Hedgehog Inhibitors Beyond Clinical Complete Response in Basal Cell Carcinoma: Should I Stop or Should I Go?

INTRODUCTION: In advanced basal cell carcinoma (BCC), the issue of whether Hedgehog inhibitors (HHIs) should be stopped or not after clinical complete response (cCR) achievement remains an unmet clinical need. MATERIALS AND METHODS: We conducted a retrospective, multicenter study across 7 Italian dermato-oncology units including patients with BCC who continued vismodegib after cCR between 2012 and 2019. We assessed the relationship between the duration of vismodegib intake (days to cCR [DTCR], days to stop after cCR [DTS], total treatment days [TTD]), and disease-free survival (DFS). Reasons to stop vismodegib were (R1) toxicity and (R2) disease recurrence. The relationship between DTCR, DTS, TTD, and DFS in the whole population and in R1 subgroup was assessed by Pearson's correlation coefficient (P < .05) and Bayesian statistics (BF10). RESULTS: Sixty-eight BCC patients with a median (m) age of 75.5 years (39-100) were included. Most patients were male (N = 43, 63%), without Gorlin syndrome (N = 56, 82%) and with head and neck area as primary site (N = 51, 75%). After cCR, out of 68 patients, 90% (N = 61/68) discontinued vismodegib: 82% (N = 50/61) due to toxicity (R1), and 18% (N = 11/61) due to recurrence (R2). Conversely, 10% (N = 7/68) continued vismodegib until last follow-up. In the whole population (N = 68), cCR was achieved with a mDTCR of 180.50 days. DFS showed a significant correlation with DTS (P < .01, BF10 = 39.2) and TTD (P < .01, BF10 = 35566), while it was not correlated to DTCR (BF10 < 0.1). The analysis of R1 subgroup (N = 50) confirmed these results. DFS correlated with DTS in all recurrent patients (N = 38, r = 0.44, P < .01) and in the recurrent patients who stopped vismodegib for toxicity (N = 26, r = 0.665, P < .01). DFS was longer when vismodegib was maintained for >2 months after cCR (mDFS > 2 months, N = 54 vs. ≤ 2 months, N = 14: 470 vs. 175 d, P < .01). CONCLUSIONS: Our retrospective results suggest that HHIs should be continued after cCR to improve DFS in BCC.

Gender Difference in sidE eFfects of ImmuNotherapy: a possible clue to optimize cancEr tReatment (G-DEFINER): study protocol of an observational prospective multicenter study.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have significantly improved outcomes in various cancers. ICI treatment is associated with the incidence of immune-related adverse events (irAEs) which can affect any organ. Data on irAEs occurrence in relation to sex- differentiation and their association with gender-specific factors are limited. AIMS: The primary objective of the G-DEFINER study is to compare the irAEs incidence in female and male patients who undergo ICI treatment. Secondary objectives are: to compare the irAEs incidence in pre- and postmenopausal female patients; to compare the irAEs incidence in female and male patients according to different clinical and gender-related factors (lifestyle, psychosocial, and behavioral factors). Exploratory objectives of the study are to compare and contrast hormonal, gene-expression, SNPs, cytokines, and gut microbiota profiles in relation to irAEs incidence in female and male patients. METHODS AND RESULTS: The patients are recruited from Fondazione IRCCS Istituto Nazionale dei Tumori, Italy, St Vincent's University Hospital, Ireland, Oslo University Hospital, Norway, and Karolinska Insitutet/Karolinska University Hospital, Sweden. The inclusion of patients was delayed due to the Covid pandemic, leading to a total of 250 patients recruited versus a planned number of 400 patients. Clinical and translational data will be analyzed. INTERPRETATION: The expected outcomes are to improve the management of cancer patients treated with ICIs, leading to more personalized clinical approaches that consider potential toxicity profiles. The real world nature of the trial makes it highly applicable for timely irAEs diagnosis.

Prognostic role of pre-treatment magnetic resonance imaging (MRI)-based radiomic analysis in effectively cured head and neck squamous cell carcinoma (HNSCC) patients.

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 2 years 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<.0001) and OS (p=.0004). A combined model of RFs plus TNM improved prognostic performance as compared to TNM alone, both for VS 5-year DFS (C-index: 0.76 vs. 0.60) and OS (C-index: 0.74 vs. 0.64). CONCLUSIONS: Radiomics of b-MRI can help to predict recurrence and survival outcomes in HNSCC.

Management of loco-regionally advanced squamous laryngeal cancer in elderly patients.

PURPOSE: To describe the management and outcomes of loco-regionally advanced (stages III-IV) laryngeal cancer (LRALC) in elderly patients. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Patients with adenoid cystic carcinomas of the salivary glands treated with lenvatinib: Activity and quality of life.

BACKGROUND: The treatment of patients with recurrent and/or metastatic (R/M) salivary gland adenoid cystic carcinoma (ACC) remains an unmet need. METHODS: 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-H&N35]), progression-free survival and overall survival, duration of response, and toxicities. RESULTS: 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. CONCLUSIONS: Lenvatinib appears to have modest activity in ACC. Toxicities are common but manageable and QOL was found to deteriorate in some domains.

Cohort analysis of safety and efficacy of vismodegib in Italian patients from the Phase II, multicenter STEVIE study.

Aim: To assess safety and efficacy of vismodegib in the Italian cohort from the SafeTy Events in VIsmodEgib study. Materials & methods: Data from Italian patients with locally advanced basal cell carcinoma (laBCC) or metastatic BCC were analyzed. Results: Among 182 Italian patients, adverse events occurred with similar incidence to the overall population. Overall response rate was 67.1% in laBCC, 20% in metastatic BCC; complete response rate was 33.1% overall and 37.4% in laBCC. Median time to response was 2 months in complete responders versus 3.6 months overall. Quality of life improved from baseline. Conclusion: In the Italian cohort of STEVIE, vismodegib showed a safety profile consistent with the whole population; older age did not affect safety or efficacy. ClinicalTrials.gov registration: NCT01367665.

PD-L1 Expression in Unresectable Locally Advanced or Metastatic Skin Squamous Cell Carcinoma Treated with Anti-Epidermal Growth Factor Receptor Agents.

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.

Role of pretreatment 18F-FDG PET/CT parameters in predicting outcome of non-endemic EBV DNA-related nasopharyngeal cancer (NPC) patients treated with IMRT and chemotherapy.

PURPOSE: To evaluate the prognostic role of pretreatment 18F-FDG PET/CT metabolic parameters in non-endemic Epstein-Barr Virus (EBV DNA)-related nasopharyngeal cancer (NPC) patients treated with curative intensity-modulated radiation therapy (IMRT) with or without chemotherapy (CHT). MATERIALS/METHODS: We retrospectively reviewed clinical data of 160 consecutive non-metastatic NPC patients who received IMRT with or without CHT. Forty-nine out of 160 patients that underwent whole body 18F-FDG PET/CT at our institution for disease staging with a minimum follow-up to 12 months were included in this study. We evaluated the relationship between maximum and mean standardized uptake values (SUVmax and SUVmean, respectively), metabolic tumor volume and total lesion glycolysis (TLG) of primary tumor and cervical lymph nodes with disease-free survival (DFS) and overall survival (OS). We also investigated the prognostic role of clinical variables such as age, disease stage, plasma EBV DNA load (copies/ml), gross tumor volume of primary tumor and lymph nodes. RESULTS: Median follow-up was 55 months. Two- and 5-year OS were 95.8% and 90.5%, respectively, while DFS was 83.4% at both time points. SUVmax of primary tumor ≥ 18.8 g/ml and primary tumor TLG ≥ 203.1 g were significant prognostic factors of worse OS. Furthermore, stages IVB and EBV DNA load ≥ 3493 copies/ml were significantly associated with lower DFS. No correlation was found between PET parameters and plasma EBV DNA load. CONCLUSION: Even in a limited series, our data suggested that SUVmax, SUVmean and TLG of primary tumor could predict a poor outcome in NPC patients also in non-endemic area hypothesizing their use for refinement of prognostication.

Stakeholders' views on vocational rehabilitation programs: a call for collaboration with Occupational Health Physicians.

BACKGROUND: The triple-dip recession taking place in Italy in 2008-2014 impacted negatively on health, mainly by increasing the rate of unemployment. This increased the prevalence of mental health disorders, while reducing the number of available places on vocational rehabilitation programs (VRPs) delivered by the psychiatric services. OBJECTIVES: To explore the different points of views of stakeholders (namely, users and professionals) involved in VRPs developed inside an Italian Community Mental Health Center (CMHC). METHODS: A sample of users, psychiatrists, educators and nurses of an Italian CMHC involved in VRPs took part in a focus group. Content analysis was performed with MAXQDA 12, by developing a hierarchical code system a posteriori (i.e., derived from the data). The respondent validation phase was carried out by means of a multiple-choice questionnaire, administered to all participants. RESULTS: A total of 86 emerging issues were coded, divided into two macro-areas: Positive and Negative Reinforcements (48 contributions, 56%, and 38 contributions, 44%, respectively), further subdivided into three areas: professional (service) factors, personal (i.e, user-related) factors, and work environment features (including relationships in the workplace). Some contributions raised issues concerning occupational health protection (e.g. need of information about the rights and duties of the users-workers, as well as the risks they are exposed to in the workplace). CONCLUSIONS: The analysis suggested to address specific issues concerning work and VRPs by means of psycho-education group interventions currently carried out at CMHCs, and pointed to the need to foster collaboration between mental health professionals and the occupational health physician of the company where the VRP is started and where the user might be employed.

Eliciting Preferences for Clinical Follow-Up in Patients with Head and Neck Cancer Using Best-Worst Scaling.

OBJECTIVES: There are no commonly accepted standards for monitoring patients treated for head and neck cancer. The aim of this study was to assess patients' preferences for different aspects of follow-up. METHODS: A best-worst survey was conducted in a sample of head and neck cancer patients in clinical follow-up at the National Cancer Institute (Milan, Italy). Conditional logit regression with choice as the dependent variable was run to analyse the data. A covariate-adjusted analysis was performed in order to identify socio-demographic and clinical factors related to the selection of best-worst items. The participants were asked to report any difficulties encountered during the survey. RESULTS: A total of 143 patients, predominantly male (74%) and with a mean age of 58 years were enrolled in the survey. The strongest positive preference was expressed for a hospital-based program of physical examinations with frequency decreasing over time. Conversely, the lowest valued item was not performing any positron emission tomography (PET) scan during follow-up. Patients with high educational levels were more likely to value attending a primary care-based program and undergoing intensive radiological investigations. Other patient-specific variables significantly associated with the choice of items were employment and living status, time already spent in follow-up and number of treatments received. CONCLUSIONS: Overall, patients were more likely to choose an intensive follow-up scheme broadly consistent with the program currently administered by the hospital. There is little evidence of preference heterogeneity that might justify customized programs based on demographics. The best-worst scaling task appeared feasible for most participants.

The Case Volume Issue in Head and Neck Oncology.

OPINION STATEMENT: In the past few years, several evidences reported better outcomes, in terms of reduced toxicities and longer survival, for head and neck cancer (HNC) patients when "regionalized," namely if they are managed at "high-volume" cancer referral centers (CRC). The benefit of case volume has been demonstrated in HNC patients primarily treated with surgery and in those receiving curative radiotherapy and chemotherapy. Many factors could explain these positive results: organization, facilities, processes of care, quality assurance programs, professional expertise, technology, and patient referral bias. In other words, the "high volume" could be linked both to all hospital-related volume and to the expertise of each involved professional figure (e.g., surgeon, radiation oncologist, medical oncologist, etc.). In this context, it is still debatable whether there is a need to understand which one of these factors is more able to influence the final outcomes of HNC patients. Considering the complexity and heterogeneity of HNC, all of these aspects are likely to impact and plot each other. However, there is no consensus regarding the criteria and the cut-off used to define as "high" the case volume. Moreover, some limitations or biases of the regionalization process have to be highlighted: (1) personal and financial discomfort of patients, their caregivers, and families; (2) a frequent referral of the healthiest or youngest patients to CRC could change the survival outcomes; (3) potential higher difficulties for colleagues working outside of CRC in the emergency. Nevertheless, the case volume represents one of the factors impacting on the quality of the treatment itself, in terms of reduced toxicity and better treatment outcome. Therefore, it should be considered as a stratifying factor in randomized controlled trials for HNC patients.

Gene Expression Signatures for Head and Neck Cancer Patient Stratification: Are Results Ready for Clinical Application?

OPINION STATEMENT: Head and neck squamous cell carcinoma (HNSCC) is the sixth leading cancer by incidence worldwide and considering the recent EUROCARE-5 population-based study the 5-year survival rate of HNSCC patients in Europe ranges between 69% in localized cases and 34% in patients with regional involvement. The development of high-throughput gene expression assays in the last two decades has provided the invaluable opportunity to improve our knowledge on cancer biology and to identify predictive signatures in the most deeply analyzed malignancies, such as hematological and breast cancers. At variance, till 2010, the number of reliable reports referring gene expression data related to HSNCC biology and prediction was quite limited. A critical revision of the literature reporting gene expression data in HNSCC indicated that in the last 6 years, there were new important studies with a relevant increase in the sample size and a more accurate selection of cases, the publication of a growing number of studies applying a computational integration (meta-analysis) of different microarray datasets addressing similar clinical/biological questions, the increased use of molecular sub-classification of tumors according to their gene expression, and the release of the publicly available largest dataset in HNSCC by The Cancer Genome Atlas (TCGA) consortium. Overall, also for this disease, it become evident that the expression analysis of the entire transcriptome has been enabling to achieve the identification of promising molecular signatures for (i) disclosure of the biology behind carcinogenesis with special focus on the HPV-related one, (ii) prediction of tumor recurrence or metastasis development, (iii) identification of subgroups of tumors with different biology and associated prognosis, and (iv) prediction of outcome and/or response to therapy. The increasing awareness of the relevance of strict collaboration among clinicians and translational researchers would in a near future enable the application of a personalized HNSCCs patients' treatment in the clinical practice based also on gene expression signatures.

Preemptive treatment with Xonrid®, a medical device to reduce radiation induced dermatitis in head and neck cancer patients receiving curative treatment: a pilot study.

PURPOSE: The purpose of this study was to investigate efficacy, safety and tolerability of Xonrid®, a new medical device, in preventing radiation dermatitis associated with head and neck cancer (HNC) radiotherapy (RT). METHODS: In this monocentric, prospective pilot study, adult consecutive HNC patients who were planned to receive curative RT with or without chemotherapy were enrolled. Patients were instructed to apply Xonrid® on the irradiated area during treatment continuing until 2 weeks after the completion of RT or the development of severe skin toxicity. Toxicity was assessed using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 scale. The patient reported outcome measures included the Skindex-16 questionnaire and patient satisfaction. Skin reflectance spectra were analyzed to objectively evaluate dermatitis. RESULTS: In total, 41 subjects were enrolled (30 males, median age 60 years). No skin adverse events were recorded either in the skin area where the product was applied or in the nearby skin over the entire period of administration. At the end of RT, nine patients (22%) presented G1, 31 (76%) G2, and one patient (2%) G3 skin toxicity (after 5 weeks). Seven and 20 patients reached skin maximum toxicity at the fourth week and after the seventh week, respectively. An increasing trend of median spectrophotometry scores along with skin toxicity grades was observed. A correlation between Skindex-16 scores and skin toxicity grade during treatment was found. CONCLUSIONS: Our study results suggest that Xonrid® is well tolerated, safe, and effective in minimizing and delaying high-grade radiation dermatitis in HNC patients.

The Benefit of a Multidisciplinary Approach to the Patient Treated with (Chemo) Radiation for Head and Neck Cancer.

OPINION STATEMENT: In the past two decades, multidisciplinary care has emerged as new way to manage cancer given the need to gather together specific areas of expertise and to discuss the variety of treatment approaches available for each patient. Of all the cancer subtypes, head and neck cancer might be considered one of the most valid areas, from an oncological point of view, for a multidisciplinary approach to be applied. Head and Neck Cancer is a complex disease area due to its varied histology and subsites, its numerous feasible treatments, its multiple typical comorbidities, and its treatment-induced toxicities whose management requires the simultaneous involvement of several professionals as part of the same health care team. However, the benefits of a multidisciplinary team approach in this particular area have not yet been properly documented in terms of survival outcomes. Moreover, there are some concerns and the limitations of a multidisciplinary team approach for Head and Neck Cancer patients are still open to question: cost-efficiency, the implications from a medical law perspective, the level of expertise required and the timing of each intervention (fixed or as required; before, during or after oncological treatment), and the role of the leader with other interested specialists to optimize all multidisciplinary care mechanisms.

HER2-targeted therapies for salivary gland cancers.

Salivary gland cancers (SGCs) are a heterogeneous group of rare tumors including various histological subtypes with different molecular profiling. Human epidermal growth factor receptor 2 (HER2) is one of the most intriguing and studied molecular alterations with prognostic and predictive roles. Indeed, HER2 overexpression is commonly correlated with aggressive histological subtypes and poorer prognosis. However, HER2 may represent the target of personalized treatment. We performed a literature review of use of anti-HER2 targeted agents for treatment of recurrent or metastatic SGCs. The efficacy and safety of anti-HER2 were firstly evaluated in patients affected with other solid tumors, mostly breast and gastric cancers. For SGCs the literature is mainly comprised of case reports or case series and small clinical trials. The most common used drug is trastuzumab in combination with chemotherapy (i.e. taxanes, capecitabine, carboplatin, eribulin) or with another anti-HER2 targeted agent (i.e. pertuzumab). The use of anti-HER2 therapies induces improvement in clinical responses, which are mostly durable. Besides, new anti-HER2 drugs such as antibody-drug conjugates (ADC) (i.e. trastuzumab emtansine, trastuzumab deruxtecan) have been introduced in this setting inducing further therapeutic advances. Anti-HER2 treatment strategy is emerging as potentially effective in selected HER2 overexpressing SGCs. However, prospective and multicentric clinical trials are needed to evaluate the efficacy of these therapeutic regimens within larger cohorts and to assess the most appropriate treatment sequence strategy.

Tumor molecular landscape of Epstein-Barr virus (EBV) related nasopharyngeal carcinoma in EBV-endemic and non-endemic areas: Implications for improving treatment modalities.

Epstein-Barr virus (EBV) related- nasopharyngeal carcinoma (NPC) is a squamous carcinoma of the nasopharyngeal mucosal lining. Endemic areas (EA) are east and Southeast Asia, were NPC was recorded with higher incidence and longer estimated survival than in non-endemic area (NEA) such as Europe, We analyzed the gene expression and microenvironment properties of NPC in both areas to identify molecular subtypes and assess biological and clinical correlates that might explain the differences in incidence and outcome between EA- and NEA-NPCs. Six EA-NPC transcriptomic datasets, including tumor and normal samples, were integrated in a meta-analysis to identify molecular subtypes using a ConsensusClusterPlus bioinformatic approach. Based on the biological/functional characterization of four identified clusters were identified: Cl1, Immune-active; Cl2, defense-response; Cl3, proliferation; Cl4, perineural-interaction/EBV-exhaustion. Kaplan-Meier survival analysis, applied to the single dataset with available disease-free survival indicated Cl3 as the cluster with the worst prognosis (P = 0.0476), confirmed when applying four previously published prognostic signatures. A Cl3 classifier signature was generated and its prognostic performance was confirmed (P = 0.0368) on a validation dataset. Prediction of treatment response suggested better responses to: radiotherapy and immune checkpoint inhibitors immune-active and defense-response clusters; chemotherapy proliferation cluster; cisplatin perineural-interaction/EBV-exhaustion cluster. RNA sequencing for gene expression profiling was performed on 50 NEA-NPC Italian samples. In the NEA cohort, Cl1, Cl2 and Cl3 were represented, while perineural-interaction/EBV-exhaustion was almost absent. The immune/biological characterization and treatment-response prediction analyses of NEA-NPC partially replicated the EA-NPC results. Well characterized EA- and NEA-NPC retrospective and prospective cohorts are needed to validate the obtained results and can help designing future clinical studies.

Adenoid Cystic carcinoma of minor salivary glands (AdCCmSG): a multidisciplinary update.

INTRODUCTION: Adenoid cystic carcinoma of minor salivary glands (AdCCmSG) represents a 'rarity in the rarity,' posing a clinical challenge in lack of standardized, evidence-based recommendations. At present, AdCCmSG management is mostly translated from major salivary gland cancers (MSGCs). Ideally, AdCCmSG diagnostic-therapeutic workup should be discussed and carried out within a multidisciplinary, high-expertise setting, including pathologists, surgeons, radiation oncologists and medical oncologists. AREAS COVERED: The present review provides an overview of epidemiology and pathologic classification. Moreover, the most recent, clinically relevant updates in the treatment of AdCCmSG (Pubmed searches, specific guidelines) are critically discussed, aiming to a better understanding of this rare pathologic entity, potentially optimizing the care process, and offering a starting point for reflection on future therapeutic developments. EXPERT OPINION: The management of rare cancers is often hindered by limited data and clinical trials, lack of evidence-based guidelines, and hardly represented disease heterogeneity, which cannot be successfully tackled with a 'one-size-fits-all' approach. Our goal is to address these potential pitfalls, providing an easy-to-use, updated, multidisciplinary collection of expert opinions concerning AdCCmSG management as of today's clinical practice. We will also cover the most promising future perspectives, based on the potential therapeutic targets highlighted within AdCCmSG's molecular background.

Translational Insights in the Landscape of Salivary Gland Cancers: Ready for a New Era?

Salivary gland carcinomas (SGCs) are rare neoplasms, representing less than 10% of all head and neck tumors, but they are extremely heterogeneous from the histological point of view, their clinical behavior, and their genetics. The guidelines regarding their treatment include surgery in most cases, which can also play an important role in oligometastatic disease. Where surgery cannot be used, systemic therapy comes into play. Systemic therapy for many years has been represented by polychemotherapy, but recently, with the affirmation of translational research, it can also count on targeted therapy, at least in some subtypes of SGCs. Interestingly, in some SGC histotypes, predominant mutations have been identified, which in some cases behave as "driver mutations", namely mutations capable of governing the carcinogenesis process. Targeting these driver mutations may be an effective therapeutic strategy. Nonetheless, it is not always possible to have drugs suitable for targeting driver mutations-and targeting driver mutations is not always accompanied by a clinical benefit. In this review, we will analyze the main mutations predominant in the various histotypes of SGCs.

The Tumor Microenvironment and the Estrogen Loop in Thyroid Cancer.

Thyroid cancer (TC) cells employ multiple signaling pathways, such as PI3K/AKT/mTOR and RAS/Raf/MAPK, fostering cell proliferation, survival and metastasis. Through a complex interplay with immune cells, inflammatory mediators and stroma, TC cells support an immunosuppressive, inflamed, pro-carcinogenic TME. Moreover, the participation of estrogens in TC pathogenesis has previously been hypothesized, in view of the higher TC incidence observed among females. In this respect, the interactions between estrogens and the TME in TC could represent a relevant, unexplored area of research. We thereby collectively reviewed the available evidence concerning the potential carcinogenic role of estrogens in TC, specifically focusing on their crosstalk with the TME.

Multidisciplinary management of pregnancy-associated and early post-partum head and neck cancer patients.

Background: Pregnancy-associated cancer (PAC) occurs during pregnancy or within 12 months after the delivery. Head and neck cancer (HNC) during pregnancy is infrequent, therefore diagnosis and personalized therapy are intricate. Methods: We investigated outcomes of 15 PAC patients (5 salivary, 4 nasopharyngeal, 3 thyroid, 2 oral cavity, one HPV-related carcinoma) diagnosed in the period 2005-2019. A literature review on PAC is provided. Results: Median gestational age at PAC diagnosis was 28 weeks (range: 16-40 weeks) in ten cases, at 5 months after delivery (range: 1 week-6 months) in the remaining five. Treatments included surgery (3 during pregnancy, 5 after childbirth), chemoradiation (8), and 3 patients with upfront metastatic disease received chemotherapy. Median survival was 6.6 years (eight women remain with no evidence of disease six years after diagnosis). Conclusion: All patients received state-of-the-art therapy, with encouraging long-term results, highlighting treatment safety in women with HNC during pregnancy.