Epithelial-to-mesenchymal transition and its association with PD-L1 and CD8 in thyroid cancer.

Programmed cell death-ligand 1 (PD-L1) has recently been shown to play a role in the regulation of epithelial-to-mesenchymal transition (EMT); however, the relationship between PD-L1 expression, EMT and the inflammatory tumour microenvironment has yet to be investigated in thyroid cancer. To address this issue, we examined the expression of CD8, PD-L1 and the EMT markers E-cadherin and vimentin in a cohort of 74 papillary thyroid cancer (PTC) patients and investigated the association of these with clinicopathologic characteristics and disease-free survival (DFS). The relationship between PD-L1 and EMT was further examined in three thyroid cancer cell lines via Western blot and live cell imaging. In order to expand our in vitro findings, the normalised gene expression profiles of 516 thyroid cancer patients were retrieved and analysed from The Cancer Genome Atlas (TCGA). PD-L1 positivity was significantly higher in PTC patients exhibiting a mesenchymal phenotype (P = 0.012). Kaplan-Meier analysis revealed that PD-L1 (P = 0.045), CD8 (P = 0.038) and EMT status (P = 0.038) were all significant predictors for DFS. Sub-analysis confirmed that the poorest DFS was evident in PD-L1 positive patients with EMT features and negative CD8 expression (P < 0.0001). IFN-γ treatment induced upregulation of PD-L1 and significantly promoted an EMT phenotype in two thyroid cancer cell lines. Our findings suggest that PD-L1 signalling may play a role in stimulating EMT in thyroid cancer. EMT, CD8 and PD-L1 expression may serve as valuable predictive biomarkers in patients with PTC.

Outcomes of a church-based lifestyle intervention among Australian Samoans in Sydney - Le Taeao Afua diabetes prevention program.

AIMS: To evaluate the effectiveness of a culturally adapted, church-based lifestyle intervention among Australian Samoans living in Sydney. METHODS: This was a prospective, pre-post study of a church-wide education and support programme delivered by Community Coach Facilitators and Peer Support Facilitators to prevent, and promote self-management of, Type 2 diabetes. Participants completed questionnaires, anthropometric and HbA1c measurements before and 3-8 months after the intervention. The primary outcome was HbA1c. RESULTS: Overall, 68/107(63.5%) participants completed both before and after intervention data collection (mean age 48.9 ± 14.2 years; 57.2% female). HbA1c dropped significantly between baseline and follow-up among participants with known diabetes (8.1 ± 2.4% (65 mmol/mol) vs 7.4 ± 1.8% (57 mmol/mol); p = 0.040) and non-significantly among participants with newly diagnosed diabetes (8.0 ± 2.1% (64 mmol/mol) vs 7.1 ± 2.3 (54 mmol/mol); p = 0.131). Participants with no diabetes increased their weekly moderate and vigorous physical activity (316.1 ± 291.6mins vs 562.4 ± 486.6mins; p = 0.007) and their diabetes knowledge also improved post-intervention (42.0 ± 13.5% to 61.3 ± 20.2%; p < 0.001). There were no significant reductions in blood pressure, BMI or waist circumference at follow-up. CONCLUSIONS: A structured, church-based, culturally tailored lifestyle intervention showed a number of improvements in diabetes risk among Samoans in Sydney. The intervention however, requires a more rigorous testing in a larger randomised controlled trial over a longer time period.

Pembrolizumab for anaplastic thyroid cancer: a case study.

Blockade of the PD-1/PD-L1 pathway with targeted monoclonal antibodies has demonstrated encouraging anti-tumour activity in multiple cancer types. We present the case of a patient with BRAF-negative stage IVC anaplastic thyroid cancer (ATC) treated with the anti-PD-1 monoclonal antibody, pembrolizumab, following radiographic progression on chemoradiation. Blood samples were collected prior to and at four time points during treatment with pembrolizumab. Mass cytometry was used to determine expression of relevant biomarkers by peripheral blood mononuclear cells. Faecal samples were collected at baseline and 4 weeks following treatment initiation; taxonomic profiling using 16S ribosomal RNA (rRNA) gene sequencing was performed. Following treatment, a marked expansion in CD20+ B cell, CD16+ CD56lo NK cell and CD45RO+ CCR7+ central memory CD4+ T-cell populations was observed in the peripheral blood. Proportions of cells expressing the co-receptors TIGIT, OX40 and CD86 also increased during treatment. A high abundance of bacteria of the order Bacteroidales, specifically from the Bacteroidaceae and Rikenellaceae families, was identified in the faecal microbiota. Moreover, the patient's microbiome was enriched in Clostridiales order members Ruminococcaceae, Veillonellaceae and Lachnospiraceae. Alpha diversity of the gut microbiome was significantly higher following initiation of checkpoint therapy as assessed by the Shannon and Simpson index. Our results suggest that treatment with pembrolizumab promotes expansion of T-, B- and NK cell populations in the peripheral blood at the time of tumour regression and have the potential to be implemented as predictive biomarkers in the context of checkpoint blockade therapy. Larger studies to confirm these findings are warranted.

Elevated levels of soluble PD-L1 are associated with reduced recurrence in papillary thyroid cancer.

To date, no research evaluating the predictive capabilities of soluble programmed cell death-ligand 1 (sPD-L1) in thyroid cancer patients has been performed. We aimed to investigate the prognostic significance of sPD-L1 expression in papillary thyroid cancer (PTC) and to evaluate the association between sPD-L1 levels with tumoural PD-L1 expression and patient outcomes. Pre-treatment levels of serum and plasma sPD-L1 were measured by ELISA in 101 PTC patients. Tissue microarrays were stained with an anti-PD-L1 antibody, clone SP263 (Ventana). The median serum sPD-L1 concentration in PTC patients was significantly higher compared to healthy controls (P = 0.028). An increased incidence of extrathyroidal extension was significantly associated with an elevated serum sPD-L1 level (P = 0.015). Patients with high serum sPD-L1 levels had significantly shorter median disease-free survival (DFS) as compared to those with low sPD-L1 levels (P = 0.011). Following multivariate analysis, serum sPD-L1 was the only statistically significant predictor for DFS. Patients with both positive serum and tumoural PD-L1 expression had a significantly shorter DFS than those in any other subgroup (P = 0.007). Our study is the first to confirm that sPD-L1 concentration is significantly associated with patient outcome in PTC. Soluble PD-L1 may provide clinicians with a non-invasive biomarker that can lessen dependence on tissue biopsies and diagnose aggressive thyroid cancers at a more treatable stage.

An update on gastrointestinal endoscopy-associated infections and their contributing factors.

INTRODUCTION: During clinical use, gastrointestinal endoscopes are grossly contaminated with patient's native flora. These endoscopes undergo reprocessing to prevent infectious transmission upon future use. Endoscopy-associated infections and outbreaks have been reported, with a recent focus on the transmission of multi-drug resistant organisms. This review aims to provide an update on endoscopy-associated infections, and the factors contributing to their occurrence. METHODS: PubMed, ScienceDirect, and CINAHL were searched for articles describing gastrointestinal endoscopy-associated infections and outbreaks published from 2008 to 2018. Factors contributing to their occurrence, and the outcomes of each outbreak were also examined. RESULTS: This review found 18 articles, 16 of which described duodenoscope-associated infections, and the remaining two described colonoscope- and gastroscope-associated infection respectively. Outbreaks were reported from the United States, France, China, Germany, the Netherlands and the United Kingdom. The causative organisms reported were Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli and Salmonella enteritidis. CONCLUSIONS: A number of factors, including lapses in reprocessing, biofilm formation, endoscope design issues and endoscope damage, contribute to gastrointestinal endoscopy associated infection. Methods of improving endoscope reprocessing, screening for contamination and evaluating endoscope damage may be vital to preventing future infections and outbreaks.

Clinicopathologic and Prognostic Significance of Programmed Cell Death Ligand 1 Expression in Patients with Non-Medullary Thyroid Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: Evidence has shown that programmed cell death ligand 1 (PD-L1) overexpression is associated with poor prognosis and resistance to immune therapies in several human cancers. However, data on the prognostic significance of PD-L1 expression in thyroid cancer are limited and remain controversial. This systematic review and meta-analysis aimed to evaluate comprehensively the clinicopathologic significance and prognostic value of PD-L1 expression in non-medullary thyroid cancers. METHODS: Electronic databases, including Medline/PubMed, EMBASE, and the Cochrane Library, were searched up until July 5, 2017. In total, seven comparisons (from six articles) comprising 1421 patients were included in the pooled analysis. RESULTS: There was moderate quality evidence from four studies (n = 721) that shows positive PD-L1 expression was significantly associated with poor survival among thyroid cancer patients (pooled hazard ratio = 3.73 [confidence interval (CI) 2.75-5.06]). Increased PD-L1 expression was also found to be significantly associated with disease recurrence (odds ratio = 1.95 [CI 1.15-3.32]) and concurrent thyroiditis (odds ratio = 1.65 [CI 1.09-2.51]). CONCLUSIONS: The results confirm the prognostic significance of PD-L1 expression in thyroid cancer patients. PD-L1 expression has the potential to be implemented as a prognostic biomarker used to guide clinicians in identifying patients with more aggressive cancers, and for the selection of individuals that would derive durable clinical benefit from anti-PD-1/PD-L1 immunotherapy. Prospective clinical trials will be useful to support these findings.

Predictive relevance of programmed cell death protein 1 and tumor-infiltrating lymphocyte expression in papillary thyroid cancer.

BACKGROUND: Co-signaling molecule programmed cell death 1 ligand 1 has been shown to induce potent inhibition of T cell-mediated antitumoral immunity. Our study aimed to investigate the prognostic value of programmed cell death 1 ligand 1 expression and tumor-infiltrating lymphocyte density as biomarkers in specimens from patients with papillary thyroid cancer. METHODS: We retrospectively analyzed the data and tissue samples of 75 patients with papillary thyroid cancer. Stained cells were counted manually and analyzed for clinical and histopathologic correlations and disease-free survival. RESULTS: Programmed cell death 1 ligand 1 expression was significantly correlated with increased incidence of lymphovascular invasion (P = .038), extrathyroidal extension (P = .026), and concurrent lymphocytic thyroiditis (P = .003). Patients with low CD8+ and CD3+ expression presented with a significantly higher incidence of lymph node metastasis (P = .042) and extrathyroidal extension (P = .015). The subgroup of cases with positive programmed cell death 1 ligand 1 expression and low CD8+ T cell infiltration demonstrated a significantly increased incidence of lymph node metastasis (P = .031). Univariate and multivariate analysis confirmed that a high CD8+ T cell density was significantly associated with favorable disease-free survival (P = .017). Subanalysis revealed that the shortest disease-free survival was evident in the programmed cell death 1 ligand 1+/CD8low group (P = .004). CONCLUSION: Our findings indicate that CD8+ tumor-infiltrating lymphocyte density and programmed cell death 1 ligand 1 expression may serve as valuable predictive biomarkers in patients with papillary thyroid cancer.