Ectopic cervical thymoma: a rare entity in the anterior neck.

Thymoma is a rare malignancy with usual location in the antero-superior mediastinum. Ectopic cervical thymoma (ECT) is an extremely rare tumor that originates from ectopic tissue, and is caused by the aberrant migration of the embryonic thymus. Our patient was a 56-year-old man who had a nodular lesion in the neck for several years. Computed tomography and Enhanced magnetic resonance imaging were performed. He underwent surgery, and a histological examination resulted in a diagnosis of type AB thymoma.

[Analysis of cases of cervical cystic lymph node metastasis with an unknown primary misdiagnosed as branchial cleft carcinoma].

Objectives: To analyze the location, discovery time and possible causes of cases of cervical cystic lymph node metastasis with an unknown primary misdiagnosed as branchial cleft carcinoma. Methods: A retrospective analysis was performed on clinical and pathological data of 15 patients misdiagnosed as branchiogenic carcinoma at Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College between January 2000 and December 2020. Results: Among the 15 patients, 6 were nasopharyngeal squamous cell carcinoma, 4 tonsil squamous cell carcinoma, 2 tongue root squamous cell carcinoma, 2 hypopharyngeal squamous cell carcinoma and 1 thyroid papillary carcinoma. The median time from the diagnosis of branchial cleft carcinoma to the discovery of primary lesions was 3.58 months (0-76 months). The causes of misdiagnosis might be the lack of experience in the diagnosis and treatment of branchial cleft carcinoma, and not enough attention to comprehensive examination and close follow-up. Conclusions: Different from oropharyngeal cancer reported internationally, the proportion of misdiagnosed cases with nasopharyngeal carcinoma as the primary site in the current article is higher. As a country with a high incidence of nasopharyngeal carcinoma, the examination of nasopharynx should not be taken lightly. Most hidden cases can be found in the comprehensive examination in a short time, while a few cases need long-term follow-up. Finding the primary sites should not rely too much on imaging examination, and we cannot ignore the importance of clinical physical examination.

Tigilanol Tiglate-Induced Changes in Secretome Profiles Alter C-Met Phosphorylation and Cell Surface Protein Expression in H357 Head and Neck Cancer Cells.

Tigilanol tiglate (TT, also known as EBC-46) is a novel, plant-derived diterpene ester possessing anticancer and wound-healing properties. Here, we show that TT-evoked PKC-dependent S985 phosphorylation of the tyrosine kinase MET leads to subsequent degradation of tyrosine phosphorylated p-Y1003 and p-Y1234/5 MET species. PKC inhibition with BIM-1 blocked S985 phosphorylation of MET and led to MET cell surface accumulation. Treatment with metalloproteinase inhibitors prevented MET-ECD release into cell culture media, which was also blocked by PKC inhibitors. Furthermore, unbiased secretome analysis, performed using TMT-technology, identified additional targets of TT-dependent release of cell surface proteins from H357 head and neck cancer cells. We confirm that the MET co-signalling receptor syndecan-1 was cleaved from the cell surface in response to TT treatment. This was accompanied by rapid cleavage of the cellular junction adhesion protein Nectin-1 and the nerve growth factor receptor NGFRp75/TNFR16. These findings, that TT is a novel negative regulator of protumorigenic c-MET and NGFRp75/TNFR16 signalling, as well as regulating Nectin-1-mediated cell adhesion, further contribute to our understanding of the mode of action and efficacy of TT in the treatment of solid tumours.

Effective Radiosensitization of HNSCC Cell Lines by DNA-PKcs Inhibitor AZD7648 and PARP Inhibitors Talazoparib and Niraparib.

(1) Head and neck squamous cell carcinoma (HNSCC) is common, while treatment is difficult, and mortality is high. Kinase inhibitors are promising to enhance the effects of radiotherapy. We compared the effects of the PARP inhibitors talazoparib and niraparib and that of the DNA-PKcs inhibitor AZD7648, combined with ionizing radiation. (2) Seven HNSCC cell lines, including Cal33, CLS-354, Detroit 562, HSC4, RPMI2650 (HPV-negative), UD-SCC-2 and UM-SCC-47 (HPV-positive), and two healthy fibroblast cell lines, SBLF8 and SBLF9, were studied. Flow cytometry was used to analyze apoptosis and necrosis induction (AnnexinV/7AAD) and cell cycle distribution (Hoechst). Cell inactivation was studied by the colony-forming assay. (3) AZD7648 had the strongest effects, radiosensitizing all HNSCC cell lines, almost always in a supra-additive manner. Talazoparib and niraparib were effective in both HPV-positive cell lines but only consistently in one and two HPV-negative cell lines, respectively. Healthy fibroblasts were not affected by any combined treatment in apoptosis and necrosis induction or G2/M-phase arrest. AZD7648 alone was not toxic to healthy fibroblasts, while the combination with ionizing radiation reduced clonogenicity. (4) In conclusion, talazoparib, niraparib and, most potently, AZD7648 could improve radiation therapy in HNSCC. Healthy fibroblasts tolerated AZD7648 alone extremely well, but irradiation-induced effects might occur. Our results justify in vivo studies.

Molecular Aspects of Piperine in Signaling Pathways Associated with Inflammation in Head and Neck Cancer.

Piperine, an active plant alkaloid from black pepper (Piper nigrum), has several pharmacological effects, namely antioxidant, anti-inflammatory and immunomodulatory effects, which involve inhibiting molecular events associated with various stages of cancer development. The aim of this study was to investigate the molecular mechanisms of action of piperine in relation to its potential anticancer effect on head and neck cancer cells. Parameters related to neoplastic potential and cytokine, protein and gene expression were investigated in head and neck cancer cell lines (HEp-2 and SCC-25) treated with piperine. The results of the tests indicated that piperine modified morphology and inhibited viability and the formation of cell colonies. Piperine promoted genotoxicity by triggering apoptosis and cell cycle arrest in the G2/M and S phases. A decrease in cell migration was also observed, and there was decreased expression of MMP2/9 genes. Piperine also reduced the expression of inflammatory molecules (PTGS2 and PTGER4), regulated the secretion of cytokines (IFN-γ and IL-8) and modulated the expression of ERK and p38. These results suggest that piperine exerts anticancer effects on tumor cells by regulating signaling pathways associated with head and neck cancer.

The potential therapeutic targets of glutamine metabolism in head and neck squamous cell carcinoma.

Targeting metabolic reprogramming may be an effective strategy to enhance cancer treatment efficacy. Glutamine serves as a vital nutrient for cancer cells. Inhibiting glutamine metabolism has shown promise in preventing tumor growth both in vivo and in vitro through various mechanisms. Therefore, this review collates recent scientific literature concerning the correlation between glutamine metabolism and cancer treatment. Novel treatment modalities based on amino acid transporters, metabolites, and glutaminase are discussed. Moreover, we demonstrate the relationship between glutamine metabolism and tumor proliferation, drug resistance, and the tumor immune microenvironment, offering new perspectives for the clinical treatment of head and neck squamous cell carcinoma, particularly for combined therapies. Identifying innovative approaches for enhancing the efficacy of glutamine-based metabolic therapy is crucial to improving HNSCC treatment.

Clinical Value of Fine Needle Aspiration Cytology and Core Needle Biopsy in Head and Neck Pathology - A Nationwide Survey in Germany.

BACKGROUND/AIM: Fine-needle aspiration cytology (FNA) and core needle biopsy (CNB) of the thyroid gland, salivary glands, and lymph nodes are considered simple and rapid methods for minimally invasive tissue collection. We performed a postal survey to analyse the diagnostic value and complication rate of FNA and CNB in Germany. PATIENTS AND METHODS: A questionnaire comprising 11 questions was sent to all 161 German ENT departments in September 2015. RESULTS: The response rate was 45%. In 33 of the 73 responding clinics neither FNA nor CNB were carried out. Of the 26 clinics that provided detailed reasons, the majority (n=18) cited a lack of expertise among the collaborating pathologists. Overall, FNA was used more often, regardless of the anatomical region investigated. The study was based on a total of 36,684 FNAs and 9,624 CNBs. The rate of estimated meaningful and correct findings was 63% (10%-90%) for FNA, and 83% (50%-100%) for CNB. In eight cases (<0.001%) a potential tumor cell spread was reported. CONCLUSION: This is the first nationwide survey in Germany to investigate the utility of FNA and CNB across different localizations in the head and neck region. This study revealed comparable results to the literature regarding the diagnostic value of FNA and CNB. Cell spreading was only observed in individual cases. The appraisal of needle biopsies in the head and neck area seems to be rather inhomogeneous in Germany.

Surgical margins in head and neck squamous cell carcinoma: A narrative review.

Head and neck squamous cell carcinoma (HNSCC), a prevalent and frequently recurring malignancy, often necessitates surgical intervention. The surgical margin (SM) plays a pivotal role in determining the postoperative treatment strategy and prognostic evaluation of HNSCC. Nonetheless, the process of clinical appraisal and assessment of the SMs remains a complex and indeterminate endeavor, thereby leading to potential difficulties for surgeons in defining the extent of resection. In this regard, we undertake a comprehensive review of the suggested surgical distance in varying circumstances, diverse methods of margin evaluation, and the delicate balance that must be maintained between tissue resection and preservation in head and neck surgical procedures. This review is intended to provide surgeons with pragmatic guidance in selecting the most suitable resection techniques, and in improving patients' quality of life by achieving optimal functional and aesthetic restoration.

Nuclear miR-451a activates KDM7A and leads to cetuximab resistance in head and neck squamous cell carcinoma.

Cetuximab resistance has been a major challenge for head and neck squamous cell carcinoma (HNSCC) patients receiving targeted therapy. However, the mechanism that causes cetuximab resistance, especially microRNA (miRNA) regulation, remains unclear. Growing evidence suggests that miRNAs may act as "nuclear activating miRNAs" for targeting promoter regions or enhancers related to target genes. This study elucidates a novel mechanism underlying cetuximab resistance in HNSCC involving the nuclear activation of KDM7A transcription via miR-451a. Herein, small RNA sequencing, quantitative real-time polymerase chain reaction (qRT‒PCR) and fluorescence in situ hybridization (FISH) results provided compelling evidence of miR-451a nuclear enrichment in response to cetuximab treatment. Chromatin isolation via RNA purification, microarray analysis, and bioinformatic analysis revealed that miR-451a interacts with an enhancer region in KDM7A, activating its expression and further facilitating cetuximab resistance. It has also been demonstrated that the activation of KDM7A by nuclear miR-451a is induced by cetuximab treatment and is AGO2 dependent. Logistic regression analyses of 87 HNSCC samples indicated the significance of miR-451a and KDM7A in the development of cetuximab resistance. These discoveries support the potential of miR-451a and KDM7A as valuable biomarkers for cetuximab resistance and emphasize the function of nuclear-activating miRNAs.

A druggable cascade links methionine metabolism to epigenomic reprogramming in squamous cell carcinoma.

Upper aerodigestive squamous cell carcinoma (UASCC) is a common and aggressive malignancy with few effective therapeutic options. Here, we investigate amino acid metabolism in this cancer, surprisingly noting that UASCC exhibits the highest methionine level across all human cancers, driven by its transporter LAT1. We show that LAT1 is also expressed at the highest level in UASCC, transcriptionally activated by UASCC-specific promoter and enhancers, which are directly coregulated by SCC master regulators TP63/KLF5/SREBF1. Unexpectedly, unbiased bioinformatic screen identifies EZH2 as the most significant target downstream of the LAT1-methionine pathway, directly linking methionine metabolism to epigenomic reprogramming. Importantly, this cascade is indispensable for the survival and proliferation of UASCC patient-derived tumor organoids. In addition, LAT1 expression is closely associated with cellular sensitivity to inhibition of the LAT1-methionine-EZH2 axis. Notably, this unique LAT1-methionine-EZH2 cascade can be targeted effectively by either pharmacological approaches or dietary intervention in vivo. In summary, this work maps a unique mechanistic cross talk between epigenomic reprogramming with methionine metabolism, establishes its biological significance in the biology of UASCC, and identifies a unique tumor-specific vulnerability which can be exploited both pharmacologically and dietarily.

Clinicopathological Factors as Predictors for Establishment of Patient Derived Head and Neck Squamous Cell Carcinoma Organoids.

INTRODUCTION: Patient derived organoids (PDOs) are 3D in vitro models and have shown to better reflect patient and tumor heterogeneity than conventional 2D cell lines. To utilize PDOs in clinical settings and trials for biomarker discovery or drug response evaluation, it is valuable to determine the best way to optimize sample selection for maximum PDO establishment. In this study, we assess patient, tumor and tissue sampling factors and correlate them with successful PDO establishment in a well-documented cohort of patients with head and neck squamous cell carcinoma (HNSCC). METHODS: Tumor and non-tumorous adjacent tissue samples were obtained from HNSCC patients during routine biopsy or resection procedures at the University Medical Center Utrecht. The tissue was subsequently processed to establish PDOs. The sample purity was determined as the presence of epithelial cells in the culture on the day of organoid isolation as visualized microscopically by the researcher. PDO establishment was recorded for all samples. Clinical data was obtained from the medical records and was correlated to PDO establishment and presence of epithelial cells. RESULTS: Organoids could be established in 133/250 (53.2%) primary tumor site tissues. HNSCC organoid establishment tended to be more successful if patients were younger than the median age of 68 years (74/123 (60.2%) vs. 59/127 (46.5%), p = 0.03). For a subset of samples, the presence of epithelial cells in the organoid culture on the day of organoid isolation was recorded in 112/149 (75.2%) of these samples. When cultures were selected for presence of epithelial cells, organoid establishment increased to 76.8% (86/112 samples). CONCLUSION: This study found a trend between age and successful organoid outgrowth in patients with HNSCC younger than 68 years and emphasizes the value of efficient sampling regarding PDO establishment.

The Prognostic Significance of Tumor SUVmax Value in Pre- and Post-Chemoradiotherapy 18F-FDG PET/CT Imaging in Patients with Localized and Advanced Head and Neck Squamous Cell Carcinoma.

BACKGROUND: Some parameters of 18F-2-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) can predict tumor chemosensitivity and survival in patients with head and neck squamous cell carcinoma (HNSCC). AIM: The aim of the study was to investigate the prognostic value of pre- and post-treatment maximum standardized uptake values (SUVmax) in 18F-FDG PET/CT imaging for predicting mortality in patients with HNSCC, as well as its prognostic value in terms of disease progression, overall survival (OS), and progression-free survival (PFS). METHODS: This retrospective study included 37 patients with a histopathological diagnosis of HNSCCs between 2015 and 2018. In patients with HNSCC, the first 18F-FDG PET/CT imaging was performed for pre-treatment staging, and the second imaging was performed to evaluate post-treatment response. In these imaging studies, SUVmax values of the primary tumor before and after treatment were determined. After the second imaging, patients were re-evaluated and followed up. ROC analysis was used to determine the predictive value of 18F-FDG PET/CT SUVmax parameters in terms of death and progression, and Cox regression analysis was used to investigate the prognostic value in terms of OS and PFS. RESULTS: Cut-off value 15 for SUVmax1 (pre-treatment) had a significant predictive value for mortality (P = 0.02). Cut-off value 3.1 for SUVmax2 (post-treatment) had a significant predictive value for progression (P = 0.024). In univariate analysis, both SUVmax1 and SUVmax2 values were significant prognostic factors for OS (P = 0.047, P = 0.004). However, for PFS, only the SUVmax2 value was a significant prognostic factor (P = 0.001). CONCLUSION: SUVmax1 value of the primary tumor at diagnosis in HNSCC patients has a predictive value for mortality and a prognostic value for OS. However, the SUVmax2 value in the primary tumor after treatment is a predictive factor for progression and a prognostic factor for both OS and PFS.

CD28-CD57+ T cells from head and neck cancer patients produce high levels of cytotoxic granules and type II interferon but are not senescent.

T lymphocytes expressing CD57 and lacking costimulatory receptors CD27/CD28 have been reported to accumulate with aging, chronic infection, and cancer. These cells are described as senescent, with inability to proliferate but enhanced cytolytic and cytokine-producing capacity. However, robust functional studies on these cells taken directly from cancer patients are lacking. We isolated these T cells and their CD27/28+ counterparts from blood and tumor samples of 50 patients with previously untreated head and neck cancer. Functional studies confirmed that these cells have enhanced ability to degranulate and produce IFN-γ. They also retain the ability to proliferate, thus are not senescent. These data suggest that CD27/28-CD57+ CD8+ T cells are a subset of highly differentiated, CD45RA+ effector memory (TEMRA) cells with retained proliferative capacity. Patients with > 34% of these cells among CD8+ T cells in the blood had a higher rate of locoregional disease relapse, suggesting these cells may have prognostic significance.

[A rapidly enlarging neck mass]. / Een snelgroeiende zwelling in de hals.

The differential diagnosis of a rapidly enlarging neck mass consists of many different benign ((haemorrhagic) cyst) and malignant (anaplastic thyroid cancer (ATC) and lymphoma) causes. ATC is a rare disease with a median survival of 6 months. As early diagnosis and management are key for fast-growing cancers, in our centre we have implemented a dedicated short-stay in-hospital fast-track diagnostic work-up for patients with a rapid growing mass in the neck. The goal of this track is to have a fast diagnostic and therapeutic plan for this disease. Based on three clinical cases we discuss our experience with this fast-track diagnostic work-up for rapidly growing mass in the neck and illustrate the additional value in this clinical entity.

Standardised definitions and diagnostic criteria for extranodal extension detected on histopathological examination in head and neck cancer: Head and Neck Cancer International Group consensus recommendations.

Detection of extranodal extension on histopathology in surgically treated head and neck squamous cell carcinoma indicates poor prognosis. However, there is no consensus on the diagnostic criteria, interpretation, and reporting of histology detected extranodal extension, which has contributed to conflicting evidence in the literature, and likely clinical inconsistency. The Head and Neck Cancer International Group conducted a three-round modified Delphi process with a group of 19 international pathology experts representing 15 national clinical research groups to generate consensus recommendations for histology detected extranodal extension diagnostic criteria. The expert panel strongly agreed on terminology and diagnostic features for histology detected extranodal extension and soft tissue metastasis. Moreover, the panel reached consensus on reporting of histology detected extranodal extension and on nodal sampling. These consensus recommendations, endorsed by 19 organisations representing 34 countries, are a crucial development towards standardised diagnosis and reporting of histology detected extranodal extension, and more accurate data collection and analysis.

Criteria for the diagnosis of extranodal extension detected on radiological imaging in head and neck cancer: Head and Neck Cancer International Group consensus recommendations.

Extranodal extension of tumour on histopathology is known to be a negative prognostic factor in head and neck cancer. Compelling evidence suggests that extranodal extension detected on radiological imaging is also a negative prognostic factor. Furthermore, if imaging detected extranodal extension could be identified reliably before the start of treatment, it could be used to guide treatment selection, as patients might be better managed with non-surgical approaches to avoid the toxicity and cost of trimodality therapy (surgery, chemotherapy, and radiotherapy together). There are many aspects of imaging detected extranodal extension that remain unresolved or are without consensus, such as the criteria to best diagnose them and the associated terminology. The Head and Neck Cancer International Group conducted a five-round modified Delphi process with a group of 18 international radiology experts, representing 14 national clinical research groups. We generated consensus recommendations on the terminology and diagnostic criteria for imaging detected extranodal extension to harmonise clinical practice and research. These recommendations have been endorsed by 19 national and international organisations, representing 34 countries. We propose a new classification system to aid diagnosis, which was supported by most of the participating experts over existing systems, and which will require validation in the future. Additionally, we have created an online educational resource for grading imaging detected extranodal extensions.

Assessment of endpoint definitions in curative-intent trials for mucosal head and neck squamous cell carcinomas: Head and Neck Cancer International Group consensus recommendations.

Robust time-to-event endpoint definitions are crucial for the assessment of treatment effect and the clinical value of trial interventions. Here, the Head and Neck Cancer International Group investigated endpoint use in phase 3 trials and trials considered potentially practice-changing published between 2008 and 2021 in the curative-intent setting for patients with mucosal head and neck squamous cell carcinoma. Of the 92 trials reviewed, we show that all core components of endpoint reporting were heterogeneous, including definitions of common terms, such as overall survival and progression-free survival. Our report highlights the urgent need for harmonisation of fundamental components of clinical trial endpoints and the engagement of all stakeholders to ensure the transparent reporting of endpoint details.

Assessment of endpoint definitions in recurrent and metastatic mucosal head and neck squamous cell carcinoma trials: Head and Neck Cancer International Group consensus recommendations.

Transparent and precise endpoint definitions are a crucial aspect of clinical trial conduct and reporting, and are used to communicate the benefit of an intervention. Previous studies have identified inconsistencies in endpoint definitions across oncological clinical trials. Here, the Head and Neck Cancer International Group assessed endpoint definitions from phase 3 trials or trials considered practice-changing for patients with recurrent or metastatic mucosal head and neck squamous cell carcinoma, published between 2008 and 2021. We identify considerable and global heterogeneity in endpoint definitions, which undermines the interpretation of results and development of future studies. We show how fundamental components of even incontrovertible endpoints such as overall survival vary widely, highlighting an urgent need for increased rigour in reporting and harmonisation of endpoints.

Paclitaxel-Ifosfamide-based Therapy as Salvage Treatment in Platinum-resistant Recurrent/Metastatic Head and Neck Cancer.

BACKGROUND: Treatment options are limited, and the prognosis is poor for patients with platinum-resistant recurrent metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). This study evaluated the efficacy and safety of a paclitaxel and ifosfamide (TI) regimen in patients with R/M HNSCC whose disease had progressed following platinum-based therapy. PATIENTS AND METHODS: In this retrospective study, we included 53 patients with R/M HNSCC who underwent at least one cycle of TI-based therapy, post platinum failure, between February 2020 and August 2023. Some patients received the TI regimen in combination with immunotherapy and/or cetuximab. Key metrics assessed included the objective response rate (ORR), disease control rate, and progression-free as well as overall survival. RESULTS: The study observed an ORR of 15.8% and a disease control rate of 36.8%. The median progression-free survival for the entire cohort was 3.3 months, and the median overall survival was 9.6 months. Notably, the combination of TI with immunotherapy yielded a higher ORR of 30.8%, compared to 14.3% with TI alone. The most prevalent grade 1-2 adverse events were anemia (81%), weight loss (68%) and hypernatremia (55%). CONCLUSION: The TI-based regimen demonstrated favorable efficacy and safety profile in treating R/M HNSCC. Enhanced outcomes may be attainable when combining it with immunotherapy. This study suggests that TI-based therapy could serve as a potential salvage option for this specific patient group.