Localized application of SAG21k-loaded fibrin hydrogels for targeted modulation of the hedgehog pathway in facial nerve injury.

Given the broad biological effects of the Hedgehog (Hh) pathway, there is potential clinical value in local application of Hh pathway modulators to restrict pathway activation of target tissues and avoid systemic pathway activation. One option to limit Hh pathway activation is using fibrin hydrogels to deliver pathway modulators directly to tissues of interest, bypassing systemic distribution of the drug. In this study, we loaded the potent Hh pathway agonist, SAG21k, into fibrin hydrogels. We describe the binding between fibrin and SAG21k and achieve sustained release of the drug in vitro. SAG21k-loaded fibrin hydrogels exhibit strong biological activity in vitro, using a pathway-specific reporter cell line. To test in vivo activity, we used a mouse model of facial nerve injury. Application of fibrin hydrogels is a common adjunct to surgical nerve repair, and the Hh pathway is known to play an important role in facial nerve injury and regeneration. Local application of the Hh pathway agonist SAG21k using a fibrin hydrogel applied to the site of facial nerve injury successfully activates the Hh pathway in treated nerve tissue. Importantly, this method appears to avoid systemic pathway activation when Hh-responsive organs are analyzed for transcriptional pathway activation. This method of local tissue Hh pathway agonist administration allows for effective pathway targeting surgically accessible tissues and may have translational value in situations where supranormal pathway activation is therapeutic.

Deep Learning for the Assessment of Facial Nerve Palsy: Opportunities and Challenges.

Automated evaluation of facial palsy using machine learning offers a promising solution to the limitations of current assessment methods, which can be time-consuming, labor-intensive, and subject to clinician bias. Deep learning-driven systems have the potential to rapidly triage patients with varying levels of palsy severity and accurately track recovery over time. However, developing a clinically usable tool faces several challenges, such as data quality, inherent biases in machine learning algorithms, and explainability of decision-making processes. The development of the eFACE scale and its associated software has improved clinician scoring of facial palsy. Additionally, Emotrics is a semiautomated tool that provides quantitative data of facial landmarks on patient photographs. The ideal artificial intelligence (AI)-enabled system would analyze patient videos in real time, extracting anatomic landmark data to quantify symmetry and movement, and estimate clinical eFACE scores. This would not replace clinician eFACE scoring but would offer a rapid automated estimate of both anatomic data, similar to Emotrics, and clinical severity, similar to the eFACE. This review explores the current state of facial palsy assessment, recent advancements in AI, and the opportunities and challenges in developing an AI-driven solution.

Evidence-Based Medicine: Facial Reanimation.

This article provides a brief historical overview of the assessment instruments that have been developed to categorize the severity of disease in patients with facial palsy. Important advances in the quality of these instruments are discussed. The modern-day instruments that are commonly required for evidence-based patient assessment are then presented, with emphasis on the level of evidence of the studies that describe these instruments.

Synkinesis and Communicative Participation.

Background: Facial palsy (FP) impacts verbal and nonverbal communication, but the effect of synkinesis on communicative ability is unknown. Objective: Among patients with nonflaccid FP, or synkinesis, is there a correlation between disease-specific quality-of-life and communicative ability or dysfunction? Methods: Retrospective study of a series of adult patients with unilateral synkinesis. Subjects were evaluated using the Communicative Participation Item Bank (CPIB) Short Form, Facial Clinimetric Evaluation (FaCE) scale, and Synkinesis Assessment Questionnaire (SAQ). Associations between these scales were evaluated by computing Pearson correlation coefficients. Results: A total of 69 confirmed synkinesis patients were included. Synkinesis patient mean (standard deviation) CPIB score was 20.68 (±8.27; range of scale 0-30), indicative of communication restriction. A strong correlation was observed between total CPIB and FaCE scores (r = 0.66), indicating patients with synkinesis who reported better facial function also reported greater communicative ability. There was a weak correlation between CPIB and SAQ scores (r = -0.27). Conclusion: Synkinesis is associated with significant deficits in communicative ability. Communication restrictions track strongly with the FaCE scale.

Dual Nerve Transfer for Facial Reanimation.

This article describes a method of performing a dual nerve transfer procedure and provides illustrative cases for analysis and discussion. Clinical indications, technical pearls, and pitfalls are discussed. Dual nerve transfer for facial reanimation efficiently combines the strengths of the hypoglossal and masseteric nerve transfers and builds on existing nerve transfer techniques.

Facial Nerve Paralysis Following Endovascular Embolization: A Case Report and Review of the Literature.

OBJECTIVE: We report a case of facial nerve paralysis post-endovascular embolization of a sigmoid sinus dural arterio-venous fistula from initial presentation to current management and discuss the merits of observation versus decompression through a systematic review of relevant literature. PATIENT: 61 F with right facial palsy. INTERVENTION: Following a single intravenous dexamethasone injection with oral steroids over 2 months, patient was observed with no additional treatment other than Botox chemodenervation and facial rehabilitation. OUTCOME AND RESULTS: The patient initially presented with complete right facial palsy (HB 6/6). Post-op CT imaging indicated Onyx (ev3, Irvine, California, USA) particles present at the geniculate segment of the facial nerve. Observation was chosen over surgical intervention. At the most current follow up of 8 months, facial function has improved substantially (HB 2/6). CONCLUSION: Facial palsy is a serious, though rare, complication of transarterial endovascular embolization. With our case report and literature review, we highlight not only how conservative observation is the recommended treatment, but also that facial nerve recovery should be expected to reach near complete recovery, but not sooner than in 3 months.

How do we teach surgical residents in the COVID-19 era?

OBJECTIVE: In response to ongoing concerns regarding transmission of the novel coronavirus (COVID-19), surgical practice has changed for the foreseeable future. Practice guidelines recommend only urgent or emergent surgical procedures be performed to minimize viral transmission. This effectively limits standard training and practice for surgical residents. The purpose of this article is to describe opportunities in surgical simulation, and highlights the challenges associated with training in the COVID-19 era. DESIGN: This is a perspective summarizing the potential role of surgical simulation to target training gaps caused by decreased surgical caseloads. CONCLUSIONS: This manuscript concisely discusses simulation options available to training programs, including the novel concept of "surgical kits." These kits include all instruments necessary to simulate a procedure at home, effectively pairing safety and utility.

Facial Paralysis and Communicative Participation: The Importance of Facial Symmetry at Rest.

OBJECTIVE: There is a paucity of research devoted to understanding the communication restrictions encountered by facial paralysis patients. We aim to explore the relationship between patient-reported restrictions in communicative participation and objective facial paralysis severity using validated scales of facial movement. METHODS: We performed a pilot retrospective study using a consecutive series of adult patients with a diagnosis of unilateral facial paralysis. In addition to baseline demographics, subjects were evaluated using the Communicative Item Participation Bank Short Form (CPIB), Electronic Facial Assessment by Computer Evaluation (eFACE), and Sunnybrook Facial Grading System (SFGS). RESULTS: Twenty patients were included, 10 (50%) of whom were female with a mean age of 61 ± 13 years and mean duration of facial paralysis of 53 ± 82 months. The mean CPIB score was 14.6 ± 10.0 (range 0-29) and was comparable to scores of patients with conditions known to cause significant communicative disability. The mean eFACE scores were 67.4 ± 29.2, 44.2 ± 30.1, and 73.8 ± 30.0 for the static, dynamic, and synkinesis domains, respectively, with a composite smile score of 58.5 ± 16.9. After adjusting for age, gender, and duration of facial paralysis, significant moderate correlations were observed between the CPIB and the static eFACE domain (r = -0.51, P = .03) and smile composite score (r = 0.48, P = 0.0049), in addition to between the CPIB and SFGS synkinesis domain (r = 0.48, P = 0.04). CONCLUSIONS: Patients with unilateral facial paralysis experience significant limitations in communicative participation. These restrictions demonstrate moderate to strong correlations with objective assessments of facial paralysis and quality of life measures. Communicative participation may be a helpful means of tracking response to treatment. LEVEL OF EVIDENCE: IV.

Contrast-Enhanced Ultrasound With Perflubutane for Sentinel Lymph Node Mapping in Cutaneous Melanoma: A Pilot Study.

OBJECTIVE: To study the feasibility of contrast-enhanced ultrasound (CEUS) for identification of SLN associated with cutaneous melanoma. STUDY DESIGN: Single arm pilot study in a swine animal model. METHODS: One milliliter of perflubutane (Sonazoid, GE Healthcare, Milwaukee, WI) was injected into the peritumoral dermis in five swine with cutaneous melanoma. Ultrasonography was used to follow enhancing lymphatic channels to lymph nodes (LN). Intradermal injection of vital blue (VB) dye was used as a positive control. LN identified by either method were excised and examined histologically. RESULTS: There were five primary cutaneous melanomas with mean area of 4.36 ± 4.75 cm2 and Breslow depth of 3.6 ± 1.5 mm. Six possible sentinel lymph node (SLN)s were identified with CEUS, and nine were identified with VB. SLN averaged 12.44 ± 6.15 cm from the primary tumor. Four of six (67%) SLNs identified by CEUS and four of nine (44%) candidate SLNs identified by VB contained histologically confirmed metastatic melanoma. All six CEUS-identified SLNs were also identified with VB. Two LNs not containing melanoma were identified by CEUS; three were identified with VB. In all SLN with metastases, metastatic cells were scattered throughout the LN and not clustered in a discrete mass. CONCLUSION: CEUS with perflubutane feasibly identifies SLN associated with cutaneous melanoma and may be a useful adjunct technology in facilitating precise SLN dissection. Our work supports a clinical trial investigating the use of CEUS for this application. LEVEL OF EVIDENCE: NA Laryngoscope, 129:1117-1122, 2019.

Health Outcome Studies in Skin Cancer Surgery.

As cutaneous cancers are the most common malignancies affecting US citizens, they represent a significant public health problem and health care cost burden. There are a variety of treatment options available to manage cutaneous malignancies, but limited data are available regarding outcomes, including quality of life, recurrence, and mortality. Here, we examine outcomes of skin cancer surgery as they relate to sociodemographic data and treatment factors.

Speech and Communicative Participation in Patients With Facial Paralysis.

Importance: Problems with speech in patients with facial paralysis are frequently noted by both clinicians and the patients themselves, but limited research exists describing how facial paralysis affects verbal communication. Objective: To assess the influence of facial paralysis on communicative participation. Design, Setting, and Participants: A nationwide online survey of 160 adults with unilateral facial paralysis was conducted from March 1 to June 1, 2017. To assess communicative participation, respondents completed the Communicative Participation Item Bank (CPIB) Short Form questionnaire and the Facial Clinimetric Evaluation (FaCE) Scale. Main Outcomes and Measures: The CPIB Short Form and the correlation between the CPIB Short Form and FaCE Scale. In the CPIB, the level of interference in communication is rated on a 4-point Likert scale (where not at all = 3, a little = 2, quite a bit = 1, and very much = 0). Total scores for the 10 items range from 0 (worst) to 30 (best). The FaCE Scale is a 15-item instrument that produces an overall score ranging from 0 (worst) to 100 (best), with higher scores representing better function and higher quality of life. Results: Of the 160 respondents, 145 (90.6%) were women and 15 were men (mean [SD] age, 45.1 [12.6] years). Most respondents reported having facial paralysis for more than 3 years. Causes of facial paralysis included Bell palsy (86 [53.8%]), tumor (41 [25.6%]), and other causes (33 [20.6%]), including infection, trauma, congenital defects, and surgical complications. The mean (SD) score on the CPIB Short Form was 0.16 (0.88) logits (range, -2.58 to 2.10 logits). The mean (SD) score of the FaCE Scale was 40.92 (16.05) (range, 0-83.3). Significant correlations were observed between the CPIB Short Form and overall FaCE Scale scores, as well as the Social Function, Oral Function, Facial Comfort, and Eye Comfort subdomains of the FaCE Scale, but not with the Facial Movement subdomain. Conclusions and Relevance: Patients with facial paralysis in this study sample reported restrictions in communicative participation that were comparable with restrictions experienced by patients with other known communicative disorders, such as laryngectomy and head and neck cancer. We believe that communicative participation represents a unique domain of dysfunction and can help quantify the outcome of facial paralysis and provide an additional frame of reference when assessing treatment outcomes.

The role of Hedgehog-responsive fibroblasts in facial nerve regeneration.

BACKGROUND: Facial nerve paralysis is a significant cause of morbidity, affecting facial appearance, emotional expression, speech, oral competence, and vision. A more complete understanding of the complex cellular events required for successful nerve regeneration may reveal new therapeutic targets. The role of fibroblasts in regeneration, and the process by which the nerve reforms its three-dimensional structure after a transection injury, are not fully understood. The Hedgehog signaling pathway has been shown to mediate nerve sheath formation during development. We therefore sought to characterize the role of Hedgehog-responsive cells following transection of the facial nerve. METHODS: Two transgenic mouse lines with reporters for the downstream effector of Hedgehog signaling, Gli1, were used. The animals underwent a unilateral facial nerve transection injury, and the contralateral side served as a control. Facial nerves were analyzed via immunohistochemistry and immunofluorescence at predetermined time points as the facial nerve regenerated after the transection injury. RESULTS: There was a statistically significant increase in Gli1+ cells both at the site of injury and within the distal nerve segment over time. Gli1+ cells are fibroblasts within the nerve and appear to contribute to the reformation of the nerve sheath after injury. CONCLUSION: These findings describe a key signaling pathway by which fibroblasts participate in motor nerve regeneration. Fibroblasts that reside within the nerve respond to injury and may represent a novel therapeutic target in the context of facial nerve regeneration after transection injury.

Age-related histologic and biochemical changes in auricular and septal cartilage.

OBJECTIVES/HYPOTHESIS: To characterize the histologic and biochemical properties of auricular and septal cartilage and analyze age-related changes in middle-aged to older adults. STUDY DESIGN: Cross-sectional study of auricular and septal cartilage from 33 fresh cadavers. METHODS: Auricular and septal cartilage specimens were stained using Safranin O for glycosaminoglycans, Verhoeff's stain for elastin, and Masson's trichrome for collagen. Percentage of tissue stained, cell density and size were quantified. Relationships between donor characteristics and histologic properties were evaluated using mixed model analyses. RESULTS: The average donor age was 75 years (standard deviation = 11 years; range, 55-93 years). In auricular cartilage, each 1-year increase in age was associated with a 0.97% decrease in glycosaminoglycans (P < .001) and a 0.98% decrease in elastin (P < .001). In septal cartilage, glycosaminoglycans decreased 2.4% per year (P < .001). Age did not affect collagen content significantly in auricular (P = .417) or septal cartilage (P = .284). Cell density and cell size declined with age in auricular (both P < .001) and septal cartilage (P = .044, P = .032, respectively). Compared to septal cartilage in patients of all ages, auricular cartilage had more glycosaminoglycans, less collagen, higher cell density, and smaller cells. CONCLUSIONS: In auricular and septal cartilage, glycosaminoglycans, elastin, cell density, and cell size decrease significantly with age in patients over 55 years of age. Glycosaminoglycan content declines faster with age in septal cartilage than auricular cartilage. These age-related changes may affect biomechanical properties and tissue viability, and thereby have implications for graft choice in functional, aesthetic, and reconstructive nasal surgery. LEVEL OF EVIDENCE: NA. Laryngoscope, 127:E399-E407, 2017.

Human Induced Pluripotent Stem Cell-Derived Motor Neuron Transplant for Neuromuscular Atrophy in a Mouse Model of Sciatic Nerve Injury.

IMPORTANCE: Human motor neurons may be reliably derived from induced pluripotent stem cells (iPSCs). In vivo transplant studies of human iPSCs and their cellular derivatives are essential to gauging their clinical utility. OBJECTIVE: To determine whether human iPSC-derived motor neurons can engraft in an immunodeficient mouse model of sciatic nerve injury. DESIGN, SETTING, AND SUBJECTS: This nonblinded interventional study with negative controls was performed at a biomedical research institute using an immunodeficient, transgenic mouse model. Induced pluripotent stem cell-derived motor neurons were cultured and differentiated. Cells were transplanted into 32 immunodeficient mice with sciatic nerve injury aged 6 to 15 weeks. Tissue analysis was performed at predetermined points after the mice were killed humanely. Animal experiments were performed from February 24, 2015, to May 2, 2016, and data were analyzed from April 7, 2015, to May 27, 2016. INTERVENTIONS: Human iPSCs were used to derive motor neurons in vitro before transplant. MAIN OUTCOMES AND MEASURES: Evidence of engraftment based on immunohistochemical analysis (primary outcome measure); evidence of neurite outgrowth and neuromuscular junction formation (secondary outcome measure); therapeutic effect based on wet muscle mass preservation and/or electrophysiological evidence of nerve and muscle function (exploratory end point). RESULTS: In 13 of the 32 mice undergoing the experiment, human iPSC-derived motor neurons successfully engrafted and extended neurites to target denervated muscle. Human iPSC-derived motor neurons reduced denervation-induced muscular atrophy (mean [SD] muscle mass preservation, 54.2% [4.0%]) compared with negative controls (mean [SD] muscle mass preservation, 33.4% [2.3%]) (P = .04). No electrophysiological evidence of muscle recovery was found. CONCLUSIONS AND RELEVANCE: Human iPSC-derived motor neurons may have future use in the treatment of peripheral motor nerve injury, including facial paralysis. LEVEL OF EVIDENCE: NA.

Cisplatin and Cetuximab Treatment for Metastatic Cutaneous Squamous Cell Carcinoma: A Systematic Review.

BACKGROUND: Cutaneous squamous cell carcinoma (cSCC) is the second most common form of skin cancer and metastasizes in 2% to 5% of cases. OBJECTIVE: Systematic evaluation of published cases of metastatic cSCC (mSCC) treated with cisplatin or cetuximab from 1989 to 2014. MATERIALS AND METHODS: A literature search was performed to identify cases of mSCC treated with cisplatin or cetuximab. Patient demographics, tumor characteristics, response rates, and disease-free survivals were extracted. RESULTS: A total of 60 cases of mSCC treated with cisplatin and 9 cases treated with cetuximab reported in the literature from 1989 to 2014 were included in the analysis. Patients treated with cetuximab obtained a complete response of 67%, an overall response of 78%, and a median disease-free survival of 25 (range 3-48) months. Patients treated with cisplatin obtained a complete response of 22%, an overall response of 45%, and a median disease-free survival of 14.6 (range 3-112) months. CONCLUSION: Head-to-head prospective clinical studies between cetuximab and cisplatin are needed to determine which is more efficacious. In addition, prospective tumor registries and randomized controlled trials should be developed in order to establish the ideal systemic regimen in cSCC.

Nasopharyngeal airway to prevent tension pneumocephalus after open resection of anterior skull base tumors.

We conducted a retrospective study to assess the efficacy of using a nasopharyngeal airway in lieu of a tracheotomy or prolonged intubation for the diversion of airflow to prevent tension pneumocephalus after an open resection of anterior skull base tumors. Our study population was made up of 120 patients-74 males and 46 females, aged 12 to 84 years (mean: 48.7)-who had undergone an anterior skull base resection with documented nasopharyngeal airway placement from 1996 through 2009. Our main outcome measure was the presence of tension pneumocephalus while controlling for the placement of a lumbar drain, the development of a cerebrospinal fluid (CSF) leak, and the type of reconstruction. All patients had been extubated on the day of surgery, and their nasopharyngeal airway had remained in place for 3 days. No documented complications of nasopharyngeal airway placement (e.g., nasal septum pressure necrosis or the displacement of tubes) had been documented. Tension pneumocephalus occurred in 3 patients (2.5%). A total of 33 patients (27.5%) received a lumbar drain, 14 (11.7%) experienced a CSF leak, and 5 (4.2%) had both. There was a statistically significant difference in the rate of tension pneumocephalus between patients who did and did not receive a lumbar drain placement (p = 0.02), between those who did and did not experience a CSF leak (p = 0.04), and between those who did and did not meet both criteria (p = 0.004). We conclude that resection of anterior skull base tumors does not necessitate a prophylactic tracheotomy or prolonged intubation and that the use of a nasopharyngeal airway to divert airflow is well tolerated and highly successful. Lumbar drainage, the development of a CSF leak, or both may increase the risk of tension pneumocephalus.

Current state of stem cell-mediated therapies for facial nerve injury.

PURPOSE OF REVIEW: Interest in the application of stem cell therapy to nerve injury has grown exponentially in recent years, as the armamentarium of potential stem cell sources has increased. This article reviews literature on the recent developments in the application of stem cell therapy for facial nerve injury. RECENT FINDINGS: Current stem cell therapy for the treatment of peripheral nerve injury can be generalized into those that either enhance native neural regeneration via an anti-inflammatory effect or growth factor secretion, replace Schwann cells, or replace motor neurons. Animal studies have shown that nerve conduits seeded with stem cells (either undifferentiated or differentiated into Schwann-like cells) in sciatic and facial nerve injury models can promote nerve regeneration with similar efficacy to autologous nerve autografts. In-vivo studies have also shown that induced pluripotent stem cell-derived motor neurons, when transplanted into transected mouse tibial nerves, can form functional neuromuscular junctions with the denervated mouse triceps surae. SUMMARY: The authors believe that induced pluripotent stem cells have significant therapeutic potential. This source of human stem cells can be harvested with little morbidity, is isogenic to the donor, and has fewer ethical concerns compared with embryonic cellular sources. Further research is required to determine stem cell efficacy and safety. Questions of stem cell fate unpredictability and possible tumorigenesis must be addressed prior to human trials.