Efficacy of Systemic Bevacizumab for Recurrent Respiratory Papillomatosis with Pulmonary Involvement.

OBJECTIVES: Pulmonary papillomatosis is a rare but severe manifestation of recurrent respiratory papillomatosis (RRP). Efficacy data of systemic bevacizumab for pulmonary RRP are limited. This study's objective was to characterize disease response of pulmonary RRP to systemic bevacizumab. METHODS: A retrospective review was performed to identify patients with pulmonary RRP seen at three medical institutions. Clinical symptoms, CT findings, and disease response were compared before and after initiation of systemic bevacizumab therapy. Disease response was categorized as complete response, partial response, stabilization, or progression for each subsite involved by papilloma. RESULTS: Of the 12 pulmonary RRP patients treated with systemic bevacizumab, 4 (33.3%) were male, and 11 (91.7%) were juvenile-onset RRP patients. All presented with laryngeal, tracheal, and pulmonary RRP. The median (range) age at first bevacizumab infusion was 48.1 (19.5-70.2) years. Progression to pulmonary malignancy was identified in 3 (25.0%) patients, 2 before initiation of and 1 after complete cessation of bevacizumab therapy. Clinical symptoms such as dyspnea (75.0% vs. 25.0%; p = 0.01) and dysphagia and/or odynophagia (33.3 vs. 0.0%; p = 0.03) were significantly decreased following bevacizumab therapy. Compared with pre-treatment baseline, 9 (75.0%) patients experienced a stable-to-partial response in the lungs to systemic bevacizumab, and 10 (83.3%) experienced partial-to-complete responses in the larynx and trachea. CONCLUSION: Systemic bevacizumab is effective in stabilizing progression in even the most severe cases of RRP, with both a dramatic reduction in laryngeal and tracheal disease as well as a stable-to-partial response of pulmonary involvement in a majority of patients. LEVEL OF EVIDENCE: 4 Laryngoscope, 134:577-581, 2024.

Long-Term Follow-up of Parenteral Bevacizumab In Patients with Recurrent Respiratory Papillomatosis.

OBJECTIVE: The clinical course of recurrent respiratory papillomatosis (RRP) varies from spontaneous remission to severe airway obstruction with wide variability in recurrence. Standard treatment involves debulking to improve voice and/or breathing. Non-surgical therapies are emerging in hopes of non-operative disease control. This retrospective review analyzes long-term safety, efficacy, and durability of clinical control in the largest reported series of parenteral bevacizumab in adults with RRP. METHODS: Twenty-three patients with known RRP who have been receiving off-label systemic bevacizumab were included. Dosage, infusion interval, number of cycles, debulking requirements, subjective outcomes, adverse events, and reasons for treatment termination were investigated. RESULTS: Patients have been followed for an average of 791.43 (21-1468) days. The most common starting dosing regimen was 15 mg/kg at 3 weeks in 11 followed by 10 mg/kg at 6 weeks intervals in 6 individuals. Long-term maintenance dosage varied with the least intensive regimen being 10 mg/kg at 14-week intervals. Subjective improvement of voice and/or breathing was reported in 18/23 subjects. The median time for patients that needed a procedure after treatment was 634 days. Procedures after infusions decreased from 3.08 ± 2.48 procedures in the year prior to 0.52 ± 1.12 during systemic Bevacizumab, and to 0.86 ± 2.05 after stopping bevacizumab. Therapy termination occurred in 8 subjects where only 3 were due to adverse events. CONCLUSION: Parenteral bevacizumab remains a well-tolerated treatment for patients with recalcitrant RRP. There appears to be a durable reduction in the frequency of debulking surgery requirements although on a maintenance regimen. Laryngoscope, 133:2725-2733, 2023.

Trends in recurrent respiratory papillomatosis treatment. / Tendencias en el tratamiento de la papilomatosis respiratoria recurrente.

Recurrent respiratory papillomatosis (RRP) consist of benign tumours along the airway caused by human papillomavirus infection. Papillomas may cause changes in phonation and obstruct the airway. The purpose of this study was to evaluate the different surgical and adjuvant therapies available for the treatment of this condition reported between 2014-2018. A PubMed search was performed for RRP treatment articles published between 2014 -2018. Forty articles that encompassed 1425 patients with RRP met the criteria. Of these, 24 articles evaluate the use of adjuvant therapies such as bevacizumab, human papillomavirus vaccine and cidofovir. There has been an increase in adjuvant therapy options for RRP in the literature in recent years. An awareness of these options highlights gaps and opportunities in the care of these patients, opens the door to new protocols to control disease and increase intersurgical intervals, and guides us towards new management paradigms in the future.

JAGGED1 stimulates cranial neural crest cell osteoblast commitment pathways and bone regeneration independent of canonical NOTCH signaling.

Craniofacial bone loss is a complex clinical problem with limited regenerative solutions. Currently, BMP2 is used as a bone-regenerative therapy in adults, but in pediatric cases of bone loss, it is not FDA-approved due to concerns of life-threatening inflammation and cancer. Development of a bone-regenerative therapy for children will transform our ability to reduce the morbidity associated with current autologous bone grafting techniques. We discovered that JAGGED1 (JAG1) induces cranial neural crest (CNC) cell osteoblast commitment during craniofacial intramembranous ossification, suggesting that exogenous JAG1 delivery is a potential craniofacial bone-regenerative approach. In this study, we found that JAG1 delivery using synthetic hydrogels containing O9-1 cells, a CNC cell line, into critical-sized calvarial defects in C57BL/6 mice provided robust bone-regeneration. Since JAG1 signals through canonical (Hes1/Hey1) and non-canonical (JAK2) NOTCH pathways in CNC cells, we used RNAseq to analyze transcriptional pathways activated in CNC cells treated with JAG1 ± DAPT, a NOTCH-canonical pathway inhibitor. JAG1 upregulated expression of multiple NOTCH canonical pathway genes (Hes1), which were downregulated in the presence of DAPT. JAG1 also induced bone chemokines (Cxcl1), regulators of cytoskeletal organization and cell migration (Rhou), signaling targets (STAT5), promoters of early osteoblast cell proliferation (Prl2c2, Smurf1 and Esrra), and, inhibitors of osteoclasts (Id1). In the presence of DAPT, expression levels of Hes1 and Cxcl1 were decreased, whereas, Prl2c2, Smurf1, Esrra, Rhou and Id1 remain elevated, suggesting that JAG1 induces osteoblast proliferation through these non-canonical genes. Pathway analysis of JAG1 + DAPT-treated CNC cells revealed significant upregulation of multiple non-canonical pathways, including the cell cycle, tubulin pathway, regulators of Runx2 initiation and phosphorylation of STAT5 pathway. In total, our data show that JAG1 upregulates multiple pathways involved in osteogenesis, independent of the NOTCH canonical pathway. Moreover, our findings suggest that JAG1 delivery using a synthetic hydrogel, is a bone-regenerative approach with powerful translational potential.

The Role of Sex on Early Cochlear Implant Outcomes.

OBJECTIVE: To determine the presence of sex differences in cochlear implant outcomes. STUDY DESIGN: Retrospective chart review. SETTING: Tertiary referral center. PATIENTS: Adult patients having undergone cochlear implantation from 2009 to 2017. INTERVENTION(S): Standard electrode length cochlear implantation. MAIN OUTCOME MEASURE(S): AzBio scores in quiet of the implanted ear at the 1 to 3 months and 6 to 9 months postoperative time points. RESULTS: Of 55 patients with complete demographic and speech recognition testing, 36.4% (n = 20) were men. The mean age at time of surgery was 59.81 ±â€Š16.54 years and the mean duration of hearing loss was 26.33 ±â€Š18.54 years; there was no significant difference between men and women. The mean preoperative AzBio score was 11 ±â€Š15.86% and there was no difference between men and women. Through 2 (sex) × 3 (time point) analysis of covariance (ANCOVA), there was no main effect of sex (F[1, 48] = 0.74, p = 0.39, η = 0.02) on postoperative AzBio scores, but there was a significant sex by time point interaction, (F[1.77, 85.03] = 4.23, p = 0.02, η = 0.08). At the 1 to 3 months postoperative time point, women exhibited higher relative improvement in AzBio scores than men (67 ±â€Š27% versus 55 ±â€Š31%). Further, this relative improvement increased and remained significant at the 6 to 9 months postoperative time point (women: 71 ±â€Š22% versus 58 ±â€Š30%). CONCLUSIONS: Sex may play a role in early speech recognition outcomes after adult cochlear implantation.

Improving hard palate wound healing using immune modulatory autotherapies.

Oral cavity wound healing occurs in an environment that sustains ongoing physical trauma and is rich in bacteria. Despite this, injuries to the mucosal surface often heal faster than cutaneous wounds and leave less noticeable scars. Patients undergoing cleft palate repair have a high degree of wound healing complications with up to 60% experiencing oronasal fistula (ONF) formation. In this study, we developed a mouse model of hard palate mucosal injury, to study the endogenous injury response during oral cavity wound healing and ONF formation. Immunophenotyping of the inflammatory infiltrate following hard palate injury showed delayed recruitment of non-classical LY6Clo monocytes and failure to resolve inflammation. To induce a pro-regenerative inflammatory response, delivery of FTY720 nanofiber scaffolds following hard palate mucosal injury promoted complete ONF healing and was associated with increased LY6Clo monocytes and pro-regenerative M2 macrophages. Alteration in gene expression with FTY720 delivery included increased Sox2 expression, reduction in pro-inflammatory IL-1, IL-4 and IL-6 and increased pro-regenerative IL-10 expression. Increased keratinocyte proliferation during ONF healing was observed at day 5 following FTY720 delivery. Our results show that local delivery of FTY720 from nanofiber scaffolds in the oral cavity enhances healing of ONF, occurring through multiple immunomodulatory mechanisms. STATEMENT OF SIGNIFICANCE: Wound healing complications occur in up to 60% of patients undergoing cleft palate repair where an oronasal fistula (ONF) develops, allowing food and air to escape from the nose. Using a mouse model of palate mucosal injury, we explored the role of immune cell infiltration during ONF formation. Delivery of FTY720, an immunomodulatory drug, using a nanofiber scaffold into the ONF was able to attract anti-inflammatory immune cells following injury that enhanced the reepithelization process. ONF healing at day 5 following FTY720 delivery was associated with altered inflammatory and epithelial transcriptional gene expression, increased anti-inflammatory immune cell infiltration, and increased proliferation. These findings demonstrate the potential efficacy of immunoregenerative therapies to improve oral cavity wound healing.

Cirugía de feminización de voz con técnica glotoplastia de Wendler en Barranquilla Colombia / Voice feminization surgery with Wendler glottoplasty technique in Barranquilla Colombia

Introducción: La glotoplastia de Wendler es la técnica que en la actualidad ofrece mejores resultados entre los diferentes tipos de cirugías para la feminización de la voz. Objetivo: Describir nuestra experiencia con la Glotoplastia de Wendler durante el proceso de feminización de la voz de mujeres transgénero. Diseño: Pseudoexperimental (antes-después) Materiales y Métodos: 36 pacientes transexuales en proceso de transformación de hombre a mujer se sometieron a cirugía y rehabilitación con terapias de voz con el equipo de VOICEFEM - Voice Feminization Colombia. La técnica utilizada consiste en la creación de una sinequia de las cuerdas vocales (CCVV) previa desepitelización de la cara interna del tercio anterior de las mismas, 2 puntos de sutura con Vicryl 4/0 y vaporización con electrocauterio en la región lateral de la cara superior de las CCVV y utilización de goma biológica en la sinequia creada. La medición de la frecuencia fundamental, el tiempo máximo de fonación, y la realización del cuestionario TSEQ, se llevaron a cabo antes y después de la cirugía. Resultados: Se obtuvo un aumento de la Frecuencia fundamental promedio de 112Hz(P<0.05) a los 6 meses posteriores al procedimiento quirúrgico y una disminución de cerca de 30 puntos en los resultados del cuestionario TSEQ. Conclusión: La glotoplastia de Wendler, llevada a cabo por cirujanos con experiencia en este campo, ofrece resultados favorables con aumentos significativos de la frecuencia fundamental a mediano plazo y debe estar necesariamente asociada al manejo postquirúrgico con terapias de voz, para obtener el desenlace óptimo esperado.

"Introduction: Wendler's Glottoplasty is the technique that offers the best results among the different types of voice feminization surgeries. Male to Female Transgender patients have in this technique the last step for their successful transformation. Objective: To describe our experience in carrying out Wendler's glottoplasty during the process of feminization of the voice of transgender women. Design: Pseudoexperimental (before-after) study. Materials and methods: In 36 Male to Female Transgender patients, Wendler's glottoplasty was conducted by VOICEFEM - Voice Feminization Colombia's team, with further speech therapy rehabilitation. This technique consists of the creation of a synechia of the vocal cords which is carried out after the de-epithelization of the vocal cords on the inner face of its anterior third, 2 stitches with Vicryl 4/0 and vaporization with electrocautery in the lateral region of vocal cords upper face, and the use of biological glue in the created synechia. The measurement of the Fundamental Frequency, Maximum Phonation time, and the completion of the TSEQ questionnaire were carried out before and after the surgery. Results: There was an increase of 112 Hz in the average of Fundamental Frequency (P<0.05) 6 months after the surgery, and a decrease of approximately 30 points in the TSEQ questionnaire results. Conclusion: Wendler's Glottoplasty conducted by an expert surgeon, provides positive results with a significant increase for fundamental frequency in the medium term, and it is imperative to do also voice therapy rehabilitation posterior to the procedure in order to obtain the expected optimal outcome.