Psychometric properties of the Norwegian translation of the Tinnitus Handicap Inventory (THI-NOR).

OBJECTIVE: To assess the psychometric properties of a Norwegian translation of the Tinnitus Handicap Inventory (THI-NOR). DESIGN: A survey was sent by post to patients referred with tinnitus as their main complaint to an audiology department. Patients completed a Norwegian version of the Tinnitus Handicap Inventory (THI-NOR), a Norwegian translation of two revised subscales of the Abbreviated profile of hearing aid benefit (APHAB), the General Health Questionnaire (GHQ-12) as well as questionnaires measuring coping expectancies (TOMCATS) and neuroticism (EPI). STUDY SAMPLE: Ninety-nine persons with tinnitus. RESULTS: No associations were found between THI-scores or pure-tone audiometry, gender or age. The proposed subscales of the original THI were not formed by responses from responders. The total scale shows good psychometric properties. Significant correlations were found between distress as measured by the GHQ-12, coping expectancies as measured by TOMCATS and neuroticism as measured by EPI and THI scores. CONCLUSIONS: THI-NOR has psychometric properties similar to those of the Danish translation (THI-DK), from which it was adapted, and to the original THI. THI-NOR seems to be a valid measure of the impact of tinnitus on a person's everyday life. Findings show that the suggested subscales of the questionnaire should be interpreted with caution.

Psychometric properties for the Norwegian translations of two revised APHAB-subscales and an adapted IOI-HA (IOI-CI) in patients with cochlear implants.

OBJECTIVE: The objective was to examine the psychometric properties of two questionnaires in Norwegian for the self-assessment of satisfaction following cochlear implantation. DESIGN: The International Outcome Inventory for Hearing Aids adapted for cochlear implants (IOI-CI) and two revised subscales from the Norwegian translation of the Abbreviated Profile of Hearing Aid Benefit (APHAB) were applied. Internal consistency was tested using Cronbach's α. Testing of psychometric properties included the calculation of inter-item correlations and corrected item-total correlations. Spearman's rho was used to investigate associations. Exploratory principal component analyses with Kaiser normalisation were performed. STUDY SAMPLE: One hundred and twenty-one patients (51 males) with cochlear implants (27-88 years, M = 59). RESULTS: For IOI-CI, Cronbach's α was 0.79. Corrected item-total correlations ranged from 0.29 to 0.69. The factor analysis revealed two components. For APHAB, Cronbach's α was 0.91. Two components were revealed by the factor analysis. Corrected item-total correlations for the two subscales "communication in quiet situations" and "communication in adverse situations" were 0.47-0.81 and 0.58-0.80, respectively. The convergent validity of the questionnaires was adequate as reflected by a Spearman's coefficient of 0.67. CONCLUSION: Both questionnaires show good psychometric properties.

Importance of personality and coping expectancy on patient-reported hearing disability, quality of life and distress level: a study of patients referred to an audiology service.

PURPOSE: According to the World Health Organization (WHO), hearing loss (HL) affects up to 15% of the world's adult population. Coping and personality are hypothesized to underlie quality of life (QoL) and distress scores. We aimed to study the importance of personality and coping in persons with HL for self-reported hearing disability, QoL, and distress. METHODS: A cross-sectional survey was carried out, including one hundred and fifty-eight adults seeking hearing aids. Pure-tone average hearing thresholds (PTA) were determined for each ear. A revised version of the Abbreviated Profile of Hearing Aid Benefit (APHAB) served as a measure of self-reported hearing disability. Further, the generic part of the European Organization for Research and Treatment (EORTC) QoL questionnaire and the General Health Questionnaire (GHQ) (distress measure) were answered. Levels of neuroticism and the Theoretically Originated Measure of the Cognitive Activation Theory of Stress (TOMCATS) coping expectancy were determined. RESULTS: Hearing disability was determined by PTA (better ear) and level of neuroticism. Distress and QoL were determined by neuroticism and coping. CONCLUSION: More neuroticism was associated with worse outcome for the variables hearing disability, distress, and QoL. Helplessness and hopelessness were associated with worse hearing disability, increased distress, and lowered QoL. Patient reported hearing disability was also associated with PTA (better ear). There is a need to investigate further the associations between hearing disability and QoL to psychosocial parameters.

EORTC Quality of Life Questionnaire Head and Neck (H&N)-35 scores from H&N squamous cell carcinoma patients obtained at diagnosis and at 6, 9 and 12 months following diagnosis predict 10-year overall survival.

PURPOSE: To study the 10-year overall survival predictions, and mechanisms behind, of head and neck (HN) quality of life (QoL) scores obtained at diagnosis and 6, 9, and 12 months following diagnosis in a cohort of HN squamous cell carcinoma (HNSCC) patients. METHODS: Consecutive HNSCC patients (N = 109) subjected to standard workup and treatment self-reported their QoL measured by the EORTC Quality of Life Questionnaire (QLQ) H&N-35 between November 2002 and June 2005. Each QoL index was calculated and additionally aggregated to one sum score. The included patients were at diagnosis younger than 78 years, judged adequately cognitive functioning, and scheduled for curative treatment. Self-reported smoking, alcohol consumption, and socio-demographic information were registered. Twenty-two patients were high-risk (hr)-HPV DNA tumor positive. If the treatment goal was changed to palliative, no new QoL information was collected. All living patients were followed until 10 years after diagnosis. RESULTS: Median survival was 105 months. Significant overall survival predictions were found from the EORTC H&N-35 QLQ sum scores continuously measured at diagnosis (p = 0.006) and obtained at 6 (p = 0.02), 9 (p = 0.002) and 12 (p = 0.05) months. Lower QoL predicted lower overall survival. These sum score survival predictions were in part independent of TNM stage, hr-HPV status, gender, age, alcohol and smoking status. The indices "pain", "swallowing", "social eating", and "feeling ill" were predictive of survival at 3 out of 4 measuring points (diagnosis, 6, 9 and 12 months) in univariate analyses. CONCLUSION: EORTC H&N-35 QLQ scores at diagnosis and throughout the first year thereafter harbor prognostic power.

Quality of life in persons with hearing loss: a study of patients referred to an audiological service.

Objective: To investigate the relationship between hearing loss (HL) and general quality of life (QoL) in adults seeking hearing aids (HAs). Design: The patients completed the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire's general part and a questionnaire measuring self-assessed communication ability (Abbreviated Profile of hearing Aid Benefit-APHAB). These responses were compared with EORTC scores from a general population and patients with former head and neck cancer. Study sample: One-hundred and fifty-eight adults with HL were recruited prior to hearing aid (HA) fitting with one half seeking renewal of their HA. Results: General QoL scores among patients with HL were similar to those in the general population, but higher than in many chronic serious diseases. Patients with unilateral HL reported slightly worse social function and more fatigue than patients with bilateral HL. Self-assessed communication ability correlated with general QoL scores. Also, we found that best ear pure tone average (PTA), cognitive and physical QoL function predicted APHAB scores. Conclusion: In the investigated HL group, general QoL scores seem to be relatively close to those seen in the general population.

Generic quality of life in persons with hearing loss: a systematic literature review.

BACKGROUND: To the best of our knowledge, no empirically based consensus has been reached as to if, and to what extent, persons with hearing loss (HL) have reduced generic Quality of life (QoL). There seems to be limited knowledge regarding to what extent a hearing aid (HA) would improve QoL. The main aim of the present study was to review studies about the relationship between HL and QoL. A supporting aim was to study the association between distress and HL. METHODS: Literature databases (Cinahl, Pub Med and Web of Science) were searched to identify relevant journal articles published in the period from January 2000 to March 17, 2016. We performed a primary search pertaining to the relationship between HL, HA and QoL (search number one) followed by a supporting search pertaining to the relationship between distress/mood/anxiety and HL (search number two). After checking for duplications and screening the titles of the papers, we read the abstracts of the remaining papers. The most relevant papers were read thoroughly, leaving us with the journal articles that met the inclusion criteria. RESULTS: Twenty journal articles were included in the present review: 13 were found in the primary search (HL and QoL), and seven in the supporting search (HL and distress). The literature yields equivocal findings regarding the association between generic QoL and HL. A strong association between distress and HL was shown, where distressed persons tend to have a lowered generic QoL. It is suggested that QoL is lowered among HL patients. Some studies suggest an increased generic QoL following the use of HA, especially during the first few months after initiation of treatment. Other studies suggest that HA use is one of several possible factors that contribute to improve generic QoL. CONCLUSIONS: The majority of the studies suggest that HL is associated with reduced generic QoL. Using hearing aids seem to improve general QoL at follow-up within the first year. HL is a risk factor for distress. Further research is needed to explore the relationship between HL and generic QoL, in addition to the importance of influencing variables on this relationship.

General health-related quality of life scores from head and neck squamous cell carcinoma patients obtained throughout the first year following diagnosis predicted up to 10-year overall survival.

OBJECTIVES: To evaluate the 5- and 10-year survival prediction of health-related quality of life (HRQoL) scores obtained at diagnosis and at 6, 9 and 12 months after diagnosis in a cohort of curable head and neck squamous cell carcinoma (HNSCC) patients. MATERIALS AND METHODS: HNSCC patients (n = 109) reported their HRQoL measured by the EORTC Quality of Life Questionnaire (QLQ) general (C30) questionnaire. At diagnosis, the included patients were below 78 years of age and at diagnosis planned treated with curative intent. Clinical variables and self-reported smoking, alcohol consumption and socio-demographic information were registered. From diagnostic blocks, we found 22 patients to be human papillomavirus (HPV) positive. New HRQoL scores were not obtained if the patient treatment changed from curative to palliative throughout the HRQoL data acquisition. Survival was determined from the National Population Register of Norway. RESULTS: Decreased survival with low HRQoL scores from EORTC QLQ scores was demonstrated with HRQoL scores obtained from different time points of the four time points studied. These survival predictions were mostly independent of HPV status, gender, age, TNM stage, tumor site, alcohol consumption, present smoking status and whether comorbidities were present at diagnosis; as well as to some extent with an adjustment of the same HRQoL score/index obtained at diagnosis. The specific indices "physical function", "general pain" and "sleep disturbance" were in particular predictive of survival. CONCLUSION: HRQoL scores obtained throughout the first year after diagnosis contained prognostic power to overall survival when measured both at 5 and 10 years of observation.

Primary surgery results in no survival benefit compared to primary radiation for oropharyngeal cancer patients stratified by high-risk human papilloma virus status.

We changed the primary oropharynx squamous cell carcinoma (OPSCC) treatment recommendation from primary radiation therapy (RT) to tumor surgery and neck dissection, followed by RT around the year 2000 with apparently improved survival. However, high-risk human papilloma virus (hr-HPV)-16-caused OPSCCs have increased during this period. Furthermore, hr-HPV+ OPSCC carry a better prognosis than hr-HPV-negative patients. We have, therefore, evaluated the 5-year survival in the period from 1992 to 1999 versus 2000 to 2008 stratified by hr-HPV tumor infection status. Ninety-six OPSCC patients were treated from 1992 to 1999 compared with 136 patients from 2000 to 2008. The 5-year disease-specific survival (DDS) and overall survival (OS) were recorded, while the health-related quality of life (HRQoL) scores were obtained from some of the cured patients. Thirty-eight (40 %) in the first period and 86 OPSCCs (63 %) in the second period were hr-HPV+. In the first period, 16 versus 62 patients in the last period were treated by neck dissection, primary tumor surgery, and RT. DSS among all the hr-HPV-negative patients in the first period was 51 versus 55 % in the second period, and the corresponding OS was 33 versus 31 %, respectively. The DSS among all the hr-HPV+ patients was 78 % in the first period versus 77 % in the second period, while the OS was 71 versus 69 %, respectively. The HRQoL scores among successfully treated patients were worse following surgery, plus RT than RT only. The hr-HPV-adjusted 5-year survival in OPSCC patients was similar between the two time periods. A decreased HRQoL was associated with surgical therapy, which indicates that hr-HPV+ OPSCC patients may be treated by primary RT followed by major surgery only if RT treatment fails.

Live Attenuated Influenza Vaccine in Children Induces B-Cell Responses in Tonsils.

BACKGROUND: Tonsils play a key role in eliciting immune responses against respiratory pathogens. Little is known about how tonsils contribute to the local immune response after intranasal vaccination. Here, we uniquely report the mucosal humoral responses in tonsils and saliva after intranasal live attenuated influenza vaccine (LAIV) vaccination in children. METHODS: Blood, saliva, and tonsils samples were collected from 39 children before and after LAIV vaccination and from 16 age-matched, nonvaccinated controls. Serum antibody responses were determined by a hemagglutination inhibition (HI) assay. The salivary immunoglobulin A (IgA) level was measured by an enzyme-linked immunosorbent assay. Antibody-secreting cell (ASC) and memory B-cell (MBC) responses were enumerated in tonsils and blood. RESULTS: Significant increases were observed in levels of serum antibodies and salivary IgA to influenza A(H3N2) and influenza B virus strains as early as 14 days after vaccination but not to influenza A(H1N1). Influenza virus-specific salivary IgA levels correlated with serum HI responses, making this a new possible indicator of vaccine immunogenicity in children. LAIV augmented influenza virus-specific B-cell responses in tonsils and blood. Tonsillar MBC responses correlated with systemic MBC and serological responses. Naive children showed significant increases in MBC counts after LAIV vaccination. CONCLUSIONS: This is the first study to demonstrate that LAIV elicits humoral B-cell responses in tonsils of young children. Furthermore, salivary IgA analysis represents an easy method for measuring immunogenicity after vaccination.

The Norwegian Voice Handicap Index (VHI-N) patient scores are dependent on voice-related disease group.

The aim of this study is to determine to what extent the Voice Handicap Index-Norwegian (VHI-N) is scored depending on specific laryngological disease. In a multi-center study, 126 healthy subjects and 355 patients with different voice-related diseases answered the VHI-N. The VHI-N scores showed high Cronbach's alpha. Analyses of variance were performed with VHI-N dependent and specific voice-related disease as independent variable, and showed highly significant dependence by group allocation (F(7,461) = 28.0; p < 0.001). When studying post hoc analyses secondary to this ANOVA analysis, we have shown that the control group scored lower than the entire patient groups (all p < 0.001) except the dysplasia group. Aphonic patients scored higher than all the other groups (all p < 0.001) except those with spasmodic dysphonia. The cancer patient group furthermore scored lower than patient groups with recurrent palsy, dysfunctional disease or spasmodic dysphonia (all p < 0.001). In addition, patients with recurrent palsy scored higher than patients with degenerative/inflammatory disease (p < 0.001). No influences of patient age, gender, or smoking were observed in the VHI-N scores. The VHI-N is a psychometrically well-functioning instrument, also at disease-specific levels and discriminates well between health and voice diseases, as well as between different voice-related diseases. The VHI-N may be recommended to be used when monitoring voice-related disease treatment.

Plasma IL-1 and IL-6 Family Cytokines with Soluble Receptor Levels at Diagnosis in Head and Neck Squamous Cell Carcinoma: High Levels Predict Decreased Five-Year Disease-Specific and Overall Survival.

Activation of the acute-phase cascade (APC) has been correlated with outcomes in various cancers, including head and neck squamous cell carcinoma (HNSCC). Primary drivers of the APC are the cytokines within the interleukin-6 (IL-6) and IL-1 families. Plasma levels of IL-6 family cytokines/soluble receptors (IL-6, IL-27, IL-31, OSM, CNTF, soluble (s-)gp130, s-IL-6Rα) and IL-1 family members (IL-1RA, s-IL-33Rα) were determined at diagnosis for 87 human papillomavirus (HPV)-negative (-) HNSCC patients. We then studied the 5-year Disease-Specific Survival (DSS) and Overall Survival (OS). Increased plasma levels of IL-6 (p < 0.001/p < 0.001) (DSS/OS), IL-31 (p = 0.044/p = 0.07), IL-1RA (p = 0.004/p = 0.035), soluble (s)-IL-6Rα p = 0.022/p = 0.035), and s-gp130 (p = 0.007/p = 0.003) at diagnosis were predictors of both OS and DSS from HPV(-) HNSCC patients. The cytokine DSS/OS predictions were associated with TNM stage and smoking history, whereas the soluble receptors IL-6Rα, gp130, and IL33Rα more uniquely predicted DSS/OS. Clinically, IL-6 levels above 2.5 pg/mL yielded 75% specificity and 70% sensitivity for DSS. In conclusion, high plasma levels of IL-6, IL-31, and IL-1RA, as well as the soluble receptors IL-6Rα, gp130, and IL33Rα, predicted clinical outcome. This shows their potential as candidates for both general therapy and immune therapy stratification, as well as being future platforms for the development of new immunotherapy.

Development of a high dimensional imaging mass cytometry panel to investigate spatial organization of tissue microenvironment in formalin-fixed archival clinical tissues.

To decipher the interactions between various components of the tumor microenvironment (TME) and tumor cells in a preserved spatial context, a multiparametric approach is essential. In this pursuit, imaging mass cytometry (IMC) emerges as a valuable tool, capable of concurrently analyzing up to 40 parameters at subcellular resolution. In this study, a set of antibodies was selected to spatially resolve multiple cell types and TME elements, including a comprehensive panel targeted at dissecting the heterogeneity of cancer-associated fibroblasts (CAF), a pivotal TME component. This antibody panel was standardized and optimized using formalin-fixed paraffin-embedded tissue (FFPE) samples from different organs/lesions known to express the markers of interest. The final composition of the antibody panel was determined based on the performance of conjugated antibodies in both immunohistochemistry (IHC) and IMC. Tissue images were segmented employing the Steinbock framework. Unsupervised clustering of single-cell data was carried out using a bioinformatics pipeline developed in R program. This paper provides a detailed description of the staining procedure and analysis workflow. Subsequently, the panel underwent validation on clinical FFPE samples from head and neck squamous cell carcinoma (HNSCC). The panel and bioinformatics pipeline established here proved to be robust in characterizing different TME components of HNSCC while maintaining a high degree of spatial detail. The platform we describe shows promise for understanding the clinical implications of TMA heterogeneity in large patient cohorts with FFPE tissues available in diagnostic biobanks worldwide.

The TP53 Codon 72 Arginine Polymorphism Is Found with Increased TP53 Somatic Mutations in HPV(-) and in an Increased Percentage among HPV(+) Norwegian HNSCC Patients.

BACKGROUND: Somatic TP53 mutations are frequent in head and neck squamous cell carcinoma (HNSCC) and are important pathogenic factors. OBJECTIVE: To study TP53 mutations relative to the presence of human papillomavirus (HPV) in tumors in HNSCC patients. METHODS: Using a custom-made next-generation sequencing (NGS) panel on formalin-fixed, paraffin-embedded tumor tissue, we analyzed somatic TP53 mutations and the TP53 single-nucleotide polymorphism (SNP) codon 72 (P72R; rs1042522) (proline → arginine) from 104 patients with HNSCC. RESULTS: Only 2 of 44 patients with HPV-positive (HPV(+)) HNSCC had a TP53 somatic mutation, as opposed to 42/60 HPV-negative (HPV(-)) HNSCC patients (p < 0.001). Forty-five different TP53 somatic mutations were detected. Furthermore, in HPV(-) patients, we determined an 80% prevalence of somatic TP53 mutations in the TP53 R72 polymorphism cohort versus 40% in the TP53 P72 cohort (p = 0.001). A higher percentage of patients with oral cavity SCC had TP53 mutations than HPV(-) oropharyngeal (OP) SCC patients (p = 0.012). Furthermore, 39/44 HPV(+) tumor patients harbored the TP53 R72 polymorphism in contrast to 42/60 patients in the HPV(-) group (p = 0.024). CONCLUSIONS: Our observations show that TP53 R72 polymorphism is associated with a tumor being HPV(+). We also report a higher percentage of somatic TP53 mutations with R72 than P72 in HPV(-) HNSCC patients.

Cross-cultural adaption and translation of the voice handicap index into Norwegian.

AIMS: To examine the psychometric properties of a Norwegian translation of the Voice Handicap Index (VHI) and test its ability to discriminate between patients and controls. Abbreviated versions of VHI were also studied. METHOD: Following standard translation, 126 healthy subjects and 126 patients with laryngeal disease answered the Norwegian translation of the VHI-30 [hereafter, VHI-30(N)]. RESULTS: The VHI(N) showed a high Cronbach α. Control/patient scores were as follows: Emotional (E): 0.88/0.90; Functional (F): 0.77/0.91; Physical (P): 0.86/0.83, and total: 0.93/0.94. One three-level question where the subjects rated the level of voice disease correlated well with the VHI(N) scores. The 90th (95th) percentile of the control score was 18 (33), whereas the mean ± SEM patient score was 52.3 ± 2.04 of a maximum of 120 points. Differences between patient and control groups were significant for all questions on the VHI(N). Receiver operating characteristic analyses demonstrate that the F, P, E and total VHI scores discriminated very well between patients and controls. This was also the case when the abbreviated scales were analyzed as published by Nawka et al. [Folia Phoniatr Logop 2009;61:37-48] and Rosen et al. [Laryngoscope 2004;114:1549-1556]. CONCLUSION: This Norwegian version of the VHI questionnaire seems to be psychometrically sound.

Tumor Infiltration Levels of CD3, Foxp3 (+) Lymphocytes and CD68 Macrophages at Diagnosis Predict 5-Year Disease-Specific Survival in Patients with Oropharynx Squamous Cell Carcinoma.

Head and neck cancer (HNC) is the sixth most common cancer worldwide. Oropharyngeal (OP) cancers are of special interest because of possible underlying HPV infection which is tied to prognosis. Influxes of inflammatory cells into tumors may vary with prognoses. We wanted to study whether the number of tumor-infiltrating lymphocytes (TIL) and tumor-associated macrophages (TAM) in tumors correlated to HPV status and predicted 5-year disease-specific survival (DSS). Formalin-fixed paraffin-embedded (FFPE) biopsies cut sections from 170 patients treated for OP cancer were stained by immunohistochemistry and evaluated for the number of CD68 (+) TAMs, CD3 (+), and Foxp3 (+) (T regulatory) TILs. From FFPE slides HPV by PCR and p16 by immunohistochemistry were established. From FFPE Hematoxylin-Eosin slides, levels of tumor nuclear polymorphism, tumor invasion, desmoplasia, and inflammation were determined as previously published. Levels of TIL CD3 (+) and TIL Foxp3 (+) were increased among the HPV (+) compared to the HPV (-) patients. High levels of TIL Foxp3 (+) and CD68 (+) macrophages predicted better 5-year DSS. TIL Foxp3 (+) levels predicted independent of age, gender, TNM stage, and HPV infection as well as level of stromal desmoplasia, tumor invasion, and nuclear polymorphism, but more pronounced among tumor HPV (+) than HPV (-) patients.

The Romberg sign, unilateral vestibulopathy, cerebrovascular risk factors, and long-term mortality in dizzy patients.

Objectives: Describe the relationship between unsteadiness, canal paresis, cerebrovascular risk factors, and long-term mortality in patients examined for dizziness of suspected vestibular origin. Study design: Observational cohort with prospective collection of survival data. Setting: University clinic neurotological unit. Patients: Consecutive patients aged 18-75 years examined in the period 1992-2004 for dizziness of suspected vestibular origin. Outcome measures: Overall survival. Standardized mortality ratio (SMR). Factors: Unsteadiness, canal paresis, age, sex, patient-reported diabetes, hypertension, heart disease, stroke, or TIA/minor stroke. Patients were classified as steady or unsteady based on static posturography at baseline compared to normative values. Results: The study included 1,561 patients with mean age 48 years and 60 % females. Mean follow-up was 22 years. Unsteadiness was associated with higher age, heart disease, diabetes, hypertension, and cerebrovascular dizziness. There were 336 deaths over 31,335 person-years (SMR 0.96; 95 % confidence interval: 0.86-1.07). Canal paresis was not related to unsteadiness (chi square: p = 0.46) or to mortality (unadjusted Cox hazard ratio: 1.04, 95% CI: 0.80-1.34). Unsteadiness was an independent predictor of mortality (adjusted Cox hazard ratio: 1.44, 95% CI: 1.14-1.82). Conclusions: Unsteadiness measured by static posturography is associated with higher age, known cerebrovascular risk factors, and with increased long-term mortality, but not with canal paresis in patients evaluated for dizziness. The study highlights the importance of evaluating patients with conspicuous postural instability for non-vestibular causes.

Maturation of monocyte derived dendritic cells with OK432 boosts IL-12p70 secretion and conveys strong T-cell responses.

BACKGROUND: Design of tumour specific immunotherapies using the patients' own dendritic cells (DC) is a fast advancing scientific field. The functional qualities of the DC generated in vitro are critical, and today's gold standard for maturation is a cytokine cocktail consisting of IL-1ß, IL-6, TNF-α and PGE2 generating cells lacking IL-12p70 production. OK432 is an immunotherapeutic agent derived from killed Streptococcus pyogenes that has been used clinically to treat malignant and benign neoplasms for decades. METHODS: In this study, we analysed the effects of OK432 on DC maturation, DC migration, cytokine and chemokine secretion as well as T-cell stimulatory capacity, and compared it to the cytokine cocktail alone and combinations of OK432 with the cytokine cocktail. RESULTS: OK432 induced a marked up-regulation of CD40 on the cell surface as well as a strong inflammatory response from the DC with significantly more secretion of 19 different cytokines and chemokines compared to the cytokine cocktail. Interestingly, secretion of IL-15 and IL-12p70 was detected at high concentrations after maturation of DC with OK432. However, the OK432 treated DC did not migrate as well as DC treated with cytokine cocktail in a transwell migration assay. During allogeneic T-cell stimulation OK432 treated DC induced proliferation of over 50 percent of CD4 and 30 percent of CD8 T-cells for more than two cell divisions, whereas cytokine cocktail treated DC induced proliferation of 12 and 11 percent of CD4 and CD8 T-cells, respectively. CONCLUSIONS: The clinically approved compound OK432 has interesting properties that warrants its use in DC immunotherapy and should be considered as a potential immunomodulating agent in cancer immunotherapy.

Exercise-induced laryngeal obstruction: natural history and effect of surgical treatment.

The current follow-up study concerning the supraglottic type of exercise-induced laryngeal obstruction (EILO) was performed to reveal the natural history of supraglottic EILO and compare the symptoms, as well as the laryngeal function in conservatively versus surgically treated patients. A questionnaire-based survey was conducted 2-5 years after EILO was diagnosed by a continuous laryngoscopy exercise (CLE) test in 94 patients with a predominantly supraglottic obstruction. Seventy-one patients had been treated conservatively and 23 with laser supraglottoplasty. The questionnaire response rate was 70 and 100% in conservatively treated (CT) and surgically treated (ST) patients, respectively. A second CLE test was performed in 14 CT and 19 ST patients. A visual analogue scale on symptom severity indicated improvements in both the groups, i.e. mean values (± standard deviations) declined from 73 (20) to 53 (26) (P < 0.001) in the CT group and from 87 (26) to 25 (27) (P < 0.001) in the ST group. At follow-up, ST patients reported lower scores regarding current level of complaints, and higher ability to perform exercise, as well as to push themselves physically, all compared to CT patients (P < 0.001). CLE scores were normalized in 3 of 14 (21%) CT and 16 of 19 (84%) ST patients (Z = -3.6; P < 0.001). In conclusion, symptoms of EILO diagnosed in adolescents generally decreased during 2-5 years follow-up period but even more after the surgical treatment. Patients with supraglottic EILO may benefit from supraglottoplasty both as to laryngeal function and symptom relief.

Long-Term Survival in 1,931 Patients With Dizziness: Disease- and Symptom-Specific Mortality.

OBJECTIVE: To evaluate mortality among patients referred for suspected vestibular disorder and to examine whether specific symptoms or disorders predict long-term survival among patients with dizziness or vertigo. STUDY DESIGN: Retrospective cohort study. METHODS: This retrospective cohort study analyzed long-term survival data. Consecutive patients examined for suspected vestibular disease at an otolaryngology clinic completed a detailed questionnaire regarding symptoms and comorbidities. RESULTS: The study included 1,931 patients. Their mean age (standard deviation) was 50.5 (16.5) years, and 60% were women. The mean follow-up period was 20.6 years (range, 15.3-27.5 years). The standardized mortality ratio for the entire cohort compared with the Norwegian age- and sex-matched population was 1.03 (95% confidence interval [CI]: 0.94-1.12), illustrating no difference in overall survival. Patients with a cerebrovascular cause of dizziness had higher mortality in adjusted Cox regression analyses (hazard ratio [HR] 1.56, 95% CI: 1.11-2.19), whereas patients reporting periodic or short attacks of dizziness had lower mortality (HR 0.62 [0.50-0.77] and 0.76 [0.63-0.93], respectively). Reported unsteadiness between dizziness attacks was associated with higher mortality with an HR of 1.30 (95% CI: 1.08-1.57). CONCLUSION: This long-term study found comparable mortality rates between patients evaluated for suspected vestibular disorder and that of the general population. However, subgroup analyses showed reduced mortality in patients with periodic or short attacks of dizziness and increased mortality in patients with unsteadiness between attacks or cerebrovascular causes of dizziness. The time course of vestibular symptoms should be determined, and thorough evaluation including fall risk and comorbidities must be considered in patients with nonepisodic symptoms. LEVEL OF EVIDENCE: 3 Laryngoscope, 131:E2031-E2037, 2021.

Targeted Next-Generation Sequencing of Cancer-Related Genes in a Norwegian Patient Cohort With Head and Neck Squamous Cell Carcinoma Reveals Novel Actionable Mutations and Correlations With Pathological Parameters.

BACKGROUND: Targeted next-generation sequencing (NGS) is increasingly applied in clinical oncology to advance personalized treatment. Despite success in many other tumour types, use of targeted NGS panels for assisting diagnosis and treatment of head and neck squamous cell carcinomas (HNSCC) is still limited. AIM: The focus of this study was to establish a robust NGS panel targeting most frequent cancer mutations in long-term preserved formalin-fixed paraffin-embedded (FFPE) tissue samples of HNSCC from routine diagnostics. MATERIALS AND METHODS: Tumour DNA obtained from archival FFPE tissue blocks of HNSCC patients treated at Haukeland University Hospital between 2003-2016 (n=111) was subjected to mutational analysis using a custom made AmpliSeq Library PLUS panel targeting 31 genes (Illumina). Associations between mutational burden and clinical and pathological parameters were investigated. Mutation and corresponding clinicopathological data from HNSCC were extracted for selected genes from the Cancer Genome Atlas (TCGA) and used for Chi-square and Kaplan-Meier analysis. RESULTS: The threshold for sufficient number of reads was attained in 104 (93.7%) cases. Although the specific number of PCR amplified reads detected decreased, the number of NGS-annotated mutations did not significantly change with increased tissue preservation time. In HPV-negative carcinomas, mutations were detected mainly in TP53 (73.3%), FAT1 (26.7%) and FLG (16.7%) whereas in HPV-positive, the common mutations were in FLG (24.3%) FAT1 (17%) and FGFR3 (14.6%) genes. Other less common pathogenic mutations, including well reported SNPs were reproducibly identified. Presence of at least one cancer-specific mutations was found to be positively associated with an extensive desmoplastic stroma (p=0.019), and an aggressive type of invasive front (p=0.035), and negatively associated with the degree of differentiation (p=0.041). Analysis of TCGA data corroborated the association between cancer-specific mutations and tumour differentiation and survival analysis showed that tumours with at least one mutation had shorter disease-free and overall survival (p=0.005). CONCLUSIONS: A custom made targeted NGS panel could reliably detect several specific mutations in archival samples of HNSCCs preserved up to 17 years. Using this method novel associations between mutational burden and clinical and pathological parameters were detected and actionable mutations in HPV-positive HNSCC were discovered.