FAP Serves as a Prognostic Biomarker in Head and Neck Squamous Cell Carcinoma.

Head and neck squamous cell carcinoma (HNSCC) poses significant challenges with poor survival rates and limited therapeutic strategies. Our study, using The Cancer Genome Atlas (TCGA) data, assesses cancer-associated fibroblast (CAF) gene signatures' clinical relevance. In our analysis across TCGA tumor types, differential gene expression analysis revealed that fibroblast activation protein (FAP) is upregulated in tumor tissues and associated with poorer survival rates in HNSCC. Furthermore, mechanistic studies employing gene-silencing techniques substantiated that FAP knockout led to a significant decrease in cellular proliferation, invasion, and migration in HNSCC cell lines. Through Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses, we established that high FAP expression correlates with vital biological processes such as extracellular matrix organization, angiogenesis, and cellular motility. Importantly, FAP was found to regulate these processes by promoting the expression of key proteins involved in epithelial-mesenchymal transition-related pathways. Additionally, our analysis revealed a significant correlation between FAP expression and the expression profiles of immune checkpoint molecules, underscoring its potential role in immune modulation. Collectively, our findings illuminate FAP's pivotal role in HNSCC pathogenesis and its potential as a prognostic biomarker and therapeutic target. This research lays the groundwork for understanding the multifaceted roles and regulatory mechanisms of CAFs in HNSCC, thereby offering valuable perspectives for the development of targeted therapeutic strategies aimed at improving patient outcomes.

[Cervical CUP Syndrome: Diagnosis and Therapy]. / Zervikales CUP-Syndrom: Diagnostik und Therapie.

In CUP syndrome (CUP = cancer of unknown primary) there are 1 or more metastases of a primary tumor that cannot be localized despite extensive diagnostics. CUP syndrome accounts for 5% of all human malignancies, making it one of the 10 most common forms of cancer. In addition to inflammatory lymph node enlargement and benign changes such as cervical cysts, lymph node metastases are among the most common cervical masses. Cervical CUP syndrome is a histologically confirmed cervical lymph node metastasis with an unknown primary tumor. In addition to anamnesis, clinical examination and histological confirmation, diagnostics include radiological imaging using PET-CT and panendoscopy with histological primary tumor search. Treatment options include surgical therapy with neck dissection and chemoradiotherapy.

Interdisciplinary plastic and reconstructive surgery of head and neck squamous cell carcinomas. / Interdisziplinäre Plastische und Rekonstruktive Chirurgie von Plattenepithelkarzinomen des Kopf-Hals-Bereichs.

Squamous cell carcinomas are the most common malignancies in the oral cavity, pharynx, and larynx. Even in the age of the most modern drug treatment methods, radical resection of these tumors is and currently remains the therapeutic gold standard. The loss of anatomical structures associated with surgery inevitably increases the functional deficits caused by the tumor itself. In this context, the extent of functional deficits is largely determined by the extent of resection. Complete organ resections, such as glossectomy, complete palate resection, laryngectomy, or transverse pharyngo-laryngectomy, lead to severe functional deficits, such as swallowing disturbances with life-threatening aspiration and articulation disorders up to the inability to speak. With the help of plastic reconstructive surgery, the lost tissue can be replaced and the specific functions of the upper aerodigestive tract can be preserved or restored.In recent decades, reconstructive surgical procedures have developed enormously in the treatment of malignant tumors of the head and neck. In order to make optimal use of them, a comprehensive, interdisciplinary therapy concept is a prerequisite for positive oncological and functional outcome. In addition to general medical and social parameters, surgical parameters play a crucial role in the choice of the reconstruction method. The extent to which the surgical measures must be interdisciplinary depends on the localization of the defects in the head and neck region and on the type of replacement tissue required. Here, the expertise of plastic surgery, oral and maxillofacial surgery, and abdominal surgery comes into play in particular. The use of different tissues, the combination of different grafts and flaps, or the preforming of donor regions allow reconstructions far beyond the level of simply restoring surface integrity. The functional results and thus the quality of life of patients after surgical therapy of extensive tumors of the mentioned localizations depend decisively on the type of reconstruction. Therefore, in the following review, special emphasis 1 be placed on the choice of reconstruction method and reconstruction technique for tissue loss after resections of HNSCC.

Research progress of immunotherapy for advanced head and neck cancer.

Head and neck cancer accounts for about one-fifth of all malignant tumors, and the incidence is increasing year by year. The overall mortality rate was high and the 5-year survival rate was low. At present, the combination of surgery, radiotherapy, and chemotherapy is the main treatment in clinical practice, but the treatment of recurrent or metastatic advanced head and neck cancer is still a challenge. With the rise of immunotherapy, more and more studies on immune checkpoint inhibitors have been conducted. This review summarizes the mechanism, clinical application and safety of immunotherapy for advanced head and neck cancer.

[Concurrent simultaneous integrated boost radiotherapy and cetuximab in head and neck squamous cell cancer patients: is it feasible in daily clinical practice?] / Radioterapia a intensità modulata con boost simultaneo più cetuximab in pazienti con carcinoma a cellule squamose in stadio localmente avanzato del distretto testa collo: è fattibile nella pratica clinica quotidiana?

INTRODUCTION AND AIM: Locally advanced head and neck squamous cell carcinoma (LA-Hnscc) is a true therapeutical challenge in the modern era and the scientific community is trying to face this challenge with new therapeutical strategies, including combinations of monoclonal antibodies and radiation therapy. The aim of this study is to evaluate clinical outcomes in LA-Hnscc patients unfit to receive platinum-based chemotherapy, treated with concurrent simultaneous integrated boost-intensity modulated radiotherapy (Sib-Imrt) + cetuximab (Ctx) in daily clinical practice. METHODS: LA-Hnscc patients not included in other prospective studies treated in 4 Italian radiotherapy units (2 Messina, 1 Rome, and 1 Lecce) using Sib-Imrt and Ctx were included in this study. Acute and late toxicities and overall survival (OS) have been evaluated. RESULTS: Data regarding 27 patients with squamous tumour were collected and reviewed. The primary tumour sites were oropharynx in 14 patients (51.9%), oral cavity in 7 (25.9%), larynx in 3 (11%) and other sites in 3(11%). There were 20 (74%) patients had stage IV (16 IVa and 4 IVb). Complete remission was observed in 18 patients (66.7%), a partial remission in 4 (14.8%) whilst 4 had a progression disease (14.8%). After 3 year of follow-up 7/27 patients were deaths. The OS was 95.5%, 62.5% and 52.9% respectively at 1,2 and 3 years. Acute toxicities were observed in all treated patients (mucositis, dermatitis and dysphagia) while 66.7% of patients developed late toxicities. All observed toxicities were grade 1 to 3 and just 1 patient developed a G4 toxicity. CONCLUSION: The concurrent bio-radiotherapy of Sib-Imrt and cetuximab is feasible in real-life daily clinical practice for LA-Hnscc patients unfit for platinum-based chemoradiotherapy.

Identification of immunogenic cell death-related damage-related molecular patterns (DAMPs) to predict outcomes in patients with head and neck squamous cell carcinoma.

PURPOSE: Head and neck cancer is the sixth most common type of cancer worldwide, wherein the immune responses are closely associated with disease occurrence, development, and prognosis. Investigation of the role of immunogenic cell death-related genes (ICDGs) in adaptive immune response activation may provide cues into the mechanism underlying the outcome of HNSCC immunotherapy. METHODS: ICDGs expression patterns in HNSCC were analyzed, after which consensus clustering in HNSCC cohort conducted. A 4-gene prognostic model was constructed through LASSO and Cox regression analyses to analyze the prognostic index using the TCGA dataset, followed by validation with two GEO datasets. The distribution of immune cells and the response to immunotherapy were compared between different risk subtypes through multiple algorithms. Moreover, immunohistochemical (IHC) analyses were conducted to validate the prognostic value of HSP90AA1 as a predictor of HNSCC patient prognosis. In vitro assays were performed to further detect the effect of HSP90AA1 in the development of HNSCC. RESULTS: A novel prognostic index based on four ICDGs was constructed and proved to be useful as an independent factor of HNSCC prognosis. The risk score derived from this model grouped patients into high- and low-risk subtypes, wherein the high-risk subtype had worse survival outcomes and poorer immunotherapy response. IHC analysis validated the applicability of HSP90AA1 as a predictor of prognosis of HNSCC patients. HSP90AA1 expression in tumor cells promotes the progression of HNSCC. CONCLUSIONS: Together, these results highlight a novel four-gene prognostic signature as a valuable tool to assess survival status and prognosis of HNSCC patients.

Comparative analysis of the tumor microbiome, molecular profiles, and immune cell abundances by HPV status in mucosal head and neck cancers and their impact on survival.

Head and Neck Squamous Cell Carcinoma (HNSCC) comprises a diverse group of tumors with variable treatment response and prognosis. The tumor microenvironment (TME), which includes microbiome and immune cells, can impact outcomes. Here, we sought to relate the presence of specific microbes, gene expression, and tumor immune infiltration using tumor transcriptomics from The Cancer Genome Atlas (TCGA) and associate these with overall survival (OS). RNA sequencing (RNAseq) from HNSCC tumors in TCGA was processed through the exogenous sequences in tumors and immune cells (exotic) pipeline to identify and quantify low-abundance microbes. The detection of the Papillomaviridae family of viruses assessed HPV status. All statistical analyses were performed using R. A total of 499 RNAseq samples from TCGA were analyzed. HPV was detected in 111 samples (22%), most commonly Alphapapillomavirus 9 (90.1%). The presence of Alphapapillomavirus 9 was associated with improved OS [HR = 0.60 (95%CI: 0.40-0.89, p = .01)]. Among other microbes, Yersinia pseudotuberculosis was associated with the worst survival (HR = 3.88; p = .008), while Pseudomonas viridiflava had the best survival (HR = 0.05; p = .036). Microbial species found more abundant in HPV- tumors included several gram-negative anaerobes. HPV- tumors had a significantly higher abundance of M0 (p < .001) and M2 macrophages (p = .035), while HPV+ tumors had more T regulatory cells (p < .001) and CD8+ T-cells (p < .001). We identified microbes in HNSCC tumor samples significantly associated with survival. A greater abundance of certain anaerobic microbes was seen in HPV tumors and pro-tumorigenic macrophages. These findings suggest that TME can be used to predict patient outcomes and may help identify mechanisms of resistance to systemic therapies.

Targeting histone deacetylases in head and neck squamous cell carcinoma: molecular mechanisms and therapeutic targets.

The onerous health and economic burden associated with head and neck squamous cell carcinoma (HNSCC) is a global predicament. Despite the advent of novel surgical techniques and therapeutic protocols, there is an incessant need for efficacious diagnostic and therapeutic targets to monitor the invasion, metastasis and recurrence of HNSCC due to its substantial morbidity and mortality. The differential expression patterns of histone deacetylases (HDACs), a group of enzymes responsible for modifying histones and regulating gene expression, have been demonstrated in neoplastic tissues. However, there is limited knowledge regarding the role of HDACs in HNSCC. Consequently, this review aims to summarize the existing research findings and explore the potential association between HDACs and HNSCC, offering fresh perspectives on therapeutic approaches targeting HDACs that could potentially enhance the efficacy of HNSCC treatment. Additionally, the Cancer Genome Atlas (TCGA) dataset, CPTAC, HPA, OmicShare, GeneMANIA and STRING databases are utilized to provide supplementary evidence on the differential expression of HDACs, their prognostic significance and predicting functions in HNSCC patients.

Campothecin suppresses cell proliferation and migration in head and neck squamous cell carcinoma by blocking RAB27A-mediated phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT) pathway.

Camptothecin (CPT), a naturally occurring alkaloid derived from the Camptotheca acuminate plant, exerts anti-tumor properties. However, its specific impact on head and neck squamous cell carcinoma (HNSCC) remains uncertain. The study was to explore the action and mechanism of CPT on HNSCC cells. First, two HNSCC cell lines (FaDu and TU686) and a normal immortalized keratinocyte (HEK001) cell line, were exposed to a spectrum of CPT concentrations (ranging from 10 to 50 µM) for durations of 24 h and 48 h. Cell viability, proliferation, migration, and invasion were assessed by CCK-8 assay, EdU incorporation assay, wound healing assay and transwell assay. Subsequently, si-RAB27A or negative control (NC) was introduced into FaDu and TU686 cells through transfection, and the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway was manipulated with L740Y-P, an activator of this pathway. The expression of proliferating cell nuclear antigen (PCNA), E-cadherin, PI3K/AKT signaling factors and RAB27A were determined by Western blot analysis. RAB27A was detected by immunofluorescence assay. It was found that CPT significantly hindered the viability, proliferation (p<0.01), migration (p<0.001), and invasion (p<0.001) of FaDu and TU686 cells. At the molecular level, administration of CPT caused a decline in the expression of PCNA, P-PI3K, P-AKT, and RAB27A, alongside an elevation in E-cadherin levels within HNSCC cells (p<0.05, p<0.01 and p<0.001). Reducing RAB27A expression enhanced the suppressive impacts of CPT on HNSCC cell viability (p<0.05 and p<0.01), migration (p<0.001) and invasion (p<0.01), these effects that were reversed upon treatment with L740Y-P in HNSCC cells (p<0.001). In summary, our study highlights the efficacy of CPT in HNSCC, demonstrating its influence on cell processes via the RAB27A-mediated PI3K/AKT pathway.

Prognostic and chemotherapeutic implications of a novel four-gene pyroptosis model in head and neck squamous cell carcinoma.

Background: Head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers. Chemotherapy remains one dominant therapeutic strategy, while a substantial proportion of patients may develop chemotherapeutic resistance; therefore, it is particularly significant to identify the patients who could achieve maximum benefits from chemotherapy. Presently, four pyroptosis genes are reported to correlate with the chemotherapeutic response or prognosis of HNSCC, while no study has assessed the combinatorial predicting efficacy of these four genes. Hence, this study aims to evaluate the predictive value of a multi-gene pyroptosis model regarding the prognosis and chemotherapeutic responsiveness in HNSCC. Methods: By utilizing RNA-sequencing data from The Cancer Genome Atlas database and the Gene Expression Omnibus database, the pyroptosis-related gene score (PRGscore) was computed for each HNSCC sample by performing a Gene Set Variation Analysis (GSVA) based on four genes (Caspase-1, Caspase-3, Gasdermin D, Gasdermin E). The prognostic significance of the PRGscore was assessed through Cox regression and Kaplan-Meier survival analyses. Additionally, chemotherapy sensitivity stratified by high and low PRGscore was examined to determine the potential association between pyroptosis activity and chemosensitivity. Furthermore, chemotherapy sensitivity assays were conducted in HNSCC cell lines in vitro. Results: As a result, our study successfully formulated a PRGscore reflective of pyroptotic activity in HNSCC. Higher PRGscore correlates with worse prognosis. However, patients with higher PRGscore were remarkably more responsive to chemotherapy. In agreement, chemotherapy sensitivity tests on HNSCC cell lines indicated a positive association between overall pyroptosis levels and chemosensitivity to cisplatin and 5-fluorouracil; in addition, patients with higher PRGscore may benefit from the immunotherapy. Overall, our study suggests that HNSCC patients with higher PRGscore, though may have a less favorable prognosis, chemotherapy and immunotherapy may exhibit better benefits in this population.

Transcriptomic analysis-guided assessment of precision-cut tumor slices (PCTS) as an ex-vivo tool in cancer research.

With cancer immunotherapy and precision medicine dynamically evolving, there is greater need for pre-clinical models that can better replicate the intact tumor and its complex tumor microenvironment (TME). Precision-cut tumor slices (PCTS) have recently emerged as an ex vivo human tumor model, offering the opportunity to study individual patient responses to targeted therapies, including immunotherapies. However, little is known about the physiologic status of PCTS and how culture conditions alter gene expression. In this study, we generated PCTS from head and neck cancers (HNC) and mesothelioma tumors (Meso) and undertook transcriptomic analyses to understand the changes that occur in the timeframe between PCTS generation and up to 72 h (hrs) in culture. Our findings showed major changes occurring during the first 24 h culture period of PCTS, involving genes related to wound healing, extracellular matrix, hypoxia, and IFNγ-dependent pathways in both tumor types, as well as tumor-specific changes. Collectively, our data provides an insight into PCTS physiology, which should be taken into consideration when designing PCTS studies, especially in the context of immunology and immunotherapy.

Prognostic value of CDKN2A in head and neck squamous cell carcinoma via pathomics and machine learning.

This study aims to enhance the prognosis prediction of Head and Neck Squamous Cell Carcinoma (HNSCC) by employing artificial intelligence (AI) to analyse CDKN2A gene expression from pathology images, directly correlating with patient outcomes. Our approach introduces a novel AI-driven pathomics framework, delineating a more precise relationship between CDKN2A expression and survival rates compared to previous studies. Utilizing 475 HNSCC cases from the TCGA database, we stratified patients into high-risk and low-risk groups based on CDKN2A expression thresholds. Through pathomics analysis of 271 cases with available slides, we extracted 465 distinctive features to construct a Gradient Boosting Machine (GBM) model. This model was then employed to compute Pathomics scores (PS), predicting CDKN2A expression levels with validation for accuracy and pathway association analysis. Our study demonstrates a significant correlation between higher CDKN2A expression and improved median overall survival (66.73 months for high expression vs. 42.97 months for low expression, p = 0.013), establishing CDKN2A's prognostic value. The pathomic model exhibited exceptional predictive accuracy (training AUC: 0.806; validation AUC: 0.710) and identified a strong link between higher Pathomics scores and cell cycle activation pathways. Validation through tissue microarray corroborated the predictive capacity of our model. Confirming CDKN2A as a crucial prognostic marker in HNSCC, this study advances the existing literature by implementing an AI-driven pathomics analysis for gene expression evaluation. This innovative methodology offers a cost-efficient and non-invasive alternative to traditional diagnostic procedures, potentially revolutionizing personalized medicine in oncology.

[Swelling on the neck]. / Schwellung am Hals.

INTRODUCTION: A 30-year-old female patient presented with a swelling of a cervical left lymph node measuring 1x3 cm, which had been presenting for three weeks. Lymph node excision revealed a metastasis of a malignant melanoma, but the primary tumor was not found. The guidelines recommend neck dissection and adjuvant systemic or immunotherapy. The patient opted for immunotherapy with pembrolizumab and was tumor-free one year later.

Large atypical lipomatous tumour of the neck with mediastinal extension managed by transcervical excision.

Tumours of adipose tissue origin are relatively rare in the head and neck. Here, we report a case of an unfamiliar lipomatous lesion that involved the neck and mediastinum. A nil-comorbid man in his 40s presented with a slowly progressive anterior neck swelling of 3 years, which was diagnosed as lipoma by histopathological sampling. Computed tomography demonstrated the lesion to be involving parapharyngeal and retropharyngeal spaces with mediastinal extension. The lesion was removed by the transcervical approach. The final histology of the excised specimen, with immunohistochemistry for mouse double minute 2 (MDM2) and p16, suggested an atypical lipomatous tumour (ALT). This report accentuates the occurrence of this rare neoplasm in the neck, which often mimics lipoma clinically. Although radiology can demonstrate suggestive features, histology with MDM2 and/or p16 positivity can confirm the diagnosis of ALT as against the lipoma. A successful transcervical excision, despite the deeper extension of the lesion between the critical structures of the neck and mediastinum, demonstrates the non-infiltrating nature of the tumour.

Identification and validation of a novel risk model based on cuproptosis­associated m6A for head and neck squamous cell carcinoma.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is a prevalent cancer with a poor survival rate due to anatomical limitations of the head and a lack of reliable biomarkers. Cuproptosis represents a novel cellular regulated death pathway, and N6-methyladenosine (m6A) is the most common internal RNA modification in mRNA. They are intricately connected to tumor formation, progression, and prognosis. This study aimed to construct a risk model for HNSCC using a set of mRNAs associated with m6A regulators and cuproptosis genes (mcrmRNA). METHODS: RNA-seq and clinical data of HNSCC patients from The Cancer Genome Atlas (TCGA) database were analyzed to develop a risk model through the least absolute shrinkage and selection operator (LASSO) analysis. Survival analysis and receiver operating characteristic (ROC) analysis were performed for the high- and low-risk groups. Additionally, the model was validated using the GSE41613 dataset from the Gene Expression Omnibus (GEO) database. GSEA and CIBERSORT were applied to investigate the immune microenvironment of HNSCC. RESULTS: A risk model consisting of 32 mcrmRNA was developed using the LASSO analysis. The risk score of patients was confirmed to be an independent prognostic indicator by multivariate Cox analysis. The high-risk group exhibited a higher tumor mutation burden. Additionally, CIBERSORT analysis indicated varying levels of immune cell infiltration between the two groups. Significant disparities in drug sensitivity to common medications were also observed. Enrichment analysis further unveiled significant differences in metabolic pathways and RNA processing between the two groups. CONCLUSIONS: Our risk model can predict outcomes for HNSCC patients and offers valuable insights for personalized therapeutic approaches.

Circulating tumour cells predict recurrences and survival in head and neck squamous cell carcinoma patients.

Patients with head and neck squamous cell carcinoma (HNSCC) are at a high risk of developing recurrence and secondary cancers. This study evaluates the prognostic and surveillance utilities of circulating tumour cells (CTCs) in HNSCC. A total of 154 HNSCC patients were recruited and followed up for 4.5 years. Blood samples were collected at baseline and follow-up. CTCs were isolated using a spiral microfluid device. Recurrence and death due to cancer were assessed during the follow-up period. In patients with HNSCC, the presence of CTCs at baseline was a predictor of recurrence (OR = 8.40, p < 0.0001) and death (OR= ∞, p < 0.0001). Patients with CTCs at baseline had poor survival outcomes (p < 0.0001). Additionally, our study found that patients with CTCs in a follow-up appointment were 2.5 times more likely to experience recurrence or death from HNSCC (p < 0.05) prior to their next clinical visit. Our study highlights the prognostic and monitoring utilities of CTCs' in HNSCC patients. Early identification of CTCs facilitates precise risk assessment, guiding treatment choices and ultimately enhancing patient outcomes.