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Lo studio della proteomica salivare, test economico e non invasivo, rappresenta una fonte di numerose informazioni, ed è utile per la diagnosi di svariate malattie. Da quando siamo entrati nellera della tecnologia genomica e delle scienze omiche, la raccolta di campioni salivari è aumentata esponenzialmente. Recenti piattaforme proteomiche hanno analizzato il proteoma salivare umano, caratterizzando circa 3000 peptidi e proteine, espressi in maniera differente: più del 90% in peso deriva dalla secrezione delle tre ghiandole salivari maggiori, mentre la restante parte proviene dalle ghiandole salivari minori, dal fluido crevicolare gengivale, da essudati mucosi e dalla microflora orale. Lobiettivo principale dellanalisi proteomica è discriminare tra condizioni fisiologiche e patologiche. Ad oggi, tuttavia, non esiste un preciso protocollo che permetta di analizzare lintero proteoma salivare, pertanto sono state realizzate svariate strategie. Innanzitutto, è possibile distinguere due tipologie di piattaforme proteomiche: lapproccio top-down prevede lanalisi delle proteine sotto esame come entità intatte; nellapproccio bottom-up la caratterizzazione della proteina avviene mediante lo studio dei peptidi ottenuti dopo digestione enzimatica (con tripsina tipicamente). A causa di questa eterogeneità, per una stessa patologia sono stati proposti differenti biomarkers. Il proteoma salivare è stato caratterizzato in numerose malattie: carcinoma squamoso e leucoplachie orali, malattia del trapianto contro lospite (GVHD) cronica, sindrome di Sjögren e altri disordini autoimmuni come la sindrome SAPHO (sinovite, acne, pustolosi, iperostosi e osteite), schizofrenia e disordine bipolare, malattie genetiche come la sindrome di Down o la malattia di Wilson. In conclusione, i risultati delle ricerche riportate in questa review suggeriscono che nel prossimo futuro la saliva diverrà un fluido di indubbia rilevanza diagnostica utile per fini clinici, sia diagnostici, sia prognostici.

Ophthalmic vein thrombosis is a severe clinical entity with proptosis, eyelid swelling, orbital pain and reduction of visual acuity; its incidence is rare with 3-4 cases /million /year. Clinical manifestations result from venous congestion caused by septic (orbital cellulitis) or aseptic aetiologies (coagulopathies, trauma) and in some cases it could be associated with cavernous sinus thrombosis. In this paper, we describe a case report unique in the literature, of bilateral cavernous sinus and ophthalmic veins thrombosis due to both septic and aseptic causes characterized by unilateral sphenoid sinusitis sustained by Trueperella pyogenes infection. Trueperella pyogenes is an opportunistic animal pathogen, and its infections occur in both domestic and wild animals worldwide but are rare in humans; this is the first instance of human infection in the head and neck with an unknown hypercoagulable state., Competing Interests: Ethical StatementAll authors declare the absence of any financial support or relationship that may pose a conflict of interest. The patient gave her informed consent for the publication of the case report., (© The Author(s) 2024.)

BACKGROUND The columella has many fundamental functions, such as nasal breathing and support of the nasal tip, in addition to the aesthetic role it plays. The columella is one of the most difficult nasal subunits, both from the point of view of disease control and from that of reconstruction. Lesions involving the columella can be difficult to control, and malignancies can spread to the septum, subcutaneous tissues of the lip, and floor of the nasal cavities. Many columella reconstruction methods after resection have been proposed (local nasal flaps, skin grafts, regional flaps, free flaps), depending on the size of the defect, patient's features, surgeon's experience, and patient's aesthetic wishes. CASE REPORT We present a case of an 82-year-old woman with various comorbidities who had squamous cell carcinoma (G2) originating from the skin of the right side of the columella. The lesion infiltrated the cartilage, arriving to the skin of the columella on the left side and extending to the mucosa of the nasal septum bilaterally. Reconstruction was conducted using a bilateral nasolabial flap, with good functional and aesthetic result. Surgical revision for the autonomization of pedicled flaps was not necessary, nor desired by the patient. CONCLUSIONS The bilateral nasolabial flap is an effective and safe solution for reconstructing the columella, with good support of the tip even without cartilaginous graft. This technique is especially feasible in elderly patients and those with concomitant pathologies, who benefit from rapid healing of the wound.

In the large field of bioactive peptides, peptaibols represent a unique class of compounds. They are membrane-active peptides, produced by fungi of the genus Trichoderma and known to elicit plant defenses. Among the short-length peptaibols, trichogin GA IV is nonhemolytic, proteolysis-resistant, antibacterial, and cytotoxic. Several trichogin analogs are endowed with potent activity against phytopathogens, thus representing a sustainable alternative to copper for plant protection. In this work, we tested the activity of trichogin analogs against a breast cancer cell line and a normal cell line of the same derivation. Lys-containing trichogins showed an IC 50 below 12 µM, a peptide concentration not significantly affecting the viability of normal cells. Two analogs were found to be membrane-active but noncytotoxic. They were anchored to gold nanoparticles (GNPs) and further investigated for their ability to act as targeting agents. GNP uptake by cancer cells increased with peptide decoration, while it decreased in the corresponding normal epithelial cells. This work highlights the promising biological properties of peptaibol analogs in the field of cancer therapy either as cytotoxic molecules or as active targeting agents in drug delivery.

Background: Parathyroid hormone-related peptide (PTHrP) overexpression and poor patient outcome have been reported for many human tumors, but no studies are available in laryngeal cancer. Therefore, we studied the expression of PTHrP and its receptor, parathyroid hormone-related peptide receptor type 1 (PTH1R), in primary locally advanced laryngeal squamous cell carcinomas (LALSCC) also in relation to the clinical outcome of patients., Methods: We conducted a retrospective exploratory study, using immunohistochemistry, on PTHrP, PTH1R and HER1 expressions in LALSCC of 66 patients treated with bio-radiotherapy with cetuximab., Results: The expressions of PTHrP and PTH1R in LALSCC were associated with the degree of tumor differentiation (p = 0.01 and 0.04, respectively). Poorly differentiated tumors, with worse prognosis, expressed PTHrP at nuclear level and were PTH1R negative. PTHrP and PTH1R were expressed at cytoplasmic level in normal larynx epithelium and more differentiated laryngeal cancer cells, suggesting an autocrine/paracrine role of PTHrP in squamous cell differentiation of well differentiated tumors with good prognosis. Eighty-one percent HER1 positive tumors expressed PTHrP (p < 0.0001), mainly at nuclear level, consistent with the known up-regulation of PTHrP gene by HER1 signaling. In multivariable analyses, patients with PTHrP positive tumors had a higher relative risk of relapse (HR = 5.49; CI 95% = 1.62-22.24; p = 0.006) and survival (HR = 8.21; CI 95% = 1.19-105.00; p = 0.031) while those with PTH1R positive tumors showed a lower relative risk of relapse (HR = 0.18; CI 95% = 0.04-0.62; p = 0.002) and survival (HR = 0.18; CI 95% = 0.04-0.91; p = 0.029)., Conclusions: In LALSCC nuclear PTHrP and absence of PTH1R expressions could be useful in predicting response and/or resistance to cetuximab in combined therapies, contributing to an aggressive behavior of tumor cells downstream to HER1., (© 2022. The Author(s).)

Objective: Polidocanol sclerotherapy of head and neck venous malformations (VMs) and lymphatic malformations (LMs) has been reported only in limited series. In this manuscript we evaluated the efficacy and safety of polidocanol sclerotherapy in a series of head and neck venous and lymphatic malformations., Methods: This retrospective observational study analysed data on 20 head and neck VMs and LMs that underwent to percutaneous or endoscopic intra-lesional 3% polidocanol microfoam sclerotherapy at our institution. Clinical response was ranked as excellent, moderate and poor based on volume reduction by MRI and resolution of symptoms., Results: The median volume decreased from 19.3 mL to 5.8 mL after sclerotherapy (mean volume reduction: 72.98 ± 16.1%). An excellent-moderate response was observed in 94.4% of cases. We observed a mean volume reduction of 79.5 ± 16.1 in macrocystic LMs, of 76.1 ± 13.0% in VMs, of 60.5 ± 10.9% in mixed lymphatic ones and 42.5% in microcystic lymphatic ones., Conclusions: Polidocanol sclerotherapy appears to be an effective and safe treatment for venous and lymphatic head and neck malformations. We observed the best responses in macrocystic LMs and VMs, whereas mixed lymphatic ones showed a moderate response and microcystic lymphatic ones a poor response., (Copyright © 2022 Società Italiana di Otorinolaringoiatria e Chirurgia Cervico-Facciale, Rome, Italy.)

The role of elective neck dissection during salvage surgery in patients with a clinically negative neck (cN0) is still discussed. The main objective of this work was to estimate the prevalence and predictive factors of occult neck nodes metastasis; we therefore aimed to evaluate the survival rate and the main oncologic outcomes of cN0 patients who underwent salvage total laryngectomy and elective bilateral neck dissection. In this retrospective observational study, we enrolled 80 cN0 patients affected by recurrent laryngeal cancer and who underwent salvage total laryngectomy and bilateral selective elective neck dissection. Several parameters were collected in order to find prognostic factors; finally, postoperative complications were reviewed and survival analysis was performed. Occult lymph node metastases were reported in 18 out of 80 patients (22.5%). Significant statistical correlation between lymphovascular invasion ( p = 0.007), perineural invasion ( p = 0.025) and occult nodal metastasis was found. Other variables (glottic subsite of recurrence, clinical T, pathological T, previous chemotherapy) were not significantly predictive of occult nodal metastasis. The 5-year OS, DSS, and RFS were 50.4%, 64.7%, and 63.4%, respectively. In conclusion, our single-institution data on a large cohort of patients, suggest performing routinely elective selective bilateral neck dissection during salvage total laryngectomy in cN0 patients due to the biological attitude of the tumor to spread to cervical nodes, considering an acceptable complications rate.

Background: Compared to the other members of human epidermal growth factor family receptors (HER), the role of HER3 has not been well defined in laryngeal cancer. The predictive and prognostic role of HER3 has been the focus of clinical attention but the research findings are contradictory, especially in laryngeal squamous cell carcinoma (LSCC). The variable localization of HER3 within cancer cells and the role of HER3 in primary and acquired resistance to HER1-targeted therapies remain unclear., Methods: We performed a retrospective analysis of two cohorts of 66 homogeneous consecutive untreated primary advanced LSCC patients, in which co-expression of HER1, HER2 and HER3 receptors was investigated by semi-quantitative immunohistochemistry. The association of their pattern of expression with survival was evaluated by Kaplan-Meier and Cox's proportional hazard analyses. Multivariable Cox proportional hazards models were developed to predict median 2- and 3-year RFS and 2.5- and 5-year OS. The Akaike information criterion technique and backwards stepwise procedure were used for model selections. The performance of the final Cox models was assessed with respect to calibration and discrimination., Results: Immunohistochemical labeling for HER1 and HER2 was localized both in the cell membrane and in the cytoplasm, while HER3 labeling was observed both in the cell cytoplasm and in the nucleus. HER3 expression was inversely correlated with HER1 positivity. The expression patterns of HERs were associated with tumor differentiation. In both cohorts of patients, HER1 expression was associated with reduced relapse-free (RFS) and overall survival (OS). In HER1 positive tumors, the co-expression with nuclear HER3 was associated with better RFS and OS, compared with HER3 negative tumors or tumors expressing HER3 at cytoplasmic level. HER3 expressing tumors had a higher Geminin/MCM7 ratio than HER3 negative ones, regardless of HER1 co-expression. Multivariable analyses identified age at diagnosis, tumor site, HER1, HER3 and age at diagnosis, tumor stage, HER1, HER3, as covariates significantly associated with RFS and OS, respectively. Bootstrapping verified the good fitness of these models for predicting survivals and the optimism-corrected C-indices were 0.76 and 0.77 for RFS and OS, respectively., Conclusions: Nuclear HER3 expression was strongly associated with favourable prognosis and allows to improve the prognostic stratification of patients with HER1 positive advanced LSCC carcinoma., (© 2021. The Author(s).)

Purpose: Parastomal recurrence of squamous cell carcinoma (SCC) with tracheal involvement following salvage total laryngectomy after prior concurrent chemoradiotherapy is one of the most insidious challenges in head and neck surgery because a complex reconstruction is often required for covering a large area of skin loss, filling the dead space beneath, tracheal reconstruction and suspension, and tracheostome resurfacing. The aim is to describe our experience with the internal mammary artery perforator (IMAP) propeller flap for tracheal and tracheostome reconstruction and neck resurfacing after parastomal and cervical trachea resection, especially for suspension and anchoring the stump of the residual distal trachea to the island flap itself., Methods: We describe IMAP flap reconstruction after resection of parastomal recurrence of SCC requiring cervical trachea resection in five patients between January 1, 2005 and August 30, 2019., Results: IMAP propeller flap was successfully used for reconstruction after complex resection of parastomal recurrence of SCC with cervical trachea involvement in all cases. The mean length and width were, respectively, 16.8 cm (range 13-23) and 6.9 cm (range 5.5-8). We did not report complications of both the donor and the recipient site. Pharyngo-cutaneous or tracheoesophageal fistulas and wound dehiscence were not observed., Conclusions: to the best of our knowledge, this is the first report about the use of the IMAP propeller flap in this more complex clinical setting and we provide the message that this surgical procedure is worthy of consideration.

Objectives/hypothesis: To analyze stapler benefits in salvage total laryngectomy in terms of surgical time, hospitalization length, oral feeding time, and occurrence of pharyngocutaneous fistula, and to evaluate risk factors for its onset., Study Design: Retrospective analysis., Methods: One hundred fourteen patients affected by endolaryngeal squamous cell carcinoma who underwent salvage total laryngectomy following primary treatment failure were reviewed. We divided patients into two groups based on type of pharyngeal suture performed: mechanical suture with stapler (group A) and manual suture (group B). These two groups were compared for surgical time, start of oral feeding, hospitalization length, surgical margins and pharyngocutaneous fistula incidence considering its relationship with diabetes mellitus, nutritional status, primary treatment, and neck dissection., Results: In group A and group B, oral feeding restarting time was 15 ± 9.33 versus 20.03 ± 13.81 days, hospitalization was 17.63 ± 10.08 versus 23.72 ± 14.29 days, and surgery lasted 268.39 ± 76.93 versus 294.26 ± 140.58 minutes, respectively (P < .05). Surgical margins resulted infiltrated in two patients (4.3%) in group A and 12 patients in group B (17.6%) (P = .03). Twenty-one patients (18.4%) presented with pharyngocutanoeus fistula. In group A and group B the incidence of fistula was 15.2% and 20.6%, respectively (P = .468). Fistula occurred in 7 of 18 diabetic patients (38.9%) and 14 of 96 (14.6%) nondiabetic patients (P = .015). Nineteen fistulas (90.5%) occurred in patients who had undergone previous radiation treatment (P = .013)., Conclusions: Using a stapler shortened operative time and hospitalization, while also providing a faster restart of oral feeding. Moreover, mechanical pharyngeal suture seems to decrease fistula rate even though its prevention role in salvage laryngectomy should be confirmed by further studies., Level of Evidence: 4 Laryngoscope, 131:E473-E478, 2021., (© 2020 The American Laryngological, Rhinological and Otological Society, Inc.)

Purpose: Surgery, external beam radiotherapy (EBRT), and interventional radiotherapy (IRT, BrachyTherapy BT) are the current therapeutic options for nose vestibule (NV) squamous cell carcinoma (SCC). In this article, we evaluate the nose functional parameters of patients affected by SCCs of the NV, primarily treated by interstitial IRT comparing them with healthy controls and with patients treated with intensity-modulated EBRT., Methods: Ten patients treated by using IRT (group 1), 10 healthy controls and eight patients treated by EBRT (group 2) on the region of the nose were submitted to clinical evaluation (with the NOSE scale score), rhinomanometry, olfactory testing, nasal citology, and evaluation of mucociliary clearance through saccharine test., Results: No long-term skin or cartilaginous toxicity are recorded. The olfactometry threshold discrimination identification TDI is lower in EB group. The mean NOSE scale score was significantly higher in group 2 than in group 1 and healthy controls (p < 0.05). The distribution of cytologic patterns resulted significantly different as well. Patients treated by EB have a significantly impaired mucociliary clearance, with a mean time for the transport of the stained marker, which is more than double in the patients treated by EB than in those treated with IRT (p < 0.001)., Conclusions: Nasal function and cytological findings are significantly better, substantially preserved, in patients treated by IRT than in those treated by EBRT, bringing new relevant evidence for the establishment of interstitial IRT as the new standard for the treatment of the primary lesion in cT1 and cT2 -Wang staging NV SCCs., (Copyright © 2021 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Objectives: The primary end point of this study was to evaluate the impact of bile acids on severity of laryngo-pharyngeal reflux (LPR) and the possible correlation with esophagitis and upper airway malignancies. The second end point was to evaluate if salivary bile acids and molecules other than pepsin might serve as diagnostic biomarkers of LPR., Design: Observational prospective comparative study., Setting: Otorhinolaryngology unit of a tertiary hospital., Participants: Sixty-two consecutive adult outpatients suspected of LPR., Main Outcome Measures: Bile acids, bilirubin and pepsinogen I-II were measured in saliva. Patients underwent pH metry and based on the results of bile acids were subdivided as acid, mixed and alkaline LPR., Results: Significantly higher Reflux Findings Score (RFS) and Reflux Symptoms Index (RSI) were seen in patients with alkaline and mixed LPR compared to acid LPR. Salivary bile acids >1 µmol/L seem to be a reliable indicator of the severity of LPR. Compared to those without, patients with esophagitis or a history of upper airway malignancy have high concentrations of bile acids in saliva. Among the molecules studied, bile acids were the most suitable for diagnosis of LPR, with a sensitivity of 86% and a positive predictive value of 80.7%., Conclusions: Our data suggest that high concentrations of bile acids are associated with higher values of RSI and RFS in LPR as well as a higher risk of esophagitis and history of upper airway malignancies. We finally observed that bile acids provided the best biometric parameters for diagnosis of LPR among the molecules tested., (© 2020 John Wiley & Sons Ltd.)

Purpose: We aim to propose a new protocol for olfaction rehabilitation after total laryngectomy based on training of sensory perception levels using the Nasal Airflow-Inducing Maneuver., Methods: This is a randomized clinical trial including patients undergoing total laryngectomy between March 2010 and March 2019. Patients with nasal or oral abnormalities, prior olfaction impairment, a muco-ciliary transport time higher than 30 min, positive history for feeding, and neurological disorders were excluded. Thirty-three patients were enrolled and were randomized into two groups: an Experimental group, submitted to the new protocol (olfactory perception rehabilitation after total laryngectomy-OPRAT) and a Control group that did not receive any treatment. Subjective Olfactometry, Chemosensory Complaints Score, and University of Washington Quality of Life version 4 questionnaires were used to assess the outcomes before and after treatment, and at 3-month, 6-month, and 10-month follow-up., Results: Among the 33 patients included (32 men and 1 woman; mean age, 67.94 ± 5.64 years), 17 were subjected to olfaction rehabilitation and 16 did not receive any treatment. At baseline evaluation, there were not significant differences between the two groups. At the end of treatment, the rehabilitated group improved their olfaction capability significantly. Such improvement remained stable over time, and after 10 months, only the Experimental group had significant improvements in all outcome measures., Conclusions: The OPRAT may guarantee excellent results in the short- and long-term time with positive effects on the Quality of Life.

Background: Salvage total laryngectomy (TL) and laryngopharyngectomy (LP) after chemoradiotherapy may produce disfiguring defects with severe complications that require complex reconstructions., Methods: Between January 2012 and December 2018, we enrolled 25 patients who underwent internal mammary artery perforator (IMAP) flap reconstruction after salvage TL or LP. We performed retrospective review of clinical charts to collect information such as history, timing of reconstruction, type of defect, follow-up, donor and recipient site complications, and overall flap survival (OFS) rate. Three years overall survival (OS), relapse-free survival (RFS), and disease-specific survival (DSS) were calculated., Results: The OFS rate was 95%. One partial flap necrosis was recorded. No donor-site complications were found. The mean follow-up was 18 months. Three years OS was 44%, RFS was 47%, and DSS was 54%., Conclusions: IMAP flap appears to be safe, versatile, and easy to harvest, with minimal donor site morbidity. It is a reliable option in Head&Neck reconstruction, in salvage surgery as well., (© 2019 Wiley Periodicals, Inc.)

After a control phase, 10 normal men received cyproterone acetate (CPA) at a dose of 25 mg/day (CPA-25; n=5) or 12.5 mg/day (CPA-12.5; n=5) plus testosterone enanthate (TE) 100 mg/week, for 16 weeks. Throughout the study sperm counts were performed every 2 weeks, and luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone, biochemical and haematological tests were performed every 4 weeks. All five men in group CPA-25 and three men in group CPA-12.5 achieved azoospermia. One man in group CPA-25 was azoospermic by week 12 of hormone administration, but had a sperm count of 0.1 x 10(6)/ml at week 16. Time to azoospermia was 9.0+/-1.3 and 8.7+/-0.7 weeks in groups CPA-25 and CPA-12.5 respectively. Gonadotrophins were decreased by week 4 of hormone administration, remained around the minimum detectability of the assay for the duration of hormone administration and returned to baseline after stopping hormone administration. Testosterone values did not change. No change in any biochemical parameters was found. Haematological parameters were decreased at week 16 of hormone administration and returned to baseline after stopping hormone administration. In conclusion, these results suggest that an hormonal regimen consisting of testosterone plus a progestin with anti-androgenic properties holds promise as an effective, safe and reversible male contraceptive.