A functional gene expression analysis in epithelial sinonasal cancer: Biology and clinical relevance behind three histological subtypes

Epithelial sinonasal cancers (SNCs) are rare diseases with overlapping morphological features and a dismal prognosis. We aimed to investigate the expression differences among the histological subtypes for discerning their molecular characteristics. We selected 47 SNCs: (i) 21 nonkeratinizing squamous cell carcinomas (NKSCCs), (ii) 13 sinonasal neuroendocrine cancers (SNECs), and (iii) 13 sinonasal undifferentiated cancers (SNUCs). Gene expression profiling was performed by DASL (cDNA-mediated annealing, selection, extension, and ligation) microarray analysis with internal validation by quantitative RT-PCR (RT-qPCR). Relevant molecular patterns were uncovered by sparse partial-least squares discriminant analysis (sPLS-DA), microenvironment cell type (xCell), CIBERSORT, and gene set enrichment (GSEA) analyses. The first two sPLS-DA components stratified samples by histological subtypes. xCell highlighted increased expression of immune components (CD8 + effector memory cells, in SNUC) and \u201cother cells\u201d: keratinocytes and neurons in NKSCC and SNEC, respectively. Pathway enrichment was observed in NKSCC (six gene sets, proliferation related), SNEC (one gene set, pancreatic \u3b2-cells), and SNUC (twenty gene sets, some of them immune-system related). Major neuroendocrine involvement was observed in all the SNEC samples. Our high-throughput analysis revealed a good diagnostic ability to differentiate NKSCC, SNEC, and SNUC, but indicated that the neuroendocrine pathway, typical and pathognomonic of SNEC is also present at lower expression levels in the other two histological subtypes. The different and specific profiles may be exploited for elucidating their biology and could help to identify prognostic and therapeutic opportunities

Immunotherapy in Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma: biological landscape and prognostic biomarkers to improve patients' stratification

Head and neck squamous cell carcinoma (HNSCC) is the eight most frequent cancer in the world, and approximately 2/3 of the patients are diagnosed at locally advanced stages (stage III or IV). Despite improvements in HNSCC management and the aggressiveness of first-line curative treatment, 65% of treated patients experience local recurrence or distant metastasis. Moreover, patients diagnosed with recurrence or distant metastasis have a poor prognosis (from 6 to 12 months) and 5-years survival less than 50%. From 2016 the clinical practice was revolutionized by the introduction of immuno-checkpoint inhibitors, approved for the treatment of recurrent/metastatic HNSCC patients. Nevertheless, only a small subset of patients respond to this therapy and currently predictive biomarkers are still under investigation. Herein, we investigated the tumor biology of R/M HNSCC patients, platinum-refractory, enrolled in the phase IIIb clinical trial Nivactor (EudraCT Number: 2017-000562-30), in which patients were treated with nivolumab. Across the study of single biomarkers and the extensive profiling through genomic and transcriptomic analyses, we aimed to characterize the tumor molecular peculiarity of patients that experienced response or those with the longer survival. While the prognostic/predictive role of Programmed Cell Death Ligand-1 (PD-L1; studied by IHC), Tumor mutational burden (TMB) and microsatellite instability (MSI) appeared to be relatively limited for R/M HNSCC patients, 8 expression signatures (retrieved from literature) showed up significant association with survival and contributed to highlight and extricate the extreme complexity of the tumor microenvironment of HNSCC, which appeared to be strongly immunosuppressive (suggesting and corroborating the activation of several mechanisms of immune evasion). Nevertheless, the testing of previously identified six HNSCC subtypes (De Cecco et al.) with specific biological and prognostic characteristics, indicated for two of them a strong prognostic role and a significant correlation with response. In conclusion, the current study demonstrated the strong relevance of gene expression signatures in HNSCC context (over the mere study of somatic mutations) to identify the biological features associated with benefits from immunotherapy. However, additional analyses for the validation of their significance are required

Solitary juvenile xanthogranuloma of the hypopharynx. Clinico-pathologic study in a child with β-thalassemia major and cutaneous mastocytosis

Juvenile Xanthogranuloma (JXG), the most common pediatric non-Langerhans cell histiocytosis, may rarely occur in association with Neurofibromatosis (types 1 and 2), Juvenile Myelomonocytic Leukemia and Cutaneous Mastocytosis (CM) and, morphologically, mimics Erdheim-Chester Disease tissue lesions and ALK-positive histiocytosis. We describe a 4-year-old girl with Beta-Thalassemia Major who developed an hypopharyngeal BRAFV600E- and ALK-negative JXG and CM. JXG has been rarely reported in the aerodigestive tract and in association with CM. In this molecular era, knowledge of genetic heterogeneity of JXG and clinical scenarios in which it may develop is essential for the appropriate diagnosis and treatment of each individual patient

Biological properties of hypoxia-related gene expression models/signatures on clinical benefit of anti-EGFR treatment in two head and neck cancer window-of-opportunity trials

Not applicable (letter

An Inflammatory Signature to Predict the Clinical Benefit of First-Line Cetuximab Plus Platinum-Based Chemotherapy in Recurrent/Metastatic Head and Neck Cancer

Epidermal growth factor receptor (EGFR) pathway has been shown to play a crucial role in several inflammatory conditions and host immune-inflammation status is related to tumor prognosis. This study aims to evaluate the prognostic significance of a four-gene inflammatory signature in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients treated with the EGFR inhibitor cetuximab plus chemotherapy. The inflammatory signature was assessed on 123 R/M HNSCC patients, enrolled in the multicenter trial B490 receiving first-line cetuximab plus platinum-based chemotherapy. The primary endpoint of the study was progression free survival (PFS), while secondary endpoints were overall survival (OS) and objective response rate (ORR). The patient population was subdivided into 3 groups according to the signature score groups. The four-genes-signature proved a significant prognostic value, resulting in a median PFS of 9.2 months in patients with high vs. 6.2 months for intermediate vs. 3.9 months for low values (p = 0.0016). The same findings were confirmed for OS, with median time of 18.4, 13.4, and 7.5 months for high, intermediate, and low values of the score, respectively (p = 0.0001). When ORR was considered, the signature was significantly higher in responders than in non-responders (p = 0.0092), reaching an area under the curve (AUC) of 0.65 (95% CI: 0.55-0.75). Our findings highlight the role of inflammation in the response to cetuximab and chemotherapy in R/M-HNSCC and may have translational implications for improving treatment selection

Association of a gene-expression subtype to outcome and treatment response in patients with recurrent/metastatic head and neck squamous cell carcinoma treated with nivolumab

Background Immune checkpoint inhibitors have been approved and currently used in the clinical management of recurrent and metastatic head and neck squamous cell carcinoma (R/M HNSCC) patients. The reported benefit in clinical trials is variable and heterogeneous. Our study aims at exploring and comparing the predictive role of gene-expression signatures with classical biomarkers for immunotherapy-treated R/M HNSCC patients in a multicentric phase IIIb trial.Methods Clinical data were prospectively collected in Nivactor tiral (single-arm, open-label, multicenter, phase IIIb clinical trial in platinum-refractory HNSCC treated with nivolumab). Findings were validated in an external independent cohort of immune-treated HNSCC patients, divided in long-term and short-term survivors (overall survival >18 and <6 months since the start of immunotherapy, respectively). Pretreatment tumor tissue specimen from immunotherapy-treated R/M HNSCC patients was used for PD-L1 (Tumor Proportion Score; Combined Positive Score (CPS)) and Tumor Mutational Burden (Oncopanel TSO500) evaluation and gene expression profiling; classical biomarkers and immune signatures (retrieved from literature) were challenged in the NIVACTOR dataset.Results Cluster-6 (Cl6) stratification of NIVACTOR cases in high score (n=16, 20%) and low score (n=64, 80%) demonstrated a statistically significant and clinically meaningful improvement in overall survival in the high-score cases (p=0.00028; HR=4.34, 95% CI 1.84 to 10.22) and discriminative ability reached area under the curve (AUC)=0.785 (95% CI 0.603 to 0.967). The association of high-score Cl6 with better outcome was also confirmed in: (1) NIVACTOR progression-free survival (p=4.93E-05; HR=3.71, 95% CI 1.92 to 7.18) and objective-response-rate (AUC=0.785; 95% CI 0.603 to 0.967); (2) long survivors versus short survivors (p=0.00544). In multivariate Cox regression analysis, Cl6 was independent from Eastern Cooperative Oncology Group performance status, PDL1-CPS, and primary tumor site.Conclusions These data highlight the presence of underlying biological differences able to predict survival and response following treatment with immunotherapy in platinum-refractory R/M HNSCC that could have translational implications improving treatment selection.Trial registration number EudraCT Number: 2017-000562-30

Development of a multiomics database for personalized prognostic forecasting in head and neck cancer: The Big Data to Decide EU Project

27Despite advances in treatments, 30% to 50% of stage III-IV head and neck squamous cell carcinoma (HNSCC) patients relapse within 2 years after treatment. The Big Data to Decide (BD2Decide) project aimed to build a database for prognostic prediction modeling.nonenoneCavalieri, Stefano; De Cecco, Loris; Brakenhoff, Ruud H; Serafini, Mara Serena; Canevari, Silvana; Rossi, Silvia; Lanfranco, Davide; Hoebers, Frank J P; Wesseling, Frederik W R; Keek, Simon; Scheckenbach, Kathrin; Mattavelli, Davide; Hoffmann, Thomas; López Pérez, Laura; Fico, Giuseppe; Bologna, Marco; Nauta, Irene; Leemans, C René; Trama, Annalisa; Klausch, Thomas; Berkhof, Johannes Hans; Tountopoulos, Vasilis; Shefi, Ron; Mainardi, Luca; Mercalli, Franco; Poli, Tito; Licitra, LisaCavalieri, Stefano; De Cecco, Loris; Brakenhoff, Ruud H; Serafini, Mara Serena; Canevari, Silvana; Rossi, Silvia; Lanfranco, Davide; Hoebers, Frank J P; Wesseling, Frederik W R; Keek, Simon; Scheckenbach, Kathrin; Mattavelli, Davide; Hoffmann, Thomas; López Pérez, Laura; Fico, Giuseppe; Bologna, Marco; Nauta, Irene; Leemans, C René; Trama, Annalisa; Klausch, Thomas; Berkhof, Johannes Hans; Tountopoulos, Vasilis; Shefi, Ron; Mainardi, Luca; Mercalli, Franco; Poli, Tito; Licitra, Lis