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    • Importantly no significant difference in cytoplasmic PD L ex

    2018-10-23

    Importantly, no significant difference in cytoplasmic PD-L1 ion channel between benign and NIFTP subgroups suggests that NIFTPs are more close to benign nodules, supporting the new paradigm for classification of NIFTP as non-malignant neoplasms (Maletta et al., 2016; Nikiforov et al., 2016; Patel, 2016; Thompson, 2016). The EFVPTC with invasion subgroup in which the cases were mainly classified as stage I and II at resection showed increased PD-L1 cytoplasmic staining. Using a completely different patient cohort in our previous study, a significant increase in both membrane and cytoplasmic PD-L1 expression was shown in patients with stage IV disease and correlated with high risk of aggressive disease, distant metastasis or death (Chowdhury et al., 2016). The correlation of cytoplasmic PD-L1 expression with risk of invasion in EFVPTC is in accord with our recent report of PD-L1 as a marker of thyroid cancer prognosis and aggressiveness (Chowdhury et al., 2016) and other cancers (Hamanishi et al., 2007; Leite et al., 2015). The cytoplasmic PD-L1 expression was significantly increased in EFVPTC with invasion comparing to NIFTP subgroup. These findings support the concept that NIFTP behaves primarily as a benign neoplasm. Based on several studies, including our previous report (Chowdhury et al., 2016), we classified cases of FVPTC without detectable capsular/vascular invasion and having coexisting diffuse lymphocytic infiltration into a separate LT subgroup since the mononuclear infiltration can influence the expression of PD-L1 and lead to a false positive result. The level of cytoplasmic PD-L1 expression was significantly higher in cases with lymphocytic infiltration than benign thyroid nodules, but similar to EFVPTC with invasion. This emphasizes that overexpression of PD-L1 in benign thyroid nodules should be interpreted with caution and that coexistence of chronic lymphocytic thyroiditis or Hashimoto\'s thyroiditis can cause a misleading false positive result (Taube et al., 2012; Cunha et al., 2013). We are cognizant of the limitations that our findings are based on patients from a single clinical center; validation in independent patient cohorts is needed. Further, limited follow up period (1.5–5years) did not permit a clear statement regarding the relationship of cytoplasmic PD-L1 overexpression with progression of invasive EFVPTC, their aggressiveness and/or recurrence.
    Funding The Mount Sinai Hospital Foundation of Toronto Da Vinci Gala Fundraiser, Mount Sinai Hospital Department of Medicine Research Fund, Alex and Simona Shnaider Chair in Thyroid Cancer (PGW) and Canadian Institutes of Health Research (CIHR) for CIHR Chair in Advanced Cancer Diagnostics (RR).
    Disclosure statement
    Authors\' contributions
    Acknowledgments This study was supported by The Mount Sinai Hospital Foundation of Toronto Da Vinci Gala Fundraiser, Mount Sinai Hospital Department of Medicine Research Fund, Alex and Simona Shnaider Chair in Thyroid Cancer (PGW) and Canadian Institutes of Health Research (CIHR) for CIHR Chair in Advanced Cancer Diagnostics (RR). The funding sources had no role in the study design or its execution. The excellent technical assistance of Ronald S. Chazen in data analyses is gratefully acknowledged. Presentations
    Introduction Although advanced melanoma still remains a challenging diagnosis, significant enthusiasm has been generated by new therapeutic agents that have demonstrated increases in survival. Ipilimumab (IPI) is a monoclonal antibody that inhibits cytotoxic T-lymphocyte associated antigen 4 (CTLA-4), thereby acting as a “checkpoint inhibitor” to enhance native immune function. In randomized trials, IPI produced objective responses in 11% of patients, but some degree of disease control in 29% (Hodi et al., 2010). Moreover, there is a pattern of delayed but often durable response, and long-term survival is possible in patients who respond to treatment (Prieto et al., 2012). In fact, some groups treated with IPI may have 4year survival rates up to 49.5% (Wolchok et al., 2013a). Despite promising outcomes, immune-related adverse events have been described in a significant proportion of patients who receive the agent. These include diarrhea (30%), colitis (7%), hepatitis (3%), and hypophysitis (2%). In a randomized trial, 2.1% of enrolled patients died as a direct result of treatment (Hodi et al., 2010). The therapeutic effect of ipilimumab led to rapid investigation of other checkpoint blocking agents and antibodies blocking the PD-1 pathway have demonstrated 40–45% response rates with 35%>3year survival and reduced toxicity, compared with ipilimumab (Hamid et al., 2013; Robert et al., 2015a; Hodi et al., 2016). Further, combined checkpoint blockade with ipilimumab+nivolumab results in response rates up to 60% in melanoma, albeit with higher rates of toxicity (Wolchok et al., 2013b; Postow et al., 2015).