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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Prosthetics for nasal perforations: a systematic review and meta-analysis.

OBJECTIVE: Prosthetics serve as an option for nasoseptal perforation treatment in patients who have active systemic disease, are poor surgical candidates, or wish to avoid surgery. Through systematic review of the literature on prosthetics for nasoseptal perforation treatment, the objective of the present study is to critically appraise previous studies, evaluate the success rate for nasoseptal prosthetics, provide evidence-based guidelines for nasoseptal prosthetic use, and identify areas for further investigation. DATA SOURCES: Cochrane Controlled Trials Register, EMBASE, PubMed, and Web of Science. REVIEW METHODS: Data sources were queried for relevant articles published from 1965 to 2013. Articles were selected for inclusion if they presented primary data for human nasoseptal perforation treatment utilizing prosthetic materials. Each included article's level of evidence and risk of bias were identified and grades of recommendation were assigned. A quantitative meta-analysis was performed on articles with low risk of bias. RESULTS: The search yielded 4756 abstracts for review, with 23 included case series and 5 case reports; 706 total cases of prosthetic nasoseptal perforation treatment were identified. All articles provided level 4 evidence, with an overall conclusion grade of C for improvement in nasoseptal perforation symptoms, prosthetic in situ rate, and complication rate. Meta-analysis of 6 low-risk-of-bias studies with 297 patients demonstrated an overall success rate of 65%. CONCLUSIONS: The literature provides level 4 evidence for the efficacy and safety of prosthetics for nasoseptal perforation treatment with favorable success rates and few reports of complications--only 1 fungal infection and 9 unspecified infections-in 706 cases.

An immunologic test for chronic rhinosinusitis based on free intranasal eosinophilic major basic protein.

BACKGROUND: A histologic hallmark of chronic rhinosinusitis (CRS) is an eosinophilic inflammation, present with and without nasal polyposis and independent of atopy. Eosinophils migrate through nasal tissue including the epithelium into the nasal airway mucus, where they form clusters and degranulate, releasing granule proteins including the toxic major basic protein (MBP). Specific biomarkers for CRS, which could be used as a diagnostic test for CRS with a high sensitivity and specificity, are presently lacking. Recently, an enzyme-linked immunosorbent assay (ELISA)-based test for MBP in nasal airway mucus received regulatory approval. METHODS: A new assay was specifically developed to detect released MBP in airway mucus. MBP levels in nasal mucus of 85 randomly selected CRS patients diagnosed by endoscopy, computed tomography (CT) scans and symptoms were compared to 13 healthy controls and 5 disease controls (allergic rhinitis). RESULTS: Overall, 92% (78/85) of CRS patients' mucus were positive for MBP (mean 7722 ng/mL) vs none of 13 healthy controls and none of 5 allergic rhinitis patients (<7.8 ng/mL; p < 0.000000000002). In this study, the MBP ELISA had a 92% sensitivity and 100% specificity for CRS. CONCLUSION: Free MBP in nasal mucus can be used as a biomarker to diagnose CRS. The MBP ELISA represents the first immunologically-based test to potentially distinguish CRS from the eosinophilic inflammation in allergic rhinitis.

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.