Choroidal melanoma is the most frequently occurring intraocular tumor in adults. The aim of this work is to assess the potential of state-of-the art in-vivo and ex-vivo imaging modalities for the characterization of choroidal melanoma. Multimodal imaging of a choroidal melanoma was performed in a 53-year-old male patient. In-vivo ophthalmoscopy, ultrasound microscopy, duplex ultrasound, and 7.0 T MRI were performed. Ex-vivo examination of the enucleated eye included 7.0 and 9.4 T magnetic resonance microscopy as well as histopathology with hematoxylin and eosin staining. Imaging of choroidal melanoma with ultrahigh field MRI and duplex sonography provides detailed morphologic and functional information of the eye. High-spatial-resolution MRI at 9.4 T shows details of the internal texture of melanoma and other structures of the eye with an in-plane spatial resolution of 32 μm. Ultrahigh field in-vivo MRI at 7.0 T and ex-vivo MRI at 7.0 and 9.4 T correlate well with histologic evaluation. In-vivo ultrahigh field MRI is an emerging technique for the characterization and staging of ocular tumors. The combination of in-vivo ultrahigh-field MRI and duplex sonography has the potential to complement or even substitute complex and invasive biopsies.

The 5-year survival rate for head and neck squamous cell carcinoma (HNSCC) is approximately 65%. In addition to radio-chemotherapy, immunotherapy is an approach in the treatment of advanced HNSCC. A better understanding of the immune context would allow personalized treatment by identifying patients who are best suited for different treatment options. In our discovery cohort, we evaluated the expression profiles of CMTM6, PD-L1, CTLA-4, and FOXP3 in 177 HNSCCs from Caucasian patients of all tumor stages and different treatment regimens, correlating marker expression in tumor and immune cells with outcomes. Patients with CMTM6^high-expressing tumors had a longer overall survival regardless of treatment. This prognostic benefit of CMTM6 in HNSCC was validated in an independent cohort. Focusing on the in the discovery cohort (n = 177), a good predictive effect of CMTM6^high expression was seen in patients receiving radiotherapy (p = 0.07; log rank), but not in others. CMTM6 correlated with PD-L1, CTLA-4 and FOXP3 positivity, with patients possessing CMTM6^high/FOXP3^high tumors showing the longest survival regardless of treatment. In chemotherapy-treated patients, PD-L1 positivity was associated with longer progression-free survival (p < 0.05). In the 27 patients who received immunotherapy, gene expression analysis revealed lower levels of CTLA-4 and FOXP3 with either partial or complete response to this treatment, while no effect was observed for CMTM6 or PD-L1. The combination of these immunomodulatory markers seems to be an interesting prognostic and predictive signature for HNSCC patients with the ability to optimize individualized treatments.

This study aimed to refine combined targeted approaches on well-characterized, low-passage tumor models. Upon in vivo xenografting in immunodeficient mice, three cell lines from locally advanced or metastatic HNSCC were established. Following quality control and basic characterization, drug response was examined after therapy with 5-FU, Cisplatin, and cyclin-dependent kinase inhibitors (abemaciclib, THZ1). Our cell lines showed different in vitro growth kinetics, morphology, invasive potential, and radiosensitivity. All cell lines were sensitive to 5-FU, Cisplatin, and THZ1. One cell line (HNSCC48 P0 M1) was sensitive to abemaciclib. Here, Cyto-FISH revealed a partial CDKN2a deletion, which resulted from a R58* mutation. Moreover, this cell line demonstrated chromosome 12 polysomy, accompanied by an increase in CDK4-specific copy numbers. In HNSCC16 P1 M1, we likewise identified polysomy-associated CDK4-gains. Although not sensitive to abemaciclib per se, the cell line showed a G1-arrest, an increased number of acidic organelles, and a swollen structure. Notably, intrinsic resistance was conquered by Cisplatin because of cMYC and IDO-1 downregulation. Additionally, this Cisplatin-CDKI combination induced HLA-ABC and PD-L1 upregulation, which may enhance immunogenicity. Performing functional and molecular analysis on patient-individual HNSCC-models, we identified CDK4-gains as a biomarker for abemaciclib response prediction and describe an approach to conquer intrinsic CDKI resistance.

Glioblastoma (GBM) is one of the most frequent primary brain tumors. Limited therapeutic options and high recurrency rates lead to a dismal prognosis. One frequent, putative driver mutation is the genomic amplification of the oncogenic receptor tyrosine kinase EGFR. Often accompanied by variants like EGFRvIII, heterogenous expression and ligand independent signaling render this tumor subtype even more difficult to treat, as EGFR-directed therapeutics show only weak effects at best. So EGFR-amplified GBM is considered to have an even worse prognosis, and therefore, deeper understanding of molecular mechanisms and detection of potential targets for novel therapeutic strategies is urgently needed. In this study, we looked at the level of microRNAs (miRs), small non-coding RNAs frequently deregulated in cancer, both acting as oncogenes and tumor suppressors. Comparative analysis of GBM with and without EGFR amplification should give insight into the expression profiles of miRs, which are considered both as potential targets for directed therapies or as therapeutic reagents. Comparison of miR profiles of EGFR-amplified and EGFR-normal GBM revealed an upregulation of the miR-183/96/182 cluster, which is associated with oncogenic properties in several tumor entities. One prominent target of this miR cluster is FOXO1, a pro-apoptotic factor. By observing FOXO1 downregulation in EGFR-amplified tumors, we can see a significant correlation of EGFR amplification, miR-183/96/182 cluster upregulation, and repression of FOXO1. Although no significant difference in overall survival is shown, these data may contribute to the molecular understanding of this tumor subtype and offer potential targets for miR-based therapies.