Marcel M. Miyake

The blood-brain barrier and nasal drug delivery to the central nervous system.

Background The blood-brain barrier (BBB) is a highly efficient system that separates the central nervous system (CNS) from general circulation and promotes selective transport of molecules that are essential for brain function. However, it also limits the distribution of systemically administered therapeutics to the brain; therefore, there is a restricted number of drugs available for the treatment of brain disorders. Several drug-targeting strategies have been developed to attempt to bypass the BBB, but none has proved sufficiently effective in reaching the brain. Methods The objective of this study is to generally review these strategies of drug administration to the CNS. Results Noninvasive methods of drug delivery, such as chemical and biologic transport systems, do not represent a feasible platform, whereas for most drugs, it is still not possible to achieve therapeutic levels within the brain tissue after intravenous or oral administration, and the use of higher potency or more concentrated doses may cause serious toxic side effects. Direct intrathecal drug delivery through a catheter into the CNS also presents several problems. Intranasal drug delivery is a potential alternative method due to the direct transport into the cerebrospinal fluid (CSF) compartment along the olfactory pathway, but the studys conclusions are controversial. An endoscopic intranasal surgical procedure using established skull base surgery reconstruction techniques based on the use of a nasal mucosa surgical flap as the only obstacle between the nose and the subarachnoid space has appeared as a potential solution to increase the absorption of intranasal drugs to the CNS. Conclusion Despite extensive efforts to develop new techniques to cross the BBB, none has proved sufficiently effective in reaching the brain, whereas minimizing adverse effects and the endoscopic mucosal grafting technique offers new potential promise.

Postoperative otorhinolaryngologic complications in transnasal endoscopic surgery to access the skull base.

INTRODUCTION The large increase in the number of transnasal endoscopic skull base surgeries is a consequence of greater knowledge of the anatomic region, the development of specific materials and instruments, and especially the use of the nasoseptal flap as a barrier between the sinus tract (contaminated cavity) and the subarachnoid space (sterile area), reducing the high risk of contamination. OBJECTIVE To assess the otorhinolaryngologic complications in patients undergoing endoscopic surgery of the skull base, in which a nasoseptal flap was used. METHODS This was a retrospective study that included patients who underwent endoscopic skull base surgery with creation of a nasoseptal flap, assessing for the presence of the following post-surgical complications: cerebrospinal fluid leak, meningitis, mucocele formation, nasal synechia, septal perforation (prior to posterior septectomy), internal nasal valve failure, epistaxis, and olfactory alterations. RESULTS The study assessed 41 patients undergoing surgery. Of these, 35 had pituitary adenomas (macro- or micro-adenomas; sellar and suprasellar extension), three had meningiomas (two tuberculum sellae and one olfactory groove), two had craniopharyngiomas, and one had an intracranial abscess. The complications were cerebrospinal fluid leak (three patients; 7.3%), meningitis (three patients; 7.3%), nasal fossa synechia (eight patients; 19.5%), internal nasal valve failure (six patients; 14.6%), and complaints of worsening of the sense of smell (16 patients; 39%). The olfactory test showed anosmia or hyposmia in ten patients (24.3%). No patient had mucocele, epistaxis, or septal perforation. CONCLUSION The use of the nasoseptal flap has revolutionized endoscopic skull base surgery, making the procedures more effective and with lower morbidity compared to the traditional route. However, although mainly transient nasal morbidities were observed, in some cases, permanent hyposmia and anosmia resulted. An improvement in this technique is therefore necessary to provide a better quality of life for the patient, reducing potential complications.

Impact of endoscopic dacryocystorhinostomy on sinonasal quality of life.

Background Dacryocystorhinostomy (DCR) is the criterion standard of surgical treatment for complete nasolacrimal obstruction and dacryocystitis. There has been an expansion in the indication of the endonasal DCR (eDCR), but the impact of surgical manipulating an otherwise healthy nasal mucosa on postoperative sinonasal quality of life remains unknown. The purpose of this study was to determine whether patients who underwent eDCR experienced any decrement in sinonasal quality of life. Methods A retrospective chart review of 44 patients who underwent eDCR between June 2012 and May 2015. The primary outcome was the total and nasal-specific domain 1 scores of the disease specific validated Sino-Nasal Outcomes Test 22. Preoperative scores were compared with the postoperative scores on days 0-30, 30-90, and 90-180 visits. A subgroup analysis of patients without nasal symptoms who underwent concomitant nasal surgical procedures was also performed. Results A statistically significant increase was observed between the preoperative score and the first postoperative score (days 0-30) in both total (7.5 [0-44] to 24 [0-51], median [interquartile range]) and domain 1 (2.5 [0-11] to 9 [0-18]) scores (p = 0.0066 and p = 0.0001, respectively). In contrast, there was no statistically significant difference between the pre- and postoperative scores on days 30-90 or 90-180. Similar results were observed in the subgroup analysis. Conclusion Analysis of our findings indicated that, in general, eDCR was well tolerated by patients and nasal symptom scores returned to baseline values within 30-90 days of surgery. The concomitant performance of septoplasty in the setting of asymptomatic septal deviation did not confer any long-term improvement in symptoms of nasal obstruction.

Clinical and otorhinolaryngological aspects of extranodal NK/T cell lymphoma, nasal type

INTRODUCTION Extranodal NK/T-Cell lymphoma, nasal type (NKTLN) is a disease that mainly affects the nasal cavity and the paranasal sinuses. Early nasal symptoms are nonspecific, simulating sinus infection. With disease progression, necrosis of the nasal mucosa increases, hindering histological diagnosis. Thus, multiple biopsies may be necessary until definitive diagnosis. Most studies on NKTLN address the hematological and immunological aspects of the disease. OBJECTIVES To present data from a Brazilian quaternary hospital, with emphasis on the clinical aspects of the disease, and to correlate the findings with the most recent literature data. METHODS Case study of seven patient files. RESULTS Patients were evaluated on their medical history, number of biopsies necessary, association with Epstein-Barr virus, treatment, and outcome. All patients had nonspecific nasal complaints and underwent at least three cycles of antibiotic therapy. The earlier a biopsy was performed, the fewer biopsies were required to diagnose the disease and start treatment. However, this fact did not translate into better prognosis. CONCLUSION The otolaryngologist plays a fundamental role in the prognosis of NKTLN and can shorten time between symptom onset and treatment of the patient.

Exosomes mediate interepithelial transfer of functional P-glycoprotein in chronic rhinosinusitis with nasal polyps

P‐glycoprotein (P‐gp) drives type‐2 helper T‐cell inflammation in chronic rhinosinusitis with nasal polyps (CRSwNP) through unknown posttranslational mechanisms of overexpression. A recent randomized clinical trial demonstrated that inhibition of P‐gp was as effective as oral steroids and biologics in treating CRSwNP. Exosomes are 30‐ to 150‐nm vesicles capable of intercellular membrane protein transfer. The aims of this study were 1) to determine whether CRSwNP mucus exosomes are enriched with P‐gp, and 2) whether exosomal P‐gp can be functionally transferred to autologous epithelial cells as a putative mechanism for the proinflammatory overexpression of P‐gp in CRSwNP.

Secreted P-glycoprotein is a noninvasive biomarker of chronic rhinosinusitis

The discovery of noninvasive biomarkers of chronic rhinosinusitis (CRS) is critical to enable our ability to provide prognostic information and targeted medical therapy. Epithelial P‐glycoprotein (P‐gp) is overexpressed in CRS and exists in an extracellular, secreted form. The objective of this study was to determine whether secreted P‐gp concentrations are elevated in CRS and can be used to predict disease severity.

Bypassing the blood–brian barrier using established skull base reconstruction techniques

Background Neurological disorders represent a profound healthcare problem accounting for 6.3% of the global disease burden. Alzheimers disease alone is expected to impact over 115 million people worldwide by 2050 with a cost of over

P-glycoprotein and chronic rhinosinusitis

1 trillion per year to the U.S. economy. Despite considerable advances in our understanding of the pathogenesis and natural history of neurological disorders, the development of disease modifying therapies have failed to keep pace. This lack of effective treatments is directly attributable to the presence of the blood–brain and blood–cerebrospinal fluid barriers (BBB and BCSFB) which prevent up to 98% of all potential neuropharmaceutical agents from reaching the central nervous system (CNS). These obstacles have thereby severely limited research and development into novel therapeutic strategies for neurological disease. Current experimental methods to bypass the BBB, including pharmacologic modification and direct transcranial catheter implantation, are expensive, are associated with significant complications, and cannot be feasibly scaled up to meet the chronic needs of a large, aging patient population. Transmucosal drug delivery An innovative method of direct CNS drug delivery using heterotopic mucosal grafts was described. This method is based on established endoscopic skull base nasoseptal flap reconstruction techniques. The model has successfully demonstrated CNS delivery of chromophore-tagged molecules 1000 times larger than those typically permitted by the BBB. Conclusions This innovative technique represents the first described method of permanently bypassing the blood–brain barrier using purely autologous tissues. This has the potential to dramatically improve the current treatment of neurological disease by providing a safe and chronic transnasaldelivery pathway for high molecular weight neuropharmaceuticals.

Long-term impact of endoscopic orbital decompression on sinonasal-specific quality of life

Chronic rhinosinusitis (CRS) is a heterogeneous definition that includes different disease states that usually are associated with abnormal inflammatory responses. Besides being prevalent, the mechanisms involved in its pathogenesis are not clear and there are few therapeutic options with tolerable side effects. P-glycoprotein (P-gp) is an efflux pump responsible of extruding xenobiotics and cellular metabolites from multiple cell types. It has been widely studied in the cancer field, due to its ability to confer resistance to chemotherapy. It also promotes Type 2 helper T-cell polarizing cytokine secretion in CRS and may represent a potential target to differentiate subtypes of CRS and personalize treatment. This state-of-the-art review explores current knowledge on the participation of P-gp in the pathogenesis of CRS, the P-gp inhibition as a novel targeted therapeutic strategy and the exosomal P-gp test, a non-invasive biomarker that can represent an important advance in the field of rhinology.

Expanding the limits of endoscopic intraorbital tumor resection using 3-dimensional reconstruction

Endoscopic orbital decompression (EOD) is the workhorse surgical intervention for severe thyroid eye disease in Graves disease. Although EOD is a safe and effective procedure, the objective of this study is to determine the impact of orbital decompression on long‐term sinonasal‐pecific quality of life.