A multicenter protocol to assess the prognostic significance of the tumor microenvironment in patients with squamous cell carcinoma of the larynx.

BACKGROUND: The purpose of this multicenter study was to retrospectively investigate the prognostic significance of the tumor microenvironment, in relation to survival in a large cohort of patients with laryngeal squamous cell carcinoma (LSCC), using the method proposed by the International TILs Working Group in breast cancer. METHODS: All consecutive patients with biopsy-proven LSCC who underwent total laryngectomy (TL) between January 2014 and January 2023 were retrospectively included in the study. A retrospective review of medical records including surgical, pathological and follow-up reports was performed. The density of TILs was determined according to the recommendations of the International TILs Working Group. RESULTS: The study group included 186 patients with LSCC. High TILs were statistically correlated with reduced size and extension of primary tumor (pT stage) with a statistically significant value (S: p = 0.01; P: p = 0.0003) and without needs of salvage therapy (S: p = 0.03; P: p = 0.004). Low TILs were indicative of worse prognosis. CONCLUSIONS: Our study confirmed the protective value of TILs and the prognostic role of the tumor microenvironment in LSCC; furthermore, our results showed that the score proposed by the International TILs Working Group for breast cancer can be applied to LSCC.

Impact of Surgeon's Experience and Tumor's Nature in the Use of Intraoperative Facial Nerve Monitoring in Superficial Parotidectomy. Preliminary Results from a Single-Center Retrospective Analysis.

To assess the effectiveness of intraoperative facial nerve monitoring (IFNM) compared to non-monitoring in the prevention of post-operative facial nerve palsy during superficial parotidectomy. Patients treated with curative intent for parotid gland tumors between January 2020 and January 2022 were included. The study population has been divided in 2 groups, based on IFNM: the group A included patients operated with IFNM, whilst group B was the non-monitoring group. A further classification focused on the pathologies and the surgeons' experience. The study group included 58 patients, 27 female and 31 male. The mean age was 45.7 yr (range 36-78). No statistical difference has been found in post-operative HB grade between group A and B. The analysis of patients affected by pleomorphic surface lobe adenomas of the parotid did not show a statistical difference in HB outcome (p > 0.05). The analysis of the effect of surgeons' experience in IFNM advantage did not show statistical difference for superficial parotid tumors. The results of the present study suggest that the use of IFNM during parotid surgery is not mandatory to preserve the VII nerve function, both in case of primary tumor and in case of recurrence, and even when surgery is performed by less experienced surgeon compared to those cases treated by a more experienced surgeon.

Role of Tumor-Infiltrating Lymphocytes and the Tumor Microenvironment in the Survival of Malignant Parotid Gland Tumors: A Two-Centre Retrospective Analysis of 107 Patients.

Background: This study aims to retrospectively investigate the prognostic significance of the tumor microenvironment, with a focus on TILs (tumor-infiltrating lymphocytes), in relation to survival in a large cohort of patients with parotid gland cancer, and it uses the method proposed by the International TILs Working Group in breast cancer. Methods: We included a cohort of consecutive patients with biopsy-proven parotid cancer who underwent surgery between January 2010 and September 2023. A retrospective review of medical records, including surgical, pathological and follow-up reports, was performed. The density of TILs was determined according to the recommendations of the International TILs Working Group for breast cancer. Results: A weak negative correlation (p = 0.3) between TILs and time of survival and a weak positive correlation (p = 0.05) between TILs and months of survival (high TILs were correlated with longer survival in months) were identified. High TILs were weakly negatively, but not statistically significantly p (0.7), correlated with the grading of tumor; this means that high TILs were associated with low-grade tumors. Conclusions: Contrary to previous preliminary reports, this retrospective work found no statistically significant prognostic role of TILs in parotid gland malignancies. This case series represents the largest cohort ever reported in the literature and includes all malignant histological types. Future larger molecular studies may be useful in this regard.

Tissue expression of miR-449a as risk factor for occult neck metastasis in patients with cT3-T4 N0 laryngeal cancer. A pilot study.

OBJECTIVE: To explore the potential role of miR-449a as biomarker for laryngeal squamous cell carcinoma (LSCC), especially in the decision strategy of neck dissection (ND). METHODS: Each patient underwent total laryngectomy and bilateral ND (levels II-IV); during surgery, tissue samples of around 1 × 0.5 cm were extracted from both healthy tissue adjacent to the tumor and the visibly affected tumor tissue. The extraction of total RNA, encompassing miRNA, was performed using a mirVana PARIS kit. To detect miR449a, cDNA was synthesized from 200 ng of RNA using a TaqMan miRNA reverse transcription kit. RESULTS: The study group was formed of 66 patients (62 males, and 4 females) with LSCC, aged between 39 and 77 years (mean 60 + 14.56 yr). MiR-449a was up-regulated in twenty-eight tumors (42%), while it was down-regulated in 38 samples (58%). In the present study, there was a statistical relevance for miR-449a tissue expression for pN staging (p = 0.017), and PNI (p = 0.005). Eight tumors (12%) cN0 became pN + showing occult cervical lymph node metastases at the final histopathological examination, and all of these patients showed miR-449a downregulation. CONCLUSION: Super-selective ND (sparing the sub evels IIb and IV) might be the approach to cT3-T4 N0 LSCCs with upregulation of miR-449a; on the other hand, to ensure and effective control of occult neck metastases it would be appropriate to reserve elective ND (including sublevels IIb and IV) for cT3-T4 N0 LSCCs with miR-449a downregulation. Although promising, due to the small size of the cohort, the results of this work can be considered preliminary and need to be confirmed by prospective and larger studies.

A pilot study to evaluate the expression of microRNA­let­7a in patients with intestinal­type sinonasal adenocarcinoma.

Despite its histological resemblance to colorectal adenocarcinoma, there is little information about the molecular events involved in the pathogenesis of intestinal-type sinonasal adenocarcinoma (ITAC). The present study investigated the possible role and clinical value of microRNA (miR)-let-7a, a head and neck squamous cell carcinoma-related miR, in a well-characterized and homogeneous cohort of patients with ethmoidal ITAC associated with occupational exposure, treated by primary surgery. miR-let-7a expression levels were analyzed in 23 pairs of ethmoidal ITAC and adjacent normal formalin-fixed paraffin-embedded tissues by reverse transcription-quantitative PCR. The expression was evaluated in tumor and healthy tissues according to: Tumor grade (G) of differentiation and extension, and pTNM stage, and presence/absence of recurrence. Comparisons within and between groups were performed using two-tailed Student's paired t-test and one-way ANOVA with Tukey's post hoc test. P<0.05 was considered to indicate a statistically significant difference. miR-let-7a expression in ethmoidal ITAC tissues was significantly lower than that in adjacent normal tissues (P<0.05; mean expression level ± SD, 1.452707±1.4367189 vs. 4.094017±2.7465375). miR expression varied with pT stage. miR-let-7a was downregulated (P<0.05) in advanced stages (pT3-pT4) compared with earlier stages (pT1-pT2). Furthermore, downregulation of miR-let-7a in ITAC was associated with poorly-differentiated (G3) cancer (P<0.05). No other associations were observed between miR-let-7a expression and the other clinicopathological parameters, including disease-free survival. In conclusion, downregulation of miR-let-7a in ITAC was associated with advanced-stage (pT3 and pT4) and poorly-differentiated (G3) disease, suggesting that the mutation of this gene, combined with additional genetic events, could serve a role in ITAC pathogenesis.

Fitostimoline® in fibro-endoscopic and trans-nasal trans-speculum septoplasty as a beneficial tool to improve post-surgical outcome: Preliminary results of a case-control study.

OBJECTIVES: Topic treatment can be useful to improve short and long-term nasal outcomes after nasal surgery, reducing discomfort and risk of synechia. This study aimed at evaluating the effect on clinical outcomes of nasal packaging using Fitostimoline® gauze in FESS and septoplasty. METHODS: A case-control study on hospitalized patients was performed in a tertiary referral center. The control group included 20 patients treated with the standard surgical protocol for septoplasty and standard nasal packaging; treatment group included 21 patients underwent same surgical procedure but in whom the nasal tampon was wrapped with a gauze containing Fitostimoline® before being placed into the nose. RESULTS: Patients in treatment group had better outcomes than control; nasal mucosa showed better healing - recovery of normal color- in those patients in whom we applied the Fitostimoline® gauze around tampons. Moreover, 100 % patients in the treatment group did not refer discomfort during at tampon removal versus 60 % subjects in the control group who referred pain, tension or tearing during the same action. CONCLUSION: Our results, although preliminary because of the small cohort of subjects included, suggest that the apposition of a gauze with Fitostimoline® after nasal surgery might improve the mucosal healing with consequent reduction of patients discomfort during the post-surgical period.

A Retrospective Multicenter Italian Analysis of Epidemiological, Clinical and Histopathological Features in a Sample of Patients with Acinic Cell Carcinoma of the Parotid Gland.

BACKGROUND: The acinic cell carcinoma (AciCC) of the parotid gland is a rare tumor with an indolent behavior; however, a subgroup of this tumor presents an aggressive behavior with a tendency to recur. The aim of this multicenter study was to identify and stratify those patients with AciCC at high risk of tumor recurrence. METHODS: A retrospective study was carried out involving 77 patients treated with surgery between January 2000 and September 2022, in different Italian referral centers. Data about tumor characteristics and its recurrence were collected. The histological specimens and slides were independently reviewed by a senior pathologist coordinator (L.C.) and the institution's local head and neck pathologist. RESULTS: The patients' age average was 53.6 years, with a female prevalence in the group. The mean follow-up was 67.4 months (1-258, SD 59.39). The five-year overall survival (OS) was 83.2%. The 5-year disease-free survival (DFS) was 60% (95% CI 58.2-61.7). A high incidence of necrosis, extraglandular spread, lymphovascular invasion (LVI), atypical mitosis, and cellular pleomorphism was observed in the high-risk tumors compared to the low-risk ones. CONCLUSION: AciCC generally had an indolent behavior, optimal OS, DFS with few cervical node metastases, and rare distant relapses. This multicenter retrospective case series provides evidence of the need for clinical-epidemiological-histological stratification for patients at risk of poor outcomes. Our results suggest that the correct definition of high-risk AciCC should include tumor size, the presence of necrosis, extraglandular spread, LVI, atypical mitosis, and cellular pleomorphism.

Systematic Review of Management and Survival Outcome of Parotid Cancers with Lateral Skull Base Invasion.

Lateral skull base involvement from parotid cancers is a rare condition and is considered a poor prognostic indicator. The aim of this study was to systematically review the literature of parotid tumors with temporal bone invasion to analyze the survival outcome. A systematic literature review was performed in August 2022, without time limits, and 289 patients affected by parotid gland cancers and lateral skull base involvement were included. The most common symptoms in parotid tumors at the onset were indolent mass, facial weakness, pain, and hearing loss; the chi-square value is 23.1063, with a statistically significance (p = < 0.000121). The five most common histologies were adenoid cystic carcinoma, acinic cell carcinoma, mucoepidermoid carcinoma, adenocarcinoma, and squamous cell carcinoma. The facial nerve function after surgery showed statistically significance (functional vs. non-functional; chi-square was 91.7698, p = < 0.00001). Mean follow-up was 36.2 months (range 0.3-192). At the last follow-up, more patients died of disease (DOD; 60/289, 21%) than other causes (DOOC; 5/289, 2%). There is a statistically significant correlation between patients died for tumor (DOD) and patients died for other causes (DOOC) (p = < 0.0001), suggesting that the lateral skull base invasion negatively impacts on survival. Basing on the results of our systematic review, lateral skull base involvement from parotid recurrent/advance tumors should be considered a poor prognostic factor, as the majority of patients die due to this condition. It also would be necessary to have "clear"works, with full data (demographic, clinical, surgical data), and with a longer follow up, in order to assess the best treatment modality of these patients.

Partial Horizontal Supracricoid Laryngectomy: Which Factors Impact on Post-decannulation Swallowing Outcomes? A Prospective Single-Center Experience.

Early decannulation, performed within the first ten days after supracricoid partial laryngectomy, can result in a more rapid recovery of swallowing function with a semisolid bolus in the short term, about 30 days. We selected 20 patients with squamous cell carcinoma of larynx, who underwent supracricoid laryngectomies: 10 cricohyoidopexy (CHP) and 10 cricohyoidoepiglottopexy (CHEP). Staging was pT2 (10 pts), and pT3 (10 pts). Fiberoptic endoscopic evaluation of swallowing was used to assess postoperative swallowing function after a mean of 12 and 22 days from surgery. A modified PAS score (penetration-aspiration scale) was assigned for subtotal laryngectomies. Decannulation occurred after 6.7 ± 2.1 days. Univariate analysis showed that the type of surgery (CHP or CHEP), pT, resection of one arytenoid, and decannulation time are significantly associated with the 12-day PAS score. The 22-day PAS score is significantly associated with only 3 variables: type of surgery, pT, and resection of one arytenoid. From the data presented, the factors that most delay an effective recovery of swallowing are T3 and the resection of one arytenoid. Early decannulation has been shown statistically to improve PAS score in the short term, but not in the long term.

Recurrent acinic cell carcinoma of the parotid gland with lateral skull base invasion: Case report and discussion of the literature.

Medical records of a 76-year-old woman with a recurrent acinic cell carcinoma of the left parotid gland with lateral skull base invasion were reviewed. She underwent subtotal petrosectomy followed by radiation therapy. After surgery, she remained disease-free for more than 16 months.

Treatment of COVID-19 olfactory dysfunction with olfactory training, palmitoylethanolamide with luteolin, or combined therapy: a blinded controlled multicenter randomized trial.

PURPOSE: Few evidence-based therapies are available for chronic olfactory dysfunction after COVID-19. This study investigated the relative efficacy of olfactory training alone, co-ultramicronized palmitoylethanolamide with luteolin (um-PEA-LUT, an anti-neuroinflammatory supplement) alone, or combined therapy for treating chronic olfactory dysfunction from COVID-19. METHODS: This double-blinded controlled, placebo-controlled multicenter randomized clinical trial was conducted in 202 patients with persistent COVID-19 olfactory dysfunction of > 6 month duration. After a screening nasal endoscopy, patients were randomized to: (1) olfactory training and placebo; (2) once daily um-PEA-LUT alone; (3) twice daily um-PEA-LUT alone; or (4) combination of once daily um-PEA-LUT with olfactory training. Olfactory testing (Sniffin' Sticks odor identification test) was performed at baseline and at 1, 2, and 3 months. The primary outcome was recovery of over three points on olfactory testing, with outcomes compared at T0, T1, T2 and T3 across groups. Statistical analyses included one-way ANOVA for numeric data and chi-square for nominal data. RESULTS: All patients completed the study, and there were no adverse events. At 90 days, odor identification scores improved by > 3 points in 89.2% of patients receiving combined therapy vs. 36.8% receiving olfactory training with placebo, 40% receiving twice daily um-PEA-LUT alone, and 41.6% receiving once daily um-PEA-LUT alone (p < 0.00001). Patients receiving treatment with um-PEA-LUT alone demonstrated subclinical improvement (< 3 point odor identification improvement) more often than patients receiving olfactory training with placebo (p < 0.0001.) CONCLUSIONS: Olfactory training plus once daily um-PEA-LUT resulted in greater olfactory recovery than either therapy alone in patients with long-term olfactory function due to COVID-19. TRIAL REGISTRATION: 20112020PGFN on clinicaltrials.gov. LEVEL OF EVIDENCE: 1b (Individual Randomized Clinical Trial).

Vitamin D Deficit as Inducer of Adenotonsillar Hypertrophy in Children with Obstructive Sleep Apnea-A Prospective Case-Control Study.

(1) Objective: This prospective case-control study aimed to assess the level of serum vitamin D comparing pediatric non-allergic patients with obstructive sleep apnea (OSA) and healthy controls. (2) Methods: The period of the enrollment was from November 2021 to February 2022. Children with uncomplicated OSA caused by adenotonsillar hypertrophy (ATH) were recruited. Allergy was excluded by skin prick test (SPT), and the determination of serum IgE level using ELISA test. Plasma concentration of 25-hydroxy vitamin D (25-OHD) was quantitatively determined; then, the vitamin D concentration in patients was compared with healthy controls matched for sex, age, ethnicity, and characteristics. (3) Results: Plasma 25-OHD levels were significantly lower in patients than in healthy subjects (mean 17 ng/mL, 6.27 DS, range 6-30.7 ng/mL, vs. mean 22 ng/mL, 9.45 DS, range 7-41.2 ng/ ml; p < 0.0005). The prevalence of children with vitamin D deficiency was significantly higher in the ATH group than controls. The plasma 25-OHD level did not change following the ATH clinical presentation (III or IV grade according to the Brodsky scale), while the different categories of 25-OHD status (insufficiency, deficiency, and adequacy) in the ATH group were statistically significantly different (p < 0.001) from healthy controls. (4) Conclusions: This study identified statistically significant differences between the ATH group and control regarding the plasma concentration of vitamin D; this data, despite not being directly linkable to the lymphoid tissue hypertrophy (p-value not significant), might suggest a negative effect of vitamin D deficit on the immune system.

Comment on Marra et al. Metastatic Renal Cell Carcinoma to the Soft Tissue 27 Years after Radical Nephrectomy: A Case Report. Medicina 2023, 59, 150.

Recently, Marra et al. [...].

Italian Guidelines for the Management of Non-Functioning Benign and Locally Symptomatic Thyroid Nodules.

AIM: This guideline (GL) is aimed at providing a reference for the management of non-functioning, benign thyroid nodules causing local symptoms in adults outside of pregnancy. METHODS: This GL has been developed following the methods described in the Manual of the National Guideline System. For each question, the panel appointed by Associazione Medici Endocrinology (AME) identified potentially relevant outcomes, which were then rated for their impact on therapeutic choices. Only outcomes classified as "critical" and "important" were considered in the systematic review of evidence and only those classified as "critical" were considered in the formulation of recommendations. RESULTS: The present GL contains recommendations about the respective roles of surgery and minimally invasive treatments for the management of benign symptomatic thyroid nodules. We suggest hemithyroidectomy plus isthmectomy as the first-choice surgical treatment, provided that clinically significant disease is not present in the contralateral thyroid lobe. Total thyroidectomy should be considered for patients with clinically significant disease in the contralateral thyroid lobe. We suggest considering thermo-ablation as an alternative option to surgery for patients with a symptomatic, solid, benign, single, or dominant thyroid nodule. These recommendations apply to outpatients, either in primary care or when referred to specialists. CONCLUSION: The present GL is directed to endocrinologists, surgeons, and interventional radiologists working in hospitals, in territorial services, or private practice, general practitioners, and patients. The available data suggest that the implementation of this GL recommendations will result in the progressive reduction of surgical procedures for benign thyroid nodular disease, with a decreased number of admissions to surgical departments for non-malignant conditions and more rapid access to patients with thyroid cancer. Importantly, a reduction of indirect costs due to long-term replacement therapy and the management of surgical complications may also be speculated.

Parapharyngeal space tumors: a twenty-year single-center retrospective analysis on the effectiveness of transcervical and transoral approaches on local control and disease-specific survival.

INTRODUCTION: To retrospectively analyzed our twenty-years single-center experience in the treatment of PPS tumors, focusing on the selection of surgical approach and the survival outcome. METHODS: Tumors involving the PPS between January 2000 and February 2022 were retrospectively included. The surgical approach was dictated by the localization of the tumor, its dimensions, the relation to anatomic structures and its etiology. RESULTS: 34 patients were included in the study. The median age was 50.5 yr, with a gender female prevalence. Most tumors were benign and non recurrent. 20 tumors were treated through lateral approach (transcervical or transcervical-transparotid), 11 through medial approach (transoral), and only 3 tumors were approached by multiple corridors. The 5 years disease free survival (DFS) was 78.8 % (CI 78-79.3 %). CONCLUSIONS: In our experience, the transcervical and transoral approaches can be considered the ideal surgical approach to manage tumors of PPS, especially in cases of benign neoplasms.

MicroRNAs' Crucial Role in Salivary Gland Cancers' Onset and Prognosis.

Salivary gland cancer (SGC) is an uncommon and heterogeneous disease that accounts for around 8.5% of all head and neck cancers. MicroRNAs (miRNAs) consist of a class of highly conserved, short, single-stranded segments (18-25 nucleotides) of noncoding RNA that represent key gene-transcription regulators in physiological and pathological human conditions. However, their role in SGC development and progression is not completely clear. This review aims to compile and summarize the recent findings on the topic, focusing on the prognostic and diagnostic value of the major modulated and validated microRNAs in SGC. Their differential expression could possibly aid the clinician in delivering an early diagnosis, therapeutic strategy and precision medicine.

Central mucoepidermoid carcinoma of the mandible deriving from odontogenic cyst: A case report and review of the literature.

Mucoepidermoid Carcinoma (MEC) it can origin from a mandibular odontogenic cyst. We report the case of a 63-year-old man with MEC of the right retromolar trigonum of the mandibula. We performed a wide mandibular excision and immediate reconstruction with a fibula bone free flap.