p16 Expression in Laryngeal Squamous Cell Carcinoma: A Surrogate or Independent Prognostic Marker?

Laryngeal squamous cell carcinoma (LSCC) is a common malignancy that, despite scientific advancements, has not seen an improvement in its prognosis in the last decades. Few promising predictive markers have been found and none are relevant in clinical practice. p16ink4a, an oncosuppressor protein involved in cell cycle arrest, with a prognostic impact on other cancers, has been widely used in the head and neck region as a surrogate marker of HPV infection. Published papers and recent meta-analyses seem to minimize the biological role of HPV in the context of LSCC's cancerogenesis, and to disprove the reliability of p16ink4a as a surrogate prognostic marker in this context, while still highlighting its potential role as an independent predictor of survival. Unfortunately, the available literature, in particular during the last two decades, is often not focused on its potential role as an independent biomarker and few relevant data are found in papers mainly focused on HPV. The available data suggest that future research should focus specifically on p16ink4a, taking into account both its potential inactivation and overexpression, different patterns of staining, and immunohistochemistry cutoffs, and should focus not on its potential role as a surrogate marker but on its independent role as a predictor of survival.

Vocal Fold Paralysis After Spinal and Epidural Anesthesia: A Case Report and Scoping Review.

OBJECTIVES: Cranial nerve paralysis is a rare complication of spinal and epidural anesthesia, and some cases of vocal fold paralysis (VFP) have been reported. The aim of this article is to report a case, identify evidence supporting the possibility of VFP being a complication of spinal and epidural anesthesia and to investigate the frequency, the characteristics, and the possible mechanisms of such a complication. DATA SOURCES: CINAHL Complete, Google Scholar, Cochrane Library, Pubmed, and EMBASE. METHODS: Case report according to CARE guidelines; scoping review according to PRISMA-ScR criteria. All types of studies that reported on patients of any age and sex, all types of spinal/epidural anesthesia regardless of the location and of drugs used were included. A data extraction sheet was completed for each study selected for inclusion based on the full-text screenings. Extracted data included: study characteristics, participant characteristics, intervention characteristics, outcome measures, clinical investigations. The study did not receive external funding. RESULTS: Eight studies met inclusion criteria and a total of 13 events (in 12 patients, including ours) were reported to date. Although there are some hypotheses in regard to the mechanism underlying the phenomena, including mechanical and inflammatory ones, the exact cause is still unclear. CONCLUSIONS: Only few cases of VFP after spinal or epidural anesthesia have been reported to date; however, it seems possible that VFP might be a potential underreported complication of such procedures. We believe that more research on the topic is warranted, especially considering the wide population potentially at risk. LEVEL OF EVIDENCE: NA Laryngoscope, 2024.

Preoperative Diagnosis of Warthin Tumors Combining Cytological, Clinical and Ultrasonographic Information within a Multidisciplinary Approach in a Lump Clinic.

(1) Background: Warthin tumors account for about 20% of all benign salivary tumors, approaching 50% if we consider only the parotid gland. Wait and see is considered a reasonable option, but the diagnosis should be certain. Diagnosis can be based on morphological and cytological data, but the sensitivity of the fine needle aspiration cytology (FNAC) is not absolute, with a high rate of non-diagnostic findings in the event of a Warthin tumor, hindering the counseling and therapeutic decisions. The aim of the study is to evaluate the reliability of FNAC and its combination with anamnestic, clinical, and ultrasonographic data in diagnosing Warthin tumors. (2) Methods: A total of 413 patients affected by masses within the major salivary gland and managed between 2017 and 2022 at our institution have been included in the present retrospective study. Each patient underwent fine needle aspiration biopsy (FNAB) with a subsequent cytological diagnosis; successively, for each patient, the clinician (otolaryngologist) and the histopathologist discussed the combination of cytological (even non-diagnostic), clinical, and ultrasonographic data in order to make a "multiparametric" diagnosis. A total of 214 cases were subsequently submitted to surgical resection and had a final histopathology report, to which the cytological and the multiparametric diagnoses can be compared. We extracted all the patients with a cytological, multiparametric, and/or histological diagnosis of Warthin tumors in order to assess the sensitivity and specificity of FNAC and of multiparametric analysis in diagnosing Warthin tumors in case of a major salivary gland mass. (3) Results: One hundred thirty-two cases had a cytological, multiparametric, and/or histological diagnosis of Warthin tumors. FNAC displays a sensitivity of 68.4% and a specificity of 98.7% in diagnosing Warthin tumors. The multiparametric evaluation allowed a considerable improvement in sensitivity (92.9% vs. 68.4%), minimizing the number of non-diagnostic results and preserving at the same time a similar value of specificity (95.5% vs. 98.7%). Notably, none of the patients with a cytological or multiparametric diagnosis of Warthin were affected by a malignant lesion in the final histopathological report. (4) Conclusions: In the case of Warthin tumors, a multiparametric evaluation encompassing anamnestic, clinical, and cytological data is effective in reducing the number of non-diagnostic reports and can safely guide the management of a tumor (e.g., antibiotic treatment of infectious complications, assign a low priority to surgery, even consider observation avoiding surgery) which is absolutely benign and can be associated with no clinically relevant issues.

New standards for the management of nose vestibule malignancies.

BACKGROUND: Nasal vestibule squamous cell carcinoma (NVSCC) is an ill-defined underestimated condition. AIM/OBJECTIVE: To define the current standard of care. MATERIAL AND METHODS: We review recent acquisitions concerning clinical features and therapeutic approaches. RESULTS: The current AJCC staging system, which attributes to nasal vestibule the same topographic code as nasal cavity proper and the same T-classification criteria as ethmoid, appears inadequate.As for treatment of primary lesions without bone invasion, current evidence suggests that brachytherapy is at least equivalent to surgery and superior to external beams in terms of oncological outcomes, and superior to both modalities in terms of cosmesis and function. CONCLUSIONS: As for classification and staging, the nasal vestibule should be defined as a subsite of the nose and paranasal sinuses, distinct from the 'nasal cavity proper and ethmoid', with specific topographic code and T-classification criteria. This will improve the assessment of prognosis and prevalence, underestimated also because of misdiagnosis with skin cancers.Secondly, brachytherapy should become the new standard for the treatment of primary lesions without bone invasion. To optimize the advantages of brachytherapy, we propose novel anatomic criteria for the implantation. SIGNIFICANCE: Increasing evidence supports a paradigm shift in staging and treatment of NVSCC.

Parapharyngeal Space Tumors: Our Experience.

Para-pharyngeal space (PPS) tumors include an heterogeneous group of neoplasms, accounting for approximatively 0.5-1.5% of all head and neck tumors. Management of these neoplasms requires a careful diagnostic workout and an appropriate surgical approach to obtain good outcomes associated with minimal aesthetic drawbacks. In this study we investigated clinical onset, histologic features, surgical treatment outcomes, peri operative complications and follow up of 98 patients treated for PPS tumors in our Centre between 2002 and 2021. Furthermore, we reviewed our preliminary experience of preoperative embolization of hyper vascular PPS tumors trough SQUID12, an ethylene vinyl alcohol copolymers (EVOH) which exhibits many advantages over other embolic agents, due to its better devascularization rate and lower risk of systemic complications. Our data support the hypothesis that transoral surgery scenario should be significantly revised, as it could represent a valid treatment for tumors located in lower and prestyloyd portion of PPS. Moreover, SQUID12, a novel embolization agent, may be a very promising choice for PPS hyper vascularized tumors, ensuring higher devascularization rate, safer procedures and lower risk of systemic dispersion compared to traditional Contour treatment.

Do We Have Enough Evidence to Specifically Recommend Transoral Robotic Surgery in HPV-Driven Oropharyngeal Cancer? A Systematic Review.

Introduction: International guidelines include transoral robotic surgery (TORS) as an option for selected oropharyngeal squamous cell carcinomas (OPSCCs). In the perspective of treatment de-intensification, many surgeons have started recommending and performing TORS preferentially in p16- positive OPSCC in order to reduce the long-term morbidity related to chemoradiotherapy. The aim of the present review is to analyze the current evidence supporting the above-cited strategy. Materials and Methods: The study was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Results: Twenty-two studies were included in this review, with a total of 3992 patients treated with primary TORS. The majority of patients were classified as HPV+ (n = 3655, 91.6%), and 8.2% (n = 327) as HPV-. The HPV status was unknown in only 10 (0.3%) patients. In particular, only five of the included studies compared survival outcomes of HPV-positive patients with HPV-negative ones treated with primary TORS, and only two of these found a significant improvement in survival in the HPV-driven cohort. Discussion: The current literature does not clarify whether HPV+ OPSCCs treated with TORS, alone or with adjuvant treatments, are associated with a better oncologic and/or functional outcome compared to those treated with radio- or chemoradiotherapy. However, TORS alone obtained good oncological outcomes in a high percentage of cases in the reviewed series. Recent data, on the other hand, suggest that TORS could represent a promising strategy for intensifying treatments in HPV- OPSCC.

Accuracy of p16 IHC in Classifying HPV-Driven OPSCC in Different Populations.

High-risk human papillomavirus (HPV) infection is a defined etiopathogenetic factor in oropharyngeal carcinogenesis with a clear prognostic value. The P16 IHC (immunohistochemistry) is a widely accepted marker for HPV-driven carcinogenesis in oropharyngeal squamous cell carcinoma (OPSCC); in the present paper, we discuss its reliability as a standalone marker in different populations. The literature suggests that rates of p16 IHC false positive results are inversely correlated with the prevalence of HPV-driven carcinogenesis in a population. We propose a formula that can calculate such a false positive rate while knowing the real prevalence of HPV-driven OPSCCs in a given population. As it has been demonstrated that p16 positive/HPV negative cases (i.e., false positives at p16 IHC) have the same prognosis as p16 negative OPSCC, we conclude that despite the valuable prognostic value of p16 IHC, relying only on a p16 IHC positive result to recommend treatment de-intensification could be risky. For this aim, confirmation with an HPV nucleic acid detection system, especially in areas with a low prevalence of HPV-related OPSCCs, should be pursued.

Low Prevalence of HPV Related Oropharyngeal Carcinogenesis in Northern Sardinia.

HPV infection is a clear etiopathogenetic factor in oropharyngeal carcinogenesis and is associated with a markedly better prognosis than in smoking- and alcohol-associated cases, as specified by AJCC classification. The aim of the present work is to evaluate the prevalence of HPV-induced OPSCC in an insular area in the Mediterranean and to assess the reliability of p16 IHC (immunohistochemistry) alone, as accepted by AJCC, in the diagnosis of HPV-driven carcinogenesis in such a setting. All patients with OPSCC consecutively managed by the referral center in North Sardinia of head and neck tumor board of AOU Sassari, were recruited. Diagnosis of HPV-related OPCSS was carried out combining p16 IHC and DNA testing on FFPE samples and compared with the results of p16 IHC alone. Roughly 14% (9/62) of cases were positive for HPV-DNA and p16 IHC. Three more cases showed overexpression of p16, which has a 100% sensitivity, but only 75% specificity as standalone method for diagnosing HPV-driven carcinogenesis. The Cohen's kappa coefficient of p16 IHC alone is 0.83 (excellent). However, if HPV-driven carcinogenesis diagnosed by p16 IHC alone was considered the criterion for treatment deintensification, 25% of p16 positive cases would have been wrongly submitted to deintensified treatment for tumors as aggressive as a p16 negative OPSCC. The currently accepted standard by AJCC (p16 IHC alone) harbors a high rate of false positive results, which appears risky for recommending treatment deintensification, and for this aim, in areas with a low prevalence of HPV-related OPSCC, it should be confirmed with HPV nucleic acid detection.

Audiological Risk Factors, Referral Rates and Dropouts: 9 Years of Universal Newborn Hearing Screening in North Sardinia.

Background: Objectives of the present work were to analyze the prevalence of hearing loss in our population of screened newborns during the first 9 years of the universal newborn hearing screening (UNHS) program at University Hospital Sassari (Italy) (AOU Sassari), to analyze the risk factors involved, and to analyze our effectiveness in terms of referral rates and dropout rates. Methods: Monocentric retrospective study whose target population included all the newborns born or referred to our hospital between 2011 and 2019. Results: From 2011 to 2019, a total of 11,688 babies were enrolled in our screening program. In total, 3.9‱ of wellborn babies and 3.58% of neonatal intensive care unit (NICU) babies had some degree of hearing loss. The most frequently observed risk factors among non-NICU babies were family history of hearing loss (3.34%) and craniofacial anomalies (0.16%), among NICU babies were low birth weight (54.91%) and prematurity (24.33%). In the multivariate analysis, family history of hearing loss (p < 0.001), NICU (p < 0.001), craniofacial anomalies (p < 0.001), low birth weight (<1500 g) (p = 0.04) and HIV (p = 0.03) were confirmed as risk factors. Conclusions: Our data are largely consistent with the literature and most results were expected, one relevant exception being the possible role of NICU as a confounding factor and the limited number of risk factors confirmed in the multivariate analysis.

Clinical Validation of a Deep-Learning Segmentation Software in Head and Neck: An Early Analysis in a Developing Radiation Oncology Center.

BACKGROUND: Organs at risk (OARs) delineation is a crucial step of radiotherapy (RT) treatment planning workflow. Time-consuming and inter-observer variability are main issues in manual OAR delineation, mainly in the head and neck (H & N) district. Deep-learning based auto-segmentation is a promising strategy to improve OARs contouring in radiotherapy departments. A comparison of deep-learning-generated auto-contours (AC) with manual contours (MC) was performed by three expert radiation oncologists from a single center. METHODS: Planning computed tomography (CT) scans of patients undergoing RT treatments for H&N cancers were considered. CT scans were processed by Limbus Contour auto-segmentation software, a commercial deep-learning auto-segmentation based software to generate AC. H&N protocol was used to perform AC, with the structure set consisting of bilateral brachial plexus, brain, brainstem, bilateral cochlea, pharyngeal constrictors, eye globes, bilateral lens, mandible, optic chiasm, bilateral optic nerves, oral cavity, bilateral parotids, spinal cord, bilateral submandibular glands, lips and thyroid. Manual revision of OARs was performed according to international consensus guidelines. The AC and MC were compared using the Dice similarity coefficient (DSC) and 95% Hausdorff distance transform (DT). RESULTS: A total of 274 contours obtained by processing CT scans were included in the analysis. The highest values of DSC were obtained for the brain (DSC 1.00), left and right eye globes and the mandible (DSC 0.98). The structures with greater MC editing were optic chiasm, optic nerves and cochleae. CONCLUSIONS: In this preliminary analysis, deep-learning auto-segmentation seems to provide acceptable H&N OAR delineations. For less accurate organs, AC could be considered a starting point for review and manual adjustment. Our results suggest that AC could become a useful time-saving tool to optimize workload and resources in RT departments.

The Impact of COVID-19 on Universal Newborn Hearing Screening.

OBJECTIVES: To report the direct and indirect impact of coronavirus disease 2019 pandemic on the Universal Newborn Hearing Screening program of our institution (Azienda Ospedaliero Universitaria di Sassari). DESIGN: Monocentric retrospective study whose target population included all the newborns born in or referred to our hospital in 2019 and 2020. RESULTS: There is no statistically significant difference in time to retest or loss to follow-up rate between the 2 years considered (2019 to 2020). Referral rate is not higher for newborns born to severe acute respiratory syndrome coronavirus 2 polymerase chain reaction positive mothers. CONCLUSIONS: In relation to the analyzed variables, coronavirus disease 2019 seems to have a limited impact on our screening program. Severe acute respiratory syndrome coronavirus 2 did not behave as an audiological risk factor in our series.

Prevalence of HPV Infection and p16INK4a Overexpression in Surgically Treated Laryngeal Squamous Cell Carcinoma.

Background: The mucosal high-risk (HR) human papillomavirus (HPV) is associated with oropharyngeal carcinogenesis. Aims of this study were to evaluate the prevalence of HR-HPV infection in laryngeal squamous cell carcinoma (LSCC) from different subsites, and the clinico-biological meaning of p16 overexpression. Methods: Ninety-seven LSCCs submitted to primary surgery (n = 75) or to post-irradiation salvage laryngectomy (n = 22) were evaluated for HR-HPV DNA and RNA using Luminex-based assays. p16 immunohistochemistry was performed. Results: HR-HPV DNA from HPV16 was detected in seven cases (8.75%), without significant differences between supraglottic and glottic lesions. HPV RNA was never detected. p16 overexpression correlated with HR-HPV DNA, but the kappa agreement score was poor. HPV DNA showed no impact on prognosis. p16 overexpression was associated with a better survival (OS, RFS) in primarily operated cases, while an inverse association with OS was observed in the salvage surgery group. Conclusions: HR-HPV infection appears to have a marginal role in LSCC independent of the anatomical subsite. p16 expression is deregulated in LSCC independent of HPV but displays a prognostic role in patients submitted to primary surgery. The negative predictive role of p16 overexpression in patients undergoing salvage surgery deserves more investigations for validation and elucidation of its clinical relevance.

Submandibular gland degloving: A minimally invasive function-preserving surgical approach for benign diseases.

In the Video S1, a modified technique for submandibular gland resection in benign disease is shown. The main plane of dissection is below the fascia and immediately superficial to the fibrous capsule of the gland. The video shows the surgical steps and the structures that become evident along the procedure and illustrates some tips and tricks. Facial vessels are dissected, easily spared, and not ligated as it occurs in the classical technique. This technical variant is minimally invasive, respectful of anatomy, and through preservation of the fascial layer investing the gland aims at reducing the risk of injury to the marginalis mandibulae branch of the facial nerve, which lies within the fascia itself.

Audiovestibular symptoms and sequelae in COVID-19 patients.

BACKGROUND: since the beginning of COVID-19 outbreak a growing number of symptoms and deficits associated with the new pathology have emerged, among them cochlear damage in otherwise asymptomatic COVID-19 patients has been described. OBJECTIVE: to investigate general and audiovestibular symptoms and sequelae in healed patients, and to seek for any sign of residual or permanent hearing or vestibular loss. METHODS: we reviewed the data coming from 48 Covid-19 patients whose nasopharyngeal swabs have turned negative, all employed at our facility, that opted in for a free screening of audiovestibular symptoms offered by our hospital after the aforementioned report was published. The screening included a tonal pure tone audiometry, a vHIT and SHIMP test, as well as a survey including known symptoms and audiovestibular symptoms. RESULTS: general symptoms as reported by our patients largely reflect what reported by others in the literature. 4 (8.3%) patients reported hearing loss, 2 (4.2%) tinnitus, 4 dizziness (8.3%), 1 spinning vertigo (2%), 1 dynamic imbalance (2%), 3 static imbalance (6.3%). Most audiovestibular symptoms have regressed. Thresholds at pure tone audiometry and vHIT gain were within normality range in all post-Covid-19 patients. CONCLUSIONS: even if some patients suffer from audiovestibular symptoms, these are mostly transitory and there is no clear evidence of clinically relevant persistent cochlear or vestibular damage after recovery.

Utility of ultrasound-guided fine needle aspiration cytology in assessing malignancy in head and neck pathology.

OBJECTIVE: Fine needle aspiration cytology (FNAC) is a well-established diagnostic procedure for head and neck masses not clearly originating from mucosal or cutaneous surfaces. We analysed head and neck masses evaluated over a 2-year period, to assess the reliability of FNAC for the evaluation of malignancy. METHODS: We enrolled all patients undergoing FNAC, from April 2013 to July 2015, in a single service of a large Italian university hospital. Relevant clinical data and ultrasonographic parameters of the lesions were recorded. We performed both conventional and thin-prep smears. Clinical presentation, ultrasonographic features and final cytology diagnoses were analysed and correlated with histology. RESULTS: The series included 301 lesions in 285 patients, with a single (94.4%) or two (5.6%) lesions. Only eight samples were considered non-diagnostic/inadequate (2.6%). Among the cases, 139 FNAC (46.1%) underwent surgery. Cytological-histological correspondence was found in 89% of the cases. Concerning malignancy, we documented less than 4% false positives and less than 2.5% false negatives, with 92.7% sensitivity and 94.6% specificity. CONCLUSION: FNAC diagnosis can be highly specific. Most importantly, it is highly reliable in assessing malignancy, thus defining the priority and guiding the management procedures.

Relationship between calcium metabolism and benign paroxysmal positional vertigo in north Sardinia population.

BACKGROUND: Benign paroxysmal positional vertigo (BPPV) has a reported recurrence ranging from 26.8 to 50%. Osteoporosis and Vitamin D deficiency seems to have an impact on recurrence of BPPV. OBJECTIVE: to evaluate the impact of osteoporosis and Vitamin D deficiency on recurrence of BPPV. METHODS: 73 consecutive patients were divided in two groups according to the presence (group 1) or absence (group 0) of a recurrent episode. BMD, femoral and lumbar T-scores and Vitamin D levels were recorded. Statistical analysis was performed to investigate correlations. RESULTS: patients in group 1 had statistically significant lower values of both femoral (-1,62±1,06 vs. -0,53±1,51; p = 0,001), lumbar T-score (-2,10±1,19 vs -0, 53±1.51, p = 0.001) and Vitamin D (19.53±15.33). The values of femoral T-score and Vitamin D could be combined in a model able to properly classify 65.8% of the cases (p = 0.002) as isolated or recurrent BPPV, with high accuracy (AUC 0.710 [0.590 -0.830]). CONCLUSION: present data show a probable correlation between osteoporosis and Vitamin D with recurrent BPPV.

Does the involvement of first-year residents have a negative impact on the performance of a newborn hearing screening program?

OBJECTIVES: We aimed to evaluate the efficiency of our hearing screening program, prior to hospital discharge, together with the consistency of our teamwork including first year residents by assessing a learning curve for the operators involved. METHODS: We evaluated all the data collected during the first stage of the screening program of all non-NICU neonates from March 2009 to July 2013, analyzing by means of a linear regression model, the monthly referral rate for the whole period of activity of each group of residents. RESULTS: performances of each group of screeners were statistically different (chi square test p < 0.005). The nptrend test showed that group 2 (p = 0.01) and group 4 (p = 0.01) reached a statistical significance in higher and lower referral rates respectively. No statistical differences were found in other groups (Group 1 p = 0.161; Group 3 p = 0.853). CONCLUSION: Despite a statistically significant difference in the performances between the groups of residents, the referral rates for each group (range 6.18%-9.29%) and the overall referral rate for the whole period (7.84%) agree with the values commonly reported for TEOAEs in the literature. It means that our screening program is reasonably effective despite a yearly turnover of operators.