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BackgroundRecurrent and metastatic head and neck squamous cell carcinoma (HNSCC) is characterized by a complex therapeutic management that needs to be discussed in multidisciplinary tumor boards (MDT). While artificial intelligence (AI) improved significantly to assist healthcare professionals in making informed treatment decisions for primary cases, an application in the even more complex recurrent/metastatic setting has not been evaluated yet. This study also represents the first evaluation of the recently published LLM ChatGPT 4o, compared to ChatGPT 4.0 for providing therapy recommendations.MethodsThe therapy recommendations for 100 HNSCC cases generated by each LLM, 50 cases of recurrence and 50 cases of distant metastasis were evaluated by two independent reviewers. The primary outcome measured was the quality of the therapy recommendations measured by the following parameters: clinical recommendation, explanation, and summarization.ResultsIn this study, ChatGPT 4o and 4.0 provided mostly general answers for surgery, palliative care, or systemic therapy. ChatGPT 4o proved to be 48.5% faster than ChatGPT 4.0. For clinical recommendation, explanation, and summarization both LLMs obtained high scores in terms of performance of therapy recommendations, with no significant differences between both LLMs, but demonstrated to be mostly an assisting tool, requiring validation by an experienced clinician due to a lack of transparency and sometimes recommending treatment modalities that are not part of the current treatment guidelines.ConclusionThis research demonstrates that ChatGPT 4o and 4.0 share a similar performance, while ChatGPT 4o is significantly faster. Since the current versions cannot tailor therapy recommendations, and sometimes recommend incorrect treatment options and lack information on the source material, advanced AI models at the moment can merely assist in the MDT setting for recurrent/metastatic HNSCC.

Abstract Background The unknown tissue of origin in head and neck cancer of unknown primary (hnCUP) leads to invasive diagnostic procedures and unspecific and potentially inefficient treatment options for patients. The most common histologic subtype, squamous cell carcinoma, can stem from various tumor primary sites, including the oral cavity, oropharynx, larynx, head and neck skin, lungs, and esophagus. DNA methylation profiles are highly tissue-specific and have been successfully used to classify tissue origin. We therefore developed a support vector machine (SVM) classifier trained with publicly available DNA methylation profiles of commonly cervically metastasizing squamous cell carcinomas (n = 1103) in order to identify the primary tissue of origin of our own cohort of squamous cell hnCUP patient’s samples (n = 28). Methylation analysis was performed with Infinium MethylationEPIC v1.0 BeadChip by Illumina. Results The SVM algorithm achieved the highest overall accuracy of tested classifiers, with 87%. Squamous cell hnCUP samples on DNA methylation level resembled squamous cell carcinomas commonly metastasizing into cervical lymph nodes. The most frequently predicted cancer localization was the oral cavity in 11 cases (39%), followed by the oropharynx and larynx (both 7, 25%), skin (2, 7%), and esophagus (1, 4%). These frequencies concord with the expected distribution of lymph node metastases in epidemiological studies. Conclusions On DNA methylation level, hnCUP is comparable to primary tumor tissue cancer types that commonly metastasize to cervical lymph nodes. Our SVM-based classifier can accurately predict these cancers’ tissues of origin and could significantly reduce the invasiveness of hnCUP diagnostics and enable a more precise therapy after clinical validation.

BackgroundHead and neck squamous cell carcinoma (HNSCC) is a complex malignancy that requires a multidisciplinary approach in clinical practice, especially in tumor board discussions. In recent years, artificial intelligence has emerged as a tool to assist healthcare professionals in making informed decisions. This study investigates the application of ChatGPT 3.5 and ChatGPT 4.0, natural language processing models, in tumor board decision-making.MethodsWe conducted a pilot study in October 2023 on 20 consecutive head and neck cancer patients discussed in our multidisciplinary tumor board (MDT). Patients with a primary diagnosis of head and neck cancer were included. The MDT and ChatGPT 3.5 and ChatGPT 4.0 recommendations for each patient were compared by two independent reviewers and the number of therapy options, the clinical recommendation, the explanation and the summarization were graded.ResultsIn this study, ChatGPT 3.5 provided mostly general answers for surgery, chemotherapy, and radiation therapy. For clinical recommendation, explanation and summarization ChatGPT 3.5 and 4.0 scored well, but demonstrated to be mostly an assisting tool, suggesting significantly more therapy options than our MDT, while some of the recommended treatment modalities like primary immunotherapy are not part of the current treatment guidelines.ConclusionsThis research demonstrates that advanced AI models at the moment can merely assist in the MDT setting, since the current versions list common therapy options, but sometimes recommend incorrect treatment options and in the case of ChatGPT 3.5 lack information on the source material.

Abstract Background and Objectives Previous studies have shown an association between environmental exposure to heavy metals and hearing loss. However, the findings regarding the relationship between exposure to different metals and hearing loss development are inconsistent. To address this, we conducted a meta‐analysis to explore the link between common heavy metal exposures and hearing loss. This study examined the effects of lead (Pb), cadmium (Cd), and mercury (Hg) pollution on hearing loss at various levels, and systematically reviewed the literature on manganese (Mn), barium (Ba), arsenic (As), and hearing loss. Methods We conducted systematic searches in five major databases, including PubMed, Web of Science, Embase, Cochrane Library, and Scopus. In addition, we searched three Chinese digital libraries: CNKI, Wanfang Data, and Wipu. From an initial pool of 649 articles, we carefully screened and selected 15 articles for further analysis. The effect sizes from these selected studies were synthesized through a meta‐analysis to calculate the overall effect size. Results Our findings showed that: (1) There was a significant association between Pb and Cd exposure and hearing loss; (2) There is a proportional relationship between the increase of metal index detected in blood and hearing loss; (3) In the PTA measurement of hearing loss at different frequencies, the 4 kHz high frequency range had a stronger correlation with hearing loss than the low frequency, with OR 1.44 (1.22, 1.71); and (4) There was a more significant correlation between Barium (Ba) levels in nails and hair than in urine. Conclusions The study presented evidence of a significant association between human hearing loss and exposure to lead (Pb) and cadmium (Cd). It not only revealed a positive correlation between blood heavy metal concentrations and the incidence of hearing loss but also highlighted that long‐term exposure indicators of heavy metals were more indicative of the correlation with hearing loss. Lastly, the study recommends utilizing high frequency 4 kHz for the effective assessment and diagnosis of hearing loss caused by exposure to heavy metals.

Reliable preoperative diagnosis between salivary gland tumor entities is difficult. In this monocentric retrospective study, we examined the somatostatin receptor 2 (SSTR2) status of salivary gland tumors after salivary gland tumor resection via immunohistochemistry (IHC), and stains were compared in analogy to the HER2 mamma scale. A total of 42.3% of all pleomorphic adenoma (PA) tumors (42 of 99, 95% confidence interval 32.5–52.8%) demonstrated ≥20% of cells displaying the SSTR2 as compared to just 1% of all other tumors (1/160, 95% CI 0.02–3.4%). The other tumor was a neuroendocrine carcinoma. PA had a higher intensity of SSTR2 staining, with 90.9% staining ≥ an intensity of 2 (moderate). Tumors with an intensity of SSTR2 expression equal to or greater than 2 had an 89.9% likelihood of being a PA (95% CI: 82.2–95.0%, AUC: 0.928). Only one Warthin tumor demonstrated a ‘strong’ SSTR2 staining intensity. No Warthin tumor showed a percentage of cells staining for SSTR2 above ≥20%. This result demonstrates consistent and strong expression of SSTR2 in PAs as compared to Warthin tumors, which may allow physicians to utilize radioligand-somatostatin analog PET CT/MR imaging to diagnose the PA. SSTR2 positivity, if shown to be clinically relevant, may allow peptide receptor radionuclide therapy in the future.

Objective: The human gut microbiome is strongly influenced by the administration of drugs, namely antibiotics. We hypothesized that the effectiveness of immunotherapy with pembrolizumab in oral squamous cell carcinoma patients is decreased by the administration of antibiotics three months before and after immunotherapy. Methods: We retrieved data from patients diagnosed with head and neck squamous cell carcinoma (HNSCC) (International Classification of Diseases [ICD]-10 codes C00-C14) and receiving immunotherapy with pembrolizumab from the TriNetX network. Two cohorts were built: patients in cohort I did not receive any antibiotics within three months before or up to three months after immunotherapy, while patients in cohort II were administered antibiotics at least once within three months before or after immunotherapy. To exclude confounders, we matched cohorts 1:1 for age, sex, secondary lymph node metastases, nicotine dependence, the insertion of feeding devices, body mass index (BMI) and severe sepsis. After defining the primary outcome as “death”, a Kaplan–Meier analysis was performed, and the risk ratio (RR), odds ratio (OR) and hazard ratio (HR) were calculated. Results: A total of 3651 patients were enrolled, and after matching, each cohort consisted of 1362 patients. Among cohorts I and II, 346 and 511 patients were deceased within one year (risk of death = 25.5 and 38.3%, respectively), whereby the risk difference was significant (p = 0.000; log-rank test). The RR was 0.68 (95% confidence interval: 0.60–0.76), OR was 0.57 (0.48–0.67) and HR was 0.58 (0.51–0.67). Conclusions: Our hypothesis was confirmed: administering antibiotics significantly decreases the drug effectiveness of immunotherapy. We hypothesize that this finding is associated with antibiotic-related changes in the gut microbiome. Prospective clinical studies on the gut microbiome in cancer patients are necessary to understand the complex ecosystem of microbiota during immunotherapy. Trial Registration: Due to the retrospective nature of the study, no registration was necessary.

(1) Background: Currently, there is no clinically used liquid biomarker in head and neck squamous cell carcinoma (HNSCC) patients. One reason could be the limited shedding of tumor material in early disease stages. Molecular diagnostics assessing both blood and especially saliva could potentially improve the accuracy of biomarkers. In this prospective study, two markers, tissue inhibitor of metalloprotease-1 (TIMP-1) and heat shock protein 70 (Hsp70), were analyzed in HNSCC patients. The purpose of the study was to evaluate differences between saliva and serum as sample material. Further, their prognostic and predictive value and usefulness for early detection was assessed. (2) Methods: A total of 73 HNSCC patients were prospectively monitored by collecting blood and saliva before, during, and after therapy, as well as in the follow-up period between 2018 and 2021. In total, 212 serum and 194 saliva samples were collected. A control group consisting of 40 subjects (15 patients with local infections in the head and neck area and 25 without infections) were examined as well. The collected samples were evaluated for the two proteins by using an enzyme-linked immunosorbent assay (ELISA). (3) RESULTS: The TIMP-1 concentration correlated significantly in blood and saliva, whereas the Hsp70 concentration did not. Saliva TIMP-1 was significantly higher in tumor patients compared to the control group (p = 0.013). High pretreatment TIMP-1 saliva levels were associated with significantly poorer disease-free survival (DFS) (p = 0.02). A high saliva TIMP-1/Hsp70 ratio was significantly associated with poorer DFS (HR: 1.4; 95% CI: 1.04–1.88; p = 0.026) and a high TIMP-1 serum concentration was significantly associated with poorer PFS (HR: 1.9; 95% CI: 1.2, 2.8; p = 0.003) and poorer overall survival (OS) (HR: 2.9; 95% CI: 1.4, 5.9; p = 0.003) in the Cox proportional hazards model. The saliva TIMP-1 to Hsp70 ratio was significantly higher at the time of recurrence (p = 0.015). Conclusion: TIMP-1 in serum is a promising prognostic marker for HNSCC. Saliva TIMP-1 and the saliva TIMP-1 to Hsp70 ratio provides additional information on the disease-free survival.

(1) Background: NOTCH1 is the second most common mutated gene in whole-exome sequencing of HNSCC. The aim of this project was to gain further insight into the relevance of NOTCH1 in HNSCC, potentially establishing NOTCH1 as a prognostic marker or therapeutic target; (2) Methods: NOTCH1 was silenced via RNA interference in six HNSCC cell lines and the impact was evaluated in migration and proliferation assays. Subsequently, the protein expression of NOTCH1 intracellular domain (NICD) and NOTCH1 mRNA expression were examined in 70 oropharyngeal squamous cell cancer tissue samples. Lastly, the NICD expression was compared with the local infiltration of lymphocytes, measured with the immunoscore; (3) Results: Knockdown of NOTCH1 decreased migration and proliferation. A high NICD expression was associated with lower OS. A high immunoscore resulted in significantly better OS. NICD expression was independent of the immunoscore and as a whole differentiated three distinct prognostic groups; (4) Conclusions: These data suggest that NOTCH1 is involved in migration and proliferation of HNSCC cell lines. In vivo, NICD expression was associated with overall survival and could, therefore, be used as a prognostic marker. NICD expression differs from NOTCH1 mRNA levels, potentially explaining the previously suggested bimodal role as an oncogene and tumor suppressor in HNSCC.

Background: Tracheostomy is a common procedure in critical care. The aim of this study was to evaluate the application of a liposomal inhalation compared to standard physiologic saline (SPS) inhalation on basis of objective and subjective parameters of airway inflammation. Methods: We evaluated in this two-armed, double-blinded and randomized control group study the effect of liposomal compared with SPS inhalation in newly tracheotomized patients. The primary endpoint was defined as trend of tracheobronchial IL-6 secretion at day 1 compared to day 10. Further objective and subjective parameter were evaluated. Results: Fifty patients were randomized in each arm. Tracheal IL-6 levels decreased significantly only after liposomal inhalation. Both inhalative agents seem to have an effect on the respiratory impairment after tracheostomy. Subjective patient impairment was reduced significantly from day 1 to day 10 after tracheostomy with liposomal inhalation. Conclusions: Liposomal inhalation demonstrated an advantage over SPS inhalation in newly tracheotomized patients.

Maximizing performance success in sports is about continuous learning and adaptation processes. Aside from physiological, technical and emotional performance factors, previous research focused on perceptual skills, revealing their importance for decision-making. This includes deriving relevant environmental information as a result of eye, head and body movement interaction. However, to evaluate visual exploratory activity (VEA), generally utilized laboratory settings have restrictions that disregard the representativeness of assessment environments and/or decouple coherent cognitive and motor tasks. In vivo studies, however, are costly and hard to reproduce. Furthermore, the application of elaborate methods like eye tracking are cumbersome to implement and necessitate expert knowledge to interpret results correctly. In this paper, we introduce a virtual reality-based reproducible assessment method allowing the evaluation of VEA. To give insights into perceptual-cognitive processes, an easily interpretable head movement-based metric, quantifying VEA of athletes, is investigated. Our results align with comparable in vivo experiments and consequently extend them by showing the validity of the implemented approach as well as the use of virtual reality to determine characteristics among different skill levels. The findings imply that the developed method could provide accurate assessments while improving the control, validity and interpretability, which in turn informs future research and developments.

The clinical impact of the expression of NOTCH1 signaling components in squamous cell carcinoma of the pharynx and larynx has only been evaluated in subgroups. The aim of this study was therefore to evaluate NOTCH1 expression in head and neck squamous cell cancer (HNSCC) patient tissue and cell lines. We analyzed tissue from 195 HNSCCs and tissue from 30 normal patients for mRNA expression of NOTCH1, NOTCH3, HES1, HEY1, and JAG1 using quantitative real-time PCR. Association of expression results and clinical orpathological factors was examined with multivariate Cox regression. NOTCH1 expression was determined in three Human Papilloma Virus (HPV)-positive and nine HPV-negative HNSCC cell lines. High expression of NOTCH1 was associated with better overall survival (p = 0.013) and disease-free survival (p = 0.040). Multivariate Cox regression confirmed the significant influence of NOTCH1 expression on overall survival (p = 0.033) and disease-free survival (p = 0.029). A significant correlation was found between p16 staining and NOTCH1 mRNA expression (correlation coefficient 0.28; p = 0.01). NOTCH1 was expressed at higher levels in HPV-positive HNSCC cell lines compared with HPV-negative cell lines, which was not statistically significant (p = 0.068). We conclude that NOTCH1 expression is associated with overall survival, and that inhibition of NOTCH1 therefore seems less promising.

The second most common cause of diving fatalities is cardiovascular diseases. Monitoring the cardiovascular system in actual underwater conditions is necessary to gain insights into cardiac activity during immersion and to trigger preventive measures. We developed a wearable, current-based electrocardiogram (ECG) device in the eco-system of the FitnessSHIRT platform. It can be used for normal/dry ECG measuring purposes but is specifically designed to allow underwater signal acquisition without having to use insulated electrodes. Our design is based on a transimpedance amplifier circuit including active current feedback. We integrated additional cascaded filter components to counter noise characteristics specific to the immersed condition of such a system. The results of the evaluation show that our design is able to deliver high-quality ECG signals underwater with no interferences or loss of signal quality. To further evaluate the applicability of the system, we performed an applied study with it using 12 healthy subjects to examine whether differences in the heart rate variability exist between sitting and supine positions of the human body immersed in water and outside of it. We saw significant differences, for example, in the RMSSD and SDSD between sitting outside the water (36 ms) and sitting immersed in water (76 ms) and the pNN50 outside the water (6.4%) and immersed in water (18.2%). The power spectral density for the sitting positions in the TP and HF increased significantly during water immersion while the LF/HF decreased significantly. No significant changes were found for the supine position.