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Cancer genetics has to date focused on epithelial malignancies, identifying multiple histotype-specific pathways underlying cancer susceptibility. Sarcomas are rare malignancies predominantly derived from embryonic mesoderm. To identify pathways specific to mesenchymal cancers, we performed whole-genome germline sequencing on 1644 sporadic cases and 3205 matched healthy elderly controls. Using an extreme phenotype design, a combined rare-variant burden and ontologic analysis identified two sarcoma-specific pathways involved in mitotic and telomere functions. Variants in centrosome genes are linked to malignant peripheral nerve sheath and gastrointestinal stromal tumors, whereas heritable defects in the shelterin complex link susceptibility to sarcoma, melanoma, and thyroid cancers. These studies indicate a specific role for heritable defects in mitotic and telomere biology in risk of sarcomas.

Hintergrund: Die Laparoskopie spielt im modernen, chirurgischen Klinikalltag eine wichtige Rolle, welche sich zum jetzigen Zeitpunkt noch nicht in den Lehrplänen der Universitäten widerspiegelt. Laparoskopie-Simulatoren bieten die Möglichkeit, Studierenden laparoskopische Basiskenntnisse außerhalb des Operationssaals zu lehren. Zielsetzung: Ziel dieser Studie war es, Laparoskopie-Fertigkeiten der Studierenden und die darauf wirkenden Einflussfaktoren zu untersuchen. Außerdem sollten die Laparoskopie-Fertigkeiten mit anderen praktischen Fähigkeiten der Studierenden korreliert werden. Methodik: Im Rahmen der OSCE-Prüfungen wurde eine Laparoskopie-Station eingerichtet, an der n=306 (OSCE1 n=148, OSCE2 n=158) Medizinstudierende am Laparoskopie-Simulator eine definierte Laparoskopie-Übung (rope pass) durchführten. Die Durchführung wurde auf Video aufgezeichnet, standardisiert ausgewertet und mit Angaben aus einem demographischen Fragebogen, mit den Ergebnissen aus der OSCE-Prüfung und einem Fragebogen zur subjektiven Arbeitsbelastung (NASA-TLX-Score) korreliert. Ergebnisse: Laparoskopie-Vorerfahrung war der stärkste Einflussfaktor auf die Laparoskopie-Fertigkeit der Studierenden. Probanden, die die Übung schneller durchführten, zeigten eine reduzierte subjektive Arbeitsbelastung. Es gab keine Korrelation zwischen den Fähigkeiten, die zum Laparoskopieren benötigt werden und dem Abschneiden an den anderen OSCE-Stationen. Schlussfolgerung/Ausblick: Laparoskopie-Simulatoren können zur studentischen Lehre von laparoskopischen Basisfertigkeiten sowie deren Evaluation eingesetzt werden. Eine Integration von Laparoskopie-Simulation in die Lehrpläne der Universitäten bedarf weiterer Forschung zum optimalen Zeitpunkt, zum Umfang und zur konkreten Umsetzung.

BackgroundMerkel cell carcinoma (MCC) is an aggressive skin cancer associated with poor survival. Programmed cell death-1 (PD-1) pathway inhibitors have shown high rates of durable tumor regression compared with chemotherapy for MCC. The current study was undertaken to assess baseline and on-treatment factors associated with MCC regression and 3-year survival, and to explore the effects of salvage therapies in patients experiencing initial non-response or tumor progression after response or stable disease following first-line pembrolizumab therapy on Cancer Immunotherapy Trials Network-09/KEYNOTE-017.MethodsIn this multicenter phase II trial, 50 patients with advanced unresectable MCC received pembrolizumab 2 mg/kg every 3 weeks for ≤2 years. Patients were followed for a median of 31.8 months.ResultsOverall response rate to pembrolizumab was 58% (complete response 30%+partial response 28%; 95% CI 43.2 to 71.8). Among 29 responders, the median response duration was not reached (NR) at 3 years (range 1.0+ to 51.8+ months). Median progression-free survival (PFS) was 16.8 months (95% CI 4.6 to 43.4) and the 3-year PFS was 39.1%. Median OS was NR; the 3-year OS was 59.4% for all patients and 89.5% for responders. Baseline Eastern Cooperative Oncology Group performance status of 0, greater per cent tumor reduction, completion of 2 years of treatment and low neutrophil-to-lymphocyte ratio were associated with response and longer survival. Among patients with initial disease progression or those who developed progression after response or stable disease, some had extended survival with subsequent treatments including chemotherapies and immunotherapies.ConclusionsThis study represents the longest available follow-up from any first-line anti-programmed death-(ligand) 1 (anti-PD-(L)1) therapy in MCC, confirming durable PFS and OS in a proportion of patients. After initial tumor progression or relapse following response, some patients receiving salvage therapies survived. Impro

We perform an immunogenomics analysis utilizing whole-transcriptome sequencing of 657 pediatric extracranial solid cancer samples representing 14 diagnoses, and additionally utilize transcriptomes of 131 pediatric cancer cell lines and 147 normal tissue samples for comparison. We describe patterns of infiltrating immune cells, T cell receptor (TCR) clonal expansion, and translationally relevant immune checkpoints. We find that tumor-infiltrating lymphocytes and TCR counts vary widely across cancer types and within each diagnosis, and notably are significantly predictive of survival in osteosarcoma patients. We identify potential cancer-specific immunotherapeutic targets for adoptive cell therapies including cell-surface proteins, tumor germline antigens, and lineage-specific transcription factors. Using an orthogonal immunopeptidomics approach, we find several potential immunotherapeutic targets in osteosarcoma and Ewing sarcoma and validated PRAME as a bona fide multi-pediatric cancer target. Importantly, this work provides a critical framework for immune targeting of extracranial solid tumors using parallel immuno-transcriptomic and -peptidomic approaches.

Merkel cell carcinoma (MCC) is an aggressive skin cancer associated with poor survival. Programmed cell death-1 (PD-1) pathway inhibitors have shown high rates of durable tumor regression compared with chemotherapy for MCC. The current study was undertaken to assess baseline and on-treatment factors associated with MCC regression and 3-year survival, and to explore the effects of salvage therapies in patients experiencing initial non-response or tumor progression after response or stable disease following first-line pembrolizumab therapy on Cancer Immunotherapy Trials Network-09/KEYNOTE-017. In this multicenter phase II trial, 50 patients with advanced unresectable MCC received pembrolizumab 2 mg/kg every 3 weeks for ≤2 years. Patients were followed for a median of 31.8 months. Overall response rate to pembrolizumab was 58% (complete response 30%+partial response 28%; 95% CI 43.2 to 71.8). Among 29 responders, the median response duration was not reached (NR) at 3 years (range 1.0+ to 51.8+ months). Median progression-free survival (PFS) was 16.8 months (95% CI 4.6 to 43.4) and the 3-year PFS was 39.1%. Median OS was NR; the 3-year OS was 59.4% for all patients and 89.5% for responders. Baseline Eastern Cooperative Oncology Group performance status of 0, greater per cent tumor reduction, completion of 2 years of treatment and low neutrophil-to-lymphocyte ratio were associated with response and longer survival. Among patients with initial disease progression or those who developed progression after response or stable disease, some had extended survival with subsequent treatments including chemotherapies and immunotherapies. This study represents the longest available follow-up from any first-line anti-programmed death-(ligand) 1 (anti-PD-(L)1) therapy in MCC, confirming durable PFS and OS in a proportion of patients. After initial tumor progression or relapse following response, some patients receiving salvage therapies survived. Improving the management of anti-PD-(

We perform an immunogenomics analysis utilizing whole-transcriptome sequencing of 657 pediatric extracranial solid cancer samples representing 14 diagnoses, and additionally utilize transcriptomes of 131 pediatric cancer cell lines and 147 normal tissue samples for comparison. We describe patterns of infiltrating immune cells, T cell receptor (TCR) clonal expansion, and translationally relevant immune checkpoints. We find that tumor-infiltrating lymphocytes and TCR counts vary widely across cancer types and within each diagnosis, and notably are significantly predictive of survival in osteosarcoma patients. We identify potential cancer-specific immunotherapeutic targets for adoptive cell therapies including cell-surface proteins, tumor germline antigens, and lineage-specific transcription factors. Using an orthogonal immunopeptidomics approach, we find several potential immunotherapeutic targets in osteosarcoma and Ewing sarcoma and validated PRAME as a bona fide multi-pediatric cancer target. Importantly, this work provides a critical framework for immune targeting of extracranial solid tumors using parallel immuno-transcriptomic and -peptidomic approaches.

PURPOSE:Merkel cell carcinoma (MCC) is an aggressive skin cancer often caused by the Merkel cell polyomavirus. Clinical trials of programmed cell death-1 pathway inhibitors for advanced MCC (aMCC) demonstrate increased progression-free survival (PFS) compared with historical chemotherapy data. However, response durability and overall survival (OS) data are limited. PATIENTS AND METHODS:In this multicenter phase II trial (Cancer Immunotherapy Trials Network-09/Keynote-017), 50 adults naïve to systemic therapy for aMCC received pembrolizumab (2 mg/kg every 3 weeks) for up to 2 years. Radiographic responses were assessed centrally per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. RESULTS:Among 50 patients, the median age was 70.5 years, and 64% had Merkel cell polyomavirus-positive tumors. The objective response rate (ORR) to pembrolizumab was 56% (complete response [24%] plus partial response [32%]; 95% CI, 41.3% to 70.0%), with ORRs of 59% in virus-positive and 53% in virus-negative tumors. Median follow-up time was 14.9 months (range, 0.4 to 36.4+ months). Among 28 responders, median response duration was not reached (range, 5.9 to 34.5+ months). The 24-month PFS rate was 48.3%, and median PFS time was 16.8 months (95% CI, 4.6 months to not estimable). The 24-month OS rate was 68.7%, and median OS time was not reached. Although tumor viral status did not correlate with ORR, PFS, or OS, there was a trend toward improved PFS and OS in patients with programmed death ligand-1-positive tumors. Grade 3 or greater treatment-related adverse events occurred in 14 (28%) of 50 patients and led to treatment discontinuation in seven (14%) of 50 patients, including one treatment-related death. CONCLUSION:Here, we present the longest observation to date of patients with aMCC receiving first-line anti-programmed cell death-1 therapy. Pembrolizumab demonstrated durable tumor control, a generally manageable safety profile, and favorable OS compared with historical data

Victoria T Rizk,1 Christine M Walko,2 Andrew S Brohl3,41University of South Florida Hematology/Oncology Fellowship, 2DeBartolo Family Personalized Medicine Institute, 3Sarcoma Department, 4Chemical Biology and Molecular Medicine Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA Abstract: Advancements in molecular and genetic techniques have significantly furthered our biological understanding of Ewing sarcoma (ES). ES is typified by a driving TET–ETS fusion with an otherwise relatively quiet genome. Detection of one of several characteristic fusions, most commonly EWSR1–FLI1, is the gold standard for diagnosis. We discuss the current role of precision medicine in the diagnosis, treatment, and monitoring of ES. Continued efforts toward molecularly guided approaches are actively being pursued in ES to better refine prognosis, identify germline markers of disease susceptibility, influence therapeutic selection, effectively monitor disease activity in real time, and identify genetic and immunotherapeutic targets for therapeutic development. Keywords: Ewing sarcoma, next generation sequencing, genomics, liquid biopsy, targeted therapy

The Ewing sarcoma family of tumors (EFT) is a group of highly malignant small round blue cell tumors occurring in children and young adults. We report here the largest genomic survey to date of 101 EFT (65 tumors and 36 cell lines). Using a combination of whole genome sequencing and targeted sequencing approaches, we discover that EFT has a very low mutational burden (0.15 mutations/Mb) but frequent deleterious mutations in the cohesin complex subunit STAG2 (21.5% tumors, 44.4% cell lines), homozygous deletion of CDKN2A (13.8% and 50%) and mutations of TP53 (6.2% and 71.9%). We additionally note an increased prevalence of the BRCA2 K3326X polymorphism in EFT patient samples (7.3%) compared to population data (OR 7.1, p = 0.006). Using whole transcriptome sequencing, we find that 11% of tumors pathologically diagnosed as EFT lack a typical EWSR1 fusion oncogene and that these tumors do not have a characteristic Ewing sarcoma gene expression signature. We identify samples harboring novel fusion genes including FUS-NCATc2 and CIC-FOXO4 that may represent distinct small round blue cell tumor variants. In an independent EFT tissue microarray cohort, we show that STAG2 loss as detected by immunohistochemistry may be associated with more advanced disease (p = 0.15) and a modest decrease in overall survival (p = 0.10). These results significantly advance our understanding of the genomic and molecular underpinnings of Ewing sarcoma and provide a foundation towards further efforts to improve diagnosis, prognosis, and precision therapeutics testing.

The Ewing sarcoma family of tumors (EFT) is a group of highly malignant small round blue cell tumors occurring in children and young adults. We report here the largest genomic survey to date of 101 EFT (65 tumors and 36 cell lines). Using a combination of whole genome sequencing and targeted sequencing approaches, we discover that EFT has a very low mutational burden (0.15 mutations/Mb) but frequent deleterious mutations in the cohesin complex subunit STAG2 (21.5% tumors, 44.4% cell lines), homozygous deletion of CDKN2A (13.8% and 50%) and mutations of TP53 (6.2% and 71.9%). We additionally note an increased prevalence of the BRCA2 K3326X polymorphism in EFT patient samples (7.3%) compared to population data (OR 7.1, p = 0.006). Using whole transcriptome sequencing, we find that 11% of tumors pathologically diagnosed as EFT lack a typical EWSR1 fusion oncogene and that these tumors do not have a characteristic Ewing sarcoma gene expression signature. We identify samples harboring novel fusion genes including FUS-NCATc2 and CIC-FOXO4 that may represent distinct small round blue cell tumor variants. In an independent EFT tissue microarray cohort, we show that STAG2 loss as detected by immunohistochemistry may be associated with more advanced disease (p = 0.15) and a modest decrease in overall survival (p = 0.10). These results significantly advance our understanding of the genomic and molecular underpinnings of Ewing sarcoma and provide a foundation towards further efforts to improve diagnosis, prognosis, and precision therapeutics testing.

Uncertainty impacts many crucial issues the world is facing today from climate change prediction, to scientific modelling, to the interpretation of medical data. Decisions typically rely on data which can be aggregated from different sources and further transformed using a variety of algorithms and models. Such data processing pipelines involve different types of uncertainty. As visual data representations are able to mediate between human cognition and computational models, a trustworthy conveyance of data characteristics requires effective representations of uncertainty which take productivity and cognitive abilities, as important human factors, into account. We summarize findings resulting from prior work on interactive uncertainty visualizations. Subsequently, an evaluation study is presented which investigates the effect of different visualizations of uncertain data on users’ efficiency (time, error rate) and subjectively perceived cognitive load. A table, a static graphic, and an interactive graphic containing uncertain data were compared. The results of an online study (N = 146) showed a significant difference in the task completion time between the visualization type, while there are no significant differences in error rate. A non-parametric K-W test found a significant difference in subjective cognitive load [H (2) = 7.39, p $1amp;lt; 0.05]. Subjectively perceived cognitive load was lower for static and interactive graphs than for the numerical table. Given that the shortest task completion time was produced by a static graphic representation, we recommend this for use cases in which uncertain data are to be used time-efficiently.

Uncertainty impacts many crucial issues the world is facing today from climate change prediction, to scientific modelling, to the interpretation of medical data. Decisions typically rely on data which can be aggregated from different sources and further transformed using a variety of algorithms and models. Such data processing pipelines involve different types of uncertainty. As visual data representations are able to mediate between human cognition and computational models, a trustworthy conveyance of data characteristics requires effective representations of uncertainty which take productivity and cognitive abilities, as important human factors, into account. We summarize findings resulting from prior work on interactive uncertainty visualizations. Subsequently, an evaluation study is presented which investigates the effect of different visualizations of uncertain data on users’ efficiency (time, error rate) and subjectively perceived cognitive load. A table, a static graphic, and an interactive graphic containing uncertain data were compared. The results of an online study (N = 146) showed a significant difference in the task completion time between the visualization type, while there are no significant differences in error rate. A non-parametric K-W test found a significant difference in subjective cognitive load [H (2) = 7.39, p < 0.05]. Subjectively perceived cognitive load was lower for static and interactive graphs than for the numerical table. Given that the shortest task completion time was produced by a static graphic representation, we recommend this for use cases in which uncertain data are to be used time-efficiently.

Uncertainty impacts many crucial issues the world is facing today from climate change prediction, to scientific modelling, to the interpretation of medical data. Decisions typically rely on data which can be aggregated from different sources and further transformed using a variety of algorithms and models. Such data processing pipelines involve different types of uncertainty. As visual data representations are able to mediate between human cognition and computational models, a trustworthy conveyance of data characteristics requires effective representations of uncertainty which take productivity and cognitive abilities, as important human factors, into account. We summarize findings resulting from prior work on interactive uncertainty visualizations. Subsequently, an evaluation study is presented which investigates the effect of different visualizations of uncertain data on users’ efficiency (time, error rate) and subjectively perceived cognitive load. A table, a static graphic, and an interactive graphic containing uncertain data were compared. The results of an online study (N = 146) showed a significant difference in the task completion time between the visualization type, while there are no significant differences in error rate. A non-parametric K-W test found a significant difference in subjective cognitive load [H (2) = 7.39, p < 0.05]. Subjectively perceived cognitive load was lower for static and interactive graphs than for the numerical table. Given that the shortest task completion time was produced by a static graphic representation, we recommend this for use cases in which uncertain data are to be used time-efficiently.

To examine their luminescence behavior, two air-stable BN addition compounds were synthesized by the reaction of 5-fluoro-2-(2′-pyridyl)indole with 1,4- and 1,3-bis(bromo(methyl)boryl)benzene, respectively. Both BN adducts are luminescent. Their emission maxima (1,3-substituted BN adduct: 495 nm; 1,4-substituted BN adduct: 497 nm) are comparable with the value (490 nm) of the related mono-borylated benzene species, which is composed of a BPh2 fragment and a 5-fluoro-2-(2′-pyridyl) indole unit. The starting materials 1,4- and 1,3-bis(bromo(methyl)boryl)benzene were accessible by treatment of 1,4- or 1,3-bis(dibromoboryl)benzene with two equivalents of SnMe4. In addition, the results of the X-ray structure analyses of the B,B′-bis-5-fluoro-2-(2′-pyridyl)indolyl-complexed meta-bismethylborylbenzene fragment (9, triclinic, P1̅) as well as of 5-chloro-2-(2′-pyridyl)indole (2, monoclinic, P21/c) and 5-fluoro-2-(2′-pyridyl)indole (1, orthorhombic, Pca21) are reported. The pyridylindole derivatives of this approach were synthesized by an optimized two-step procedure from 2-acetylpyridine and 4-fluoro- or 4-chlorophenylhydrazine hydrochloride.

In the title compound, C11H14O4, an inter­mediate for the synthesis of a new kind of estrogen receptor modulator, all non-H atoms lie on a common plane (r.m.s. deviation = 0.0472 Å). All C-C bonds in the side chain are in a trans conformation, and the hydroxyl group is also trans to the methyl­ene chain. In the crystal structure, mol­ecules form centrosymmetric dimers showing a head-to-head arrangement which is stabilized by O-H...O hydrogen bonds. A weak C-H...O contact is also present.

In the title compound, C11H14O4, an inter­mediate for the synthesis of a new kind of estrogen receptor modulator, all non-H atoms lie on a common plane (r.m.s. deviation = 0.0472 Å). All C-C bonds in the side chain are in a trans conformation, and the hydroxyl group is also trans to the methyl­ene chain. In the crystal structure, mol­ecules form centrosymmetric dimers showing a head-to-head arrangement which is stabilized by O-H...O hydrogen bonds. A weak C-H...O contact is also present.