Vivostat®: an autologous fibrin sealant as useful adjunct in endoscopic transnasal CSF-leak repair.

The benefit of fibrin glue for reduction of postoperative CSF-leaks after endoscopic skull base surgery is not clearly evident in literature. However, its use is supposed to be beneficial in fixing grafting material. As of today there is no specific data available for otolaryngological procedures. A retrospective data analysis at a tertiary care referral center on 73 patients treated endoscopically transnasally for CSF-leaks at the ENT-department Graz between 2009 and 2012 was performed. Primary closure rate between conventional fibrin glue and autologous fibrin glue were analyzed. The Vivostat(®) system was used in 33 CSF-leak closures and in 40 cases conventional fibrin glue was used. Comparing the two methods the primary closure rate using the autologous Vivostat(®) system was 75.8 and 85.0 % with conventional fibrin glue. The secondary closure the rates were 90.9 % with Vivostat(®) 92.5 % with conventional fibrin glue. The Vivosat(®) system is a useful adjunct in endoscopic CSF-leak closure. Its advantages over conventional fibrin glue are its application system for fixation of grafting material particularly in underlay techniques. Despite this advantage it cannot replace grafting material or is a substitute for proper endoscopic closure which is reflected by the closure rates.

Feasibility of piezoelectric endoscopic transsphenoidal craniotomy: a cadaveric study.

OBJECTIVE: Endoscopic transsphenoidal approach has become the gold standard for surgical treatment of treating pituitary adenomas or other lesions in that area. Opening of bony skull base has been performed with burrs, chisels, and hammers or standard instruments like punches and circular top knives. The creation of primary bone flaps-as in external craniotomies-is difficult.The piezoelectric osteotomes used in the present study allows creating a bone flap for endoscopic transnasal approaches in certain areas. The aim of this study was to prove the feasibility of piezoelectric endoscopic transnasal craniotomies. Study Design. Cadaveric study. METHODS: On cadaveric specimens (N = 5), a piezoelectric system with specially designed hardware for endonasal application was applied and endoscopic transsphenoidal craniotomies at the sellar floor, tuberculum sellae, and planum sphenoidale were performed up to a size of 3-5 cm(2). RESULTS: Bone flaps could be created without fracturing with the piezoosteotome and could be reimplanted. Endoscopic handling was unproblematic and time required was not exceeding standard procedures. CONCLUSION: In a cadaveric model, the piezoelectric endoscopic transsphenoidal craniotomy (PETC) is technically feasible. This technique allows the surgeon to create a bone flap in endoscopic transnasal approaches similar to existing standard transcranial craniotomies. Future trials will focus on skull base reconstruction using this bone flap.

Intraoperative medialization of medial rectus muscle as a new endoscopic technique for approaching intraconal lesions.

BACKGROUND: Intraconal tumors of the orbit are rare entities and surgical treatment is challenging. Endoscopic transnasal approaches to the orbit offer a new perspective for surgery, although only few reports exist in literature. This study displays the Graz experience with endoscopic approaches to intraorbital tumors between 2006 and 2010 introducing a novel endoscopic technique for temporary medialization of the medial rectus muscle facilitating access to the orbital cone. METHODS: A retrospective analysis of patients' charts was performed. RESULTS: For approaches to intraconal lesions a special endoscopic temporary medialization technique of the medial rectus muscle through applying transseptal sutures was developed. Six patients (four male and two female patients) have been included in this study presenting with intraconal/intraorbital tumors. Three patients underwent endoscopic surgery for two hemangiomas and one Schwannoma, respectively, and three patients were successfully biopsied endoscopically revealing one malignant melanoma, one malignant lymphoma, and one optic glioma each. Both hemangiomas were completely resected without any deterioration of vision. The Schwannoma was partially resected with postoperative imaging showing no tumor progression within 3 months. No intraoperative complications occurred. Five cases were performed with computer assisted surgery using CT/MR fusion navigation. CONCLUSION: Although technically challenging, the endoscopic approach to the orbit, even for intraconal lesions with medialization of the medial rectus muscle, can be safe and promising for well-selected cases. Good postoperative results and sufficient material acquisition for proper histological examination can be obtained. Advantages are good visualization of the surgical field and avoidance of external scars. Limitations to endoscopic techniques are tumors in the lateral superior and lateral inferior quadrant of the orbit.

Endoscopic rhino-neurosurgical approach for non-adenomatous sellar and skull base lesions.

OBJECTIVE: Since endoscopic endonasal transsphenoidal surgery requires skills of both neurosurgeons and otorhinolaryngologists, and the nose is the primary corridor of approach, we favour the term `endoscopic rhino-neurosurgery` and report on our interdisciplinary experience treating non-adenomatous lesions with skull base extension. METHODS: Between 2004 and 2009, 58 patients with 21 different disease patterns underwent endoscopic rhino-neurosurgical procedures. Mean age was 39.9 years, 50% were female. Seven had undergone prior surgery. Clinically, 34.5% presented with visual field deficits and with nerve palsies. Preoperatively, 62.1% showed a normal pituitary function. RESULTS: Mean follow-up was 13.1 months. The surgical goal depended on type of lesion; the intended extent of resection was achieved in 81%. Recovery from visual field deficits occurred in 80%. Neither deteriorated nor new cranial nerve palsies were observed. A normal endocrinological function could be maintained in 94.4%. Permanent diabetes insipidus occurred in 7 patients. Surgical complications included cerebrospinal fluid (CSF) leaks in 6 patients and meningitis in 4. All complications were managed successfully. There was no surgery-related mortality. CONCLUSION: The endoscopic rhino-neurosurgical approach is applicable for a wide variety of lesions comprising sella and skull base. As our data prove, this technique can be performed with satisfying results in non-adenomatous lesions as well.

Released intranasal eosinophilic major basic protein as a diagnostic marker for polypoid chronic rhinosinusitis.

OBJECTIVE: To investigate the hypothesis that eosinophil major basic protein is released in high concentrations in the nasal mucus of patients with polypoid chronic rhinosinusitis. STUDY DESIGN: Single center, open, prospective trial. SETTING: Medical University of Graz, Austria. SUBJECTS AND METHODS: Patients with polypoid chronic rhinosinusitis (n = 23) were compared to three different control groups: patients with chronic rhinosinusitis-like symptoms but without general mucosal thickening, patients who underwent functional endoscopic sinus surgery for reasons other than chronic rhinosinusitis, and patients without sinus disease (total n = 21). Mucus was harvested from each patient using a standardized technique and analyzed for eosinophil major basic protein with an enzyme-linked immunosorbent assay. RESULTS: In the patient group with polypoid chronic rhinosinusitis, 20 of 23 (87%) were positive for eosinophil major basic protein. In contrast, only one control patient was positive, whereas the remainder had no detectable amount of eosinophil major basic protein in the mucus (P < 0.001 vs chronic rhinosinusitis). CONCLUSION: Toxic eosinophil major basic protein levels are elevated in polypoid chronic rhinosinusitis patients compared to control groups that have similar clinical presentations but upon closer examination turn out not to have chronic rhinosinusitis. In the future, the detection of eosinophil major basic protein in nasal mucus may become a sensitive and specific marker for chronic rhinosinusitis and a helpful diagnostic tool.

European position paper on endoscopic management of tumours of the nose, paranasal sinuses and skull base.

Tumours affecting the nose, paranasal sinuses and adjacent skull base are fortunately rare. However, they pose significant problems of management due their late presentation and juxtaposition to important anatomical structures such eye and brain. The increasing application of endonasal endoscopic techniques to their excision offers potentially similar scales of resection but with reduced morbidity. The present document is intended to be a state-of-the art review for any specialist with an interest in this area 1. to update their knowledge of neoplasia affecting the nose, paranasal sinuses and adjacent skull base; 2. to provide an evidence-based review of the diagnostic methods; 3. to provide an evidence-based review of endoscopic techniques in the context of other available treatments; 4. to propose algorithms for the management of the disease; 5. to propose guidance for outcome measurements for research and encourage prospective collection of data. The importance of a multidisciplinary approach, adherence to oncologic principles with intent to cure and need for long-term follow-up is emphasised.

Ensemble-docking approach on BACE-1: pharmacophore perception and guidelines for drug design.

Beta-secretase (BACE-1), a key enzyme in the etiopathogenesis and progression of Alzheimer disease, is the focus of medicinal chemistry efforts both in the pharmaceutical industry and in academia. Despite the availability of diverse peptidomimetic BACE-1 inhibitors, nonpeptidic compounds suitable for oral delivery and transport across the blood brain barrier are in great demand. Herein, a number of active and structurally diverse inhibitors were selected and subjected to an ensemble-docking process into five BACE-1 X-ray structures. The calculated bioactive conformations of these inhibitors allowed us to build an exhaustive pharmacophore model, which captures both the common geometric and electronic features essential for enzyme inhibition. The model is intended to aid the rational design of new BACE-1 inhibitors. Furthermore, a comparison of BACE/cathepsin D X-ray structures was made to provide guidelines for the design of BACE-selective inhibitors.

The role of interleukin-16 in eosinophilic chronic rhinosinusitis.

Eosinophilic granulocytes (Eos) are found in great numbers both in the tissue and in the mucus of patients suffering from chronic rhinosinusitis with polyposis (ECRS). Interleukin-16 (IL-16) is known as a highly potent chemotactic and chemoattractant molecule (ED 10-11) for Eos. In an open, explorative, controlled study we examined the presence of IL-16 in mucosa tissue, mucus and serum in patients suffering from ECRS and its association to Eos activation. Tissue and nasal mucus specimen from 10 previously untreated, non allergic ECRS-patients undergoing paranasal sinus surgery and from 10 healthy non sinusitis subjects, undergoing nasal surgery because of anatomic nasal obstruction were investigated by real-time (RT-) PCR targeting human IL-16 mRNA. Haematoxylin-eosin (HE) staining and immunohistochemistry of formalin embedded tissue and mucus were applied for detection and determination of the proportion of activated Eos (aEos) and IL-16. Serum IL-16 was analyzed by enzyme-linked-immunosorbent assay (ELISA). IL-16 mRNA and IL-16 protein levels were elevated in nasal mucus, polyp tissue and in the serum of ECRS patients compared to healthy controls. There was a high proportion of aEos in ECRS patients compared to healthy subjects. Serum IL-16, IL-16 mRNA expression and IL-16 protein in mucus and tissue specimens were significantly associated with the presence of aEos in polyps of ECRS patients. Immunohistochemically IL-16 protein was mainly expressed in aEos, mast cells, lymphocytes and epithelial cells. In conclusion our data indicate that IL-16 may stimulate the migration and persistence of activated Eos in ECRS. IL-16 production in ECRS patients is not mediated by Immunglobuline-E (IgE).

Modulators and inhibitors of gamma- and beta-secretases.

Most gene mutations associated with Alzheimer's disease point to the metabolism of amyloid precursor protein as a potential cause. The beta- and gamma-secretases are two executioners of amyloid precursor protein processing resulting in amyloid-beta. Significant progress has been made in the selective inhibition of both proteases, regardless of structural information for gamma-secretase. Several peptidic and nonpeptidic leads were identified for both targets.

Inhibitors and modulators of beta- and gamma-secretase.

Most gene mutations associated with Alzheimer's disease point to the metabolism of amyloid precursor protein as potential cause. The beta- and gamma-secretases are two executioners of amyloid precursor protein processing resulting in amyloid beta. Significant progress has been made in the selective inhibition of both proteases, regardless of structural information for gamma-secretase. Several peptidic and non-peptidic leads were identified and first drug candidates are in clinical trials. This review focuses on the developments since 2003.

Drug development and PET-diagnostics for Alzheimer's disease.

The exact cause of Alzheimer's disease is still unknown; despite the dramatic progress in understanding. Most gene mutations associated with Alzheimer's disease point to the amyloid precursor protein and amyloid beta. The alpha-, beta- and gamma-secretases are the three executioners of amyloid precursor protein processing. Significant progress has been made in the selective inhibition of these proteases, regardless of the availability of structural information. Several peptidic and non-peptidic leads were identified and first drug candidates are in clinical trials. Cholesterol lowering drugs and metal chelators are also in advanced clinical stages as disease modifiers. Successful trials demand either large cohorts or reliable markers for Alzheimer's disease. Therefore, several radiomarkers are under investigation to support such clinical trials.

Fungi: a normal content of human nasal mucus.

BACKGROUND: In recent studies, we showed that 91.3% of both CRS patients and healthy controls grew positive fungal cultures out of their nasal mucus, which therefore appears to be a common finding within the adult population. However, it still was unknown as of when fungi could be cultured from nasal mucus in human beings. We attempted to ascertain this point of time in the nasal mucus of neonates. METHODS: We examined nasal mucus from 30 neonates immediately after birth, on the 1st and 4th day postpartum and after 2 and 4 months of life. The samples obtained with sterile cotton swabs were cultured on agar plates. Fungal cultures were identified either conventionally by microscopy or with molecular techniques. To prove possible contamination during birth, mucus of the maternal birth canal was examined as well. RESULTS: In 6 of 30 (20%) of our neonates we found positive fungal cultures immediately after birth in (3 of them Candida albicans) most likely because of contamination passing the maternal birth canal. In 2 of 29 (7%) of our neonates, positive fungal cultures were obtained on the 1st day postpartum, and in 4 of 26 (15%) positive fungal cultures were obtained on the 4th day, all limited to 1 day only and without clinical symptoms of colonization. After the 2nd month of life, examination of nasal mucus yielded positive fungal cultures in 8 of 11 (72%), and after 4 months examination of nasal mucus yielded positive fungal cultures in 17 of 18 (94%) of our babies, with a wide array of different species. CONCLUSION: Fungi can be cultured from nasal mucus as soon as contact with the environmental air exists but they are not persistent in the 1st day of life. However, after 4 months, the situation is similar to the one in adults: fungal cultures can be obtained from almost everyone's nose. Therefore, fungi must be considered a normal content of nasal mucus.

Tripeptide mimetics inhibit the 20 S proteasome by covalent bonding to the active threonines.

Proteasomes play an important role in protein turnover in living cells. The inhibition of proteasomes affects cell cycle processes and induces apoptosis. Thus, 20 S proteasomal inhibitors are potential tools for the modulation of neoplastic growth. Based on MG132, a potent but nonspecific 20 S proteasome inhibitor, we designed and synthesized 22 compounds and evaluated them for the inhibition of proteasomes. The majority of the synthesized compounds reduced the hydrolysis of LLVY-7-aminomethylcoumarin peptide substrate in cell lysates, some of them drastically. Several compounds displayed inhibitory effects when tested in vitro on isolated 20 S proteasomes, with lowest IC(50) values of 58 nm (chymotrypsin-like activity), 53 nm (trypsin-like activity), and 100 nm (caspase-like activity). Compounds 16, 21, 22, and 28 affected the chymotrypsin-like activity of the beta5 subunit exclusively, whereas compounds 7 and 8 inhibited the beta2 trypsin-like active site selectively. Compounds 13 and 15 inhibited all three proteolytic activities. Compound 15 was shown to interact with the active site by x-ray crystallography. The potential of these novel inhibitors was assessed by cellular tolerance and biological response. HeLa cells tolerated up to 1 microm concentrations of all substances. Intracellular reduction of proteasomal activity and accumulation of polyubiquitinated proteins were observed for compounds 7, 13, 15, 22, 25, 26, 27, and 28 on HeLa cells. Four of these compounds (7, 15, 26, and 28) induced apoptosis in HeLa cells and thus are considered as promising leads for anti-tumor drug development.

Bipolaris spicifera causes fungus balls of the sinuses and triggers polypoid chronic rhinosinusitis in an immunocompetent patient.

We report the rare case of a 19-year-old immunocompetent male suffering both from fungus balls of the sinuses and from chronic rhinosinusitis with massive polyposis. Endoscopic sinus surgery revealed grayish brown necrotic masses embedded in viscous eosinophilic mucus. Inoculated onto petri dishes, these masses as well as the mucus grew a dark pigmented fungus, which was identified as Bipolaris spicifera.

Pneumatization of turbinates.

OBJECTIVES: To present unusual computed tomography (CT) findings concerning huge pneumatization of turbinates and paranasal sinuses in one patient. In current world literature the authors only found nine reports of pneumatization of inferior turbinates, which, therefore, must be considered an extremely rare anatomical finding. STUDY DESIGN: Case report and literature review. METHODS: Computed tomography findings in a 35-year-old white woman with nasal obstruction are presented; and the authors describe this additional case of pneumatization of an inferior turbinate, as well as other variants. The literature and nomenclature are reviewed. RESULTS: Besides the rare anatomical finding of a pneumatized inferior turbinate, in addition, both patient middle and superior turbinates were pneumatized bilaterally. Frontal and sphenoid sinuses were huge, with pneumatization of the crista galli and the posterior parts of the septum. The floor of the orbit presented with an orbitoethmoid (Haller) cell on one side. Thus, five of the six turbinates present were pneumatized. To the authors' knowledge, no other case of such extreme pneumatization has been published in world literature to date. CONCLUSIONS: Whereas pneumatization of the ethmoturbinals is a frequent finding on sinus computed tomography scans, pneumatization of the maxilloturbinal remains an extremely rare anatomical variant. Pneumatization of ethmoid cells and secondary sinuses is considered an active achievement of nasal and sinus mucosa during fetal development and adolescence. The underlying mechanisms of this process are not yet understood. The inferior turbinate is the least likely to present with pneumatization. In clinical practice, the pneumatization status should well be studied on the scans before any sinus and turbinate surgery is undertaken.

Case report of bilateral cervical chondrocutaneous branchial remnants.

Cervical chondrocutaneous branchial remnants are rare and not well known lesions. Histologically the lesion per definition presents as a Choristoma. Choristoma is the pathohistological term for a developmental tumor-like anomaly consisting of tissues foreign to the site at which it is located. Treatment is complete surgical removal as promptly as possible in order to get an exact histopathological diagnosis. A case of a 4-month-old boy with cervical chondrocutaneous branchial remnants anterior to the sternocleidomastoid muscles on both sides is presented. According to literature search this appears to be the second case published on such a bilateral lesion.

'Eosinophilic fungal rhinosinusitis': a common disorder in Europe?

OBJECTIVES/HYPOTHESIS: The traditional criteria for the diagnosis of allergic fungal sinusitis include chronic rhinosinusitis, "allergic mucin" (mucus containing clusters of eosinophils), and detection of fungi by means of histological examination or culture. In 1999, a group of Mayo Clinic researchers, with a novel method of mucus collection and fungal culturing technique, were able to find fungi in 96% of patients with chronic rhinosinusitis. Immunoglobulin E-mediated hypersensitivity to fungal allergens was not evident in the majority of their patients. Because the presence of eosinophils in the allergic mucin, not a type I hypersensitivity, is probably the common denominator in the pathophysiology of allergic fungal sinusitis, the Mayo Clinic group proposed a change in terminology from allergic fungal sinusitis to eosinophilic fungal rhinosinusitis. Using new techniques of culturing fungi from nasal secretion, as well as preservation and histological examination of mucus, we investigated the incidence of "eosinophilic fungal rhinosinusitis" in our patient population. STUDY DESIGN METHODS: In an open prospective study nasal mucus from patients with chronic rhinosinusitis as well as from healthy volunteers was cultured for fungi. In patients, who underwent functional endoscopic sinus surgery, nasal mucus was investigated histologically to detect fungi and eosinophils within the mucus. RESULTS: Fungal cultures were positive in 84 of 92 patients with chronic rhinosinusitis (91.3%). In all, 290 positive cultures grew 33 different genera, with 3.2 species per patient, on average. Fungal cultures from a control group of healthy volunteers yielded positive results in 21 of 23 (91.3%). Histologically, fungal elements were found in 28 of 37 patients (75.5%) and eosinophilic mucin in 35 of 37 patients (94.6%). Neither fungi nor eosinophils were present in 2 of 37 patients (5.4%). CONCLUSIONS: Our data show that the postulated criteria of allergic fungal sinusitis are present in the majority of patients with chronic rhinosinusitis. Either those criteria will be found to be invalid and need to be changed or, indeed, "eosinophilic fungal rhinosinusitis" exists in the majority of patients with chronic rhinosinusitis. Based on our results, fungi and eosinophilic mucin appear to be a standard component of nasal mucus in patients with chronic rhinosinusitis.

Detection and identification of fungi from fungus balls of the maxillary sinus by molecular techniques.

The aim of this study was to find a reliable method for the detection and identification of fungi in fungus balls of the maxillary sinus and to evaluate the spectrum of fungi in these samples. One hundred twelve samples were obtained from patients with histologically proven fungal infections; 81 samples were paraffin-embedded tissue sections of the maxillary sinus. In 31 cases, sinus contents without paraffin embedding were sent for investigation. PCR amplification with universal fungal primers for 28S ribosomal DNA and amplicon identification by hybridization with species-specific probes for Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Aspergillus terreus, Aspergillus glaucus, Pseudallescheria boydii, Candida albicans, and Candida glabrata were performed for all samples. Furthermore, PCR products were sequenced. Fresh samples were also cultivated. Fungal DNA was detected in all of the fresh samples but only in 71 paraffin-embedded tissue samples (87.7%). Sequence analysis was the most sensitive technique, as results could be obtained for 28 (90.3%) fresh samples by this method in comparison to 24 (77.4%) samples by hybridization and 16 (51.6%) samples by culture. However, sequence analysis delivered a result for only 36 (50.7%) of the paraffin-embedded specimens. Hybridization showed reliable results for A. fumigatus, which proved to be the most common agent in fungus balls of the maxillary sinus. Other Aspergillus species and other genera were rarely found.

Solitary fibrous tumor of the submandibular gland.

Solitary fibrous tumors (SFT) are generally benign, well-circumscribed soft-tissue tumors of mesenchymal origin. CD34 antigen expression is characteristic for this tumor. A rare subgroup shows malignant histological patterns with aggressive behavior. The common site of occurrence is the pleura, but various other sites, including the head and neck, have been described. We present a 56-year-old, white, female patient with a solitary fibrous tumor developing in the right submandibular salivary gland. The tumor was surgically removed, and no recurrence or metastases have occurred during the 43 months of follow-up. All solitary fibrous tumors reported in the salivary glands were benign. However, new cases should be presented and followed up carefully to monitor their biological behavior.