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      PD-L1 expression in tumor tissue and peripheral blood of patients with oral squamous cell carcinoma

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          Abstract

          Background

          Immune checkpoints like programmed cell death-1 (PD-1) and its ligand PD-L1 are involved in immune escape mechanisms of solid tumors including oral squamous cell carcinoma (OSCC). Inhibitors of the pathway are successfully used for treating especially advanced disease. However, the physiological relevance of PD-1/PD-L1-signaling in OSCC is insufficiently understood. The aim of the study was to analyze if PD-L1 expression in tumor tissue and peripheral blood samples of OSCC patients is associated with histomorphological tumor parameters and if PD-L1 expression in patients is different from controls.

          Results

          OSCC tumor specimens showed a significantly higher PD-L1 expression than oral mucosa controls ( p < 0.001; upregulation more than 3-fold). Cross-tabulation revealed an association of increased expression of PD-L1 mRNA in tissue specimens with malignancy ( p < 0.001).

          OSCC cases with higher tumor grade and cases with lymph node metastases (N+) were significantly ( p < 0.05) associated with increased PD-L1 expression in peripheral blood. Cross-tabulation revealed an significant association with lymph node metastases (N+) ( p ≤ 0.002).

          Materials and Methods

          PD-L1 mRNA expression was analyzed in tumor specimens and corresponding samples of healthy oral mucosa and peripheral blood of 45 OSCC patients and 36 healthy control persons using RT-qPCR analysis. A Mann-Whitney U-test, a cut-off point analysis and a Chi-square test were carried out.

          Conclusions

          PD-L1 expression in OSCC could contribute to the immunosuppressive local tumor microenvironment. Increased malignant behavior (higher tumor grade, positive nodal status) might be associated with PD-L1 mediated systemic immune tolerance. Thus, PD-L1 expression in peripheral blood might be an indicator of the existence of metastatic disease (N+) in OSCC.

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          Most cited references28

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          The blockade of immune checkpoints in cancer immunotherapy.

          Among the most promising approaches to activating therapeutic antitumour immunity is the blockade of immune checkpoints. Immune checkpoints refer to a plethora of inhibitory pathways hardwired into the immune system that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. It is now clear that tumours co-opt certain immune-checkpoint pathways as a major mechanism of immune resistance, particularly against T cells that are specific for tumour antigens. Because many of the immune checkpoints are initiated by ligand-receptor interactions, they can be readily blocked by antibodies or modulated by recombinant forms of ligands or receptors. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibodies were the first of this class of immunotherapeutics to achieve US Food and Drug Administration (FDA) approval. Preliminary clinical findings with blockers of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD1), indicate broad and diverse opportunities to enhance antitumour immunity with the potential to produce durable clinical responses.
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            Estimation of the Youden Index and its associated cutoff point.

            The Youden Index is a frequently used summary measure of the ROC (Receiver Operating Characteristic) curve. It both, measures the effectiveness of a diagnostic marker and enables the selection of an optimal threshold value (cutoff point) for the marker. In this paper we compare several estimation procedures for the Youden Index and its associated cutoff point. These are based on (1) normal assumptions; (2) transformations to normality; (3) the empirical distribution function; (4) kernel smoothing. These are compared in terms of bias and root mean square error in a large variety of scenarios by means of an extensive simulation study. We find that the empirical method which is the most commonly used has the overall worst performance. In the estimation of the Youden Index the kernel is generally the best unless the data can be well transformed to achieve normality whereas in estimation of the optimal threshold value results are more variable.
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              Overview of the 8th Edition TNM Classification for Head and Neck Cancer.

              The main purpose of the TNM system is to provide an anatomic-based classification to adequately depict cancer prognosis. Accurate cancer staging is important for treatment selection and outcome prediction, research design, and cancer control activities. To maintain clinical relevance, periodical updates to TNM are necessary. The recently published 8th edition TNM classification institutes the following changes to the staging of head and neck (excluding thyroid cancer): new stage classifications [HPV-related oropharyngeal cancer (HPV+ OPC) and soft tissue sarcoma of the head and neck (HN-STS)] and modification of T and N categories [T and N categories for nasopharyngeal cancer (NPC), T categories for oral cavity squamous cell carcinomas (OSCC), N categories for non-viral related head and neck cancer and unknown primary (CUP), and T categories for head and neck cutaneous carcinoma]. These changes reflect better understanding tumor biology and clinical behavior (e.g., HPV+ OPC and HN-STS), improved outcomes associated with technical advances in diagnosis and treatment (e.g., NPC), evolving knowledge about additional prognostic factors and risk stratification from research and observation (e.g., inclusion of depth of invasion variable for OSCC, inclusion of extranodal extension variable for all non-viral head and neck cancer, and reintroduction of size criteria for non-Merkel cell cutaneous carcinoma of the head and neck). This review summarizes the changes and potential advantages and limitations/caveats associated with them. Further evidence is needed to evaluate whether these changes would result in improvement in TNM stage performance to better serve the needs for clinical care, research, and cancer control.
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                Author and article information

                Journal
                Oncotarget
                Oncotarget
                Oncotarget
                ImpactJ
                Oncotarget
                Impact Journals LLC
                1949-2553
                22 December 2017
                8 November 2017
                : 8
                : 68
                : 112584-112597
                Affiliations
                1 Department of Oral and Maxillofacial Surgery, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
                2 Institute of Pathology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
                3 Institute of Pathology, Department of Nephropathology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
                Author notes
                Correspondence to: Manuel Weber, manuel.weber@ 123456uk-erlangen.de
                Article
                22576
                10.18632/oncotarget.22576
                5762533
                06bea0e4-e756-42ab-a7f3-5515fa0199d8
                Copyright: © 2017 Weber et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 29 August 2017
                : 5 October 2017
                Categories
                Research Paper

                Oncology & Radiotherapy
                pd-l1,mrna,pcr,oscc,peripheral blood
                Oncology & Radiotherapy
                pd-l1, mrna, pcr, oscc, peripheral blood

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