Larry Kalish

Deregulated Cyclin D1 Expression Is Associated with Decreased Efficacy of the Selective Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Gefitinib in Head and Neck Squamous Cell Carcinoma Cell Lines

Purpose: Despite promising initial results, recent Phase III trials of the selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib (“Iressa”; AstraZeneca, Wilmington, Delaware) in advanced head and neck squamous cell carcinoma (HNSCC) have been equivocal. Cyclin D1, an EGFR target gene, is frequently overexpressed in HNSCC, has been implicated in its pathogenesis, and is strongly associated with poor prognosis in this disease. Therefore, we examined the relationship between deregulated cyclin D1 expression and sensitivity to gefitinib to determine whether this frequently occurring oncogenic change affected the cellular response to gefitinib. Experimental Design: A panel of six EGFR-overexpressing HNSCC cell lines was used to correlate CCND1 gene copy number, cyclin D1 expression, and response to gefitinib. The effect of constitutive overexpression of cyclin D1 was assessed by establishing stably transfected clonal SCC-9 cell lines. Results: Three of six cell lines displayed cyclin D1 amplification and/or overexpression, and these cell lines were resistant to gefitinib. SCC 9 clones overexpressing cyclin D1 continued to proliferate and maintained their S-phase fraction when treated with gefitinib, whereas empty vector control clones and the parental SCC 9 cells were profoundly inhibited and displayed marked reductions in S-phase. The resistance of cyclin D1-overexpressing clones and cyclin D1-amplified cell lines was associated with maintenance of cyclin D1 expression after gefitinib treatment. Conclusions: These data suggest that deregulated cyclin D1 overexpression may be associated with resistance of HNSCC to EGFR inhibitors. Therefore, the role of cyclin D1 as a marker of therapeutic response and its utility as a prognostic marker in HNSCC warrant additional analysis.

Structured histopathology profiling of chronic rhinosinusitis in routine practice

Tissue eosinophilia in chronic rhinosinusitis (CRS) is a marker of inflammatory disorders recalcitrant to surgical intervention. Eosinophilic chronic rhinosinusitis (ECRS) is traditionally associated with asthma, polyps, aspirin sensitivity, high serum eosinophilia, and elevated immunoglobulin E (IgE). However, patients with ECRS may not present with these associations and there is a need to establish other surrogate markers. The objective of the study was to determine the associations between the histopathology, serology, and clinical characteristics in CRS patients.

Topical Steroids in Chronic Rhinosinusitis Without Polyps: A Systematic Review and Meta-Analysis

OBJECTIVE: To evaluate whether topical steroids provide symptomatic relief in patients with chronic rhinosinusitis without polyps. DATA SOURCES: MEDLINE, EMBASE, and Cochrane CENTRAL databases. REVIEW METHODS: Systematic review and meta-analysis was performed of the articles identified by two independent reviewers of all randomized controlled trials that had evaluated intranasal corticosteroids in patients with chronic rhinosinusitis (CRS) without polyps. The quality of included studies was evaluated, and results synthesized using standard random-effects meta-analytical methods. RESULTS: Of 424 potential studies, only nine randomized trials involving 657 patients in total were eligible. Quality of design and reporting was suboptimal, with only one trial adhering to accepted standards for reporting. Five trials combined outcome measures and reported on overall response of CRS without polyps to topical steroids. The summary estimate for overall response to treatment showed no significant benefit and substantial variability among studies (5 trials: RR 0.75, 95% CI 0.50–1.10, P = 0.14, χ2 = 13.78, I2 = 66.2%). Total symptom score was reported in three trials with a standardized mean difference favoring topical steroids (RR 0.63, 95% CI 0.16–1.09, P = 0.009), with no evidence of heterogeneity (χ2 = 3.03, P = 0.22). Although the data were limited, there were no reports of increased adverse effects with topical steroids. CONCLUSION: There is insufficient evidence to demonstrate a clear overall benefit for topical steroids in CRS without polyps; however, their use appears safe and may show some symptomatic benefit. A class effect among different topical steroids cannot be assumed, and further trials are required.

Sinus surgery and delivery method influence the effectiveness of topical corticosteroids for chronic rhinosinusitis: systematic review and meta-analysis.

Background Published randomized controlled trials (RCTs) on the efficacy of intranasal corticosteroid (INCS) in chronic rhinosinusitis (CRS) use either nasal delivery (nasal drop or nasal spray) or sinus delivery (sinus catheter or sinus irrigation) in patients with or without sinus surgery. This influences topical drug delivery and distribution. The effect of these factors on the published results of RCTs is assessed. This systematic review explores the strength of evidence supporting the influence of sinus surgery and delivery methods on the effectiveness of topical steroids in studies for CRS with meta-analyses. Methods A systematic review was conducted of RCTs comparing INCS with either placebo or no intervention for treating CRS. Data were extracted for meta-analysis and subgroup analyses by sinus surgery status and topical delivery methods. Results Forty-eight studies (3961 patients) met the inclusion criteria. INCS improved overall symptoms (standardized mean difference [SMD], −0.49; p < 0.00001) and the proportion of responders (risk ratio [RR], 0.59; p < 0.00001) compared with placebo. It decreased nasal polyp size with a greater proportion of responders (RR, 0.48; p < 0.00001) and prevented polyp recurrence (RR, 0.59; p = 0.0004) compared with placebo. Reduction of polyp size was greater in patients with sinus surgery (RR, 0.31; 95% confidence interval [CI], 0.20, 0.48) than those without (RR, 0.61; 95% CI, 0.46, 0.81; p = 0.009). Greater symptom improvement occurred when sinus delivery methods (SMD, −1.32; 95% CI, −2.26, −0.38) were compared with nasal delivery methods (SMD, −0.38; 95% CI, −0.55, −0.22; p < 0.00001). Conclusion INCS is effective for CRS. Prior sinus surgery and direct sinus delivery enhance the effectiveness of INCS in CRS.

Interleukin-25 and interleukin-33 as mediators of eosinophilic inflammation in chronic rhinosinusitis.

Background The initiating mediators of T-helper 2 inflammation, often seen in eosinophillic chronic rhinosinusitis (CRS), remains poorly understood. Interleukin (IL) 25, IL-33, and thymic stromal lymphopoietin (TSLP) are epithelial-derived cytokines implicated in the initiation of T-helper 2 inflammation and eosinophilia in other diseases. The expression of these cytokines was compared with phenotypic and histopathologic markers to investigate the factors that may drive eosinophilic inflammation in CRS. Method Sinus mucosal samples from patients with CRS who were undergoing sinus surgery as part of their management were analyzed for IL-25, IL-33, and TSLP messenger RNA (mRNA) expression by quantitative polymerase chain reaction. Patients with tumor and who were undergoing surgery via an endonasal approach with normal sinus mucosa were controls. The mRNA expression was compared with CRS phenotype and histopathologic measures of eosinophilic inflammation. Immunohistochemical staining was used to confirm mRNA expression. Results Thirty-nine patients (mean ± standard deviation age; 48.2 ± 15.0 years, 38% women), 12 patients with CRS with nasal polyps, 20 patients with CRS without nasal polyps, and 7 controls were recruited. Higher IL-25 (p = 0.005) and IL-33 (p = 0.003) mRNA and protein expression was observed in patients with >10 eosinophil/hpf. TSLP showed no significant associations (p = 0.39). Similar overexpression was seen in eosinophilic dominated inflammation (IL-25, p = 0.01; IL-33, p = 0.02) and patients with greater inflammatory severity. Conclusion IL-25 and IL-33 overexpression was observed in eosinophilic CRS, The release of these cytokines by dysfunctional endothelium may perpetuate the eosinophillic inflammation in CRS.

The outside-in approach to the modified endoscopic Lothrop procedure.

Drilling in modified endoscopic Lothrop procedure (MELP) is traditionally described as commencing from the frontal recess (FR). This is challenging when the FR is involved by tumor, inflammatory disease, or scarring. The outside‐in MELP, where the limits of the sinusotomy are first defined and the FR is addressed last, is described.

p14ARF Protein Expression Is a Predictor of Both Relapse and Survival in Squamous Cell Carcinoma of the Anterior Tongue

Purpose: The INK4A-ARF locus at chromosome 9p21 is frequently altered in head and neck squamous cell carcinoma (SCC) and encodes two distinct tumor suppressors, p16INK4A and p14ARF. This study addressed the role of p14ARF as a potential prognostic marker in this disease. Experimental Design: p14ARF protein expression was assessed by immunohistochemistry in a cohort of 140 patients with SCC of the anterior tongue. Using univariate and multivariate Coxs proportional hazards models, the outcomes examined were time to disease recurrence or death, with or without clinicopathologic covariates, including nodal status, disease stage, treatment status, Ki-67 staining, and molecular markers with known functional or genetic relationships with p14ARF (p16INK4A, p53, pRb, p21WAF1/CIP1, E2F-1). Results: On multivariate analysis, p14ARF positivity (nucleolar p14ARF staining and/or nuclear p14ARF staining in ≥30% of tumor cells) was an independent predictor of improved disease-free survival (DFS; P = 0.002) and overall survival (OS; P = 0.002). This was further enhanced when p14ARF positivity was cosegregated with positive (≥1%) p16INK4A staining (DFS, P < 0.001; OS, P < 0.001). Patients whose cancers were p14ARF negative and p53 positive (>50%) had the poorest outcome (DFS, P < 0.001; OS, P < 0.001) of any patient subgroup analyzed. Conclusions: These data show that in patients with SCC of the tongue, combined nuclear and nucleolar expression of p14ARF protein predicts for improved DFS and OS independent of established prognostic markers.

Intranasal corticosteroids do not affect intraocular pressure or lens opacity: a systematic review of controlled trials.

BACKGROUND Intranasal corticosteroids (INCS) are prescribed for the long-term prophylactic treatment of inflammatory upper airway conditions. Although some systemic absorption can occur via topical routes, the clinical relevance is controversial. The effects of orally administered corticosteroids on intraocular pressure (IOP) and lens opacity (LO) are well established, but the impact of the INCS is less well defined. This study aims to systematically review the literature for evidence of adverse occular events with INCS use. METHODOLOGY A systematic review of literature from Medline and Embase databases (January 1974 to 21st of November 2013) was performed. Using the PRISMA guidelines, all controlled clinical trials of patients using INCS, that reported original measures of IOP, LO, glaucoma or cataract incidences were included. Studies with adjuvant administration of oral, inhaled and intravenous steroids were excluded. RESULTS 665 articles were retrieved with 137 were considered for full-text review. Of these, 116 (85%) were literature reviews and two were case reports. 19 studies (10 RCTs, 1 case-control, 8 case series) were included for the qualitative review, of which 18 reported data on IOP and 10 on cataract/LO. None (n=0) of the 10 RCT reporting data on glaucoma or IOP demonstrated changes in IOP compared to control. Also none (n=0) of the 6 RCTs reporting cataract or lens opacity demonstrated changes compared to control. CONCLUSION Data from studies with low levels of bias, do not demonstrate a clinically relevant impact of INCS on neither ocular pressure, glaucoma, lens opacity nor cataract formation.

Radiological Features of the Intraosseous Lipoma of the Sphenoid

Objective. Benign intraosseous lesions of the skull base are often identified in the course of routine radiological investigation. Imaging features associated with suspected intraosseous lipoma (IOL) can mimic more aggressive pathology. The features of this poorly described entity in the skull base were analyzed to aid the otolaryngologist in differentiation from other pathology. Study Design. Retrospective analysis of computed tomography (CT) and magnetic resonance imaging (MRI) images over the period from March 2007 to March 2009. Setting. Radiology service, tertiary hospital, Sydney, Australia. Methods. Images with diagnosis of incidental suspected IOL within the sphenoid were selected. Radiological features including trabecular pattern, secondary calcification, cortical bone thinning, and size and the presence of fat (defined as <−5 HU) were recorded. Results. Ten patients (5 male) were identified. Seventy percent had unilateral, single lesions occurring within the sphenoid bone. The mean size was 13.1 ± 5.6 mm (range, 4-21 mm). Fat was demonstrated in all lesions. There were 3 cases of multiple lesions occurring within the sphenoid bone. In addition, 61.5% were associated with cortical bone thinning and 46.2% with secondary calcification within the lesion. Changes to normal trabecular bone occurred: 46.2% with a partial loss of and 53.8% with a complete absence of trabecular pattern. Histopathologic confirmation of IOL is presented. Conclusion. IOL is believed to be a more common benign intraosseous lesion within the skull base than previously reported. Cortical bone thinning and other features normally suggestive of aggressive pathology commonly occur. Otolaryngologists should be aware of these common lesions to avoid unnecessary further investigation.

Modified Lund Mackay Postoperative Endoscopy Score for defining inflammatory burden in chronic rhinosinusitis

BACKGROUND According to the Federal Institution of Health Insurance, ENT doctors perform more skin prick tests for the diagnosis of allergic rhinitis (AR) than other medical specialties in Belgium. However, immunotherapy (IT) is not practiced by all. This study aims to obtain insight into IT practice by ENT doctors, the type of IT performed and the reasons not to perform IT. METHODOLOGY A questionnaire was sent to all registered ENT doctors of Belgium (n=648), involving questions on type and duration of ENT practice, geography and gender. In addition, the questionnaire informed about diagnosis of AR, indication for IT, type of IT performed, and reasons not to perform IT and referral pattern. RESULTS The response rate among ENT doctors was 54%, with 7% of responders being excluded as they do not diagnose AR. 81% of Belgian ENT doctors make the indication for IT in AR patients, with 19% neglecting the indication for IT in AR patients. The two main reasons for not indicating IT are lack of expertise and the perception of high costs associated with IT. 70% of ENT specialists are practicing IT themselves, with sublingual IT being mostly performed. Interestingly, IT is mostly frequently performed by those ENT doctors with long-standing ENT practice, in private practice and in Wallonia. CONCLUSION Despite the high prevalence of AR in ENT practice, IT is most frequently performed by ENT doctors with longstanding practice, working in private practice and/or in the French speaking part of Belgium. Among the different types of IT, sublingual IT is the most frequently performed means of IT by ENT doctors.OBJECTIVE To investigate the role of inflammation in non-allergic rhinitis (NAR) patients in a large series to establish the prevalence of different NAR-subtypes, clinical features and the role of nasal cytology in the diagnostic algorithm. METHODOLOGY Patients were selected out of 3650 individuals who spontaneously presented at our institution. We consecutively enrolled 519 NAR-patients in an analytical cross-sectional study between November 2007 and June 2013 (level of evidence: 3b). All patients underwent rhinological evaluation including symptoms questionnaire, endoscopy, CT scan, allergy tests and nasal cytology. RESULTS The inflammatory cell infiltrate affects the severity of symptoms differently, allowing for identification of different phenotypes of NAR. We distinguished two groups: “NAR without inflammation”(NAR-) and “NAR with inflammation”(NAR+), in addition to different NAR-subtypes with inflammation. A significant difference was observed in terms of clinical symptoms and association with comorbidities (previously diagnosed asthma and aspirin intolerance) between NAR–, NAR+ and between different NAR+ subtypes. CONCLUSION Our data suggest that NAR- and NAR with neutrophils behave similarly, showing lower symptom score values and a lower risk of association with comorbidities compared to NAR with eosinophils and mast cells (singularly or mixed). In our belief it is very important to establish the presence and type of inflammation in non-allergic rhinitis patients and nasal cytology is a very useful test in correct differential diagnosis.OBJECTIVE To assess the applicability of the Peak Nasal Inspiratory Flow (PNIF) curves in follow-up of children in the treatment of allergic rhinitis. METHODS Prospective study of 40 patients with AR, grouped in corticosteroid spray versus physiological saline solution use. Follow up for 10 weeks through clinical score and PNIF percentages in relation to the reference curves, with was-out at week 8. Statistical assessment of the effect of treatment on variation of PNIF and clinical score was calculated by ANOVA model and Multiple Comparison of Means Test - Least Significant Difference. RESULTS There was a statistically significant influence of the group, time and interaction between time and group on PNIF percentages. Throughout follow up, patients from the treatment group had mean PNIF percentages significantly higher than the placebo group. Clinical score results also demonstrated a statistically significant influence between the groups, time and interaction between time and group. CONCLUSION Increase in PNIF percentage values observed in children treated with intranasal corticosteroids revealed the applicability of PNIF curves in their follow up.OBJECTIVE This study aims to examine humans ́ abilities to localize odorants within the open field. METHODOLOGY Young participants were tested on a localization task using a relatively selective olfactory stimulus (2-phenylethyl-alcohol, PEA) and cineol, an odorant with a strong trigeminal component. Participants were blindfolded and had to localize an odorant source at 2 m distance (far-field condition) and a 0.4 m distance (near-field condition) with either two nostrils open or only one open nostril. RESULTS For the odorant with trigeminal properties, the number of correct trials did not differ when one or both nostrils were used, while more PEA localization trials were correctly completed with both rather than one nostril. In the near-field condition, correct localization was possible in 72-80% of the trials, irrespective of the odorant and the number of nostrils used. Localization accuracy, measured as spatial deviation from the olfactory source, was significantly higher in the near-field compared to the far-field condition, but independent of the odorant being localized. CONCLUSION Odorant localization within the open field is difficult, but possible. In contrast to the general view, humans seem to be able to exploit the two-nostril advantage with increasing task difficulty.BACKGROUND This study was designed to assess if illness perception, mood state and coping strategies differ according to allergic rhinitis (AR) persistence and severity. METHODS Illness perception, mood profiles, coping behaviors and rhinitis symptoms were assessed by means of validated tools inpatients classified according to the Allergic Rhinitis and Its Impact on Asthma (ARIA) guidelines. RESULTS Two hundred and thirty-one patients underwent data analysis. No difference in age, sex, socio-economic status, smoking habits was detected comparing patients according to AR severity, duration or 4 ARIA classes. Patients with intermittent AR reported higher scores than those with persistent AR in confusion-bewilderment of Profile of Mood States (POMS); patients with moderate/severe rhinitis had significantly higher scores than those with mild rhinitis in TSSS, Identity and Consequences. No differences were detected in all assessed outcomes in the 4 ARIA classes. CONCLUSIONS The patients perspective about AR is independent of persistence and severity of symptoms. This may explain why AR remains under-diagnosed and under-treated, even in its most severe forms. Self-management plans should consider the patients perspective.The assessment of Chronic Rhinosinusitis, like any other disease, may involve multiple possible disease manifestations, including subjective patient-reported outcomes, objective disease (e.g. endoscopy or radiographic), and physician-driven (e.g. need for systemic medications). Disease control is often used as a global metric of disease burden and represents the extent to which disease manifestations are within an acceptable range. Achieving control is an important treatment goal.The European Position Paper on Rhinosinusitis and Nasal Polyps 2020 is the update of similar evidence based position papers published in 2005 and 2007 and 2012(1-3). The core objective of the EPOS2020 guideline is to provide revised, up-to-date and clear evidence-based recommendations and integrated care pathways in ARS and CRS. EPOS2020 provides an update on the literature published and studies undertaken in the eight years since the EPOS2012 position paper was published and addresses areas not extensively covered in EPOS2012 such as paediatric CRS and sinus surgery. EPOS2020 also involves new stakeholders, including pharmacists and patients, and addresses new target users who have become more involved in the management and treatment of rhinosinusitis since the publication of the last EPOS document, including pharmacists, nurses, specialised care givers and indeed patients themselves, who employ increasing self-management of their condition using over the counter treatments. The document provides suggestions for future research in this area and offers updated guidance for definitions and outcome measurements in research in different settings.BACKGROUND Endoscopic dacryocystorhinostomy (EN-DCR) is a commonly used procedure in the treatment of nasolacrimal duct obstruction (NLDO). However, there is no generally accepted disease-specific questionnaire for assessing outcomes. METHODOLOGY We conducted a prospective study to initially validate a Nasolacrimal Duct Obstruction Symptom Score questionnaire(NLDO-SS) and to evaluate the long-term success of EN-DCR procedures. Seventy-six patients (86 eyes) were evaluated in follow-up visits at 1-8 years after EN-DCR. The patients completed the NLDO-SS questionnaire twice, first, at home and, second,after receiving information from the otorhinolaryngologist, during the visit. The surgical outcome was considered successful if the irrigation succeeded and if the patient symptoms were relieved as assessed with the NLDO-SS. RESULTS The diagnostic accuracy of the NLDO-SS was 84%, sensitivity 82%, specificity 85%, positive predictive value 58%, negative predictive value 95%, odds ratio 26, risk ratio 11 and usefulness index 0.55. Cronbachs alpha was 0.85, and the test-retest reliability coefficient was 0.87. The long-term success rate after EN-DCR was 79%. CONCLUSION The NLDO-SS iss a feasible clinical tool in assessing the success of EN-DCR. The success rate was found to decrease EN-DCR at long-term follow-up.