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Background: Immunosuppressive therapy places pediatric patients at risk of developing life-threatening sinonasal infections. Diagnosis and treatment are challenging owing to nonspecific signs and symptoms. The aim of this study was to present our department's experience with the surgical management of acute rhinosinusitis in immunosuppressed children., Methods: The records of all children with a hematologic or oncologic disease who underwent endoscopic sinus surgery (ESS) for acute rhinosinusitis from January 2005 to May 2014 were reviewed. Data were retrospectively collected on demographics, clinical and imaging characteristics, microbiology, pathology, treatment and outcome., Results: Thirty-four-immunosuppressed children underwent ESS for acute rhinosinusitis. Most patients had a fungal infection. Nineteen patients died at the end of follow-up; 10 deaths were infection-related. Facial swelling was the only symptom that correlated with death of infection. Relapse of the underlying disease, bone marrow transplantation, and long duration of neutropenia correlated with infection-related mortality. Fungal infection, and specifically Aspergillus, correlated with death from infection., Conclusions: ESS is a safe and efficient procedure for diagnosing and treating immunosuppressed pediatric patients with acute rhinosinusitis. Early detection and aggressive medical and surgical treatment, with control of underlying risk factors, are crucial to improve outcome.

Objective: The clinical presentation of sphenoid sinusitis can be highly variable. Rarely, sphenoid sinusitis may present with cranial nerve complications due to the proximity of these structures to the sphenoid sinus., Method: A case series from Rabin Medical Center and all cases of cranial nerves palsies secondary to sphenoid sinusitis that have been reported in the literature were reviewed., Results: Seventeen patients were identified. The abducent nerve was the most common cranial nerve affected (76%), followed by the oculomotor nerve (18%). One patient had combined oculomotor, trochlear and abducent palsies. The most common pathology was isolated purulent sphenoid sinusitis in 64% followed by allergic fungal sinusitis (AFS) in 18%, and fungal infection in 18%. 94% had an acute presentation. The majority (85%) received a combined intravenous antibiotics and surgical treatment. The remainder received conservative treatment alone. Complete recovery of cranial nerve palsy was noted in 82% during follow up., Conclusion: Sphenoid sinusitis presenting as diplopia and headaches is rare. A neoplastic process must be ruled out and early surgical intervention with intravenous antimicrobial therapy carry an excellent outcome with complete resolution of symptoms.

Background: Medullary thyroid carcinoma management consists mainly of surgical resection and is largely chemoresistant. There is ongoing effort to discover novel therapies for medullary thyroid carcinoma. Increased levels of heat shock proteins have been associated with multiple cancers and are being studied as potential therapeutic targets. The purpose of this study was to determine the expression levels of heat shock proteins 90 and 70 and of glucose related protein 78 in medullary thyroid carcinoma tissues compared with normal thyroid tissues., Methods: 20 tissue specimens of medullary thyroid carcinoma and 10 specimens of thyroids without malignancy were analyzed by immunohistochemistry., Results: Medullary thyroid carcinoma specimens showed 27% higher expression level of heat shock protein 90 immunostaining, and a 43% higher expression level of heat shock protein 70 immunostaining versus normal controls. These differences, however, were not statistically significant. A significantly higher expression level was noted for glucose related protein 78 in the medullary thyroid carcinoma specimens than in the controls., Conclusion: This study indicates increased expression levels of heat shock proteins 90 and 70 and glucose related protein 78 levels in medullary thyroid carcinoma. These findings, though preliminary imply that these proteins may have a role in medullary thyroid carcinoma's tumor biology and may have and future therapeutic options. Larger cohorts are needed to corroborate these results., (Copyright © 2016 Elsevier Inc. All rights reserved.)

We investigated if prenatal exposures to tobacco smoke lead to changes in mitochondrial DNA content (mtDNA) in cord serum and adversely affect newborns' health. Umbilical cord serum cotinine levels were used to determine in utero exposure to smoking. Cord serum mtDNA was measured by quantitative polymerase chain reaction analysis of the genes coding for cytochrome c oxidase1 (MT-CO1) and cytochrome c oxidase2 (MT-CO2). Log transformed levels of mtDNA coding for MT-CO1 and MT-CO2 were significantly higher among infants of active smokers with higher serum level of cotinine (p < 0.05) and inversely associated with gestational age (p = 0.08; p = 0.02). Structural equation modeling results confirmed a positive association between cotinine and MT-CO1 and2 (p < 0.01) and inverse associations with gestational age (p = 0.02) and IGF-1 (p < 0.01). We identified a dose-dependent increase in the level of MT-CO1 and MT-CO2 associated to increased cord serum cotinine and decreased gestational age.

Objective: Malignant external otitis (MEO) is an aggressive infection, primarily affecting elderly diabetic patients. It begins in the external ear canal and spreads to adjacent structures. This study investigated the clinical characteristics of patients diagnosed and treated for MEO and analyzed factors affecting patient outcomes., Study Design: Historical cohort., Setting: Tertiary medical center., Methods: Medical records of all patients diagnosed and treated for MEO from 1990 to 2013, were retrospectively reviewed. Clinical features, laboratory, imaging and outcomes were analyzed., Results: 88 patients were included, mean age was 73±11.5years, 61 (69%) were male. Of these, 75% had diabetes. Mean follow-up was 60months. The most common presenting symptoms were otalgia (89%), external ear canal edema (86%) and otorrhea (84%). Pseudomonas aeruginosa was isolated in 61% of ear cultures. All patients were treated with antibiotics, 22% had surgery and 8% hyperbaric oxygen. Overall survival rate was 38% in 5years, with disease specific mortality 14%. DM, facial nerve palsy, positive CT scan and age above 70 were found to correlate and predict disease-specific mortality., Conclusions: MEO carries a grave prognosis. The presence of two or more of the following features, DM, facial nerve palsy, positive CT scan and age above 70, predicts poor outcome, and highlights the need for prolonged, vigorous treatment., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Although the safety of topical nasal steroids is well established for nasal spray forms, data regarding the safety of steroid irrigations is limited. We studied the effect of long-term budesonide nasal irrigations (>6 months) on hypothalamic-pituitary-adrenal axis (HPAA) function and intraocular pressure (IOP) in patients post-endoscopic sinus surgery., Methods: This was retrospective case series. Adrenal function was assessed by using the high-dose cosyntropin stimulation test., Results: A total of 48 patients were assessed, with a mean duration of budesonide irrigations of 22 months. Stimulated cortisol levels were abnormally low in 11 patients (23%). None reported to have symptoms of adrenal suppression. Three of 4 patients who repeated the study being off budesonide for at least 1 month returned to near normal levels. Logistic regression analysis revealed that concomitant use of both nasal steroid sprays and pulmonary steroid inhalers was significantly associated with HPAA suppression (p = 0.024). Patients with low stimulated cortisol levels were able to continue budesonide irrigations under the supervision of an endocrinologist without frank clinical manifestations of adrenal insufficiency. IOP was within normal limits in all patients., Conclusion: Long-term use of budesonide nasal irrigations is generally safe, but asymptomatic HPAA suppression may occur in selected patients. Concomitant use of both nasal steroid sprays and pulmonary steroid inhalers while using daily budesonide nasal irrigations is associated with an increased risk. Rhinologists should be alerted to the potential risks of long-term use of budesonide nasal irrigations, and monitoring for HPAA suppression may be warranted in patients receiving long-term budesonide irrigation therapy., (© 2016 ARS-AAOA, LLC.)

There are only limited data in the literature, and none specifically from the Middle East, on the pathogenic bacteria in chronic rhinosinusitis (CRS) as opposed to healthy nasal cavities and their association with disease severity. The present study was conducted in the department of head and neck surgery of a tertiary medical center. Middle meatal swabs were taken preoperatively from patients with CRS with nasal polyposis (CRSwNP) (n = 60), CRS without nasal polyposis (CRSsNP) (n = 50), and control patients with septal deviation (n = 26) or no nasal abnormalities (n = 27). Culture findings were compared among the groups and correlated with CRS severity. Positive pathogenic culture rates were 78% in the CRSwNP group and 64% in the CRSsNP group. Twenty pathogenic bacterial species were identified; the most common was Staphylococcus aureus (27%). The most common Gram-negative isolate was Citrobacter spp. (17%). Gram-negative species were significantly more prevalent in the CRSwNP group than the others. Mean Lund-Mackay scores were 12.8 in the CRSwNP group and 6.9 in the CRSsNP group, and were unrelated to the culture findings. Positive culture rates were significantly higher in the septal deviation (54%) than the nasal healthy group (26%), although both values were significantly lower than in the CRS groups. In conclusion, patients with CRS have higher rates of bacterial isolates than patients without CRS. CRSwNP is associated with more Gram-negative bacteria than CRSsNP, regardless of disease severity. The relatively high positive culture rate in patients with septal deviation merits investigation., (© 2016 S. Karger AG, Basel.)

We examined the relationship between the O(6)-methylguanine-methyltransferase (MGMT) methylation status and clinical outcomes in newly diagnosed glioblastoma multiforme (GBM) patients who were treated with Gliadel wafers (Eisai, Tokyo, Japan). MGMT promoter methylation has been associated with increased survival among patients with GBM who are treated with various alkylating agents. MGMT promoter methylation, in DNA from 122 of 160 newly diagnosed GBM patients treated with Gliadel, was determined by a quantitative methylation-specific polymerase chain reaction, and was correlated with overall survival (OS) and recurrence-free survival (RFS). The MGMT promoter was methylated in 40 (32.7%) of 122 patients. The median OS was 13.5 months (95% confidence interval [CI] 11.0-14.5) and RFS was 9.4 months (95% CI 7.8-10.2). After adjusting for age, Karnofsky performance score, extent of resection, temozolomide (TMZ) and radiation therapy (RT), the newly diagnosed GBM patients with MGMT methylation had a 15% reduced mortality risk, compared to patients with unmethylated MGMT (hazard ratio 0.85; 95% CI 0.56-1.31; p=0.46). The patients aged over 70 years with MGMT methylation had a significantly longer median OS of 13.5 months, compared to 7.6 months in patients with unmethylated MGMT (p=0.027). A significant difference was also found in older patients, with a median RFS of 13.1 versus 7.6 months for methylated and unmethylated MGMT groups, respectively (p=0.01). Methylation of the MGMT promoter in newly diagnosed GBM patients treated with Gliadel, RT and TMZ, was associated with significantly improved OS compared to the unmethylated population. In elderly patients, methylation of the MGMT promoter was associated with significantly better OS and RFS., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objectives/hypothesis: To analyze complications associated with nasoseptal flap elevation and reconstruction in endoscopic skull base surgery., Study Design: Case series., Methods: Retrospective chart review of all patients who underwent nasoseptal flap procedure in our institution between 2008 and 2013., Results: A total of 121 patients were identified with a mean follow-up time of 10.4 months. Complications associated with this procedure occurred in 33 patients (27%). The majority of complications were related to the septal donor site and included septal perforation, cartilage necrosis, and prolonged crusting. Other complications included intraoperative injury to the flap pedicle (n = 4) or recurrent/persistent cerebrospinal fluid leak occurring in the early postoperative period (n = 7). Long-term quality-of-life data assessed via Sinonasal Outcome Test-22 questionnaires did not reveal notable differences when compared to preoperative scores., Conclusion: The complication rate associated with nasoseptal flap elevation and inset is higher than previously described. The majority of complications became manifest beyond the immediate postoperative period and were associated with the septal donor site, including septal perforation, prolonged crusting, and cartilage necrosis. We hypothesize that donor site morbidity may be related to compromise of the contralateral septal vascular supply during the procedure. The range and frequency of complications of nasal septal flap surgery should be considered in counseling patients who may receive a nasoseptal flap for skull base reconstruction., (© 2014 The American Laryngological, Rhinological and Otological Society, Inc.)

Spontaneous meningoencephalocele (SME) of the sphenoid wing is a rare cause of cerebrospinal fluid (CSF) leakage. Surgical closure of the fistula is usually required. The approach taken depends on the location of the defect and the extension of the meningoencephalocele. The endoscopic transpterygoid approach may be useful. We prospectively analyzed the three cases of SME of the sphenoid wing with lateral sphenoid sinus extension treated endoscopically at Stanford over the last 3 years with regard to imaging findings, operative technique, and operative morbidity. In our three cases, the extent of pterygopalatine fossa (PPF) exposure undertaken, complete in one and partial in two, depended on the defect site. Follow-up ranged from 17 to 25 months. The fistula was completely closed in all three cases. Extant literature reports a 97% rate of successful closure (N = 65 of 67, with a mean follow-up of 25 months) and no major complications. Endoscopic transpterygoid repair is a useful, safe alternative to traditional approaches for repair of SME of the sphenoid wing. Its feasibility depends on the site of the defect, which can be identified by preoperative imaging. Larger PPF exposure and postoperative lumbar drainage of CSF can be useful and have a low risk of morbidity.

Objective: This study aimed to assess sinonasal outcomes in patients with aspirin exacerbated respiratory disease (AERD) undergoing aspirin desensitization following endoscopic sinus surgery (ESS)., Study Design: Case series with chart review., Setting: University hospital., Subjects and Methods: A retrospective review of sinonasal outcomes was conducted for 30 AERD patients undergoing aspirin desensitization and maintenance therapy following ESS. Sinonasal outcomes were prospectively assessed by the Sinonasal Outcomes Test-22 (SNOT-22) and endoscopic polyp grading system. Data were collected preoperatively, 1 and 4 weeks postsurgery (before desensitization), and 1, 6, 12, 18, 24, and 30 months after aspirin desensitization., Results: Twenty-eight of 30 patients (93.3%) successfully completed aspirin desensitization, whereas 2 of 30 (6.7%) were unable to complete desensitization due to respiratory intolerance. Of the 21 patients who successfully completed a minimum of 24 weeks of follow-up, 20 (95.2%) patients demonstrated sustained endoscopic and symptomatic improvement for a median follow-up period of 33 months. After surgical treatment but before desensitization, patients experienced significant reductions in SNOT-22 and polyp grade scores. In the first 6 months after aspirin desensitization, patients experienced further significant reductions in SNOT-22 scores, whereas polyp grade remained stable. The improvements in symptom endoscopic scores were preserved throughout the follow-up period after desensitization. No patients required additional sinus surgery. One patient had to discontinue aspirin therapy due to gastrointestinal side effects. No other adverse reactions to aspirin were noted., Conclusion: Aspirin desensitization following ESS appears to be a well-tolerated and effective adjunctive therapy for long-term control of nasal polyposis in patients with AERD., (© American Academy of Otolaryngology—Head and Neck Surgery Foundation 2014.)

Obstructive sleep apnea (OSA) is a common disorder, characterized by cyclic cessation of airflow for 10 seconds or more. There is growing awareness that OSA is related to the development and progression of cardiovascular disease. However, only a few studies have associated OSA directly to major cardiovascular events. The aim of this study was to evaluate the relationship between OSA and cardiovascular morbidity in a well defined population of patients.The electronic database of the central district of a major health management organization was searched for all patients diagnosed with OSA in 2002-2010. For each patient identified, an age- and sex-matched patient was randomly selected from the members of the same health management organization who did not have OSA. Data on demographics, socioeconomic status, and relevant medical parameters were collected as well.The study population included 2797 patients, average age 58.1, in which 76.6% were males. There was a significant correlation between OSA and the presence of ischemic heart disease (P < 0.001), pulmonary hypertension (P < 0.001), congestive heart failure (P < 0.001), cardiomyopathy (P = 0.003), and arrhythmia (P < 0.001). OSA was also significantly correlated with low socioeconomic status (P < 0.001).OSA and cardiovascular disease were strongly correlated. As such, early diagnosis and treatment of OSA may change the course of both diseases. We suggest that sleep disordered breathing should be routinely assessed in patients with cardiovascular problems. An ear-nose-throat evaluation may also be important to rule out anatomic disorders that cause upper airway obstruction.

Methylation alterations of CpG islands, CpG island shores and first exons are key events in the formation and progression of human cancer, and an increasing number of differentially methylated regions and genes have been identified in breast cancer. Recent studies of the breast cancer methylome using deep sequencing and microarray platforms are providing a novel insight on the different roles aberrant methylation plays in molecular subtypes of breast cancer. Accumulating evidence from a subset of studies suggests that promoter methylation of tumor-suppressor genes associated with breast cancer can be quantified in circulating DNA. However, there is a paucity of studies that examine the combined presence of genetic and epigenetic alterations associated with breast cancer using blood-based assays. Dysregulation of DNA repair capacity (DRC) is a genetic risk factor for breast cancer that has been measured in lymphocytes. We isolated plasma DNA from 340 participants in a breast cancer case control project to study promoter methylation levels of five genes previously shown to be associated with breast cancer in frozen tissue and in cell line DNA: MAL, KIF1A, FKBP4, VGF and OGDHL. Methylation of at least one gene was found in 49% of the cases compared to 20% of the controls. Three of the four genes had receiver characteristic operator curve values of ≥ 0.50: MAL (0.64), KIF1A (0.51) and OGDHL (0.53). KIF1A promoter methylation was associated with breast cancer and inversely associated with DRC. This is the first evidence of a significant association between genetic and epigenetic alterations in breast cancer using blood-based tests. The potential diagnostic utility of these biomarkers and their relevance for breast cancer risk prediction should be examined in larger cohorts.

Background: An increasing number of adult patients with cystic fibrosis (CF) are becoming candidates for elective endoscopic sinus surgery (ESS). We sought to identify perioperative factors in this patient population that were predictive of postoperative admission., Methods: Retrospective chart review of CF patients who underwent ESS during the years 2005 through 2012. Multiple preoperative, intraoperative, and immediate postoperative variables were analyzed., Results: Thirty-three patients who underwent 37 outpatient ESSs were identified. Successful same-day discharge was observed in 54%. In 46% of cases, postoperative admission was necessary, with a mean postoperative stay of 1.4 days. Pulmonary function, CF-related comorbidities, and history of lung transplant were not predictors of postoperative admission. Univariate analysis demonstrated that patients were more likely to be admitted if they had 1 of the following conditions: history of ≥4 prior ESS; procedure duration >2.5 hours; intraoperative blood loss greater than 150 mL; increased immediate postoperative pain scores; or larger narcotic requirements for pain control. On logistic regression analysis, a maximum pain score ≥ 7 out of 10 in the postanesthesia recovery unit was the only significant predisposing factor for postoperative admission., Conclusion: Although over 50% of adult CF patients can successfully undergo ESS on a same-day discharge basis, it is prudent to have contingent plans for potential inpatient observation postoperatively. Multivariate analysis suggests that preoperative demographics and pulmonary status cannot predict the need for postoperative admission, whereas higher pain scores in the postanesthesia care unit are predictive of the necessity for inpatient observation., (© 2014 ARS-AAOA, LLC.)

Objectives: To systematically review the literature concerning techniques of closure of endoscopically created skull base defects based on site of skull base defect and flow rate of cerebrospinal fluid (CSF)., Data Sources: PubMed, SCOPUS, and Cochrane databases., Review Methods: A comprehensive systematic literature review., Results: The literature search produced a total of 1708 studies. Of these, 1585 studies were excluded based on title and/or abstract review. A total of 123 articles remained for full-text review, 101 of which were subsequently excluded primarily because of lack of detailed information as to the reconstructive techniques used or clinical outcomes. Of the 22 studies remaining for final analysis, all were case series. A total of 673 patients were included in the analysis, with an overall postoperative CSF leak rate of 8.5%. Subgroup analysis was performed based on location of the skull base defect and presence and quality of intraoperative CSF leak., Conclusions: Based on level 4 evidence, in cases of low-flow intraoperative CSF leaks, skull base reconstruction with multilayered free grafts and synthetic materials offers similar outcomes to vascularized flaps. In cases of high-flow intraoperative CSF leaks, pedicled vascularized flaps appear to be superior. Location of the defect does not seem to be a significant factor in determining successful closure, with the exception of clival defects. In all other sites, good closure may be achieved by multiple reconstructive approaches. More consistency in data reporting and higher levels of evidence will ultimately be necessary to make definitive recommendations.

Purpose: Prior studies have demonstrated tumor-specific alternative splicing events in various solid tumor types. The role of alternative splicing in the development and progression of head and neck squamous cell carcinoma (HNSCC) is unclear. Our study queried exon-level expression to implicate splice variants in HNSCC tumors., Experimental Design: We performed a comparative genome-wide analysis of 44 HNSCC tumors and 25 uvulopalatopharyngoplasty (UPPP) tissue samples at an exon expression level. In our comparison we ranked genes based upon a novel score-the Maximum-Minimum Exon Score (MMES)--designed to predict the likelihood of an alternative splicing event occurring. We validated predicted alternative splicing events using quantitative RT-PCR on an independent cohort., Results: After MMES scoring of 17,422 genes, the top 900 genes with the highest scores underwent additional manual inspection of expression patterns in a graphical analysis. The genes LAMA3, DST, VEGFC, SDHA, RASIP1, and TP63 were selected for further validation studies because of a high frequency of alternative splicing suggested in our graphical analysis, and literature review showing their biological relevance and known splicing patterns. We confirmed TP63 as having dominant expression of the short DeltaNp63 isoform in HNSCC tumor samples, consistent with prior reports. Two of the six genes (LAMA3 and DST) validated by quantitative RT-PCR for tumor-specific alternative splicing events (Student's t test, P<0.001)., Conclusion: Alternative splicing events of oncologically relevant proteins occur in HNSCC. The number of genes expressing tumor-specific splice variants needs further elucidation, as does the functional significance of selective isoform expression.

Object: In this study the authors share their experience using intraoperative spinal navigation and imaging for endoscopic transnasal approaches to the odontoid in 5 patients undergoing C1-2 surgery for basilar invagination at Stanford Hospital and Clinics from 2010 to 2013., Methods: Of these 5 patients undergoing C1-2 surgery for basilar invagination, 4 underwent a 2-tiered anterior C1-2 resection with posterior occipitocervical fusion during a first stage surgery, followed by endoscopic endonasal odontoidectomy in a separate setting. Intraoperative stereotactic navigation was performed using a surgical navigation system in all cases. Navigation accuracy, characterized as target registration error, ranged between 0.8 mm and 2 mm, with an average of 1.2 mm. Intraoperative imaging using a CT scanner was also performed in 2 patients., Results: Endoscopic decompression of the brainstem was achieved in all patients, and no intraoperative complications were encountered. All patients were extubated within 24 hours after surgery and were able to swallow within 48 hours. After appropriate initial reconstruction of the defect at the craniocervical junction, no postoperative CSF leakage, arterial injury, or need for reoperation was encountered; 1 patient developed mild postoperative velopharyngeal insufficiency that resolved by the 6-month follow-up evaluation. There were no deaths and no patients required tracheostomy placement. The average inpatient stay after surgery varied between 72 and 96 hours, without extended intensive care unit stays for any patient., Conclusions: Technologies such as intraoperative CT scanning and merged MRI/CT can provide the surgeon with detailed, virtual real-time information about the extent of complex endoscopic vertebral segment resection and brainstem decompression and lessens the prospect of revision or secondary procedures in this challenging surgical corridor. Moreover, patients experience limited morbidity and can tolerate early oral intake after transnasal endoscopic odontoidectomy. Essential to the successful undertaking of these endoscopic adventures is 1) an understanding of the endoscopic nasal, skull base, and neurovascular anatomy; 2) advanced and extended-length instrumentation including navigation; and 3) a team approach between experienced rhinologists and spine surgeons comfortable with endoscopic skull base techniques.

Cervical cancer is a major health concern among women in Latin America due to its high incidence and mortality. Therefore, the discovery of molecular markers for cervical cancer screening and triage is imperative. The aim of this study was to use a genome wide DNA methylation approach to identify novel methylation biomarkers in cervical cancer. DNA from normal cervical mucosa and cervical cancer tissue samples from Chile was enriched with Methylated DNA Immunoprecipitation (MeDIP), hybridized to oligonucleotide methylation microarrays and analyzed with a stringent bioinformatics pipeline to identify differentially methylated regions (DMRs) as candidate biomarkers. Quantitative Methylation Specific PCR (qMSP) was used to study promoter methylation of candidate DMRs in clinical samples from two independent cohorts. HPV detection and genotyping were performed by Reverse Line Blot analysis. Bioinformatics analysis revealed GGTLA4, FKBP6, ZNF516, SAP130, and INTS1 to be differentially methylated in cancer and normal tissues in the Discovery cohort. In the Validation cohort FKBP6 promoter methylation had 73% sensitivity and 80% specificity (AUC = 0.80). ZNF516 promoter methylation was the best biomarker, with both sensitivity and specificity of 90% (AUC = 0.92), results subsequently corroborated in a Prevalence cohort. Together, ZNF516 and FKBP6 exhibited a sensitivity of 84% and specificity of 81%, when considering both cohorts. Our genome wide DNA methylation assessment approach (MeDIP-chip) successfully identified novel biomarkers that differentiate between cervical cancer and normal samples, after adjusting for age and HPV status. These biomarkers need to be further explored in case-control and prospective cohorts to validate them as cervical cancer biomarkers.

The majority of the epigenomic reports in hepatocellular carcinoma have focused on identifying novel differentially methylated drivers or passengers of the oncogenic process. Few reports have considered the technologies in place for clinical translation of newly identified biomarkers. The aim of this study was to identify epigenomic technologies that need only a small number of samples to discriminate HCC from non-HCC tissue, a basic requirement for biomarker development trials. To assess that potential, we used quantitative Methylation Specific PCR, oligonucleotide tiling arrays, and Methylation BeadChip assays. Concurrent global DNA hypomethylation, gene-specific hypermethylation, and chromatin alterations were observed as a hallmark of HCC. A global loss of promoter methylation was observed in HCC with the Illumina BeadChip assays and the Nimblegen oligonucleotide arrays. HCC samples had lower median methylation peak scores and a reduced number of significant promoter-wide methylated probes. Promoter hypermethylation of RASSF1A, SSBP2, and B4GALT1 quantified by qMSP had a sensitivity ranging from 38% to 52%, a specificity of 100%, and an AUC from 0.58 to 0.75. A panel combining these genes with HCC risk factors had a sensitivity of 87%, a specificity of 100%, and an AUC of 0.91.

Objectives/hypothesis: To determine whether radial forearm free flap reconstruction of the tongue after partial glossectomy is associated with obstructive sleep apnea., Study Design: Retrospective case series., Methods: Fifteen patients (5 men, 10 women) treated for tongue cancer in 2006-2010 by partial glossectomy and immediate radial forearm free flap reconstruction completed the Epworth Sleepiness Scale and underwent polysomnographic studies. Background, clinical, and pathologic data were collected from the medical files., Results: Mean ± SD age of the study group was 57 ± 19 years; body mass index, 24 ± 4; follow-up, 5.6 ± 2.8 years. Mean ± SD Epworth scale score was 8.18 ± 6.18 (normal, <8). Disordered sleep was documented in 11 patients, of whom 8 (53.3% of the cohort) had OSA (5 mild, 2 moderate, 1 severe). The OSA rate was significantly higher than reported in the general population (P = 0.001)., Conclusion: Patients after partial glossectomy and radial forearm free flap reconstruction appear to be at high risk of obstructive sleep apnea. Testing for OSA should be considered in these patients., (Copyright © 2013 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: New epithelial cells are generated through the proliferation and differentiation of resident progenitor cells in the nasal cavity. In several upper airway diseases, such as cystic fibrosis and chronic rhinosinusitis, self-renewing progenitor cells may be functionally defective, or compromised in their ability, to regenerate cells that maintain normal mucociliary clearance. Herein, we describe our early work to define and characterize a rare population of human nasal epithelial putative progenitors., Methods: Single-cell suspensions of human ethmoid sinus tissues were prepared following endoscopic sinus surgery. Cell surface antibodies were analyzed as candidate markers for detecting progenitor cells. A panel of antibodies, including epithelial cell adhesion molecule (EpCAM, epithelial cells), CD45 (hematopoietic cells), nerve growth factor receptor (NGFR/CD271), intercellular adhesion molecule-1 (ICAM1/CD54), and integrin-α6 (ITGA6/CD49f) were used to resolve epithelial progenitor candidates by high-dimensional flow cytometry and the gating technique of fluorescence minus one (FMO) controls., Results: A rare population of approximately 0.06% of total ethmoid cells was discriminated as EpCAM(-) CD45(-) NGFR(+) ICAM1(+) by surface markers. Use of ITGA6 was excluded based on FMO control analysis. This lineage-negative population was purified to 99% homogeneity by cell sorting and analyzed by immunofluorescence microscopy. Sorted cells were subsequently confirmed to uniformly express the transcription factor p63. Upon in vitro culture, lineage-negative clonal cells were confirmed to spontaneously differentiate into epithelial lineage-positive cells., Conclusion: Using the NGFR and ICAM1 cellular coordinates, we have identified a promising population of native human nasal epithelial progenitor cells that require more formal investigation for their role in upper airway regeneration., (© 2013 ARS-AAOA, LLC.)

Objectives: The incidence of oral tongue squamous cell carcinoma is rising in young patients. This study evaluated the clinical, pathological, and prognostic characteristics of oral tongue squamous cell carcinoma in the under-30-year age group., Materials and Methods: The computerized database of the Department of Otolaryngology-Head and Neck Surgery of a tertiary, university-affiliated medical center was searched for all patients with oral tongue squamous cell carcinoma treated by glossectomy with curative intent in 1996-2012. Data were collected by chart review., Results: Of the 113 patients identified, 16 (14%) were aged ⩽30years at presentation and 62 (55%) >60years. Mean follow-up time was 30months. Comparison by age group revealed no sex predilection and no differences in histologic grade or rates of advanced T-stage, perineural and vascular invasion, or nodal extracapsular extension. Rates of node-positive disease were 75% in the younger group and 19% in the older group (p<0.001). Kaplan-Meier analysis yielded no between-group difference in disease-free or overall survival. Recurrence was documented in a similar proportion of patients (38% and 29.9%, respectively), but half the recurrences in the younger group were distant versus none in the older group (p=0.01) All younger patients with recurrent disease died within 16months of its appearance compared to 50% 3-year disease-specific survival in the older group., Conclusions: Oral tongue squamous cell carcinoma is more advanced at presentation in younger than in older patients, with higher rates of regional metastases and distant failure. Recurrent disease is more aggressive, with a fatality rate of 100%., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Objectives/hypothesis: Acute invasive fungal sinusitis (AIFS) is an aggressive and often fatal infection. Despite improvements in medical and surgical therapy, survival remains limited and the factors that contribute to patient outcomes remain poorly understood. The current study systematically reviews and quantitatively synthesizes the published literature to characterize prognostic factors associated with survival., Study Design: Systematic review., Methods: Fifty-two studies comprising a total of 807 patients met inclusion criteria and were used for analysis of treatment, presentation, and outcomes. Univariate and multivariate logistic regression was used to identify prognostic factors., Results: All studies were classified as level 4 evidence, as per definitions provided by the Oxford Center for Evidence-Based Medicine. The most common presenting symptoms of patients with AIFS were facial swelling (64.5%), fever (62.9%), and nasal congestion (52.2%). Most patients were treated with a combination of intravenous antifungal medication and surgery. The overall survival rate was 49.7%. On univariate analysis, poor prognosis was associated with renal/liver failure, altered mental status, and intracranial extension. Patients who were diabetic, had surgery, or received liposomal amphotericin B had an improved chance of survival. On multivariate analysis, advanced age and intracranial involvement were identified as independent negative prognostic factors. Positive prognostic factors again included diabetes and surgical resection., Conclusions: The overall mortality of patients with AIFS remains high, with only half of the patients surviving. Diabetic patients appear to have a better overall survival than patients with other comorbidities. Patients who have intracranial involvement, or who do not receive surgery as part of their therapy, have a poor prognosis., Level of Evidence: N/A., (Copyright © 2013 The American Laryngological, Rhinological, and Otological Society, Inc.)

Background: Reports regarding the incidence and antibiotic susceptibility of methicillin-resistant Staphylococcus aureus (MRSA) in rhinosinusitis (RS) are limited. This study was designed to identify epidemiology and trends of MRSA incidence and antimicrobial resistance in the sinonasal cavities., Methods: This is a retrospective case series. All intranasal/sinus cultures obtained by otolaryngologists at Stanford over a 20-year period (1990-2010) were retrospectively reviewed by mining the microbiology database. Nested searches were then made for all S. aureus and MRSA cultures. Patterns of incidence and changes in antibiotic susceptibilities were tabulated and statistical analysis was performed., Results: Our search retrieved 10,387 positive intranasal culture samples, with S. aureus found in 800 (7.7%), and MRSA comprising 110 (1.06%) of this subset. Between the years of 1990 and 1999, only 2/112 (1.7%) of S. aureus-positive nasal cultures were positive for MRSA, with a sharp rise in incidence to 86/606 (14.2%) from 2000 to 2005, and to 22/82, 26.8% from 2006 to 2010. On a percent basis, using logistic regression modeling, this represents a statistically significant increasing trend (p < 0.0001) for MRSA sinusitis. However, over the 20-year interval studied, the patterns of antibiotic resistance among MRSA remained unaltered, especially with regard to trimethoprim-sulfamethoxazole and vancomycin., Conclusion: S. aureus and MRSA isolates from intranasal cultures, which were essentially absent before the year 2000, became significantly more common earlier this decade. These data show the increased role of MRSA in sinusitis. MRSA antibiotic susceptibilities have remained, however, largely stable during this time period.

Mitochondrial DNA (mtDNA) mutations were reported in different cancers. However, the nature and role of mtDNA mutation in never-smoker lung cancer patients including patients with epidermal growth factor receptor (EGFR) and KRAS gene mutation are unknown. In the present study, we sequenced entire mitochondrial genome (16.5 kb) in matched normal and tumors obtained from 30 never-smoker and 30 current-smoker lung cancer patients, and determined the mtDNA content. All the patients' samples were sequenced for KRAS (exon 2) and EGFR (exon 19 and 21) gene mutation. The impact of forced overexpression of a respiratory complex-I gene mutation was evaluated in a lung cancer cell line. We observed significantly higher (P = 0.006) mtDNA mutation in the never-smokers compared to the current-smoker lung cancer patients. MtDNA mutation was significantly higher (P = 0.026) in the never-smoker Asian compared to the current-smoker Caucasian patients' population. MtDNA mutation was significantly (P = 0.007) associated with EGFR gene mutation in the never-smoker patients. We also observed a significant increase (P = 0.037) in mtDNA content among the never-smoker lung cancer patients. The majority of the coding mtDNA mutations targeted respiratory complex-I and forced overexpression of one of these mutations resulted in increased in vitro proliferation, invasion, and superoxide production in lung cancer cells. We observed a higher prevalence and new relationship between mtDNA alterations among never-smoker lung cancer patients and EGFR gene mutation. Moreover, a representative mutation produced strong growth effects after forced overexpression in lung cancer cells. Signature mtDNA mutations provide a basis to develop novel biomarkers and therapeutic strategies for never-smoker lung cancer patients., (Copyright © 2011 Wiley Periodicals, Inc.)

Background: Failure rate of surgery for early tongue carcinoma remains high. We sought to identify patterns of failure and recurrence risk factors., Methods: Data review was carried out on 50 patients treated for early tongue carcinoma (T1/2N0M0); surgery was unsuccessful in 11 of these patients. All patients underwent transoral resection of the tongue tumor and prophylactic neck dissection (supraomohyoid)., Results: Tumor recurred within 3 to 18 months. Nine died of disease. Four had failure in neck level 4, 6 in level 1, and 1 simultaneously in level 1 and locally. Most tumors were moderately differentiated. Average depth was 6.64 mm., Conclusions: We report 11 patients with early tongue carcinoma who failed local excision with neck dissection. Failures occurred in level 4 (4 patients) and level 1 (7 patients). This group may benefit from extended neck surgery. Sex, age, stage, and depth of tumor were not significantly different in the group with treatment failure. Tumors in the group with treatment failure were more poorly differentiated., (Copyright © 2011 Wiley Periodicals, Inc.)

The methylated DNA immunoprecipitation method (MeDIP) is a genome-wide, high-resolution approach that detects DNA methylation with oligonucleotide tiling arrays or high throughput sequencing platforms. A simplified high-throughput MeDIP assay will enable translational research studies in clinics and populations, which will greatly enhance our understanding of the human methylome. We compared three commercial kits, MagMeDIP Kit TM (Diagenode), Methylated-DNA IP Kit (Zymo Research) and Methylamp™ Methylated DNA Capture Kit (Epigentek), in order to identify which one has better reliability and sensitivity for genomic DNA enrichment. Each kit was used to enrich two samples, one from fresh tissue and one from a cell line, with two different DNA amounts. The enrichment efficiency of each kit was evaluated by agarose gel band intensity after Nco I digestion and by reaction yield of methylated DNA. A successful enrichment is expected to have a 1:4 to 10:1 conversion ratio and a yield of 80% or higher. We also evaluated the hybridization efficiency to genome-wide methylation arrays in a separate cohort of tissue samples. We observed that the MagMeDIP kit had the highest yield for the two DNA amounts and for both the tissue and cell line samples, as well as for the positive control. In addition, the DNA was successfully enriched from a 1:4 to 10:1 ratio. Therefore, the MagMeDIP kit is a useful research tool that will enable clinical and public health genome-wide DNA methylation studies.

Purpose: Although promoter hypermethylation has been an accepted means of tumor suppressor gene inactivation, activation of otherwise normally repressed proto-oncogenes by promoter demethylation has been infrequently documented., Experimental Design: In this study we performed an integrative, whole-genome analysis for discovery of epigenetically activated proto-oncogenes in head and neck cancer tumors. We used the 47K GeneChip U133 Plus 2.0 Affymetrix expression microarray platform to obtain re-expression data from 5-aza treated normal cell line and expression data from primary head and neck squamous cell carcinoma (HNSCC) tumor tissues and normal mucosa tissues. We then investigated candidate genes by screening promoter regions for CpG islands and bisulfite sequencing followed by QUMSP and RT PCR for the best candidate genes. Finally, functional studies were performed on the top candidate gene., Results: From the top 178 screened candidates 96 had CpG islands in their promoter region. Seven candidate genes showed promoter region methylation in normal mucosa samples and promoter demethylation in a small cohort of primary HNSCC tissues. We then studied the demethylation of the top 3 candidate genes in an expanded cohort of 76 HNSCC tissue samples and 17 normal mucosa samples. We identified MAGEB2 as having significant promoter demethylation in primary head and neck squamous cell carcinoma tissues. We then found significantly higher expression of MAGEB2 in tumors in a separate cohort of 73 primary HNSCC tissues and 31 normal tissues. Finally, we found that MAGEB2 has growth promoting effects on minimally transformed oral keratinocyte cell lines but not a definite effect on HNSCC cell lines., Conclusion: In conclusion, we identified MAGEB2 as activated by promoter demethylation in HNSCCand demonstrates growth promoting effects in a minimally transformed oral keratinocyte cell line. More studies are needed to evaluate MAGBE2's exact role in HNSCC.

Background and Aims: Squamous cell carcinoma (SCC) of the oral tongue is one of the most frequent head and neck cancers. The over-70-year age group is the fastest growing segment of the population. Age, however, is not considered a prognostic factor in oral tongue SCC. This study investigated the clinical and histopathological characteristics, disease course, and outcome of SCC of the oral tongue in patients over 75 years old compared with younger patients., Methods: We reviewed the files of 85 patients with histologically proven SCC of the oral tongue who were treated in our department in 1992-2007 and followed for a minimum of 2 years. Findings were compared between those aged 75 years or more and younger patients., Results: Twenty-eight patients (33%) were aged 75 to 94 years (average 80.5±4.5 yrs), including 14 who were over 80 years old, and 57 patients were aged 15-74 years (average 51.1±18.2 yrs). No statistically significant differences were found between the groups in clinical or histopathological characteristics or patient outcome. The 5-year disease-free survival rate was 65% for patients over 75 and 58% for younger patients. Corresponding rates for 5-year disease-specific survival were 69% and 70%. These differences were not statistically significant., Conclusions: Patients over 75 with oral tongue SCC should be managed like younger patients in terms of clinical staging and co-morbidities. They should be given a chance for treatment, as their prognosis is no different from that of younger patients.

Objective: To study the effect of specific clinical, laboratory, and imaging parameters on the course of severe (type 1) malignant external otitis (MEO)., Study Design: Case series with chart review., Setting: Tertiary, university-affiliated medical center., Subjects and Methods: Fifty-seven patients hospitalized with severe MEO were followed for disease course and survival in a tertiary center between 1990 and 2008., Results: In 20% of patients, disease was persistent and/or aggressive despite prolonged and extensive treatment. Of this subgroup, 45% died of the disease. Prognostic factors of persistent/aggressive disease were facial nerve paralysis, bilateral disease, and significant major computed tomography findings (temporomandibular joint destruction, infratemporal fossa or nasopharyngeal soft tissue involvement). Cultures grew fungi in 5 patients, and follow-up imaging revealed disease progression. The overall 5-year survival was 55% for patients with short-term disease and 40% for patients with persistent/ aggressive disease (P = .086). By age, 5-year survival was 75% in patients younger than 70 years old and 44% in older patients (P = .029)., Conclusions: A significant subset of patients with MEO has a prolonged, aggressive, and highly fatal disease that needs to be identified early. These patients more frequently have bilateral disease, cranial nerve paralysis, and positive computed tomography findings. Their follow-up should routinely include imaging studies to evaluate disease progression, and every effort should be made to identify and treat underlying fungal infection.

Objective: To investigate the clinical characteristics and outcome of fungal malignant external otitis (MEO)., Methods: The files of 60 patients treated for MEO in 1990-2008 at a tertiary medical center were reviewed for clinical characteristics and outcome, and findings were compared between patients with fungal and nonfungal infection., Results: Mean duration of follow-up was 4 years. Nine patients (15%) had fungal disease; the main pathogen was Candida spp. Compared with the nonfungal MEO group, patients with a fungal infection were younger at diagnosis (average 68 vs. 74 years, p = 0.01) and had more facial nerve palsies (55% vs. 14%, p = 0.01), fewer positive bacterial cultures at presentation (33% vs. 75%, p = 0.02), and higher rates of surgery (78% vs. 18%, p = 0.0008) and hyperbaric treatment (78% vs. 4%, p = 0.0001). Eighty-nine percent had persistent infection (>2 courses of systemic antibiotics before antifungal treatment) compared with 12% in the nonfungal group (p = 0.0001). Fungal disease was associated with more persistently positive imaging findings (87.5% vs. 25%, p = 0.0001). There was no significant between-group difference in survival., Conclusion: Fungal MEO probably occurs secondary to prolonged antibiotic treatment for bacterial MEO. The fungal disease is more invasive than the bacterial disease, although survival is the same. Treatment should be aggressive and hyperbaric oxygen therapy should be considered., (Copyright © 2011 The British Infection Association. Published by Elsevier Ltd. All rights reserved.)

Background: Acral lentiginous melanoma (ALM) is associated with low survival., Objective: The aim of the study was to compare the clinical course of ALM, non-ALM hand and foot melanoma, and melanoma of the extremities in nonacral locations., Methods: Data on 168 patients operated on for cutaneous melanoma of the extremities from 1993 to 2005 were examined. Twenty-nine had ALM, 16 non-ALM, and 123 other-extremity melanoma. All known melanoma prognosticators were analyzed for their impact on survival at a median of 53 months' follow-up., Results: The ALM group was significantly older (p=.015). No differences between the ALM and non-ALM groups were noted in tumor characteristics, lymph node status, and survival. However, the other-extremity melanoma group presented with significantly thinner lesions, fewer positive sentinel lymph nodes, and lower tumor stage and, consequently, had significantly better disease-specific and disease-free survival (p=.006, p=.0001). The acral lesions were nearly free of peritumoral lymphocytic infiltration. Multivariate analysis identified only tumor thickness (p=.0127), stage (p=.00001), and patient age (p=.012) as independent prognosticators of disease-specific survival., Conclusion: Cutaneous melanomas in acral sites, regardless of histology, tend to be diagnosed at an advanced stage probably owing to older patient age, difficult-to-see sites, and biologic factors, leading to reduced patient survival.

Objective: To compare the characteristics and prognosis of patients with malignant (necrotizing) external otitis (MEO) with and without facial nerve palsy in today's era of third-generation antibiotics., Design: Comparative retrospective case series., Setting: Department of Otolaryngology-Head and Neck Surgery, Rabin Medical Center, a tertiary care medical center., Patients: Forty-eight patients with MEO diagnosed and treated from 1990 to 2004. Eight had facial paralysis and 40 had normal facial nerve function., Main Outcome Measures: Clinical, laboratory, and imaging findings and survival., Results: There was no statistically significant difference between patients with and without facial nerve involvement in terms of age, comorbidities, duration of complaints, physical findings, erythrocyte sedimentation rate, and bone scan findings. Computed tomography indicated a more progressive disease in patients with facial nerve involvement. However, no statistically significant between-group difference was found in overall survival., Conclusion: Although facial nerve involvement is a sign of progression of MEO, it does not, by itself, worsen prognosis.

The management of uncontrolled bleeding in trauma patients is difficult in the prehospital setting, especially when transfer time to a care facility is prolonged. The goal of treatment is to stabilize the patient until surgery can be performed. In modem practice, the major aspects of optimal patient stabilization are the timing and volume of resuscitation and the use of blood products. The main problems are the logistics of handling the blood products as well as achieving the appropriate endpoint of resuscitation, while balancing the need to maintain blood pressure with the need to avoid deleterious coagulopathy. This work reviews current therapeutic modalities for prehospital management of uncontrolled bleeding trauma patients, namely low volume resuscitation, packed red blood cells, hemoglobin solutions, perfluorocarbons, hypertonic saline solutions, and recombinant activated factor VII.

Objective: To evaluate the attitudes of Israeli intensive care physicians regarding intensive care unit (ICU) triage issues., Design: An opinion survey using questionnaires similar to those used in a previous study in the United States., Setting and Participants: Forty-three physicians, members of the Israel Society of Critical Care Medicine (45%)., Results: Important factors for admission to the last ICU bed were: small likelihood of surviving hospitalization, irreversibility of acute disorder, nature of chronic disorders and the physician's personal attitude. Most respondents would admit a patient with a predicted survival of a few weeks (70%) or a patient whose quality of life would be poor according to the physician's (98%) or patient's (77%) definition, to the last ICU bed. The personal attitude of the respondents and their own view of the patient's quality of life were considered as important as the quality of life as viewed by the patient. Israeli physicians tended to refuse patient admission into the ICU more than their US counterparts. Most Israeli physicians refused to discharge an ICU patient in order to admit another, despite bed shortage., Conclusions: The attitudes of Israeli intensive care physicians towards distribution of ICU resources differ from those of their United States counterparts; they are more paternalistic and comply less with requests for admission. Such attitudes are comparable to those expressed by some European intensive care physicians, highlighting the existence of diversity in the factors important to physicians' decision-making.

Background: Physicians' decisions regarding provision of life-sustaining treatment may be influenced considerably by non-medical variables., Objectives: To examine physicians' attitudes towards end-of-life decisions in Israel, comparing them to those found in the United States., Methods: A survey was conducted among members of the Israel Society of Critical Care Medicine using a questionnaire analogous to that used in a similar study in the USA., Results: Forty-three physicians (45%) responded, the majority of whom hold responsibility for withholding or withdrawing life-sustaining treatments. Preservation of life was considered the most important factor by 31 responders (72%). The quality of life as viewed by the patient was generally considered less important than the quality of life as viewed by the physician. Twenty-one responders (49%) considered withholding treatment more acceptable than withdrawing it. The main factors for decisions to withhold or withdraw therapy were a very low probability of survival of hospitalization, an irreversible acute disorder, and prior existence of chronic disorders. An almost similar percent of physicians (93% for Israel and 94% for the U.S.) apply Do Not Resuscitate orders in their intensive care units, but much less (28% vs. 95%) actually discuss these orders with the families of their patients., Conclusions: Critical care physicians in Israel place similar emphasis on the value of life as their U.S. counterparts and assign DNR orders with an incidence equaling that of the U.S. They differ from their U.S. counterparts in that they confer less significance to the will of the patient, and do not consult as much with families of patients regarding DNR orders.

Rifampin, in addition to interfering with intracellular growth of the ribonucleic acid-containing phage MS2, also inhibits the release of mature phage particles from Escherichia coli cells.

The release of the ribonucleic acid (RNA)-containing phage MS2 from Escherichia coli is accompanied by cellular lysis at 37 C, whereas at 30 C phage are released from intact cells. Chloramphenicol or rifampin prevents the release of progeny phage particles at both temperatures. Neither drug causes an immediate cessation of phage release and after inhibition of protein synthesis by chloramphenicol phage release proceeds for about 17 min at 37 C and about 35 min at 30 C. Rifampin does not inhibit phage release from mutant cells possessing a rifampin-resistant deoxyribonucleic acid-dependent RNA polymerase. The results indicate that a short-lived host-controlled protein(s) is essential for the release of RNA phage particles at both temperatures.