Laryngotracheal stenosis treated with multiple surgeries: experience, results and prognostic factors in 70 patients

Laryngotracheal stenosis is a complex condition that usually requires multiple procedures to restore physiological respiration. The aim of this study was to evaluate the percentage of decannulation compared to different or multiple surgical treatments. We retrospectively reviewed the charts of 70 patients treated between 1990 and 2005 for laryngotracheal stenosis of various aetiology: iatrogenic stenosis (n = 55), post-traumatic stenosis (n = 11) or other causes (autoimmune disease, n = 3; diphtheria, n = 1). In order to maintain laryngotracheal patency, a Montgomery Safe-T tube was used in all patients as a single dilation treatment or associated with endoscopic and/or open-neck surgery. Fifty-four of the 70 patients (77.1%) were eventually decannulated; 39 of these (72.2%) underwent 3 or fewer surgical procedures, showing a significant difference compared to patients who underwent more than 3 surgeries (p = 0.00002). A total of 257 surgeries were performed. Only seven of 54 patients (13%) were decannulated after more than 5 surgical procedures. Patients over 60 years of age and with a higher grade of stenosis showed a significantly lower success rate (p = 0.0017 and p = 0.007, respectively). There was no significant correlation between the rate of decannulation and gender, aetiology, site of stenosis or surgery. Patients undergoing dilation for laryngotracheal stenosis usually require multiple procedures. The T tube plays an important role in the treatment of this pathology. However, if the tracheostomy is not removed within 3 surgical interventions, the odds of decannulating the patient decrease significantly, and additional surgeries may be of questionable therapeutic benefit

How do cardiologists select patients for dual antiplatelet therapy continuation beyond 1 year after a myocardial infarction? Insights from the EYESHOT Post-MI Study

Background: Current guidelines suggest to consider dual antiplatelet therapy (DAPT) continuation for longer than 12 months in selected patients with myocardial infarction (MI). Hypothesis: We sought to assess the criteria used by cardiologists in daily practice to select patients with a history of MI eligible for DAPT continuation beyond 1 year. Methods: We analyzed data from the EYESHOT Post-MI, a prospective, observational, nationwide study aimed to evaluate the management of patients presenting to cardiologists 1 to 3 years from the last MI event. Results: Out of the 1633 post-MI patients enrolled in the study between March and December 2017, 557 (34.1%) were on DAPT at the time of enrolment, and 450 (27.6%) were prescribed DAPT after cardiologist assessment. At multivariate analyses, a percutaneous coronary intervention (PCI) with multiple stents and the presence of peripheral artery disease (PAD) resulted as independent predictors of DAPT continuation, while atrial fibrillation was the only independent predictor of DAPT interruption for patients both at the second and the third year from MI at enrolment and the time of discharge/end of the visit. Conclusions: Risk scores recommended by current guidelines for guiding decisions on DAPT duration are underused and misused in clinical practice. A PCI with multiple stents and a history of PAD resulted as the clinical variables more frequently associated with DAPT continuation beyond 1 year from the index MI

Therapeutic and Prognostic Implications of BRAF V600E in Pediatric Low-Grade Gliomas

Purpose BRAF V600E is a potentially highly targetable mutation detected in a subset of pediatric low-grade gliomas (PLGGs). Its biologic and clinical effect within this diverse group of tumors remains unknown. Patients and Methods A combined clinical and genetic institutional study of patients with PLGGs with long-term follow-up was performed (N = 510). Clinical and treatment data of patients with BRAF V600E mutated PLGG (n = 99) were compared with a large international independent cohort of patients with BRAF V600E mutated-PLGG (n = 180). Results BRAF V600E mutation was detected in 69 of 405 patients (17%) with PLGG across a broad spectrum of histologies and sites, including midline locations, which are not often routinely biopsied in clinical practice. Patients with BRAF V600E PLGG exhibited poor outcomes after chemotherapy and radiation therapies that resulted in a 10-year progression-free survival of 27% (95% CI, 12.1% to 41.9%) and 60.2% (95% CI, 53.3% to 67.1%) for BRAF V600E and wild-type PLGG, respectively (P < .001). Additional multivariable clinical and molecular stratification revealed that the extent of resection and CDKN2A deletion contributed independently to poor outcome in BRAF V600E PLGG. A similar independent role for CDKN2A and resection on outcome were observed in the independent cohort. Quantitative imaging analysis revealed progressive disease and a lack of response to conventional chemotherapy in most patients with BRAF V600E PLGG. Conclusion BRAF V600E PLGG constitutes a distinct entity with poor prognosis when treated with current adjuvant therapy. (C) 2017 by American Society of Clinical Oncolog

A phase I/II study of intrathecal idursulfase-IT in children with severe mucopolysaccharidosis II

Approximately two-thirds of patients with the lysosomal storage disease mucopolysaccharidosis II have progressive cognitive impairment. Intravenous (i.v.) enzyme replacement therapy does not affect cognitive impairment because recombinant iduronate-2-sulfatase (idursulfase) does not penetrate the blood-brain barrier at therapeutic concentrations. We examined the safety of idursulfase formulated for intrathecal administration (idursulfase-IT) via intrathecal drug delivery device (IDDD). A secondary endpoint was change in concentration of glycosaminoglycans in cerebrospinal fluid. Sixteen cognitively impaired males with mucopolysaccharidosis II who were previously treated with weekly i.v. idursulfase 0.5 mg/kg for ≥6 months were enrolled. Patients were randomized to no treatment or 10-mg, 30-mg, or 1-mg idursulfase-IT monthly for 6 months (four patients per group) while continuing i.v. idursulfase weekly. No serious adverse events related to idursulfase-IT were observed. Surgical revision/removal of the IDDD was required in 6 of 12 patients. Twelve total doses were administrated by lumbar puncture. Mean cerebrospinal fluid glycosaminoglycan concentration was reduced by approximately 90% in the 10-mg and 30-mg groups and approximately 80% in the 1-mg group after 6 months. These preliminary data support further development of investigational idursulfase-IT in MPS II patients with the severe phenotype who have progressed only to a mild-to-moderate level of cognitive impairment.Genet Med advance online publication 02 April 2015Genetics in Medicine (2015); doi:10.1038/gim.2015.36

Pharmacokinetics and bioavailability of a therapeutic enzyme (idursulfase) in cynomolgus monkeys after intrathecal and intravenous administration.

Intravenous enzyme replacement therapy with iduronate-2-sulfatase is an approved treatment for Hunter syndrome, however, conventional intravenous delivery cannot treat the neurologic manifestations of the disease due to its limited central nervous system penetration. Intrathecal administration of iduronate-2-sulfatase for delivery to the central nervous system is currently under investigation. The objective of this study was to evaluate the pharmacokinetics of idursulfase in the central nervous system of cynomolgus monkeys (Macaca fasicularis) after intravenous and intrathecal administration. Twenty-seven monkeys, treatment-naïve to enzyme replacement therapy, were placed into 4 groups according to body weight: Group 1 was administered 0.5 mg/kg idursulfase intravenously, Groups 2-4 were administered an intrathecal formulation (1-, 10-, and 30-mg doses). Blood samples and cerebrospinal fluid (sampled at the cisterna magna or lumbar level) were collected at the same time points for 72 hours post dosing. Following intravenous administration, a high maximum serum concentration and rapid distribution of iduronate-2-sulfatase out of the central compartment were observed (elimination half-life: 4.3 hours). Iduronate-2-sulfatase exposure in the cerebrospinal fluid was limited, suggesting intravenous administration provided minimal penetration of the blood-brain barrier. Following intrathecal administration, a high maximum observed concentration was immediately noted and elimination half-life ranged between 7.8-10 hours and 5.9-6.7 hours (cisterna magna and lumbar sampling, respectively). Cerebrospinal fluid pharmacokinetic profiles at different doses of iduronate-2-sulfatase were similar and the dose/exposure relationship was proportional. After intrathecal administration, movement of iduronate-2-sulfatase from cerebrospinal fluid to serum was observed (systemic bioavailability was 40-83%). The clear penetration of iduronate-2-sulfatase into the cerebrospinal fluid and the dose response suggest that intrathecal delivery of iduronate-2-sulfatase may be suitable for treating the central nervous system manifestations associated with Hunter syndrome

Lipoma of the larynx: a case report

Lipoma is a benign tumour of mesenchymal origin with a very rare occurrence in the upper aero-digestive tract. To date, approximately 100 cases have been described in the literature. This lesion has a slow growth and, therefore, can present with various symptoms due to the mass effect with obstruction and compression on neighbouring structures, including dysphagia for liquid and solid food, dyspnoea and hoarseness. For a precise pre-operative diagnosis, indirect or direct laryngoscopy (flexible fibre-optic laryngoscopy) can be employed or, if necessary, also imaging techniques such as computed tomography scan and magnetic resonance imaging scan. These offer more useful information for better treatment planning. Surgery is the treatment of choice and includes endoscopic techniques and an external surgical approach (cervicotomy). It is very important to completely remove these benign neoplasms in order to avoid local recurrence. The present report refering to a case of laryngeal lipoma removed through an external surgical approach, aims to demonstrate that the choice of an external surgical approach is required for complete surgical removal of a large lipoma in order to prevent any possible recurrence. Furthermore, it is useful to keep in mind the possibility of recurrence of lipomas after long free intervals; therefore, it is mandatory to observe these patients at long-term follow-up

Mean CSF I2S concentration-time profiles.

<p>After intravenous and IT-L dosing, mean CSF I2S concentration-time profiles were determinedwith CSF sampled at the CM level (A) and at the IT-L level (B). Error bars represent standard deviation. CSF, cerebrospinal fluid; I2S, iduronate-2-sulfatase; IT-L, intrathecal lumbar; IV, intravenous.</p

Mean intravenous and IT-L serum I2S concentration-time profiles.

<p>Error bars represent standard deviation.I2S, iduronate-2-sulfatase; IT-L, intrathecal lumbar; IV, intravenous.</p

Bioavailability and exposure fraction (<i>AUC</i>_inf) of I2S in the serum and CSF after IT-L dosing.

<p><i>AUC</i>_inf, area under the concentration-time curve extrapolated to infinity; CM, cisterna magna; CSF, cerebrospinal fluid; EF, exposure fraction; F, bioavailability; I2S, iduronate-2-sulfatase; IT-L, intrathecal lumbar; IV, intravenous.</p><p>^aMean body weights were calculated from the animals whose CSF samples were collected at the CM level.</p><p>^bSampled at CM level.</p><p>Bioavailability and exposure fraction (<i>AUC</i>_inf) of I2S in the serum and CSF after IT-L dosing.</p