Thyroid cancer is frequently difficult to diagnose due to an overlap of cytologic features between malignant and benign nodules. This overlap leads to unnecessary removal of the thyroid in patients without cancer. While providing some improvement over cytopathologic diagnostics, molecular methods frequently fail to provide a correct diagnosis for thyroid nodules. These approaches are based on the difference between cancer and adjacent thyroid tissue and assume that adjacent tissues are the same as benign nodules. However, in contrast to adjacent tissues, benign thyroid nodules can contain genetic alterations that can be found in cancer. For the development of a new molecular diagnostic test for thyroid cancer, we evaluated DNA methylation in 109 thyroid tissues by using genome-wide single-base resolution DNA methylation analysis. The test was validated in a retrospective cohort containing 65 thyroid nodules. By conducting reduced representation bisulfite sequencing in 109 thyroid specimens, we found significant differences between adjacent tissue, benign nodules, and cancer. These tissue-specific signatures are strongly linked to active enhancers and cancer-associated genes. Based on these signatures, we developed a new epigenetic approach for thyroid diagnostics. According to the validation cohort, our test has an estimated specificity of 97% [95% confidence interval (CI), 81-100], sensitivity of 100% (95% CI, 87-100), positive predictive value of 97% (95% CI, 83-100), and negative predictive value of 100% (95% CI, 86-100). These data show that epigenetic testing can provide outstanding diagnostic accuracy for thyroid nodules.
vomiting (25%), and fatigue (23%). Most AEs were Grade (G) 1-2. The G3 treatment-related AEs were rash (6 pts), fatigue (1 pt), decreased appetite (1 pt), dehydration (1 pt), pruritus (1 pt), and face edema (1 pt). In particular, no G3 treatment-related gastrointestinal toxicity or liver enzyme elevation has been reported. To date, 24 ALKþ NSCLC pts treated at doses 200 mg are evaluable for response; partial response (PR) was achieved in 16 pts (67%) and stable disease (SD) in 3 pts (13%). In the crizotinib-naïve pts (n¼8), responses were observed in 6 pts (75%) and SD in 1 pt (13%). In the 12 pts with prior crizotinib but no other ALK TKI, 10 pts (83%) achieved PR and 1 (8%) SD. CNS responses have been observed in both crizotinib naïve and crizotinib resistant pts. The median duration of treatment in the 24 evaluable ALKþ pts is 23.8þ weeks, with the longest being 112þ weeks.Conclusion: X-396 is well-tolerated and induces responses in both crizotinib-naïve and crizotinib-resistant ALKþ NSCLC pts, as well as patients with CNS lesions. Enrollment is ongoing in the expansion cohorts.
<p>Genomic locations associated with benign and malignant epigenetic signatures for thyroid nodule diagnostics and an association of these locations with H3K27Ac peaks and H3K27Ac associated areas (peaks including enhancer shores).</p>
<p>Genes associated with DDMS locations are frequently linked to cancer according to Ingenuity® Pathway Analysis (Qiagen Inc.). Number of genes in each group is indicated.</p>
<p>DDMS diagnostics of thyroid nodules. The table contains post-surgical diagnosis according to participating pathologists, diagnosis based on fine needle aspiration biopsy, presence of thyroiditis and Hurthle cells, cancer risk scores according to DDMS and diagnosis according to DDMS.</p>
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