The impact of ivacaftor on sinonasal pathology in S1251N-mediated cystic fibrosis patients.

IMPORTANCE: Sinonasal symptoms in patients suffering from cystic fibrosis can negatively influence the quality of life and sinuses can be a niche for pathogens causing infection and inflammation leading to a decrease of lung function. Ivacaftor, a potentiator of the Cystic Fibrosis Transmembrane Conductance Regulator protein, has shown improvement in pulmonary function in cystic fibrosis patients with different forms of class III gating mutations. However, the effects of ivacaftor on sinonasal pathology have hardly been studied. OBJECTIVE: To determine the impact of ivacaftor therapy on sinonasal pathology in patients with cystic fibrosis with an S1251N mutation. DESIGN: Prospective observational mono-center cohort study, between June 2015 and December 2016. SETTING: A tertiary referral center in Utrecht, The Netherlands. PARTICIPANTS: Eight patients with cystic fibrosis with an S1251N mutation, treated with the potentiator ivacaftor were investigated. EXPOSURES: Ivacaftor (Kalydeco, VX-770) therapy. Computed tomography imaging of paranasal sinuses. Nasal nitric oxide concentration measurements and nasal endoscopy. MAIN OUTCOMES AND MEASURES: Primary outcome is opacification of paranasal sinuses examined with computed tomography scan analysis and scaled by the modified Lund-Mackay score before and one year after treatment. Secondary outcomes are nasal nitric oxide concentration levels, sinonasal symptoms and nasal endoscopic findings before and approximately two months and in some cases one year after treatment. RESULTS: Computed tomography scan analysis showed a significant decrease in opacification of the majority of paranasal sinuses comparing the opacification score per paranasal sinus before and after one year of treatment with ivacaftor. Median nasal nitric oxide levels significantly improved from 220.00 (IQR:136.00-341.18) to 462.84 (IQR:233.17-636.25) (p = 0.017) parts per billion. Likewise, the majority of sinonasal symptoms and nasal endoscopic pathology decreased or resolved at two months after the use of ivacaftor. CONCLUSION AND RELEVANCE: Ivacaftor appears to improve sinonasal outcome parameters and thereby sinonasal health in patients with cystic fibrosis with an S1251N mutation.

Further delineation of the GDF6 related multiple synostoses syndrome.

A mutation in GDF6 was recently found to underlie a multiple synostoses syndrome. In this report, we describe the second family with GDF6-related multiple synostoses syndrome (SYNS4), caused by a novel c.1287C>A/p.Ser429Arg mutation in GDF6. In addition to synostoses of carpal and/or tarsal bones, at least 6 of 10 affected patients in this family have been diagnosed with mild to moderate hearing loss. In four of them otosclerosis was said to be present, one patient had hearing loss due to severe stapes fixation at the age of 6 years, providing evidence that hearing loss in the GDF6-related multiple synostoses syndrome can be present in childhood. Two others had surgery for stapes fixation at adult age. We hypothesize that, identical to the recently published GDF6-related multiple synostoses family, the p.Ser429Arg mutation also leads to a gain of function. The previously reported c.1330T>A/pTyr444Asn mutation was located in a predicted Noggin and receptor I interacting domain and the gain of function was partly due to resistance of the mutant GDF6 to the BMP-inhibitor Noggin. The results in our family show that mutations predicting to affect the type II receptor interface can lead to a similar phenotype and that otosclerosis presenting in childhood can be part of the GDF6-related multiple synostoses syndrome.

Surgery versus endoscopic cauterization in patients with third or fourth branchial pouch sinuses: A systematic review.

OBJECTIVES: To systematically review the current literature on treatment of third and fourth branchial pouch sinuses with endoscopic cauterization, including chemocauterization and electrocauterization, in comparison to surgical treatment. DATA SOURCES: PubMed, Embase, and the Cochrane Library. REVIEW METHODS: We conducted a systematic search. Studies reporting original study data were included. After assessing the directness of evidence and risk of bias, studies with a low directness of evidence or a high risk of bias were excluded from analysis. Cumulative success rates after initial and recurrent treatments were calculated for both methods. A meta-analysis was conducted comparing the success rate of electrocauterization and surgery. RESULTS: A total of 2,263 articles were retrieved, of which seven retrospective and one prospective article were eligible for analysis. The cumulative success rate after primary treatment with cauterization ranged from 66.7% to 100%, and ranged from 77.8% to 100% after a second cauterization. The cumulative success rate after the first surgical treatment ranged from 50% to 100% and was 100% after the second surgical attempt. Meta-analysis on electrocauterization showed a nonsignificant risk ratio of 1.35 (95% confidence interval: 0.78-2.33). CONCLUSIONS: The effectiveness of cauterization in preventing recurrence seems to be comparable to surgical treatment. However, we suggest endoscopic cauterization as the treatment of choice for third and fourth branchial pouch sinuses because of the lower morbidity rate.

Tracheostomy versus mandibular distraction osteogenesis in infants with Robin sequence: a comparative cost analysis.

Many treatments have been described for infants with Robin sequence and severe respiratory distress, but there have not been many comparative studies of outcome and cost-effectiveness. The aim of this study was to compare the cost and complications of two common interventions - mandibular distraction osteogenesis and tracheostomy. Nine patients with isolated Robin sequence (mandibular distraction osteogenesis, n=5, and tracheostomy, n=4) were included in the analyses. Predetermined costs and complications were obtained retrospectively from medical records and by questionnaires to the parents over a 12-month period. Overall direct costs (admission to hospital, diagnostics, surgery, and homecare) were 3 times higher for tracheostomy (€105.523 compared with €33.482, p=0.02). Overall indirect costs (absence from work) were almost 5 times higher (€2.543 compared with €543, p=0.02). There was a threefold increase in overall total cost/patient (both direct and indirect) for tracheostomy (€108.057 compared with 34.016, p=0.02) and 4 times more complications were encountered. This study shows that mandibular distraction osteogenesis in infants diagnosed with Robin sequence costs significantly less and results in fewer complications than tracheostomy, and this contributes to our current knowledge about the ideal approach for infants with Robin sequence and might provide a basis for institutional protocols in the future.

Nasal nitric oxide levels and nasal polyposis in children and adolescents with cystic fibrosis.

IMPORTANCE: The counterintuitive decrease of exhaled nitric oxide (NO) levels in a severe inflammatory disorder like cystic fibrosis (CF) is only scarcely understood. Because NO is important in a variety of regulatory processes in the lung, including host defense, inflammation, and bronchomotor control, it is necessary to search for clarifying mechanisms. OBJECTIVES: To explore whether fractional exhaled NO (FENO) and nasal NO (nNO) levels are associated with CF genotype, nutritional status, presence of nasal polyps, pulmonary function, and airway colonization with Staphylococcus aureus and Pseudomonas aeruginosa in children with CF, and to investigate the effect of functional endoscopic sinus surgery (FESS) on FENO and nNO levels in children with CF and persistent sinonasal disease. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional study (association with NO) and prospective study (effect of FESS on NO) in a tertiary care referral center. Patients included 95 children with CF in clinically stable condition at routine annual multidisciplinary examination, 13 of whom were referred for a FESS procedure. INTERVENTIONS: Functional endoscopic sinus surgery in children with CF and persistent sinonasal disease. MAIN OUTCOMES AND MEASURES: Body mass index (BMI), FENO and nNO levels, results of flexible nasal endoscopy, pulmonary function tests (forced expiratory volume in 1 second and forced vital capacity), and airway cultures. RESULTS: Children with nasal polyposis have significantly lower nNO levels than those without polyposis (median, 53 vs 140 parts per billion; P = .001); these values are negatively associated with colonization with S aureus (ß = -.22; P = .04). After FESS, nNO values increase significantly, although not to normal levels. CONCLUSIONS AND RELEVANCE: In children with CF, the presence of nasal polyps is associated with significantly lower nNO levels than in children without nasal polyps. After FESS for nasal polyposis, nNO levels increase significantly, but not to normal levels. Low nNO levels are associated with S aureus colonization in the oropharynx and lower airways.

[Paediatric breathlessness caused by aspiration of a foreign body in food]. / Benauwd kind door aspiratie van een corpus alienum uit de voeding.

Two one-year-old boys were seen by a paediatrician with symptoms of increasing breathlessness and inspiratory stridor. Upon the probable diagnosis subglottic laryngitis and toddler's asthma, respectively, they were admitted to hospital for medical treatment. Because they failed to recover sufficiently with this treatment, an ENT specialist subsequently performed a laryngotracheobronchoscopy under general anaesthesia. A fish-bone and chicken-bone, respectively, were found and removed from the larynx. In retrospect, the parents of both children realized that onset of symptoms followed a choking incident. These case histories illustrate the importance of active questioning concerning the onset of symptoms in order to differentiate between possibly causes. Endoscopy of the airways is required when parents mention a triggering moment or if the course of respiratory complaints is atypical.

Segmental facial hemangiomas and associated structural defects.

PHACE syndrome refers to the association of large segmental facial hemangiomas with 1 or more of the following anomalies: posterior fossa malformations, arterial anomalies, cardiac anomalies, and eye abnormalities. In this review, we present a newborn with a large segmental facial hemangioma and abnormal genesis of the cerebropetal arteries. Furthermore, we give an overview of the anomalies associated with the PHACE syndrome. Patients with large segmental facial hemangiomas are at risk for 1 of these anomalies and should be investigated accordingly. We present a clinical algorithm for screening of patients with large segmental hemangiomas suggestive of the PHACE syndrome.

Treatment of lymphatic malformations with OK-432 (Picibanil): review of the literature.

INTRODUCTION: Lymphatic malformations (LM) are benign structural defects that can cause serious complications because of their size and location. Traditionally, surgical removal was the first treatment modality, but this could be associated with many complications and risks. Since Ogita introduced OK-432 (picibanil) in 1987 as a treatment method, this sclerosant has become popular. This paper is a review of the trials published so far on this topic. PATIENTS AND METHODS: A literature search of English trials with 5 or more patients in it with LM who had never been treated before was done. The paper had to use the microcystic-macrocystic classification and have a mean follow-up of more than a year to be included in this review. Results were classified as "excellent" when the lesions show a regression of more than 90%, "good" when regression is more than 50%, and "poor" when shrinkage is less than 50% (this also includes no response at all). RESULTS: Twenty-seven percent of microcystic LMs show an excellent result; 33%, a good result; and 40%, a poor result. Of the macrocystic LMs, 88% have excellent results. Recurrence rates vary from 5% to 8%. The adverse effects are mostly mild. DISCUSSION: Most trials have a short follow-up; therefore, there are uncertainties when it comes to cure and regression. Mostly, the adverse effects of OK-432 are trivial and disappear after a week, but the need for a temporary tracheostomy has been described. Screening for allergic reactions to penicilline is needed, with the risk of anaphylactic shock in mind. It is difficult to compare the different techniques used by the authors, and none of the trials included in this study are randomized controlled trials; most are retrospective and were so-called level 4 studies. CONCLUSIONS: This review demonstrates that OK-432 is an effective way to treat LM. Because of a possible risk of airway obstruction, treatment should always take place in specialized treatment facilities. Macrocystic lesions show a better response to OK-432 treatment than microcystic lesions. Serious complications with OK-432 are infrequent, and this type of sclerotherapy seems to have no influence on future surgery. We therefore suggest the use of OK-432 as an effective first-line treatment of LMs.

Prognostic value of plasminogen activator inhibitor-1 in head and neck squamous cell carcinoma.

BACKGROUND: Tumor cell biological factors, such as urokinase plasminogen activator (uPA) and its inhibitor plasminogen activator inhibitor-1 (PAI-1), cathepsin D, and c-myc play a role in tumor invasion, metastasis, and proliferation. In this study, the prognostic importance of these factors in patients with primary head and neck squamous cell carcinoma (HNSCC) was evaluated and correlated with clinicopathologic variables. METHODS: In 46 paired primary tumors and normal tissues, levels of uPA, PAI-1, cathepsin D, and c-myc amplification were determined. The clinical follow-up was over 10 years. Relationships between cell biological factors and patient and tumor characteristics were studied by the Mann-Whitney test. The Cox proportional hazard model was used for univariate and multivariate analysis. RESULTS: In this study, only a high level of PAI-1 was associated with a significantly shorter disease-free survival (p < .01). PAI-1 levels were higher in tumors with perineural invasion (p < .01). Both PAI-1 and uPA levels were higher in patients who smoked (p < .01 and p = .02). In univariate analysis, smoking (p= .04), excessive alcohol intake (p = .02), perineural invasion (p = .001), and vaso-invasion (p = .009) were associated with a shorter disease-free survival. The only factor related to overall survival was perineural invasion (p = .045). The combination of a high PAI-1 level and perineural invasion appeared to be a significant predictor of a shorter disease-free interval (p = .01). CONCLUSION: PAI-1 may present a novel prognostic factor for patients with HNSCC. Perineural invasion and PAI-1 level combined seemed to be prognostic for disease-free survival.

Colony lift assay using cell-coated filters: a fast and efficient method to screen phage libraries for cell-binding clones.

For efficient screening of phage antibody libraries obtained by selection on whole cells, we have developed a modified colony lift assay using cell-coated filters. Both cells growing in suspension as well as adherent cells can be coated onto nitrocellulose filters and used to detect bacterial colonies responsible for the production of cell-binding (specific) single chain variable fragment (scFv) antibodies. We demonstrate, using a selected library developed in our laboratory (named "AB" library) as a model system, that the frequency of specific clones as detected by colony lift assay using cell-coated filter is comparable to the frequency of positive clones as detected by the "classical" method (i.e. random picking and flow cytometric analysis). However, the colony lift assay enables detection and isolation of a higher number of specific clones as compared to the random pick. This is due to screening of a much higher number of clones simultaneously (it is possible to screen at least 1000 clones plated on one 9-cm agar dish). Using this method, clones occurring at a low frequency (such as present in early selection rounds) can be detected and isolated efficiently. We clearly demonstrate the usefulness of the colony lift assay with cell-coated filter by applying it to screen the head-and-neck carcinoma (HN) library (a selected library generated in our laboratory). Using the assay, but not the random picking, we were able to isolate specific clones from 2nd to 3rd selection rounds of the HN library.