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Objectives: A combination of chemotherapy and radiotherapy is employed in the curative and postoperative treatment of locally advanced head and neck cancers (HNC). Integrated chemoradiation (CRT) treatments result in a non-negligible rate of severe toxic effects. Treatment-related death (TRD) is a crucial topic for physicians involved in the curative treatment of HNC. This meta-analysis aimed to better address TRD in locally advanced HNC patients treated with CRT through available and relevant literature. Methods: We performed a systematic review of the literature according to the PRISMA statement. The studies fulfilling these criteria included the following: concurrent or alternating CRT; both radical and postoperative settings; published from 2000 to 2020; involving 100+ patients; and available toxicity data. TRD was defined as death occurring from CRT start until a month from the end of CRT. Potential TRD predictors were evaluated. Results: In all, 65 studies were retrieved, with a total of 235 TRDs reported accounting for an overall risk rate of 1.4%. At meta-regression analysis, T stage and neutropenia grade >3 were potential predictors of higher TRD risk, both in univariate and multivariate analyses. Considering only the studies reporting at least one event, laryngeal/hypopharyngeal, oral cavity subsites and renal failure were significant predictors for TRD. The oropharyngeal subsite was protective in both analyses. None of the predictors proved to be independently correlated with TRD at multivariable analysis. Conclusion: CRT in HNC resulted in 1.4% of TRDs. TRD rate reduction may imply better patient selection and more intensive supportive care programs.

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.

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 < 0.1), indicating increased mitotic and transcriptional activity in aggressive ACC. Similar functions were enriched in ACC samples classified by immunohistochemical staining as p63-negative, which exhibited increased protein burden and activation of pro-survival stress response pathways compared to p63-positive tumors. Compared to ACC tissues, ACC (h-TERT) cells share transcriptional features of aggressive p63-negative tumors. These data suggest association of specific pathway alterations with histopathological features of ACC, as recapitulated by p63 testing in patient prognostic stratification, anticipating new avenues for therapeutic intervention.

Adenoid cystic carcinoma (ACC) is a rare malignancy characterized by high incidence of relapse. When relapsing, ACC has an indolent but relentless behaviour, thus leading to a poor long-term prognosis. The treatment of choice of relapsing ACC remains surgery followed by radiotherapy, whenever feasible. Therapeutic weapons are limited to systemic drugs. The most widely used chemotherapy regimen is the combination of cisplatin and doxorubicin, however with low response rate and not long lasting; there is also a lack of alternatives for second line therapies in case of disease progression. Therefore, a more comprehensive strategy aimed at identifying at preclinical level the most promising drugs or combination is clearly needed. In this study, the cytotoxic effects of two standard chemotherapy drugs, cisplatin and doxorubicin, and of five targeted therapy-drugs was tested in vitro, on an h-TERT immortalized ACC cell line, and in vivo, on zebrafish embryos with ACC tumoral cell xenograft. Then, combinations of one standard chemotherapy drug plus one targeted therapy drug were also evaluated, in order to find the best treatment strategy for ACC. Data obtained demonstrated that both vorinostat and olaparib significantly increased the standard chemotherapy cytotoxic effects, suggesting new interesting therapeutic options for ACC.

Background/Objectives: Extramammary Paget’s disease (EMPD) is a rare cutaneous malignancy arising in areas rich in apocrine glands that poses diagnostic and therapeutic difficulties. Although surgery remains the standard of care, achieving clear margins is challenging and recurrence rates are high. This review explores the contribution of non-invasive imaging for diagnosis and monitoring, and evaluates conservative, non-surgical therapies as alternatives to radical surgery. Methods: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), a systematic review was conducted: eligible studies included interventional and observational research, as well as case series and reports, assessing non-invasive diagnostic methods or non-surgical treatments for EMPD. Data extraction and risk-of-bias evaluation were performed independently by multiple reviewers, and a narrative synthesis summarized therapeutic outcomes and diagnostic performance. Results: Of 808 identified records, 82 met the inclusion criteria: 66 focused on non-surgical therapies, 15 on diagnostic techniques, and one on both. Reflectance confocal microscopy (RCM) and photodynamic diagnosis (PDD) showed high concordance with histopathology, aiding both diagnosis and margin delineation. Among therapies, topical imiquimod and photodynamic therapy (PDT) demonstrated encouraging response rates, while radiotherapy, laser ablation, and systemic chemotherapy were less consistently reported. Evidence quality was limited by small cohorts, heterogeneous regimens, and variable follow-up. Conclusions: Non-invasive imaging enhances diagnostic accuracy and surgical planning, while non-surgical treatments—particularly imiquimod and PDT—offer viable alternatives in selected cases. Larger prospective studies are needed to establish standardized protocols and clarify long-term outcomes.

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.

Background and purposeLoss of Heterozygosity (LOH) is a key genetic alteration associated with progression of oral cavity dysplasia to oral squamous cell carcinoma, yet non-invasive methods to predict LOH status are lacking. The aim of this study is to investigate whether vascular pattern abnormalities detected through Narrow Band Imaging (NBI) can predict LOH status in oral dysplasia using machine learning-based quantitative analysis.MethodsThis was a retrospective analysis of prospectively collected data from the IMPEDE multicenter clinical trial (NCT04504552). The study sample included 31 patients with oral potentially malignant disorders (13 LOH-positive, 18 LOH-negative) and 125 region-of-interest (ROI) images. Predictor variables were quantitative vascular morphology features: vessel length, number of intersections, tortuosity, branching angles, fractal dimensions, which were extracted from NBI images using the Jerman Vesselness Filter and pvbm library. Main outcome variable was LOH status (positive versus negative) by genetic testing per EPOC trial criteria. Patient demographics, smoking status, alcohol consumption were the covariates. A Support Vector Machine (SVM) classifier with class balancing and probability calibration was trained using Leave-One-Group-Out Cross-Validation (LOGO-CV) at the patient level.ResultsOf 31 patients (median age 65 years; 19 males, 12 females), 13 (42%) were LOH-positive. Significant differences in vascular morphology were observed between LOH-positive and LOH-negative samples. The SVM classifier achieved a patient-level accuracy of 77.4% (24/31 correctly classified), with an area under the ROC curve (AUC) of 0.75.ConclusionsNon-invasive quantitative vascular pattern analysis from NBI images demonstrates good discriminative ability for predicting LOH status in oral dysplasia. This approach has potential as an adjunct diagnostic tool for early cancer risk stratification, potentially reducing the need for invasive biopsies.

Background Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, but predictive biomarkers of adverse events and outcomes remain limited. Recently, nutritional and inflammatory markers have emerged as potentially predictors of ICI toxicity and efficacy. Materials and methods In this retrospective, monocentric study we evaluated the impact of baseline nutritional and inflammatory markers on ICI safety, activity and efficacy in patients affected by solid tumors treated with mono-immunotherapy. Baseline clinical, nutritional, and inflammatory parameters - including BMI, weight loss, albumin, prognostic nutritional index (PNI), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) - were analyzed in relation to immune-related adverse events (irAEs), best response, progression-free survival (PFS), and overall survival (OS). Results Between 2015 and 2021, 297 patients were included. Median age was 67 (range: 32–91), with 200 (67.3%) patients being male and 218 patients affected by either skin melanoma (41.8%) or lung cancer (31.7%). In 87% of cases, ICI was initiated with palliative intent. Univariate analysis showed associations between high PNI, low NLR, female sex, and first treatment line with increased risk of all-grade irAEs, while no factor predicted grade ≥ 3 toxicity. Higher BMI and receiving immunotherapy as first treatment line were associated with improved response rate and longer OS, while hypoalbuminemia, hyperglicemia, low PNI, and high NLR correlated with worse survival outcomes. In multivariate models, only receiving immunotherapy as first treatment line independently predicted better objective response (HR 0.55) and longer PFS (HR 0.57), while high NLR independently predicted shorter OS (HR 1.93). Conclusion Nutritional and inflammation parameters represent new potential biomarkers which could help reshaping treatment with ICI in cancer patients.

Despite the progress of surgery, radiotherapy, and neoadjuvant chemotherapy, the prognosis for advanced sinonasal cancers (SNCs) remains poor. In the era of precision medicine, more research has been conducted on the molecular pathways and recurrent mutations of SNCs, with the aim of understanding carcinogenesis, helping with diagnosis, identifying prognostic factors, and finding potentially targetable mutations. In the treatment of SNC, immunotherapy is rarely used, and no targeted therapies have been approved, partly because these tumors are usually excluded from major clinical trials. Data on the efficacy of targeted agents and immune checkpoint inhibitors are scarce. Despite those issues, a tumor-agnostic treatment approach based on targeted drugs against a detected genetic mutation is growing in several settings and cancer subtypes, and could also be proposed for SNCs. Our work aims to provide an overview of the main molecular pathways altered in the different epithelial subtypes of sinonasal and skull base tumors, focusing on the possible actionable mutations for which potential target therapies are already approved in other cancer types.

Myeloid growth factors, either granulocyte colony-stimulating factor (CSF) or granulocyte-macrophage CSF, are widely used to reduce the incidence and severity of chemotherapy-induced neutropenia by prophylactic or therapeutic administration. However, their activity in the novel therapeutic regimens, which often rely on the association between immunotherapy and chemotherapy, has not been thoroughly characterized yet. This paper presents some of the preclinical and clinical research regarding the putative interplay between myeloid growth factors and the immune system, advocating further studies to elucidate their potential positive or negative consequences on the outcomes when administered with immunotherapeutic agents.