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Abstract Background The primary goal of phase 2 and 3 clinical trials is to evaluate the safety and effectiveness of therapeutic interventions, and efficient and reproducible ascertainment of important clinical events, either as clinical outcome events (COEs) or adverse events (AEs), is critical. Clinical outcomes require consistency and clinical judgment, so these events are often adjudicated centrally by clinical events classification (CEC) physician reviewers using standardized definitions. In contrast, AEs are reported by sites to the trial coordinating center based on common reporting criteria set by regulatory authorities and trial sponsors. These different requirements have led to the development of separate tracks for COE and AE review. Main body Potential COEs that fail to meet standardized definitions for CEC adjudication – i.e. negatively adjudicated events (NAE) – may meet criteria for AEs. Trial oversight practices require the sponsor to process AEs regardless of how the AEs are submitted; therefore, review of NAEs may be necessary to ensure that important AEs do not go unreported. The Duke Clinical Research Institute (DCRI) developed and implemented a process for scrutinizing NAEs to detect potential missed serious AEs. Initial experience with this process across two trials suggests that approximately 0.2% of NAEs are serious unexpected AEs that were not otherwise reported and another 1.5% are serious expected AEs. Conclusions Given their infrequent concealment of serious AEs in two large trials assessing cardiovascular outcomes, routine scrutiny of NAEs to identify AEs is not recommended at this time, though it may be useful in some trials and should be carefully considered by the trial team. Closer integration of data across safety surveillance and endpoint adjudication systems may enable scrutiny of NAEs when indicated while limiting complexity associated with this process.

Eugenia Allegra,1 Ignazio La Mantia,2 Maria Rita Bianco,1 Gaetano Davide Drago,3 Maria Cristina Le Fosse,1 Alfio Azzolina,4 Calogero Grillo,2 Vincenzo Saita41Otolaryngology, Department of Health Science, University of Catanzaro, Catanzaro, Italy; 2Otolaryngology, "G.F Ingrassia" Department, University of Catania, Catania, Italy; 3Grand Hôpital de l’Est Francilien, Jossigny, France; 4Otolaryngology Unit, Cannizzaro Hospital, University of Catania, Catania, ItalyIntroduction: Total laryngectomy has important psychophysical and social consequences for patients’ quality of life because of the functional changes resulting from the removal of the larynx. Voice deprivation is perhaps the most relevant limiting factor in social relationships, increasing feelings of solitude and tending to drive individuals into social isolation. Multiple voice rehabilitation methods after total laryngectomy are available. This study aimed to determine the acoustic quality of the rehabilitated voice achieved with esophageal speech (ES) and tracheoesophageal speech (TES), and acoustic quality impacts on patients’ perceptions of their quality of life.Materials and methods: The patient inclusion criterion was the completion of a speech rehabilitation course with ES or TES at least 6 months after total laryngectomy. The voice acoustic analysis was carried out automatically by using the Multidimensional Voice Program. The following parameters were extracted: fundamental frequency (F0), Jitter% (Jitt), Shimmer% (Shim), and noise-to-harmonic ratio (NHR). Subjective voice evaluation was performed by using the following questionnaires: Voice Handicap Index (VHI), Voice-related Quality of Life (V-RQOL), and Voice Performance Questionnaire (VPQ).Results: The acoustic analysis showed a difference between ES and TES patients on all acoustic parameters; this difference was significant for F0 (133.09±2.4 and 119±3.3, respectively; p

Eugenia Allegra,1 Vincenzo Saita,2 Alfio Azzolina,2 Massimo De Natale,2 Maria Rita Bianco,1 Domenico Michele Modica,3 Aldo Garozzo1 1Otolaryngology, Department of Health Sciences, University of Catanzaro, Catanzaro, Italy; 2Otolaryngology Unit, Cannizzaro Hospital, Catania, Italy; 3Otolaryngology Unit, University of Palermo, Palermo, Italy Background: Laryngeal early glottic tumors can benefit from different treatment modalities, including transoral laser microsurgery, open partial horizontal laryngectomy (OPHL), and radiotherapy. However, the treatment of early glottic tumors with the involvement of the anterior commissure remains controversial. The studies about the role of anterior commissure involvement in oncologic outcomes in patients with early glottic cancer treated with supracricoid laryngectomy (SCL) are very few. For this reason, we conducted a retrospective study to evaluate local recurrence-free survival and specific survival in patients with and without involvement of the anterior commissure who underwent SCL with cricohyoidoepiglottopexy.Methods: This retrospective study has been carried out on patients with T1b–T2 glottic squamous cell carcinoma submitted to SCL with cricohyoidoepiglottopexy. The patients’ demographic and clinical data were collected, and the histological findings of the surgical specimens were reviewed to identify patients who had involvement of the anterior commissure.Results: A total of 72 patients were included in the study; two of them were female and 70 were male. The mean age at diagnosis was 61.5±8.0 SD years. In 26 of the 72 (36.2%) patients, anterior commissure was not pathologically involved (group A), while in 46 (63.8%) patients, it was involved (group B). The 5-year local recurrence-free survival rate was 96.1% and 93.48% in groups A and B, respectively, P=0.09. The 5-year disease-specific survival rate was 92.31% and 95.65% in groups A and B, respectively, P=0.057.Conclusion: SCL with cricohyoidoepiglottopexy seems to be an adequate treatment modality, even for T1b–T2 glottic tumors with anterior commissure involvement. Keywords: open partial horizontal laryngectomy, laryngeal cancer, supracricoid laryngectomy, cricohyoidoepiglottopexy

Rossana Domanico,1 Serena Trapasso,1 Mariaquila Santoro,2 Domenico Pingitore,2 Eugenia Allegra1 1Division of Otolaryngology – Head and Neck Surgery, Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy; 2Division of Radiation Oncology and Radiobiology, Department of Hematology, Oncology and Transfusion Medicine, Pugliese–Ciaccio Hospital, Catanzaro, Italy Introduction: Electrochemotherapy (ECT) is a new therapeutic method that is used in oncology as palliative treatment in patients with recurrent head and neck tumors and who are not candidates for standard therapeutic options. The aim of our study was to evaluate the cytoreductive effect of ECT in patients subjected to chemoradiotherapy for squamous cell carcinoma of the oral cavity. The primary endpoint of the study was to verify tumor debulking after ECT treatment as neoadjuvant, before conventional chemoradiotherapy. The secondary endpoint was to assess the safety and tolerability of ECT treatment. Materials and methods: This experimental study was conducted at the Division of Otolaryngology, University of Catanzaro, Italy. From February 2013 to February 2014, four patients were enrolled, two males and two females, with a mean age of 56 years (range: 47–65 years), and with squamous cell carcinoma of the oral cavity in advanced stages of disease (T3–T4). All patients, with their informed consent, received ECT treatment in accordance with the Standard Operating Procedures defined in the European Standard Operating Procedures on Electrochemotherapy (ESOPE) study, followed by conventional chemoradiotherapy. Their response to ECT treatment was assessed after 30 days. For each patient, the following parameters were evaluated with the appropriate forms: local tumor control, control of pain (analgesia postsurgery scale [APS]), and quality of life (Short Form [36] Health Survey [SF-36]; v1). Results: Three of four patients (75%) showed a partial response, whereas in one patient (25%), the disease remained stable. The treatment was well-tolerated by all patients, according to the APS and SF-36 results. Conclusion: Although the study was conducted on a small number of cases, data from this study show that ECT represents a safe and effective treatment in terms of tumor cytoreduction and locoregional control of the disease. It also allows good control of postoperative pain and short hospitalization. Keywords: neoadjuvant treatment, squamous cell carcinoma, oral cavity

Maria Rita Bianco, Alessandro La Boria, Teresa Franco, Pierpaolo Ferrise, Eugenia AllegraDepartment of Otolaryngology-Head and Neck Surgery, University of Catanzaro, Catanzaro, ItalyBackground: Lingual thyroid represents 90% of ectopic thyroid tissue localizations. The first case was described by Hickman in 1869. An ectopic thyroid is often asymptomatic, but pathological or physiological conditions inducing hyperproduction of thyroid-stimulating hormone can lead an ectopic thyroid to become symptomatic. Treatment of the symptomatic ectopic thyroid can be medical, with hormone-suppressing therapy, or surgical.Case presentation: A 17-year-old female presented to our outpatient clinic complaining of a sensation of a lump in her throat. Ear, nose, and throat (ENT) examination identified a swelling of the base of the tongue in the glossoepiglottic area. Thyroid scintigraphy showed a single contrast enhancement in the sublingual region, instead of in the normal anatomical position of the thyroid. She was treated surgically after failed hormone-suppressing therapy. An arteriography performed before the surgery showed vascular anomalies and was useful in surgical planning.Conclusion: Recognition of vascular anomalies in an ectopic thyroid is fundamental before surgical planning, therefore, accurate radiological study of the vasculature should always be planned before surgical treatment of this disease.Keywords: ectopic thyroid, arteriography, transoral approach, tongue

Serena Trapasso, Eugenia AllegraOtolaryngology – Head and Neck Surgery, University Magna Graecia of Catanzaro, Catanzaro, ItalyAbstract: In recent years, many studies have shown that some types of tumors are characterized by the presence of cells with stem-like characteristics, called cancer stem cells (CSCs). These are considered cells that initiate the tumor and are probably responsible for tumor recurrence. CSCs have the capacity for self-renewal, the potential to give rise to one or more cell types within the tumor, and the ability to drive, in a continuous manner, the proliferation of malignant cells. The failure of current cancer therapies can be attributed to the relative ineffectiveness of drugs against CSCs, which remain viable while retaining their full ability to reproduce the tumor. The development of new strategies is currently hampered by the lack of reliable markers to identify CSCs. One promising surface marker of CSCs in head and neck cancer is the CD44 molecule, which has been shown in preliminary studies to have high specificity, although there are discrepant data because its prognostic value may depend on the specific tumor location. More rigorous studies are needed to investigate the usefulness of CD44 expression in head and neck tumors for possible clinical applicability.Keywords: CD44, head and neck squamous cell carcinoma, cancer stem cells

Eugenia Allegra, Teresa Franco, Serena Trapasso, Rossana Domanico, Alessandro La Boria, Aldo GarozzoDepartment of Otolaryngology- Head and Neck Surgery, University of Catanzaro, Catanzaro, ItalyBackground: Supracricoid laryngectomy is an organ preservation surgical technique for early-stage glottic tumors. Modified supracricoid laryngectomy using sternohyoid muscles for neoglottis reconstruction is a new surgical technique. This report evaluates oncological and functional outcomes of this new technique and its feasibility in elderly patients.Methods: Clinical records from 21 consecutive patients affected by glottic cancer and treated by modified SCL between 2004 and 2009 were retrospectively reviewed. Postoperative parameters and quality of voice after modified SCL were retrospectively reviewed. Actuarial overall survival, disease-specific survival rates, and recurrence-free survival rates were assessed. The functional and oncological outcomes of patients over 65 years were compared with those of patients younger than 65 years of age.Results: There were no postoperative complications and all of the patients had complete swallowing rehabilitation. Twenty of the 21 patients had decannulation. Two patients received total laryngectomy for locoregional relapse. Overall survival and disease-specific survival rates were 100%. Recurrence-free survival rates were 90.1% and 90% in patients younger and older than 65 years of age, respectively. The larynx preservation index was lower in patients who were older than 65 years of age. The postoperative courses with regard to functional outcome and voice quality in elderly patients were similar to those of patients younger than 65 years of age.Conclusion: Modified SCL is a new open organ preservation surgical technique that is oncologically safe. The positive functional and oncological outcomes of this surgical procedure allow it to be performed in elderly patients.Keywords: supracricoid laryngectomy, modified, early glottic cancer, cricohyoidoepiglottopexy, cricohyoidopexy, elderly, larynx, cancer

Eugenia Allegra, Teresa Franco, Serena Trapasso, Teodoro Aragona, Rossana Domanico, Aldo GarozzoDepartment of Otolaryngology, Head and Neck Surgery, University of Catanzaro, Catanzaro, ItalyBackground and objective: Supracricoid partial laryngectomy (SCL) was introduced as an organ preservation procedure for treating selected early laryngeal cancer. However, the recovery of the voice after SCL may result in different degrees of dysphonia. To improve the functional recovery and quality of the voice, we realized a modified supracricoid laryngectomy (MSCL) using sternohyoid muscles for neoglottic reconstruction in selected patients affected by T1b–T2 laryngeal cancer. In this study, we evaluate the quality of life (QoL) in patients treated by SCL and MSCL.Methods: The quality of life (QoL) evaluation was undertaken using the Italian version of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire.Results: The overall QoL, assessed with European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30, was better in patients treated with MSCL than in those treated with SCL. The better QoL correlates with the highest response scores to the questions on the relative global functioning scales in patients treated with MSCL.Conclusion: The new surgical technique has improved the QoL of patients with early laryngeal cancer, with improved communication ability achieved. Reconstruction of neocords in MSCL improves speech function in comparison to SCL, and patients experience less discomfort and achieve an almost normal communication performance.Keywords: supracricoid laryngectomy, quality of life, laryngeal carcinoma, EORTC QLQ

OBJECTIVE: Alterations of the olfactory function in patients affected by COVID-19 often have an early onset and a variable duration ranging from a few weeks to months. The aim of this study was to evaluate olfactory dysfunction persistence after recovery from COVID-19, and potential related clinical-demographic conditions. PATIENTS AND METHODS: A total of 76 patients recovered from COVID-19 from at least 20 days with olfactory dysfunction during the infection were included in the study. For the subjective evaluation of olfactory function, a visual analogic scale (VAS) was used. The objective evaluation was performed with the use of the Sniffin' Sticks test. RESULTS: Objective assessment of olfactory function revealed that 48 (63.16%) patients were found to be normosmic (TDI = 30.5), 26 (34.21%) were hyposmic (TDI from 30.5 to 16.5) and two (2.63%) were anosmic (TDI = 16.5) at the time of the evaluation. These results did not show a significant difference between subjective and objective tests (p = 0.45). Most patients recovered their sense of smell within the first two months after recovery while a portion (22.2%) still experienced olfactory alterations 4-6 months after SARS-CoV-2 infection. Patients who had not recovered their sense of smell had a significantly longer period of SARSCoV-2 positivity compared to patients that fully recovered (36.07 ± 7.78 days vs. 29 ± 7.89 days; p = 0.04). CONCLUSIONS: Our results suggest that the duration of the infection negatively correlates with the recovery of olfactory function. [ABSTRACT FROM AUTHOR]

The n-back task is widely used to investigate the neural basis of Working Memory (WM) processes. The principal aim of this study was to explore and compare the EEG power spectra during two n-back tests with different levels of difficulty (1-back vs 3-back).Fourteen healthy subjects were enrolled (7 men and 7 women, mean age 31.21±7.05 years, range: 23-48). EEG was recorded while performing the N-back test, by means of 19 surface electrodes referred to joint mastoids. EEG analysis were conducted by means of the standardized LOw Resolution brain Electric Tomography (sLORETA) software. The statistical comparison between EEG power spectra in the two conditions was performed using paired t-statistics on the coherence values after Fisher’s z transformation available in the LORETA program package. The frequency bands considered were: delta (0.5-4 Hz); theta (4.5–7.5 Hz); alpha (8–12.5 Hz); beta (13–30 Hz); gamma (30.5–100 Hz). Significant changes occurred in the delta band: in the 3-back condition an increased delta power was localized in a brain region corresponding to the Brodmann Area (BA) 28 in the left posterior entorhinal cortex (T = 3.112; p

Abstract Background The main cause of treatment failure and death in laryngeal squamous cell carcinoma is metastasis to the regional lymph nodes. The current clinical staging criteria fail to differentiate patients with occult metastasis from patients without metastasis. Identifying molecular markers of the disease might improve our understanding of the molecular mechanisms underlying the pathogenesis and development of laryngeal carcinoma and may help improve clinical staging and treatment. Methods Sixty-four previously untreated patients who underwent surgical excision of laryngeal squamous cell carcinoma with neck dissection were included in this study. The expression of B cell-specific Moloney murine leukemia virus integration site 1 (BMI-1) was examined immunohistochemically on formalin-fixed paraffin-embedded primary tissue specimens. Results Nuclear expression of BMI-1 (nBMI-1) was detected in 32 of the 64 tumors (50%), cytoplasmic expression of BMI-1 (cBMI-1) was detected in 22 (34.4%), and 10 tumors (15.6%) showed no BMI-1 immunoreactivity. High nBMI-1 expression levels (≥10) were detected in 28 of the 32 (87.5%) nBMI-1-positive patients. Multivariate analysis including age at diagnosis, grade, tumor location, TNM status, and nBMI-1 expression showed that a high nBMI-1 expression level was an independent prognostic factor for lymph node metastasis. Conclusion The expression of BMI-1 in patients with laryngeal carcinoma seems to correlate with lymph node metastasis.