Heterogeneous response and progression patterns reveal phenotypic heterogeneity of tyrosine kinase inhibitor response in metastatic renal cell carcinoma

SC was funded by fellowships from NIHR and Cancer Research UK. IK was funded by the UCLH Experimental Cancer Centre and UCLH NIHR Biomedical Research Centre. TP was funded by grants from Cancer Research UK (the Experimental Cancer Medicine Centre). MG was funded by grants from Cancer Research UK, Prostate Cancer UK, the Prostate Cancer Foundation, the Schottlander Research Charitable Trust, the Royal Marsden NIHR Biomedical Research Centre for Cancer and the Wellcome Trust (grant number: 105104/Z/14/Z

Teaching breast ultrasound skills including core-needle biopsies on a phantom enhances undergraduate student's knowledge and learning satisfaction

Purpose To investigate whether a training program on breast ultrasound skills including core-needle biopsies to undergraduate students can improve medical knowledge and learning satisfaction. Methods Medical students attending mandatory classes at the Medical School of the University of Saarland received a supplemental theoretical and hands-on training program on ultrasound (US) breast screening and on US-guided core-needle biopsy using an agar–agar phantom. Experienced breast specialists and ultrasound examiners served as trainers applying Peyton’s 4-step training approach. The students’ theoretical knowledge and hands-on skills were tested before and after the training program, using a multiple-choice questionnaire (MCQ), the Objective Structured Clinical Examination (OSCE) and a student curriculum evaluation. Results The MCQ results showed a significant increase of the student’s theoretical knowledge (50.2–75.2%, p < 0.001). After the course, the OSCE showed a mean total of 17.3/20 points (86.5%), confirming the practical implementation of the new skills. The student curriculum evaluation in general was very positive. A total of 16/20 questions were rated between 1.2 and 1.7 (very good) and 3 questions were rated as 2.1 (good). Conclusion Undergraduate student’s medical education can be enhanced by teaching breast US skills

Proteomics uncover EPHA2 as a potential novel therapeutic target in colorectal cancer cell lines with acquired cetuximab resistance.

BACKGROUND: In metastatic colorectal cancer (mCRC), acquired resistance against anti-EGFR targeted monoclonal antibodies, such as cetuximab (CET), was shown to be frequently caused by activating alterations in the RAS genes KRAS or NRAS. To this day, no efficient follow-up treatment option has emerged to treat mCRC in such a setting of resistance. METHODS: To uncover potential targets for second-line targeted therapies, we used mass-spectrometric proteomics to shed light on kinome reprogramming in an established cellular model of acquired, KRAS-associated CET resistance. RESULTS: This CET resistance was reflected by significant changes in the kinome, most of them individual to each cell line. Interestingly, all investigated resistant cell lines displayed upregulation of the Ephrin type-A receptor 2 (EPHA2), a well-known driver of traits of progression. Expectedly resistant cell lines displayed increased migration (p < 0.01) that was significantly reduced by targeting the EPHA2 signalling axis using RNA interference (RNAi) (p < 0.001), ephrin-A1 stimulation (p < 0.001), dasatinib (p < 0.01), or anti-EPHA2 antibody treatment (p < 0.001), identifying it as an actionable target in mCRC with acquired CET resistance. CONCLUSION: These results highlight EPHA2 and its role in mCRC with KRAS-gene mutated acquired CET resistance and support its use as a potential actionable target for the development of future precision medicine therapies

Characterization of the “frequent exacerbator phenotype” in bronchiectasis

Rationale: Exacerbations are key events in the natural history of bronchiectasis, but clinical predictors and outcomes of patients with frequently exacerbating disease are not well described. Objectives: To establish if there is a \u201cfrequent exacerbator phenotype\u201d in bronchiectasis and the impact of exacerbations on long-term clinical outcomes. Methods: We studied patients with bronchiectasis enrolled from 10 clinical centers in Europe and Israel, with up to 5 years of follow-up. Patients were categorized by baseline exacerbation frequency (zero, one, two, or three or more per year). The repeatability of exacerbation status was assessed, as well as the independent impact of exacerbation history on hospitalizations, quality of life, and mortality. Measurements and Main Results: A total of 2,572 patients were included. Frequent exacerbations were the strongest predictor of future exacerbation frequency, suggesting a consistent phenotype.The incident rate ratios for future exacerbations were 1.73 (95% confidence interval [CI], 1.47-2.02; P, 0.0001) for one exacerbation per year, 3.14 (95% CI, 2.70-3.66; P, 0.0001) for two exacerbations, and 5.97 (95% CI, 5.27-6.78; P, 0.0001) for patients with three or more exacerbations per year at baseline. Additional independent predictors of future exacerbation frequency were Haemophilus influenzae and Pseudomonas aeruginosa infection, FEV1, radiological severity of disease, and coexisting chronic obstructive pulmonary disease. Patients with frequently exacerbating disease had worse quality of life and were more likely to be hospitalized during followup. Mortality over up to 5 years of follow-up increased with increasing exacerbation frequency. Conclusions: The frequent exacerbator phenotype in bronchiectasis is consistent over time and shows high disease severity, poor quality of life, and increased mortality during follow-up

Glioblastoma adaptation traced through decline of an IDH1 clonal driver and macro-evolution of a double-minute chromosome

Background: Glioblastoma (GBM) is the most common malignant brain cancer occurring in adults, and is associated with dismal outcome and few therapeutic options. GBM has been shown to predominantly disrupt three core pathways through somatic aberrations, rendering it ideal for precision medicine approaches. Methods: We describe a 35-year-old female patient with recurrent GBM following surgical removal of the primary tumour, adjuvant treatment with temozolomide and a 3-year disease-free period. Rapid whole-genome sequencing (WGS) of three separate tumour regions at recurrence was carried out and interpreted relative to WGS of two regions of the primary tumour. Results: We found extensive mutational and copy-number heterogeneity within the primary tumour. We identified a TP53 mutation and two focal amplifications involving PDGFRA, KIT and CDK4, on chromosomes 4 and 12. A clonal IDH1 R132H mutation in the primary, a known GBM driver event, was detectable at only very low frequency in the recurrent tumour. After sub-clonal diversification, evidence was found for a whole-genome doubling event and a translocation between the amplified regions of PDGFRA, KIT and CDK4, encoded within a double-minute chromosome also incorporating miR26a-2. The WGS analysis uncovered progressive evolution of the double-minute chromosome converging on the KIT/PDGFRA/PI3K/mTOR axis, superseding the IDH1 mutation in dominance in a mutually exclusive manner at recurrence, consequently the patient was treated with imatinib. Despite rapid sequencing and cancer genome-guided therapy against amplified oncogenes, the disease progressed, and the patient died shortly after. Conclusion: This case sheds light on the dynamic evolution of a GBM tumour, defining the origins of the lethal sub-clone, the macro-evolutionary genomic events dominating the disease at recurrence and the loss of a clonal driver. Even in the era of rapid WGS analysis, cases such as this illustrate the significant hurdles for precision medicine success