Long-term efficacy and safety of pegvisomant in combination with long-acting somatostatin analogs in acromegaly.

BACKGROUND: Treatment for acromegaly patients with long-acting somatotropin release-inhibiting factor (LA-SRIF) often does not result in complete normalization of IGF-1. Addition of pegvisomant (PEGV), a GH receptor antagonist, could improve this; however, the literature has not described long-term follow-up. OBJECTIVE: To assess long-term efficacy and safety of this combined treatment in the largest current single-center cohort of patients, from 2004-2013. DESIGN: Acromegaly patients were treated for at least 6 months with a high-dose LA-SRIF. To patients with persistently elevated IGF-1 levels (>1.2 × upper limit of normal) or poor quality of life, PEGV was added as one weekly injection. RESULTS: The patients (n = 141) were treated with PEGV and LA-SRIFs for a median period of 4.9 years (range, 0.5-9.2). Efficacy, defined as the lowest measured IGF-1 level during treatment, was 97.0%. The median PEGV dose to achieve this efficacy was 80 mg weekly (interquartile range, 60-120 mg). Combination treatment-related adverse events were recorded in 26 subjects (18.4%). Pituitary tumor size increase was observed in one patient. Injection-site reactions were observed in four subjects. In 19 patients (13.5%), transiently elevated liver transaminases of more than three times the upper limit of normal were observed, of which 83% occurred within the first year of combination treatment. Eight patients died, at a mean age of 71 years; none of them were considered treatment-related. CONCLUSIONS: The combination treatment with LA-SRIFs and PEGV was effective in 97% of the patients, it appears to be a safe medical treatment and it reduces the required dose of PEGV.

The in vitro and in vivo capacity of culture-expanded human cells from several sources encapsulated in alginate to form cartilage.

Cartilage has limited self-regenerative capacity. Tissue engineering can offer promising solutions for reconstruction of missing or damaged cartilage. A major challenge herein is to define an appropriate cell source that is capable of generating a stable and functional matrix. This study evaluated the performance of culture-expanded human chondrocytes from ear (EC), nose (NC) and articular joint (AC), as well as bone-marrow-derived and adipose-tissue-derived mesenchymal stem cells both in vitro and in vivo. All cells (≥ 3 donors per source) were culture-expanded, encapsulated in alginate and cultured for 5 weeks. Subsequently, constructs were implanted subcutaneously for 8 additional weeks. Before and after implantation, glycosaminoglycan (GAG) and collagen content were measured using biochemical assays. Mechanical properties were determined using stress-strain-indentation tests. Hypertrophic differentiation was evaluated with qRT-PCR and subsequent endochondral ossification with histology. ACs had higher chondrogenic potential in vitro than the other cell sources, as assessed by gene expression and GAG content (p < 0.001). However, after implantation, ACs did not further increase their matrix. In contrast, ECs and NCs continued producing matrix in vivo leading to higher GAG content (p < 0.001) and elastic modulus. For NC-constructs, matrix-deposition was associated with the elastic modulus (R² = 0.477, p = 0.039). Although all cells--except ACs--expressed markers for hypertrophic differentiation in vitro, there was no bone formed in vivo. Our work shows that cartilage formation and functionality depends on the cell source used. ACs possess the highest chondrogenic capacity in vitro, while ECs and NCs are most potent in vivo, making them attractive cell sources for cartilage repair.

Obstructive sleep apnoea in Treacher Collins syndrome: prevalence, severity and cause.

This cohort study in 35 patients (13 children) evaluates the prevalence, severity and anatomical cause of obstructive sleep apnoea syndrome (OSAS) in patients with Treacher Collins syndrome. Ambulatory polysomnography was performed cross-sectionally to determine OSAS prevalence and severity. All upper airway related surgical interventions were evaluated retrospectively. In 11 patients, sleep endoscopy, and flexible and rigid endoscopy were applied to determine the level of anatomical obstruction of the upper airway. The overall prevalence of OSAS in Treacher Collins patients was 46% (54% in children; 41% in adults). Thirty-eight upper airway related surgical interventions were performed in 17 patients. Examination of the upper airway revealed various anatomical levels of obstruction, from the nasal septum to the trachea. Most significant obstruction was found at the level of the oro/hypopharynx. OSAS in Treacher Collins patients is an important problem so all patients should be screened for OSAS by polysomnography. Endoscopy of the upper airways was helpful in determining the level of obstruction. Surgical treatment at one level will not resolve OSAS in most patients because OSAS in Treacher Collins has a multilevel origin. Non-invasive ventilation (continuous positive airway pressure or bilevel positive airway pressure) or tracheotomy should be considered as a treatment modality.

Post-trauma mucocele formation in the frontal sinus; a rationale of follow-up.

The aim of the investigation was the evaluation of the follow-up for mucocele formation as a complication of frontal sinus fractures. A review of the literature was performed which showed only 10 adequately documented cases of mucocele formation after trauma. In our hospital between June 2001 and July 2002 three patients were treated for mucocele as a late complication following trauma to the frontal sinus. Our patients presented themselves with a mucocele, respectively 13, 22 and 35 years after the initial trauma. From this a suggestion is done for the follow-up of post-trauma patients. Mucocele formation is a complication, which can develop years after trauma to the frontal sinus. Treatment of these forms of mucocele is multidisciplinary. The review of the literature in combination with our own data showed no peak incidence of mucocele formation after trauma. We therefore advocate following the at-risk-patients for life, and to properly inform them about the possible development and symptoms, like swelling, diplopia, etc., of a mucocele.

Fluticasone propionate aqueous nasal spray does not influence the recurrence rate of chronic rhinosinusitis and nasal polyps 1 year after functional endoscopic sinus surgery.

BACKGROUND: Local corticosteroids are widely used in the treatment of nasal polyps and chronic rhinosinusitis both before and after nasal surgery. Their efficacy after functional endoscopic sinus surgery (FESS) has not been fully established by placebo-controlled trials. OBJECTIVE: This double-blind placebo-controlled randomized study was performed in order to investigate whether fluticasone propionate aqueous nasal spray (FPANS) reduces the recurrence rate of nasal polyps and chronic rhinosinusitis during the first year after FESS. PATIENTS AND METHODS: The trial looked at 162 patients aged 18 years and older requiring FESS for chronic rhinosinusitis or nasal polyps. After FESS combined with peri-operative systemic corticosteroids, patients were randomized and given FPANS 400 microg b.i.d., FPANS 800 microg b.i.d. or placebo b.i.d. for the duration of 1 year. Patients were withdrawn from the trial (but still included in the study for statistical purposes) if there were recurrent or persistent diseases, defined as progressive regrowth of nasal polyps, recurrent signs and symptoms of chronic sinusitis combined with abnormalities on computed tomography scan and persistent complaints for at least 2 months after FESS. RESULTS: A significant reduction of symptoms was seen after FESS. After 1 year, 46 patients had been withdrawn from the trial because of recurrent diseases and 32 patients because of persistent symptoms. No differences in the number of patients withdrawn because of recurrent or persistent diseases were found between the patients treated with FPANS and patients treated with placebo. We were also unable to find a positive effect of FPANS compared with placebo in several subgroups such as patients with nasal polyps, high score at FESS or no previous sinus surgery. CONCLUSION: This placebo-controlled study does not show that treatment with FPANS up to 1 year after FESS had a positive effect compared with placebo.

Cerebrospinal fluid leakage during transsphenoidal surgery: postoperative external lumbar drainage reduces the risk for meningitis.

Postoperative meningitis is a well known complication of transsphenoidal surgery (TSS). The objective of this study was to evaluate whether postoperative external cerobrospinal fluid (CSF) drainage in case of intraoperative CSF-leakage, reduces the risk of postoperative meningitis. We retrospectively reviewed a series of 278 consecutive transsphenoidal operations. In all operations with intraoperative CSF leakage, an external lumbar drain (ELD) was inserted directly postoperatively, and removed after at least 5 days. The incidence of postoperative meningitis was compared with that in a previously studied series of 228 consecutive transsphenoidal operations, without insertion of an ELD in cases with intraoperative CSF leakage. In the present series, postoperative meningitis occurred in 2/278 (0.7%) operations, compared to 7/228 (3.1%) operations in the previous study period (P < 0.05). Intraoperative CSF leakage was noted in 70/278 (25.2%) operations. All these patients received an ELD immediately after surgery for at least 5 days. There were no reported complications of ELD insertion. In the present series, 1 of 70 (1.4%) patients with intraoperative CSF leakage developed meningitis, compared to 3 of 22 (13.6%) patients in the previous study (P < 0.05). The present report on 278 consecutive transsphenoidal operations shows that the routine insertion of an ELD in patients in whom intraoperative CSF leakage is observed significantly reduces the incidence of postoperative meningitis. Possibly, diversion of CSF prevents the formation of a CSF fistula and thereby the risk of infection. The role of prophylactic antibiotic treatment in patients with CSF rhinorrhea after TSS remains to be established.

[Trigeminal trophic syndrome: 2 patients with a non-healing ulcer on the ala nasi]. / Het trofisch syndroom van de N. trigeminus: 2 patiënten met een niet-genezend ulcus op de ala nasi.

Two female patients, aged 74 and 91 years respectively, had a skin ulcer on a nostril and ipsilateral sensory paralysis in the area covered by the N. trigeminus. This is known as trigeminal trophic syndrome. It may be caused by (iatrogenic) damage to the trigeminal nerve by chronic manipulation of the senseless skin. Only in case of doubt, histological examination of a tissue sample is advised to exclude malignancy. The main treatment consists of instructing the patient not to manipulate the skin. In some patients surgical reconstruction is necessary.

Long-term results of uvulopalatopharyngoplasty for obstructive sleep apnea syndrome.

OBJECTIVES: Assessment of the long-term effect of uvulopalatopharyngoplasty (UPPP) on snoring, excessive daytime sleepiness, and nocturnal oxygen desaturation index (ODI) in patients with obstructive sleep apnea syndrome. STUDY DESIGN: Evaluation of snoring, excessive daytime sleepiness, and ODI in patients treated by UPPP earlier. MATERIALS AND METHODS: Patients (n = 58) with a follow-up period of 11 to 74 months (median, 34 mo) were included in this study. Snoring and excessive daytime sleepiness were scored on specially designed semiquantitative scales. In all patients ODI was calculated from pulse-oximetry combined with polysomnography at base line and by polygraphy (MESAM 4) during follow-up in 38 patients. Long-term response was compared with 6-month response in the same cohort. RESULTS: There was a long-term improvement of snoring in 63% of patients, no change in 23%, and a deterioration in 14% (P < .00001). Overall snoring increased slightly between 6 months and long-term follow-up. There was an improvement of excessive daytime sleepiness in 38%, no change in 27%, and a deterioration in 35% (P = .80). Excessive daytime sleepiness showed a relapse to preoperative levels between 6 months and long-term follow-up. The median improvement of ODI was -1 (95% interpercentile range, 73-51) and was not significant (P = .35). In 5 of 13 patients in whom ODI at baseline exceeded 20, ODI was reduced to less than 20. In 4 of the 38 patients ODI was reduced to less than 5. The improvement of ODI decreased significantly between 6 months and long-term follow-up (P = .03). No relation was found between body mass index, Mueller maneuver, X-cephalometry, and long-term outcome. An additional finding was that the ODI decreased after UPPP in combination with tonsillectomy, compared with a slight increase after UPPP alone; the difference was significant (P = .008). CONCLUSION: The response to UPPP for obstructive sleep apnea syndrome decreases progressively over the years after surgery. UPPP in combination with tonsillectomy was more effective than UPPP alone.

Rhinocerebral mycosis in immunocompromised patients. A case report and review of the literature.

Continuous awareness of systemic mycosis in immunocompromised patients is important. Early diagnosis is based on (direct) histologal examination and CT scan. Since treatment should start as early as possible, there is usually no time to await results of tissue cultures. Systemic treatment with amphotericin B and aggressive surgical débridement should be performed as soon as possible, while the place of hyperbaric oxygen and G-CSF remains to be established. In addition to routine preventive measures, prophylactic intranasal application of amphotericin B seems to be of value.

Risk factors for meningitis after transsphenoidal surgery.

To evaluate possible risk factors for meningitis, we retrospectively reviewed 228 transsphenoidal operations (in which a standard regimen of amoxicillin prophylaxis was used) for sellar pathology. The incidence of meningitis was 3.1% (seven of 228 cases). Cultures of preoperative specimens from the anterior nasal vestibule in three of seven patients yielded Staphylococcus aureus, but none of these patients developed S. aureus meningitis. Two of three patients with significant preoperative paranasal sinus abnormalities developed meningitis compared with only five of 225 patients without significant paranasal sinus abnormalities (P < .005). Three of 22 patients with intraoperative cerebrospinal fluid (CSF) leakage developed meningitis compared with four of 206 patients without intraoperative CSF leakage (P < .05). Six of seven patients with postoperative CSF rhinorrhea and only one of 221 patients without postoperative CSF rhinorrhea developed meningitis (P < .00001). In conclusion, postoperative CSF leakage is an important risk factor for meningitis after transsphenoidal surgery. Cultures of preoperative specimens from the anterior nasal vestibule did not have any predictive value in our study.

Uvulopalatopharyngoplasty for the obstructive sleep apnoea syndrome: value of polysomnography, Mueller manoeuvre and cephalometry in predicting surgical outcome.

Sixty consecutive patients with the obstructive sleep apnoea syndrome (53 men and seven women) were analysed by questionnaire, polysomnography, röntgenographic cephalometry and the Mueller manoeuvre before and 6 months after uvulopalatopharyngoplasty (UPPP), to assess the surgical outcome and the prognostic value of preoperative evaluation. Seventy-three per cent of patients reported improvement of snoring and 55% reported improvement of excessive daytime sleepiness. Thirty-five per cent showed a decrease of at least 50% in the desaturation index, and 13% had a postoperative desaturation index below 5. Although the improvement of desaturation parameters was marked in some patients, the overall change was not significant. Neither the Body Mass Index (BMI), nor any of the cephalometric variables were significantly correlated to surgical outcome. Increased difference in collapsibility between the soft palate and the base of the tongue showed a close to significant relation with the improvement of desaturation index. High desaturation index, low mean saturation and deep lowest saturation were found to be slightly predictive of improvement in nocturnal desaturation. In a multivariate analysis however no significant predictors could be identified. It is concluded that UPPP is effective in reducing snoring and daytime sleepiness over a 6-month follow-up period, but that the overall improvement in nocturnal desaturation is limited and difficult to predict. Further research is needed to evaluate the long-term efficacy of UPPP.

Upper airway patency and nocturnal desaturation in habitual snoring and obstructive sleep apnea: pathogenesis of sleep-related breathing disorders.

Sixty patients, 53 men and 7 women, referred for excessive snoring or suspected sleep apnea syndrome were analyzed by polysomnography, Mueller maneuver, cephalometric roentgenography, and pulmonary function testing, to evaluate the contribution of static and dynamic upper airway obstruction in the pathogenesis of sleep-related breathing disorders and OSAS. Desaturation index and maximal desaturation were used in the analysis as indicators of severity of sleep-related breathing disorders. Body Mass Index, increased collapsibility at the base of the tongue by the Mueller maneuver, increased distance between hyoid and mandibular plane, and increased soft palate diameters by cephalometry as well as a decreased peak inspiratory flow by pulmonary function testing were found to be related to increased oxygen desaturation parameters. In a multivariate analysis the significant obstruction parameters could explain only 37% of the variability of maximum desaturation and 31% of the variability of desaturation index, 63 and 69%, respectively, must therefore be explained by other mechanisms. We conclude that instability of respiratory and muscular control, possibly enhanced by sleep-phase-related changes, is more important in the pathogenesis of sleep-related breathing disorders than pure anatomic narrowing of the airway.

Indices from flow-volume curves in relation to cephalometric, ENT- and sleep-O2 saturation variables in snorers with and without obstructive sleep-apnoea.

In a group of 37 heavy snorers with obstructive sleep apnoea (OSA, Group 1) and a group of 23 heavy snorers without OSA (Group 2) cephalometric indices, ENT indices related to upper airway collapsibility, and nocturnal O2 desaturation indices were related to variables from maximal expiratory and inspiratory flow-volume (MEFV and MIFV) curves. The cephalometric indices used were the length and diameter of the soft palate (spl and spd), the shortest distance between the mandibular plane and the hyoid bone (mph) and the posterior airway space (pas). Collapsibility of the upper airways was observed at the level of the tongue base and soft palate by fibroscopy during a Müller manoeuvre (mtb and msp) and ranked on a five point scale. Sleep indices measured were the mean number of oxygen desaturations of more than 3% per hour preceded by an apnoea or hypopnoea of more than 10 s (desaturation index), maximal sleep oxygen desaturation, baseline arterial oxygen saturation (Sa,O2) and, in the OSA group, percentage of sleep time with Sa,O2 < 90%. The variables obtained from the flow-volume curves were the forced vital capacity (FVC), forced expiratory and inspiratory volume in 1 s (FEV1 and FIV1), peak expiratory and peak inspiratory flows (PEF and PIF), and maximal flow after expiring 50% of the FVC (MEF50). The mean of the flow-volume variables, influenced by upper airway aperture (PEF, FIV1) was significantly greater than predicted.(ABSTRACT TRUNCATED AT 250 WORDS)

The Rotterdam Daytime Sleepiness Scale: a new daytime sleepiness scale.

A new daytime sleepiness scale was constructed on the basis of interviews with 96 apnea patients (the Rotterdam Daytime Sleepiness Scale) and included three subscales of Global Evaluation, Behavioral Impact, and Affected Life Domains. The scale showed satisfactory convergent and discriminant validity.

Nasal and paranasal disease in adult cystic fibrosis patients.

Children with cystic fibrosis frequently have nasal polyps and sinusitis. This study addresses (para-) nasal disease in 39 adult cystic fibrosis patients. Fifteen patients (39%) had recently had serious nasal symptoms and 26% sinusitis. Seventeen (44%) had nasal polyposis. Almost all sinus radiographs taken showed opacification, which was unrelated to symptoms. Polypectomies and antral irrigations were usually ineffective, whilst more extensive surgery generally gave better results. It is concluded that a substantial number of adult cystic fibrosis patients frequently have upper airway symptoms. Sinus radiographs have little or no diagnostic value. Treatment of (para-) nasal disease in cystic fibrosis patients can be difficult; a guideline for treatment is suggested, calling for simple interventions coupled with intranasal steroids and nasal irrigation in early disease and for endoscopic to radical sinus surgery in recurrent advanced disease.

The detrimental effect of aminohydroxypropylidene bisphosphonate (APD) in otospongiosis.

Two middle-aged female patients with active stapedial otosclerosis and sensorineural hearing loss have been treated with aminohydroxypropylidene bisphosphonate (APD). No effect on the Schwartze sign was observed either during or following therapy. No changes were seen in the audiometric data of the patients during the 1st year. Then, within a few weeks, both patients complained of sudden deterioration of the existing hearing losses in both ears, with an alteration of tinnitus. One patient became totally, bilaterally deaf, while the other retained minimal auditory function in the low frequencies in one ear. A sudden bilateral hearing loss in cochlear otosclerosis never develops under normal circumstances and we are convinced that in the cases that we have observed it is due to the treatment with APD.

Anatomy of the upper lateral cartilages in the human newborn.

The morphology of the upper lateral cartilages in the newborn child was studied by dissection of the nose in two stillborns. It was found that the cartilaginous nasal dorsum extends from the tip of the nose for the full length under the nasal bones and in lateral direction on the inner surface of the frontal process of the maxilla. Septum and upper lateral cartilages form a double vaulted structure as in the fetal stages. The marked differences between the neonate and adult anatomy must be respected in rhino- and facial surgery in young children.