Novel cellular systems unveil mucosal melanoma initiating cells and a role for PI3K/Akt/mTOR pathway in mucosal melanoma fitness.

BACKGROUND: Mucosal Melanomas (MM) are highly aggressive neoplasms arising from mucosal melanocytes. Current treatments offer a limited survival benefit for patients with advanced MM; moreover, the lack of pre-clinical cellular systems has significantly limited the understanding of their immunobiology. METHODS: Five novel cell lines were obtained from patient-derived biopsies of MM arising in the sino-nasal mucosa and designated as SN-MM1-5. The morphology, ultrastructure and melanocytic identity of SN-MM cell lines were validated by transmission electron microscopy and immunohistochemistry. Moreover, in vivo tumorigenicity of SN-MM1-5 was tested by subcutaneous injection in NOD/SCID mice. Molecular characterization of SN-MM cell lines was performed by a mass-spectrometry proteomic approach, and their sensitivity to PI3K chemical inhibitor LY294002 was validated by Akt activation, measured by pAkt(Ser473) and pAkt(Thr308) in immunoblots, and MTS assay. RESULTS: This study reports the validation and functional characterization of five newly generated SN-MM cell lines. Compared to the normal counterpart, the proteomic profile of SN-MM is consistent with transformed melanocytes showing a heterogeneous degree of melanocytic differentiation and activation of cancer-related pathways. All SN-MM cell lines resulted tumorigenic in vivo and display recurrent structural variants according to aCGH analysis. Of relevance, the microscopic analysis of the corresponding xenotransplants allowed the identification of clusters of MITF-/CDH1-/CDH2 + /ZEB1 + /CD271 + cells, supporting the existence of melanoma-initiating cells also in MM, as confirmed in clinical samples. In vitro, SN-MM cell lines were sensitive to cisplatin, but not to temozolomide. Moreover, the proteomic analysis of SN-MM cell lines revealed that RICTOR, a subunit of mTORC2 complex, is the most significantly activated upstream regulator, suggesting a relevant role for the PI3K-Akt-mTOR pathway in these neoplasms. Consistently, phosphorylation of NDRG1 and Akt activation was observed in SN-MM, the latter being constitutive and sustained by PTEN loss in SN-MM2 and SN-MM3. The cell viability impairment induced by LY294002 confirmed a functional role for the PI3K-Akt-mTOR pathway in SN-MM cell lines. CONCLUSIONS: Overall, these novel and unique cellular systems represent relevant experimental tools for a better understanding of the biology of these neoplasms and, as an extension, to MM from other sites.

Facial surface electromyography: A systematic review on the state of the art and current perspectives.

PURPOSE: Peripheral facial nerve palsy is a severely disabling condition. In current clinical practice, the commonest tools to assess facial palsy are grading scales, digital face image analyses or facial muscle electrophysiology. However, these techniques suffer from subjectivity or invasiveness and cannot be applied as part of a routine clinical assessment. Therefore, novel non-invasive office-based tools are needed. Surface electromyography (sEMG) may potentially fulfill the requirements of objectivity, low examiner-dependence, and minimal invasiveness. The aim of this systematic review is to define the state of the art on the use of sEMG for facial nerve functional assessment. MATERIALS AND METHODS: Pubmed, Scopus and Web of Science databases were systematically searched. The study protocol was registered on PROSPERO in January 2023. The review was conducted according to the PRISMA guidelines. RESULTS: After the application of inclusion-exclusion criteria, 15 manuscripts with adequate relevance to this topic were included in the review. CONCLUSIONS: Facial sEMG represents a potentially useful tool to implement objective quantification of facial nerve function in clinical practice. Given the heterogeneity of methods and analysis in the available studies, sEMG results are hardly comparable. The introduction of methodological guidelines, followed by large prospective studies on well-defined subsets of patients with facial nerve impairment, is advocated.

Isoprognostic functional CT map for open partial horizontal laryngectomy.

PURPOSE: To identify a radiological map of laryngeal subsites whose involvement by the tumor could predict patients' functional outcomes after open partial horizontal laryngectomy (OPHL). METHODS: The present retrospective analysis concerned 96 patients with glottic squamous cell carcinoma, who were radiologically staged with contrast-enhanced neck CT scans before undergoing supracricoid or supratracheal laryngectomy. A radiological map of patients' functional risk was developed by considering the distribution of functional outcomes in relation to the laryngeal subsites involved. The functional outcomes considered were: (i) decannulation at discharge; (ii) time to removal of the nasogastric feeding tube (NFT); (iii) postoperative complication rate; and (iv) length of hospital stay. RESULTS: Involvement of the anterior supraglottis was related to a longer need for NFT, and a longer hospital stay (p = 0.003, and p = 0.003, respectively). Involvement of the posterior glottis negatively affected the time to decannulation, and the likelihood of postoperative complications (p = 0.000, and p = 0.002, respectively). CONCLUSIONS: Anterior glottic small tumors (without significant subglottic and/or supraglottic extension) are related to the best functional outcomes after OPHL, since the suprahyoid epiglottis and both the arytenoids are likely to be spared.

The role of central neck dissection and adjuvant treatment in pT4aN0 laryngeal carcinoma treated with open partial horizontal laryngectomy.

PURPOSE: The study aimed to identify parameters that could predict oncological and functional outcomes in patients with pT4aN0 laryngeal squamous cell carcinoma (LSCC) who underwent open partial horizontal laryngectomy (OPHL). The role of paratracheal neck dissection (PTND) was analyzed as the primary outcome. Additionally, the study compared the outcomes of patients who underwent postoperative radio/chemotherapy (PORT/PORCT) with those who refused or did not adhere to adjuvant treatments. METHODS: Twenty-nine OPHL patients whose pathological exam was consistent with pT4aN0-x disease were enrolled and their clinical charts were retrospectively reviewed. The study analyzed oncological outcomes, such as local, regional, and distant recurrence rates (RR), overall survival (OS), disease-free survival (DFS), and disease-specific survival (DSS). Additionally, functional results were analyzed, including decannulation rate, hospitalization time, and postoperative complication rate. RESULTS: The study revealed and overall recurrence rate of 27%. The final rates for OS and DSS were 68% and 79%, respectively. Based on the univariate analysis the PTND was significantly associated with longer DFS. No significant differences inoncological outcomes were observed between pT4a patients who underwent adjuvant radio/radiochemotherapy and those who did not, in terms of RR, DFS, DSS or OS. However, adjuvant treatment was found to significantly increase decannulation time. CONCLUSIONS: In a properly super-selected subgroup of patients with pT4aN0 LSCC, OPHL may beconsidered as a conservative surgical option even without adjuvant treatment. However, for optimal oncological outcomes, it is strongly recommended to consider a central compartment dissection in cases of hypoglottic and anterior extra-laryngeal tumor extension.

Computer-aided designed 3D-printed polymeric scaffolds for personalized reconstruction of maxillary and mandibular defects: a proof-of-concept study.

PURPOSE: To investigate the potential reconstruction of complex maxillofacial defects using computer-aided design 3D-printed polymeric scaffolds by defining the production process, simulating the surgical procedure, and explore the feasibility and reproducibility of the whole algorithm. METHODS: This a preclinical study to investigate feasibility, reproducibility and efficacy of the reconstruction algorithm proposed. It encompassed 3 phases: (1) scaffold production (CAD and 3D-printing in polylactic acid); (2) surgical simulation on cadaver heads (navigation-guided osteotomies and scaffold fixation); (3) assessment of reconstruction (bone and occlusal morphological conformance, symmetry, and mechanical stress tests). RESULTS: Six cadaver heads were dissected. Six types of defects (3 mandibular and 3 maxillary) with different degree of complexity were tested. In all case the reconstruction algorithm could be successfully completed. Bone morphological conformance was optimal while the occlusal one was slightly higher. Mechanical stress tests were good (mean value, 318.6 and 286.4 N for maxillary and mandibular defects, respectively). CONCLUSIONS: Our reconstructive algorithm was feasible and reproducible in a preclinical setting. Functional and aesthetic outcomes were satisfactory independently of the complexity of the defect.

Blood Markers Predicting Clinically Occult Lymph Node Metastasis in Head and Neck Squamous Cell Carcinoma.

INTRODUCTION: The presence of cervical lymph node metastases is an unfavorable prognostic factor in head and neck squamous cell carcinoma (HNSCC) and a potential cause of treatment failure. Occult lymph node metastasis occurs in approximately 15-20% of HNSCC patients with a clinically negative neck (cN0), greatly impacting on their prognosis. The present study aimed to investigate the role of pre-treatment peripheral blood markers in predicting clinically occult cervical lymph node metastasis. METHODS: This multicenter, retrospective study was performed in a cohort of 472 patients diagnosed with cN0 HNSCC who underwent up-front surgery. Baseline neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), systemic inflammatory marker (SIM), and systemic immune-inflammation index (SII) were calculated from available blood parameters. RESULTS: Oro-hypopharyngeal and oral cancers, locally advanced stage, moderately (G2), and poorly (G3) differentiated grade were associated with an increased risk of pathological lymph node involvement. NLR, LMR, PLR, SIM, and SII were significantly associated at multivariable analysis. NLR >2.12 was the most reliable at predicting occult lymph node metastasis (OR = 5.22; 95% CI: 2.14-12.75). We describe a predictive score integrating cancer site, local stage, and NLR which is effective at predicting positive lymph node pathological status. CONCLUSIONS: The present study provides evidence that pre-treatment peripheral blood markers, in particular NLR, represent reliable predictors of clinically occult cervical lymph node metastasis in cN0 HNSCC. Therefore, the present study provides a novel useful predictive score for directing the elective management of the neck in patients with cN0 HNSCC.

Does social distancing impact pediatric upper airway infections? An observational controlled study and a brief literature review.

PURPOSE: SARS-CoV-2 pandemic has reduced social interaction even among children. The objective of the study was to assess the role of social distancing in the course of common pediatric upper airway recurrent diseases. MATERIALS AND METHODS: Patients aged ≤14 years with at least one ENT-related clinical condition were retrospectively recruited. All patients had two outpatient evaluations in the same period (April - September): the control group had the first evaluation in 2018 and second in 2019, whereas the case group had the first evaluation in 2019 and second in 2020. Patients of each group were individually compared between their two visits and deemed improved/unchanged/worsened for each specific ENT condition. The percentage of children improved/unchanged/worsened were then collectively compared between the two groups for each condition. RESULTS: Patients who experienced social distancing presented a significantly higher improvement rate than controls for recurrent acute otitis media episodes (35.1 % vs. 10.8 %; Fisher's exact test p = 0.033) and for tympanogram type (54.5 % vs. 11.1 %, Fisher's exact test p = 0.009). CONCLUSIONS: The anti-contagion social restrictions decreased the prevalence of middle ear infections and effusion in children. Further studies on larger cohorts are required to better elucidate these findings.

Different inflammatory blood markers correlate with specific outcomes in incident HPV-negative head and neck squamous cell carcinoma: a retrospective cohort study.

BACKGROUND: Inflammatory blood markers have been associated with oncological outcomes in several cancers, but evidence for head and neck squamous cell carcinoma (HNSCC) is scanty. Therefore, this study aims at investigating the association between five different inflammatory blood markers and several oncological outcomes. METHODS: This multi-centre retrospective analysis included 925 consecutive patients with primary HPV-negative HNSCC (median age: 68 years) diagnosed between April 2004 and June 2018, whose pre-treatment blood parameters were available. Neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), lymphocyte to monocyte ratio (LMR), systemic inflammatory marker (SIM), and systemic immune-inflammation index (SII) were calculated; their associations with local, regional, and distant failure, disease-free survival (DFS), and overall survival (OS) was calculated. RESULTS: The median follow-up was 53 months. All five indexes were significantly associated with OS; the highest accuracy in predicting patients' survival was found for SIM (10-year OS = 53.2% for SIM < 1.40 and 40.9% for SIM ≥ 2.46; c-index = 0.569) and LMR (10-year OS = 60.4% for LMR ≥ 3.76 and 40.5% for LMR < 2.92; c-index = 0.568). While LMR showed the strongest association with local failure (HR = 2.16; 95% CI:1.22-3.84), PLR showed the strongest association with regional (HR = 1.98; 95% CI:1.24-3.15) and distant failure (HR = 1.67; 95% CI:1.08-2.58). CONCLUSION: Different inflammatory blood markers may be useful to identify patients at risk of local, regional, or distant recurrences who may benefit from treatment intensification or intensive surveillance programs.

Parotid pleomorphic and non-pleomorphic adenomas: a mono-institutional series of 512 patients.

PURPOSE: 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). METHODS: 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. RESULTS: 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 < 18 years (HR = 31.31, p < 0.001), intraoperative tumor spillage (HR = 6.57, p = 0.041), extensive pseudo-capsule interruption (HR = 5.85, p = 0.023), and resection margins < 1 mm (HR = 3.16, p = 0.085) were associated with RFS. CONCLUSION: Patients affected by NPA were significantly older and treated with more conservative surgical procedures compared to those with PA. In PA, younger age, major pseudo-capsule defects, and surgical margins were the most relevant factors affecting local control. These results confirm the importance of an appropriate surgical management and long-term follow-up in PA.

Regional disease in head and neck cutaneous squamous cell carcinoma: the role of primary tumor characteristics and number of nodal metastases.

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.

Clinical implications of alpha, beta, and gamma HPV infection in juvenile onset recurrent respiratory papillomatosis.

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.

Liquid Crystalline Nanoparticles Conjugated with Dexamethasone Prevent Cisplatin Ototoxicity In Vitro.

The conjugation of drugs with nanoparticles represents an innovative approach for controlled and targeted administration of therapeutic agents. Nanoparticle-based systems have been tested for the inner ear therapy, increasing the drug diffusion and being detected in all parts of the cochlea when locally applied near the round window. In this study, glycerol monooleate liquid crystalline NanoParticles were conjugated with Dexamethasone (NPD), a hydrophobic drug already used for inner ear treatments but defective in solubility and bioavailability. NPD has been tested in vitro in the cell line OC-k3, a model of sensory cells of the inner ear, and the therapeutic efficacy has been evaluated against cisplatin, a chemotherapeutic compound known to induce ototoxicity. After comparing the physical chemical characteristics of NPD to the equivalent naïve nanoparticles, an initial investigation was carried out into the nanoparticle's uptake in OC-k3 cells, which takes place within a few hours of treatment without causing toxic damage up to a concentration of 50 µg/mL. The NPD delivered the dexamethasone inside the cells at a significantly increased rate compared to the equivalent free drug administration, increasing the half-life of the therapeutic compound within the cell. Concerning the co-treatment with cisplatin, the NPD significantly lowered the cisplatin cytotoxicity after 48 h of administration, preventing cell apoptosis. To confirm this result, also cell morphology, cell cycle and glucocorticoids receptor expression were investigated. In conclusion, the NPD system has thus preliminarily shown the potential to improve the therapeutic efficacy of treatments delivered in the inner ear and prevent drug-induced ototoxicity.

Hybrid Core-Shell Polymer Scaffold for Bone Tissue Regeneration.

A great promise for tissue engineering is represented by scaffolds that host stem cells during proliferation and differentiation and simultaneously replace damaged tissue while maintaining the main vital functions. In this paper, a novel process was adopted to develop composite scaffolds with a core-shell structure for bone tissue regeneration, in which the core has the main function of temporary mechanical support, and the shell enhances biocompatibility and provides bioactive properties. An interconnected porous core was safely obtained, avoiding solvents or other chemical issues, by blending poly(lactic acid), poly(ε-caprolactone) and leachable superabsorbent polymer particles. After particle leaching in water, the core was grafted with a gelatin/chitosan hydrogel shell to create a cell-friendly bioactive environment within its pores. The physicochemical, morphological, and mechanical characterization of the hybrid structure and of its component materials was carried out by means of infrared spectroscopy, thermogravimetric analysis, scanning electron microscopy, and mechanical testing under different loading conditions. These hybrid polymer devices were found to closely mimic both the morphology and the stiffness of bones. In addition, in vitro studies showed that the core-shell scaffolds are efficiently seeded by human mesenchymal stromal cells, which remain viable, proliferate, and are capable of differentiating towards the osteogenic phenotype if adequately stimulated.

Health-Related Quality of Life in Patients With ANCA-Associated Vasculitis and Sinonasal Involvement: A Single-Center Cross-Sectional Study.

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.

The risk of recurrence in surgically treated head and neck squamous cell carcinomas: a conditional probability approach.

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.

Beta human papillomaviruses infection and skin carcinogenesis.

During the last decade, the worldwide incidence of keratinocyte carcinomas (KC) has increased significantly. They are now the most common malignancy, representing approximately 30% of all cancers. The role of ultraviolet (UV) radiation as a major environmental risk factor for skin cancers is well recognized. The aim of this review is to analyse the current understanding of the nature of beta-human papillomavirus (HPV) and its association with KC and explore the implications for the management and prevention of these cancers. A comprehensive review of the literature on beta-HPV and its association with KC was undertaken, the results reported in the form of a narrative review. A subgroup of HPV that infects the mucosal epithelia of the genital tract has been firmly associated with carcinogenesis. In addition, some HPV types with cutaneous tropism have been proposed to cooperate with UV in the development of KC. The first evidence for this association was reported in 1922 in patients with epidermodysplasia verruciformis (EV). Since then, epidemiological studies have highlighted the higher risk of skin cancer in patients with EV and certain cutaneous HPV types, and in vitro studies have elucidated molecular mechanisms and transforming properties of beta-HPV. Furthermore, in vivo research conducted on transgenic mice models has shown the possible role of beta-HPV in cutaneous carcinogenesis as a co-factor with UV radiation and immunosuppression. There is good evidence supporting the role of beta-HPV in the oncogenesis of KC. The high prevalence of beta-HPV in human skin and the worldwide burden of KC makes the search for an effective vaccine relevant and worthwhile.

Elective neck dissection in primary parotid carcinomas: A systematic review and meta-analysis.

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.

Advanced lung cancer inflammation index and its prognostic value in HPV-negative head and neck squamous cell carcinoma: a multicentre study.

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.

Transclival approaches for intradural pathologies: historical overview and present scenario.

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.

Transorbital endoscopic approaches to the skull base: a systematic literature review and anatomical description.

Transorbital endoscopic approaches are increasing in popularity as they provide corridors to reach various areas of the ventral skull base through the orbit. They can be used either alone or in combination with different approaches when dealing with the pathologies of the skull base. The objective of the current study is to evaluate the surgical anatomy of transorbital endoscopic approaches by cadaver dissections as well as providing objective clinical data on their actual employment and morbidity through a systematic review of the current literature. Four cadaveric specimens were dissected, and step-by-step dissection of each endoscopic transorbital approach was performed to identify the main anatomic landmarks and corridors. A systematic review with pooled analysis of the current literature from January 2000 to April 2020 was performed and the related studies were analyzed. Main anatomical landmarks are presented based on the anatomical study and systematic review of the literature. With emphasis on the specific transorbital approach used, indications, surgical technique, and complications are reviewed through the systematic review of 42 studies (19 in vivo and 23 anatomical dissections) including 193 patients. In conclusion, transorbital endoscopic approaches are promising and appear as feasible techniques for the surgical treatment of skull base lesions. Surgical anatomy of transorbital endoscopic approaches can be mastered through knowledge of a number of anatomical landmarks. Based on data available in the literature, transorbital endoscopic approaches represent an important complementary that should be included in the armamentarium of a skull base team.