Sinonasal Stent Coated with Sustained-Release Varnish of Mometasone Furoate Inhibits Pro-Inflammatory Cytokine Release from Macrophages: An In Vitro Study.

The aim of the study was to develop a sustained-release varnish (SRV) containing mometasone furoate (MMF) for sinonasal stents (SNS) to reduce mucosa inflammation in the sinonasal cavity. The SNS' segments coated with SRV-MMF or an SRV-placebo were incubated daily in a fresh DMEM at 37 °C for 20 days. The immunosuppressive activity of the collected DMEM supernatants was tested on the ability of mouse RAW 264.7 macrophages to secrete the cytokines' tumor necrosis factor α (TNFα) and interleukin (IL)-10 and IL-6 in response to lipopolysaccharide (LPS). The cytokine levels were determined by respective Enzyme-Linked Immunosorbent Assays (ELISAs). We found that the daily amount of MMF released from the coated SNS was sufficient to significantly inhibit LPS-induced IL-6 and IL-10 secretion from the macrophages up to days 14 and 17, respectively. SRV-MMF had, however, only a mild inhibitory effect on LPS-induced TNFα secretion as compared to the SRV-placebo-coated SNS. In conclusion, the coating of SNS with SRV-MMF provides a sustained delivery of MMF for at least 2 weeks, maintaining a level sufficient for inhibiting pro-inflammatory cytokine release. This technological platform is, therefore, expected to provide anti-inflammatory benefits during the postoperative healing period and may play a significant role in the future treatment of chronic rhinosinusitis.

Sleep-related breathing disorders in young orthodontic patients.

INTRODUCTION: This study aimed to find out the frequency of sleep-related breathing disorders (SRBD) in young orthodontic patients in Israel. SRBD is characterized by prolonged upper airway obstruction during sleep. METHODS: The study group consisted of 309 children aged 6-17 years who attended the Orthodontic Clinic at Hadassah Medical Center. Parents were asked to complete a translated validated Pediatric Sleep Questionnaire. RESULTS: Of the examined children, 10% were at high risk for SRBD. Boys were at higher risk for SRBD and were at high risk at a younger age than girls. Girls had a low risk of SRBD after adenotonsillectomy, whereas 50% of the boys that underwent adenotonsillectomy were at high risk for SRBD. CONCLUSIONS: Our findings propose that 10% of the children aged 6-17 years, who were seeking orthodontic consultation at our medical center, were at high risk for SRBD. Boys were significantly at a higher risk for SRBD than girls and were at high risk at a younger age. It is important to screen young orthodontic patients for SRBD and to refer high-risk patients to their physicians for further evaluation and treatment.

Effect of irradiation on cytokine production in cancer patients.

BACKGROUND: Irradiation, which affects cytokine secretion, is used to treat cancer patients. Cytokine levels have correlations to disease parameters, serving as biomarkers for patients. We aim to explore the effect of irradiation on cytokine production both in vitro (using lymphocytes from healthy donors) and in vivo (using serum levels of head and neck cancer patients following irradiation) and correlating them to mucositis severity/need for percutaneous endoscopic gastroscopy (PEG) tube installation. METHODS: Cytokine production by cultured lymphocytes from healthy donors, in vitro, following irradiation of 5 or 10 Gy. In addition, blood from 23 patients with head and neck cancers, irradiated by 60-72G in vivo, were assessed for inflammatory cytokines (tumor necrosis factor (TNF)α, interleukin (IL)-6, IL-8, IL-18), the anti-inflammatory cytokine IL-10, and the general marker sIL-2R. Following radiation, selected patients who were developing mucositis were treated by PEG tube installation. Changes in cytokine levels were studied as predictive biomarkers of response to therapy/PEG tube installation. Cytokine production levels were measured using ELISAs kits. RESULTS: Irradiation decreased the levels of all tested cytokines, most notably IL-6 and IL-8, proportional to irradiation dose. In patients, increases in cytokine levels, correlated with mucositis severity and potentially the need for PEG tube installation. CONCLUSIONS: Irradiation decreased the levels of all cytokines of healthy lymphocytes in a dose-dependent manner, especially those of IL-6 and IL-8. This study shows a correlation between high and increasing levels of inflammatory cytokines, sIL-2R, plus radiation toxicity and the need for PEG. The reduction of cytokine levels after radiotherapy predicts that PEG will not be required. Thus, our study shows that cytokine changes are predictive biomarkers in head and neck cancer patients.

Voice Prosthesis Coated with Sustained Release Varnish Containing Clotrimazole Shows Long-Term Protection against Candida albicans: An In Vitro Study.

Fungal biofilm formation on voice prosthesis (VP) is a major health problem that requires repeated replacement of the prosthesis. Candida albicans is one of the pathogens that frequently inhabits the VP. We proposed that coating VPs with sustained-release varnish (SRV) containing clotrimazole (CTZ) might prevent fungal biofilm formation. The long-term antifungal activities of SRV-CTZ- versus SRV-placebo-coated VPs was tested daily by measuring the inhibition zone of C. albicans seeded on agar plates or by measuring the fungal viability of C. albicans in suspension. The extent of biofilm formation on coated VPs was analyzed by confocal microscopy and scanning electron microscopy. We observed that SRV-CTZ-coated VPs formed a significant bacterial inhibition zone around the VPs and prevented the growth of C. albicans in suspension during the entire testing period of 60 days. Fungal biofilms were formed on placebo-coated VPs, while no significant biofilms were observed on SRV-CTZ-coated VPs. HPLC analysis shows that CTZ is continuously released during the whole test period of 60 days at a concentration above the minimal fungistatic concentration. In conclusion, coating VPs with an SRV-CTZ film is a potential effective method for prevention of fungal infections and biofilm formation on VPs.

Clinical Applicability of the Proliferation Marker Thymidine Kinase 1 in Head and Neck Cancer Patients.

BACKGROUND/AIM: Prognostic factors serve as a vital tool in the treatment of patients with head and neck cancer (HNC). The aim of this study was to evaluate the clinical potential of Thymidine-kinase-1 (TK1) marker in the prognosis of HNC patients. PATIENTS AND METHODS: We evaluated 366 blood samples from 278 HNC patients and 88 healthy controls, using an ELISA assay. Correlations of TK1 levels with disease stage, lymph node involvement and response to radiation therapy, were determined. RESULTS: In HNC patients, TK1 levels were significantly higher compared to healthy controls. Significantly higher TK1 levels were demonstrated in node positive cases and in advanced disease stages compared to node negative and early disease stages. Levels were higher prior to radiation and decreased significantly thereafter, in patients responding to treatment. Increasing levels of TK1 post-radiation were indicative of recurrence or of non-response to treatment, while decreasing levels indicated a positive response. CONCLUSION: TK1 is a tumor marker in HNC patients with the ability to assess response to therapy. High or increasing levels correlated to a poor prognosis, whereas low levels correlated to an overall increased survival.

The association between video-nystagmography and sensory organization test of computerized dynamic posturography in patients with vestibular symptoms.

OBJECTIVE: Vertigo is a complex symptom which imposes diagnostic and treatment challenges. Laboratory evaluation of vertigo includes video-nystagmography (VNG) and computerized dynamic posturography (CDP) for the evaluation of different aspects of this complaint. There are vague indications for each test and potential disagreements between them. The aim of this study is to examine the association between the test results of the VNG and sensory organization test (SOT) of CDP in patients referred for both vestibular tests. METHODS: Retrospective data regarding 56 patients age 17-82 years were collected. Patients suffered vestibular complaints and were referred for VNG and CDP evaluation on the same day. The level of agreement between VNG (including caloric test) and the vestibular input of the SOT for each patient was calculated. RESULTS: Among the study group, 10 showed abnormal caloric test results, of which 3 (5.4%) had normal vestibular input in the SOT, and 7 (12.5%) had impaired input (p = 0.724). Spontaneous nystagmus was recorded in 13 patients by VNG, of which 2(3.6%) had normal vestibular input and 11(19.6%) had impaired vestibular input (p = 0.056). CONCLUSIONS: This study shows no statistically significant association between the VNG test and SOT test results. Our results emphasize the difference between the tested aspects in each laboratory test, and the need to define specific indications for each of them. There is a marginally significant association between impaired vestibular input and spontaneous nystagmus, demonstrating the non-localizing nature of this sign.

Intervening in the Acute Phase of Postradiation Carotid Blowout Syndrome.

Introduction Acute carotid blowout syndrome (aCBS) is a severe complication of head and neck cancer (HNC). It can be defined as a rupture of the extracranial carotid arteries, or one of their branches, that causes life-threatening hemorrhage, and which nowadays can be treated with urgent endovascular intervention. Objective We retrospectively evaluate the endovascular management of aCBS and its outcome in years of survival. Methods Retrospectively, we describe our experience with endovascular control of aCBS in patients treated for HNC. We review the characteristics, pathology, endovascular treatment and morbidity and assess the gain in life years. Results Nine individuals were included in this study. Four patients had been previously diagnosed with laryngeal squamous cell carcinoma (SCC), one with paranasal SCC, one with nasopharyngeal carcinoma and three with oral or maxillary adenocarcinoma. All subjects underwent radiotherapy and surgical excision to different extents. Twelve endovascular procedures were performed for injuries to the internal carotid artery ( n = 3; 25%), external carotid artery ( n = 1; 7%) or one of their branches ( n = 8; 67%). Deconstructive methods were used in nine procedures, and three procedures were mainly reconstructive with deployment of covered stents. Total control of bleeding was achieved in all individuals with no intraprocedural complications. Conclusion Endovascular therapy is an effective alternative for the management of exsanguinating CBS. In our series, this palliative therapy increased the overall patient survival by an estimated 9 months.

Intervening in the acute phase of postradiation carotid blowout syndrome

Introduction: Acute carotid blowout syndrome (aCBS) is a severe complication of head and neck cancer (HNC). It can be defined as a rupture of the extracranial carotid arteries, or one of their branches, that causes life-threatening hemorrhage, and which nowadays can be treated with urgent endovascular intervention. Objective: We retrospectively evaluate the endovascular management of aCBS and its outcome in years of survival. Methods: Retrospectively, we describe our experience with endovascular control of aCBS in patients treated for HNC. We review the characteristics, pathology, endovascular treatment and morbidity and assess the gain in life years. Results: Nine individuals were included in this study. Four patients had been previously diagnosed with laryngeal squamous cell carcinoma (SCC), one with paranasal SCC, one with nasopharyngeal carcinoma and three with oral or maxillary adenocarcinoma. All subjects underwent radiotherapy and surgical excision to different extents. Twelve endovascular procedures were performed for injuries to the internal carotid artery (n = 3; 25%), external carotid artery (n = 1; 7%) or one of their branches (n = 8; 67%). Deconstructive methods were used in nine procedures, and three procedures were mainly reconstructive with deployment of covered stents. Total control of bleeding was achieved in all individuals with no intraprocedural complications. Conclusion: Endovascular therapy is an effective alternative for the management of exsanguinating CBS. In our series, this palliative therapy increased the overall patient survival by an estimated 9 months (AU)

Autoimmune Inner Ear Disease: Immune Biomarkers, Audiovestibular Aspects, and Therapeutic Modalities of Cogan's Syndrome.

Cogan's syndrome (CS) is a rare autoimmune disorder characterized by audiovestibular dysfunction and ocular inflammation. Currently, there is no specific serum autoantibody used in the diagnostic workup of CS. Treatment is based on immunosuppressive agents, mainly corticosteroids as first-line choice. Recently, novel therapeutic modalities in CS have emerged. These include tumor necrosis factor-α inhibitors and other biologicals. Despite medical treatment, hearing loss may progress to irreversible bilateral profound SNHL in approximately half of CS patients resulting in candidacy for cochlear implantation (CI). Due to the inflammatory nature of the disease that is causing endosteal reaction with partial obliteration or complete neoossification of the intracochlear ducts, early CI is recommended. CI provides excellent and stable hearing rehabilitation with high score of word and sentence recognition. In this review, we will discuss different aspects of CS including clinical presentation, diagnosis, treatment, and future directives.

A homozygous founder missense variant in arylsulfatase G abolishes its enzymatic activity causing atypical Usher syndrome in humans.

PURPOSE: We aimed to identify the cause of disease in patients suffering from a distinctive, atypical form of Usher syndrome. METHODS: Whole-exome and genome sequencing were performed in five patients from three families of Yemenite Jewish origin, suffering from distinctive retinal degeneration phenotype and sensorineural hearing loss. Functional analysis of the wild-type and mutant proteins was performed in human fibrosarcoma cells. RESULTS: We identified a homozygous founder missense variant, c.133G>T (p.D45Y) in arylsulfatase G (ARSG). All patients shared a distinctive retinal phenotype with ring-shaped atrophy along the arcades engirdling the fovea, resulting in ring scotoma. In addition, patients developed moderate to severe sensorineural hearing loss. Both vision and hearing loss appeared around the age of 40 years. The identified variant affected a fully conserved amino acid that is part of the catalytic site of the enzyme. Functional analysis of the wild-type and mutant proteins showed no basal activity of p.D45Y. CONCLUSION: Homozygosity for ARSG-p.D45Y in humans leads to protein dysfunction, causing an atypical combination of late-onset Usher syndrome. Although there is no evidence for generalized clinical manifestations of lysosomal storage diseases in this set of patients, we cannot rule out the possibility that mild and late-onset symptoms may appear.

Hearing loss in vitiligo: current concepts and review.

The objective of this study was to describe the occurrence, clinical manifestations, audiometric findings, pathogenesis and approach to sensorineural hearing loss (SNHL) among patients diagnosed with vitiligo with a review of the literature. We present a systematic review of the literature on cases of SNHL in patients diagnosed with vitiligo and studies conducted to investigate audiometric changes in such patients. Data on presentation, diagnosis and medical approach were reviewed. A total of 21 studies and case reports revealed at least 102 cases of SNHL in patients diagnosed with vitiligo. Arguments for a common causative etiology related to melanocyte function were mentioned in most of the literature. Evaluation of hearing function among all patients diagnosed with vitiligo seems to be an accepted approach; it should include audiometry, otoacoustic emissions (OAE) and ABR measurements. Extra precaution to prevent ototoxic or noise-induced hearing loss is strongly recommended. Further research is needed to better understand its pathogenesis.

The Diagnostic and Prognostic Value of sIL-2R as an Immune Biomarker in Head and Neck Cancers.

BACKGROUND/AIM: Head and neck cancer (HNC) patients are usually diagnosed with advanced disease and multimodality therapies are required, as well as prognostic biomarkers to predict their response and assess survival. In this study, we aimed to evaluate the ability and clinical significance of the immune biomarker sIL-2R in HNC patients, to assess therapy response and prognosis. MATERIALS AND METHODS: We evaluated 328 blood samples from 145 head and neck cancer patients (HNC) from several subgroups: 84 larynx carcinomas pre- and 39 post-therapy, 46 oral cavity carcinomas pre- and 29 post-therapy, 12 nasopharynx carcinomas, 16 parotid and other salivary gland carcinoma patients. The control group included 45 healthy subjects. Serum sIL-2R levels were evaluated by ELISA assays and correlated to disease stage, lymph nodes, response to therapy, survival and cancer differentiation. RESULTS: Significantly higher sIL-2R levels were recorded in all HNC patients, as opposed to controls, in advanced versus early-stage disease that decreased following therapy. sIL-2R distinguished best, in comparison to other tumor markers, between HNC patients and controls. Survival was strongly associated to lower sIL-2R levels in patients entering the study. CONCLUSION: sIL-2R is a sensitive immune marker for HNC patients. Its levels correlate to disease stage, assess response to therapy and are predictive of recurrence or better survival. We suggest, therefore, using sIL-2R as a reliable prognostic marker in HNC patients as a single marker, or in a combined panel of biomarkers.

The Diagnostic and Prognostic Value of Tumor Markers (CEA, SCC, CYFRA 21-1, TPS) in Head and Neck Cancer Patients.

BACKGROUND/AIM: Establishing prognostic factors is very important in the management of cancer patients. Our aim was to evaluate the clinical significance of a panel of tumor markers, including CEA (Carcino Embryonic Antigen), SCC (Squamous Cell Carcinoma Antigen), TPS (Tissue Polypeptide Specific Antigen) and CYFRA 21-1 in head and neck cancer patients, for assessing treatment response and prognosis of patients. PATIENTS AND METHODS: We evaluated 312 blood samples from 143 head and neck cancer patients, from several sub-groups: 82 Larynx Carcinoma pre- and 38 post-therapy, 46 Oral Cavity pre and 29 post-therapy, 12 nasopharynx, 16 parotid and other salivary gland patients. Blood tumor markers levels were evaluated by conventional ELISA assays. Correlations of marker levels to stage of disease, lymph node involvement and therapy, were performed. RESULTS: Serum levels of all four tumor markers were higher before therapy and decreased thereafter in all patients. The decrease in TPS level following therapy was significant (p=0.03). Significantly higher levels of TPS and similarly higher levels of the other tumor markers were demonstrated in advanced disease (stages III and IV) patients, as opposed to early disease (stages I and II) patients (p=0.012). Node positive patients had significantly higher TPS levels as compared to node negative (p=0.02). The same trend was shown by the other markers as well, but did not reach statistical significance. TPS was best correlated to survival of patients; those having low levels had the best clinical outcome and longer survival. CONCLUSION: CEA, SCC, TPS and CYFRA 21-1 can all serve as useful tumor markers in HNC patients. They assessed response to therapy and were prognostic for recurrence. TPS proved to be the most sensitive predictor of advanced disease and poor prognosis.

Diagnosis and conservative management of late tracheotomy complications in chronic ventilator-dependent patients.

BACKGROUND: Complications associated with long-term tracheotomy are obstruction of the distal end of the tube by granulation tissue and tracheomalacia. These complications have traditionally been surgically treated. METHODS: Prospective study in a chronic ventilator-dependent division, including 234 consecutive patients with tracheotomy and mechanical ventilation. Endoscopic evaluation was performed in patients in whom there was respiratory distress with difficulty in passing a suction catheter through the tube, and/or increased inspiratory resistance and increased peak inspiratory pressure. RESULTS: Nineteen patients were diagnosed with granulation or tracheomalacia. Two patients were treated by surgical removal of the obstructing tissue. Nonsurgical patients were conservatively managed with symptoms' resolution by bypassing the pathology with a longer tube than the previous one or by an adjustable flange tube under endoscopic visualization, with a median symptom-free period of 433 days (range, 55-1230 days). CONCLUSION: In nonsurgical candidates, insertion of a longer tube is a conservative and feasible long-term treatment.

VPS 45-associated primary infantile myelofibrosis--successful treatment with hematopoietic stem cell transplantation.

PMF of infancy is a recently described autosomal recessive disorder presenting with severe bone marrow failure, accelerated neutrophil apoptosis, and significant platelet dysfunction, caused by a mutation in the VPS45 gene. In this study, we update our group of patients with PMF, highlighting different aspects of this disease, and evaluating the effectiveness of HSCT for the treatment of this disorder. Update of clinical data, hematological features, molecular studies, treatment and final outcome of four children diagnosed with VPS 45-associated PMF of infancy. The patients described had clinical and hematological findings consistent with MF. Molecular studies showed that all patients were homozygous for the Thr224Asn mutation in the VPS 45 gene. HSCT was carried out in three patients and was successful in two. VPS 45-associated MF is a novel primary immune deficiency that can be successfully corrected by HSCT if applied early in the course of disease using appropriate conditioning. The diagnosis of VPS 45-associated PMF should be considered in all children presenting with SCN with subsequent development of pancytopenia. Long-term follow-up of these patients is necessary to identify extra-hematological manifestations of VPS45 deficiency.

Mutations in ARL2BP, encoding ADP-ribosylation-factor-like 2 binding protein, cause autosomal-recessive retinitis pigmentosa.

Retinitis pigmentosa (RP) is a genetically heterogeneous retinal degeneration characterized by photoreceptor death, which results in visual failure. Here, we used a combination of homozygosity mapping and exome sequencing to identify mutations in ARL2BP, which encodes an effector protein of the small GTPases ARL2 and ARL3, as causative for autosomal-recessive RP (RP66). In a family affected by RP and situs inversus, a homozygous, splice-acceptor mutation, c.101-1G>C, which alters pre-mRNA splicing of ARLBP2 in blood RNA, was identified. In another family, a homozygous c.134T>G (p.Met45Arg) mutation was identified. In the mouse retina, ARL2BP localized to the basal body and cilium-associated centriole of photoreceptors and the periciliary extension of the inner segment. Depletion of ARL2BP caused cilia shortening. Moreover, depletion of ARL2, but not ARL3, caused displacement of ARL2BP from the basal body, suggesting that ARL2 is vital for recruiting or anchoring ARL2BP at the base of the cilium. This hypothesis is supported by the finding that the p.Met45Arg amino acid substitution reduced binding to ARL2 and caused the loss of ARL2BP localization at the basal body in ciliated nasal epithelial cells. These data demonstrate a role for ARL2BP and ARL2 in primary cilia function and that this role is essential for normal photoreceptor maintenance and function.

Olfactory and sinonasal outcomes in endoscopic transsphenoidal skull-base surgery.

BACKGROUND: Endoscopic anterior skull-base surgery has been previously suggested to cause a significant deterioration in olfactory function. Given the impact on quality of life, the objective of this study was to determine the effect of a unilateral middle-turbinate-sacrificing approach on olfactory function and sinonasal outcome. METHODS: Prospective cohort study comparing olfactory and sinonasal outcomes pre- and post-transsphenoidal skull-base surgery. Olfaction was the primary outcome and was measured prospectively using the University of Pennsylvania Smell Identification Test (SIT). Sinonasal symptoms were assessed subjectively via sinonasal-specific questions from the 22-item Sino-Nasal Outcome Test (SNOT-22), and objectively via the Lund-Kennedy Endoscopic Scoring system (LKES). RESULTS: Twenty-two patients met study inclusion criteria and completed all data acquisition. The mean preoperative SIT score was 34.8 and the mean postoperative SIT value was 35.1 (p = 0.37). The average change in score (delta) was an increase of 0.3, with changes ranging from -3 to +4. When examined categorically, 91% of patients maintained their preoperative olfactory function classification. There was no significant difference in mean pre- and postoperative symptom scores. A small increase in the LKES was noted, from a mean of 0.6 to 2.5 (p = 0.001) in the early postoperative period. CONCLUSION: Olfactory function, as measured by the SIT test, was preserved with a middle-turbinate-sacrificing skull-base approach. Subjective sinonasal symptom scores were unaffected, but a slight worsening of objective endoscopic appearance was noted.

Laryngeal involvement in Behcet's disease--a challenge for treatment.

A patient with severe Behcet's disease (BD) was referred to our clinic because of severe pharyngolaryngeal involvement. This complication developed under treatment of prednisone and etanercept (Enbrel) 25 mg twice a week. A surgical approach was considered, but following three daily doses of Solu-Medrol (500 mg each) and 300 mg infliximab on the fourth day, the patient improved significantly. This is the first case reporting treatment with infliximab in laryngeal involvement of BD. Although some cases may still require surgical intervention, the therapeutic option of anti-TNF agents, specifically anti-TNF antibodies such as infliximab, may decrease the need for the surgical option.

Radial forearm free flap with titanium mesh sandwich reconstruction in complex anterior skull base defects.

BACKGROUND: Skull base reconstruction presents a number of challenges from anatomical and functional perspectives. This is especially the case with large anterior skull base defects with compromised recipient beds from repeated infection, multiple surgeries, or previous radiation. The purpose of the study was to demonstrate the use of the titanium mesh/radial forearm free flap (RFFF) mesh sandwich for reconstruction of large anterior skull base defects with a poor recipient bed or excessive bony defect. METHODS: Retrospective case series of 3 patients with complex anterior skull base defects reconstructed with a titanium mesh/RFFF mesh sandwich technique. RESULTS: Reconstruction of 3 cases using the titanium mesh/RFFF sandwich technique resulted in definitive treatment with no recurrent cerebral spinal fluid leaks, meningitis, or complications. CONCLUSIONS: The titanium mesh/RFFF sandwich is an excellent reconstructive option for large anterior skull base defects with a poor recipient bed. This approach is facilitated using a combined open and endonasal endoscopic approach in a multidisciplinary team composed of head and neck surgery, rhinology, and neurosurgery.