julilili42/papers huggingface dataset:
Pathological complete response rate and survival in patients with BRCA-associated triple-negative breast cancer after 12 weeks of de-escalated neoadjuvant chemotherapy: Translational results of the WSG-ADAPT TN randomized phase II trial (NCT01815242).
2021-05-20

579 Background: The phase II trial WSG-ADAPT TN randomized triple-negative breast cancer (TNBC) patients to receive 12 weeks of neoadjuvant nab-paclitaxel (nab-pac) combined with carboplatin (carbo) vs gemcitabine (gem) and showed a substantial improvement of pathological complete response (pCR: ypT0/is, ypN0) with carbo (45.9% vs 28.7%). pCR had a strong favorable impact on iDFS after 3-year follow-up. Distribution of tumor mutations in BC-associated genes and impact of BRCA mutation status on pCR and outcome are analyzed here. Methods: NGS-based mutational analysis of BRCA1/2 and 18 further (potentially) BC-associated genes was performed on DNA derived from pretreatment FFPE samples (gem: n = 158, carbo: n = 108) using a customized gene panel. Variants with a variant fraction of ≥5% were included and classified according to IARC and ENIGMA guidelines. Results: In 42 of the 266 analyzed samples, at least one deleterious BRCA1/2-variant was found (15.8%; BRCA1 n = 37, BRCA2 n = 3, BRCA1+ BRCA2 n = 2) one of which displayed an additional STK11-mutation. In the BRCA1/2-negative cohort, a mutation in one of 14 further analyzed (potential) BC-risk genes was found in 19 samples (7.1%; BARD1 n = 3, CHEK2 n = 2, CDH1 n = 2, FANCM n = 3, PALB2 n = 5, RAD50 n = 1, RAD51C n = 1, RAD51D n = 1, XRCC2 n = 1; no deleterious mutations were found in ATM, BRIP1, MRE11A, NBN). At least one deleterious variant in TP53, PIK3CA, PTEN or MAP3K1 was seen in 89.1% (n = 237; TP53 n = 233, PIK3CA n = 22 PTEN n = 15, MAP3K1 n = 1). In 22 samples (8.3%) no deleterious mutation was identified in the analyzed genes. Overall, patients with tumor BRCA mutation (carbo n = 14, gem n = 28) had 45.2% vs 34.4% pCR (OR = 1.58, 95%-CI: 0.81-3.07, p =.18) without a mutation. pCR in the small group with mutation receiving carbo (n = 14) was 64.3% vs. 34.5% in all others (OR = 3.41, 95%-CI: 1.11-10.50; p =.03); direct comparison to BRCA-positive patients receiving gem (n = 28, 35.7%, OR = 3.2, 95%-CI: 0.85-12.36, p = 0.079) did not reach statistical significance. The results suggest that the strong favorable impact of pCR on iDFS is preserved even among BRCA-positive patients (n = 42, p =.07), as well as in the BRCA-negative subgroup (p &lt;.001). No evidence for a predictive impact of BRCA mutation on efficacy of 4xEC additional chemotherapy was seen overall or within pCR subgroups. Conclusions: Twelve weeks of neoadjuvant nab-pac/carbo is a highly effective anthracycline-free regimen that leads to an excellent pCR-rate of 64% in tumor BRCA1/2-mutated cases. BRC A1/2 mutation status could support this de-escalation strategy in early TNBC, but further prospective validation of survival impacts in larger cohorts and with longer follow up is needed. More detailed survival analyses will be presented at the meeting. Clinical trial information: NCT01815242.
Tumor-derived GDF-15 to suppress t-lymphocyte recruitment to the tumor microenvironment resulting in resistance to ANTI-PD-1 treatment.
2021-05-20

e14532 Background: Growth and differentiation factor 15 (GDF-15) is a divergent member of the TGF-β superfamily with low to absent expression in healthy tissue. GDF-15 has been linked to feto-maternal immune tolerance, to prevention of excessive immune cell infiltration during tissue damage, and to anorexia. Various major tumor types secrete high levels of GDF-15. In cancer patients, elevated GDF-15 serum levels correlate with poor prognosis and reduced overall survival (OS). Methods: Impact of a proprietary GDF-15 neutralizing antibody (CTL-002) regarding T cell trafficking was analyzed by whole blood adhesion assays, a HV18-MK melanoma-bearing humanized mouse model and a GDF-15-transgenic MC38 model. Additionally, patient GDF-15 serum levels were correlated with clinical response and overall survival in oropharyngeal squamous cell carcinoma (OPSCC) and melanoma brain metastases. Results: In whole blood cell adhesion assays GDF-15 impairs adhesion of T and NK cells to activated endothelial cells. Neutralization of GDF-15 by CTL-002 rescued T cell adhesion. In HV18-MK-bearing humanized mice CTL-002 induced a strong increase in TIL numbers. Subset analysis revealed an overproportional enrichment of T cells, in particular CD8 + T cells. As immune cell exclusion is detrimental for checkpoint inhibitor (CPI) therapy, a GDF-15-transgenic MC38 model was tested for anti-PD-1 therapy efficacy. In GDF-15 overexpressing MC38 tumors response to anti PD-1 therapy was reduced by 90% compared to wtMC38 tumors. Combining aPD-1 with CTL-002 resulted in 50% of the mice rejecting their GDF-15 overexpressing tumors. Clinically, inverse correlations of GDF-15 levels with CD8 + T cell infiltration were shown for HPV + OPSCC and for melanoma brain metastases. GDF-15 serum levels were significantly higher in HPV- than in HPV+ OPSCC patient (p &lt; 0.0001). Low GDF-15 levels corresponded to longer OS in both HPV- and HPV+ OPSCC. In two independent melanoma patient cohorts treated with nivolumab or pembrolizumab low baseline serum GDF-15 levels were predictive for clinical response to anti-PD1 treatment and superior OS. Bivariate analysis including LDH indicates that GDF-15 independently predicts poor survival in aPD-1 treated melanoma patients. Conclusions: Taken together our in vitro and in vivo data show that elevated GDF-15 levels block T-cell infiltration into tumor tissues. Neutralizing GDF-15 with CTL-002 restores the ability of T cells to extravasate blood vessels and enter tumor tissue both in vitro and in vivo. In melanoma, patients with higher GDF-15 levels have significantly shorter survival and are less likely to respond to anti-PD1 therapy. GDF-15 may thus serve as a new predictive biomarker for anti-PD1 response, but most importantly also represents a novel target for cancer immunotherapy to improve tumor immune cell infiltration and response to anti-PD1 therapy.
Development of the First Covalent Monopolar Spindle Kinase 1 (MPS1/TTK) Inhibitor
2021-05-20

Monopolar spindle kinase 1 (MPS1/TTK) is a key element of the mitotic checkpoint securing proper chromosome segregation. It is being evaluated as a target in the treatment of aggressive tumors such as triple-negative breast cancer with several reversible inhibitors currently undergoing clinical trials. While long drug–target residence times have been suggested to be beneficial in the context of therapeutic MPS1 inhibition, no irreversible inhibitors are known. Here we present the design and characterization of the first irreversible covalent MPS1 inhibitor RMS-07 targeting a cysteine (Cys604) in the kinase's hinge region present only in few other protein kinases. The compound showed excellent MPS1 inhibitory potency and high selectivity against all protein kinases harboring an equivalent cysteine as well as in a larger differential scanning fluorimetry-based screening panel. Covalent binding was confirmed by mass spectrometry and X-ray crystal structure. We expect this tool compound to open new avenues for the design of MPS1-specific covalent chemical probes or drugs.
Parenteral nutrition for preterm infants: correcting for arachidonic and docosahexaenoic acid may not suffice
2021-05-20

In their review, Frazer and Martin1 address imbalanced supply with arachidonic (ARA) and docosahexaenoic acid (DHA) as central to preterm infant parenteral nutrition, advocating administration in adequate amounts and ratios, that fish oil containing suspensions corrupt physiological fatty acid profile and that supplying DHA without ARA is harmful to preterm infants <29 weeks. At 4 g/kg/d fat supply, SMOFlipid (2–7 mg/mL DHA) delivers 40–140 mg/kg/d DHA, but <10 mg/kg/d ARA (own unpublished data), contrasting with ~140–212 mg/kg/d ARA and ~43 mg/kg/d DHA physiological accretion during the third trimester. While we fully agree, additional aspects should be taken into account: 1. The authors suggest an ARA:DHA ratio of 2:1, which was associated with superior outcome when compared with lower ...
The efficacy of enzalutamide (ENZA) plus androgen deprivation therapy (ADT) on bone oligometastatic hormone-sensitive prostate cancer: A post hoc analysis of ARCHES.
2021-05-20

5071 Background: In ARCHES (NCT02677896), ENZA + ADT reduced the risk of radiographic progression and improved secondary clinical outcomes in patients with metastatic hormone-sensitive prostate cancer (mHSPC) with variable patterns of disease spread over placebo (PBO) + ADT. This post hoc analysis aimed to evaluate the efficacy of ENZA + ADT in patients with bone oligometastatic mHSPC compared to polymetastatic mHSPC in ARCHES. Methods: Patients with mHSPC (n = 1150) were randomized 1:1 to ENZA (160 mg/day) + ADT or PBO + ADT, stratified by disease volume and prior docetaxel chemotherapy. This post hoc analysis included patients with bone metastases only, categorized as oligometastatic (1–≤5 metastases) or as polymetastatic (≥6 metastases) based on central review at screening. Efficacy outcomes were compared across treatment arms. Results: Of the ARCHES population with bone metastases (n = 512), the largest subgroup included patients with ≤5 metastases (ENZA + ADT, n = 160; PBO + ADT, n = 136). Baseline characteristics were generally comparable between treatment arms and across subgroups. When compared to PBO + ADT, ENZA + ADT improved rPFS and secondary endpoints in patients with ≤5 metastases (Table). Similar results were observed across other oligometastatic subgroups (1–≤4) as well as in polymetastatic disease (≥6). The safety profile of ENZA + ADT versus PBO + ADT was similar across subgroups and consistent with previous findings. Conclusions: This post hoc analysis demonstrates that ENZA + ADT provides clinical benefit across bone oligometastatic as well as polymetastatic mHSPC, supporting the utility of ENZA irrespective of metastatic burden in the ARCHES study. Clinical trial information: NCT02677896. [Table: see text]
Treatment outcome and functional characterization of uncommon EGFR mutations in the German National Network Genomic Medicine Lung Cancer (nNGM).
2021-05-20

9036 Background: The nNGM centralizes molecular diagnostics, treatment recommendations and follow-up reporting in NSCLC in Germany. Uncommon EGFR mutations pose a clinical challenge because they comprise a heterogenous group and analyses of treatment outcome are still scarce. Here, we analyzed follow-up data of patients with rare EGFR mutations and performed functional characterization of recurrent mutations with unknown function. Methods: This multicenter, retrospective analysis of uncommon EGFR mutations (excluding L858R-, T790M mutations and exon 19 deletions) includes stage IV patients with NSCLC from 12 nNGM centers. We categorized EGFR-mutations into 3 groups: uncommon EGFR mutations with known driver function, for instance E709X, G719X, S768I and L861Q (group 1), exon 20 insertions (group 2) and all other very rare mutations (group 3). Functional characterization of unknown mutations was performed by insertion mutagenesis in Ba/F3 cells and monitoring of growth factor-independent proliferation. Results: In total, 834 cases with uncommon EGFR mutations were reported. Follow-up data after EGFR-TKI (Erlotinib, Gefitinib, Afatinib and Osimertinib), chemotherapy and/or mono-PD(L)1 blockade was available for 252 patients. Mean progression free survival (mPFS) on EGFR-TKIs vs. chemotherapy was 6.6 months vs. 5.0 months (HR 0.54, 95%CI 0.35 to 0.81, P =.003) in group 1 (n = 84), and 6.7 months vs. 3.4 months (HR 0.66, 95%CI 0.47 to 0.92, P =.015) in group 3 (n = 104). Mono-anti-PD(L1) blockade was not superior to chemotherapy (group 1, mPFS 3.0 months, HR 1.32, 95% 0.55 – 3.15, P =.535 and group3, mPFS 4.3 months, HR 1.02, 95% CI 0.64 – 1.62, P = 0.951). Exon 20 insertions (group 2, n = 63) did not benefit from EGFR-TKIs or anti-PD(L1) blockade vs. chemotherapy. Overall survival (OS) analysis (n = 218) following chemotherapy (56%) or EGFR-TKI treatment (44%) showed median OS (mOS) of 18.0 months vs. 13.9 months in patients treated with EGFR-TKI and chemotherapy, respectively in group 1 (HR 0.97, 95%CI 0.54 to 1.75, P =.929). In group 3 patients treated with EGFR-TKI and chemotherapy had a mOS of 35.4 months vs. 12.0 months, respectively (HR 0.59, 95%CI 0.35 to 1.01, P =.056). In the Ba/F3 system we could identify 8 recurrent driver and 12 non-driver mutations with a clinically applicable assay turnaround time of 4 weeks to inform clinical decision-making in the future. Conclusions: This real-world dataset confirms that patients with group 1(uncommon) EGFR mutations benefit from EGFR-TKIs and indicates that mono-anti PD(L)1 blockade is not superior to chemotherapy. Furthermore, patients with very rare EGFR mutations (group 3) also experienced a PFS benefit from EGFR-TKI compared to chemotherapy while immune therapy was not beneficial.
Attention Trade-Off for Localization and Saccadic Remapping
2021-05-20

Predictive remapping may be the principal mechanism of maintaining visual stability, and attention is crucial for this process. We aimed to investigate the role of attention in predictive remapping in a dual task paradigm with two conditions, with and without saccadic remapping. The first task was to remember the clock hand position either after a saccade to the clock face (saccade condition requiring remapping) or after the clock being displaced to the fixation point (fixation condition with no saccade). The second task was to report the remembered location of a dot shown peripherally in the upper screen for 1 s. We predicted that performance in the two tasks would interfere in the saccade condition, but not in the fixation condition, because of the attentional demands needed for remapping with the saccade. For the clock estimation task, answers in the saccadic trials tended to underestimate the actual position by approximately 37 ms while responses in the fixation trials were closer to veridical. As predicted, the findings also revealed significant interaction between the two tasks showing decreased predicted accuracy in the clock task for increased error in the localization task, but only for the saccadic condition. Taken together, these results point at the key role of attention in predictive remapping.
Modeling the oxygen uptake, transport and consumption in an estivating terrestrial snail, Xeropicta derbentina, by the Colburn analogy
2021-05-20

The present work gives insight into the internal heat management of the respiratory system in the terrestrial snail Xeropicta derbentina , which has to cope with extreme climate conditions in its habitat. A realistic model of the lung ́s vein system was constructed and the active diffusive surface of capillaries and main vein was calculated and confirmed by geometrical measurements. We here present a model that is able to validate the measured oxygen consumption by the use of the Colburn analogy between mass and momentum transfer. By combining basic diffusion laws with the momentum transfer, i.e. wall shear stress, at the inner wall of the lung capillaries and the main vein, the progression of the oxygen mass fraction in the hemolymph can be visualized.
An Early Bronze Age Burial with a Golden Spiral Ring from Ammerbuch-Reusten, Southwestern Germany
2021-05-20

Abstract A women’s burial of the Early Bronze Age that was uncovered near Ammerbuch-Reusten, Tübingen district in autumn 2020 shows clear relations to burial rites of the Final Neolithic in central Europe. The only grave good was in the rear of the burial. A small spiral ring made of gold wire at the left side of the burial at hip level, which can be considered to be the earliest securely dated precious metal find in southwestern Germany. The find fits into a small series of early spiral rings made of gold wire, which are among the oldest precious metal finds in central Europe. Its composition with c. 20 % silver and less than 2 % copper as well as traces of platinum and tin indicates the use of a naturally occurring gold alloy, most likely from so-called alluvial deposits obtained by panning from rivers. The trace element pattern strongly suggests that this type of gold derives from Cornwall, specifically from River Carnon. The burial matches a group of other burials from the Bronze Age on the plateau and is apparently related to a hilltop settlement on the nearby Kirchberg of Reusten.
Encorafenib plus Binimetinib in patients with locally advanced, unresectable or metastatic BRAFV600-mutant melanoma: First data of the multicenter, multinational, prospective, non-interventional longitudinal study BERINGMELANOMA.
2021-05-20

9555 Background: For the treatment of advanced BRAF V600 -mutated melanoma, targeted therapy (BRAF/MEK-inhibition) is a standard of care. Encorafenib + binimetinib (EB) were approved in the EU in Sep 2018 and in Switzerland in Nov 2019, based on positive results from COLUMBUS (NCT01909453), with a median progression-free survival (PFS) of 14.9 mo (4-year PFS: 26%) and overall survival (OS) of 33.6 mo (4-year OS: 39%). As data from controlled trials are based on selected populations, BERING MELANOMA investigates the use of EB under real-world conditions in a broader population. Methods: BERING MELANOMA is an ongoing, multi-national, multi-center, prospective, longitudinal, non-interventional study. It analyzes the effectiveness, quality of life and tolerability of EB-treatment under real-world conditions (primary endpoint: 1-year PFS-rate), focusing on the first- (1L) and second-line setting and including an evaluation of the impact of prognostic factors. The project aims to enroll up to 750 patients (pts) in a total of 80 German, Austrian and Swiss sites with a study duration of 8 yrs. So far, from Oct 2019 to Jan 2021, 153 pts have been included. Pts with prior BRAF-/MEK-inhibition (except adjuvant use completed &gt; 6 mo) and &gt; 1 prior treatment line were excluded. Results: Here we present the first planned interim analysis based on the initial 100 enrolled pts (91 treated / 89 evaluable; median follow-up: 8.1 mo). This analysis set shows a median age of 63.0 yrs (range 29.0-88.0), 52% of pts were female. 81% presented with distant metastases (brain: 31%), with an involvement of ≥3 organ systems in 51% and an elevated LDH in 42%. 54% of pts underwent prior systemic therapy (adjuvant: 28%; 1L: 24%, with ipilimumab + nivolumab as main 1L-treatment: 52%). EB was mainly administered in the 1L-setting (65%). Main reasons for EB-selection were: physician's preference (37%), efficacy (34%), quality of life (21%). Median estimated EB treatment duration was 12.7 mo (95%CI 8.3-NE), median relative dose intensity was 100% for both drugs. Treatment adaptations were required in 34% of pts. Adverse events (AE) were reported in 76% of pts (grade 3/4: 26%). Main AE (≥10%, all grades) were: nausea (18%), diarrhea (17%), CK increase (15%), fatigue (11%), gamma-GT increase (11%). No fatal toxicities were observed. Conclusions: This first interim analysis of BERING MELANOMA shows an investigation of EB in a real-world population with advanced disease. Despite the poorer prognosis configuration as compared to the pivotal study, the observed treatment duration and tolerability profile are largely consistent with data derived from COLUMBUS without any new safety signals. The second interim analysis will be performed after enrollment of 200 pts and will include an initial analysis of effectiveness data. Clinical trial information: NCT04045691.
TMB and BRAF mutation status are independent predictive factors in stage IIIC/D/IV melanoma patients receiving adjuvant PD-1 antibodies.
2021-05-20

9524 Background: High tumor mutational burden (TMB) is associated with a favorable outcome in metastatic melanoma patients treated with immune checkpoint inhibitors. However, data are limited in the adjuvant setting. As BRAF mutated patients have an alternative with targeted adjuvant therapy, it is important to identify predictive factors for relapse and recurrence-free survival (RFS) in patients receiving adjuvant PD-1 antibodies. Methods: We systematically evaluated all melanoma patients who started adjuvant PD-1 antibody therapy at our center between March 2018 and September 2019 to identify predictive factors for outcome. The median follow-up time from start of adjuvant anti-PD-1 therapy was 22 months. Tumor and normal tissue of all stage IIIC/D/IV patients and of stage IIIA/B patients with relapse were sequenced using a 700 genes panel. Predictive factors for relapse and RFS were identified using univariate and multivariate logistic and Cox regression analysis. RFS was estimated by the Kaplan-Meier method. TMB high was defined as the top 20 % of the cohort, corresponding to TMB values ≥ 20 Var/Mb. Results: A total of 165 patients were included in this study. According to AJCC 8 th the initial tumor stages at the beginning of adjuvant anti-PD-1 therapy were as follows: N = 80 stage IIIA/B (48 %), N = 85 stage IIIC/D/IV (52 %). 72/165 patients (44 %) suffered a relapse, 44/72 (61 %) with loco regional and 28/72 (39 %) with distant metastases. Sequencing results were available from 79 / 85 patients with stage IIIC/D/IV. Here we present the results of this cohort. TMB low (OR 17.46, 95%CI 4.03-75.55; p &lt; 0.0001) or absence of BRAF V600E/K mutation (OR 4.13, 95%CI 1.36-12.53; p = 0.012) were statistically significant, independent predictive factors for relapse. Also, with regard to RFS, BRAF mutation status and TMB were statistically significant and independent predictive factors. In the table below we display results for the combined variables. Patients with BRAF V600E/K mutation and TMB high had the best outcome. Conclusions: We identified TMB high as positive predictive marker in stage IIIC/D/IVmelanoma patients with adjuvant PD-1 antibody therapy. In tumors with BRAF V600E/K mutation and concurrent low TMB, adjuvant targeted therapy with BRAF- and MEK-inhibitors may be an alternative. This is also supported by the data on adjuvant dabrafenib and trametinib, which showed a greater advantage in patients with low TMB, presumably due to less tumor heterogeneity.[Table: see text]
Development of the First Covalent Monopolar Spindle Kinase 1 (MPS1/TTK) Inhibitor
2021-05-20

Monopolar spindle kinase 1 (MPS1/TTK) is a key element of the mitotic checkpoint securing proper chromosome segregation. It is being evaluated as a target in the treatment of aggressive tumors such as triple-negative breast cancer with several reversible inhibitors currently undergoing clinical trials. While long drug–target residence times have been suggested to be beneficial in the context of therapeutic MPS1 inhibition, no irreversible inhibitors are known. Here we present the design and characterization of the first irreversible covalent MPS1 inhibitor &lt;b&gt;RMS-07&lt;/b&gt; targeting a cysteine (Cys604) in the kinase's hinge region present only in few other protein kinases. The compound showed excellent MPS1 inhibitory potency and high selectivity against all protein kinases harboring an equivalent cysteine as well as in a larger differential scanning fluorimetry-based screening panel. Covalent binding was confirmed by mass spectrometry and X-ray crystal structure. We expect this tool compound to open new avenues for the design of MPS1-specific covalent chemical probes or drugs.