The genomic landscape of thyroid cancer tumourigenesis and implications for immunotherapy

Thyroid cancer is the most prevalent endocrine malignancy that comprises mostly indolent differentiated cancers (DTCs) and less frequently aggressive poorly differentiated (PDTC) or anaplastic cancers (ATCs) with high mortality. Utilisation of next-generation sequencing (NGS) and advanced sequencing data analysis can aid in understanding the multi-step progression model in the development of thyroid cancers and their metastatic potential at a molecular level, promoting a targeted approach to further research and development of targeted treatment options including immunotherapy, especially for the aggressive variants. Tumour initiation and progression in thyroid cancer occurs through constitutional activation of the mitogen-activated protein kinase (MAPK) pathway through mutations in BRAF, RAS, mutations in the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) pathway and/or receptor tyrosine kinase fusions/translocations, and other genetic aberrations acquired in a stepwise manner. This review provides a summary of the recent genetic aberrations implicated in the development and progression of thyroid cancer and implications for immunotherapy

Prognostic Implications of Lymph Node Yield and Lymph Node Ratio in Papillary Thyroid Carcinoma

<p>Background: The lymph node yield (LNY) and the lymph node ratio (LNR) have been shown to be important prognostic factors in oral, colon, and gastric cancers. The role of the LNY and LNR in papillary thyroid cancer (PTC) is unclear. The aims of this study were to determine if a high LNR and a low LNY decrease disease-free survival rates. This study further aimed to determine an optimum nodal yield.</p><p>Methods: A retrospective analysis was conducted of 198 patients with PTC undergoing total thyroidectomy with neck dissection between 1987 and 2011. The LNY and LNR were adjusted by relevant covariates in a multivariate Cox regression analysis with Andersen-Gill extension.</p><p>Results: The LNR was associated with a decrease in disease-free survival (hazard ratio 3.2 [95% confidence interval 1.4-7.3], p = 0.005). Patients with an LNR of 0.30 or higher had a 3.4 times higher risk of persistent or recurrent disease compared with patients with an LNR of 0.00 ([95% confidence interval 1.1-10.5], p = 0.031). Conversely, patients with an LNR of 0.11 or lower had an 80% chance of remaining disease free during 5 years of follow-up. The LNY showed no significant independent effect and an optimum nodal yield was not determined.</p><p>Conclusions: The LNR is an important independent prognostic factor in PTC and can be used in conjunction with existing staging systems. A clinical relevant cut-off point of 0.3 (one positive lymph node out of three total) is proposed. No prognostic implications for LNY were identified.</p>

Perforator variability in the anterolateral thigh free flap: a systematic review

The use of free flaps greatly improves reconstruction options and quality of life for patients undergoing oncological resections. The anterolateral thigh (ALT) free flap is frequently used in the head and neck. The aim of this review was to provide a summary of published evidence assessing perforator anatomy of this flap. A broad search was undertaken through the PubMed database using the terms "anterolateral thigh free flap" and "perforator". Search limits included English language and human subjects. Studies that examined more than or equal to ten patients were analysed. A total of 23 studies were identified, which included both clinical and cadaver studies. 1251 thighs were examined with the mean number of perforators ranging from 1.15 to 4.26. In the majority of cases, the descending branch of the lateral circumflex femoral artery was the dominant pedicle and took a musculocutaneous route. In some series, up to 5.4% of thighs were identified as having no cutaneous perforators. Venous data is limited with most studies reporting the presence of two concomitant veins of which the largest concomitant vein is selected for venous anastomoses. The ALT free flap is a reconstruction option in head and neck cancer. Adequate perforators for reconstruction are identified in the majority of cases. Increased anatomical perforator knowledge may lead to further uptake of ALT free flap reconstruction and improved intraoperative troubleshooting. Further studies investigating those patients with no perforators in the ALT may lead to improved clinical outcomes

Social perception of morbidity in facial nerve paralysis

Background: There are many patient-based and clinician-based scales measuring the severity of facial nerve paralysis and the impact on quality of life, however, the social perception of facial palsy has received little attention. The purpose of this pilot study was to measure the consequences of facial paralysis on selected domains of social perception and compare the social impact of paralysis of the different components. Method: Four patients with typical facial palsies (global, marginal mandibular, zygomatic/buccal, and frontal) and 1 control were photographed. These images were each shown to 100 participants who subsequently rated variables of normality, perceived distress, trustworthiness, intelligence, interaction, symmetry, and disability. Statistical analysis was performed to compare the results among each palsy. Results: Paralyzed faces were considered less normal compared to the control on a scale of 0 to 10 (mean, 8.6; 95% confidence interval [CI] = 8.30–8.86) with global paralysis (mean, 3.4; 95% CI = 3.08–3.80) rated as the most disfiguring, followed by the zygomatic/buccal (mean, 6.0; 95% CI = 5.68–6.37), marginal (mean, 6.5; 95% CI = 6.08–6.86), and then temporal palsies (mean, 6.9; 95% CI = 6.57–7.21). Similar trends were seen when analyzing these palsies for perceived distress, intelligence, and trustworthiness, using a random effects regression model. Conclusion: Our sample suggests that society views paralyzed faces as less normal, less trustworthy, and more distressed. Different components of facial paralysis are worse than others and surgical correction may need to be prioritized in an evidence-based manner with social morbidity in mind.6 page(s

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

Cancer-associated fibroblasts (CAFs) in thyroid papillary carcinoma : molecular networks and interactions

In 1989, Stephen Paget proposed the 'seed and soil' theory of cancer metastasis. This theory has led to previous researchers focusing on the role of a tumour as a cancer seed and antiangiogenesis agents as cancer soil fumigant; for the latter to be effective, it is important for them to be able to distinguish cancer cells from stromal cells. However, antiangiogenesis agents have not produced dramatic survival benefits in vivo. This may be related to their inability to destroy the supporting stroma that promote cancer cell growth. Therefore, in order to effectively arrest cancer cell growth for therapeutic purposes, a paradigm shift is required in our fundamental approach to decipher the molecular events and networks in the stromal environment that cancer cells can thrive and proliferate. The pathogenesis of cancer is a multidimensional process of pathological molecular and cellular pathways, influencing different stromal properties and achieving a mutually negotiated crosstalk between cancer cells and stromal cells. This review summarises the clinical presentation of current knowledge of classical papillary thyroid carcinoma (PTC), emerging molecular diagnostics and future directions of classical PTC research

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

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

Differences in LC3B expression and prognostic implications in oropharyngeal and oral cavity squamous cell carcinoma patients

Abstract Background This study examined the prognostic significance of microtubule-associated protein light chain 3B (LC3B) expression in oropharyngeal and oral cavity squamous cell carcinoma (SCC). The prognostic significance of LC3B expression in relation to human papillomavirus (HPV) status in oropharyngeal SCC was also examined. Methods Tissue microarrays (TMAs) were constructed from formalin-fixed, paraffin-embedded oropharyngeal (n = 47) and oral cavity (n = 95) SCC tissue blocks from patients with long-term recurrence and overall survival data (median = 47 months). LC3B expression on tumour was assessed by immunohistochemistry and evaluated for associations with clinicopathological variables. LC3B expression was stratified into high and low expression cohorts using ROC curves with Manhattan distance minimisation, followed by Kaplan–Meier and multivariable survival analyses. Interaction terms between HPV status and LC3B expression in oropharyngeal SCC patients were also examined by joint-effects and stratified analyses. Results Kaplan–Meier survival and univariate analyses revealed that high LC3B expression was correlated with poor overall survival in oropharyngeal SCC patients (p = 0.007 and HR = 3.18, 95% CI 1.31–7.71, p = 0.01 respectively). High LC3B expression was also an independent prognostic factor for poor overall survival in oropharyngeal SCC patients (HR = 4.02, 95% CI 1.38–11.47, p = 0.011). In contrast, in oral cavity SCC, only disease-free survival remained statistically significant after univariate analysis (HR = 2.36, 95% CI 1.19–4.67, p = 0.014), although Kaplan-Meier survival analysis showed that high LC3B expression correlated with poor overall and disease-free survival (p = 0.046 and 0.011 respectively). Furthermore, oropharyngeal SCC patients with HPV-negative/high LC3B expression were correlated with poor overall survival in both joint-effects and stratified presentations (p = 0.024 and 0.032 respectively). Conclusions High LC3B expression correlates with poor prognosis in oropharyngeal and oral cavity SCC, which highlights the importance of autophagy in these malignancies. High LC3B expression appears to be an independent prognostic marker for oropharyngeal SCC but not for oral cavity SCC patients. The difference in the prognostic significance of LC3B between oropharyngeal and oral cavity SCCs further supports the biological differences between these malignancies. The possibility that oropharyngeal SCC patients with negative HPV status and high LC3B expression were at particular risk of a poor outcome warrants further investigation in prospective studies with larger numbers

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