Characterization of Medical Malpractice Litigation After Rhinoplasty in the United States.

BACKGROUND: When complications following rhinoplasty occur or when the desired outcome is not achieved, patients may seek litigation on the premise that there was a violation in the standard of care. Knowledge of malpractice claims can inform rhinoplasty surgeons on how to minimize risk of future litigation as well as improve patient satisfaction. OBJECTIVES: The aims of this study were to identify motives for seeking medical malpractice litigation after rhinoplasty, and to examine outcomes of malpractice litigation after rhinoplasty in the United States. METHODS: The Westlaw legal database was reviewed for all available court decisions related to malpractice after rhinoplasty. Data collected and analyzed included plaintiff gender, location, specialty of defendant(s), plaintiff allegation, and adjudicated case outcomes. RESULTS: Twenty-three cases were identified between 1960 and 2018, located in 12 US states; 70% of the plaintiffs were female. Otolaryngologists were cited in 11 cases, whereas 12 cases involved a plastic surgeon. All cases alleged negligence. Cases involved "technical" errors (69.6%), "unsatisfactory" outcomes (39.1%), inadequate follow-up or aftercare (30.4%), issues with the informed consent process (21.7%), unexpectedly extensive surgery (8.7%), improper medication administration (4.3%), and failure to recognize symptoms (4.3%). Twenty of the 23 adjudicated cases (86.9%) were ruled in favor of the surgeon. The main contributing factor in cases alleging malpractice was poor aesthetic outcome/disfigurement (60.7%). CONCLUSIONS: Malpractice litigation after rhinoplasty favored the surgeon in the majority of the adjudicated cases reviewed. The principal reason for litigating was dissatisfaction with aesthetic outcomes. Rhinoplasty surgeons may mitigate possible litigation by developing a positive doctor-patient relationship, clearly understanding the patient's surgical expectations, and obtaining detailed informed consent while maintaining frequent and caring communication with the patient.

Neurotoxins.

Botulinum toxin is integral to the practice of facial plastic surgery. Since it was approved by the U.S. Food and Drug Administration for the temporary improvement of glabellar rhytids in 2002, botulinum toxin has achieved a growing number of off-label clinical applications. These include the management of facial rhytids, brow ptosis, excessive gingival display, masseteric hypertrophy, platysmal banding, facial nerve paralysis, hypertrophic scars, and keloids. Many forms of botulinum toxin have been developed, and their safety and efficacy have been thoroughly established. This article will review the aesthetic and functional uses of botulinum toxin as it relates to the field of facial plastic and reconstructive surgery. In addition, the authors will discuss the suggested quantity of units per injection site based on onabotulinumtoxinA.

Characterization of Small Molecules Inhibiting the Pro-Angiogenic Activity of the Zinc Finger Transcription Factor Vezf1.

Discovery of inhibitors for endothelial-related transcription factors can contribute to the development of anti-angiogenic therapies that treat various diseases, including cancer. The role of transcription factor Vezf1 in vascular development and regulation of angiogenesis has been defined by several earlier studies. Through construction of a computational model for Vezf1, work here has identified a novel small molecule drug capable of inhibiting Vezf1 from binding to its cognate DNA binding site. Using structure-based design and virtual screening of the NCI Diversity Compound Library, 12 shortlisted compounds were tested for their ability to interfere with the binding of Vezf1 to DNA using electrophoretic gel mobility shift assays. We identified one compound, T4, which has an IC50 of 20 µM. Using murine endothelial cells, MSS31, we tested the effect of T4 on endothelial cell viability and angiogenesis by using tube formation assay. Our data show that addition of T4 in cell culture medium does not affect cell viability at concentrations lower or equal to its IC 50 but strongly inhibits the network formation by MSS31 in the tube formation assays. Given its potential efficacy, this inhibitor has significant therapeutic potential in several human diseases.

The Novel mTOR Complex 1/2 Inhibitor P529 Inhibits Human Lung Myofibroblast Differentiation.

Idiopathic pulmonary fibrosis is a progressive and deadly disorder with very few therapeutic options. Palomid 529 (8-(1-hydroxyethyl)-2-methoxy-3-(4-methoxybenzyloxy)-benzo[c]chromen-6-one; P529) is a novel dual inhibitor of mechanistic target of rapamycin complex 1/2 (mTORC1/2). In these studies, we investigated the effect of P529 on TGF-ß-dependent signaling and myofibroblast differentiation. TGF-ß-induced phosphorylation of the mTORC1 targets, p70 S6 kinase 1 (S6K1), and eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1), were both dose dependently inhibited by P529 in human lung fibroblasts with maximal inhibition occurring between 10 and 20 µM. mTORC2-mediated phosphorylation of Akt at the S473 site was partially inhibited with a similar dose dependency, as was TGF-ß-induced myofibroblast differentiation. Protein levels of TGF-ß-induced fibronectin and collagen were similarly decreased by P529. At this dose, there was also inhibition of mRNA transcript levels for Col1 and α-SMA, suggesting inhibition of transcriptional activation. However, there was no effect of P529 on canonical TGF-ß-induced Smad signaling, as assessed by receptor-associated Smad2/3 phosphorylation, Smad2/3/4 translocation, or Smad-driven gene expression, as assessed by Smad-binding element driven luciferase. Conversely, activation of mTORC1/2 signaling was dependent on TGF-ß type I receptor (ALK5) signaling and on Smad2/3 expression. P529 treatment disrupted TGF-ß-induced actin stress fiber formation during myofibroblast differentiation, the deposition of new extracellular fibronectin matrix, and linear wound closure by fibroblasts. Likewise, mTOR knockdown inhibited TGF-ß-induced myofibroblast differentiation. In conclusion, P529 inhibits TGF-ß-induced myofibroblast differentiation, actin stress fiber formation, and matrix protein expression and deposition. Inhibition of mTORC1/2 by P529 may be a promising approach to inhibit in vivo fibrosis. J. Cell. Biochem. 118: 2241-2249, 2017. © 2017 Wiley Periodicals, Inc.

Torc1/Torc2 inhibitor, Palomid 529, enhances radiation response modulating CRM1-mediated survivin function and delaying DNA repair in prostate cancer models.

BACKGROUND: P529, a Torc1/Torc2 inhibitor, has demonstrated its potential as a radiosensitizer. However the molecular mechanisms underlying this phenomenon still need to be elucidated. Aim of this study is to dissect molecular mechanisms regulating the radiosensitizing properties of P529 in a wide panel of prostate cancer models. METHODS: Six tumor cell lines and xenograft models were used for in vitro and in vivo studies. Clonogenic survival, apoptotic, autophagic, and senescence assays were used to examine the effects of ionizing radiation (IR) alone and in combination with P529. CRM1, survivin, GSK-3ß, and DNA-DSBs expression and modulation, upon P529 and RT, were monitored by western blot. In vivo treatment response upon P529, irradiation or combination of P529 with IR was monitored by tumor volume, time to progression (TTP), and immunohistochemical analysis. RESULTS: P529 treatment induced significantly more apoptosis and DNA double-strand break (DSB) when combined with radiotherapy resulting in cellular radiosensitization and growth delay of irradiated tumor xenografts. Upon P529 treatment Rad51, DNA-PKcs, and Ku70 protein expression was downregulated, indicating delayed DNA double-strand damage repair. The radiosensitizing properties of P529 were partially linked to GSK-3ß, cyclin-D1, and c-myc modulation with associated inhibition of CRM1-mediated nuclear export of survivin. Importantly, autophagy and tumor senescence were involved in the enhanced P529 radioresponse. CONCLUSIONS: Impaired DNA double-strand damage repair, inhibition of CRM1-mediated nuclear export of survivin, modulation of cyclin-D1 and c-myc with associated pro-apoptotic and autophagic and senescent events explain the radiosensitizing properties of P529 in preclinical models of prostate cancer.

Dual mTORC1 and mTORC2 inhibitor Palomid 529 penetrates the blood-brain barrier without restriction by ABCB1 and ABCG2.

Palomid 529, a novel dual mTORC1/2 inhibitor has displayed interesting activities in experimental models and is a candidate for clinical evaluation. We have assessed the interaction of Palomid 529 with ATP-binding cassette (ABC) drug efflux transporters ABCB1 (P-gp/P-glycoprotein) and ABCG2 (BCRP/Breast Cancer Resistant Protein) by in vitro transwell assays, and their effects on the brain penetration using drug disposition analysis of i.v. and oral Palomid 529 in wild-type (WT) and Abcb1 and/or Abcg2 knockout (KO) mice. Palomid 529 lacked affinity for these transporters in vitro, in contrast to GDC-0941, a small molecule PI3K inhibitor, which we used as control substance for in vitro transport. The plasma AUCi.v. of micronized and DMSO formulated Palomid 529 was similar in WT and KO mice. Importantly, the brain and brain tumor concentration of Palomid 529 at a high dose (54 mg/kg) was also similar in both strains, whereas a less than 1.4-fold difference (p < 0.05) was found at the low (5.4 mg/kg) dose. Because of poor solubility, the oral bioavailability of micronized Palomid 529 was only 5%. Olive oil or spray-dried formulation greatly improved the bioavailability up to 50%. Finally, Palomid 529 effectively inhibits the orthotopic U87 glioblastoma growth. In summary, Palomid 529 is the first mTOR targeting drug lacking affinity for ABCB1/ABCG2 and having good brain penetration. This warrants further evaluation of Palomid 529 for treatment of high-grade gliomas and other intracranial malignancies.

Keloid disease can be inhibited by antagonizing excessive mTOR signaling with a novel dual TORC1/2 inhibitor.

Keloid disease (KD) is a fibroproliferative lesion of unknown etiopathogenesis that possibly targets the PI3K/Akt/mTOR pathway. We investigated whether PI3K/Akt/mTOR inhibitor, Palomid 529 (P529), which targets both mammalian target of rapamycin complex 1 (mTORC-1) and mTORC-2 signaling, could exert anti-KD effects in a novel KD organ culture assay and in keloid fibroblasts (KF). Treatment of KF with P529 significantly (P < 0.05) inhibited cell spreading, attachment, proliferation, migration, and invasive properties at a low concentration (5 ng/mL) and induced substantial KF apoptosis when compared with normal dermal fibroblasts. P529 also inhibited hypoxia-inducible factor-1α expression and completely suppressed Akt, GSK3ß, mTOR, eukaryotic initiation factor 4E-binding protein 1, and S6 phosphorylation. P529 significantly (P < 0.05) inhibited proliferating cell nuclear antigen and cyclin D and caused considerable apoptosis. Compared with rapamycin and wortmannin, P529 also significantly (P < 0.05) reduced keloid-associated phenotypic markers in KF. P529 caused tissue shrinkage, growth arrest, and apoptosis in keloid organ cultures and substantially inhibited angiogenesis. pS6, pAkt-Ser473, and mTOR phosphorylation were also suppressed in situ. P529 reduced cellularity and expression of collagen, fibronectin, and α-smooth muscle actin (substantially more than rapamycin). These pre-clinical in vitro and ex vivo observations are evidence that the mTOR pathway is a promising target for future KD therapy and that the dual PI3K/Akt/mTOR inhibitor P529 deserves systematic exploration as a candidate agent for the future treatment of KD.

Surgical Pearls: Combined Septal Extension-Columellar Strut Graft for Rhinoplasty.

Importance: The nasal tip projection, rotation, and support are essential components to address during rhinoplasty surgery. Objective: To describe a novel combined septal extension-columellar strut autologous cartilage graft for use in rhinoplasty to control tip projection, shape, and rotation while restoring strength to the nasal tip. Design: Surgical pearls-description of a novel surgical technique. Setting: An academic practice. Participants: Patients who underwent the operation.

Botulinum toxin to minimize facial scarring.

Chemoimmobilization with botulinum toxin A is an ideal biochemical agent that allows near-total elimination of muscle pull on the healing facial wound. The goal of chemoimmobilization of facial cutaneous wounds is to eliminate dynamic tension on the healing tissues to improve wound healing and minimize scarring for optimal aesthetic results.

Human acellular dermal matrix grafts for rhinoplasty.

Rhinoplasty often relies on graft material for structural support in the form of cartilage, bone grafts, or fascia. In addition, pliable grafts are often helpful for contouring and can function as a barrier. Unfortunately, grafts carry the disadvantage of requiring an additional donor site, with associated complications. Human acellular dermal matrix (ADM) biological implants offer an exciting alternative for structural support and nonstructural implantation in rhinoplasty procedures. To examine the efficacy of ADM placement in rhinoplasty and septoplasty, the authors report the results from a series of 51 patients. In this series, there were no cases of infection, skin discoloration, seroma formation, septal perforation, significant resorption, extrusion, or other complications related to ADM placement. Therefore, the authors believe that ADM offers a safe and effective alternative to traditional grafting methods for functional and aesthetic rhinoplasty.

Complications Secondary to Nonsurgical Rhinoplasty: A Systematic Review and Meta-analysis.

OBJECTIVE: The popularity of nonsurgical rhinoplasty with injectable fillers continues to rise, and it is important to understand the scope of potential adverse outcomes. The purpose of our study is to determine the prevalence and types of adverse outcomes secondary to nonsurgical rhinoplasty. DATA SOURCES: PubMed, Cochrane, Embase. REVIEW METHODS: The data sources were explored using the following combination of terms: (("inject*" OR "nonsurgical" OR "augmentation" OR "filler") AND "rhinoplast*") AND ("complication" OR "adverse" OR "embol*"). Studies on human nonsurgical rhinoplasty using injectable fillers were included. A quantitative meta-analysis was performed on articles with low risk of bias. RESULTS: The search yielded 37 publications for review, with 23 included cohort studies and 14 case reports with 8604 patients undergoing nonsurgical rhinoplasty with reported complications. The overall rate of adverse outcome across all cohort studies was 2.52%. The most commonly reported complications were bruising (1.58%) and hematoma (0.13%). While uncommon, there are several reports of major complications including 30 episodes of vessel occlusion (0.35%), 7 reports of skin necrosis (0.08%), 8 reports of vision loss (0.09%), and 6 reports of infection (0.07%). CONCLUSION: Overall, nonsurgical rhinoplasty with injectable fillers is safe with low rates of complications. However, serious complications, such as vision loss, skin necrosis, and vessel occlusion, can occur. Further studies are needed to optimize delivery of injectable fillers in the nose to decrease the rate of adverse outcomes.

Open Structure Approach to the European or Caucasian Nose.

This article discusses common abnormalities found in the European or Caucasian nose. The treatments of the disorders via open structure rhinoplasty techniques are presented in a case-based manner. Multiple references are provided for further study of these techniques.

Staphylococcus lentus Sinusitis: A New Sinonasal Pathogen.

BACKGROUND: The pathogens most commonly associated with acute bacterial rhinosinusitis include Streptococcus pneumonia, Haemophilus influenza, and Moraxella catarrhalis. The pathogens most commonly associated with chronic rhinosinusitis include Staphylococcus aureus and various anaerobic organisms, including Prevotella, Porphyromonas, Fusobacterium, and Peptostreptococcus. This case report illustrates a case of chronic rhinosinusitis associated with the Staphylococcus lentus organism, a well-known animal pathogen that has never been documented in the sinonasal cavity before. METHODS: The medical records of an adult patient who presented to the otolaryngology office were reviewed. The literature available was reviewed. RESULTS: A 62-year-old man presented with chronic rhinosinusitis refractory to medical management. He was taken to the operating room for functional endoscopic sinus surgery and cultures were obtained, which returned positive for Staphylococcus lentus. He had no known animal contacts at home or work. He improved with surgery and appropriate antibiotic therapy. CONCLUSIONS: Staphylococcus lentus has never before been reported as a human pathogen in the sinonasal cavities. Otolaryngologists must routinely obtain cultures of mucus or tissue during sinus surgery in order to ensure appropriate antibiotic treatment after surgery and resolution of patient symptoms.

Therapeutic Antibodies for Nasal Polyposis Treatment: Where Are We Headed?

This review article aims to outline what is known in the pathophysiology of chronic rhinosinusitis with nasal polyposis (CRSwNP) and describe the mechanism of the biologic agents being investigated for this disease. Chronic rhinosinusitis with nasal polyposis is an inflammatory disease of the nasal and paranasal mucosa, which causes symptoms of nasal obstruction, hyposmia, and rhinorrhea. Conventional therapy for CRSwNP includes intranasal corticosteroids (INCS) and polypectomy, but INCS offer only modest benefits, and recurrence after surgery is common. Therefore, effective pharmacologic therapies for CRSwNP are being actively sought. Monoclonal antibodies have been successful in other chronic diseases involving eosinophilic inflammation, such as chronic urticaria and asthma. Thus, researchers have begun expanding their scope and investigating the efficacy of these drugs in the treatment of nasal polyposis. The monoclonal antibodies under investigation (omalizumab (anti IgE), dupilumab (anti IL-4/IL-13), and reslizumab and mepolizumab (both anti IL-5), benralizumab (anti IL-5Rα), and etokimab (anti IL-33)) target key players in the pathophysiology of nasal polyposis (NP). Dupilumab has just completed phase III trials for CRSwNP with positive results, while omalizumab, mepolizumab, and benralizumab are currently in phase III trials for this indication. At this time, while there are no FDA-approved biologics for use in NP, research has highlighted the contributions of IL-4, IL-5, IL-13, and IgE as disease mediators in the pathogenesis of NP. The current FDA-approved treatment of intranasal steroids does not provide significant relief for many patients; therefore, these phase III trials of monoclonal antibodies bring hope for an exciting new treatment option.

Association of Corrugator Supercilii and Procerus Myectomy With Endoscopic Browlift Outcomes.

IMPORTANCE: Glabellar wrinkling is a critical component of upper facial aging. OBJECTIVE: To compare the long-term outcomes on the wrinkle lines of the glabella and forehead following browlifts with vs without corrugator and procerus muscle resection. DESIGN, SETTING, AND PARTICIPANTS: A prospective cohort comparative trial was conducted of 23 patients who underwent browlift procedures by a single surgeon at a single institution (16 with glabellar muscle resection and 7 without muscle resection) between May 1, 2016, and July 1, 2017. All analysis took place between May 1, 2016, and May 14, 2018. The mean follow-up period was 16 months (range, 12-21 months). Sixteen of the 23 patients underwent a browlift with muscle resection procedure alone or in combination with other facial rejuvenation procedures to the brow, midface, jowl, and neck. Four of the 23 patients underwent browlifts only, and 19 had browlifts with other procedures. Seven of the 23 patients had browlift procedures without muscle resection and were designated as controls. INTERVENTIONS: Endoscopic browlift surgery was performed either with procerus and corrugator muscle resection or without muscle resection. MAIN OUTCOMES AND MEASURES: Neutral gaze and dynamic photographs of the upper face obtained preoperatively and after the 1-year postoperative mark were reviewed and scored in a blinded fashion by 2 physicians not affiliated with the study team using a modified Fitzpatrick Wrinkle Assessment score (FWA; from 0 [no wrinkling] to 5 [deep wrinkling with redundant skin]). RESULTS: The 23 study patients had a mean age of 60 years (range, 48-74 years); 21 were women, and 2 were men. There was a significant difference between the myectomy and control groups in the 12-month postoperative improvement in dynamic glabellar FWA scores (2.56 vs 1.07, P = .01). There was a difference between the myectomy and control groups in the improvements in resting glabellar FWA scores at 12-month follow-up, but it did not reach statistical significance (1.28 vs 1.00, P = .38). The 12-month postoperative improvements in dynamic (1.19 vs 1.29, P = .86) and resting forehead (1.0 vs 1.1, P = .70) FWA scores were not significantly different. CONCLUSIONS AND RELEVANCE: In this study, the use of procerus and corrugator myectomy techniques appeared to achieve a superior long-term reduction in glabellar wrinkles vs forehead rejuvenation techniques without muscle resection. LEVEL OF EVIDENCE: 3.

The Brain Penetrating and Dual TORC1/TORC2 Inhibitor, RES529, Elicits Anti-Glioma Activity and Enhances the Therapeutic Effects of Anti-Angiogenetic Compounds in Preclinical Murine Models.

Background. Glioblastoma multiforme (GBM) is a devastating disease showing a very poor prognosis. New therapeutic approaches are needed to improve survival and quality of life. GBM is a highly vascularized tumor and as such, chemotherapy and anti-angiogenic drugs have been combined for treatment. However, as treatment-induced resistance often develops, our goal was to identify and treat pathways involved in resistance to treatment to optimize the treatment strategies. Anti-angiogenetic compounds tested in preclinical and clinical settings demonstrated recurrence associated to secondary activation of the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway. Aims. Here, we determined the sensitizing effects of the small molecule and oral available dual TORC1/TORC2 dissociative inhibitor, RES529, alone or in combination with the anti-VEGF blocking antibody, bevacizumab, or the tyrosine kinase inhibitor, sunitinib, in human GBM models. Results. We observed that RES529 effectively inhibited dose-dependently the growth of GBM cells in vitro counteracting the insurgence of recurrence after bevacizumab or sunitinib administration in vivo. Combination strategies were associated with reduced tumor progression as indicated by the analysis of Time to Tumor Progression (TTP) and disease-free survival (DSF) as well as increased overall survival (OS) of tumor bearing mice. RES529 was able to reduce the in vitro migration of tumor cells and tubule formation from both brain-derived endothelial cells (angiogenesis) and tumor cells (vasculogenic mimicry). Conclusions. In summary, RES529, the first dual TORC1/TORC2 dissociative inhibitor, lacking affinity for ABCB1/ABCG2 and having good brain penetration, was active in GBM preclinical/murine models giving credence to its use in clinical trial for patients with GBM treated in association with anti-angiogenetic compounds.

The use of botulinum toxin A in perioral rejuvenation.

Botulinum toxin A is an effective and safe treatment for perioral rejuvenation. This article explores the application of this toxin for cosmetic use in the perioral region, facial asymmetry, and improved facial wound healing. This article also describes how the use of botulinum toxin A, which has traditionally been used on the upper one third of the face, has expanded to the lower two thirds with the advent of a new formulation that consists of botulinum toxin combined with an anesthetic agent and a vasoconstrictor. The new formula provides the injecting physician with immediate feedback on the eventual treatment effect and reduces local diffusion of the simultaneously injected agents, potentially limiting systemic absorption and diffusion to neighboring muscle groups and adding to an already remarkable safety profile.

Flap Basics I: Rotation and Transposition Flaps.

In many cases of complex facial defects, because of advanced cutaneous malignancies, primary wound closure is impossible. In these instances, ideal results can be obtained through recruitment of adjacent tissue with the use of local flaps. Advances in local flap techniques have raised the bar in facial reconstruction; however, acceptable results to the surgeon and patient require high levels of planning and surgical technique. Defects resulting from Mohs surgery and other traumatic injuries can typically be repaired with local flaps. A well-planned and executed local flap can lead to excellent cosmetic results with minimal distortion of the surrounding facial landmarks.

Correlation of Symptoms, Clinical Signs, and Biomarkers of Inflammation in Postsurgical Chronic Rhinosinusitis.

OBJECTIVE: The study aimed to evaluate symptoms described by patients with chronic rhinosinusitis with polypoid changes/nasal polyps and their correlation with computed tomography (CT), nasal endoscopy, and intranasal biomarkers. STUDY DESIGN: Prospective multicenter study symptom data from postsurgical adult chronic rhinosinusitis study participants with recurrent disease refractory to medical therapy were analyzed in comparison with objective data. METHODS: Using logistic regression analysis, participant-rated 16-question surveys from 258 participants were assessed for correlation with nasal endoscopy scores, CT percentage of sinus occlusion, and intranasal biomarkers of fungal antigens (Alternaria and Aspergillus), eosinophilic inflammation (eosinophil-derived neurotoxin [EDN] and major basic protein [MBP]), and inflammatory cytokines (interleukins 5 and 13). RESULTS: Study participant assessments revealed increased CT occlusion in participants presenting with greater inability to smell ( P < .019). Mucosal inflammation identified on nasal endoscopy was positively correlated with congestion ( P < .028), runny nose ( P < .002), and ear pain ( P < .007). Elevated EDN was positively correlated in patients with bothersome congestion ( P < .031) and runny nose ( P < .011). Sneezing was positively correlated with multiple markers: Alternaria ( P < .024), interleukin-13 ( P < .027), MBP ( P < .034), and interleukin-5 ( P < .019). CONCLUSION: Nasal endoscopy, not CT imaging, has the strongest correlation with the 2 cardinal symptoms of congestion and runny nose in CRS patients; these correlate with biomarkers of eosinophilic inflammation.