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Purpose: To identify the tumor portrait of the minority of head and neck squamous cell carcinoma (HNSCC) patients with recurrent–metastatic (RM) disease who upon treatment with platinum-based chemotherapy plus cetuximab present a long-lasting response.Experimental Design: The gene expression of pretreatment samples from 40 HNSCC-RM patients, divided in two groups [14 long-progression-free survival (PFS) and 26 short-PFS (median = 19 and 3 months, respectively)], was associated with PFS and was challenged against a dataset from metastatic colon cancer patients treated with cetuximab. For biologic analysis, we performed functional and subtype association using gene set enrichment analysis, associated biology across all currently available HNSCC signatures, and inferred drug sensitivity using data from the Cancer Genomic Project.Results: The identified genomic profile exhibited a significant predictive value that was essentially confirmed in the single publicly available dataset of cetuximab-treated patients. The main divergence between long- and short-PFS groups was based on developmental/differentiation status. The long-PFS patients are characterized by basal subtype traits such as strong EGFR signaling phenotype and hypoxic differentiation, further validated by the significantly higher association with the hypoxia metagene. The short-PFS patients presented a strong activation of RAS signaling confirmed in an in vitro model of two isogenic HNSCC cell lines sensitive or resistant to cetuximab. The predicted drug sensitivity for all four EGFR inhibitors was higher in long- versus short-PFS patients (P range: Conclusions: Our data uncover the biology behind response to platinum-based chemotherapy plus cetuximab in RM-HNSCC cancer and may have translational implications improving treatment selection. Clin Cancer Res; 22(15); 3961–70. ©2016 AACR.See related commentary by Chau and Hammerman, p. 3710

Fig S2. Technical validation using NuGEN's Ovation System. The scatter plot shows the fold change consistency of genes differentially expressed using WG-DASL and NuGEN methods. Only 6 out of the 509 DE genes were found discordant, confirming the WG-DASL patterns. Data are plotted as log2 fold change (FC) expression long/short PFS; positive log2(FC) values stand for genes up-regulated in long-PFS cases, while negative values stand for up-regulation in short-PFS cases. Statistical significance was tested through Monte Carlo test (1000 interactions) yielding p-value

Fig S1. Volcano plot for the 17,378 genes detected by microarray analysis. The x-axis is the fold-change, and the y-axis is log10 p value. A total of 509 probes (blue dots) were differentially expressed in long-PFS patients (14) compared with short-PFS patients (26), imposing a FDR < 15%. Probability of finding by chance 509 significant DE genes between the classes: p = 0.016.

FigS3: Biasogram representing the influence of tissue origin on outcome. Y axes indicate the outcome vector (long- versus short- PFS), while B indicates the nuisance variable (tissue origin; primary versus recurrence/metastatic). The colorgram represents a bivariate histogram of all the 17,378 detected genes; the green circles indicate the genes present in our signature.

Fig S4. Ability of existing gene signatures to predict outcome following cetuximab treatment. Five available prognostic gene-expression based signatures were taken into account: i) the hypoxia metagene (Winter, 2007); ii) the 13-gene OSCC signature (Lohavanichbutr, 2013); iii) the RSI-index (Eschrich, 2009); iv) the 42-gene Chung's high risk signature (Chung, 2006); v) the 172-gene signature (De Cecco, 2014). A score was assessed for each sample entering into our study following the model developed by the authors and compared among long- and short PFS cases. The boxplots depicts the data in the two groups. Green: long-PFS; Red: short-PFS.

Supplementary Table S2 Gene sets associated to long- and short-PFS patients

PURPOSE The activity of androgen-deprivation therapy (ADT) in androgen receptor–positive (AR+) salivary gland carcinomas (SGCs) has been established in the past few years. Second-line treatment in castration-resistant patients is still unknown. We investigated the activity of abiraterone acetate as second-line treatment in ADT-resistant, AR+ patients with SGC. METHODS This was a single-institution phase II trial. A two-stage Simon's design was applied. The primary end point was confirmed objective response rate. Secondary end points were disease control rate, safety, progression-free survival, and overall survival. Patients were eligible when the following criteria were met: histologic diagnosis of AR-overexpressing SGC, measurable disease according to RECIST 1.1, clinical and/or radiologic progression on ADT, suppressed serum testosterone, and no limits for the number of previous chemotherapy lines. All patients received abiraterone 1 g daily plus prednisone 10 mg and luteinizing hormone-releasing hormone agonist until progression or unacceptable toxicities. RESULTS From 2015 to 2019, 24 AR+ patients with SGC (23 men; median age 65.8 years) were treated within the study. The overall response rate was 21% (5 partial responses), with a disease control rate of 62.5%. The median duration of response was 5.82 months. Median progression-free survival was 3.65 months (95% CI, 1.94 to 5.89), and median overall survival was 22.47 months (95% CI, 6.74 to not reached). Objective response to previous ADT did not correlate with the activity of abiraterone. Adverse events (AEs) were recorded in 22 cases (92%) with grade 3 AEs in six patients (25%): fatigue (two), flushing (one), supraventricular tachycardia (one), and two non–drug-related AEs. No drug-related grade 4 or 5 AEs were recorded. CONCLUSION Abiraterone plus luteinizing hormone-releasing hormone agonist is active and safe as a second-line option in AR-expressing, castration-resistant SGC.

Anaplastic thyroid carcinoma (ATC) is a rare cancer accounting for 40% of thyroid cancer-specific deaths. In the last 5 years, improved insights into molecular pathways led the Food and Drug Administration to license BRAF/MEK inhibitors (B/Mi) in BRAF

Contains fulltext : 287669.pdf (Publisher’s version ) (Open Access) The incidence of differentiated thyroid cancer (DTC) has been increasing worldwide, mostly, as an increase in the incidental detection of micro papillary thyroid carcinomas (microPTCs), many of which are potentially overtreated, as suggested by the unchanged mortality. Several international guidelines have suggested a less aggressive approach. More recently, it has been shown that active surveillance or minimally invasive treatments (MIT) are good alternatives for the management of these patients. In this context, patient participation in the decision-making process is paramount. The Endocrine Task Force of the European Organisation for Research and Treatment of Cancer (EORTC) has undertaken the task to establish consensus and define its position based on the scientific evidence concerning, 1) the current state of diagnostic and management options in microPTCs, including the current opinion of physicians about shared decision making (SDM), 2) the available evidence concerning patients' needs and the available decision instruments, and 3) to provide practical suggestions for implementation of SDM in this context. To improve SDM and patients' participation, knowledge gaps and research directions were highlighted.

Salivary gland cancers (SGCs) are rare malignancies with highly heterogeneous histological features. Patients affected with SGCs are at increased risk of secondary malignancies, including breast cancer (BC). Previous studies enlightened a possible link between SGCs and hereditary predisposition to BC. Here, we searched for SGC-affected patients in 1796 high-risk BC families recruited at the Genetic Unit of the Istituto Nazionale dei Tumori of Milan, 516 of which carried pathogenic variants in BRCA1 and/or BRCA2, the main genetic risk factors for BC. We detected five families with an individual affected with SGC, including two male patients, one carrying a constitutional mutation in BRCA1 and the other in BRCA2. Loss of heterozygosity of BRCA wild-type alleles was assessed in the patients' tumour DNA. We conclude that our observations support the hypothesis that genetic factors associated with BC susceptibility might play a role also in at least a subset of SGCs.

Objective: To capture and monitor flu-like symptoms in relation to the clinical characteristics and the oncologic treatment of a large head and neck cancer (HNC) patient cohort during the Coronavirus disease 2019 (COVID-19) pandemic. Methods: Patients were monitored through by 2 rounds of interviews. Clinical characteristics of patients with no symptoms (group 0) and of those reporting ⩾1 (group A), ⩾3 (group B), or ⩾5 symptoms (group C) were analyzed. Patients with ⩾1 symptom at both interviews were defined as group A2. Results: Five hundred patients with HNC were analyzed. A higher frequency of patients with the following characteristics was observed in group A vs group 0: active treatment (40% vs 24%, p = 0.0002), gastrostomy (6% vs 2%, p = 0.027), recent active treatment (48% vs 29%, p < 0.0001), and higher number of concomitant medications ( p = 0.01). A lower median age was observed in group B vs group no-B (patients with fewer than three symptoms) (59 vs 63.55 years, p = 0.016) and in group A2 vs group no-A2 (patients without at least one symptom at both interviews) (56 vs 63 years, p = 0.021); patients in group B received more recent active treatment than those in group no-B and in group A2 vs those in group no-A2 ( p = 0.024 and 0.043, respectively); patients in group B had a lower body mass index than those in group no-B (22.4 vs 23.93 kg/m2, p = 0.0066). Conclusions: This work is based on patient-reported symptoms and signs independently of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing. In the future, these results might serve as a a benchmark for clinicians triaging and managing patients with HNC during infectious outbreaks involving flu-like symptoms.

Radioactive-iodine (RAI)-resistant differentiated thyroid cancer (DTC) patients benefit from multi-kinase inhibitors (MKIs), such as lenvatinib. Incidence of treatment-related (TR) late toxicities has been not yet described. From January 2015 to June 2019 we retrospectively reviewed clinical records of patients with RAI-resistant DTC treated with lenvatinib at Istituto Nazionale dei Tumori (Milan, Italy). New side effect of any grade, appeared after 12 months of lenvatinib, was defined as late adverse event (AE). Descriptive analyses were performed. Survival curves were estimated with Kaplan–Meier method and compared with log-rank test. Thirty-seven patients were included, 65% had ≥65 years and 68% were female. Thirty patients received lenvatinib for >12 months. Lenvatinib was started at ≤20 mg/daily in 59% of patients, 64% were ≥65 years. The frequency of late AEs was 80% and cardiovascular toxicity was the most common (57%). There was no difference in the incidence of late AEs between younger/older population (77% and 82%, respectively). Median lenvatinib treatment duration (TD) was 39.96 months (95% CI 21.64-NR): 39.96 months for patients

Background This study was an open-label, 2-arms, monocentric, randomized clinical trial comparing Xonrid®, a topical medical device, versus standard of care (SOC) in preventing and treating acute radiation dermatitis (ARD) in Head and Neck Cancer (HNC) and Breast Cancer (BC) patients undergoing radiotherapy (RT). Methods Eligible HNC and BC patients were randomized 1:1 to receive Xonrid® + SOC or SOC during RT. Patients were instructed to apply Xonrid® on the irradiated area three times daily, starting on the first day of RT and until 2 weeks after RT completion or until the development of grade ≥ 3 skin toxicity. The primary endpoint was to evaluate the proportion of patients who developed an ARD grade Results Eighty patients (40 for each cancer site) were enrolled between June 2017 and July 2018. Groups were well balanced for population characteristics. All BC patients underwent 3-Dimensional Conformal RT (3D-CRT) whereas HNC patients underwent Volumetric-Modulated Arc Therapy (VMAT). At week 5 the proportion of BC patients who did not exhibit G2 ARD was higher in Xonrid® + SOC group (p = 0.091). In the same group the onset time of G2 ARD was significantly longer than in SOC-alone group (p Conclusion Despite the failure to achieve the primary endpoint, this study suggests that Xonrid® may represent a valid medical device in the prevention and treatment of ARD at least in BC patients, delaying time to develop skin toxicity and reducing the proportion of patients who experienced G2 ARD during RT treatment and 2 weeks later. Trial registration The study was approved by the Ethical Committee of Fondazione IRCCS Istituto Nazionale dei Tumori di Milano (INT 52/14 - NCT02261181). Registered on ClinicalTrial.gov on 21st August 2017.

The treatment of patients with recurrent and/or metastatic (R/M) salivary gland adenoid cystic carcinoma (ACC) remains an unmet need.Patients with R/M disease with a history of clinical or symptomatic disease progression within 6 months and a maximum of 1 previous line of chemotherapy or a multiple kinase inhibitor received oral lenvatinib at a dose of 24 mg/day. The primary endpoint was the objective response rate; secondary endpoints included quality of life (QOL) (according to the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 Items [EORTC QLQ-C30] and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core Module Head and Neck Module [EORTC QLQ-HN35]), progression-free survival and overall survival, duration of response, and toxicities.Twenty-eight patients with R/M ACC were enrolled. Among 26 evaluable patients, 3 partial responses (11.5%) were reported. Target lesion reductions between 23% to 28% were observed in 4 of 20 patients with stable disease. Treatment-related adverse events were frequent (all grades, 96%; grade≥3 in 50% of cases according to version 4.03 of the National Cancer Institute Common Terminology Criteria for Adverse Events). The dose of lenvatinib was reduced in 24 patients, whereas in 21 patients the dose was reduced within the first 12 weeks and 4 patients maintained the full dose throughout treatment. The QOL deteriorated between baseline and 6 months with regard to Fatigue and Dry Mouth. There was no evidence of changes in Swallowing and Physical Functioning. At a median follow-up of 29 months, 2 patients remained on treatment, 10 patients were off protocol for disease progression and were alive with disease, and 14 patients had died of disease progression. The median overall survival, progression-free survival, and duration of response were 27 months, 9.1 months, and 3.1 months, respectively.Lenvatinib appears to have modest activity in ACC. Toxicities are common but manageable and QOL was found to deteriorate in some domains.

The purpose of this article is to discuss the published evidence related to quality of life (QoL) and financial toxicity (FT) differences between female and male head and neck cancer patients treated with (chemo)radiotherapy. There is a need of promoting methods for assessing QoL difference between female and male patients in order to set up early rehabilitation, psychosocial care, and lifestyle interventions, as well as setting up specific interventions for minimizing financial stress.

Purpose/Objective On September 2009: We started a randomized multicenter phase III study comparing chemoradiation (CRT) (Aldestein RTOG regimen) versus induction chemotherapy followed by Cetuximab radiation (IBRT). The main study’s aim was comparison of overall survival but no formal analyses have been made between the two arms because of low accrual and high amount of missing data. The goal of this paper is to identify the reasons of difference in accrual and quality of data among participating centers. Material/Methods Statistic: We correlated data collection quality with relevance of the centers, accrual and number of scientific papers (both specific on HNC and other topics) of each PI. We created an HNC publishing score dividing the number of HNC specific papers for the overall number of published papers. Results We observed a strong difference in the accrual of pts as well as in the quality of data among the participating centers. The accrual was independent from the quality of data since some centers with low accrual produced high quality data with an excellent follow up. We found a correlation among both number of published papers of each PI and HNC publishing score with the quality of data. Conclusion The study demonstrated that expertise in HNC is important not only to ensure a better outcomes but also to provide high quality data in phase III trials.

There is no consensus on the follow-up modalities in patients with head and neck cancer. This study aims to describe the pattern and survival outcomes of recurrences/second primary cancers in patients undergoing an intensive radiologic and clinical follow-up.Retrospective analysis.Single academic tertiary care center.All patients with stage III-IV head and neck cancer treated with chemoradiotherapy at our institution between 1998 and 2010 were retrospectively reviewed. Persistent/recurrent disease within 6 months since the curative treatment and second primary cancers outside the upper aerodigestive tract were excluded. Data were analyzed by descriptive statistics. Surveillance was planned every 3 months in the first year, then with increasing intervals till the fifth year.A total of 326 patients were included. Out of all detected cancer recurrences (n = 106, 32%), 38 (36%) were locoregional, 44 (41%) were distant, and 24 (23%) were second primary cancers. Approximately 70% of recurrences were clinically and/or radiologically discovered, while 30% were diagnosed due to the patients' symptoms. Of all clinically and/or radiologically discovered recurrences/second primary cancers (n = 74), 26 (35%) were curatively treated, with respect to 9 of the 32 (28%) diagnosed by symptoms. Median overall survival of recurrent curable cases did not significantly differ according to the detection modality (89 months by clinical/radiologic examination vs 85 by symptoms).Clinical and radiologic follow-up identified more recurrences/second primary cancers than the symptom-driven monitoring, but the curability of cancer recurrence was similar regardless of detection modality. Prospective trials are needed to define the most effective follow-up strategy in head and neck cancer.

Aim: Reporting toxicities of targeted therapies (TTs) and immunotherapy in oncology requires special attention. Materials & methods: We identified TTs and immunotherapies approved by the US FDA for solid malignancies in the adult population. Publications were reviewed according to a 24-point score based on the Consolidated Standards of Reporting Trials guidance. Results: We identified 81 trials (>45,000 patients). The experimental drug was studied as single agent in 51% of the cases; setting of disease was mainly (95%) advanced/metastatic. Lowest scores in adverse event (AE) description regarded: reporting recurrent/late toxicities and duration of the AEs (>90%), time of occurrence and indication of all-grade AEs (>75%). Conclusion: Suboptimal reporting of AEs in trials leading to approval of TTs and immunotherapy was shown. Improving AE descriptions should be a priority in ongoing trials.

Xerostomia, the subjective complaint of dry mouth, is caused by therapeutic interventions or diseases. Nowadays, radiotherapy (RT) in patients with head and neck cancer (HNC) stands out as one of the most important causes of xerostomia. Currently available therapies for the treatment of xerostomia are still less than optimal and xerostomia still represents an unmet clinical need. In this article, we present the results of a prospective clinical study with a new product, AqualiefTM, in patients treated with curative RT with or without chemotherapy for HNC. AqualiefTM is based on two main ingredients, carnosine and karkadé, which have acid buffering and antioxidant properties. The study was performed on 30 patients, with 4 of the patients being lost during the study period. Each patient received randomly one of the two treatments, AqualiefTM or placebo, for 8 days. After a 10-day wash-out period, each patient received the other treatment for a further 8 days. The results show that AqualiefTM stimulated salivation in these patients and reduced the pH drop that was observed in an equivalent placebo-treated population of patients. Moreover, no serious, treatment-related adverse events were observed. AqualiefTM has shown positive results, although with limitations due to unsuccessful trial accrual. Therefore, it may be further investigated as a tool for the treatment of RT-related xerostomia.

Background: Radiation-induced xerostomia is one of the most prevalent adverse effects of head and neck cancer treatment, and it could seriously affect patients’ qualities of life. It results primarily from damage to the salivary glands, but its onset and severity may also be influenced by other patient-, tumour-, and treatment-related factors. We aimed to build and validate a predictive model for acute salivary dysfunction (aSD) for locally advanced nasopharyngeal carcinoma (NPC) patients by combining clinical and dosimetric factors. Methods: A cohort of consecutive NPC patients treated curatively with IMRT and chemotherapy at 70 Gy (2–2.12 Gy/fraction) were utilised. Parotid glands (cPG, considered as a single organ) and the oral cavity (OC) were selected as organs-at-risk. The aSD was assessed at baseline and weekly during RT, grade ≥ 2 aSD chosen as the endpoint. Dose-volume histograms were reduced to the Equivalent Uniform Dose (EUD). Dosimetric and clinical/treatment features selected via LASSO were inserted into a multivariable logistic model. Model validation was performed on two cohorts of patients with prospective aSD, and scored using the same schedule/scale: a cohort (NPC_V) of NPC patients (as in model training), and a cohort of mixed non-NPC head and neck cancer patients (HNC_V). Results: The model training cohort included 132 patients. Grade ≥ 2 aSD was reported in 90 patients (68.2%). Analyses resulted in a 4-variables model, including doses of up to 98% of cPG (cPG_D98%, OR = 1.04), EUD to OC with n = 0.05 (OR = 1.11), age (OR = 1.08, 5-year interval) and smoking history (OR = 1.37, yes vs. no). Calibration was good. The NPC_V cohort included 38 patients, with aSD scored in 34 patients (89.5%), the HNC_V cohort included 93 patients, 77 with aSD (92.8%). As a general observation, the incidence of aSD was significantly different in the training and validation populations (p = 0.01), thus impairing calibration-in-the-large. At the same time, the effect size for the two dosimetric factors was confirmed. Discrimination was also satisfactory in both cohorts: AUC was 0.73, and 0.68 in NPC_V and HNC_V cohorts, respectively. Conclusion: cPG D98% and the high doses received by small OC volumes were found to have the most impact on grade ≥ 2 acute xerostomia, with age and smoking history acting as a dose-modifying factor. Findings on the development population were confirmed in two prospectively collected validation populations.

PURPOSE Under common therapeutic regimens, the prognosis of human papillomavirus (HPV)–positive squamous oropharyngeal carcinomas (OPCs) is more favorable than HPV-negative OPCs. However, the prognosis of some tumors is dismal, and validated prognostic factors are missing in clinical practice. The present work aimed to validate the prognostic significance of our published three-cluster model and to compare its prognostic value with those of the 8th edition of the tumor-node-metastasis staging system (TNM8) and published signatures and clustering models. METHODS Patients with HPV DNA-positive OPCs with locoregionally advanced nonmetastatic disease treated with curative intent (BD2Decide observational study, NCT02832102 ) were considered as validation cohort. Patients were treated in seven European centers, with expertise in the multidisciplinary management of patients with head and neck cancer. The median follow-up was 46.2 months (95% CI, 41.2 to 50), and data collection was concluded in September 2019. The primary end point of this study was overall survival (OS). Three-clustering models and seven prognostic signatures were compared with our three-cluster model. RESULTS The study population consisted of 235 patients. The three-cluster model confirmed its prognostic value. Two-year OS in each cluster was 100% in the low-risk cluster, 96.6% in the intermediate-risk cluster, and 86.3% in the high-risk cluster ( P = .00074). For the high-risk cluster, we observed an area under the curve = 0.832 for 2-year OS, significantly outperforming TNM 8th edition (area under the curve = 0.596), and functional and biological differences were identified for each cluster. CONCLUSION The rigorous clinical selection of the cases included in this study confirmed the robustness of our three-cluster model in HPV-positive OPCs. The prognostic value was found to be independent and superior compared with TNM8. The next step includes the translation of the three-cluster model in clinical practice. This could open the way to future exploration of already available therapies in HPV-positive OPCs tailoring de-escalation or intensification according to the three-cluster model.

Background: Lenvatinib, a multikinase inhibitor, is for progressive radioiodine-refractory-differentiated thyroid cancer (RR-DTC) patients. However, there are a lot of drug-related adverse events (AEs) that can affect the quality of life (QoL) of patients. The aims of this study were (a) to evaluate, and compared with other series, the safety of lenvatinib used in RR-DTC patients enrolled in an Italian expanded access program (EAP), and (b) to evaluate their QoL during treatment with lenvatinib. Methods: To evaluate the safety, we recorded and graded all AEs during the 6 months of lenvatinib treatment in 39 RR-DTC patients. We compared the safety profile of lenvatinib observed in our patients with that reported in the study of (E7080) levatinib in differentiated cancer of the thyroid (SELECT) and tumeurs thyroidiennes refractaires (TUTHYREF) network studies. Moreover, we evaluated the QoL in our series by using the European Organization for Research and Treatment (EORTC) Quality of Life Questionnaire-Core 30 and the pain visual analogue scale (VAS). Results: The most frequent AEs among our 39 RR-DTC patients were hypertension (80.5%), fatigue (58.3%), diarrhea (36.1%), stomatitis (33.3%), hand/foot syndrome (33.3%), and weight loss (30.5%). The most prevalent grade 3/4 AE was hypertension (25%). When compared with previous studies (i.e., SELECT and TUTHYREF), a significantly lower percentage of our patients experienced diarrhea, nausea, proteinuria, and weight loss. No statistically significant differences in the QoL of our patients evaluated before, during, and at the end of follow-up (6 months after starting the therapy) were found. However, a slight improvement of the general health and emotional and cognitive status associated with a slightly worsening of physical role and social functioning was observed during these 6 months. Pain, dyspnea, insomnia, and constipation moved toward better values, while fatigue, nausea and vomiting, appetite loss, and diarrhea worsened. By comparing the pain VAS, an overall reduction of the level of pain was found. Conclusions: The safety profile of the drug was similar to that already reported with some differences in the prevalence and severity of the AEs. Regarding the QoL, the EAP showed a trend of improvement of the global health status and a reduction of symptoms correlated to the disease. The clinical impact of fatigue, anorexia/weight loss and stomatitis, mainly due to the drug itself, continues to represent the major issue in the management of these patients.

Background Coronavirus disease 2019 (COVID-19) has rapidly spread to every country around the world taking on pandemic proportions. Since 8 March 2020, the Italian government ordered a nationwide lockdown with unavoidable social isolation. Healthcare professionals (HCPs) represent the most physically and emotionally involved category. The aim of this study is to assess the social distress among HCPs in Italy. Patients and methods In this online, totally anonymous survey, 24 multiple choice questions were posed to medical staff employed in the Italian Healthcare System during the COVID-19 pandemic. Data collection was performed from 30 March to 24 April 2020. Results A total of 600 HCPs completed the questionnaire. The majority of respondents expressed the fear of being at higher risk of contagion than the general population (83.3%) and the weighty concern of infecting their families (72.5%). An insufficient supply of personal protective equipment (PPE; P = 0.0003) and inadequate training about procedures to follow (P = 0.0092) were seen to significantly coincide with these worries. More than two-thirds declared a change in family organisation, which showed a significant correlation with the concern of infecting their relatives (P < 0.0001). Conclusions This is the first Italian survey on social distress among HCPs during the COVID-19 pandemic. The unavailability of PPE, screening procedures and adequate training strongly affected HCPs' emotional status. Although there was a predominance of oncologists (especially from the North of Italy), which impairs the generalisation of our findings, this survey underlined the social impact that this health emergency has had on HCPs., Highlights • This is the first Italian survey on healthcare professionals’ (HCPs) social distress during the coronavirus disease 2019 (COVID-19) pandemic. • The majority expressed the fear of being at high risk of contagion and the weighty concern of infecting their families. • Insufficient supply of personal protective equipment and inadequate training about procedures correlate with these worries. • Reducing workers’ psychological distress will certainly yield significant positive benefits for HCPs and health system.

Objectives: To identify and validate baseline magnetic resonance imaging (b-MRI) radiomic features (RFs) as predictors of disease outcomes in effectively cured head and neck squamous cell carcinoma (HNSCC) patients. Materials and methods: Training set (TS) and validation set (VS) were retrieved from preexisting datasets (HETeCo and BD2Decide trials, respectively). Only patients with both pre- and post-contrast enhancement T1 and T2-weighted b-MRI and at least 2years of follow-up (FUP) were selected. The combination of the best extracted RFs was used to classify low risk (LR) vs. high risk (HR) of disease recurrence. Sensitivity, specificity, and area under the curve (AUC) of the radiomic model were computed on both TS and VS. Overall survival (OS) and 5-year disease-free survival (DFS) Kaplan–Meier (KM) curves were compared for LR vs. HR. The radiomic-based risk class was used in a multivariate Cox model, including well-established clinical prognostic factors (TNM, sub-site, human papillomavirus [HPV]). Results: In total, 57 patients of TS and 137 of VS were included. Three RFs were selected for the signature. Sensitivity of recurrence risk classifier was 0.82 and 0.77, specificity 0.78 and 0.81, AUC 0.83 and 0.78 for TS and VS, respectively. VS KM curves for LR vs. HR groups significantly differed both for 5-year DFS (p

Simple Summary The prognostic performance of traditional methodologies in advanced nasopharyngeal carcinoma does not allow to successfully stratify patients. Previous studies showed that MRI-radiomics has been used to give additional information to improve the prognosis for this type of pathology in patients from endemic areas (Asia). The purpose of this study was to use MRI-radiomics to develop prognostic models for overall survival in patients from non-endemic areas (Europe or United States). In particular, T1-weighted and T2-weighted MRI were used for the purpose. Radiomic features from those images allowed to successfully train a prognostic signature that improved the prognostic performance of models based on clinical variables alone for different clinical endpoints (overall survival, disease-free survival and loco-regional recurrence-free survival). These results suggest how MRI-radiomics is a useful additional tool for prognosis in nasopharyngeal cancer. Abstract Advanced stage nasopharyngeal cancer (NPC) shows highly variable treatment outcomes, suggesting the need for independent prognostic factors. This study aims at developing a magnetic resonance imaging (MRI)-based radiomic signature as a prognostic marker for different clinical endpoints in NPC patients from non-endemic areas. A total 136 patients with advanced NPC and available MRI imaging (T1-weighted and T2-weighted) were selected. For each patient, 2144 radiomic features were extracted from the main tumor and largest lymph node. A multivariate Cox regression model was trained on a subset of features to obtain a radiomic signature for overall survival (OS), which was also applied for the prognosis of other clinical endpoints. Validation was performed using 10-fold cross-validation. The added prognostic value of the radiomic features to clinical features and volume was also evaluated. The radiomics-based signature had good prognostic power for OS and loco-regional recurrence-free survival (LRFS), with C-index of 0.68 and 0.72, respectively. In all the cases, the addition of radiomics to clinical features improved the prognostic performance. Radiomic features can provide independent prognostic information in NPC patients from non-endemic areas.

Purpose Surgical complications such as hypoparathyroidism (HPT) or vocal cord palsy are seldom assessed when the quality of life (QOL) in thyroid cancer patients is investigated. The aim of this study was to measure the QOL difference in thyroid cancer survivors with and without HPT. Methods Participants for this analysis were enrolled in 13 countries from a study that pilot-tested a thyroid cancer–specific QOL instrument. They were included if they had been diagnosed with thyroid cancer at least 9 months previously. QOL was measured using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core (EORTC QLQ-C30) and some items on HPT symptoms (eg, tingling in fingers or toes). HPT status and other clinical data were extracted from the patients’ medical charts. Comparisons of QOL domains between patients with and without HPT were performed using Mann-Whitney U test. The occurrence of HPT-related symptoms was compared using chi-square tests. Multiple ordinal regression analysis was performed to evaluate factors that might affect QOL. Results Eighty-nine patients participated in this study, 17 of whom were considered to have HPT. Patients in the HPT group reported significantly reduced QOL in 9 of the 15 scales of the EORTC QLQ-C30 compared to patients without HPT. Regression analysis showed that HPT was independently negatively associated with various scales of the QLQ-C30. Both groups showed a high prevalence of typical HPT symptoms. Conclusion Thyroid cancer patients with HPT report significantly impaired QOL compared to thyroid cancer survivors without HPT. The assessment of HPT should be considered when measuring QOL in thyroid cancer patients.

To describe the management and outcomes of loco-regionally advanced (stages III-IV) laryngeal cancer (LRALC) in elderly patients. Clinical records of 88 LRALC patients treated at our Institution from 2002 to 2017 were retrospectively reviewed. Patients were divided in 2 subgroups: age > 65 years (elderly) and age ≤ 65 years (controls). Survivals were estimated with Kaplan–Meier method and compared with log-rank test, multivariate analysis were performed with Cox proportional hazard methods. Eighty-eight LRALC patients were included: 45 elderly and 43 controls. Median follow-up was 55.3 months. Median age was 66 years (range 41–84) in the overall population, 72 years (range 66–84) in the elderly cohort. The majority (98%) of elderly patients had at least one comorbidity (ACE27 1–3), while ACE27 was 0 in 37% of controls (p = 0.0001). ECOG PS was 0 in 42% of elderly vs 79% of controls (p = 0.0029). Clinical stage (TNM eighth edition) was III in 67%, IVA in 22% and IVB in 11%. Treatment consisted in total laryngectomy (TL) in 55%, chemo-radiation in 29%, exclusive radiotherapy in 9%, and conservative surgery in 7%. In elderly patients 2-year disease-free and overall survivals were 58% and 74%, respectively. Multivariate analysis performed on the overall group of 88 patients showed that age (HR 1.07, p = 0.0006) and TNM (for both 7th and 8th Editions HR 0.27 for stage III vs IV, p = 0.0005) maintained an independent statistical significant association with OS. In this monocentric cohort, age and TNM confirmed their independent prognostic role in LRALC patients. Organ-preservation is still an unmet need in a significant portion of elderly patients.

Background: Recurrent or metastatic (R/M) skin squamous cell carcinoma (sSCC) not amenable of surgery or irradiation may benefit from systemic therapies. Epidermal growth factor receptor (EGFR) inhibitors and, more recently, immune checkpoint blockers (ICBs) showed activity in R/M sSCC. In this study, we aimed at exploring the possible role of PD-L1 expression in predicting response to anti-EGFR agents. Methods: Patients affected by R/M sSCC, treated with pan-HER inhibitor dacomitinib or with platinum-based chemotherapy with cetuximab (CT-cet) from 2010 to 2016, were considered. PD-L1 expression was assessed with immunohistochemistry on tumor cells (TCs) and on microenvironment (TC and tumor-infiltrating lymphocyte [IC] scores, respectively). Prognostic role of PD-L1 and the correlation with response to EGFR inhibitors and survival were analyzed. Results: Twenty-eight R/M sSCCs were analyzed (19 treated with dacomitinib, 9 with CT-cet). TC and IC were negative in 82 and 45% of cases, respectively; 15% sSCCs were both TC and IC positive. Progression-free survival (PFS) was longer in IC-positive cases (median 7.5 months vs. 2.1 in IC0, p = 0.02). No statistically significant differences were observed between PD-L1 expression and both overall survival and response rates. Conclusion: PD-L1 expression in microenvironment predicted better PFS. The combination of EGFR inhibitors and ICB could help deepening the knowledge about the interrelations between the EGFR and PD-1/PD-L1 pathways.

The aim of this study is to compare 2 in situ hybridization (ISH) detection methods for human papilloma virus (HPV) 16 E6/E7 mRNA, that is, the RNAscope 2.0 High Definition (HD) and the upgraded RNAscope 2.5 HD version. The RNAscope 2.5 HD has recently replaced the RNAscope 2.0 HD detection kit. Therefore, this investigation starts from the need to analytically validate the new mRNA ISH assay and, possibly, to refine the current algorithm for HPV detection in oropharyngeal squamous cell carcinoma with the final goal of applying it to daily laboratory practice. The study was based on HPV status and on generated data, interpreted by a scoring algorithm. The results highlighted that the compared RNAscope HPV tests had a good level of interchangeability and enabled to identify oropharyngeal squamous cell carcinoma that are truly driven by high-risk HPV infection. This was also supported by the comparison of the RNAscope HPV test with HPV E6/E7 mRNA real-time reverse-transcription polymerase chain reaction in a fraction of cases where material for HPV E6/E7 mRNA real-time reverse-transcription polymerase chain reaction was available. Furthermore, the algorithm that associates p16 immunohistochemistry with the identification of HPV mRNA by RNAscope was more effective than the one that associated p16 immunohistochemistry with the identification of HPV DNA by ISH.

According to the new determinants of cancer immunity, head and neck squamous cell cancer (HNSCC) has to be considered as an immunogenic tumor for the relatively high number of somatic mutations giving rise to neoantigens recognized by T cell. HNSCC develop at a significant rate despite the antitumoral immune response indicating the existence of effective escape mechanisms. The lack of antigen presentation or co-stimulatory molecules required and immunosuppressive phenomena established by the tumor or the host microenvironment impair immune-mediated recognition and cancer control. Echoing the success in melanoma and NSCLC, strategies aimed to reverse this process and enhance the antitumor immunity are rapidly developing in HNSCC, as monotherapies, multidrug immunotherapies or associations with well-recognized treatments, like radiation and systemic therapies. According to the first published data, immunotherapy has shown promising results in the management of recurrent and metastatic (r/m) HNSCC. Anti-PD-1 blockers have been recently approved by US and EU regulatory agencies in this setting. The encouraging results in r/m HNSCC prompted the incorporation of this approach also in the treatment of locally advanced disease. However, the strategies for the rational and evidence-based combinations to maximize clinical benefit are only starting to emerge. In this view, knowing in depth the specific properties of HNSCC and the underlying immunological conditions of the bearing hosts is an essential step. The role of immune system in the development and the management of HNSCC, the main mechanisms of tumor escape and the most recent results from clinical trials will be discussed herein.

Retreatment with vismodegib in advanced basal cell carcinoma (BCC) patients who previously discontinued the drug due to disease progression (PD) has not been reported yet. The objective of our report is to determine whether vismodegib is still active when used in BCC patients who progressed during a first vismodegib course (FVC). We conducted a retrospective study on six advanced BCC patients enrolled in a clinical trial (STEVIE, NCT01367665) who discontinued vismodegib due to PD and were then retreated with the same drug. All patients underwent intercurrent therapies between the FVC and the second vismodegib course (SVC). Disease control (complete response, CR; partial response, PR; and stable disease) was achieved in 100% and 80% of cases in FVC and SVC, respectively. The overall response rate was 80% for FVC (50% of CR) and 50% for SVC (only PR). Median treatment duration of FVC and SVC was 19.5 months (range: 13-35) and 8 months (range: 3-14+), respectively. G3-G4 AEs were reported only during SVC (two cases), leading to permanent discontinuation in one case. The median interval between FVC and SVC was 21.5 months (range: 13-30). After a median follow-up of 54 months (range: 46-63) only one patient with metastatic disease had rapid progression, discontinued vismodegib, and died. All other patients are still alive and two are currently on therapy. We concluded that vismodegib rechallenge is feasible and potentially active in advanced BCC patients who previously discontinued the drug due to disease progression.

Background and purpose Adenoid cystic carcinoma (ACC) of salivary glands is characterized by long-term distant metastasis, most commonly in lungs. No agreement has been reached about the role of surgical treatment of pulmonary lesions. We evaluated the long-term results of lung metastasectomy for ACC in order to identify factors that should be taken into account in selecting patients eligible for surgery and treatment planning. Patients and methods A retrospective study was conducted on 109 patients selected from our institutional experience and from the International Registry of Lung Metastases. Survival was calculated by Kaplan-Meier estimate and prognostic factors endowed with a predictive power for most other metastatic cancers were investigated. Results The cumulative survival was 66.8% at 5 years and 40.5% at 10 years. In patients with a disease-free interval (DFI) greater than 36 months, the overall survival was 76.5% at 5 years. Survival in case of complete surgical resection was 69.5% at 5 years. Multivariate analysis confirmed DFI and completeness of resection resulted in the best prognostic variables. Discussion Lung metastasectomy should be considered as a therapeutic option to achieve local control of disease when 2 conditions are met: (1) complete surgical resection is feasible and (2) the time to pulmonary relapse after primary tumor treatment is greater than 36 months. Symptomatic benefits of an incomplete lung resection in slow-growing tumors such as ACC remain uncertain. The turning point in the management of disseminated cancers will be clarified with biological profiling of ACC and the development of targeted therapies.

OBJECTIVE Outcomes of locally advanced epithelial sinonasal cancers remain unsatisfactory; moreover, only limited and heterogeneous data exist on prognostic factors. METHODS We reviewed all consecutive patients with American Joint Committee Cancer stage III to IV epithelial sinonasal cancers treated with platinum-based induction chemotherapy (IC) followed by locoregional treatment between 1996 and 2015. RESULTS We identified 69 patients treated with a multimodal approach (IC, surgery, radiotherapy). Overall, 44 patients recurred (64%). Of those, 19 patients received salvage surgery, but only four remained disease-free. Median overall survival (OS) was 62.5 months. Sinonasal neuroendocrine and small cell histotypes (P = 0.0085), neuroendocrine differentiation (P = 0.006), and lack of response to IC (P = 0.03) were associated with worse OS. In patients who recurred, median OS was 13 months since recurrence. Survival was longer in patients submitted to salvage surgery (44%) than in those receiving chemotherapy alone at recurrence (29.5 vs. 4.6 months). Patients with a clinical benefit after palliative chemotherapy had a longer median OS than those with disease progression (29.2 vs. 4.4 months; P

Background Distant metastases in adenoid cystic carcinoma (ACC) are common. There is no consensus on the management of metastatic disease because no therapeutic approach has demonstrated improvement in overall survival (OS) and because of prolonged life expectancy. The aim of this study is to build and validate a prognostic nomogram for metastatic ACC patients. Methods The study end-point was OS, measured from the date of first metastatic presentation to death/last follow-up. A retrospective analysis including metastatic ACC patients was performed to build the prognostic nomogram at the INT (Milan, Italy). The model was validated on an independent cohort of patients with similar characteristics treated at Leuven (Belgium). Outcome data and covariates were modelled by resorting to a random forest method. This machine-learning approach was used to guide and benchmark the subsequent use of more conventional modelling methods. Cox model performance was assessed in terms of discrimination (Harrell's c-index). Results Two hundred ninety-eight patients with metastatic ACC (testing set 259 INT, validation set 39 Leuven) were studied. Akaike Information Criterion–based backward selection yielded a 5-factor model showing a bias-corrected c-index of 0.730. Five independent prognostic factors were found: gender, disease-free interval and presence of lung, liver or bone metastases. Nomogram discrimination in the validation series was c = 0.701. Conclusion This retrospective analysis allowed the building of an externally validated prognostic nomogram. This tool might help clinicians to discriminate patients requiring prompt management from who can benefit from a ‘watchful waiting’. In addition, the nomogram might be useful to stratify patients in clinical trials.

Background Unresectable or metastatic cutaneous squamous cell cancers (cSCCs) are rare but potentially life-threatening diseases. In this setting, systemic therapy has a palliative intent with limited benefit, but there is no established consensus regarding the proper management of this tumour. This retrospective study aimed to review outcomes in patients with non-curable cSCC treated with platinum-based chemotherapy and cetuximab. Methods We considered 12 consecutive patients treated between June 2010 and March 2016. All patients had received previous treatment for the local disease. Results The overall response rate was 50%, and the disease control rate was 67%. Median progression-free survival and overall survival were 6.6 (95% confidence interval [CI]: 1.9-8.4) and 14.6 (95% CI: 9.4-20.1) months, respectively. The median duration of response was 4.8 months (95% CI: 1.2-5.9). The most frequent toxicities were skin reactions (58%; grade 3: 25%) and anaemia (10%). No grade 4 toxicities were observed. Conclusions Cetuximab and platinum-based chemotherapy were shown to be feasible and active in cSCC, with an acceptable toxicity profile, even if with a limited duration of response.