Improved ex vivo fluorescence imaging of human head and neck cancer using the peptide tracer TPP-IRDye800 targeting membrane-bound Hsp70 on tumor cells.

BACKGROUND: The primary goal of surgery in HNSCC is the complete resection of tumor cells with maximum preservation of normal tissue. The membrane Hsp70-targeting fluorescence labelled peptide TPP-IRDye800 represents a promising tool for real-time intraoperative tumor visualization, enabling the detection of true tumor margins, critical isles of high-grade dysplasia and LN metastases. METHODS: Membrane Hsp70 (mHsp70) expression on HNSCC cell lines and primary HNSCC was determined by flow cytometry and fluorescence microscopy using FITC-conjugated mAb cmHsp70.1 and TPP. TPP-IRDye800 was sprayed on freshly resected tumor material of immunohistochemically confirmed HNSCC and LN metastases for tumor imaging. TBRs were compared using TPP-IRDye800 and Cetuximab-IRDye680, recognizing EGFR. RESULTS: mHsp70 expressing HNSCC cells specifically bind and internalize TPP in vitro. The TBR (2.56 ± 0.39) and AUC [0.98 CI, 0.95-1.00 vs. 0.91 CI, 0.85-0.97] of TPP-IRDye800 on primary HNSCC was significantly higher than Cetuximab-IRDye680 (1.61 ± 0.39) (p = 0.0068) and TPP-IRDye800 provided a superior tumor delineation. Fluorescence imaging showed higher AUC values than a visual inspection by surgeons [0.97 CI, 0.94-1.00 vs. 0.92 CI, 0.88-0.97] (p = 0.048). LN metastases could be visualized using TPP-IRDye800. Real-time tissue delineation was confirmed using the clinically applied KARL-STORZ imaging system. CONCLUSION: TPP-IRDye800 is a promising fluorescence imaging probe for HNSCC.

In Vivo Endothelial Cell Gene Silencing by siRNA-LNPs Tuned with Lipoamino Bundle Chemical and Ligand Targeting.

Although small-interfering RNAs (siRNAs) are specific silencers for numerous disease-related genes, their clinical applications still require safe and effective means of delivery into target cells. Highly efficient lipid nanoparticles (LNPs) are developed for siRNA delivery, showcasing the advantages of novel pH-responsive lipoamino xenopeptide (XP) carriers. These sequence-defined XPs are assembled by branched lysine linkages between cationizable polar succinoyl tetraethylene pentamine (Stp) units and apolar lipoamino fatty acids (LAFs) at various ratios into bundle or U-shape topologies. Formulation of siRNA-LNPs using LAF4-Stp1 XPs as ionizable compounds led to robust cellular uptake, high endosomal escape, and successful in vitro gene silencing activity at an extremely low (150 picogram) siRNA dose. Of significance is the functional in vivo endothelium tropism of siRNA-LNPs with bundle LAF4-Stp1 XP after intravenous injection into mice, demonstrated by superior knockdown of liver sinusoidal endothelial cell (LSEC)-derived factor VIII (FVIII) and moderate silencing of hepatocyte-derived FVII compared to DLin-MC3-DMA-based LNPs. Optimizing lipid composition following click-modification of siRNA-LNPs with ligand c(RGDfK) efficiently silenced vascular endothelial growth factor receptor-2 (VEGFR-2) in tumor endothelial cells (TECs). The findings shed light on the role of ionizable XPs in the LNP in vivo cell-type functional targeting, laying the groundwork for future therapeutic applications.

Isothiocyanates in medicine: A comprehensive review on phenylethyl-, allyl-, and benzyl-isothiocyanates.

In recent years, isothiocyanates (ITCs), bioactive compounds primarily derived from Brassicaceae vegetables and herbs, have gained significant attention within the biomedical field due to their versatile biological effects. This comprehensive review provides an in-depth exploration of the therapeutic potential and individual biological mechanisms of the three specific ITCs phenylethyl isothiocyanate (PEITC), allyl isothiocyanate (AITC), and benzyl isothiocyanate (BITC), as well as their collective impact within the formulation of ANGOCIN® Anti-Infekt N (Angocin). Angocin comprises horseradish root (Armoracia rusticanae radix, 80 mg) and nasturtium (Tropaeoli majoris herba, 200 mg) and is authorized for treating inflammatory diseases affecting the respiratory and urinary tract. The antimicrobial efficacy of this substance has been confirmed both in vitro and in various clinical trials, with its primary effectiveness attributed to ITCs. PEITC, AITC, and BITC exhibit a wide array of health benefits, including potent anti-inflammatory, antioxidant, and antimicrobial properties, along with noteworthy anticancer potentials. Moreover, we highlight their ability to modulate critical biochemical pathways, such as the nuclear factor erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and signal transducer and activator of transcription (STAT) pathways, shedding light on their involvement in cellular apoptosis and their intricate role to guide immune responses.

Integrated Molecular and Histological Insights for Targeted Therapies in Mesenchymal Sinonasal Tract Tumors.

PURPOSE OF REVIEW: This review aims to provide a comprehensive overview of mesenchymal sinonasal tract tumors (STTs), a distinct subset of STTs. Despite their rarity, mesenchymal STTs represent a unique clinical challenge, characterized by their rarity, often slow progression, and frequently subtle or overlooked symptoms. The complex anatomy of the sinonasal area, which includes critical structures such as the orbit, brain, and cranial nerves, further complicates surgical treatment options. This underscores an urgent need for more advanced and specialized therapeutic approaches. RECENT FINDINGS: Advancements in molecular diagnostics, particularly in next-generation sequencing, have significantly enhanced our understanding of STTs. Consequently, the World Health Organization has updated its tumor classification to better reflect the distinct histological and molecular profiles of these tumors, as well as to categorize mesenchymal STTs with greater accuracy. The growing understanding of the molecular characteristics of mesenchymal STTs opens new possibilities for targeted therapeutic interventions, marking a significant shift in treatment paradigms. This review article concentrates on mesenchymal STTs, specifically addressing sinonasal tract angiofibroma, sinonasal glomangiopericytoma, biphenotypic sinonasal sarcoma, and skull base chordoma. These entities are marked by unique histopathological and molecular features, which challenge conventional treatment approaches and simultaneously open avenues for novel targeted therapies. Our discussion is geared towards delineating the molecular underpinnings of mesenchymal STTs, with the objective of enhancing therapeutic strategies and addressing the existing shortcomings in the management of these intricate tumors.

Assessing the use of the novel tool Claude 3 in comparison to ChatGPT 4.0 as an artificial intelligence tool in the diagnosis and therapy of primary head and neck cancer cases.

OBJECTIVES: Head and neck squamous cell carcinoma (HNSCC) is a complex malignancy that requires a multidisciplinary tumor board approach for individual treatment planning. In recent years, artificial intelligence tools have emerged to assist healthcare professionals in making informed treatment decisions. This study investigates the application of the newly published LLM Claude 3 Opus compared to the currently most advanced LLM ChatGPT 4.0 for the diagnosis and therapy planning of primary HNSCC. The results were compared to that of a conventional multidisciplinary tumor board; (2) Materials and Methods: We conducted a study in March 2024 on 50 consecutive primary head and neck cancer cases. The diagnostics and MDT recommendations were compared to the Claude 3 Opus and ChatGPT 4.0 recommendations for each patient and rated by two independent reviewers for the following parameters: clinical recommendation, explanation, and summarization in addition to the Artificial Intelligence Performance Instrument (AIPI); (3) Results: In this study, Claude 3 achieved better scores for the diagnostic workup of patients than ChatGPT 4.0 and provided treatment recommendations involving surgery, chemotherapy, and radiation therapy. In terms of clinical recommendations, explanation and summarization Claude 3 scored similar to ChatGPT 4.0, listing treatment recommendations which were congruent with the MDT, but failed to cite the source of the information; (4) Conclusion: This study is the first analysis of Claude 3 for primary head and neck cancer cases and demonstrates a superior performance in the diagnosis of HNSCC than ChatGPT 4.0 and similar results for therapy recommendations. This marks the advent of a newly launched advanced AI model that may be superior to ChatGPT 4.0 for the assessment of primary head and neck cancer cases and may assist in the clinical diagnostic and MDT setting.

[Acceptance of digital apps in the follow-up of patients with head and neck tumors]. / Akzeptanz digitaler Apps in der Nachsorge von Patient*innen mit Kopf-Hals-Tumoren.

BACKGROUND: Patient-reported outcome (PRO) measures lead to improved quality of life in cancer patients and possibly to earlier detection of tumor recurrence. OBJECTIVE: Patient interest in complementing tumor follow-up care with apps for recording PROs was assessed using a questionnaire. MATERIALS AND METHODS: An independently created questionnaire to record the interest of tumor patients in a digitalized form of tumor follow-up care was evaluated (n = 110). RESULTS: In the study, the majority of tumor patients were interested in using an app for tumor disease. Taking age into account, the number increased even further for patients < 60 years of age, as expected. In line with this, human papillomavirus (HPV)-positive patients showed significantly greater interest (p = 0.021). CONCLUSION: The introduction of an app is supported by the majority of tumor patients. In addition to recording PROs, other applications (appointment reminders, patient files, sports/nutrition programs) could also be integrated.

Tumour budding-based grading as independent prognostic biomarker in HPV-positive and HPV-negative head and neck cancer.

BACKGROUND: The prognostic significance of tumour budding (TB) and minimal cell nest size (MCNS) was shown in human papillomavirus (HPV)-negative head and neck squamous cell carcinomas (HNSCC). However, the optimisation of cutpoints, the prognostic impact in HPV-positive HNSCC, and the comparison with other histopathological grading systems are insufficiently investigated. METHODS: TB and MCNS were analysed digitally in 1 and 10 high-power fields (HPF) of 331 HPV-positive and HPV-negative cases from TCGA. Optimising the cutpoints a new cellular dissociation grading (CDG) system was defined and compared to the WHO grading and the Brandwein-Gensler (BG) risk model. RESULTS: The two-tiered CDG system based solely on TB yielded optimal prognostic stratification with shortened overall survival for CDG-high cases. Optimal cut-offs were two buds (1 HPF) and six buds (10 HPF), respectively. Analysing MCNS did not add prognostic significance to quantifying TB. CDG was a significant prognostic marker in HPV-negative and HPV-positive tumours and prognostically superior to the WHO and BG systems. High CDG was associated with clinically occult lymph-node metastases. CONCLUSIONS: The most comprehensive study of TB in HNSCC so far confirmed its prognostic impact in HPV-negative tumours and for the first time in HPV-positive tumours. Further studies are warranted to evaluate its applicability for therapy guidance in HNSCC.

Comparison of PD-L1 expression in squamous cell cancer of unknown primary and oropharyngeal squamous cell carcinoma.

PURPOSE: The tumorigenesis of squamous cell cancer of unknown primary (SCCUP) in the head and neck area has not been decoded so far, while poor survival rates and limited therapeutic options pose a serious challenge. The aim of this project was to investigate immunological characteristics of SCCUPs and compare them to oropharyngeal squamous cell carcinoma (OPSCC). METHODS: PD-L1 expression (TC) was examined by immunohistochemistry in 50 lymph node metastases of SCCUP and 47 primaries of OPSCC. CD3 + and CD8 + lymphocytic infiltration was measured in 5 high power fields. Expression of p16 and HPV ISH were assessed. RESULTS: SCCUP demonstrated a significantly higher expression of PD-L1 than OPSCC. In p16-negative SCCUPs PD-L1 proved to be an independent prognostic factor to prioritize high-risk patients. CONCLUSIONS: Immunologic differences between SCCUP and OPSCC were detected. A higher PD-L1 expression in SCCUP could potentially facilitate further evaluation of checkpoint inhibitor therapy.

ChatGPT's quiz skills in different otolaryngology subspecialties: an analysis of 2576 single-choice and multiple-choice board certification preparation questions.

PURPOSE: With the increasing adoption of artificial intelligence (AI) in various domains, including healthcare, there is growing acceptance and interest in consulting AI models to provide medical information and advice. This study aimed to evaluate the accuracy of ChatGPT's responses to practice quiz questions designed for otolaryngology board certification and decipher potential performance disparities across different otolaryngology subspecialties. METHODS: A dataset covering 15 otolaryngology subspecialties was collected from an online learning platform funded by the German Society of Oto-Rhino-Laryngology, Head and Neck Surgery, designed for board certification examination preparation. These questions were entered into ChatGPT, with its responses being analyzed for accuracy and variance in performance. RESULTS: The dataset included 2576 questions (479 multiple-choice and 2097 single-choice), of which 57% (n = 1475) were answered correctly by ChatGPT. An in-depth analysis of question style revealed that single-choice questions were associated with a significantly higher rate (p < 0.001) of correct responses (n = 1313; 63%) compared to multiple-choice questions (n = 162; 34%). Stratified by question categories, ChatGPT yielded the highest rate of correct responses (n = 151; 72%) in the field of allergology, whereas 7 out of 10 questions (n = 65; 71%) on legal otolaryngology aspects were answered incorrectly. CONCLUSION: The study reveals ChatGPT's potential as a supplementary tool for otolaryngology board certification preparation. However, its propensity for errors in certain otolaryngology areas calls for further refinement. Future research should address these limitations to improve ChatGPT's educational use. An approach, with expert collaboration, is recommended for the reliable and accurate integration of such AI models.

[Laryngeal-preservation surgery in laryngeal cancer]. / Kehlkopferhaltende Operationen bei Larynxkarzinomen.

After oral cavity and pharyngeal cancer, laryngeal cancer is the third most common malignant tumor in the head and neck region. According to the current German S3 guideline on the diagnosis, treatment, and follow-up of laryngeal cancer, larynx-preserving surgical interventions are part of the standard treatment of this disease, even in advanced tumor stages. However, in order to achieve the desired function-preserving effect, an exact indication is of crucial importance. In this article, the most important larynx-preserving interventions and their indications but also the respective contraindications are presented, with the aim of illuminating the surgical treatment options up to just before total laryngectomy.

Tirofiban potentiates agonist-induced platelet activation and degranulation, despite effectively inhibiting aggregation.

We aimed to investigate the effects of integrin αIIbß3 inhibitor tirofiban on hallmarks of platelet activation, degranulation, and aggregation during its use to analyze activated but non-complexed platelets via flow cytometry. To do so, we used washed platelets from healthy human donors. We combined aggregometry, an assay of platelet functionality, with flow cytometry and ELISA to detect and correlate, respectively, platelet aggregation, activation, and granule release. While tirofiban effectively inhibited agonist-induced platelet aggregation (thrombin receptor-activating peptide 6 (TRAP), convulxin (CVX), U46619 and IV.3), the surface expression of P-selectin and CD63 and granule release of RANTES were significantly increased, indicating that tirofiban enhances degranulation, uncoupled from aggregation. The results show that tirofiban alters the activation phenotype of platelets, something that should be considered when using tirofiban to enable flow cytometric analysis of activated but unaggregated platelet suspensions.

The role of psycho-oncologic screenings in the detection and evaluation of depression in head and neck cancer aftercare patients.

PURPOSE: Cancer and morbidity during a therapeutic regimen can result in somatic and psychiatric impairment. We have evaluated the need of appropriate psychological screening by analyzing a large collective of head and neck cancer (HNC) patients with particularly burdensome symptoms. METHODS: HNC-aftercare patients were asked about somatic and psychological symptoms by means of standardized questionnaires of the European Organization for Research and Treatment of Cancer (EORTC Q30 and QLQ-H&N35). Patients with poor well-being values on the World Health Organization-5-Well-Being Index were screened for depression by using the Mini International Neuropsychiatric Interview, and adequate treatment was initiated, if necessary. RESULTS: Our sample consisted of 453 HNC-aftercare patients (average age 64.5 years; 72.0% male; 28.0% female). 25.1% showed abnormalities based on their WHO-5 questionnaire. A current major depressive episode was observed in 8.5% of the total study group. Patients with lip and oral cavity tumors showed the highest depression prevalence (18.9%). Time since initial HNC diagnosis showed no clear trend with regard to the number of depression cases. 50.0% of patients with a current major depressive episode consented to receiving assistance and/or therapy. Within the total study population, the most burdensome symptoms were found to be "dry mouth" (48.3%), "trouble doing strenuous activities" (46.0%), "trouble taking a long walk" (38.5%), and "worry" (35.5%). Aftercare patients with a depression diagnosis tended to have heavier symptom burdens than people without major depression. CONCLUSIONS: Despite the various cancer-related burdensome factors, prevalence levels of depression among the HNC-aftercare patients and the general population were similar. Nevertheless, since the number of diagnosed depression cases is high, the need for psychological treatment should be considered within the tumor collective. Furthermore, screening for depression should be implemented in clinical routines by using the appropriate standardized questionnaires.

Time-encoded stimulated Raman scattering microscopy of tumorous human pharynx tissue in the fingerprint region from 1500-1800 cm-1.

Stimulated Raman scattering (SRS) microscopy for biomedical analysis can provide a molecular localization map to infer pathological tissue changes. Compared to spontaneous Raman, SRS achieves much faster imaging speeds at reduced spectral coverage. By targeting spectral features in the information dense fingerprint region, SRS allows fast and reliable imaging. We present time-encoded (TICO) SRS microscopy of unstained head-and-neck biopsies in the fingerprint region with molecular contrast. We combine a Fourier-domain mode-locked (FDML) laser with a master oscillator power amplifier (MOPA) to cover Raman transitions from 1500-1800cm-1. Both lasers are fiber-based and electronically programmable making this fingerprint TICO system robust and reliable. The results of our TICO approach were cross-checked with a spontaneous Raman micro-spectrometer and show good agreement, paving the way toward clinical applications.

Management of patients with chronic rhinosinusitis during the COVID-19 pandemic-An EAACI position paper.

BACKGROUND: Chronic rhinosinusitis is regarded as a chronic airway disease. According to WHO recommendations, it may be a risk factor for COVID-19 patients. In most CRSwNP cases, the inflammatory changes affecting the nasal and paranasal mucous membranes are type-2 (T2) inflammation endotypes. METHODS: The current knowledge on COVID-19 and on treatment options for CRS was analyzed by a literature search in Medline, Pubmed, international guidelines, the Cochrane Library and the Internet. RESULTS: Based on international literature, on current recommendations by WHO and other international organizations as well as on previous experience, a panel of experts from EAACI and ARIA provided recommendations for the treatment of CRS during the COVID-19 pandemic. CONCLUSION: Intranasal corticosteroids remain the standard treatment for CRS in patients with SARS-CoV-2 infection. Surgical treatments should be reduced to a minimum and surgery preserved for patients with local complications and for those with no other treatment options. Systemic corticosteroids should be avoided. Treatment with biologics can be continued with careful monitoring in noninfected patients and should be temporarily interrupted during the course of the COVID-19 infection.

Measurement of leukocyte-platelet aggregates (LPA) by FACS: a comparative analysis.

In addition to their role in hemostasis and coagulation platelets bear critical roles in modulation of the innate and adaptive immune system. Upon platelet activation in response to tissue injury, bacterial or viral infections, they secrete many soluble factors or directly interact with leukocytes. An increase of leukocyte-platelet aggregates (LPA) has been described for many pathological conditions. Nevertheless, a standardized method for the reliable measurement of PLAs is not securely established. This methodical study provides a comparison of four different protocols from the literature and summarizes major pitfalls of measuring and interpreting leukocyte-platelet aggregates. The different techniques vary in the workup of the blood samples, applying variable washing and centrifugation steps or the use of erythrocyte lysis. All samples were finally analyzed by flow cytometry. Leukocyte subsets were stained with specific antibodies and platelet aggregates were identified by additional expression of CD41. The different procedures generated very heterogeneous data from the same blood sample which highlight the abundance of error measuring LPA. The most reproducible technique turned out to be a two-color whole blood flow cytometry assay with erythrocyte lysis and without washing or centrifugation steps avoiding platelet activation and artificial aggregate formation to achieve data mirroring the true situation in peripheral blood.

Optically Controlled Drug Release from Light-Sensitive Liposomes with the New Photosensitizer 5,10-DiOH.

The delivery of therapeutic drugs to a specific cellular site is a challenge in the treatment of different diseases. Liposomes have been widely studied as vehicles for drug delivery, and recent research begins to show the potential of the light-controlled opening of liposomes. Liposomes with photoactive molecules can release their cargo upon light irradiation for localized drug release. Light as an external trigger can be controlled temporally and spatially with high precision. In this study, we investigate the potential of light-sensitive liposomes with four photosensitizers and two lipid formulations for light-induced release. To investigate the permeabilization of the liposomes, calcein was encapsulated in high concentration inside the liposomes so that the calcein fluorescence is quenched. If calcein is released from the liposome, quenching is avoided, and the fluorescence increases. We demonstrated that liposomes with the sensitizers benzoporphyrine derivative monoacid (BPD), chlorine e6 (Ce6), Al(III) phthalocyanine chloride disulfonic acid (AlPcS2), and 5,10-di-(4-hydroxyphenyl)-15,20-diphenyl-21,23H-porphyrin (5,10-DiOH) release cargo effectively after irradiation. Liposomes with 5,10-DiOH showed a quicker release compared to the other sensitizers upon irradiation at 420 nm. Further, we observed through fractionated irradiation, that most of the release took place during light application, while the permeability of the liposome decreased shortly after light exposure. This effect was stronger with liposomes containing less cholesterol.

The vibrating ossicular prosthesis in children and adolescents: a retrospective study.

PURPOSE: The primary objective of the retrospective study was to collect speech intelligibility data on children and adolescents implanted with the vibrating ossicular prosthesis (VORP) 503. METHODS: This was a retrospective, multicentre study on 55 children and adolescents from 6 German clinics aged between 5 and 17 years suffering from mixed or conductive hearing loss implanted with a VORP 503. Pre- and postoperative bone-conduction pure tone thresholds were measured at 0.5, 1, 2 and 4 kHz, and word recognition scores in the unaided and VORP 503-aided conditions using monosyllabic speech intelligibility tests measured at 65-dB sound pressure level (SPL) were determined. RESULTS: Mean pre- and postoperative bone-conduction thresholds remained unchanged, showing the preservation of inner ear hearing. Speech intelligibility assessed in quiet at 65-dB SPL improved on average from 24.5% (SD ± 25.4) unaided to 86.4% (SD ± 13.4) aided. The average improvement of 61.9% (SD ± 25.3) was clinically and statistically significant. A total of three complications were found in the medical records of 55 subjects. The responsible investigators judged these events as procedure related. CONCLUSION: The treatment of children suffering from conductive or mixed hearing loss with the VORP 503 implant demonstrates excellent aided benefit in terms of speech understanding and only minor complications.

Platelet Induced Functional Alteration of CD4+ and CD8+ T Cells in HNSCC.

Platelets (PLT) are the second most abundant cell type in human blood and exert various immune-regulatory functions under both physiological and pathological conditions. In fact, immune cell regulation via platelets has been demonstrated in several studies within the past decade. However, the exact mechanisms behind T cell regulation remain poorly understood. We questioned whether the formation of aggregates of platelets and T cells has an impact on T-cell functions. In the present study, we stimulated PBMC cultures with anti-CD3 and anti-CD28 mABs and cultured them at a PLT: PBMC ratio of 1:1 or 100:1. After 24, 48, and 72 h, PD-1, PD-L1 expression, and proliferation were analyzed on T cells using flow cytometry. Cytokine production was measured in PHA stimulated CD4 cells after 6 h. We found a significant platelet-mediated decrease in PD-1 and PD-L1 expression, proliferation, as well as IFN-γ and TNF-α production. Perturbations also at least partially remained after spatial separation of PLTs from PBMCs in Transwell-assays. T cell-platelet aggregates showed similar levels of activation markers, proliferation, and secreted cytokines as their non-complexed counterparts. Results indicate a platelet mediated regulation of T cells via direct and indirect contact, but only mediocre effects of the complex formation itself.

EVI1 as a Marker for Lymph Node Metastasis in HNSCC.

BACKGROUND: HNSCC is the sixth most common cancer in humans and has still a very poor prognosis. The treatment methods so far are very often associated with mutilation and impairment in the quality of life. Except for p16 expression, there are no reliable prognostic markers in HNSCC so far. Ecotropic Viral Integration Site 1 (EVI1) is a well-described prognostic marker in leukemia and different types of solid cancers. In these, a high EVI1 expression is associated with a poor prognosis. In HNSCC, it is not known so far if EVI1 has any prognostic relevance. MATERIALS AND METHODS: We used our representative tissue cohort of 389 primary HNSCCs, of which 57.2% had one or more lymph node metastases. Here EVI1 expression was analyzed via immunohistochemistry and correlated with the clinical characteristics of these patients. RESULTS: Although in HNSCC EVI1 expression does not predict poor survival, a high EVI1 expression in the primary tumor correlates with a lymph node metastatic disease. CONCLUSION: Consequently, EVI1 may serve as a biomarker to predict an occult lymph node metastasis in a clinical nodal negative (cN0) HNSCC.

CDK19 as a Potential HPV-Independent Biomarker for Recurrent Disease in HNSCC.

The Mediator complex is a central integrator of transcription and a hub for the regulation of gene expression. Cyclin dependent kinase (CDK) 19 and its paralog CDK8 are part of its kinase domain and contribute to cancer progression in different cancer entities. STAT1 is an important immune modulator and a downstream substrate of CDK8/CDK19 mediated phosphorylation. So far, little is known about CDK19's role in head and neck squamous cell carcinoma (HNSCC) progression, its link to STAT1 activity, and related immune modulation. Immunohistochemistry for CDK19, activated pSTAT1, and PD-L1, known to be affected by STAT1, was conducted on samples of 130 primary tumors, 71 local recurrences, 32 lymph node metastases, and 25 distant metastases of HNSCC. Compared to primary tumors, CDK19 is overexpressed in local recurrences and distant metastases as well as in primary tumors that developed local recurrence after initial therapy. Patients with high-CDK19-expressing primary tumors have a significantly shorter disease-free survival. CDK19 expression correlates with pSTAT1 expression in primary tumors associated with recurrent disease, local recurrent tumors, lymph node metastases, and distant metastases. pSTAT1 expression correlates with PD-L1 expression in recurrent tumors. Our findings identify CDK19 as a potential biomarker in HNSCC to predict recurrent disease and support recent developments to target CDK19 and its paralog CDK8 in advanced cancer.