Neurofibromin Deficiency and Extracellular Matrix Cooperate to Increase Transforming Potential through FAK-Dependent Signaling

Simple SummaryNeurofibromatosis type 1 is a genetic disease that predisposes to tumors of the nervous system, primarily the neurofibroma. Plexiform neurofibromas (Pnfs) are of the greatest concern because of location, size, and frequent progression to malignancy. Although research is making great progress, the lack of in-depth understanding of the molecular mechanisms driving neoplastic progression results in the absence of prognostic indicators and therapeutic targets. We document that cell-cell cooperativity and the dynamics of the extracellular matrix play important roles in the growth and transformation of Pnf cells, directly through the cooperation of RAS and focal adhesion kinase (FAK) signaling. In turn, we found that treatment of Pnf cells with both MEK and FAK inhibitors is effective in abolishing the transforming ability of these cells.Plexiform neurofibromas (Pnfs) are benign peripheral nerve sheath tumors that are major features of the human genetic syndrome, neurofibromatosis type 1 (NF1). Pnfs are derived from Schwann cells (SCs) undergoing loss of heterozygosity (LOH) at the NF1 locus in an NF1(+/-) milieu and thus are variably lacking in the key Ras-controlling protein, neurofibromin (Nfn). As these SCs are embedded in a dense desmoplastic milieu of stromal cells and abnormal extracellular matrix (ECM), cell-cell cooperativity (CCC) and the molecular microenvironment play essential roles in Pnf progression towards a malignant peripheral nerve sheath tumor (MPNST). The complexity of Pnf biology makes treatment challenging. The only approved drug, the MEK inhibitor Selumetinib, displays a variable and partial therapeutic response. Here, we explored ECM contributions to the growth of cells lacking Nfn. In a 3D in vitro culture, NF1 loss sensitizes cells to signals from a Pnf-mimicking ECM through focal adhesion kinase (FAK) hyperactivation. This hyperactivation correlated with phosphorylation of the downstream effectors, Src, ERK, and AKT, and with colony formation. Expression of the GAP-related domain of Nfn only partially decreased activation of this signaling pathway and only slowed down 3D colony growth of cells lacking Nfn. However, combinatorial treatment with both the FAK inhibitor Defactinib (VS-6063) and Selumetinib (AZD6244) fully suppressed colony growth. These observations pave the way for a new combined therapeutic strategy simultaneously interfering with both intracellular signals and the interplay between the various tumor cells and the ECM

Huriez syndrome associated with basal cell carcinoma. A case report

Huriez syndrome is a rare cancer-prone genodermatosis confined to the hands and feet connects with an increase in squamous cell carcinoma on affected skin. Its diagnosis is complex due to not well defined symptoms and since only few cases are described in literature. The differential diagnoses are many and the treatment is focused only on symptoms control and tumours eradication. Our case report is highly interesting because add new knowledge about this disease describing a new important feature of the syndrome. For the first time in literature we describe the arising of basal cell carcinoma from affected skin. KEY WORDS: H, Basal cell carcinoma, Huriez syndrome, Palmoplantar keratoderma

The McKissock's technique in reduction mammaplasty: A comparative study of outcomes and complications in 211 consecutive patients

Reduction mammaplasty is one of the most popular plastic surgery procedures requested by patients. The areola holding flap can be sculpted using a variety of methods that have evolved over time dependent on vascularity. Our institution has always employed the vertical bipedicle technique proposed by Mckissock, and we still favor it over other methods for larger breasts. In this study, we examined the case-study data from the Padua University Hospital's Unit of Plastic and Reconstructive Surgery from January 2009 to December 2021. The rate of complications among patients who received breast reduction using the McKissock technique and all other procedures carried out at our facility was compared. We identified 90 postoperative problems in all (affecting 42.65% of the patients) and categorized them using the Clavien Dindo system. The groups were comparable in age, BMI, and follow-up time. Similar findings emerged from the study of the single groups' complication rate. The statistical analysis did not reveal any appreciable variation in total complications or scar quality across groups. Therefore, in order to guarantee NAC survival, a stable shape, and a full upper pole, we think it is preferable to bind more than one pedicle in cases of very large breasts. Based on the results of our experience, we also recommend the McKissock approach as the first option for patients with large and ptotic breasts, particularly those who have undergone bariatric surgery and need a full upper pole and a stable outcome

Persistent Sciatic Artery and its role in limb salvage in oncological surgery

The Persistent Sciatic Artery (PSA) is a rare congenital anomaly due to missed involution of embryo-fetal sciatic artery, which is the main blood supply to lower limb during embryonic development until superficial femoral artery (SFA) is formed. The PSA is frequently related to complications in adults like aneurysm and embolism. Here we present a case in which the discovery of a complete PSA resulted limb saving. In case of oncologic or trauma surgery, when no other options are available, the PSA can help in management of reconstructive surgery

Retrospective Analysis of Predictive Factors for Complications in Abdominoplasty in Massive Weight Loss Patients

Introduction Ex-obese patients present with redundancy of abdominal skin and soft tissue due to massive weight loss (MWL). The plastic surgeon can restore the body shape through body contouring procedures. Hence the need to adequately direct patients to body contouring by identifying suitable candidates exists. Our work aims to retrospectively analyze the abdominoplasty complications in our case series to identify associated risk factors and evaluate the effect of combined procedures on abdominoplasty outcomes.Materials and Methods We retrospectively investigated predictive factors of abdominoplasty procedure complications on 213 MWL patients who received abdominoplasty with and without rectus sheath plication, abdominal liposuction, and other body contouring procedures. We identified risk and protective factors with univariate and multivariate regression analysis. Furthermore, we assessed the impact of additional procedures on the complication rates.Results The overall complication rate was 49.8% (26.8% minor complications; 23% major complications). The delayed wound healing rate was 27.7%, and the revision surgery rate was 25.8% (14.7% early revision; 14.2% late revision). These results were compared with literature reports. Several negative predictors emerged as non-modifiable (advanced age, diabetes mellitus, surgical mode of weight loss) or modifiable (preoperative obesity and body mass index (BMI); active smoking; preoperative anemia; use of fibrin glue or quilting sutures). Performing rectus sheath plication improved most of the outcomes. Liposuction of hypochondriac regions and flanks led to increased safety and reduced the risk of surgical dehiscence and delayed wound healing, in contrast to epimesogastric liposuction. The other combined body contouring procedures did not worsen the outcomes, except for poor scarring.Conclusion Our findings encourage us to continue associating rectus sheath plication, liposuction, and other body contouring surgeries with abdominoplasty. We emphasize the importance of proper patient selection, particularly with regard to anemia, before body contouring surgery in the interests of offering safe surgery and satisfactory results. Further studies are needed to investigate how the optimal BMI cut-off and abstinence from smoking (in terms of time) before surgery reduce postoperative complications