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Background Endoscopic transnasal transclival intradural surgery is limited by a high postoperative cerebrospinal fluid leak rate. The aim of this study was to investigate the role of three-dimensional printing to create a personalized, rigid scaffold for clival reconstruction. Methods Two different types of clivectomy were performed in 5 specimens with the aid of neuronavigation, and 11 clival reconstructions were simulated. They were repaired with polylactide, three-dimensional–printed scaffolds that were manually designed in a computer-aided environment based either on the real or on the predicted defect. Scaffolds were printed with a fused filament fabrication technique and different offsets. They were positioned and fixed either following the gasket seal technique or with screws. Postdissection radiological evaluation of scaffold position was performed in all cases. In 3 specimens, the cerebrospinal fluid leak pressure point was measured immediately after reconstruction. Results The production process took approximately 30 hours. The designed scaffolds were satisfactory when no offset was added. Wings were added during the design to allow for screw positioning, but broke in 30% of cases. Radiological assessment documented maximal accuracy of scaffold positioning when the scaffold was created on the real defect; accuracy was satisfactory when the predicted clivectomy was performed under neuronavigation guidance. The cerebrospinal fluid leak pressure point was significantly higher when the scaffold was fixed with screws compared with the gasket technique. Conclusions In this preclinical setting, additive manufacturing allows the creation of customized scaffolds that are effective in reconstructing even large and geometrically complex clival defects.

Purpose The aim of our study was to evaluate the prevalence of different HPV genera—alpha, beta and gamma—in Juvenile onset Recurrent Respiratory Papillomatosis (JoRRP) and examine the association of type and genus-specific viral features with the clinical outcome of disease. Methods This retrospective observational study included consecutive patients with JoRRP who were treated in a referral centre between October 2000 and October 2020. All patients underwent cold excision and laser vaporisation of papillomatous lesions. Samples were analysed for the presence of 120 viral genotypes (22 alpha-HPV, 46 beta-HPV, 52 gamma-HPV) using a highly sensitive multiplex genotyping assay. Results Twenty patients with JoRRP, aged 0.3–11 years, were included, with a median follow-up of 13.5 years. All samples were HPV DNA positive: 20 (100%) for alpha-HPV DNA; 7 (35%) for beta—HPV DNA; 0 for gamma-HPV DNA. Three groups were defined according to the number of infections: seven cases (35%) with HPV mono-infection; ten cases (50%) with HPV double-infection; three cases (15%) with ≥ 3 HPV infections. At diagnosis, patients with ≥ 3 HPV infections reported higher median Derkay’s score than those with mono-infection (21 vs 14, P = 0.018). Number of HPV infections was also associated with clinical outcomes, with an average of 0.5 surgical procedures/year in patients with mono-infection, 1.2 for double-infection, 2.6 for ≥ 3 infections (P = 0.006). Conclusion Despite the small sample size, these preliminary data support an association between the number of different alpha and beta HPV co-infections and the clinical severity of the disease.

Pleomorphic adenoma (PA) is the most common benign parotid tumor, with a well-known propensity to recur. Many factors have been advocated as prognostic, but there is no consensus on how they affect local control. We studied how PA recurrence-free survival (RFS) may be affected by the most relevant risk factors in a time-to-event analysis, comparing them with those observed in a population of non-PA (NPA). Patients undergoing parotidectomy for benign lesions between 2002 and 2018 in a single academic tertiary referral center were included. A description of patients, tumors, and treatment characteristics was performed, highlighting differences between PA and NPA. Analysis of PA RFS and relative risk factors was also conducted. Eight hundred fifty patients underwent parotidectomy for benign lesions, 455 (53.5%) for PA and 57 (6.7%) for NPA. Significant differences between PA and NPA were age at surgery, surgical procedure, and resection margins. Recurrence occurred in 3.1% of PA, with a median disease-free interval of 54 months. 2-, 5-, and 10-year RFS were 99.2, 98.5, and 93.9%, respectively. Age

Resumen Objetivo El objetivo de este estudio fue investigar la precision diagnostica de la PET/TC con 18F-FDG en la estadificacion del cancer de laringe, comparar estos resultados con las tecnicas de imagen convencional ( C I) y evaluar los parametros metabolicos para predecir la supervivencia. Metodos Estudio retrospectivo que incluye cincuenta y cuatro pacientes con cancer escamoso de laringe que acudieron para realizacion de estadificacion mediante PET/TC con 18F-FDG. Las imagenes PET se analizaron visualmente y semicuantitativamente midiendo varios parametros metabolicos. Se tomo como estandar de referencia el seguimiento clinico, por imagen y/o histopatologia. Se calculo el tiempo libre de enfermedad y la supervivencia mediante curvas de Kaplan-Meier. Resultados Todos los tumores fueron identificados por las CI y 52/54 por la PET/TC con 18F-FDG, con sensibilidad del 96,3%. La sensibilidad, especificidad, valor predictivo positivo, valor predictivo negativo y precision, basada en el analisis por paciente para la deteccion de enfermedad ganglionar fue del: 100%, 85,7%, 94,6%, 100% y 95,9% para la PET/TC con 18F-FDG y del 91,4%, 85,7%, 94,1%, 80% y 89,9% para las CI. El rendimiento diagnostico de la PET/TC y las CI no fue significativamente diferente ni en analisis por paciente, ni en el de la lateralizacion ni el de los niveles ganglionares. La PET/TC con 18F-FDG detecto metastasis a distancia en 7 pacientes que permitieron una estadificacion superior. En una mediana de seguimiento de 27 meses, la recaida/progresion de la enfermedad ocurrio en 31 pacientes y muerte en 32. El volumen metabolico tumoral (VMT) y la glucolisis total (TLG) de la lesion primaria se mostraron como factores pronosticos independientes para el tiempo libre de enfermedad. Conclusiones Tanto las CI como la PET/TC con 18F-FDG mostraron resultados diagosticos en la estadificacion del cancer de laringe. Los parametros metabolicos basales (MTV y TLG) mostraron valor pronostico en la evaluacion del tiempo libre de enfermedad.

Objective: Recently, a novel host‐related index, the Host‐index (H‐index), including both inflammatory and nutritional markers, has been described and observed to stratify prognosis in patients with squamous cell carcinoma (SCC) of the oral cavity more accurately than other host‐related indexes This study aimed to investigate the prognostic performance of the H‐index using pretreatment blood tests in patients receiving up‐front surgery for SCC of the larynx. Methods: This retrospective observational study included a multicenter series of consecutive patients with SCC of the larynx diagnosed between 1 January 2009 and 31 July 2018, whose pretreatment blood tests were available and included the parameters necessary for the calculation of neutrophil to lymphocyte ratio (NLR) and the H‐index. Their association with disease‐free survival (DFS) and overall survival (OS) was measured. Results: A total of 231 patients were eligible for the present analysis (median [range] age, 68 [37‐96] years; 191 [82.7%] men). The median follow‐up was 73 months. In multivariable Cox proportional hazards regression models, increasing age (adjusted hazard ratio [aHR], 1.07 per year; 95% CI, 1.04‐1.09), advanced pT stage (aHR = 1.71 95% CI: 1.07‐2.71), and having close or positive surgical margins (aHR = 2.01; 95% CI: 1.21‐3.33) were significantly associated with poor OS. Among blood parameters, a higher neutrophil count was a strong predictor of both worse DFS (aHR for recurrence/death = 2.34; 95% CI: 1.24‐4.40) and OS (aHR for death = 2.67; 95% CI: 1.51‐4.71). Among inflammatory blood indexes, while NLR was not significantly associated with DFS or OS, patients with H‐index ≥8.37 showed a higher aHR for both recurrence/death (2.82; 95% CI: 1.65‐4.79) and death (2.22; 95% CI: 1.26‐3.89). Conclusion: In conclusion, the present study confirms the prognostic value of pretreatment H‐index, an easily measurable inflammatory and nutritional index, in patients with SCC of the larynx. Level of Evidence: III

Quando è indicato un approccio chirurgico multidisciplinare nei tumori naso-sinusali con estensione cranica?I tumouri nasosinusali includono un ampio spettro di neoplasie caratterizzate da un comportamento biologico eterogeneo e dalla localizzazione in un distretto anatomico critico. Diverse discipline mediche sono coinvolte nella diagnosi e nel trattamento di tali tumori. Una revisione narrativa della letteratura è stata condotta per identificare i ruoli delle specialità chirurgiche che appartengono al gruppo multidisciplinare. La diagnosi e la stadiazione dei tumori nasosinusali richiede la collaborazione tra chirurghi, radiologi e patologi. L’identificazione delle estensioni tumorali critiche è fondamentale per un corretto trattamento. L’intervento chirurgico necessario per la maggior parte dei tumori nasosinusali avanzati può essere eseguito da un team otorinolaringoiatrico con adeguato training. Il contributo di neurochirurghi e di specialisti in chirurgia orbitaria è necessario in scenari selezionati. Nei casi di difetti chirurgici complessi possono essere necessarie strategie ricostruttive multidisciplinari. La collaborazione chirurgica multidisciplinare è essenziale per la gestione delle complicanze nel periodo perioperatorio. Nonostante la chirurgia rimanga il trattamento principale, si sta affermando una vasta gamma di trattamenti non-chirurgici, adiuvanti o esclusivi.The term “sinonasal tumours” includes a large spectrum of diseases, which are characterized by heterogeneous biological behavior and prognosis, and located in a critical anatomic area. Diagnosis and treatment of sinonasal tumours require the contribution of different disciplines. A narrative review was performed to highlight the role of surgeons in contributing to a multidisciplinary approach to sinonasal tumours. Diagnosis and staging of sinonasal tumours is challenging and requires collaboration between surgeons, radiologists, and pathologists. The identification and management of critical extensions (orbital or intracranial encroachment, vascular abutment or encasement) is fundamental for successful treatment. Most cases of advanced sinonasal tumours can undergo surgical intervention by an adequately trained otorhinolaryngological team. The contribution of neurosurgeons and oculoplastic surgeons is required in selected scenarios. In rare circumstances, multidisciplinary reconstructive strategies can be indicated for complex tissue defects. Furthermore, a multidisciplinary approach is pivotal in the management of perioperative complications. While surgery remains the mainstay of treatment, the role of non-surgical adjuvant or even exclusive treatments is constantly expanding.

Background Nomograms applying the 8th edition of the TNM staging system aimed at predicting overall (OS), disease-specific (DSS), locoregional recurrence-free (LRRFS) and distant recurrence-free survivals (DRFS) for oral tongue squamous cell carcinoma (OTSCC) are still lacking. Methods A training cohort of 438 patients with OTSCC was retrospectively enrolled from a single institution. An external validation set of 287 patients was retrieved from two independent institutions. Results Internal validation of the multivariable models for OS, DSS, DRFS and LRRFS showed a good calibration and discrimination results with optimism-corrected c-indices of 0.74, 0.75, 0.77 and 0.70, respectively. The external validation confirmed the good performance of OS, DSS and DRFS models (c-index 0.73 and 0.77, and 0.73, respectively) and a fair performance of the LRRFS model (c-index 0.58). Conclusions The nomograms herein presented can be implemented as useful tools for prediction of OS, DSS, DRFS and LRRFS in OTSCC.

To compare the accuracy of contrast-enhanced MRI using established dimensional and morphological criteria versus integrated [18F]FDG PET/MRI in identifying regional lymph node metastases in patients with newly diagnosed head and neck squamous cell carcinoma (HNSCC). For this purpose, we compare MRI and PET/MRI using the histopathological findings in dissected lymph nodes as the gold standard. We retrospectively reviewed 26 patients with histologically proven HNSCC who underwent gadolinium-enhanced [18F]FDG PET/MRI as part of their staging. All neck lymph nodes were classified on MRI using dimensional and/or morphological criteria. Then, they were jointly assessed by a nuclear medicine physician and a radiologist using integrated [18F]PET/MR images. ROC curves were obtained to compare the techniques. Lymph node histopathology was considered as the reference standard. Out of 865 lymph nodes, 35 were malignant at histopathology (3 with micro-metastases). Sensitivity and specificity were 48.6% and 99.5% for MRI using dimensional criteria; 60.0% and 99.6% for MRI using morphological criteria; 60.0% and 99.4% for MRI using both; and 74.3% and 97.6% for PET using MR as anatomic localization. The area under the ROC curve was higher for PET and MRI localization (0.859) than for MRI using dimensional (0.740; p

BACKGROUND This study aimed to develop a novel temporal bone squamous cell carcinoma (TBSCC) prognosis scoring system and compare it with the revised Pittsburgh staging system. METHODS Forty-four consecutive TBSCC patients were assessed to identify predictors of recurrence. Each predictor's hazard ratio for recurrence was used to develop our novel scoring system. RESULTS Based on variables with P

COVID-19 e olfatto: revisione critica della letteratura sulla valutazione olfattiva.Da dicembre 2019, in seguito alla comparsa in Cina di una nuova infezione da Coronavirus (COVID-19), si è assistito alla diffusione di una pandemia. In un numero significativo di pazienti è stata riscontrata la comparsa di alterazioni dell’olfatto anche in assenza di altri sintomi tipici dell’infezione. In questa revisione della letteratura sono stati inclusi gli articoli pubblicati da gennaio 2020 sull’alterazione olfattiva nei pazienti COVID-19 e in particolare i metodi utilizzati per la diagnosi. L’analisi della letteratura ha mostrato che la diagnosi dell’alterazione olfattiva in questi pazienti è stata eseguita principalmente mediante questionari. Pochi studi si sono basati sulla valutazione olfattiva mediante test psicofisici validati. Sono emerse discrepanze tra l’alterazione olfattiva riportata nei questionari e la valutazione olfattiva eseguita mediante test psicofisici. Ad oggi lo studio dell’olfatto nei pazienti COVID-19 è stato eseguito in maniera eterogenea e principalmente basata sui sintomi riferiti dai pazienti portando a risultati spesso contrastanti. Gli autori suggeriscono di utilizzare test olfattivi psicofisici, semplici, validati e somministrabili anche in assenza di un operatore al fine di confermare l’alterazione olfattiva in questi pazienti che spesso sono in quarantena, isolati o ospedalizzati.Since December 2019, an outbreak of a newly isolated coronavirus (SARS-CoV-2) appeared in Wuhan, China, and then spread worldwide. Recently, it has emerged that a number of patients may present with sudden hyposmia, sometimes without other symptoms of the disease. We performed a critical review on the methods used to date to investigate the olfactory function in COVID-19 patients in order to establish which should be considered the most appropriate to use during this pandemic. Literature analysis showed that the diagnosis of hyposmia in COVID-19 patients was mainly made through subjective symptomatology collected by questionnaires and/or interview. Psychophysical tests were carried out in a few studies showing significant discrepancies between the self-reported sense of smell and test results. To date the methods used by authors to investigate smell impairment in COVID-19 patients have been very heterogeneous and predominantly based on self-reported questionnaires leading to confusing and inconclusive results. We suggest that simple validated self-administered psychophysical olfactory tests could be a valuable instrument to investigate isolated/quarantined or hospitalised COVID-19 patients referring smell impairment in order to confirm olfactory dysfunction.

To compare the most important techniques usually used in these patients.A multicentric retrospective evaluation on patients treated for cT1/2 N0 OTFOM SCC was conducted; patients in group A were treated by transoral approach and miomucosal local flap while those in group B were treated by pull-through and free flap reconstruction. Oncologic, functional and quality of life evaluation was assessed.55 patients were enrolled. Group A consisted of 35 patients and group B 20. At the 3-year follow-up 30 and 17 patients in group A and B were alive without disease. Tongue mobility index score was 23.3 in group A and 13.89 in group B (p .001); Sydney swallowing mean score was 118.5 and 543.22 in group A and B (p .001). EORTC QLC-C30 was of 33.57 in group A and 38.89 in group B (p = 0.057).T1/T2 cancers of the tongue and floor of the mouth can be equally treated with both techniques. Because of the fact that transoral resection with buccinators reconstruction provides better functional outcome, this technique should be preferred whenever appropriate.

ObjectiveTo date, no useful prognostic biomarker exists for patients with oral squamous cell carcinoma (OCSCC), a tumour with uncertain biological behaviour and subsequent unpredictable clinical course. We aim to investigate the prognostic significance of two recurrent somatic mutations (-124 C>T and -146 C>T) within the promoter of telomerase reverse transcriptase (TERT) gene and the impact of TERT single nucleotide polymorphism (SNP) rs2853669 in patients surgically treated for OCSCC.MethodsThe genetic frequencies of rs2853669, -124 C>T and -146 C>T as well as the telomere length were investigated in 144 tumours and 57 normal adjacent mucosal (AM) specimens from OCSCC patients.ResultsForty-five tumours harboured TERT promoter mutations (31.3%), with -124 C>T and -146 C>T accounting for 64.4% and 35.6% of the alterations respectively. Patients with -124 C>T TERT promoter mutated tumours had the shortest telomeres in the AM (p=0.016) and showed higher risk of local recurrence (hazard ratio [HR]:2.75, p=0.0143), death (HR:2.71, p=0.0079) and disease progression (HR:2.71, p=0.0024) with the effect being potentiated by the co-occurrence of T/T genotype of rs2853669.Conclusion-124 C>T TERT promoter mutation as well as the T/T genotype of the rs2853669 SNP are attractive independent prognostic biomarkers in patients surgically treated for OCSCC, with the coexistence of these genetic variants showing a synergistic impact on the aggressiveness of the disease.

BackgroundThe resection of advanced maxillary sinus cancers can be challenging due to the anatomical proximity to surrounding critical anatomical structures. Transnasal endoscopy can effectively aid the delineation of the posterior margin of resection. Implementation with 3D-rendered surgical navigation with virtual endoscopy (3D-SNVE) may represent a step forward. This study aimed to demonstrate and quantify the benefits of this technology.Material and MethodFour maxillary tumor models with critical posterior extension were created in four artificial skulls (Sawbones®). Images were acquired with cone-beam computed tomography and the tumor and carotid were contoured. Eight head and neck surgeons were recruited for the simulations. Surgeons delineated the posterior margin of resection through a transnasal approach and avoided the carotid while establishing an adequate resection margin with respect to tumor extirpation. Three simulations were performed: 1) unguided: based on a pre-simulation study of cross-sectional imaging; 2) tumor-guided: guided by real-time tool tracking with 3D tumor and carotid rendering; 3) carotid-guided: tumor-guided with a 2-mm alert cloud surrounding the carotid. Distances of the planes from the carotid and tumor were classified as follows and the points of the plane were classified accordingly: “red”: through the carotid artery; “orange”: 2 mm from the carotid and within the tumor or 2 mm from the carotid and 5–10 mm from the tumor; and “blue”: >2 mm from the carotid and >10 mm from the tumor. The three techniques (unguided, tumor-guided, and carotid-guided) were compared.Results3D-SNVE for the transnasal delineation of the posterior margin in maxillary tumor models significantly improved the rate of margin-negative clearance around the tumor and reduced damage to the carotid artery. “Green” cuts occurred in 52.4% in the unguided setting versus 62.1% and 64.9% in the tumor- and carotid-guided settings, respectively (p < 0.0001). “Red” cuts occurred 6.7% of the time in the unguided setting versus 0.9% and 1.0% in the tumor- and carotid-guided settings, respectively (p < 0.0001).ConclusionsThis preclinical study has demonstrated that 3D-SNVE provides a substantial improvement of the posterior margin delineation in terms of safety and oncological adequacy. Translation into the clinical setting, with a meticulous assessment of the oncological outcomes, will be the proposed next step.

The clivus was defined as “no man’s land” in the early 1990s, but since then, multiple approaches have been described to access it. This study is aimed at quantitatively comparing endoscopic transnasal and microsurgical transcranial approaches to the clivus in a preclinical setting, using a recently developed research method. Multiple approaches were performed in 5 head and neck specimens that underwent high-resolution computed tomography (CT): endoscopic transnasal (transclival, with hypophysiopexy and with far-medial extension), microsurgical anterolateral (supraorbital, mini-pterional, pterional, pterional transzygomatic, fronto-temporal-orbito-zygomatic), lateral (subtemporal and subtemporal transzygomatic), and posterolateral (retrosigmoid, far-lateral, retrolabyrinthine, translabyrinthine, and transcochlear). An optic neuronavigation system and dedicated software were used to quantify the working volume of each approach and calculate the exposure of different clival regions. Mixed linear models with random intersections were used for statistical analyses. Endoscopic transnasal approaches showed higher working volume and larger exposure compared with microsurgical transcranial approaches. Increased exposure of the upper clivus was achieved by the transnasal endoscopic transclival approach with intradural hypophysiopexy. Anterolateral microsurgical transcranial approaches provided a direct route to the anterior surface of the posterior clinoid process. The transnasal endoscopic approach with far-medial extension ensured a statistically larger exposure of jugular tubercles as compared with other approaches. Presigmoid approaches provided a relatively limited exposure of the ipsilateral clivus, which increased in proportion to their invasiveness. This is the first anatomical study that quantitatively compares in a holistic way exposure and working volumes offered by the most used modern approaches to the clivus.

Background Human papillomavirus (HPV)-related squamous cell carcinoma of unknown primary (SCCUP) is currently rising in incidence but lacks a validated management approach. Aims This paper reviews the clinical presentation, diagnosis, and treatment of HPV-related SCCUP. Materials and methods The Medline/Pubmed database was searched by using the following keywords "CUP", "cancer of unknown primary", "HPV", "human papilloma virus", and "head and neck". The references of the publications of interest were also screened for relevant papers. Results The clinical assessment of HPV-related SCCUP includes a complete clinical examination, an endoscopic evaluation with white-light and narrow band imaging, and radiologic assessment using morphologic and metabolic imaging. If the diagnosis remains unconfirmed, endoscopic examination under anesthesia with tonsillectomy ± base of tongue mucosectomy is performed. The therapeutic rationale aims to eradicate the involved lymph nodes and potential primary tumor with a sequence of chemoradiotherapy and neck dissection. Discussion As a general approach, p16-negative SCCUP are truly HPV negative, whereas p16-positive specimens require confirmation with HPV in situ hybridization or polymerase chain reaction to confirm HPV infection. If a cervical metastasis is considered HPV positive, the primary lesion is likely in the oropharynx, and further diagnostic interventions such as tonsillectomy seems to be mandatory. Whether the optimal treatment is neck dissection followed by adjuvant radiotherapy or concomitant chemoradiotherapy (CRT) (in case of extranodal extension or advanced lymph node stages) or definitive CRT followed by neck dissection (in case of positive 18 F-FDG-PET/CT) remains a matter of debate. Solid scientific evidence supporting treatment de-escalation in HPV-related SCCUP is lacking, and the results of ongoing trials are at the brink of reporting. Conclusion Currently, the treatment of patients with HPV-related SCCUP should not differ from the standard treatment of other SCCUP patients and is similarly based on the staging of the disease and general condition of the patient.

Oral cavity squamous cell carcinoma (OSCC) is a common head and neck cancer characterized by a poor prognosis associated with locoregional or distant failure. Among the predictors of prognosis, a dense infiltration of adaptive immune cells is protective and associated with improved clinical outcomes. However, few tools are available to integrate immune contexture variables into clinical settings. By using digital microscopy analysis of a large retrospective OSCC cohort (n = 182), we explored the clinical significance of tumor-infiltrating CD8+ T-cells. To this end, CD8+ T-cells counts were combined with well-established clinical variables and peripheral blood immune cell parameters. Through variable clustering, five metavariables (MV) were obtained and included descriptors of nodal (NODALMV) and primary tumor (TUMORMV) involvement, the frequency of myeloid (MYELOIDMV) or lymphoid (LYMPHOIDMV) peripheral blood immune cell populations, and the density of tumor-infiltrating CD8+ T-cells (TI-CD8MV). The clinical relevance of the MV was evaluated in the multivariable survival models. The NODALMV was significantly associated with all tested outcomes (p &lt, 0.001), the LYMPHOIDMV showed a significant association with the overall, disease-specific and distant recurrence-free survival (p &lt, 0.05) and the MYELOIDMV with the locoregional control only (p &lt, 0.001). Finally, TI-CD8MV was associated with distant recurrence-free survival (p = 0.029). Notably, the performance in terms of survival prediction of the combined effect of NODALMV and immune metavariables (LYMPHOIDMV, MYELOIDMV and TI-CD8MV) was superior to the TNM stage for most of the outcomes analyzed. These findings indicate that the analysis of the baseline host immune features are promising tools to complement clinical features, in stratifying the risk of recurrences.

Purpose The aim of our study is to evaluate the prevalence of different HPV genera – alpha, beta and gamma – in Juvenile onset Recurrent Respiratory Papillomatosis (JoRRP) and examine the association of type and genus-specific viral features with the clinical outcome of disease. Methods This retrospective observational study includes consecutive patients with JoRRP who were treated in a referral centre between October 2000 and October 2020. All patients underwent cold excision and laser vaporization of papillomatous lesions. Samples were analysed for the presence of 120 viral genotypes (22 alpha-HPV, 46 beta-HPV, 52 gamma-HPV) using a highly sensitive multiplex genotyping assay. Results Twenty patients with JoRRP, aged 0.3–11 years old, were included, with a median follow-up of 13.5 years. All samples were HPV DNA positive: 20 (100%) for alpha-HPV DNA; 7 (35%) for beta – HPV DNA; 0 for gamma-HPV DNA. Three groups were defined according to the number of infections: seven cases (35%) with HPV mono-infection; ten cases (50%) with HPV double-infection; three cases (15%) with ≥ 3 HPV infections. At diagnosis, patients with ≥ 3 HPV infections reported higher median Derkay’s score than those with mono-infection (21 vs 14, P = 0.018). Number of HPV infections was also associated with clinical outcomes, with an average of 0.5 surgical procedures/year in patients with mono-infection, 1.2 for double-infection, 2.6 for ≥ 3 infections (P = 0.006). Conclusion Despite the small sample size, these preliminary data support an association between the number of different alpha and beta HPV co-infections and the clinical severity of the disease.

Skull base cephaloceles (SBCs) are defined as herniation of intracranial content through the skull base and are classified based on composition, etiology, and topographic location. Anterior SBCs frequently protrude in the sinonasal cavity, and consequently are at potential risk of infection. Therefore, the current recommendation is to treat SBCs with the primary intent of preventing meningitis, and surgery represents the mainstay of treatment. Anterior SBCs may display a wide spectrum of severity and complexity, and in each case the risks and benefits of surgical approaches are to be carefully weighted based on thorough assessment of symptoms, age, general conditions, location and size of the lesion, as well as expertise of the surgeon. In the last 30 years, the evolution and diffusion of transnasal endoscopic surgery have substantially changed the surgical management of the majority of SBC. In the past, they were treated exclusively with open transcranial approaches that may be burdened by relevant morbidity and risk for severe complications. The transnasal endoscopic corridor now provides easy access to the lesion and different reconstructive strategies using endonasal pedicled flaps, without any external incision, cranioplasty or brain manipulation. However, there are still scenarios in which an exclusive transnasal endoscopic route is contraindicated. The aim of the present review was to provide an overview on the comprehensive management of anterior SBC, with a particular focus on lesions suitable for endoscopic surgery. Furthermore, special aspects of SBC management in children and adults will be highlighted.

Objective Different surgical set-ups for endoscopic transsphenoidal surgery (ETS) have been described, but studies on their ergonomics are limited. The aim of this article is to describe present trends in the ergonomics of ETS. Design and Participants A 33-question, web-based survey was sent to North American Skull Base Society members in 2018 and 116 responded to it (16% of all members). Most respondents were from North America (76%), in academic practice (87%), and neurosurgeons (65%); they had more than 5 years of experience in ETS (73%), had received specific training (66%), and performed at least 5 procedures/mo (55%). Results Mean reported time for standard and complex procedures were 3.7 and 6.3 hours, respectively. The patient's body is usually positioned in a straight, supine position (84%); the head is in a neutral position (46%) or rotated to the side (38%). Most surgeons perform a binostril technique, work with a partner (95%), and operate standing (94%), holding suction (89%) and dissector (83%); sometimes the endoscope is held by the primary surgeon (22–24%). The second surgeon usually holds the endoscope (72%) and irrigation (42%). During tumor removal most surgeons stand on the same side (65–66%). Many respondents report strain at the dorsolumbar (50%) or cervical (26%) level. Almost one-third of surgeons incorporate a pause during surgery to stretch, and approximately half exercise to be fit for surgery; 16% had sought medical attention for ergonomic-related symptoms. Conclusion Most respondents value ergonomics in ETS. The variability in surgical set-ups and the relatively high report of complaints underline the need for further studies to optimize ergonomics in ETS.

Objectives Nodal metastasis is an important prognosticator in primary parotid cancers. The management of the clinically node-negative neck is an area lacking consensus. This study investigates the occult nodal metastasis rate, and prognostic indicators in primary parotid cancers. Materials and methods We performed a multicentre retrospective case note review of patients diagnosed and treated surgically with curative intent between 1997 and 2020. Demographic, clinic-pathological and follow-up data was recorded. Results After exclusions, 334 patients were included for analysis, with a median follow-up of 48 months. The overall rate of occult lymph node metastasis amongst patients undergoing elective neck dissection was 22.4%, with older age, high-grade and more advanced primary tumours being associated with higher rates. On multivariable analysis, age ≥ 60 years (HR = 2.69, p = 0.004), high-grade tumours (HR = 2.70, p = 0.005) and advanced primary tumours (pT3-4, HR = 2.06, p = 0.038) were associated with worse overall survival. Occult nodal metastasis on final pathology was associated with a close-to-significant reduction in regional recurrence free survival (HR = 3.18, p = 0.076). Conclusion This large series confirms the significant occult lymph node metastasis rate in primary parotid cancer, and demonstrates the importance of primary histology, tumour grade and stage in predicting survival outcome. This data supports the use of elective neck dissection in patients with high-risk tumours.

Despite differences in oncological behavior, the 8th edition of AJCC TNM staging currently proposes the same N-classification for major salivary glands (MSG) carcinoma and squamous cell carcinoma of the upper aerodigestive tract. The present study aims to investigate a more reliable definition of N-categories for MSG carcinoma.A retrospective multicenter study was performed, including 307 patients treated for primary MSG carcinoma from 1995 to 2019. Outcome measures included overall survival (OS), disease specific survival, and local, regional, and distant recurrence. Survival analysis was performed using log-rank test and Cox proportional-hazards model. Overall number (ON) and largest diameter (LD) of nodal metastases, including intra-parotid metastases, were considered to develop three novel proposals of N-classification; their performance were compared with the current TNM staging using Akaike information criterion (AIC), Bayesian information criterion (BIC), and Nagelkerke pseudo-RIntra-parotid nodes, ON and LD of nodal metastases emerged as major prognosticators for OS, while extra-nodal extension did not impact on any survival. The current N-classification did not show a satisfactory OS stratification. Three novel N-classifications were developed according to number of metastatic nodes (0 vs 1-3 vs ≥ 4) and/or their maximum diameter (20 mm vs ≥ 20 mm). They all showed better accuracy in OS stratification, and achieved better AIC, BIC and Nagelkerke pseudo-RAll the proposed N-classifications improved OS stratification and could help in defining a specific N-classification for MSG carcinoma. Their validation and assessment in an external cohort is needed.

Recently, endoscopic transsphenoidal transclival approaches have been developed and their role is widely accepted for extradural pathologies. Their application to intradural pathologies is still debated, but is undoubtedly increasing. In the past five decades, different authors have reported various extracranial, anterior transclival approaches for intradural pathologies. The aim of this review is to provide a historical overview of transclival approaches applied to intradural pathologies. PubMed was searched in October 2018 using the terms transcliv*, cliv* intradural, transsphenoidal transcliv*, transoral transcliv*, transcervical transcliv*, transsphenoidal brainstem, and transoral brainstem. Exclusion criteria included not reporting reconstruction technique, anatomical studies, reviews without new data, and transcranial approaches. Ninety-one studies were included in the systematic review. Since 1966, transcervical, transoral, transsphenoidal microsurgical, and, recently, endoscopic routes have been used as a corridor for transclival approaches to treat intradural pathologies. Each approach presents a curve that follows Scott’s parabola, with evident phases of enthusiasm that quickly faded, possibly due to high post-operative CSF leak rates and other complications. It is evident that the introduction of the endoscope has led to a significant increase in reports of transclival approaches for intradural pathologies. Various reconstruction techniques and materials have been used, although rates of CSF leak remain relatively high. Transclival approaches for intradural pathologies have a long history. We are now in a new era of interest, but achieving effective dural and skull base reconstruction must still be definitively addressed, possibly with the use of newly available technologies.

Olfactory neuroblastoma (ONB) is a rare sinonasal neoplasm with a peculiar behavior, for which limited prognostic factors are available. Herein, we investigate the transcriptional pathways altered in ONB and correlate them with pathological features and clinical outcomes. We analyze 32 ONB patients treated with curative intent at two independent institutions from 2001 to 2019 for whom there is available pathologic and clinical data. We perform gene expression profiling on primary ONB samples and carry out functional enrichment analysis to investigate the key pathways associated with disease-free survival (DFS). The median age is 53.5 years, all patients undergo surgery and a pure endoscopic approach is adopted in the majority of cases (81.2%). Most patients have advanced disease (stages III–IV, 81.2%) and 84.4% undergo adjuvant (chemo)radiotherapy. The median follow-up is 35 months, 11 (26.8%) patients relapse. Clinical characteristics (gender, stage and Hyams’ grade) are not associated with the outcomes. In contrast, TGF-beta binding, EMT, IFN-alpha response, angiogenesis, IL2-STAT5 and IL6-JAK-STAT3 signaling pathways are enriched in patients experiencing recurrence, and significantly associated with shorter DFS. Clustering of transcriptional profiles according to pathological features indicates two distinct molecular groups, defined by either cytokeratin-positive or -negative immunostaining. Definition of the characterizing ONB transcriptomic pathways may pave the way towards tailored treatment approaches.

Background This study aims to develop and validate a new classification system that better predicts combined risk of neurological and neurovascular complications following CBT surgery, crucial for treatment decision-making. Methods Multinational retrospective cohort study with 199 consecutive cases. A cohort of 132 CBT cases was used to develop the new classification. To undertake external validation, assessment was made between the actual complication rate and predicted risk by the model on an independent cohort (n = 67). Results Univariate analyses showed statistically significant associations between developing a complication and the following factors: craniocaudal dimension, volume, Shamblin classification, and Mehanna types. In the multivariate prognostic model, only Mehanna type remained as a significant risk predictor. The risk of developing complications increases with increasing Mehanna type. Conclusions We have developed and then validated a new classification and risk stratification system for CBTs, which demonstrated better prognostic power for the risk of developing neurovascular complications after surgery.

Background After internal carotid artery (ICA) injury during endoscopic skull base surgery, the majority of patients undergo ICA embolization or stenting to treat active extravasation or pseudoaneurysm development. However, management practices when embolization or stenting is not required have not been well described. The objective of this study was to determine how patients with ICA injury but no embolization, stenting, or ligation do long‐term and ascertain the reconstruction methods utilized. Methods Twenty‐nine cases of ICA injury were identified in an international multi‐institutional retrospective review. Of these, we identified six cases that were not treated with embolization, stenting, or ICA sacrifice. Information was available for five cases. Results A muscle patch was used in the immediate repair of each case. A nasoseptal flap was used in one case. Prefabricated nasal tampons were used in all cases. Nasal packing was initially left in for a median of 7 days prior to removal. The initial muscle patch was reinforced with a second muscle graft in one case. One case demonstrated ICA bleeding at the time of packing removal and was repacked an additional week. Follow‐up for each of these cases was at least 2 years. No cases of subsequent carotid rupture were found and none of these cases ultimately underwent endovascular stenting. Radiation or proton therapy has not been subsequently used in any of these patients. Conclusions This study details the reconstruction, lessons learned, and long‐term follow‐up for five cases of ICA injury not treated with embolization, stenting, or ligation.

The concept of surgical margins was born a long time ago but still lacks a univocal and sound understanding. The current biological rationale behind the recommendations on margins management relies on two pillars: (1) the observation that groups of cancer cells can leave the macroscopic tumor and disseminate throughout adjacent tissues with different degrees of aggressiveness; (2) the belief that removal of all (or most of) cancer cells can cure the patient. However, this background is undermined by some pieces of evidence. For instance, it has been proven that tissues surrounding cancer often bear precancerous traits, which means that cutting through non-cancerous tissues does not equate to cut through healthy tissues. The head and neck exquisitely poses a number of challenges in the achievement of negative margins, with special reference to anatomical complexity, high density in relevant structures, and unique histological heterogeneity of cancers. Currently, intraoperative margins evaluation relies on surgeons’ sight, palpation, ability to map tumor extension on imaging, and knowledge of anatomy, with some optical imaging technologies aiding the delineation of the mucosal margins of excision. Frozen sections are currently used to intraoperatively evaluate margins, yet with debate on whether and how this practice should be performed. Future perspectives on improvement of margins control are threefold: research is oriented towards refinements of understanding of cancers local progression, implementation of technologies to intraoperatively render tumor extension, and employment of optical imaging modalities capable of detecting foci of residual tumor in the surgical bed.

Background: To evaluate the diagnostic performance of [ 18 F]fluorodeoxyglucose positron emission tomography/computed tomography ([ 18 F]FDG-PET/CT) scan in detecting local recurrences in patients with surgically treated oral tongue squamous cell cancer (OTSCC). Material and methods: Eighty-seven patients who had undergone surgery for OTSCC were monitored clinically and [ 18 F]FDGPET/CT and magnetic resonance (MR). PET uptakes were classified as functional (Type A), suspicious (Type B), or highly suggestive of local recurrence (Type C). A multidisciplinary team (MDT) evaluated case-by-case the surveillance strategy based on PET uptake. Results: Fifty-nine patients presented FDG-PET uptake during follow-up: this report was significantly more frequent in patients who received flap reconstruction than in those without (73% vs 50%; p = 0.05). In 13 patients with Type A (n = 1), Type B (n = 9), and Type C (n = 3) uptakes an additional MR was considered preferable and discovered recurrence in 12.PET-CT had 9 true positives, 17 false positives, 71 true negatives, and no false-negative, resulting in sensitivity, specificity, positive (PPV) and negative predictive values (NPV) of 100%, 80.7%, 34.6%, and 100%. Conclusions: The present results demonstrated a change in diagnostic strategy, as decided by the MDT, in about one-fifth of patients. The results should prompt in designing a rational surveillance schedule in surgically treated OTSCC.

Encroachment on the orbital cavity represents a challenge in the management of sinonasal cancer. Criteria guiding orbital preservation lack univocal consensus. Stage of orbital involvement is best assessed through magnetic resonance imaging (MRI).Patients affected by orbit-encroaching sinonasal cancer with available preoperative MRI, receiving surgery-based treatment at the University of Brescia between May 2005 and October 2018 were included. All cases were reviewed by expert radiologists and pathologists. Diagnostic performance of MRI was calculated using pathological information as reference. Survival analysis was performed.The study included 123 patients. The orbit was abutted in 53 (43.1%) patients, whereas orbital invasion reached the periorbit in 18 (14.6%), extraconal fat and/or medial lacrimal sac in 29 (23.6%), extrinsic ocular muscles in 7 (5.7%), intraconal compartment in 4 (3.3%), and orbital apex in 12 (9.8%). Seventy-six (61.8%) patients received orbit-sparing surgery, 47 (38.2%) underwent orbital ablation (OA). Accuracy of MRI in detecting involvement by cancer was ≥80.0% for the orbital wall, extraconal fat, and muscles, and80.0% for the periorbit and intraconal compartment. Previous surgery, neoadjuvant chemotherapy, and perineural invasion decreased MRI accuracy. Age, histology, tumor grade, pT category, N status, perineural invasion, orbital invasion stage, and need for OA were found to affect prognosis. Five-year orbital dysfunction-free survival was 92.8%.Conservative management of sinonasal cancers encroaching the orbit is feasible. MRI is essential to preoperatively stage orbital invasion, yet with some limitation. Given the dismal prognosis despite aggressive surgery, neoadjuvant non-surgical therapies should be considered in patients requiring OA.

Background To estimate the rate of occult cervical lymph node metastases in cN0 patients affected by primary parotid carcinomas and to scrutinize the evidence on the indication and extent of elective neck dissection in these neoplasms. Methods Medline, Embase, Web of Science, Cochrane Library and Scopus were searched until August 31, 2020, to identify studies reporting the use of elective neck dissection in the management of malignant parotid tumours. The PRISMA checklist was used. A single arm meta-analysis was then made to determine the pooled rate of occult lymph node metastases. Risk of bias of the included studies was assessed through the ROBINS-E tool. Results The initial search returned 20 541 articles, of which twelve met the inclusion criteria and were included in the meta-analysis. They comprised 1310 patients with parotid carcinoma, of whom 542 cN0 underwent elective neck dissection, which led to the diagnosis of lymph node metastasis (pN+/cN0) in 113 cases. Meta-analysis of the results of elective neck dissection showed an overall rate of occult metastases of 0.22 (99% CI: 0.14-0.30). Locally advanced or high-grade tumours were the commonest indications for elective neck dissection in the included studies. The most dissected lymph node levels were I-II-III, and level II was the commonest site of occult nodal metastases. Conclusions An occult metastasis rate of 0.22 (99% CI: 0.14-0.30) represents a not negligible percentage value, which should encourage further research to outline the most appropriate elective neck management in cN0 patients with parotid carcinomas.

Purpose To identify potential risk factors impacting on overall survival (OS) of patients affected by lymph node metastasis from cutaneous squamous cell carcinoma (cSCC) of the head and neck (HN), with special emphasis on primary tumor characteristics and pattern of nodal recurrence (intraparotid and/or cervical). Methods A bi-institutional retrospective study on consecutive patients affected by cervical and/or intraparotid NM from HN cSCC and surgically treated with curative intent from May 2010 to January 2020 was conducted. OS was considered the outcome of interest. Results The study included 89 patients (M:F = 3.4:1; median age, 78 years; range, 22–99). Among the primary tumor characteristics, the most relevant prognostic factors were diameter ≥ 4 cm (hazard ratio [HR] = 2.56, p = 0.010) and depth of infiltration ≥ 6 mm (HR = 3.54, p = 0.027). Cervical NM was associated with worse OS (HR = 2.09, p = 0.016) compared to purely intraparotid NM (5-year OS: 60.9% vs. 28.1%, p = 0.014). At multivariable analysis, age, immunosuppression, pT3-T4 categories and a high burden of nodal disease (> 2 NM) confirmed to be independent risk factors, whereas adjuvant radiotherapy was independently associated with better outcome. Conclusion This study confirms the association of several independent prognosticators related to the patient, primary tumor, and nodal burden status. Patients with cervical NM should be considered at risk for harboring a higher number of metastatic lymph nodes.

Objective The aim of this study was to investigate the diagnostic accuracy of staging 18 F-FDG-PET/CT in laryngeal cancer, compare these results with conventional imaging (CI) and assess the value of 18 F-FDG-PET/CT features to predict survival. Methods Fifty-four patients with laryngeal squamous cell cancer and baseline 18 F-FDG-PET/CT were retrospectively enrolled. The PET images were analyzed visually and semi-quantitatively by measuring several metabolic parameters. A combination of clinical follow-up/imaging follow-up and/or histopathology was taken as reference standard. Progression free survival (PFS) and disease specific survival (DSS) were computed using Kaplan-Meier curves. Results All primary tumors were clearly identified by CI, and 52/54 by 18 F-FDG-PET/CT with a sensitivity of 96.3%. Cervical nodal metastases were detected in 40/54 patients at 18 F-FDG-PET/CT and in 34/49 patients at CI. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy on a patient-based analysis for nodal disease were 100%, 85.7%, 94.6%, 100% and 95.9% at 18 F-FDG-PET/CT, and 91.4%, 85.7%, 94.1%, 80%, 89.8% at CI. Diagnostic performances of PET/CT and CI were not significantly different on a patient-based, side-by-side and level-by-level analysis. 18 F-FDG-PET/CT recognized distant metastases in 7 patients allowing to an upstaging. At a median follow-up of 27 months, relapse/progression of disease occurred in 31 patients and death occurred in 32. Metabolic tumor volume (MTV T), MTV total and total lesion glycolysis (TLG) showed to be independent prognostic factors for PFS. Conclusions Both CI and PET/CT had good diagnostic performances for the staging of laryngeal cancer; baseline metabolic features (MTV and TLG) showed an important prognostic value in assessing the rate of PFS.

Background Over 50% of patients with head-and-neck squamous cell carcinoma (HNSCC) experience locoregional recurrence, which is associated with poor outcome. In the course of follow-up for patients surviving primary surgery for HNSCC, one might ask: What is the probability of recurrence in one year considering that the cancer has not yet recurred to date? Materials and methods To answer this question, 979 patients surgically treated for HNSCC (i.e. cancer of the oral cavity, oropharynx, hypopharynx or larynx) between March 2004 and June 2018 were enrolled in a multicenter retrospective cohort study, followed up for death and recurrence over a 5 year period. The conditional probability of recurrence in 12 months - i.e. the probability of recurrence in the next 12 months given that, to date, the patient has not recurred - was derived from the cumulative incidence function (Aalen-Johansen method). Results Overall, the probability of recurrence was the highest during the first (17.3%) and the second years (9.6%) after surgery, declining thereafter to less than 5.0% a year thereafter. The probability of recurrence was significantly higher for stage III-IV HNSCCs than for stage I-II HNSCCs in the first year after surgery (20.4% versus 10.0%; p < 0.01), but not thereafter. This difference was most pronounced for oral cavity cancers. No significant differences were observed across different tumor sites. Conclusion This dynamic evaluation of recurrence risk in patients surgically treated for HNSCC provides helpful and clinically meaningful information, which can be useful to patients in planning their future life, and to clinicians in tailoring post-treatment surveillance according to a more personalized risk stratification.

Internal or common carotid artery encasement (CAE) is observed in almost 2-7% of head and neck cancers (HNC) and designates the tumor with the T4b category. This clinical scenario is associated with a dismal prognosis, owing to the risk for thrombosis and bleeding that usually characterizes such an advanced cancer. Standardized radiological criteria to infer invasion of the carotid artery are lacking. Complete surgical resection in the context of a multimodality treatment is supposed to offer the greatest chances of cure. Surgery can either be carotid-sparing or include carotidectomy. Data on probability of cerebrovascular and non-cerebrovascular complications, risk of carotid blowout, poor oncologic outcomes, and less-than-certain efficacy of diagnostic and interventional preventive procedures against cerebral infarction make it difficult to define surgery as the recommended option among other therapeutic strategies. Non-surgical therapies based on radiation therapy possibly combined with chemotherapy are more frequently employed in HNC with CAE. In this context, carotid blowout is the most feared complication, and its probability increases with tumor stage and cumulative radiation dose received by the vessel. The use of highly conformal radiotherapies such as intensity-modulated particle therapy might substantially improve the manageability of HNC with CAE by possibly reducing the risk of late sequalae. Despite evidence is frail, it appears logical that a case-by-case evaluation through multidisciplinary decision making between head and neck surgeons, radiation oncologists, medical oncologists, diagnostic and interventional radiologists, and vascular surgeons are of paramount value to offer the best therapeutic solution to patients affected by HNC with CAE.

Objectives To present an anatomical cadaver dissection study and our preliminary surgical experience with endoscopic-assisted multi-portal compartmental resection of the masticatory space (MS) in locally advanced oral squamous cell carcinoma (OSCC) of the retromolar area. Materials and methods Two fresh-frozen cadaver heads were dissected in the Laboratory of Anatomy to define the surgical steps of an endoscopic-assisted multi-portal compartmental approach to the MS. After this preclinical anatomical study, patients affected by locally advanced OSCC originating from the retromolar area with extension to the MS were prospectively enrolled and operated at two Italian referral centers for head and neck cancer between October 2019 and May 2020. Results Surgical technique of endoscopic-assisted multi-portal compartmental resection of the MS was preclinically defined step by step in 3 phases: transnasal, transoral/trancervical, and multi-portal. Compartmental resection of the MS was successfully completed in all specimens (4 MSs dissected). The surgical technique was subsequently applied in 3 patients affected by primary OSCC of the retromolar area, providing satisfactory results in terms of negative resection margins and local control. Conclusions Multi-portal compartmental resection of the MS combining the transnasal and transoral/transcervical corridors is technically feasible. Such an approach to the MS in locally advanced OSCC provides different angles of incidence to the target and full control of tumor margins.

Background Only preclinical studies and case reports have described robotic surgery for endoscopic transnasal skull base surgery. Objective To evaluate the role of a novel robotic endoscope holder, developed for transsphenoidal surgery. Methods Patients were prospectively enrolled for 3 mo at the Neurosurgery Unit of Brescia. Endoscope Robot® was used to assist during the sphenoidal phase of the approach, tumor removal, and skull base reconstruction. A Likert scale questionnaire was given to all surgeons after each procedure. Patients who underwent robotic-assisted surgery were matched with nonrobotic ones for pathology and type of procedure. All surgical videos were evaluated during bimanual phases. Results Twenty-one patients underwent robot-assisted, endoscopic transsphenoidal surgery for different pathologies (16 pituitary adenomas, 3 chordomas, 1 craniopharyngioma, 1 pituitary exploration for Cushing disease) for a total of 23 procedures (1 patient underwent 2 endoscopic revisions of a skull base reconstruction). Subjective advantages reported by surgeons included smoothness of movement, image steadiness, and improvement of maneuvers in narrow spaces and with angled endoscopes; as the main limitation, Endoscope Robot® appeared to be relatively heavy during the initial endoscope positioning. A comparative analysis with a historical matched cohort documented similar clinical outcomes, while endoscope lens cleaning and position readjustments were significantly less frequent in robotic procedures. Conclusion Although confirmation in larger studies is needed, Endoscope Robot® was a safe and effective tool, especially advantageous in lengthy interventions through deep and narrow corridors.

Funder: Università degli Studi di Trieste, PURPOSE: The aim of this study is to evaluate the prognostic value of pre-treatment advanced lung cancer inflammation index (ALI) in patients with HPV-negative HNSCC undergoing up-front surgical treatment. METHODS: The present multi-centre, retrospective study was performed in a consecutive cohort of patients who underwent upfront surgery with or without adjuvant (chemo)-radiotherapy for head and neck squamous cell carcinoma (HNSCC). Patients were stratified by ALI, and survival outcomes were compared between groups. In addition, the prognostic value of ALI was compared with two other indices, the prognostic nutritional index (PNI) and systemic inflammatory index (SIM). RESULTS: Two hundred twenty-three patients met the inclusion criteria (151 male and 72 female). Overall and progression-free survival were significantly predicted by ALI < 20.4 (HR 3.23, CI 1.51-6.90 for PFS and HR 3.41, CI 1.47-7.91 for OS). Similarly, PNI < 40.5 (HR = 2.43, 95% CI: 1.31-4.51 for PFS and HR = 2.40, 95% CI: 1.19-4.82 for OS) and SIM > 2.5 (HR = 2.51, 95% CI: 1.23-5.10 for PFS and HR = 2.60, 95% CI: 1.19-5.67 for OS) were found to be significant predictors. Among the three indices, ALI < 20.4 identified the patients with the worst 5-year outcomes. Moreover, patients with a combination of low PNI and low ALI resulted to be a better predictor of progression (HR = 5.26, 95% CI: 2.01-13.73) and death (HR = 5.68, 95% CI: 1.92-16.79) than low ALI and low PNI considered alone. CONCLUSIONS: Our results support the use of pre-treatment ALI, an easily measurable inflammatory/nutritional index, in daily clinical practice to improve prognostic stratification in surgically treated HPV-negative HNSCC.

BACKGROUND The spheno-orbital region (SOR) is a complex anatomic area that can be accessed with different surgical approaches. OBJECTIVE To quantitatively compare, in a preclinical setting, microsurgical transcranial approaches (MTAs), endoscopic endonasal transpterygoid approach (EEA), and endoscopic transorbital approaches (ETOAs) to the SOR. METHODS These approaches were performed in 5 specimens: EEA, ETOAs (superior eyelid and inferolateral), anterolateral MTAs (supraorbital, minipterional, pterional, pterional-transzygomatic, and frontotemporal-orbitozygomatic), and lateral MTAs (subtemporal and subtemporal transzygomatic). All specimens underwent high-resolution computed tomography; an optic neuronavigation system with dedicated software was used to quantify working volume and exposed area for each approach. Mixed linear models with random intercepts were used for statistical analyses. RESULTS Anterolateral MTAs offer a direct route to the greater wings (GWs) and lesser wings (LWs); only they guarantee exposure of the anterior clinoid. Lateral MTAs provide access to a large area corresponding to the GW, up to the superior orbital fissure (SOF) anteriorly and the foramen rotundum medially. ETOAs also access the GW, close to the lateral portion of SOF, but with a different angle of view as compared to lateral MTAs. Access to deep and medial structures, such as the lamina papyracea and the medial SOF, is offered only by EEA, which exposes the LW and GW only to a limited extent. CONCLUSION This is the first study that offers a quantitative comparison of the most used approaches to SOR. A detailed knowledge of their advantages and limitations is paramount to choose the ideal one, or their combination, in the clinical setting.

Background A landmark for the identification of the lingual artery (LA) through a transoral perspective can provide surgeons with an easy method to prevent and manage intraoperative bleeding during transoral approach to the base of tongue (BOT). Methods Thirteen tongue and five head and neck specimens were dissected to identify and assess the reliability of the lingual point (LP) as a new landmark for the LA at BOT. The pathway of 42 LAs was radiologically evaluated; axial depth and vertical offset were measured for each LA. Results Dissection study: a description of LP is provided; the LA was easily identified in all specimens (36/36 sides) using LP as a landmark. Radiologic study: the mean depth of the LA was 4.2 mm, the mean vertical offset was 1.3 mm. Conclusions LP is a simple and reliable landmark for identification of the LA, potentially helping surgeons to prevent and manage intraoperative bleeding.

Purpose In laryngeal carcinoma (LSCC), tumor immune microenvironment is attracting increasing interest, given the recent progresses in immunotherapy. Immune cells migrate to tumors as a result of a tumor antigen-induced immune reaction and cancer cells recruit immune regulatory cells to induce an immunosuppressive network, resulting in the escape from host immunity. This interaction reflects both on tumor microenvironment and systemic inflammatory status. Blood neutrophil-to-lymphocyte ratio (NLR), reflecting a highly pro-inflammatory status, has been related to worse oncological survival outcomes. The aim of this study was to analyze in LSCC the relationship between circulating inflammatory cells (also in terms of NLR) and tumor immune microenvironment histopathological features (programmed cell death ligand 1 [PD-L1] expression, and tumor-infiltrating lymphocytes [TILs]), also investigating their clinical-pathological and prognostic significance. Methods Blood pre-operative NLR, and, at pathology, PD-L1 (in terms of combined positive score [CPS]) and TILs were assessed on 60 consecutive cases of LSCC. Results Blood NLR, neutrophils, and lymphocytes counts showed a significant value in predicting DFS and recurrence risk. Moreover, PD-L1 CPS ≥ 1 and TILs count rate ≥30% were associated with higher disease-free survival (DFS) and reduced recurrence risk. A logistic regression model found a significant positive association between increasing NLR values, and PD-L1 CPS Conclusions Further studies are needed to better characterize the role of pre-operative blood NLR in association with PD-L1 expression and tumor immune microenvironment features as prognostic factors and markers of anti-tumor immune response in LSCCs, also with regard to the effectiveness of immunotherapeutic protocols.

Background The endoscope-assisted subtemporal key-hole epidural approach (ESKEA) has been recently described. The aim of this study was to measure working volumes and exposure of key areas of the middle cranial fossa provided by this approach. Methods Four fresh frozen cadaver heads were dissected to analyze 3 modular corridors (1A, 1B, and 2) harvested through ESKEA. A step-by-step dissection was performed, and key anatomic landmarks were recorded. A GTxEyesII-ApproachViewer was used to quantify the working volume and exposure of 4 different regions (sphenoorbital, parasellar, superior petrous apex, and squamopetrous). For each corridor, 3 incremental degrees of temporal dural retraction (5, 10, and 15 mm) were tested. Results The working volume of all corridors progressively increased with degree of retraction: Corridors 1A, 1B, and 2 showed a gain in working volume of 21%, 27%, and 19% from 5 mm to 10 mm retraction, respectively, and a gain of 40%, 45%, and 44% from 5 mm to 15 mm retraction, respectively. The sphenoorbital area was exposed (27%−45%) through corridor 1A, and exposure significantly increased with the degree of retraction. Corridor 1B provided optimal exposure of parasellar areas (86%−100%) and superior petrous apex (70%−87%) regardless of the degree of retraction. The squamopetrous area was satisfactorily addressed through corridor 2 (88%) only with the highest degree of retraction. Conclusions ESKEA can be conceived as a modular approach: the 3 surgical corridors have specific working volumes, which are clearly influenced by the degree of temporal lobe retraction, and provide exposure of different middle cranial fossa areas.

ObjectiveTo report the first use of a novel projected augmented reality (AR) system in open sinonasal tumor resections in preclinical models and to compare the AR approach with an advanced intraoperative navigation (IN) system.MethodsFour tumor models were created. Five head and neck surgeons participated in the study performing virtual osteotomies. Unguided, AR, IN, and AR + IN simulations were performed. Statistical comparisons between approaches were obtained. Intratumoral cut rate was the main outcome. The groups were also compared in terms of percentage of intratumoral, close, adequate, and excessive distances from the tumor. Information on a wearable gaze tracker headset and NASA Task Load Index questionnaire results were analyzed as well.ResultsA total of 335 cuts were simulated. Intratumoral cuts were observed in 20.7%, 9.4%, 1.2,% and 0% of the unguided, AR, IN, and AR + IN simulations, respectively (p ConclusionWe reported the use of a novel AR system for oncological resections in open sinonasal approaches, with improved margin delineation compared with unguided techniques. AR improved the gaze-toggling drawback of IN. Further refinements of the AR system are needed before translating our experience to clinical practice.

BACKGROUND/OBJECTIVE The aim of this study was to assess the impact of sinonasal morbidity on quality of life (QoL) in antineutrophil cytoplasmic antibody-associated vasculitis (AAV). METHODS This cross-sectional case-control study enrolled 71 patients-44 AAV cases with (ear, nose, and throat [ENT]-AAV) or without ENT involvement (non-ENT-AAV) undergoing multidisciplinary evaluations and 27 chronic rhinosinusitis (CRS) cases. Three validated QoL questionnaires (Sino-Nasal Outcomes Test-22 [SNOT-22], Nasal Obstruction Symptom Evaluation [NOSE], and Short-Form 36) were administered, and the 3 groups were compared. RESULTS The ENT-AAV patients were significantly younger (p = 0.01), with less antineutrophil cytoplasmic antibody positivity frequency (p = 0.035) and lower renal involvement (p = 0.003) than the non-ENT-AAV patients.The SNOT-22 questionnaire demonstrated significantly greater sinonasal morbidity in ENT-AAV patients compared with CRS patients (p < 0.001). The NOSE score of ENT-AAV patients was comparable to those of CRS patients, but higher than that of non-ENT-AAV patients (p < 0.001). The SNOT-22 and NOSE scores positively correlated with disease activity (p = 0.037; p = 0.004, respectively). Short-Form 36 domain-by-domain analysis revealed a significantly poorer QoL in ENT-AAV patients, especially with physical functioning being progressively impaired in CRS, non-ENT-AAV, and ENT-AAV patients (p < 0.001). No significant differences in QoL came to light when AAV patients were stratified according to current systemic o local treatments. CONCLUSIONS The QoL in AAV patients is significantly reduced, especially in the presence of ENT involvement. The AAV-related nasal morbidity is consistent and comparable to that reported by CRS patients. It significantly affects patients' QoL and in particular social functioning, leading to limitation in daily/work activities. Organ-focused questionnaires and multidisciplinary management are warranted to pursue a treat-to-target approach in these patients.

Oncocytic mucoepidermoid carcinoma (OMEC) is a rare but diagnostically challenging variant of mucoepidermoid carcinoma (MEC). OMEC is notable for differential diagnostic considerations that are raised as a result of overlap with other benign and low-grade oncocytic salivary gland tumors. Diffuse and strong immunoreactivity of p63 protein may be useful in distinguishing OMEC from its mimics. However, focal p63 staining can be present in benign oncytomas. Presence of mucin-containing cells, mucinous cystic formation, and foci of extravasated mucin are considered a hallmark of MEC. True mucocytes may be, however, very few and hardly discernable in OMECs. Recent evidence has shown that most MECs harbor gene fusions involving MAML2. A retrospective review of archived pathology files and the authors' own files was conducted to search for "low-grade/uncertain oncocytic tumor," "oncocytoma," and "oncocytic carcinoma" in the period from 1996 to 2019. The tumors with IHC positivity for p63 and/or p40, and S100 negativity, irrespective of mucicarmine staining, were tested by next-generation sequencing using fusion-detecting panels to detect MAML2 gene rearrangements. Two index cases from consultation practice (A.S. and A.A.) of purely oncocytic low-grade neoplasms without discernible mucinous cells showed a CRTC1-MAML2 fusion using next-generation sequencing, and were reclassified as OMEC. In total, 22 cases of oncocytic tumors, retrieved from the authors' files, and from the Salivary Gland Tumor Registry, harbored the MAML2 gene rearrangements. Presence of mucocytes, the patterns of p63 and SOX10 immunopositivity, and mucicarmine staining were inconsistent findings. Distinguishing OMEC devoid of true mucinous cells from oncocytoma can be very challenging, but it is critical for proper clinical management. Diffuse and strong positivity for p63 and visualization of hidden mucocytes by mucicarmine staining may be misleading and does not always suffice for correct diagnosis. Our experience suggests that ancillary studies for the detection of MAML2 rearrangement may provide useful evidence in difficult cases.

Highlights • Experience from 2 referral head and neck centers during the pandemic outbreak. • Description of 2 screening protocols to select SARS-CoV-2-free patients. • A narrative review of the literature on available screening methods. • Sharing data of potential help for lately hit countries and endemic phase., Background Preoperative screening had a key role in planning elective surgical activity for head and neck cancer (HNC) during the COVID-19 pandemic. Methods All patients undergoing surgery for HNC at two Italian referral hospitals (University of Padua and National Cancer Institute [NCI]) during the peak of the COVID-19 epidemic in Italy were included. Accuracy of screening protocols was assessed. Results In the Padua protocol, 41 patients were screened by pharyngeal swab. The entire sample (100%) was admitted to surgery, diagnostic accuracy was 100%. In the NCI protocol, 23 patients underwent a telephone interview, blood test, and chest CT. Twenty patients (87%) were negative and were directly admitted to surgery. In the remaining 3 (13%), pharyngeal swab was performed. The screening was repeated until a negative chest CT was found. Diagnostic accuracy was 85%. Conclusions Dedicated screening protocols for COVID-19 allow to safely perform elective HNC surgery.

Objective Oral lichen planus (OLP) is a chronic mucocutaneous immune-mediated disease affecting 1% to 4% of the worldwide population. Development of malignant lesions is reported but only affects a minority of patients. The aim of our study was to assess the diagnostic potential of narrow band imaging (NBI) in OLP patients; focusing on the identification of high-grade dysplasia/carcinoma in newly developed lesions. Methods Prospective evaluation of 56 patients with histopathologic diagnosis of OLP and presenting newly developed lesions not responding to medical treatment. All lesions were assessed by high-definition (HD) white light (WL) and HD-NBI endoscopy. All patients underwent biopsy regardless of the appearance at HD-WL and HD-NBI. Histology was defined as "positive" in case of high-grade dysplasia or carcinoma. Results Five lesions (9%) were diagnosed as high-grade dysplasia/carcinoma. In this setting, overall diagnostic potential of HD-NBI was optimal, with a sensitivity of 100% (95% CI, 48-100), specificity of 96% (95% CI, 86-99), negative predictive value of 100% (95% CI, not calculable), positive predictive value of 71% (95% CI, 39-91), and accuracy of 96% (95% CI, 88-100). Conclusions Despite the diffuse inflammatory pattern derived from OLP, NBI improved the diagnostic accuracy and the capability to detect high-grade dysplasia/carcinoma. Level of evidence 4 Laryngoscope, 131:E1156-E1161, 2021.

A picture is emerging in which advanced laryngeal cancers (LCs) are potentially not homogeneous and may be characterized by subpopulations which, if identified, could allow selection of patients amenable to organ preservation treatments in contrast to those to be treated with total laryngectomy (TL). This work aims to analyze a multicentric cohort of T3-T4a LCs treated by upfront TL, investigating the clinical and pathological features that can best predict oncologic outcomes. A total of 149 previously untreated patients who underwent TL for T3-T4a LC at four institutions were analyzed. Survival and disease-control were considered as the main outcomes. A secondary end-point was the identification of covariates associated with nodal status, investigating also the tumor thickness. T and N categories were significantly associated with both overall and disease-specific survival. The number of positive nodes and tracheal involvement were associated with loco-regional failure, post-cricoid area invasion and extra-nodal extension with distant failure. Posterior laryngeal compartment involvement was not a significant prognostic feature, by either univariable and multivariable analyses. These results support the conclusion that laryngeal compartmentalization has no impact on survival in patients treated by upfront TL and the current TNM staging system remains a robust prognosticator in advanced LC.