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

Posztoperatív vertigo vizsgálata stapedotomián és stapedectomián átesett betegeknél

INTRODUCTION AND AIM: The reason of gradually developing conductive hearing loss in otosclerotic patients is the ossification of the stapes footplate to the surrounding bony structures and the therapy of stapes fixation is mainly surgical. In stapedotomy the footplate of the stapes is fenestrated with laser and microdrill in a diameter of 0.8 mm, whereas in stapedectomy there is complete removal of the footplate followed by the reconstruction of the ossicular chain. In the early postoperative period, temporary vertigo is frequently recorded which significantly influences the recovery. METHOD: In the Department of Otorhinolaryngology, University of Pecs both stapedectomy and stapedotomy were performed on a daily basis between 01.02.2010 and 15.03.2012. Our study focused on comparing the degree of postoperative vertigo after the two types of surgery. We hypothesized that the smaller fenestration of the stapes footplate during stapedotomy limits exposure to the inner ear reducing the severity of dizziness. Vertigo was evaluated subjectively with a retrospective questionnaire and objectively with static posturography. RESULTS: On the 1st postoperative day, significantly fewer patients reported vertigo in the stapedotomy group and with significantly lower intensity. Results of the questionnaire regarding the later postoperative period showed no significant differences between the groups. Based on the analysis of the posturography test results, no significant difference was detected between the postoperative stability of the two groups. Results of the questionnaire and the posturography showed no correlation. Posturography test results did not confirm the presence of subjective vertigo. CONCLUSION: Many factors may play a role in the development of vertigo after stapes surgery, but the type of intervention does not influence it. Orv Hetil. 2017; 158(38): 1503-1511

Immunopeptidomics of colorectal cancer organoids reveals a sparse HLA class I neoantigen landscape and no increase in neoantigens with interferon or MEK-inhibitor treatment.

Patient derived organoids (PDOs) can be established from colorectal cancers (CRCs) as in vitro models to interrogate cancer biology and its clinical relevance. We applied mass spectrometry (MS) immunopeptidomics to investigate neoantigen presentation and whether this can be augmented through interferon gamma (IFNγ) or MEK-inhibitor treatment. Four microsatellite stable PDOs from chemotherapy refractory and one from a treatment naïve CRC were expanded to replicates with 100 million cells each, and HLA class I and class II peptide ligands were analyzed by MS. We identified an average of 9936 unique peptides per PDO which compares favorably against published immunopeptidomics studies, suggesting high sensitivity. Loss of heterozygosity of the HLA locus was associated with low peptide diversity in one PDO. Peptides from genes without detectable expression by RNA-sequencing were rarely identified by MS. Only 3 out of 612 non-silent mutations encoded for neoantigens that were detected by MS. In contrast, computational HLA binding prediction estimated that 304 mutations could generate neoantigens. One hundred ninety-six of these were located in expressed genes, still exceeding the number of MS-detected neoantigens 65-fold. Treatment of four PDOs with IFNγ upregulated HLA class I expression and qualitatively changed the immunopeptidome, with increased presentation of IFNγ-inducible genes. HLA class II presented peptides increased dramatically with IFNγ treatment. MEK-inhibitor treatment showed no consistent effect on HLA class I or II expression or the peptidome. Importantly, no additional HLA class I or II presented neoantigens became detectable with any treatment. Only 3 out of 612 non-silent mutations encoded for neoantigens that were detectable by MS. Although MS has sensitivity limits and biases, and likely underestimated the true neoantigen burden, this established a lower bound of the percentage of non-silent mutations that encode for presented neoantigens, which may be as low as 0.5%. This could be a reason for the poor responses of non-hypermutated CRCs to immune checkpoint inhibitors. MEK-inhibitors recently failed to improve checkpoint-inhibitor efficacy in CRC and the observed lack of HLA upregulation or improved peptide presentation may explain this

Phylogenetic analysis of metastatic progression in breast cancer using somatic mutations and copy number aberrations.

Several studies using genome-wide molecular techniques have reported various degrees of genetic heterogeneity between primary tumours and their distant metastases. However, it has been difficult to discern patterns of dissemination owing to the limited number of patients and available metastases. Here, we use phylogenetic techniques on data generated using whole-exome sequencing and copy number profiling of primary and multiple-matched metastatic tumours from ten autopsied patients to infer the evolutionary history of breast cancer progression. We observed two modes of disease progression. In some patients, all distant metastases cluster on a branch separate from their primary lesion. Clonal frequency analyses of somatic mutations show that the metastases have a monoclonal origin and descend from a common 'metastatic precursor'. Alternatively, multiple metastatic lesions are seeded from different clones present within the primary tumour. We further show that a metastasis can be horizontally cross-seeded. These findings provide insights into breast cancer dissemination

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

Genomic architecture and evolution of clear cell renal cell carcinomas defined by multiregion sequencing

Clear cell renal carcinomas (ccRCCs) can display intratumor heterogeneity (ITH). We applied multiregion exome sequencing (M-seq) to resolve the genetic architecture and evolutionary histories of ten ccRCCs. Ultra-deep sequencing identified ITH in all cases. We found that 73–75% of identified ccRCC driver aberrations were subclonal, confounding estimates of driver mutation prevalence. ITH increased with the number of biopsies analyzed, without evidence of saturation in most tumors. Chromosome 3p loss and VHL aberrations were the only ubiquitous events. The proportion of C>T transitions at CpG sites increased during tumor progression. M-seq permits the temporal resolution of ccRCC evolution and refines mutational signatures occurring during tumor development