Feasibility and outcome of reproducible clinical interpretation of high-dimensional molecular data: a comparison of two molecular tumor boards.

BACKGROUND: Structured and harmonized implementation of molecular tumor boards (MTB) for the clinical interpretation of molecular data presents a current challenge for precision oncology. Heterogeneity in the interpretation of molecular data was shown for patients even with a limited number of molecular alterations. Integration of high-dimensional molecular data, including RNA- (RNA-Seq) and whole-exome sequencing (WES), is expected to further complicate clinical application. To analyze challenges for MTB harmonization based on complex molecular datasets, we retrospectively compared clinical interpretation of WES and RNA-Seq data by two independent molecular tumor boards. METHODS: High-dimensional molecular cancer profiling including WES and RNA-Seq was performed for patients with advanced solid tumors, no available standard therapy, ECOG performance status of 0-1, and available fresh-frozen tissue within the DKTK-MASTER Program from 2016 to 2018. Identical molecular profiling data of 40 patients were independently discussed by two molecular tumor boards (MTB) after prior annotation by specialized physicians, following independent, but similar workflows. Identified biomarkers and resulting treatment options were compared between the MTBs and patients were followed up clinically. RESULTS: A median of 309 molecular aberrations from WES and RNA-Seq (n = 38) and 82 molecular aberrations from WES only (n = 3) were considered for clinical interpretation for 40 patients (one patient sequenced twice). A median of 3 and 2 targeted treatment options were identified per patient, respectively. Most treatment options were identified for receptor tyrosine kinase, PARP, and mTOR inhibitors, as well as immunotherapy. The mean overlap coefficient between both MTB was 66%. Highest agreement rates were observed with the interpretation of single nucleotide variants, clinical evidence levels 1 and 2, and monotherapy whereas the interpretation of gene expression changes, preclinical evidence levels 3 and 4, and combination therapy yielded lower agreement rates. Patients receiving treatment following concordant MTB recommendations had significantly longer overall survival than patients receiving treatment following discrepant recommendations or physician's choice. CONCLUSIONS: Reproducible clinical interpretation of high-dimensional molecular data is feasible and agreement rates are encouraging, when compared to previous reports. The interpretation of molecular aberrations beyond single nucleotide variants and preclinically validated biomarkers as well as combination therapies were identified as additional difficulties for ongoing harmonization efforts.

Annotation and initial evaluation of a large annotated German oncological corpus.

OBJECTIVE: We present the Berlin-Tübingen-Oncology corpus (BRONCO), a large and freely available corpus of shuffled sentences from German oncological discharge summaries annotated with diagnosis, treatments, medications, and further attributes including negation and speculation. The aim of BRONCO is to foster reproducible and openly available research on Information Extraction from German medical texts. MATERIALS AND METHODS: BRONCO consists of 200 manually deidentified discharge summaries of cancer patients. Annotation followed a structured and quality-controlled process involving 2 groups of medical experts to ensure consistency, comprehensiveness, and high quality of annotations. We present results of several state-of-the-art techniques for different IE tasks as baselines for subsequent research. RESULTS: The annotated corpus consists of 11 434 sentences and 89 942 tokens, annotated with 11 124 annotations for medical entities and 3118 annotations of related attributes. We publish 75% of the corpus as a set of shuffled sentences, and keep 25% as held-out data set for unbiased evaluation of future IE tools. On this held-out dataset, our baselines reach depending on the specific entity types F1-scores of 0.72-0.90 for named entity recognition, 0.10-0.68 for entity normalization, 0.55 for negation detection, and 0.33 for speculation detection. DISCUSSION: Medical corpus annotation is a complex and time-consuming task. This makes sharing of such resources even more important. CONCLUSION: To our knowledge, BRONCO is the first sizable and freely available German medical corpus. Our baseline results show that more research efforts are necessary to lift the quality of information extraction in German medical texts to the level already possible for English.

Velocity characteristics of atrial fibrillation sources determined by electrographic flow mapping before and after catheter ablation.

BACKGROUND: Electrographic-Flow-(EGF)-Mapping is a novel method to identify Atrial Fibrillation (AF) drivers. Sources of excitation during AF can be characterized and monitored. OBJECTIVE: The aim of this study was to evaluate the correlation between velocity of EGF around a respective AF source and its spatial variability (SV) and stability (SST). METHODS: 25 patients with AF were included in this study (persistent: n = 24, long-standing persistent: n = 1; mean age 70 ±â€¯8.3 years, male: n = 17). Focal impulse and Rotor-Mapping (FIRM) was performed in addition to pulmonary vein isolation. One-minute epochs of unipolar electrograms recorded via a 64-pole basket catheter in both atria were re-analyzed with EGF-Mapping. SST was calculated as the percentage of time in which a source was detected. RESULTS: AF sources identified with EGF-Mapping show a wide range of SV during 1 min covering between 0.12% and 38% of the recorded basket-catheter surface. The 12 atria where the sources showed highest temporal stability (TS; between 34% and 97% of 1 min recorded) and those 12 with the lowest TS (between 11 and 20%) differed significantly in their velocities (17.8 el/s vs 12.2 el/s; p < 0.01). In 11 atria ablation caused an average decrease of TS by 47% and of velocity by 27% while SV more than doubled. CONCLUSION: Less stable AF-sources with high spatial variability showed reduced excitation propagation velocity while stable AF sources displayed a high average velocity in their vicinity. Importantly, catheter ablation reduced stability of sources and velocity suggesting a role of these parameters in guidance of ablation. CONDENSED ABSTRACT: Electrographic Flow (EGF)-Mapping is a novel method to identify Atrial Fibrillation (AF) drivers based on modeling of an electrical potential surface and subsequent flow analysis. Sources of excitation during AF can be characterized and monitored. The aim of this study was to evaluate the correlation between velocity of EGF around a respective AF source and its spatial variability and stability. Less stable AF sources with high spatial variability showed reduced excitation propagation velocity while very stable AF sources displayed a high average velocity in their vicinity. Catheter ablation reduced stability of sources and velocity.

Identification of active atrial fibrillation sources and their discrimination from passive rotors using electrographical flow mapping.

BACKGROUND: The optimal ablation approach for the treatment of persistent atrial fibrillation (AF) is still under debate; however, the identification and elimination of AF sources is thought to play a key role. Currently available technologies for the identification of AF sources are not able to differentiate between active rotors or focal impulse (FI) and passive circular turbulences as generated by the interaction of a wave front with a functional obstacle such as fibrotic tissue. OBJECTIVES: This study introduces electrographic flow (EGF) mapping as a novel technology for the identification and characterization of AF sources in humans. METHODS: Twenty-five patients with AF (persistent: n = 24, long-standing persistent: n = 1; mean age 70.0 ± 8.3 years, male: n = 17) were included in this prospective study. Focal impulse and Rotor-Mapping (FIRM) was performed in addition to pulmonary vein isolation using radiofrequency in conjunction with a 3D-mapping-system. One-minute epochs were exported from the EP-recording-system and re-analyzed using EGF mapping after the procedure. RESULTS: 44 potential AF sources (43 rotors and one FI) were identified with FIRM and 39 of these rotors were targeted for ablation. EGF mapping verified 40 of these patterns and identified 24/40 (60%) as active sources while 16/40 (40%) were classified as passive circular turbulences. Four rotors were not identified by EGF mapping. CONCLUSION: EGF is the first method to identify active AF sources during AF ablation procedures in humans and discriminate them from passive rotational phenomena, which occur if the excitation wavefront passes conduction bariers. EGF mapping may allow improved guidance of AF ablation procedures.