Tissue Sealant Impact on Skull Base Reconstruction Outcomes: A Systematic Review and Meta-Analysis.

OBJECTIVE: Despite significant advances in understanding of skull base reconstruction principles, the role of tissue sealants in modifying postoperative cerebrospinal fluid (CSF) leak outcomes remains controversial. We evaluate postoperative CSF leak incidence associated with tissue sealant use in skull base defect repair during endoscopic skull base surgery (ESBS). DATA SOURCES: Web of Science, PubMed/MEDLINE, Scopus, and Cochrane Library. REVIEW METHODS: Systematic review and meta-analysis of risk differences (RD). A search strategy identified original studies reporting CSF leakage following ESBS with disaggregation by tissue sealant use and/or type. RESULTS: 27 non-randomized studies (n = 2,403) were included for qualitative and meta-analysis. Reconstruction with a tissue sealant did not significantly reduce postoperative CSF leak risk compared with reconstruction without sealant (RD[95% CI] = 0.02[-0.01, 0.05]). Sub-analyses of dural sealant (-0.02[-0.11, 0.07]) and fibrin glue (0.00[-0.07, 0.07]) compared with no sealant were similarly unremarkable. Postoperative CSF leakage was not significantly modulated in further sub-analyses of DuraSeal (0.02[-0.02, 0.05]), Adherus (-0.03[-0.08, 0.03]), or Bioglue (-0.06[-0.23, 0.12]) versus no dural sealant use, or Tisseel/Tissucol versus fibrin glue nonuse (0.00[-0.05, 0.05]). No significant association was seen comparing dural sealant use versus fibrin glue use on pairwise (0.01[-0.03, 0.05]) or network meta-analysis (-0.01[-0.05, 0.04]). Limitations in source literature prevented sub-analyses stratified by leak characteristics, defect size and location, and accompanying reconstruction materials. CONCLUSION: Tissue sealant use did not appear to impact postoperative CSF leak incidence when compared with nonuse. Higher quality studies are warranted to thoroughly elucidate the clinical value of adjunct sealant use in endoscopic skull base reconstruction. LEVEL OF EVIDENCE: N/A Laryngoscope, 2024.

Severe unilateral refractory epistaxis arising from the septal branch of the anterior ethmoid artery.

KEY POINTS: The septal branch of the anterior ethmoid artery (sbAEA) is an underrecognized source of severe refractory epistaxis. Herein, we describe the presentation, predisposing factors, treatment strategies, and outcomes of a series of patients with this condition.

Outcomes of Short-Term Surgical Trips in Otolaryngology-Head and Neck Surgery: A Scoping Review.

OBJECTIVE: This scoping review aims to explore the current body of literature to characterize how short-term surgical trips (STSTs) in Otolaryngology-Head and Neck Surgery (OtoHNS) contribute to surgical, educational, and sustainability-based outcomes in low- and middle-income countries (LMICs). We aim to use these data to synthesize aspects of STSTs that are successful with the hopes of shaping future global efforts. DATA SOURCES: Data sources included Ovid MEDLINE, Ovid Embase, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, and Scopus. REVIEW METHODS: A comprehensive search was conducted on several databases from inception to October 14, 2021. We included primary studies exploring any surgical or educational outcomes of global short-term surgical endeavors within LMICs. Data were then extracted to evaluate the heterogenous body of literature that exists, characterizing the surgical, educational, and sustainability-based outcomes. RESULTS: Forty-Seven studies were included in the final analysis. Most publications were focused on surgical interventions (39 of 47; 82.9%); 13 (27.7%) studies included education as the primary aim and 12 (25.5%) considered sustainability a significant aim. Of the 94 first and last authors, there were zero first authors and only one last author with an LMIC affiliation. Twenty-six studies (55%) mentioned that any patients were seen in follow-up, ranging from one day to five years. CONCLUSION: Our scoping review demonstrates that most STSTs have focused primarily on surgical procedures with a lack of appropriate long-term follow-up. However, the available outcome-based information presented helps identify factors that characterize a strong short-term global surgical program. LEVEL OF EVIDENCE: NA Laryngoscope, 134:32-39, 2024.

The impact of nasal packing on skull base reconstruction and quality-of-life outcomes following endoscopic skull base surgery.

KEY POINTS: Nasal packing type was not associated with postoperative cerebrospinal fluid leaks Nondissolvable packing conferred an increased risk for postoperative sinonasal infections Nasal packing type did not influence short- and long-term quality-of-life scores.

The Global Otolaryngology-Head and Neck Surgery Workforce.

Importance: A core component of delivering care of head and neck diseases is an adequate workforce. The World Health Organization report, Multi-Country Assessment of National Capacity to Provide Hearing Care, captured primary workforce estimates from 68 member states in 2012, noting that response rates were a limitation and that updated more comprehensive data are needed. Objective: To establish comprehensive workforce metrics for global otolaryngology-head and neck surgery (OHNS) with updated data from more countries/territories. Design, Setting, and Participants: A cross-sectional electronic survey characterizing the OHNS workforce was disseminated from February 10 to June 22, 2022, to professional society leaders, medical licensing boards, public health officials, and practicing OHNS clinicians. Main Outcome: The OHNS workforce per capita, stratified by income and region. Results: Responses were collected from 121 of 195 countries/territories (62%). Survey responses specifically reported on OHNS workforce from 114 countries/territories representing 84% of the world's population. The global OHNS clinician density was 2.19 (range, 0-61.7) OHNS clinicians per 100 000 population. The OHNS clinician density varied by World Bank income group with higher-income countries associated with a higher density of clinicians. Regionally, Europe had the highest clinician density (5.70 clinicians per 100 000 population) whereas Africa (0.18 clinicians per 100 000 population) and Southeast Asia (1.12 clinicians per 100 000 population) had the lowest. The OHNS clinicians deliver most of the surgical management of ear diseases and hearing care, rhinologic and sinus diseases, laryngeal disorders, and upper aerodigestive mucosal cancer globally. Conclusion and Relevance: This cross-sectional survey study provides a comprehensive assessment of the global OHNS workforce. These results can guide focused investment in training and policy development to address disparities in the availability of OHNS clinicians.

Racial and ethnic disparities in the presentation size and timing of pituitary adenomas resected via endoscopic endonasal approach.

KEY POINTS: In a single-center cohort of pituitary adenoma patients, non-White race independently predicted larger tumor size at initial presentation. Uninsured patients suffered a significantly higher rate of pituitary apoplexy at initial presentation. Geographically distant care appeared to present a greater barrier for non-White and Hispanic patients relative to their White and non-Hispanic counterparts.

Outcomes of perioperative vasopressor use for hemodynamic management of patients undergoing free flap surgery: A systematic review and meta-analysis.

This systematic review and meta-analysis investigates the objective evidence regarding outcomes in head and neck free flap surgeries using vasoactive agents in the perioperative period. A search was performed in PubMed, Cochrane, Web of Science, and Scopus databases. Inclusion criteria were clinical studies in which vasopressors were used in head and neck free flap surgery during the intraoperative and perioperative period. Eighteen studies (n = 5397) were included in the qualitative analysis and nine (n = 4381) in the meta-analysis. There was no difference in flap failure outcomes with perioperative vasopressor use in head and neck free flap surgery (n = 4015, OR = 0.93, 95% CI [0.60, 1.44]). When patients received vasopressors perioperatively, there was an associated decrease in flap-specific complications (n = 3881, OR = 0.69, 95% CI [0.55, 0.87]). Intraoperative vasopressor use does not negatively impact free tissue transfer outcomes in head and neck surgery and may reduce overall free flap complications.

Characteristics and Outcomes in Pediatric Versus Adult Craniopharyngiomas: A Systematic Review and Meta-Analysis.

BACKGROUND: Craniopharyngiomas account for 1.2% to 4.6% of all intracranial tumors. Although age at presentation is distributed bimodally, with a pediatric peak occurring between 5 and 15 years and an adult peak between 50 and 70 years, presentation, treatment, and outcome differences between these two craniopharyngioma populations have not been thoroughly characterized. OBJECTIVE: To compare treatments and outcomes between adult and pediatric craniopharyngiomas. METHODS: This is a systematic review and meta-analysis. Web of Science, MEDLINE, and Scopus databases were searched for primary studies reporting postoperative complications, functional outcomes, recurrence, and overall survival in patients with craniopharyngioma undergoing surgery. RESULTS: The search yielded 1,202 unique articles, of which 106 (n=4,202 patients) met criteria for qualitative synthesis and 23 (n=735 patients) met criteria for meta-analysis. Compared with adult, pediatric craniopharyngiomas were less likely to present with visual defects (odds ratio [OR] 0.54, 95% CI 0.36-0.80) or cognitive impairment (OR 0.29, 95% CI 0.12-0.71) and more likely with headaches (OR 2.08, 95% CI 1.16-3.73). Children presented with significantly larger tumors compared with adults (standardized mean difference 0.68, 95% CI 0.38-0.97). Comparing functional outcomes, pediatric patients sustained higher rates of permanent diabetes insipidus (OR 1.70, 95% CI 1.13-2.56), obesity (OR 3.15, 95% CI 1.19-8.31), and cranial nerve and/or neurological defects (OR 4.87, 95% CI 1.78-13.31) than adults. No significant differences were found in rates of postoperative cerebrospinal fluid leak, overall or progression-free survival, or recurrence. CONCLUSION: Adult and pediatric craniopharyngiomas seem to have fundamental differences in clinical presentation and functional outcomes. These patients frequently require multimodality treatment and are best managed with a multidisciplinary team and an individualized approach.

Facility Volume as a Prognosticator of Survival in Locally Advanced Papillary Thyroid Cancer.

OBJECTIVES: To evaluate the influence of facility case-volume on survival in patients with locally advanced papillary thyroid cancer (PTC), and to identify prognostic case-volume thresholds for facilities managing this patient population. STUDY DESIGN: Retrospective database study. METHODS: The 2004-2017 National Cancer Database was queried for patients receiving definitive surgery for locally advanced PTC. Using K-means clustering and multivariable Cox proportional-hazards (CPH) regression, two groups with distinct spectrums of facility case-volumes were generated. Multivariable CPH regression and Kaplan-Meier analysis assessed for the influence of facility case-volume and the prognostic value of its stratification on overall survival (OS). RESULTS: Of 48,899 patients treated at 1304 facilities, there were 34,312 (70.2%) females and the mean age was 48.0 ± 16.0 years. Increased facility volume was significantly associated with reduced all-cause mortality (HR 0.996; 95% CI, 0.992-0.999; p = 0.008). Five facility clusters were generated, from which two distinct cohorts were identified: low (LVF; <27 cases/year) and high (HVF; ≥27 cases/year) facility case-volume. Patients at HVFs were associated with reduced mortality compared to those at LVFs (HR 0.791; 95% CI, 0.678-0.923, p = 0.003). Kaplan-Meier analysis of propensity score-matched N0 and N1 patients demonstrated higher OS in HVF cohorts (all p < 0.001). CONCLUSIONS: Facility case-volume was an independent predictor of improved OS in locally advanced PTC, indicating a possible survival benefit at high-volume medical centers. Specifically, independent of a number of sociodemographic and clinical factors, facilities that treated ≥27 cases per year were associated with increased OS. Patients with locally advanced PTC may, therefore, benefit from referrals to higher-volume facilities. LEVEL OF EVIDENCE: 4 Laryngoscope, 133:443-450, 2023.

Intranasal Anticholinergics for Treatment of Chronic Rhinitis: Systematic Review and Meta-Analysis.

OBJECTIVE: Topical intranasal anticholinergics are commonly prescribed for the relief of chronic rhinitis and associated symptoms, warranting thorough assessment of the supporting evidence. The present study aimed to evaluate the safety and efficacy of anticholinergic nasal sprays in the management of allergic and non-allergic rhinitis symptom severity and duration. METHODS: A search encompassing the Cochrane Library, PubMed/MEDLINE, and Scopus databases was conducted. Primary studies describing rhinorrhea, nasal congestion, and/or postnasal drip outcomes in rhinitis patients treated with an anticholinergic spray were included for review. RESULTS: The search yielded 1,029 unique abstracts, of which 12 studies (n = 2,024) met inclusion criteria for qualitative synthesis and 9 (n = 1,920) for meta-analysis. Median follow-up was 4 weeks and ipratropium bromide was the most extensively trialed anticholinergic. Compared to placebo, anticholinergic treatment was demonstrated to significantly reduce rhinorrhea severity scores (standardized mean difference [95% CI] = -0.77 [-1.20, -0.35]; -0.43 [-0.72, -0.13]) and duration (-0.62 [-0.95, -0.30]; -0.29 [-0.47, -0.10]) in allergic and non-allergic rhinitis patients respectively. Benefit was less consistent for nasal congestion, postnasal drip, and sneezing symptoms. Reported adverse effects included nasal mucosa dryness or irritation, epistaxis, headaches, and pharyngitis, though comparison to placebo found significantly greater risk for epistaxis only (risk ratio [95% CI] = 2.19 [1.22, 3.93]). CONCLUSION: Albeit treating other symptoms with less benefit, anticholinergic nasal sprays appear to be safe and efficacious in reducing rhinorrhea severity and duration in both rhinitis etiologies. This evidence supports their continued use in the treatment of rhinitis-associated rhinorrhea. LEVEL OF EVIDENCE: 1 Laryngoscope, 133:722-731, 2023.

The Influence of Facility Volume and Type on Skull Base Chordoma Treatment and Outcomes.

OBJECTIVE: To evaluate the influence of facility case volume and type on skull base chordoma treatment and overall survival (OS). METHODS: The 2004-2016 National Cancer Database was queried for skull base chordoma patients receiving definitive treatment. Facilities were categorized into 2 cohorts by calculating the mean number of patients treated per facility and using cutoff numbers that were 0.5 SD above and below the computed mean to separate the groups. As, by definition of the inclusion criteria, all included facilities treated at least 1 patient, low-volume facilities were defined as treating 1 patient, and high-volume facilities were defined as treating ≥7 patients; mid-volume facilities (facilities treating ≥2 but ≤6 patients) were excluded. Differences in treatment course, outcomes, and OS by facility type were assessed. RESULTS: The study included 658 patients (44.8% female, 79.5% White). The 187 unique facilities were categorized into 95 low-volume facilities (treating 1 patient during timeline) and 26 high-volume facilities (treating ≥7 patients during timeline). Kaplan-Meier log-rank analysis demonstrated a significant positive association between facility volume and OS (P < 0.001) and an improvement in OS in patients at academic facilities (P = 0.018). On Cox proportional hazards multivariate regression after adjusting for sex, age, Charlson-Deyo comorbidity index, and insurance type, high-volume facilities and academic facilities were associated with a lower mortality risk than low-volume facilities and nonacademic facilities (P < 0.001 and P = 0.03, respectively). CONCLUSIONS: Higher facility case volume and academic facility type appear to be associated with improved survival outcomes in treatment of skull base chordomas.

Otolaryngology residency programs' perspectives on virtual interviews during the COVID-19 pandemic.

Objective: To evaluate perceptions of otolaryngology residency program directors (PDs) and department chairs (DCs) on virtual interviews (VIs) at the conclusion of the 2021 residency match. Study design: Cross-sectional survey study. Methods: An anonymous and voluntary survey was administered to PDs and DCs of U.S. otolaryngology residency programs from March 1, 2021 to April 11, 2021. Utilizing Likert scale ratings, the survey measured overall satisfaction with the VI format, perceived ability to assess key candidate attributes, relative importance of traditional candidate metrics, and likelihood to implement VIs in future cycles. Results: Ninety-four surveys were completed by PDs (48.9%) and DCs (51.1%). Sixty (63.8%) respondents found the VI experience to be satisfactory or strongly satisfactory. Sixty-six (70.2%) respondents felt confident in their ability to assess a candidate's professionalism and communication skills through VIs; however, confidence in gauging an applicant's clinical skills/knowledge (41.2%) and overall program fit (47.3%) was lower. Regarding candidate metrics, 64 (68.1%) respondents believed that personal prior knowledge of the applicant gained increased importance with VIs. Forty-four (46.8%) and 45 (47.9%) participants believed that letters of recommendation in the specialty and perceived commitment to their program similarly attained increased significance in evaluating applicants, respectively. Conclusion: Most PDs and DCs were satisfied with their VI experiences and expect the quality of interns to be unaffected by virtual assessment modalities. Majority opinion on the relative importance of traditional applicant metrics remained largely unchanged, the exception being an increase in importance of prior knowledge of the applicant.Level of Evidence: N/A.

Long-term outcomes in sinonasal squamous cell carcinoma arising from inverted papilloma: Systematic review.

Long-term survival and recurrence patterns of squamous cell carcinoma arising from inverted papilloma (IP-SCC) have not been thoroughly investigated. Four electronic databases were searched and primary studies describing overall survival (OS), recurrence, and mean time to recurrence of patients with IP-SCC were included for review. Our search yielded 662 studies. The 28 studies selected for inclusion identified 663 patients with IP-SCC. In 596 patients with reported T classification, 439 (73.7%) were T3/T4 on presentation. Of the 650 participants with recurrence data (local, regional, and distant), 155 (23.8%) experienced a recurrence, with an aggregate mean time-to-recurrence of 24.3 months. In 565 patients with 5-year OS rates, the aggregate 5-year OS was 62%. Based on the literature to date, IP-SCC is associated with a 5-year OS rate of 62%. 23.8% of patients experienced recurrence at a mean time of 24.3 months, suggesting the need for long-term surveillance.

Prognostic Factors and Outcomes of De Novo Sinonasal Squamous Cell Carcinoma: A Systematic Review and Meta-analysis.

OBJECTIVE: To review overall survival (OS), recurrence patterns, and prognostic factors of de novo sinonasal squamous cell carcinoma (DN-SCC). DATA SOURCES: PubMed, Scopus, OVID Medline, and Cochrane databases from 2006 to December 23, 2020. REVIEW METHODS: The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Articles were required to report either recurrence patterns or survival outcomes of adults with DN-SCC. Case reports, books, reviews, meta-analyses, and database studies were all excluded. RESULTS: Forty-one studies reported on survival or recurrence outcomes. The aggregate 5-year OS was 54.5% (range, 18%-75%) from 35 studies (n = 1903). Patients undergoing open surgery were more likely to receive radiation therapy and present at an advanced stage compared to those receiving endoscopic surgery (all P < .001). Advanced T stage, presence of cervical nodal metastases, maxillary sinus primary site, and negative human papillomavirus (HPV) status were all correlated with significantly worse 5-year OS. Direct meta-analysis of 8 studies demonstrated patients with surgery were more likely to be alive at 5 years compared to those who did not receive surgery (odds ratio, 2.26; 95% CI, 1.48-3.47; P < .001). Recurrence was reported in 628 of 1471 patients from 26 studies (42.7%) with an aggregate 5-year locoregional control rate of 67.1% (range, 50.4%-93.3%). CONCLUSION: This systematic review and meta-analysis suggests that the 5-year OS rate for DN-SCC may approach 54.5% and recurrence rate approaches 42.7%. In addition, various tumor characteristics including advanced T stage, positive nodal status, maxillary sinus origin, and negative HPV status are all associated with decreased survival.

A Web-Based Deep Learning Model for Automated Diagnosis of Otoscopic Images.

OBJECTIVES: To develop a multiclass-classifier deep learning model and website for distinguishing tympanic membrane (TM) pathologies based on otoscopic images. METHODS: An otoscopic image database developed by utilizing publicly available online images and open databases was assessed by convolutional neural network (CNN) models including ResNet-50, Inception-V3, Inception-Resnet-V2, and MobileNetV2. Training and testing were conducted with a 75:25 breakdown. Area under the curve of receiver operating characteristics (AUC-ROC), accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were used to compare different CNN models' performances in classifying TM images. RESULTS: Our database included 400 images, organized into normal (n = 196) and abnormal classes (n = 204), including acute otitis media (n = 116), otitis externa (n = 44), chronic suppurative otitis media (n = 23), and cerumen impaction (n = 21). For binary classification between normal versus abnormal TM, the best performing model had average AUC-ROC of 0.902 (MobileNetV2), followed by 0.745 (Inception-Resnet-V2), 0.731 (ResNet-50), and 0.636 (Inception-V3). Accuracy ranged between 0.73-0.77, sensitivity 0.72-0.88, specificity 0.58-0.84, PPV 0.68-0.81, and NPV 0.73-0.83. Macro-AUC-ROC for MobileNetV2 based multiclass-classifier was 0.91, with accuracy of 66%. Binary and multiclass-classifier models based on MobileNetV2 were loaded onto a publicly accessible and user-friendly website (https://headneckml.com/tympanic). This allows the readership to upload TM images for real-time predictions using the developed algorithms. CONCLUSIONS: Novel CNN algorithms were developed with high AUC-ROCs for differentiating between various TM pathologies. This was further deployed as a proof-of-concept publicly accessible website for real-time predictions.

Acquisition of Cisplatin Resistance Shifts Head and Neck Squamous Cell Carcinoma Metabolism toward Neutralization of Oxidative Stress.

Background: Cisplatin (CDDP) is commonly utilized in the treatment of advanced solid tumors including head and neck squamous cell carcinoma (HNSCC). Cisplatin response remains highly variable among individual tumors and development of cisplatin resistance is common. We hypothesized that development of cisplatin resistance is partially driven by metabolic reprogramming. Methods: Using a pre-clinical HNSCC model and an integrated approach to steady state metabolomics, metabolic flux and gene expression data we characterized the interaction between cisplatin resistance and metabolic reprogramming. Results: Cisplatin toxicity in HNSCC was driven by generation of intra-cellular oxidative stress. This was validated by demonstrating that acquisition of cisplatin resistance generates cross-resistance to ferroptosis agonists despite the fact that cisplatin itself does not trigger ferroptosis. Acquisition of cisplatin resistance dysregulated the expression of genes involved in amino acid, fatty acid metabolism and central carbon catabolic pathways, enhanced glucose catabolism and serine synthesis. Acute cisplatin exposure increased intra-tumoral levels of S-methyl-5-thiadenosine (MTA) precursors and metabotoxins indicative of generalized oxidative stress. Conclusions: Acquisition of cisplatin resistance is linked to metabolic recovery from oxidative stress. Although this portends poor effectiveness for directed metabolic targeting, it supports the potential for biomarker development of cisplatin effectiveness using an integrated approach.

Small molecule inhibitor regorafenib inhibits RET signaling in neuroblastoma cells and effectively suppresses tumor growth in vivo.

Neuroblastoma (NB), the most common extracranial pediatric solid tumor, continues to cause significant cancer-related morbidity and mortality in children. Dysregulation of oncogenic receptor tyrosine kinases (RTKs) has been shown to contribute to tumorigenesis in various human cancers and targeting these RTKs has had therapeutic benefit. RET is an RTK which is commonly expressed in NB, and high expression of RET correlates with poor outcomes in patients with NB. Herein we report that RET is required for NB cell proliferation and that the small molecule inhibitor regorafenib (BAY 73-4506) blocks glial cell derived neurotrophic factor (GDNF)-induced RET signaling in NB cells and inhibits NB growth both in vitro and in vivo. We found that regorafenib significantly inhibited cell proliferation and colony formation ability of NB cells. Moreover, regorafenib suppressed tumor growth in both an orthotopic xenograft NB mouse model and a TH-MYCN transgenic NB mouse model. Finally, regorafenib markedly improved the overall survival of TH-MYCN transgenic tumor-bearing mice. In summary, our study suggests that RET is a potential therapeutic target in NB, and that using a novel RET inhibitor, like regorafenib, should be investigated as a therapeutic treatment option for children with NB.

Novel multi-targeted ErbB family inhibitor afatinib blocks EGF-induced signaling and induces apoptosis in neuroblastoma.

Neuroblastoma is the most common extracranial solid tumor in children. The ErbB family of proteins is a group of receptor tyrosine kinases that promote the progression of various malignant cancers including neuroblastoma. Thus, targeting them with small molecule inhibitors is a promising strategy for neuroblastoma therapy. In this study, we investigated the anti-tumor effect of afatinib, an irreversible inhibitor of members of the ErbB family, on neuroblastoma. We found that afatinib suppressed the proliferation and colony formation ability of neuroblastoma cell lines in a dose-dependent manner. Afatinib also induced apoptosis and blocked EGF-induced activation of PI3K/AKT/mTOR signaling in all neuroblastoma cell lines tested. In addition, afatinib enhanced doxorubicin-induced cytotoxicity in neuroblastoma cells, including the chemoresistant LA-N-6 cell line. Finally, afatinib exhibited antitumor efficacy in vivo by inducing apoptosis in an orthotopic xenograft neuroblastoma mouse model. Taken together, these results show that afatinib inhibits neuroblastoma growth both in vitro and in vivo by suppressing EGFR-mediated PI3K/AKT/mTOR signaling. Our study supports the idea that EGFR is a potential therapeutic target in neuroblastoma. And targeting ErbB family protein kinases with small molecule inhibitors like afatinib alone or in combination with doxorubicin is a viable option for treating neuroblastoma.

Novel Src/Abl tyrosine kinase inhibitor bosutinib suppresses neuroblastoma growth via inhibiting Src/Abl signaling.

Neuroblastoma (NB) is the most common extracranial solid tumor in children. Aberrant activation of the non-receptor tyrosine kinases Src and c-Abl contributes to the progression of NB. Thus, targeting these kinases could be a promising strategy for NB therapy. In this paper, we report that the potent dual Src/Abl inhibitor bosutinib exerts anti-tumor effects on NB. Bosutinib inhibited NB cell proliferation in a dose-dependent manner and suppressed colony formation ability of NB cells. Mechanistically, bosutinib effectively decreased the activity of Src/Abl and PI3K/AKT/mTOR, MAPK/ERK, and JAK/STAT3 signaling pathways. In addition, bosutinib enhanced doxorubicin (Dox)- and etoposide (VP-16)-induced cytotoxicity in NB cells. Furthermore, bosutinib demonstrated anti-tumor efficacy in an orthotopic xenograft NB mouse model in a similar mechanism as of that in vitro. In summary, our results reveal that Src and c-Abl are potential therapeutic targets in NB and that the novel Src/Abl inhibitor bosutinib alone or in combination with other chemotherapeutic agents may be a valuable therapeutic option for NB patients.

Wip1 inhibitor GSK2830371 inhibits neuroblastoma growth by inducing Chk2/p53-mediated apoptosis.

Neuroblastoma (NB) is the most common extracranial tumor in children. Unlike in most adult tumors, tumor suppressor protein 53 (p53) mutations occur with a relatively low frequency in NB and the downstream function of p53 is intact in NB cell lines. Wip1 is a negative regulator of p53 and hindrance of Wip1 activity by novel inhibitor GSK2830371 is a potential strategy to activate p53's tumor suppressing function in NB. Yet, the in vivo efficacy and the possible mechanisms of GSK2830371 in NB have not yet been elucidated. Here we report that novel Wip1 inhibitor GSK2830371 induced Chk2/p53-mediated apoptosis in NB cells in a p53-dependent manner. In addition, GSK2830371 suppressed the colony-formation potential of p53 wild-type NB cell lines. Furthermore, GSK2830371 enhanced doxorubicin- (Dox) and etoposide- (VP-16) induced cytotoxicity in a subset of NB cell lines, including the chemoresistant LA-N-6 cell line. More importantly, GSK2830371 significantly inhibited tumor growth in an orthotopic xenograft NB mouse model by inducing Chk2/p53-mediated apoptosis in vivo. Taken together, this study suggests that GSK2830371 induces Chk2/p53-mediated apoptosis both in vitro and in vivo in a p53 dependent manner.