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Abstract Background Financial toxicity from cancer treatments is rising as an important patient-reported outcome. Its relevance was first assessed in the context of privately financed healthcare system, where the financial hardship caused by out-of-pocket payments negatively affects survival, while fewer evidence exists on its role in countries where care is financed by the public health care system. Head and Neck Cancer (HNC) patients face an increased risk for financial toxicity due to multimodal treatment and relevant out of pocket costs. The aim of this study was to develop and validate an Italian version of the Canadian Financial Index of Toxicity (FIT) questionnaire, defined FITALY. Methods FIT questionnaire was translated through a forward-backward process by two investigators independently, and the process was reviewed by a certified medical scientific English native speaker. Once reached consensus upon Italian translation, two Health Economics experts were consulted to adapt the questionnaire to Italian socio-economic context. The FITALY questionnaire v1.0 hereby developed was anonymously administered to two consecutive groups of 30 patients who had received curative, multimodal treatment for HNC cancer at ASST Spedali Civili of Brescia, Italy. A cognitive debriefing form was simultaneously administered to ask patients to exclude recurring and redundant items and include new relevant items. Results The 14-item FITALY questionnaire provides a global evaluation of financial toxicity ranging from 0 to 100. The questionnaire is divided into 4 domains: financial burden (6 items), exploring the objective financial toxicity burden; financial distress (2 items), which refers to the psychological distress related to financial toxicity; out-of-pocket costs (4 items), which focus on medical expenses paid by the patient; and loss of productivity (2 items), that investigates the disease impact on both patient’s and caregiver’s job activity. Conclusions Starting from the Canadian 9-item FIT questionnaire, we developed and validated the Italian 14-item FITALY questionnaire. Prospective application to a cohort of Italian HNC patients is ongoing.

Abstract Introduction Laryngeal chondrosarcoma (CS) is a rare indolent malignant tumor. High-grade (G3), dedifferentiated (DD), and myxoid (MY) CSs are considered more aggressive subtypes due to their metastatic potential and relatively poor outcomes. The aim of this systematic review is to evaluate treatment modalities and survival outcomes in patients affected by these rarer CS subtypes. Methods Papers published from January 1, 2000, to August 25, 2024, describing cases of laryngeal G3, DD, and MY CS were included. Results A total of 38 patients (15 G3, 13 DD, and 10 MY) were selected. Cricoid cartilage was the most common site of origin. Total laryngectomy (TL) was often performed. Primary conservative approaches in 42.8% of patients were followed by loco-regional recurrence. Conclusions Aggressive subtypes of CS require a radical approach because of the higher rate of loco-regional and distant recurrences compared to low-grade CS. TL with radical intent is the most common treatment, and adjuvant therapy should be considered after careful multidisciplinary discussion.

In locally advanced (LA) laryngeal/hypopharyngeal squamous cell carcinoma (LHSCC), larynx preservation (LP) strategies aim at the cure of the disease while preserving a functional larynx, thus avoiding total laryngectomy and the associated impact on the quality of life. In the last decades, apart from transoral and open-neck organ preservation approaches, several non-surgical regimens have been investigated: radiotherapy alone, alternate, concurrent or sequential chemoradiation, and bioradiotherapy. Despite major progress, the identification of reliable and effective predictors for treatment response remains a clinical challenge. This review examines the current state of LP in LA-LHSCC and the need for predictive factors, highlighting the importance of the PRESERVE trial in addressing this gap. The PRESERVE trial represents a pivotal initiative aimed at finding the optimal therapy for laryngeal preservation specific to each patient through a retrospective analysis of data from previous LP trials and prospectively validating findings. The goal of the PRESERVE trial is to develop a comprehensive predictive classifier that integrates clinical, molecular, and multi-omics data, thereby enhancing the precision and efficacy of patient selection for LP protocols.

Open partial horizontal laryngectomies (OPHLs) represent a valuable therapeutic option for tumors of the intermediate T-category and, in selected cases, for locally advanced tumors with low-volume extra-laryngeal extension. The eligibility of patients treated with this type of surgery has increased with the introduction of the modular approach to OPHL planning. This strategy follows the introduction of the classification proposed by the European Laryngological Society, based on the extent of horizontal resection. Optimization of the selection is the result of a meticulous work-up process involving close cooperation between experienced surgeons and radiologists, followed by final quality control by pathologists. Computed tomography and magnetic resonance imaging are study methods whose pearls and pitfalls are well known, especially when performed at a high level of expertise. In this paper, based on the experience of two high-volume centers, a checklist of 20 questions addressed by the surgeon to the radiologist before planning an OPHL was proposed. Considerations regarding case selection are reported for each of the questioned parameters. A very simple question-and-answer process is easy to understand and mainly addressed by less experienced colleagues who wish to increase their knowledge and skills in performing this type of surgery.

Abstract Adenoid cystic carcinoma (ACC) of salivary gland is a slowly growing tumor showing a propensity for delayed recurrence, with decreased survival rates. The identification of poor prognosis patients may help in defining molecular-based targeted strategies in this rare disease orphan of new treatments. Through a gene expression microarray-based approach followed by GSE functional analysis the expression profile of 46 primary untreated ACC samples and of ACC (h-TERT) tumor cells was analyzed. Patients who experienced early relapse showed enrichment in proliferation-related gene sets, including the G2-M checkpoint, E2F and myc targets, and in gene sets related to IFN signaling and aberrant proteostasis (FDR

IntroductionThe study assessed outcomes and toxicities of different treatment modalities for local and/or regional recurrent nasopharyngeal carcinoma (NPC) in a non-endemic area.MethodsPatients treated with curative intent for recurrent NPC with salvage surgery, photon-based radiotherapy, proton therapy (PT), with or without chemotherapy, at different Italian referral centers between 1998 and 2020 were included. Adverse events and complications were classified according to the Common Terminology Criteria for Adverse Events. Characteristics of the patients, tumors, treatments, and complications are presented along with uni- and multivariate analysis of prognostic factors. A survival predictive nomogram is also provided.ResultsA total of 140 patients treated from 1998 to 2020 were retrospectively assessed. Cases with lower age, comorbidity rate, stage, and shorter disease-free interval (DFI) preferentially underwent endoscopic surgery. More advanced cases underwent re-irradiation, fairly distributed between photon-based radiotherapy and PT. Age and DFI were independent factors influencing overall survival. No independent prognostic effect of treatment modality was observed. No significant difference in the morbidity profile of treatments was observed, with 40% of patients experiencing at least one adverse event classified as G3 or higher.ConclusionRecurrent NPC in a non-endemic area has dissimilar aspects compared to its endemic counterpart, suggesting the need for further studies that can guide the choice of the best treatment modality.

Abstract 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

Background: The management of cT3 laryngeal cancers remains controversial, with studies recommending surgical or non-surgical approaches. Despite the many papers that have been published on the subject, there is a lack of studies showing which treatment has better results in terms of survival. Objective: To determine the difference in survival outcomes following total laryngectomy (TL), concurrent chemoradiation (CRT) or radiation therapy (RT) alone in T3 laryngeal cancers. Methods: Search of PubMed, Scopus, and Google Scholar databases from 1995 to 2023 employing specific keywords and Boolean operators to retrieve relevant articles. Statistical analysis was conducted using a random-effects model, and heterogeneity was evaluated using the Q-test and I2 statistic. Funnel plot asymmetry was assessed using rank correlation and regression tests. Results: The qualitative data synthesis comprised 10,940 patients from 16 included studies. TL was performed in 2149 (19.4%), CRT in 6723 (61.5%), RT in 295 (2.7%), while non-surgical treatment was not specified in 1773 (16.2%) patients. The pooled 2-year overall survival (OS) rates were TL = 73%, CRT = 74.7%, RT = 57.9%, 3-year OS rates were TL = 64.3%, CRT = 62.9%, RT = 52.4%, and 5-year OS rates were TL = 54.2%, CRT = 52.7%, RT = 40.8%. There was a significant heterogeneity in the included studies. There was no statistically significant difference in 2-year OS (logOR= −0.88 (95% confidence interval (CI): −1.99 to 0.23), p = 0.12), 3-year OS (logOR = −0.6 (95% CI: −1.34 to 0.15), p = 0.11), and 5-year OS (logOR = −0.54 (95% CI: −1.29 to 0.21), p = 0.16) between TL and CRT. Instead, there was significant difference in 2-year OS (logOR= −1.2383 (95% CI: −2.1679 to −0.3087), p = 0.009), 3-year OS (−1.1262 (95% CI: −1.6166 to −0.6358), p < 0.001), and 5-year OS (−0.99 (95% CI: −1.44 to −0.53)), p < 0.001) between TL and RT alone. Conclusions and Significance: TL followed with adjuvant (chemo)radiation on indication and CRT with salvage surgery in reserve appear to have similar OS outcomes. Both resulted in better OS outcomes compared to RT alone in the treatment of T3 laryngeal cancers. If patients are unfit for chemotherapy, making CRT impossible, surgery may become the choice of treatment.

Abstract Background Oral Potentially Malignant Disorders (OPMD) have a non-negligible malignant transformation rate of up to 8%. Loss of heterozygosity (LOH) in critical chromosomal loci has proven to be the most effective marker in defining the risk of transformation and it is found in about 28% of OPMD and may therefore identify patients carrying higher risk. To date, clinical management of OPMD is limited to surgical excision and clinical surveillance, which however do not fully prevent oral cancer development. Immune system has been shown to play a key role in transformation surveillance mechanism and an immunosuppressive imbalance may be responsible for progression to cancer. Given all these considerations, we designed a clinical trial with the aim to prevent OPMD neoplastic transformation and revert the LOH status. Methods This is a phase II, open label, single arm, multicentric trial involving Italian referral centres and expected to enrol 80 patients out of a total of 175 screened. Patients who meet all inclusion criteria and test positive for LOH after an incisional biopsy of the OPMD will undergo a short course of immunotherapy with 4 administration of avelumab. After 6 months since treatment start, resection of the entire OPMD will be performed and LOH assessment will be repeated. The follow-up for malignant transformation and safety assessment will last 30 months from the end of treatment, for a total planned study duration of approximately 5.5 years. Discussion Restoring the activity of immune system through checkpoint inhibitor may play a crucial role against malignant transformation of OPMD by reverting the balance in favour of immune control and preventing cancer occurrence. Trial registration This trial was prospectively registered in ClinicalTrials.gov as NCT04504552 on 7th August 2020.

Artificial intelligence is being increasingly seen as a useful tool in medicine. Specifically, these technologies have the objective to extract insights from complex datasets that cannot easily be analyzed by conventional statistical methods. While promising results have been obtained for various -omics datasets, radiological images, and histopathologic slides, analysis of videoendoscopic frames still represents a major challenge. In this context, videomics represents a burgeoning field wherein several methods of computer vision are systematically used to organize unstructured data from frames obtained during diagnostic videoendoscopy. Recent studies have focused on five broad tasks with increasing complexity: quality assessment of endoscopic images, classification of pathologic and nonpathologic frames, detection of lesions inside frames, segmentation of pathologic lesions, and in-depth characterization of neoplastic lesions. Herein, we present a broad overview of the field, with a focus on conceptual key points and future perspectives.

BackgroundBoth anaplastic thyroid carcinoma (ATC) and thyroid lymphoma (TL) clinically present as rapidly enlarging neck masses. Unfortunately, in this situation, like in any other thyroid swelling, a routine fine-needle aspiration (FNA) cytology is the first and only diagnostic test performed at the initial contact in the average thyroid practice. FNA, however, has a low sensitivity in diagnosing ATC and TL, and by the time the often “inconclusive” result is known, precious time has evolved, before going for core-needle biopsy (CNB) or incisional biopsy (IB) as the natural next diagnostic steps.ObjectivesTo determine the diagnostic value of CNB in the clinical setting of a rapidly enlarging thyroid mass, via a systematic review and meta-analysis of the available data on CNB reliability in the differential diagnosis of ATC and TL.MethodsA PubMed, Embase and Web of Science database search was performed on June 23th 2021. Population of interest comprised patients who underwent CNB for clinical or ultrasonographical suspicion of ATC or TL, patients with a final diagnosis of ATC or TL after CNB, or after IB following CNB.ResultsFrom a total of 17 studies, 166 patients were included. One hundred and thirty-six were diagnosed as TL and 14 as ATC following CNB. CNB, with a sensitivity and positive predictive value of 94,3% and 100% for TL and 80,1% and 100% for ATC respectively, proved to be superior to FNA (reported sensitivity for TL of 48% and for ATC of 61%). Furthermore, the need for additional diagnostic surgery after CNB was only 6.2% for TL and 17.6% for ATC.ConclusionsImmediately performing CNB for a suspected diagnosis of ATC and TL in a rapidly enlarging thyroid mass is more appropriate and straightforward than a stepped diagnostic pathway using FNA first and awaiting the result before doing CNB.

IntroductionNarrow Band Imaging (NBI) is an endoscopic visualization technique useful for upper aero-digestive tract (UADT) cancer detection and margins evaluation. However, NBI analysis is strongly operator-dependent and requires high expertise, thus limiting its wider implementation. Recently, artificial intelligence (AI) has demonstrated potential for applications in UADT videoendoscopy. Among AI methods, deep learning algorithms, and especially convolutional neural networks (CNNs), are particularly suitable for delineating cancers on videoendoscopy. This study is aimed to develop a CNN for automatic semantic segmentation of UADT cancer on endoscopic images.Materials and MethodsA dataset of white light and NBI videoframes of laryngeal squamous cell carcinoma (LSCC) was collected and manually annotated. A novel DL segmentation model (SegMENT) was designed. SegMENT relies on DeepLabV3+ CNN architecture, modified using Xception as a backbone and incorporating ensemble features from other CNNs. The performance of SegMENT was compared to state-of-the-art CNNs (UNet, ResUNet, and DeepLabv3). SegMENT was then validated on two external datasets of NBI images of oropharyngeal (OPSCC) and oral cavity SCC (OSCC) obtained from a previously published study. The impact of in-domain transfer learning through an ensemble technique was evaluated on the external datasets.Results219 LSCC patients were retrospectively included in the study. A total of 683 videoframes composed the LSCC dataset, while the external validation cohorts of OPSCC and OCSCC contained 116 and 102 images. On the LSCC dataset, SegMENT outperformed the other DL models, obtaining the following median values: 0.68 intersection over union (IoU), 0.81 dice similarity coefficient (DSC), 0.95 recall, 0.78 precision, 0.97 accuracy. For the OCSCC and OPSCC datasets, results were superior compared to previously published data: the median performance metrics were, respectively, improved as follows: DSC=10.3% and 11.9%, recall=15.0% and 5.1%, precision=17.0% and 14.7%, accuracy=4.1% and 10.3%.ConclusionSegMENT achieved promising performances, showing that automatic tumor segmentation in endoscopic images is feasible even within the highly heterogeneous and complex UADT environment. SegMENT outperformed the previously published results on the external validation cohorts. The model demonstrated potential for improved detection of early tumors, more precise biopsies, and better selection of resection margins.

BackgroundThe classification of sinonasal carcinomas (SNCs) is a conundrum. Consequently, prognosis and prediction of response to non-surgical treatment are often unreliable. The availability of prognostic and predictive measures is an unmet need, and the first logical source of information to be investigated is represented by the clinicopathological features of the disease. The hypothesis of the study was that clinicopathological information on SNC could be exploited to better predict prognosis and chemoradiosensitivity.MethodsAll patients affected by SNC who received curative treatment, including surgery, at the Unit of Otorhinolaryngology—Head and Neck Surgery of the University of Brescia between October 1998 and February 2019 were included in the analysis. The institutional series was reviewed and a survival analysis was performed. Machine learning and multivariable statistical methods were employed to develop, analyze, and test 3 experimental classifications (classification #1, based on cytomorphological, histomorphological, and differentiation information; classification #2, based on differentiation information; and classification #3, based on locoregional extension) of SNC, based on the inherent clinicopathological information. The association of experimental classifications with prognosis and chemoradiosensitivity was tested.ResultsThe study included 145 patients. From a prognostic standpoint, the machine learning-generated classification of SNC provided better prediction than the current World Health Organization classification. However, the prediction of the chemoradiosensitivity of SNC was not achievable.ConclusionsReorganization of clinicopathological information, with special reference to those related to tumor differentiation, can improve the reliability of prognosis of SNC. Prediction of chemoradiosensitivity remains an unmet need and further research is required.

BackgroundOral potentially malignant disorders (OPMDs) represent a heterogeneous set of different histological lesions, characterized by the capacity to transform in oral squamous cell carcinoma (OSCC). Despite optimal surgical treatment, approximately 20%–30% of OPMDs may evolve into OSCC. No clear clinical/histological factors are able to identify OPMDs at higher risk of malignant transformation.Materials and MethodsWe considered surgically treated patients with a diagnosis of OPMDs, enrolled from 1996 to 2019 at ASST Spedali Civili of Brescia without a diagnosis of OSCC within the previous 2 years. Clinical and histological characteristics were recorded. Outcomes of interest were recurrence-free survival (RFS), defined as the time from surgery for primary OPMD to any relapse of OPMD or malignant transformation, whichever occurred first, and carcinoma-free survival (CFS), defined as the time from surgery for OPMD to malignant transformation.ResultsWe retrospectively reviewed 106 OPMDs cases. Median age at first diagnosis was 64 years old (IQR = 18.75); female patients comprise 51.9% of the cases. During a median follow-up of 30.5 months (IQR = 44), in 23.5% of patients, malignant transformation occurred. RFS at 1, 5, and 10 years was 92.4%, 60.9%, and 43.2%, respectively. Female sex and history of previous OSCC were independent risk factors for RFS. CFS at 1, 5, and 10 years of follow-up was 97.1%, 75.9%, and 64.4%, respectively. Previous OSCC was an independent risk factor for CFS.ConclusionsIn this large series of OPMDs, only previous diagnosis of OSCC was a prognostic factor for further OSCC occurrence. Given the lack of additional clinical/pathological prognostic factors, we advocate further studies into molecular characterization of OPMDs to better stratify the risk of malignant transformation.

Airway involvement by advanced thyroid carcinoma (TC) constitutes a negative prognosticator, besides being a critical clinical issue since it represents one of the most frequent causes of death in locally advanced disease. It is generally agreed that, for appropriate laryngo-tracheal patterns of invasion, (crico-)tracheal resection and primary anastomosis [(C)TRA] is the preferred surgical technique in this clinical scenario. However, the results of long-term outcomes of (C)TRA are scarce in the literature, due to the rarity of such cases. The relative paucity of data prompts careful review of the available relevant series in order to critically evaluate this surgical technique from the oncologic and functional points of view. A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement on the PubMed, Scopus, and Web of Science databases. English-language surgical series published between January 1985 and August 2021, reporting data on ≥5 patients treated for TC infiltrating the airway by (C)TRA were included. Oncologic outcomes, mortality, complications, and tracheotomy-dependency rates were assessed. Pooled proportion estimates were elaborated for each end-point. Thirty-seven studies were included, encompassing a total of 656 patients. Pooled risk of perioperative mortality was 2.0%. Surgical complications were reported in 27.0% of patients, with uni- or bilateral recurrent laryngeal nerve palsy being the most common. Permanent tracheotomy was required in 4.0% of patients. Oncologic outcomes varied among different series with 5- and 10-year overall survival rates ranging from 61% to 100% and 42.1% to 78.1%, respectively. Five- and 10-year disease specific survival rates ranged from 75.8% to 90% and 54.5% to 62.9%, respectively. Therefore, locally advanced TC with airway invasion treated with (C)TRA provides acceptable oncologic outcomes associated with a low permanent tracheotomy rate. The reported incidence of complications, however, indicates the need for judicious patient selection, meticulous surgical technique, and careful postoperative management.

Objectives The role of the immune system in head and neck squamous cell carcinoma is controversial. The aim of our study was to analyze full blood counts and distribution of T cell subsets in patients affected by laryngeal squamous cell cancer (LSCC) and their association with clinical variables and survival. Study design Retrospective study. Methods We analyzed the levels of platelets, lymphocytes, and neutrophils, as well as the CD4+, CD8+, and CD3+ T‐cell subpopulations by cytofluorometry in LSCC patients. A cohort of healthy patients was used as control group. The disease‐specific survival (DSS) was considered as survival outcome. Results Sixty‐five LSCC patients and 48 controls were enrolled. In LSCC patients, neutrophils were higher than in the healthy group (P

Purpose: The present work compares the effects produced by the application of the 7th edition of the tumor node metastasis (TNM) staging system (TNM7), 8th Edition (TNM8) with its two subsequent revisions, and pN-N+ classification on a cohort of patients with oral tongue and floor of the mouth cancer.Methods: A monocentric cohort of 148 patients was retrospectively analyzed. Patients were staged according to the TNM7, TNM8 and revisions, and pN-N+ classification. Stage migration was assessed and overall survival (OS) analyzed with the Kaplan–Meier method. The pT, pN, and stage stratification was evaluated with univariate and multivariate Cox regression and comparing adjacent categories with the log-rank method.Results: pT3-T4a categories showed significant differences in comparison to pT1-T2 for each staging metric employed in both uni- and multivariate analysis. When comparing adjacent pT categories, OS was significantly different only between pT2 and pT3 categories of the TNM8. Disproportionate patient distribution among pN categories was observed in the TNM8, and stratification was scarce. Conversely, in the pN-N+ classification the difference between pN2 and pN3a categories was significant. Only stage IVa reached statistical significance in TNM7, whereas stage III and above were significant in TNM8 and revisions in both uni- and multivariate analysis. However, no significant difference was noted comparing adjacent stages.Conclusion: The TNM8 pT classification differentiated low- from high-risk diseases. Nonetheless, it failed to separate pT1 from pT2 and pT3 from pT4a categories. Conversely, although TNM8 nodal staging was inaccurate, the number of metastatic lymph nodes was more valuable.

BackgroundThe aim of oral cancer surgery is tumor removal within clear margins of healthy tissue: the latter definition in the literature, however, may vary between 1 and 2 cm, and should be intended in the three dimensions, which further complicates its precise measurement. Moreover, the biological behavior of tongue and floor of mouth cancer can be unpredictable and often eludes the previously mentioned safe surgical margins concept due to the complexity of tongue anatomy, the intricated arrangements of its intrinsic and extrinsic muscle fibers, and the presence of rich neurovascular and lymphatic networks within it. These structures may act as specific pathways of loco-regional tumor spread, allowing the neoplasm to escape beyond its visible macroscopic boundaries. Based on this concept, in the past two decades, compartmental surgery (CS) for treatment of oral tongue and floor of mouth cancer was proposed as an alternative to more traditional transoral resections.MethodsThe authors performed three anatomical dissections on fresh-frozen cadaver heads that were injected with red and blue-stained silicon. All procedures were documented by photographs taken with a professional reflex digital camera.ResultsOne of these step-by-step cadaver dissections is herein reported, detailing the pivotal points of CS with the aim to share this procedure at benefit of the youngest surgeons.ConclusionsWe herein present the CS step-by-step technique to highlight its potential in improving loco-regional control by checking all possible routes of tumor spread. Correct identification of the anatomical space between tumor and nodes (T-N tract), spatial relationships of extrinsic tongue muscles, as well as neurovascular bundles of the floor of mouth, are depicted to improve knowledge of this complex anatomical area.

IntroductionFully convoluted neural networks (FCNN) applied to video-analysis are of particular interest in the field of head and neck oncology, given that endoscopic examination is a crucial step in diagnosis, staging, and follow-up of patients affected by upper aero-digestive tract cancers. The aim of this study was to test FCNN-based methods for semantic segmentation of squamous cell carcinoma (SCC) of the oral cavity (OC) and oropharynx (OP).Materials and MethodsTwo datasets were retrieved from the institutional registry of a tertiary academic hospital analyzing 34 and 45 NBI endoscopic videos of OC and OP lesions, respectively. The dataset referring to the OC was composed of 110 frames, while 116 frames composed the OP dataset. Three FCNNs (U-Net, U-Net 3, and ResNet) were investigated to segment the neoplastic images. FCNNs performance was evaluated for each tested network and compared to the gold standard, represented by the manual annotation performed by expert clinicians.ResultsFor FCNN-based segmentation of the OC dataset, the best results in terms of Dice Similarity Coefficient (Dsc) were achieved by ResNet with 5(×2) blocks and 16 filters, with a median value of 0.6559. In FCNN-based segmentation for the OP dataset, the best results in terms of Dsc were achieved by ResNet with 4(×2) blocks and 16 filters, with a median value of 0.7603. All tested FCNNs presented very high values of variance, leading to very low values of minima for all metrics evaluated.ConclusionsFCNNs have promising potential in the analysis and segmentation of OC and OP video-endoscopic images. All tested FCNN architectures demonstrated satisfying outcomes in terms of diagnostic accuracy. The inference time of the processing networks were particularly short, ranging between 14 and 115 ms, thus showing the possibility for real-time application.

BackgroundPatients with metastases in the lymph nodes of the neck and no obvious primary tumor, neck cancer with unknown primary (NCUP), represent a management challenge. A majority of patients have metastatic squamous cell carcinoma (SCC), although other histologies do occur.MethodsWe comprehensively reviewed the literature, compared available guidelines, and conferred with an international team of experts.ResultsPositron emission tomography-computed tomography (PET-CT) and fine needle aspiration (FNA) under ultrasound guidance increase accuracy of diagnosis. Immunohistochemistry (IHC), determination of human papilloma virus (HPV) status, by p16 staining or by in situ hybridization (ISH), and next-generation gene sequencing can guide us regarding probable primary sites and tumor biology. Narrow Band Imaging (NBI) has been introduced for the early detection of subtle mucosal lesions. Direct laryngoscopy (DL) and tonsillectomy have long been procedures used in the search for a primary site. More recently, TransOral Robotic Surgery (TORS) or Transoral LASER Microsurgery (TLM) have been introduced for lingual tonsillectomy.ConclusionsNew technologies have been developed which can better detect, diagnose, and treat occult primary tumors. Decisions regarding therapy are based on the primary tumor site (if discovered) and N stage. Options include neck dissection with or without postoperative adjuvant therapy, primary irradiation, or combined chemotherapy with irradiation. The preferred treatment of patients whose primary remains unidentified is controversial.

Objective: This study aimed to look into the relationship between intensity-modulated-radiotherapy (IMRT)- or volumetric-modulated-arc-therapy (VMAT)-based dose–volume parameters and 5-year outcome for a consecutive series of non-metastatic nasopharyngeal cancer (NPC) patients (pts) treated in a single institution in a non-endemic area in order to identify potential prognostic factors.Materials and methods: A retrospective analysis of consecutive non-metastatic NPC pts treated curatively with IMRT or VMAT and chemotherapy (CHT) between 2004 and 2014 was conducted. One patient was in stage I (0.7%), and 24 pts (17.5%) were in stage II, 38 pts (27.7%) in stage III, 29 pts (21.2%) in stage IVA, and 45 pts (32.8%) in stage IVB. Five pts (3.6%) received radiotherapy (RT) alone. Of the remaining 132 pts (96.4%), 30 pts (21.9%) received CHT concomitant to RT, and 102 pts (74.4%) were treated with induction CHT followed by RT-CHT. IMRT was given with standard fractionation at a total dose of 70 Gy. Clinical outcomes investigated in the study were local control (LC), disease-free survival (DFS), and overall survival (OS). Kaplan–Meier (KM) analysis was performed for the outcomes considering dose and coverage parameters, staging, and RT technique.Results: Overall, 137 pts were eligible for this retrospective analysis. With a median follow-up of 70 months (range 12–143), actuarial rates at 5 years were LC 90.4, DFS 77.2, and OS 82.8%. For this preliminary study, T stage was dichotomized as T1, T2, T3 vs. T4. At 5 years, the group T1–T2–T3 reported an LC of 93%, a DFS of 79%, and an OS of 88%, whereas T4 pts reported LC, DFS, and OS, respectively, of 56, 50, and 78%. Pts with V95% > 95.5% had better LC (p = 0.006). Pts with D99% > 63.8 Gy had better LC (p = 0.034) and OS (p = 0.005). The threshold value of 43.2 cm3 of GTVT was prognostic for LC (p = 0.016). To predict the risk of local recurrence at 5 years, we constructed a nomogram which combined GTVT with D99% relative to HRPTV.Conclusions: We demonstrated the prognostic value of some dose–volume parameters, although in a retrospective series, this is potentially useful to improve planning procedure. In addition, for the first time in a non-endemic area, a threshold value of GTVT, prognostic for LC, has been confirmed.

Introduction: Trans-oral laser microsurgery is an established technique for the treatment of early and moderately advanced laryngeal cancer. Objective: The authors intend to test the usefulness of narrow-band imaging in the intraoperative assessment of the larynx mucosa in terms of specifying surgical margins. Methods: Forty-four consecutive T1–T2 glottic cancers treated with trans-oral laser microsurgery Type I–VI cordectomy were presented. Suspected areas (90 samples/44 patients) were biopsied under the guidance of narrow-band imaging and white light and sent for frozen section. Results: Our study revealed that 75 of 90 (83.3%) white light and narrow-band imaging-guided samples were histopathologically positive: 30 (40%) were confirmed as carcinoma in situ or invasive carcinoma and 45 (60%) as moderate to severe dysplasia. In 6 patients mucosa was suspected only in narrow-band imaging, with no suspicion under white light. Thus, in these 6 patients 18/90 (20%) samples were taken. In 5/6 patients 16/18 (88.8%) samples were positive in frozen section: in 6/18 (33.3%) carcinoma (2 patients), 10/18 (66.6%) severe dysplasia was confirmed (3 patients). In 1 patient 2/18 (11.1%) samples were negative in frozen section. Presented analysis showed, that sensitivity, specificity and accuracy of white light was 79.5%, 20% and 71.1% respectively, while narrow-band imaging was 100%, 0.0% and 85.7%, respectively. Conclusion: The intraoperative use of narrow-band imaging proved to be valuable in the visualization of suspect areas of the mucosa. Narrow-band imaging confirms the suspicions undertaken in white light and importantly, it showed microlesions beyond the scope of white light. Resumo: Introdução: A microcirurgia transoral a laser é uma técnica bem estabelecida para o tratamento de câncer de laringe inicial e moderadamente avançado. Objetivo: Verificar a utilidade da imagem de banda estreita na avaliação intraoperatória da mucosa laríngea na especificação das margens cirúrgicas. Método: Foram avaliados 44 cânceres glóticos T1-T2 consecutivos, tratados com cordectomia Tipo I-VI, por microcirurgia transoral a laser. As áreas suspeitas (90 amostras/44 pacientes) foram submetidas a biopsia e avaliadas através de imagens de banda estreita e luz branca e enviadas para cortes por congelação. Resultados: Nosso estudo revelou que 75 (83,3%) das 90 amostras, apresentaram histopatologia positiva na análise com luz branca e imagens de banda estreita: 30 (40%) foram confirmadas como carcinoma in situ ou carcinoma invasivo e 45 (60%) como displasia moderada a grave. Em seis pacientes, a mucosa apresentou-se suspeita apenas na imagem de banda estreita, sem nenhuma suspeita sob luz branca. Assim, nesses seis pacientes 18/90 (20%) amostras foram colhidas. Em 5/6 pacientes, 16/18 (88,8%) amostras mostraram resultado positivo na análise de congelação: em 6/18 (33,3%) amostras foi confirmado carcinoma (dois pacientes) e em 10/18 (66,6%) foi confirmada displasia grave (três pacientes). Em um paciente, 2/18 (11,1%) as amostras mostraram resultado negativo na congelação. A análise apresentada mostrou que a sensibilidade, a especificidade e a acurácia da luz branca foram de 79,5%, 20% e 71,1%, respectivamente, enquanto a imagem de banda estreita apresentou como resultados 100%, 0,0% e 85,7%, respectivamente. Conclusão: O uso intraoperatório de imagem de banda estreita provou ser valioso na identificação de áreas suspeitas da mucosa, confirmou as suspeitas verificadas na análise com luz branca e, o que é mais importante, identificou microlesões além do alcance da luz branca. Keywords: Laser CO2, Early, Moderately advanced glottic cancer, Narrow-band imaging, Safe margins, Frozen sections, Palavras-chave: Laser CO2, Inicial, Câncer glótico moderadamente avançado, Imagens de banda estreita, Margens seguras, Cortes por congelação

Background: Preoperative assessment is critical to decide the most adequate surgical strategy for oral squamous cell carcinoma (SCC). Magnetic resonance (MR) and intraoral ultrasonography (US) have been reported to be of great value for preoperative estimation of depth of invasion (DOI) and/or tumor thickness (TT). This review aims to analyze the accuracy of MR and intraoral US in determining DOI/TT in oral SCC, by assuming histological evaluation as the reference method.Methods: The procedure was conducted following the modified 2009 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. We performed a systematic search of papers on PubMed, Scopus, Web of Science, and Cochrane Library databases until July 31st, 2019. For quantitative synthesis, we included nine studies (487 patients) focused on MR, and 12 (520 patients) focused on intraoral US. The Pearson correlation coefficient (r) between DOI/TT evaluated with MR or intraoral US was assumed as effect size. A meta-analysis (MA) for each study group (MR and US) was performed by using the random-effects models with the DerSimonian–Laird estimator and r-to-z transformation.Results: In the MA for MR studies, a high heterogeneity was found (I2 = 94.84%; Q = 154.915, P < 0.001). No significant risk of bias occurred by evaluating funnel plot asymmetry (P = 0.563). The pooled (overall) r of the MR studies was 0.87 (95% CI from 0.82 to 0.92), whereas the pooled r-to-z transformed was 1.44 (95% CI from 1.02 to 1.85). In the MA for US studies a high heterogeneity was found (I2 = 93.56%; Q = 170.884, P < 0.001). However, no significant risk of bias occurred (P = 0.779). The pooled r of the US studies was 0.96 (95% CI from 0.94 to 0.97), whereas the pooled r-to-z transformed was 1.76 (95% CI from 1.39 to 2.13). These outputs were confirmed in additional MA performed by enrolling only MR (n = 8) and US (n = 11) studies that evaluated TT.Conclusions: MR and intraoral US seem to be promising approaches for preoperative assessment of DOI/TT in oral SCC. Remarkably, a higher pooled r and r-to-z transformed were observed in the intraoral US studies, suggesting that this approach could be more closely related to histopathological findings.

Introduction: Surgery followed by adjuvant therapy represents the most adequate treatment for advanced oral squamous cell carcinoma (OSCC). Free flaps are considered the best reconstructive option after major oral surgery. In the last decades, OSCC has increased in the elderly due to an augmented life span. The aim of this work is to evaluate the feasibility of microvascular surgery in patients older than 75 years, focusing on clinical and surgical prognosticators.Methods: “Older old” (aged ≥ 75) and “oldest old” (>85) patients who underwent microvascular reconstruction for OSCC from 2002 to 2018 were retrospectively evaluated in three referral Head and Neck Departments. Demographic, clinical, and surgical data were collected and analyzed. Pre-operative assessment was performed by ASA and ACE-27 scores. Complications were grouped as medical or surgical, and major or minor according to the Clavien-Dindo scale.Results: Eighty-four patients (72 “older old” and 12 “oldest old”) were treated with a free flap success rate of 94.1%. Thirty-seven (44.7%) and nine (10.7%) patients had minor and major medical complications, respectively; 18 (21.4%) and 17 (20.2%) had minor and major surgical complications, respectively. Twenty-one (25%) patients had both medical and surgical complications (with a statistically significant association, p = 0.018). Overall, 52 (61.9%) patients had at least one complication: ASA score, diabetes mellitus, and duration of general anesthesia (DGA) significantly impacted the complication rate at multivariate analysis.Conclusion: Our data confirm the feasibility of free flaps for OSCC reconstruction in appropriately selected elderly patients. Pre-operative assessment and aggressive management of glycemia in patients with diabetes is mandatory. DGA should be reduced as much as possible to prevent post-surgical complications. Comprehensive geriatric assessment is of paramount importance in this subset of patients.

Objectives: To investigate the prognostic significance of preoperative neutrophil to lymphocyte ratio (NLR) and the impact of different clinical-pathologic factors in a series of primary oral squamous cell carcinomas (OSCC).Materials and Methods: All naive OSCCs treated with upfront surgery between 2000 and 2014 were retrospectively reviewed. Patients with distant metastasis, synchronous head and neck cancer, immunological disorders, or who had received previous chemotherapy and/or radiation of the head and neck area were excluded. The main outcomes were overall (OS), disease-specific (DSS), loco-regional free (LRFS), and distant metastasis free (DMFS) survivals. Univariate (Kaplan-Meier) and multivariate (Cox regression model) analysis were performed, and nomograms developed for each outcome. NLR was analyzed as a continuous variable using restricted cubic spline multivariable Cox regression models.Results: One-hundred-eighty-two patients were included. Five-year estimates for LRFS, DMFS, DSS, and OS were 67, 83.7, 69.5, and 61.2%, respectively. NLR had a complex influence on survival and risk of recurrence: negative for very low and high values, while positive in case of intermediate ratios. At univariate analysis, T classification, 7th AJCC stage, nodal metastasis, perineural spread, and lymphovascular invasion were statistically significant. At multivariate analysis, extranodal extension (ENE) and perineural spread were the most powerful independent prognostic factors. NLR was an independent prognosticator for the risk of recurrence. In nomograms, NLR and ENE had the strongest prognostic effect.Conclusions: In OSCC, very low preoperative NLR values have a negative prognostic impact on survival and recurrence, similarly to high ratios. ENE and perineural spread are the most important clinical-pathologic prognosticators.

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 < 0.001), the LYMPHOIDMV showed a significant association with the overall, disease-specific and distant recurrence-free survival (p < 0.05) and the MYELOIDMV with the locoregional control only (p < 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.

In the last decades, radiotherapy (RT) has become one of the cornerstones in the treatment of head and neck (HN) malignancies and has paralleled an increase in long-term patient survival. This lead to a concomitant increase in the incidence of radiation-induced sarcomas (RIS) of the irradiated field, with an annual rate up to 0.17%. The new techniques of irradiation do not seem to influence the risk of RIS of the HN (RISHN), which mainly develop within the middle-dose field. The median latency of RISHN after RT is 10–12 years and osteosarcoma is the most represented histotype, even though there is a high variability in time of occurrence and histological features observed. There is no clear evidence of predisposing factors for RISHN, and genetic findings so far have not revealed any common mutation. Early clinical diagnosis of RISHN is challenging, since it usually occurs within fibrotic and hardened tissues, while radiological findings are not pathognomonic and able to differentiate them from other neoplastic entities. Given the highly aggressive behavior of RISHN and its poor sensitivity to chemotherapy, radical surgery is the most important prognostic factor and the only curative option at present. Nevertheless, the anatomy of the HN district and the infiltrative nature of RIS do not always allow radical intervention. Therefore, a wise integration with systemic therapy and, when feasible, re-irradiation should be performed. Future findings in the genomic features of RISHN will be crucial to identify a possible sensitivity to specific drugs in order to optimize a multimodal treatment that will be ideally complementary to surgery and re-irradiation.

IntroductionThe Union for International Cancer Control–American Joint Committee on Cancer TNM staging system for glottic squamous cell carcinoma (SCC) includes different types of lesions defined by the involvement of specific subsites in each T category. Our study aims to identify different subcategories according to tumor local extension and determine oncologic outcomes after treatment by transoral laser microsurgery (TLM) alone.MethodsWe retrospectively evaluated 410 patients affected by previously untreated pT1-pT3 glottic SCC treated by TLM alone from January 2005 to December 2015 at the Departments of Otorhinolaryngology—Head and Neck Surgery, Universities of Genoa and Brescia, Italy. All patients had at least 2 years of follow-up. Clinical, radiological, surgical, and histopathological data were reviewed and tumors divided into six subcategories: I, pT1a not involving the anterior commissure (AC); II, pT1b involving the AC; III, pT2 extending superficially to the supraglottis or the subglottis; IV, pT2 infiltrating the vocal muscle; V, pT3 involving the anterior paraglottic space; VI, pT2 or pT3 with vertical extension across the AC with/without involvement of the pre-epiglottic space. Recurrence-free survival (RFS), local control with laser alone (LCL), and organ preservation (OP) were defined as the primary oncologic outcomes.ResultsThe 2, 5, and 10-year RFS for the entire series were 85.7, 80.3, and 73.8%, LCL rates 93.8, 92.1, and 89.6%, and OP rates 96.8, 95.9, and 93.5%, respectively. However, when comparing the rates of RFS, LCL, and OP for each subcategory, important differences emerged. In particular, subcategories V and VI showed a significantly increased risk of local recurrence [hazard ratio (HR) = 9.2 and 13.3, respectively]. These subcategories also had a significantly reduced probability to achieve LCL (HR: 73.6 and 93.5, respectively) and OP (HR: 6.4 and 8.1, respectively).ConclusionThe present classification in subcategories allows introducing the concept of a three-dimensional map of isoprognostic zones in glottic SCC treated by TLM alone as a useful tool in its management by a multidisciplinary tumor board.

IntroductionCarbon dioxide laser coagulation during transoral laser microsurgery (TLM) for laryngeal cancer allows control of bleeding from vessels smaller than 0.5 mm. Therefore, larger arteries and veins must be carefully managed by clipping and/or monopolar cautery. The aim of this paper is to detail endolaryngeal vascular anatomy and identify areas of possible bleeding during TLM.MethodsWe performed an anatomical study on a series of 11 fresh-frozen human cadavers. After injection of a bicomponent red silicone into the innominate, left common carotid, and left subclavian arteries, 22 hemilarynges were dissected, the course of the supraglottic, glottic, and subglottic vessels were traced after microdissection of the intervening structures, and their size measured at specific landmark points where such vessels are more frequently encountered during TLM.ResultsThree vessels arising from the superior laryngeal artery were identified after its entry point at the level of the thyro-hyoid membrane: (1) the epiglottic artery (EA), documented in 100% of cases, a common trunk dividing into two main vessels (2) the postero-inferior artery (PIA), present in 100% of the specimens, running downward and dividing in a posterior (pPIA), and anterior (aPIA) branches (3) the antero-inferior artery (AIA), present in 95% of our specimens, running downward to the anterior commissure (AC). Two transverse anastomotic networks (TANs) connected the AIA and PIA, both parallel to the vocal muscle, one lateral (present in 100% of cases), and another medial (91% of specimens). Finally, a fourth vessel supplying the glottic plane was found to be the endolaryngeal paracommissural branch of the crico–thyroid artery (PCA), arising from the inferior laryngeal artery and emerging just below the AC, through the crico–thyroid membrane (reported in 100% of the specimens). This vessel anastomosed in 91% of cases with the AIA, through one or both of the TANs.ConclusionThe course of the endolaryngeal arteries, their relationships with adjacent structures, and size at specific landmark points have been herein described in order to provide surgeons with a map to guide them during the steep learning curve of transoral surgery of the larynx, with special emphasis given to TLM.

BackgroundTransoral laser microsurgery (TLM) for early to intermediate laryngeal squamous cell cancer (SCC) can be technically challenging when adequate exposure of the posterior laryngeal compartment is required due to the presence of the orotracheal tube. The goal of our study was to analyze the efficacy of high frequency jet ventilation (HFJV) in achieving appropriate laryngeal exposure and safe oncologic resection of lesions located in such a position.MethodsWe reviewed the clinical records of 62 patients affected by Tis-T2 SCC of the posterior laryngeal compartment treated by TLM between 02/2012 and 12/2016. The cohort was divided into two groups according to the anesthesiologic technique used: Group A included patients treated using intraoperative infraglottic HFJV, while Group B encompassed patients treated by standard orotracheal intubation. The main outcome was postoperative surgical margin status. Group comparison analysis was performed.ResultsSignificant difference in deep margin status was observed between the two groups: in Group A, the rate of negative deep margins was 86% compared to 56% in Group B (p = 0.04). A trend of better overall and superficial margin control was observed for patients treated using HFJV (Group A), although no statistical significance was achieved.ConclusionUse of HFJV during TLM allows easier and safer management of patients affected by Tis-T2 SCC of the posterior laryngeal compartment, reducing the rates of positive superficial and deep surgical margins.

IntroductionTransoral laser microsurgery (TLM) represents one of the most effective treatment strategies for Tis–T2 glottic squamous cell carcinomas (SCC). The prognostic influence of close/positive margins is still debated, and the role of narrow band imaging (NBI) in their intraoperative definition is still to be validated on large cohort of patients. This study analyzed the influence of margin status on recurrence-free survival (RFS) and disease-specific survival (DSS).MethodsWe retrospectively studied 507 cases of pTis–T1b (Group A) and 127 cases of pT2 (Group B) glottic SCC. We identified the following margin status: negative (n = 232), close superficial (n = 79), close deep (CD) (n = 35), positive single superficial (n = 146), positive multiple superficial (n = 94), and positive deep (n = 48) and analyzed their impact on RFS and DSS. Close margins were defined by tumor-margin distance