, transformation, increased cell motility, and angiogenesis) induced by these RTKs and their extracellular ligands (Gas6, GDNF, and FGF) through either PI3K or MAPK signaling pathway. Significantly, we identify FGFR, RET, and MERTK as the first RTKs that can directly interact with and phosphorylate YAP/TAZ at multiple tyrosine residues independent of upstream Hippo signaling, thereby activating their functions in tumorigenesis. In conclusion, we have identified several novel kinases and extracellular stimuli regulating the Hippo pathway. Our findings also highlight the pivotal role of the Hippo pathway in mediating Gas6/GDNF/FGF-TAM/RET/FGFR-MAPK/PI3K signaling during tumorigenesis and provide a compelling rationale for targeting YAP/TAZ in RTK-driven cancers.

PI3K Positively Regulates YAP and TAZ in Mammary Tumorigenesis Through Multiple Signaling Pathways.

Breast cancer is a leading cause of death in women worldwide. Active mutations of PI3K catalytic subunit PIK3CA (e.g., H1047R) and amplification of its homolog PIK3CB are observed in a large number of breast cancers. In recent years, aberrant activation of Transcriptional coactivator with PDZ binding motif (TAZ) and its paralog Yes-associated protein (YAP) have also been found to be important for breast cancer development and progression. However, whether PI3K interacts with YAP/TAZ during mammary tumorigenesis is unknown. Through a systematic gain-of-function screen for kinases involved in mammary tumorigenesis, we identified PIK3CB as a transformation-inducing kinase in breast cells. We further determined that PIK3CB positively regulates YAP and TAZ to promote transformation and inhibit mammary cell death in vitro PIK3CB coexpression with TAZ, rather than PIK3CB or TAZ alone, in human MCF10A nontumorigenic mammary cells is sufficient for tumor formation in mice in vivo Interestingly, we also determined that PIK3CA-H1047R enhances YAP and TAZ activity in mammary tumorigenesis in vitro Mechanistically, the regulation of YAP/TAZ by both PIK3CA and PIK3CB occurs through multiple signaling pathways including LATS-dependent and LATS-independent pathways. Therefore, in this study, we determine that PI3K and YAP/TAZ interact to promote breast cancer cell transformation.Implications: This study provides the first evidence that the Hippo pathway effectors TAZ and YAP are critical mediators of PI3K-induced mammary tumorigenesis and synergistically function together with PI3K in transformation of mammary cells. These findings may provide a novel rationale for targeting YAP/TAZ alone or in combination with PI3K inhibitors for breast cancer therapy in the future. Mol Cancer Res; 16(6); 1046-58. ©2018 AACR.