HLA-E and Its Soluble Form as Indicators of a Sex-Specific Immune Response in Patients with Oral Squamous Cell Carcinoma.

The human leukocyte antigene E (HLA-E) is associated with tumorigenesis in various cancers. Immunoncology along with sex-specific aspects in cancer therapy are now in scientific focus. Therefore, immunohistochemical HLA-E expression was retrospectively analysed in a cohort of oral squamous cell carcinomas (OSCC) after surgical therapy. Then, serum concentration of HLA-E (sHLA-E) was quantified in a prospective cohort by enzyme-linked immunosorbent assay. High HLA-E expression was associated with advanced UICC stage (Spearman's correlation: p = 0.002) and worse survival (Cox-regression: progression-free survival: hazard ratio (HR) 3.129, confidence range (CI) 1.443-6.787, p = 0.004; overall survival: HR 2.328, CI 1.071-5.060, p = 0.033). The sHLA-E concentration was significantly higher in the control group than in tumor group (Mann-Whitney U-test (MW-U): p = 0.021). Within the tumor group, women showed significantly higher sHLA-E levels than men (MW-U: p = 0.049). A closer look at the tumor group and the control group showed that gender-specific differences exist: while no differences in sHLA-E concentration were detectable between female subjects of tumor group and control group (MW-U: p = 0.916), male subjects of tumor group had a significantly lower sHLA-E concentration compared to those of control group (MW-U: p = 0.001). In summary, our results provide evidence for sex-specific differences in immune responses in OSCC. This fact should be considered regarding future immunotherapy regimens.

Plasma Klotho is not related to kidney function and does not predict adverse outcome in patients with chronic kidney disease.

A decreased expression of the fibroblast growth factor (FGF)-23 coreceptor Klotho was postulated as an early alteration in chronic kidney disease mineral and bone disorder, resulting in a compensatory increase in plasma FGF-23 levels. Klotho exists in both membrane-bound and secreted (sKlotho) forms, the latter of which may exert vasculoprotective effects. Here we analyzed plasma sKlotho levels in a large cohort of 312 patients with stage 2-4 chronic kidney disease, and assessed plasma levels of FGF-23, sKlotho, parathyroid hormone, and urinary fractional phosphate excretion. Patients were prospectively followed for an average of 2.2 years for the occurrence of death or initiation of renal replacement therapy. The levels of sKlotho were significantly associated with age, but not with the glomerular filtration rate or other parameters of calcium-phosphate metabolism. Moreover, while patients with high FGF-23 levels faced worst outcome even after adjustment for confounders, we found no prognostic impact of sKlotho. Thus, plasma levels of sKlotho were not related to kidney function and did not predict adverse outcome in patients with chronic kidney disease. Future studies are needed to understand how tissue expression, urinary excretion, and plasma levels of Klotho diverge in progressive chronic kidney disease.

IDO1 is highly expressed in macrophages of patients in advanced tumour stages of oral squamous cell carcinoma.

PURPOSE: Strategies for Indolamine-2,3-dioxygenase 1 (IDO1) inhibition in cancer immunotherapy once produced encouraging results, but failed in clinical trials. Recent evidence indicates that immune cells in the tumour microenvironment, especially macrophages, contribute to immune dysregulation and therefore might play a critical role in drug resistance. METHODS: In this study, we investigated the significance of IDO1 expressing immune cells in primary tumours and corresponding lymph node metastases (LNMs) in oral squamous cell carcinoma (OSCC) by immunohistochemistry. The link between IDO1 and macrophages was investigated by flow cytometry in tumour tissue, healthy adjacent tissue and peripheral blood mononuclear cells (PBMCs). IDO1 activity (measured as Kynurenine/Tryptophan ratio) was assessed by ELISAs. RESULTS: High IDO1 expression in tumour-infiltrating immune cells was significantly correlated with advanced stages [Spearman's rank correlation (SRC), p = 0.027] and reduced progression-free survival (multivariate Cox regression, p = 0.034). IDO1 was significantly higher expressed in PBMCs of patients in advanced stages than in healthy controls (ANOVA, p < 0.05) and IDO1+ macrophages were more abundant in intratumoural areas than peritumoural (t test, p < 0.001). IDO1 expression in PBMCs was significantly correlated with IDO1 activity in serum (SRC, p < 0.05). IDO1 activity was significantly higher in patients with LNMs (t test, p < 0.01). CONCLUSION: All in all, IDO1 expressing immune cells, especially macrophages, are more abundant in advanced stages of OSCC and are associated with reduced progression-free survival. Further investigations are needed to explore their role in local and systemic immune response. The IDO1 activity might be a suitable biomarker of metastasis in OSCC patients.

The phosphatonin fibroblast growth factor 23 links calcium-phosphate metabolism with left-ventricular dysfunction and atrial fibrillation.

AIMS: High serum phosphate is linked to cardiovascular morbidity and mortality in the general population. Fibroblast growth factor 23 (FGF-23) is a critical phosphate regulating hormone, potentially reflecting phosphate load better than a single serum phosphate measurement. Recent pioneering echocardiographic studies associated FGF-23 with left-ventricular morphology. However, the association between FGF-23 and left-ventricular function is unknown, prompting us to investigate this relationship in our HOM SWEET HOMe study. METHODS AND RESULTS: We studied the association between C-terminal FGF-23, coronary artery disease, and left-ventricular function in 885 subjects undergoing elective coronary angiography. Left-ventricular function was assessed with ventriculography. More, pro-brain natriuretic peptide (pro-BNP) plasma levels were measured. The presence of left-ventricular hypertrophy and atrial fibrillation was assessed by electrocardiography. Patients with an ejection fraction <40% had significantly higher FGF-23 levels compared with patients with the ejection fraction >40% (P< 0.001). In multivariable regression analysis, the observed relationship between FGF-23 and left-ventricular function remained significant after adjustment for estimated glomerular filtration rate, presence of left-ventricular hypertrophy, and other confounding variables. In accordance, FGF-23 significantly correlated with pro-BNP plasma levels (r = 0.31; P< 0.001). Prevalent atrial fibrillation was associated with elevated FGF-23 levels, while the presence of coronary artery disease was not. CONCLUSIONS: Fibroblast growth factor 23 levels are associated with left-ventricular function and atrial fibrillation even in the absence of renal function impairment. Of note, these cross-sectional data cannot prove causality; therefore, future studies will have to discern whether FGF-23 exerts a direct untoward effect on the myocardium, or rather represents an 'innocent bystander' which reflects a high phosphate burden.

TREM2 Is Associated with Advanced Stages and Inferior Prognosis in Oral Squamous Cell Carcinoma.

Triggering receptor expressed on myeloid cells 2 (TREM2) is suggested to hamper antitumor immune response in multiple cancers. However, the role of TREM2 in oral squamous cell carcinoma (OSCC) and its expression in tumor-associated macrophages (TAMs) are unknown. In this study, TREM2 expression was analyzed in the primary tumors and corresponding lymph-node metastases of OSCC patients via immunohistochemistry on tissue microarrays. Human peripheral blood mononuclear cells (PBMCs) and single-cell suspensions of tumor and healthy adjacent tissues were analyzed for the presence of TREM2+ macrophages and TAMs using flow cytometry. The serum levels of soluble TREM2 (sTREM2) were quantified using an enzyme-linked immunosorbent assay. High TREM2 expression was associated with advanced UICC stages (Spearman's rank correlation (SRC), p = 0.04) and significantly reduced survival rates in primary tumors (multivariate Cox regression, progression-free survival: hazard ratio (HR) of 2.548, 95% confidence interval (CI) of 1.089−5.964, p = 0.028; overall survival: HR of 2.17, 95% CI of 1.021−4.613, p = 0.044). TREM2 expression was significantly increased in the PBMCs of OSCC patients in UICC stage IV compared with healthy controls (ANOVA, p < 0.05). The serum levels of sTREM2 were higher in advanced UICC stages, but they narrowly missed significance (SRC, p = 0.059). We demonstrated that TREM2 was multi-factorially associated with advanced stages and inferior prognosis in OSCC patients and that it could serve as a prognostic biomarker in OSCC patients. Targeting TREM2 has the potential to reshape the local and systemic immune landscape for the potential enhancement of patients' prognosis.

Ball versus Locator® Attachments: A Retrospective Study on Prosthetic Maintenance and Effect on Oral-Health-Related Quality of Life.

Locator® and ball attachments are well-established systems to attach overdentures to two inter-foraminal implants. This study aimed to evaluate differences between the two systems regarding prosthetic maintenance and patients' oral-health-related quality of life (OHRQoL). Dental records of patients with a mandibular implant-retained overdenture were retrospectively analyzed. Prosthetic maintenance measures involving the denture suprastructure and attachment matrix and patrix were analyzed. Furthermore, the Oral Health Impact Profile-G14 (OHIP-G14) was used to evaluate OHRQoL. Results were analyzed by means of Kaplan-Meier analysis and Student's t- and log-rank tests. The records of 122 patients were evaluated. Kaplan-Meier survival analysis revealed a significant difference between ball attachments (Group B; n patients = 47) and Locator® attachments (Group L; n patients = 75) regarding the occurrence of denture fractures (p < 0.001) and events affecting the matrix (p = 0.028) and patrix (p = 0.030). Group L had a significantly lower total OHIP-G14 score than Group B (p = 0.002). The most common maintenance events were matrix-related and denture relining for both attachment systems. Group B required more maintenance measures than Group L. Moreover, patients in Group L had better OHRQoL than patients in Group B.