Anaplastic thyroid carcinoma (ATC) is a rare, but devastating disease. Despite multimodal approaches combining surgery, chemotherapy and radiation therapy, ATC is associated with a dire prognosis, with a median overall survival of only three to ten months. Novel treatments are thus urgently needed. Recent efforts towards the characterization of the molecular landscape of ATC have led to the identification of pro-oncogenic targetable alterations, lending promise for novel targeted therapeutic approaches. This systematic review summarizes the results of phase II clinical trials of targeted therapy in ATC, providing an overview of efficacy and safety profiles. The majority of trials to date have consisted of small single-arm studies and have presented modest results. However, only a minority of trials have selected or stratified patients by molecular alterations. In the setting of BRAF V600E mutated ATC, dabrafenib/trametinib combination therapy and vemurafenib monotherapy have both demonstrated efficacy. Everolimus has furthermore shown promising results in patients with PI3K/mTOR/AKT pathway alterations. These studies underscore the importance of molecular profiling of tumors for appropriate patient selection and determination of genomic correlates of response. Clinical trials are underway testing additional targeted therapies as monotherapy, or as a part of multimodal treatment, and in combination with immunotherapy.

The national guideline for sore throat, endorsed by the Danish Society of General Medicine, recommends the use of the modified Centor score and streptococcal rapid antigen detection test to guide diagnosis and treatment of sore throat. The aim was to investigate Danish general practitioners (GPs) routine management of sore throat patients with a focus on the modalities used and adherence to the guideline. A cross-sectional study. GPs in the Central Denmark Region answered an online questionnaire in October 2017. The main outcome measure was modalities used in the management of sore throat patients. In total, 266 of 500 (53%) GPs answered the survey. Ten percent of participants were adherent or almost adherent to the guideline, while 82% of GPs added one or more extra modalities (general clinical assessment (67%), biochemical parameters (48%), and throat swabs for bacterial culture (18%)) to differentiate viral and bacterial etiology. Sixty-five percent of participants used the Centor Score or modified Centor Score, 96% of GPs used a streptococcal rapid antigen detection test, and all GPs chose narrow-spectrum penicillin as the first-line antibiotic. The most common reasons for non-adherence to the guideline were greater confidence in the clinical assessment (39%), time pressure (33%), and difficulty recalling the guideline (19%). Danish GPs rarely adhere to the recommended sore throat management guideline, but use various combinations of different modalities in the assessment of bacterial infection. This practice may increase antibiotic prescription rates.

The fragmentation patterns of whole genome sequenced cell-free DNA are promising features for tumor-agnostic cancer detection. However, systematic biases challenge their cross-cohort generalization. We introduce LIONHEART, a novel, open source cancer detection method specifically optimized to generalize across datasets. The method correlates bias-corrected cfDNA fragment coverage across the genome with the locations of accessible chromatin regions from 898 cell and tissue type features. We use these correlations to detect changes in the cell-free DNA cell type composition caused by cancer. We test LIONHEART on nine datasets and fourteen cancer types (1106 non-cancer controls, 1449 cancers) obtained from different studies and show that it can distinguish cancer samples from non-cancer controls across cohorts with ROC AUC scores ranging from 0.62-0.95 (mean = 0.83, std = 0.12). We further validate the method on an external dataset, achieving a ROC AUC of 0.917.

Figure S1 shows sensitivity of NCI-H2077 cells to FGFR inhibition

Figure S2 shows ORF screen for resistance to FGFR inhibition and Figure S3 shows candidate mediators of resistance to FGFR inhibition based on ORF screen.