Preventing skin toxicities induced by EGFR inhibitors by topically blocking drug-receptor interactions.

Epidermal growth factor receptor (EGFR) inhibitors are used to treat many advanced-stage epithelial cancers but induce severe skin toxicities in most treated patients. These side effects lead to a deterioration in the quality of life of the patients and compromise the anticancer treatment. Current treatment strategies for these skin toxicities focus on symptom reduction rather than preventing the initial trigger that causes the toxicity. In this study, we developed a compound and method for treating "on-target" skin toxicity by blocking the drug at the site of toxicity without reducing the systemic dose reaching the tumor. We first screened for small molecules that effectively blocked the binding of anti-EGFR monoclonal antibodies to EGFR and identified a potential candidate, SDT-011. In silico docking predicted that SDT-011 interacted with the same residues on EGFR found to be important for the binding of EGFR inhibitors cetuximab and panitumumab. Binding of SDT-011 to EGFR reduced the binding affinity of cetuximab to EGFR and could reactivate EGFR signaling in keratinocyte cell lines, ex vivo cetuximab-treated whole human skin, and A431-injected mice. Specific small molecules were topically applied and were delivered via a slow-release system derived from biodegradable nanoparticles that penetrate the hair follicles and sebaceous glands, within which EGFR is highly expressed. Our approach has the potential to reduce skin toxicity caused by EGFR inhibitors.

Ex-vivo Skin Permeability Tests of Nanoparticles for Microscopy Imaging.

Delivery of drugs through the skin is a major challenge in the field of drug delivery systems. Quantification of materials, and specifically nanoparticles, within the skin layers is essential for the development of advanced topical and transdermal delivery systems. We have developed a technique for ex-vivo segmentation and evaluation of human skin samples treated with fluorescent nanoparticles. The method is based on horizontal cryosections of skin samples, followed by confocal microscopy and image analysis. This protocol is relatively simple to perform with basic histological tools, thus it can serve for various dermatology assays.

Redefining the Reconstructive Ladder in Vulvoperineal Reconstruction: The Role of Pedicled Perforator Flaps.

BACKGROUND: Gynecological reconstruction is difficult, particularly in cases with recurrence and received previous surgeries and/or radiotherapy and necessitate secondary reconstruction. Perforator flaps can preserve other donor sites for potential later reconstruction, and they also can be better tailored to the defect. We hypothesized that the use of perforator-based flaps can better restore the defect with less complications. METHODS: A retrospective review was conducted of all patients who underwent vulvar-perineum reconstruction between 2011 and 2018 by the senior author, and oncologic and reconstructive outcomes and complications were analyzed. RESULTS: Thirty-three patients underwent 55 soft tissue reconstructions for vulvar-perineum defects during the study period. The mean follow-up time was 27.6 ± 28.9 months. Squamous cell carcinoma was the most common cancer (45.5%). For 11 patients (33.3%), the procedures were performed for the treatment of recurrent cancer. The average defect size was 39.8 ± 34.3 cm2. The overall survival rate was 90.3%. Profunda artery perforator flaps were the most commonly applied flap for reconstruction in both the primary and recurrent groups. Poor wound healing was the most common complication which occurred in 10 of the 55 flaps (18.2%). Perforator flaps presented fewer complications than myocutaneous flaps or traditional random flaps. Similarly, Island pedicle flap design also presented fewer complications than traditional rotation flaps. With proper reconstruction, previous surgery or radiotherapy did not contribute to an increase in complications. CONCLUSION: In our experience, perforator flaps can provide satisfactory reconstruction for perineum reconstruction with low postoperative complications while preserving other donor sites in the event of disease recurrence for repeat resection and reconstruction. Previous surgery or radiotherapy did not increase the complications or preclude its usage. A redefined reconstructive ladder was created to help selecting the best state-of-the-art technique for reconstruction to achieve better results.

Objective and quantifiable measuring mechanism for assessing flap pliability: Our experience with 92 patients.

BACKGROUND: Pliability describes a flaps' ability to bend under spatial limitations, yet a quantifiable measurement for this flexibility does not exist. METHODS: Between January 2015 and January 2017, we applied a novel measuring mechanism to two free flaps for head and neck reconstruction. We allocated a flap pliability score (FPS) to these flaps and observed correlations to common variables. RESULTS: Forty profunda artery perforator (PAP) and 52 anterolateral thigh (ALT) flaps were allotted a score depending on how pliable they performed on our test. Proximal PAP and distal ALT were more pliable than their respective opposite ends. Other interesting conclusions regarding these flaps were also made. CONCLUSIONS: With our technique, pliability of the proximal and distal ends of PAP and ALT flaps was ascertained. Herein, we describe an innovative measuring mechanism via which we can allocate a FPS to any flap and thus obtain information regarding how suitable they are for a given recipient site.

Complications of Post-Burn Tissue Expansion Reconstruction: 9 Years Experience with 42 Pediatric and 26 Adult Patients.

BACKGROUND: Burn scar reconstruction is extremely challenging, even for the most proficient reconstructive surgeon. Within the arsenal of tools at the plastic surgeon's disposal, tissue expansion provides an efficient modality for reconstruction despite the reported complication rates. OBJECTIVES: To critically review our experience with tissue expansion for burn scar reconstruction, comparing particularly the adult and pediatric populations. METHODS: We conducted a retrospective study of the outcomes of patients who underwent burn scar reconstruction with tissue expansion at Hadassah Medical Center between January 2003 and July 2012. The data included patient age, anatomical site of expansion, number of procedures, and associated complications. The outcomes of the above-mentioned populations were also compared with those in a control group of patients undergoing reconstruction with tissue expansion for indications other than burn scars. RESULTS: Sixty-seven tissue expansion procedures were carried out in 50 patients, 42 in the pediatric population (< 16 years of age) and 25 in the adult population. Complications were observed in 10 of the 42 pediatric procedures (23.8%) and in 3 of the 25 adult procedures (12%). This difference was found to be statistically significant. When the complication rate for each population was compared to its control group (tissue expansion for indications other than burn scar reconstruction, such as reconstruction for motor vehicle accident scarring, congenital nevi, or vascular malformations), no statistically significant difference was found between them (complication rates 19.8% and 12.5%, respectively). Furthermore, there was no statistically significant difference in complication rates between the different anatomical areas of expansion within both populations undergoing burn scar reconstruction. Most of the complicated cases completed successful reconstruction. CONCLUSIONS: Tissue expansion is a useful surgical tool in post-burn scar reconstruction, both in the adult and pediatric populations and in all anatomic sites, despite consistently high complication rates, especially in the pediatric population. This complication rate is not higher than in patients undergoing tissue expansion for indications other than burn scar reconstruction.

Expanded bi-pedicled "sleeve" flap for reconstruction of the upper extremity after large circumferential nevus excision in children.

BACKGROUND: Large congenital melanocytic nevi entail significant medical and cosmetic ramifications for patients and families. Reconstruction is a challenging endeavor, especially when the lesion is present on the limbs. The literature describes various methods by which a plastic surgeon can address reconstruction; yet, to date, there has been no series describing a method that provides consistent results with low complication rates. In this study, we describe our surgical technique for reconstruction of the upper extremity after excision of large circumferential CNM with a pre-expanded bi-pedicled flap, namely the "sleeve" flap. METHODS: A systematic review of our database of pediatric patients treated for large and giant nevi was performed. Patients with large and giant circumferential upper extremity nevi were retrieved, and their charts reviewed for demographics, number of procedures performed, duration of follow-up, and complications. RESULTS: Over a course of 12 years, eight patients with large or giant circumferential nevi of the upper extremity were treated at our institution with "sleeve" flap reconstruction. Mean follow-up time was 36 months. A single complication was seen. All reconstructions achieved satisfactory results, both functionally and cosmetically. DISCUSSION: We describe our surgical approach for treating upper extremity large and giant circumferential nevi with pre-expanded bi-pedicled "sleeve" flaps. When properly planned and executed, this technique enables successful treatment of large and giant nevi of the arm and the forearm. Although arduous and complex, the process yields excellent aesthetic results with low complication rates. This technique is promising as the reconstructive option of choice for these difficult lesions.

Complications of nonbreast tissue expansion: 9 Years experience with 44 adult patients and 119 pediatric patients.

BACKGROUND: Tissue expansion is a common reconstructive technique that has been associated with significant complications since its inception. However, the existing literature mostly focuses on complications associated with pediatric tissue expansion only or describes a combined population of adult and pediatric patients, including breast tissue expansion; despite the fact that each of these groups of patients has different characteristics that may affect tissue expansion. OBJECTIVE: In this study we present a critical review of our experience with complications of nonbreast tissue expansion in adult and pediatric patients and compare between these groups. METHODS: The charts of patients who underwent nonbreast tissue expansion at Hadassah Medical Center between January 2003 and July 2012 were reviewed. Data were collected including the age of the patient, anatomical site of the expansion, indication and complications. RESULTS: A total of 202 expansion procedures were performed on 119 pediatric patients (<16 years) and 56 expansion procedures on 44 adult patients. The overall complication rate was 18.2%, with 40 pediatric procedures having complications (19.8%) and 7 adult procedures (12.5%). The difference in complication rates between the two groups was not found to be statistically significant. There was no statistically significant difference in complication rate between the different anatomical areas of expansion in both adult and pediatric patients or between the indications for operation. Most (68%) of the cases with complications underwent subsequent successful reconstruction. CONCLUSIONS: Despite the consistent high complication rate, tissue expansion can be used as a good reconstructive method in both adult and pediatric patients in all anatomic areas and for different indications.