Angiogenesis Inhibitor Drug-induced Benign Migratory Glossitis in a Patient of Juvenile-onset Recurrent Respiratory Papillomatosis under Maintenance Therapy.

Background: Benign migratory glossitis or geographic tongue is a chronic recurring inflammatory condition of the oral cavity. With its ephemeral characteristics, there has been reported literature showing its association with the administration of certain drugs including angiogenesis inhibitors. The antiangiogenic drugs act by selectively inhibiting the vascular endothelial growth factor (VEGF) signaling. It has been widely used as an adjunct and a maintenance agent for the treatment of various cancers. Aims: This study aims to report probable characteristic oral mucosal changes in a patient with juvenile-onset recurrent respiratory papillomatosis (JORRP) under maintenance therapy with an antiangiogenesis drug. Case description: The patient was presented with a burning sensation on having spicy food. This occurred after the completion of three cycles of bevacizumab infusion. It was associated with the appearance of migratory lesions over the tongue and evolved periods of remission and exacerbation. Clinical examination revealed lesions characteristic of the geographic tongue on the anterior two-thirds of the dorsal surface as well as the lateral surface of the tongue classified as type 2, according to Hume criteria. Oral examination revealed dental caries in relation to 52, 54, 62, 63, 74, and 85 teeth and grossly decayed 64. Topical lignocaine gel was instituted for symptomatic relief of the lesion. Full mouth rehabilitation with preventive and restorative therapeutic interventions was carried out. Clinical significance and conclusion: The documented literature along with this report put forth a probable association of geographic tongue with the use of bevacizumab drugs which requires further detailed studies. These lesions generally require symptomatic treatment with assurance only. The etiology is poorly understood. How to cite this article: Kalra N, Tyagi R, Khatri A, et al. Angiogenesis Inhibitor Drug-induced Benign Migratory Glossitis in a Patient of Juvenile-onset Recurrent Respiratory Papillomatosis under Maintenance Therapy. Int J Clin Pediatr Dent 2024;17(1):92-96.

Effectiveness of combined approach to recurrent respiratory papillomatosis (RRP).

PURPOSE: Recent approaches for recurrent respiratory papillomatosis including local injection of bevacizumab and HPV vaccination show promise in reducing the need for frequent surgeries. In this study we propose a new combined approach of surgery, intralesional injection of 25 mg bevacizumab and HPV vaccine that can lead to resolution of RRP. MATERIAL AND METHODS: Our study involved 5 patients treated with a combination of transoral microsurgery, intralesional injection of 25 mg bevacizumab, and HPV vaccination with Gardasil 9 between April 2020 and May 2023. Standard video laryngoscopy was performed to assess the presence of papilloma and Derkay score was used to assess the severity of disease. RESULTS: All 5 patients completed the study successfully and a complete response was achieved by all. The follow-up ranged from 8 to 45 months. The mean total Derkay score before treatment was 41 (range 25 to 52) and after the combined approach was 0 both anatomically and clinically in all patients. CONCLUSIONS: This study demonstrates the effectiveness of a combined treatment approach for RRP involving surgical intervention, intralesional injection of bevacizumab, and HPV vaccination.

Quantification and Functional Studies of Neutrophilic Cells Identifies Distinct Papilloma Phenotypes.

OBJECTIVES: To characterize the distribution of immune cell subsets within laryngeal papillomas and to study the function of potentially immunosuppressive neutrophilic and regulatory T cells (Tregs). METHODS: Fresh clinical papilloma specimens were collected at the time of surgery and studied with multiparameter flow cytometry. Papilloma infiltrating neutrophilic cells and Tregs were sorted and studied functionally with ex vivo T cell suppression assays. RESULTS: Flow cytometric analysis of fresh laryngeal papillomas samples from 18 adult patients with recurrent respiratory papillomatosis revealed patterns in immune constituency between patients. Clearly divergent phenotypes based primarily on the degree of neutrophilic and T cell infiltration were identified. Relative neutrophilic cell enrichment and T cell depletion were observed in 50% of samples and neutrophilic cell depletion and T cell enrichment were observed in the others. Greater papilloma neutrophilic cell enrichment was positively associated with the number of clinically indicated interventions required in the 12 months prior to sample collection, linking papilloma neutrophil inflammation to disease severity. Functional assays revealed the ability of both papilloma infiltrating neutrophilic and Tregs to suppress T cell function at roughly equal magnitudes, but substantially increased infiltration of neutrophilic cells compared to Tregs across samples. CONCLUSION: Neutrophilic cells are an important contributor to immunosuppression within the respiratory papilloma microenvironment. Given these data and the association between greater neutrophilic cell infiltration and lack of clinical response to therapeutic vaccination, additional study of strategies aimed at limiting neutrophilic cell infiltration or function within papillomas is warranted. LEVEL OF EVIDENCE: 4 Laryngoscope, 2024.

Pulmonary Involvement in Recurrent Respiratory Papillomatosis: A Systematic Review.

Recurrent respiratory papillomatosis (RRP) is a non-malignant disease, characterized by the production of wart-like growths in the respiratory tract, affecting both young people and adults (juvenile-onset recurrent respiratory papillomatosis, JORRP, and adult-onset recurrent respiratory papillomatosis, AORRP, respectively). Infection caused by human papillomavirus (HPV) is known as the main factor involved in RRP development. Complications of RRP may rarely occur, including lung involvement and malignant transformation. The present systematic review aimed to evaluate the prevalence of severe complications, such as lung involvement and lung tumor in JORRP and AORRP patients, and assess the role of HPV genotypes in the progression of disease severity following the guideline for reporting systematic reviews and meta-analysis (PRISMA Statement). A total of 378 studies were found on PubMed and Scopus using the following MESH terms: "recurrent respiratory papillomatosis and lung tumor" and "pulmonary tumor and recurrent respiratory papillomatosis". Basing on inclusion and exclusion criteria, a total of 11 studies were included in the systematic review. We found a pooled prevalence of 8% (95% CI: 4-14%; I2: 87.5%) for lung involvement in RRP patients. In addition, we found a pooled risk difference of 5% in lung involvement between JORRP and AORRP (95% CI: -7-18%; I2: 85.6%, p-value: 0.41). Among patients with lung involvement, we observed a pooled prevalence of lung tumor of 4% (95% CI:1-7%; I2: 67.1%) and a pooled prevalence mortality for this group of 4% (95% CI:2-6%; I2: 0%). Overall, the positivity rate for HPV-6 and -11 in patients with RRP was 91%. Considering only cases with pulmonary involvement, the pooled prevalence for HPV-11 was 21% (95% CI: 5-45%; I2: 77.2%). Our results evidenced a low/middle risk of pulmonary involvement and lung tumor in JORRP and AORRP patients, with an increased risk for HPV-11-positive patients. Further studies should be performed to improve knowledge and adopt preventive measures to contrast the progression to severe diseases in RRP patients.

Systemic Bevacizumab for Recurrent Respiratory Papillomatosis: A Single Institution's Experience.

OBJECTIVES: Medical therapies to limit disease recurrence are critically needed for recurrent respiratory papillomatosis (RRP). Systemic bevacizumab is emerging as an exciting adjuvant therapy toward this end, but uptake has been poor due to the lack of experience and awareness of best prescribing practices. The objective of this study was to describe a single tertiary care academic medical center's experience using systemic bevacizumab for the treatment of RRP. METHODS: A retrospective review was performed to identify patients with RRP on systemic bevacizumab. Demographic and clinical characteristics, findings on imaging reports, and disease response at all anatomic subsites involved in papilloma were documented. RESULTS: Of the 17 RRP patients on systemic bevacizumab, 9 (52.9%) were male, and 12 (70.6%) were diagnosed with juvenile-onset RRP. The total lifetime number of surgeries was high, with more than half (n = 9; 52.9%) undergoing more than 50 surgeries. Following induction of systemic bevacizumab, a significant reduction in patients with laryngeal (n = 15; 94.1% vs. n = 7; 41.2%, p < 0.001) and tracheal (n = 11; 64.7% vs. n = 5; 29.4%, p = 0.04) RRP was noted. Surgical frequency was significantly lower following systemic bevacizumab (2.5 vs. 0.5 surgeries per year; p < 0.001). The most common complications were new-onset hypertension (n = 4; 23.5%) and proteinuria (n = 5; 29.4%). CONCLUSION: Systemic bevacizumab is effective in reducing the number of surgeries needed for RRP while exhibiting a relatively safe complication profile. Papillomas in the larynx and trachea are most responsive to systemic bevacizumab, while pulmonary RRP is most likely to exhibit a partial-to-stable response. LEVEL OF EVIDENCE: 4 Laryngoscope, 2024.

Human papilloma virus (HPV) vaccination is associated with reduced number of surgical treatments, an observational study on recurrent respiratory papillomatosis in Northern Sweden.

BACKGROUND: Recurrent respiratory papillomatosis (RRP) is a wart-like lesion mainly affecting the larynx, caused by human papillomavirus (HPV) genotypes 6 and 11. The disease affects both children and adults, and there is no cure. Surgery is the current symptom-relieving treatment; however, HPV vaccination is used as an adjuvant treatment. AIMS AND OBJECTIVES: The aims were to study effects of HPV vaccination in RRP cases and to compare juvenile-onset to adult-onset disease and high treatment frequency (TF) to low TF cases. MATERIAL AND METHODS: Medical records of RRP patients were studied from May 2006 to January 2023. Eighty-five RRP cases, tested for HPV genotypes with PapilloCheck®, were included. Vaccination- onset- and treatment analysis were performed. RESULTS: Twelve percent of the cases were vaccinated. The number of surgeries decreased from 2.0 to 0.8/year after HPV vaccination. Most cases had an adult-onset and less than one treatment per year. Juvenile-onset cases had a higher vaccination treatment ratio compared to adult-onset. CONCLUSIONS: HPV vaccination was associated with a lower number of treatments per year, supporting the use of vaccination as an adjuvant treatment. SIGNIFICANCE: Vaccination as adjuvant treatment to surgery may lead to increased quality of life for RRP patients and saved healthcare resources.

Clinico-pathological Factors in Malignant Transformation of RRP.

Various clinico-pathological factors play role in the papilloma proliferation and pathogenesis of Recurrent respiratory papillomatosis (RRP). However, it is not known if they are directly responsible for malignant transformation of these papillomas or not. We did this study to elucidate any such association. The most recent debrided tissue of RRP in 20 patients was evaluated for p16 expression, VEGF estimation (tissue expression and serum levels), and tissue HPV DNA concentration. The final histopathology results were then correlated with these pathological factors and with clinical factors like duration of illness, age of onset of symptoms, extent of disease, etc. Squamous papilloma was seen in 60%, dysplasia in 25%, and squamous cell carcinoma (SCC) in 15% of the patients. Positive immunostaining for p16 (staining in ≥70% of tumor cells) was seen only in one case, which was SCC. There was no statistically significant difference between p16 expression, tissue VEGF expression, serum VEGF levels, and tissue HPV DNA in any of the histological groups. The mean age of disease onset was significantly higher in patients with SCC (p = 0.03). A significantly higher number of patients with dysplasia had tracheobronchial involvement (p = 0.022). We concluded that no single pathological factor is solely responsible for development of malignancy in RRP, whereas clinical factors like tracheobronchial involvement and age of onset may contribute to development of dysplasia or carcinoma.

Diode Laser for Juvenile Recurrent Respiratory Papillomatosis: A Case Series of 13 Patients.

Juvenile recurrent respiratory papillomatosis (JRRP) is the most common benign tumor in the larynx. It is uncommon; however, it is potentially life-threatening because it compromises the respiratory tract and required several surgeries to manage recurrences. Currently, the carbon dioxide laser is the treatment of choice. There are no studies about the role of the diode laser which is easy to use and has lower usage cost. This case series presentation reported on the therapeutic effects and recurrence rate of JRRP when using Diode laser. This is a case series presentation of 13 children, who were diagnosed with JRRP and operated for laryngeal papillomatosis with Diode laser in Otorhinolaryngology and Head and Nick Surgery Department et al. Mouwasat Hospital, Damascus, Syria between 2015 and 2022. 13 children required 56 surgeries at a rate of 1-2 surgeries/year, mean number of surgeries for each child was 4.31. That suggests that Diode laser might have a role in reducing the number of surgeries compared to a study used cold instrument and CO2 laser. The complications rate was 30.8%, which is considered a high rate compared to the other studies. In conclusion, we encourage using it when the CO2 laser device is not available. However, we suggest, reducing the power as low as possible and avoiding of two opposing raw surfaces, especially at the anterior commissure and deep excision. Further longitudinal studies are recommended to validate these results.

Clinical evaluation of pediatric patients with recurrent respiratory papillomatosis.: A longitudinal study at a Saudi Arabian tertiary care center.

OBJECTIVES: To study the clinical evaluation of recurrent respiratory papillomatosis (RRP) patients and the factors associated with the improvement in the Derkay's score as a measure of disease severity. METHODS: A retrospective cohort that included all juvenile RRP patients who were admitted to King Abdulaziz University Hospital, Riyadh, Saudi Arabia, between September 2015 and June 2022 and underwent surgical debulking. RESULTS: A total of 16 patients were eligible to join our study. Among them, 7 patients were males. Hoarseness of voice was the most frequent symptom. The median period of the follow-up was 56 months. Complete remission was achieved in 31.3%. The univariate linear regression model revealed that the cidofovir-treated patients had a significant reduction in the change value of Derkay's score compared to those without treatment (regression coefficient= -5.83, 95% confidence interval [CI]: [-11.5 to -0.143], p=0.045). Also, the increased first Derkay's score decreased the change value and subsequently increased the improvement chance of the disease (regression coefficient= -0.424, 95% CI: [-0.764 to -0.083], p=0.018). However, in the multivariate regression model, both variables showed non-significant results. CONCLUSION: cidofovir treatment and higher Derkay's scores affected the disease improvement.

Off-label drugs in otolaryngological practice against the background of legal conditions of Polish legislation.

<b><br>Introduction:</b> 'Off-label drug use' refers to the administration of drugs for unapproved indications or age groups, a different dosage or other form of administration. Considering the legal issues, there clearly exists a need to implement rules that would regulate the use of pharmaceuticals outside the scope of a marketing authorisation. The brevity and diversity of Polish laws in the field of health care leads to many interpretative doubts associated with particular legal acts.</br> <b><br>Aim:</b> We aimed to present clinical examples from everyday practice of off-label drug use from the medical and legal perspectives, and to support it with relevant legal acts.</br> <b><br>Material and method:</b> Off-label drug use in various otolaryngology subspecialties - otology (mesna), laryngology (bevacizumab, cidofovir and botulinum toxin) and head and neck surgery (botulinum toxin) - are presented and discussed in detail.</br> <b><br>Results:</b> Fourteen Polish legal acts regarding off-label drug use and 4 from EU legislation are commented on. The algorithm of cascade of decision-making processes in off-label drug use is shown.</br> <b><br>Conclusions:</b> Off-label use of medicinal products is not prohibited in Poland or the EU; nevertheless, it is undeniable that the unclear legal situation regarding the use of medicinal products for nonregistered indications creates difficulties. To minimise a doctor's liability risk, obtaining the informed consent from the patient for such treatment is advisable.</br>.

Adjuvant Human Papillomavirus Vaccination in Recurrent Respiratory Papilloma Patients Older than 45.

OBJECTIVES: The primary objective was to examine the intersurgical interval (ISI) of recurrent respiratory papillomatosis (RRP) in patients older than 45 years before and after a Gardasil vaccination series. METHODS: We conducted a retrospective chart review of adult patients >45 years of age diagnosed with RRP from 2012 to 2022. Patients were excluded if they did not receive at least two doses of the Gardasil vaccine series or if they underwent two or fewer surgeries during the study period. RESULTS: Thirteen patients met the inclusion criteria, 11 males and two females. The age at initial diagnosis ranged from 46 to 80 years, with a mean of 59 years. There was a significant increase in the average ISI, from 126 ± 87 days pre-vaccination compared to 494 ± 588 days post-vaccination (p < 0.01). The average number of surgeries per patient was 6.8 ± 2.4 over an average follow-up of 49.7 ± 30.3 months. CONCLUSION: Adjuvant Gardasil use in RRP patients older than 45 years significantly increases the ISI. Current CDC recommendations include only patients ages 9 to 45, but this study provides evidence that RRP patients outside this age range may benefit from adjuvant HPV vaccination. LEVEL OF EVIDENCE: 4 Laryngoscope, 2024.

Systemic bevacizumab for treatment of recurrent respiratory papillomatosis.

OBJECTIVES: To characterize treatment response of recurrent respiratory papillomatosis (RRP) including adult-onset RRP (AORRP) and juvenile-onset RRP (JORRP) to systemic bevacizumab (bev), and share our treatment regimen experience. METHODS: Patients were enrolled in bev treatment based on a pathologically confirmed diagnosis of squamous papilloma. According to lesion characteristics and medical history, systemic bev was used as preoperative adjuvant therapy, postoperative adjuvant therapy, or primary therapy. The assessment of treatment response relied on the morphological changes of lesions. Vocalization and voice-related quality of life were evaluated using the voice handicap index-30 (VHI-30) for adults and the pediatric VHI (pVHI) for children. Adverse effect was monitored through patient self-reported symptoms and regular follow-ups. RESULTS: This study included 24 patients, comprising nine AORRP and 15 JORRP cases. In AORRP, all patients (100%) exhibited various degrees of response to systemic bev, with 5 (55.56%) achieving complete response (CR). Among JORRP patients, 14 (93.33%) showed a response to systemic bev, with 8 (53.33%) achieving CR and currently being followed up. No instances of aggravation were observed during systemic bev treatment. A total of 21 patients (21/24, 87.50%) reported voice improvement, accompanied by reduced VHI-30 or pVHI scores across all aspects, including total, functional, physical, and emotional dimensions. No grade 3 or higher adverse events occurred. The most common adverse events were grade 1 gum bleeding (n = 4, 16.67%) and grade 1 proteinuria (n = 4, 16.67%). CONCLUSIONS: Systemic bev can be used as a powerful therapy for both AORRP and JORRP. The findings provide a reference to the systemic bev treatment for RRP.

Profiling of VEGF Receptors and Immune Checkpoints in Recurrent Respiratory Papillomatosis.

OBJECTIVES: Recurrent respiratory papillomatosis (RRP) is caused by human papilloma virus (HPV) infection of the aerodigestive tract that significantly impacts quality-of-life including the ability to communicate and breathe. Treatment was traditionally limited to serial ablative procedures in the O.R. with possible local adjuvant therapy, but new systemic therapies, such as Vascular endothelial growth factor (VEGF) inhibitors, are showing significant promise. This study aims to determine whether rationale exists for combination therapeutic approaches using VEGF inhibitors and/or immune checkpoint blockade. METHODS: Using fresh specimens from the O.R., we performed flow cytometry on papilloma, normal adjacent tissue, and blood. Papilloma and surrounding tissue were examined for expression of PD-L1, PD-L2, Galectin-9, VEGFR2, and VEGFR3. CD8+ and CD4+ T cells were assayed for expression of PD-1, TIGIT, LAG3, and TIM3. RESULTS: Our data shows that papilloma tissue exhibits significantly higher levels of PD-L1 and PD-L2 compared to adjacent tissue. Elevated levels of the VEGF receptor VEGFR3 were also observed in papilloma tissue. When examining T cells within the papilloma, elevated PD-1 and TIGIT expression was observed on CD8+ T cells, while levels of PD-1, TIGIT, and TIM3 were elevated on CD4+ T cells compared to PBMCs. Heterogenous marker expression was observed between individuals. CONCLUSIONS: Our analysis shows that RRP tissue shows elevated levels of multiple immune check point targets and VEGFR3, with varied patterns unique to each papilloma patient. Some of these immune checkpoint markers already have novel immunotherapies available or in development, providing molecular rationale to offer these systemic treatments to selected patients affected by RRP alongside VEGF inhibitors. Laryngoscope, 2024.

Renal Implications of Long-Term Systemic Bevacizumab for Recurrent Respiratory Papillomatosis.

BACKGROUND: Bevacizumab is a vascular endothelial growth factor (VEGF) inhibitor that is used off-label for select cases of recurrent respiratory papillomatosis (RRP) that are severe, involve the distal airway or lung parenchyma, and refractory to other forms of adjuvant therapy. However, there is limited safety data for the use of bevacizumab in children and VEGF inhibitors are reported to have a range of adverse renal effects, including hypertension, proteinuria, and thrombotic microangiopathy (TMA). CASE-DIAGNOSIS/TREATMENT: This report describes a case of severe juvenile-onset RRP that had an exceptionally high operative burden that was refractory to several adjuvant treatment strategies (including intralesional cidofovir and subcutaneous pegylated interferon). Bevacizumab treatment resulted in a dramatic and sustained improvement in disease control over a 5-year period. However, after 3 years of treatment, the patient developed hypertension and proteinuria and was found to have evidence of a glomerular TMA on kidney biopsy. These complications were successfully managed with a reduction in bevacizumab frequency and angiotensin-converting enzyme inhibitor initiation. CONCLUSIONS: Clinicians caring for children treated with VEGF inhibitors should be aware of the potential renal complications and their management.

Cimetidine for recurrent respiratory papillomatosis in pregnancy as an alternative adjuvant treatment.

BACKGROUND: We report the first case of cimetidine as an alternative adjuvant therapy in a pregnant woman with recurrent respiratory papillomatosis (RRP). A 40 year old woman at 19 week gestation presented with progressive hoarseness and shortness of breath for 1 month. Flexible nasopharyngolaryngoscopy revealed multiple papillomatous lesions over both vocal cords and subglottic area obstructing 60% of her airway. She had previously been diagnosed with juvenile onset RRP at the age of 5 and underwent endoscopic clearance regularly every 6 months. METHOD: The patient was started on a trial of oral cimetidine at a dose of 30 mg/kg and responded well, eventually requiring endoscopic excision only after 2 years. Subsequently, she underwent in vitro fertilisation treatment and stopped taking her cimetidine. After undergoing endoscopic clearance of her papillomata under general anaesthesia, she restarted on cimetidine during her 2nd and 3rd trimester. RESULTS: Ensuing follow-up demonstrated stable minimal papillomata lesions on her right inferior surface of her vocal cord with no recurrence on her left vocal cord and subglottic area. CONCLUSION: Cimetidine is generally safe and not known to be associated with any major teratogenic risks during pregnancy. RRP is postulated to worsen in pregnant women due to the increase in oestrogen levels during pregnancy. Hence, adjuvant therapy was imperative for our patient to reduce recurrent papillomata formation during her pregnancy. Larger scale studies are warranted to assess the use of long-term high-dose cimetidine in terms of efficacy and safety in pregnancy.

Environmental Sustainability: Waste Audit Comparison Operating Roomand In-Office Laryngeal Surgery.

INTRODUCTION: With vast improvements in imaging and endoscopic technology, there has been a massive shift towards in office procedures for various laryngeal disorders with significant health system and patient benefits. Another benefit which has yet to be investigated is the potential environmental effects and waste reduction of in-office laryngeal procedures over traditional operating room surgery. OBJECTIVES: The purpose of this study is to perform a waste audit and compare the results between operating room and in-office laser laryngeal surgery. METHODS: Ten cases of in-office and operating room laser laryngeal surgery, performed for recurrent respiratory papillomatosis, were subjected to a waste audit with four waste streams identified. Recyclable, general waste, anesthesia source and sharps. All waste was included from the time of case preparation to termination. RESULTS: The cases were extremely homogeneous in the waste produced. The mean waste total produced for the operating room laser surgery was 2972 g of which 18% was recoverable/recyclable. Contamination rate was very low. Recycling was performed very well by nursing/prep staff; however, anesthesia was not recovering 13% of potential materials. The in-office waste produced was approximately one tenth of the operating room waste with almost all delegated into general waste. Potentially divertible/recyclable materials accounted for 38% of the waste in-office procedures. CONCLUSIONS: In-office laryngeal procedures produce 13% of waste compared to surgery performed for similar pathology. These procedures are cost effective, safe and have been demonstrated to enhance environmental sustainability. LEVEL OF EVIDENCE: NA Laryngoscope, 134:803-806, 2024.

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.

Intralesional cidofovir vs. bevacizumab for recurrent respiratory papillomatosis: a systematic review and indirect meta-analysis.

BACKGROUND: Specific HPV types cause recurrent respiratory papillomatosis (R.R.P.). When administered intralesionally, cidofovir, an antiviral agent, has shown favorable outcomes in reducing papilloma. Bevacizumab, an angiogenesis inhibitor, has demonstrated improved R.R.P. However, both treatments lack FDA approval for R.R.P. Our study aims to evaluate the efficacy and safety of intralesional Cidofovir and Bevacizumab for R.R.P. and compare the two interventions. METHODS: We searched five electronic databases to find relevant studies. After the screening, data were extracted from the included studies. Pooled ratios with 95% confidence intervals (CIs) were used for categorical outcomes, and mean difference (MD) was used for continuous outcomes. Statistical heterogeneity was evaluated using the chi-squared test for I2 statistics. The Cochrane Risk of Bias assessment tool was used to assess the methodological quality of randomized controlled trials (RCTs), while the National Institutes of Health's tool was used for observational studies. Analysis was done by Review Manager software. RESULTS: In our comprehensive meta-analysis of 35 articles involving 836 patients, cidofovir demonstrated an overall remission ratio of (0.90 [95% CI: 0.83, 0.98], p = 0.01), while bevacizumab (0.92 [95% CI: 0.79, 1.07]), p = 0.3). The complete remission ratio for cidofovir was (0.66 [95% CI: 0.57, 0.75], p > 0.0001), while bevacizumab was (0.29 [95% CI: 0.12, 0.71], p = 0.07). In partial remission, Bevacizumab showed a higher ratio than Cidofovir 0.74 [0.55, 0.99] vs. 0.40 [0.30, 0.54]. Bevacizumab had a pooled ratio of 0.07 [95% CI: 0.02, 0.30] in terms of no remission, indicating better outcomes compared to Cidofovir with a ratio of 0.28 [95% CI: 0.16, 0.51]. Additionally, Cidofovir showed a favorable decrease in the Derkay Severity Score (DSS) with a mean difference (MD) of 1.98 [95% CI: 1.44, 2.52]. CONCLUSION: Cidofovir had a higher impact on complete remission compared to Bevacizumab. Both showed partial remission, with Bevacizumab having a higher ratio. Moreover, Cidofovir showed a significant decrease in DSS. Bevacizumab had lower rates of no remission and recurrence and fewer adverse events compared to Cidofovir. However, the difference between the two treatments was not significant, except for partial remission.

Factors Associated with Iatrogenic Laryngeal Injury in Recurrent Respiratory Papillomatosis.

OBJECTIVE: To describe iatrogenic laryngeal injury and identify its risk factors in recurrent respiratory papillomatosis (RRP) patients receiving surgical care. STUDY DESIGN: Case-control. SETTING: Tertiary care academic hospital in a metropolitan area. METHODS: Charts of patients with RRP seen at our institution from January 2002 to December 2022 were reviewed. Patients were separated into 2 cohorts based upon whether they experienced any form of iatrogenic laryngeal injury-including anterior commissure synechiae, vocal cord scar, reduced vocal fold pliability, vocal fold motion impairment, and glottic and/or subglottic stenosis. Adjusted logistic regressions were performed to identify factors associated with iatrogenic laryngeal injury. RESULTS: Of 199 RRP patients, 133 (66.8%) had identifiable iatrogenic laryngeal injury. The most common injuries were anterior commissure synechiae (n = 67; 50.4%) and reduced vocal fold pliability (n = 54; 40.6%). On a multivariate logistic regression, patients with diabetes mellitus (adjusted odds ratio [aOR] [95% confidence interval [CI]]: 2.99 [1.02, 8.79]; P = .04) and who received at least 10 surgeries lifetime (aOR [95% CI]: 14.47 [1.70, 123.19]; P = .01) were at increased risk for iatrogenic laryngeal injury, whereas receiving less than 5 surgeries (aOR [95% CI]: 0.21 [0.09, 0.51]; P < .001) was found to be protective. When treating the lifetime number of surgeries as a continuous variable, a greater number of surgeries was a significant risk factor for iatrogenic laryngeal injury (aOR [95% CI]: 1.32 [1.14, 1.53]; P < .001). CONCLUSION: These results suggest the importance of strict glucose control for diabetic patients receiving RRP surgical care, and emphasize the clinical need to identify medical therapies to decrease RRP surgical frequency for patients.

A pilot study on salivary HPV DNA detection to monitor active disease from patients with recurrent respiratory papillomatosis.

PURPOSE: Recurrent respiratory papillomatosis (RRP) is a human papillomavirus (HPV)-related disease affecting the upper airway and saliva could be an important non-invasive sampling source for viral screening and clinical monitoring. We investigated whether HPV DNA could be detected in saliva (cellular pellets and supernatant) from RRP patients and influence on clinical manifestation of the disease. MATERIALS AND METHODS: In this pilot study, saliva samples from 14 RRP patients were obtained in preoperative condition (n = 7) and in disease-free interval (DFI; n = 7). Healthy donors (n = 14) were also included. HPV DNA was investigated by polymerase chain reaction (PCR)-based assays. RESULTS: From cellular pellets, HPV-positive saliva was only detected from preoperative collections (5/7; 71.4 %) and showed a mean cycle threshold (Ct) value of 24.33 (±1.25), whereas all patients in DFI were HPV-negative (Ct ≥ 32.16), revealing significant difference between these two clinical moments (p = 0.021). Patients in DFI and healthy donors showed similar Ct values. From saliva supernatant, detectable HPV cell-free DNA (cfDNA) occurred in 42.9 % (3/7) and 57.1 % (4/7) of preoperative collections using the commercial cfDNA kits from Norgen and Qiagen, respectively. Salivary cfDNA size distribution obtained by TapeStation analysis showed a predominant size range of 150 to 400 bp in both patients and healthy controls, corresponding to mononucleosomal and dinucleosomal fragments. CONCLUSIONS: In conclusion, HPV DNA screening in saliva (both cellular pellets and cfDNA) may have clinical utility to monitor active disease of RRP patients.