Chromosomal rearrangements of NTRK genes are oncogenic driver mutations in thyroid cancer (TC). This study aimed to identify NTRK fusion-positive thyroid tumors and to correlate them with clinical and pathological data and determine their prognostic significance. The cohort consisted of 989 different TC samples. Based on the detected mutation, samples were triaged, and those that were positive for a BRAF, HRAS, KRAS, NRAS, RET, RET/PTC or PAX8/PPARγ mutation were excluded from further analyses. NTRK fusion gene testing was performed in 259 cases, including 126 cases using next-generation sequencing. NTRK fusion genes were detected in 57 of 846 (6.7%) papillary thyroid carcinomas and in 2 of 10 (20.0%) poorly differentiated thyroid carcinomas. A total of eight types of NTRK fusions were found, including ETV6/NTRK3, EML4/NTRK3, RBPMS/NTRK3, SQSTM1/NTRK3, TPM3/NTRK1, IRF2BP2/NTRK1, SQSTM1/NTRK1 and TPR/NTRK1.NTRK fusion-positive carcinomas were associated with the follicular growth pattern, chronic lymphocytic thyroiditis and lymph node metastases. NTRK1-rearranged carcinomas showed a higher frequency of multifocality and aggressivity than NTRK3-rearranged carcinomas. Tumor size, presence of metastases, positivity for the NTRK3 or NTRK1 fusion gene and a late mutation event (TERT or TP53 mutation) were determined as factors affecting patient prognosis. NTRK fusion genes are valuable diagnostic and prognostic markers.

Purpose: The successful implementation of immune checkpoint inhibitors (ICIs) in the clinical management of various solid tumors has raised considerable expectations for patients with epithelial ovarian carcinoma (EOC). However, EOC is poorly responsive to ICIs due to immunological features including limited tumor mutational burden (TMB) and poor lymphocytic infiltration. An autologous dendritic cell (DC)-based vaccine (DCVAC) has recently been shown to be safe and to significantly improve progression-free survival (PFS) in a randomized Phase II clinical trial enrolling patients with EOC (SOV01, NCT02107937). Experimental design: We harnessed sequencing, flow cytometry, multispectral immunofluorescence microscopy, immunohistochemistry to analyze (pre-treatment) tumor and (pre-treatment and post-treatment) peripheral blood samples from 82 patients enrolled in SOV01, with the aim of identifying immunological biomarkers that would improve the clinical management of patients with EOC treated with DCVAC. Results: Although higher-than-median TMB and abundant CD8+ T cell infiltration were associated with superior clinical benefits in patients with EOC receiving standard-of-care chemotherapy, the same did not hold true in women receiving DCVAC. Conversely, superior clinical responses to DCVAC were observed in patients with lower-than-median TMB and scarce CD8+ T cell infiltration. Such responses were accompanied by signs of improved effector functions and tumor-specific cytotoxicity in the peripheral blood. Conclusions: Our findings suggest that while patients with highly infiltrated, "hot" EOCs benefit from chemotherapy, women with "cold" EOCs may instead require DC-based vaccination to jumpstart clinically relevant anticancer immune responses.

The aim of our study was to address the potential for improvements in thyroid cancer detection in routine clinical settings using a clinical examination, the American College of Radiology Thyroid Imaging Reporting and Database System (ACR TI-RADS), and fine-needle aspiration cytology (FNAC) concurrently with molecular diagnostics. A prospective cohort study was performed on 178 patients. DNA from FNA samples was used for next-generation sequencing to identify mutations in the genes BRAF, HRAS, KRAS, NRAS, and TERT. RNA was used for real-time PCR to detect fusion genes. The strongest relevant positive predictors for malignancy were the presence of genetic mutations (p < 0.01), followed by FNAC (p < 0.01) and ACR TI-RADS (p < 0.01). Overall, FNAC, ACR TI-RADS, and genetic testing reached a sensitivity of up to 96.1% and a specificity of 88.3%, with a diagnostic odds ratio (DOR) of 183.6. Sensitivity, specificity, and DOR decreased to 75.0%, 88.9%, and 24.0, respectively, for indeterminate (Bethesda III, IV) FNAC results. FNA molecular testing has substantial potential for thyroid malignancy detection and could lead to improvements in our approaches to patients. However, clinical examination, ACR TI-RADS, and FNAC remained relevant factors.