Eulerian vs Lagrangian Irreversibility in an Experimental Turbulent Swirling Flow.

In a turbulent fluid, the time-reversal symmetry is explicitly broken by viscosity, and spontaneously broken in the inviscid limit. Recently, Drivas [J. Nonlinear Sci. 29, 65 (2019).JNSCEK0938-897410.1007/s00332-018-9476-8] proved the equivalence of two different local indicators of time irreversibility: (i) an Eulerian one, based on regularity properties of the velocity field [Duchon and Robert, Nonlinearity 13, 249 (2000).NONLE50951-771510.1088/0951-7715/13/1/312]; (ii) a Lagrangian one, based on symmetry properties of the trajectories under time reversal [Jucha et al., Phys. Rev. Lett. 113, 054501 (2014).PRLTAO0031-900710.1103/PhysRevLett.113.054501]. We test this equivalence in a turbulent Von Kármán experiment at a resolution of the order of the Kolmogorov scale using a high resolution 4D-PTV technique. We use the equivalence to perform the first joined Eulerian-Lagrangian exploration of the dynamics leading to time irreversibility, and find that it is linked with vortex interaction, suggesting a link between irreversibility and singularity.

A Model of Interacting Navier-Stokes Singularities.

We introduce a model of interacting singularities of Navier-Stokes equations, named pinçons. They follow non-equilibrium dynamics, obtained by the condition that the velocity field around these singularities obeys locally Navier-Stokes equations. This model can be seen as a generalization of the vorton model of Novikov that was derived for the Euler equations. When immersed in a regular field, the pinçons are further transported and sheared by the regular field, while applying a stress onto the regular field that becomes dominant at a scale that is smaller than the Kolmogorov length. We apply this model to compute the motion of a pair of pinçons. A pinçon dipole is intrinsically repelling and the pinçons generically run away from each other in the early stage of their interaction. At a late time, the dissipation takes over, and the dipole dies over a viscous time scale. In the presence of a stochastic forcing, the dipole tends to orientate itself so that its components are perpendicular to their separation, and it can then follow during a transient time a near out-of-equilibrium state, with forcing balancing dissipation. In the general case where the pinçons have arbitrary intensity and orientation, we observe three generic dynamics in the early stage: one collapse with infinite dissipation, and two expansion modes, the dipolar anti-aligned runaway and an anisotropic aligned runaway. The collapse of a pair of pinçons follows several characteristics of the reconnection between two vortex rings, including the scaling of the distance between the two components, following Leray scaling tc-t.

Clinicopathologic and Molecular Study of Hybrid Nerve Sheath Tumors Reveals Their Common Association With Fusions Involving VGLL3.

A subset of benign peripheral nerve sheath tumors are "hybrid" combining several lines of differentiation, most often schwannian and perineurial features. The pathogenesis of these tumors was poorly described until the recent discovery of recurrent VGLL3 rearrangements in hybrid schwannoma/perineuriomas, supporting the hypothesis that this entity represents a distinct subgroup of tumors and not only a morphologic variation of other peripheral nerve sheath tumors. Following this finding, we investigated 10 cases of hybrid peripheral nerve sheath tumors with immunohistochemistry, RNA sequencing, and array comparative genomic hybridization. By light microscopy, 7 tumors were hybrid schwannoma/perineurioma tumors, and 3 were hybrid schwannoma/neurofibroma. Most cases of hybrid schwannoma/perineuriomas displayed VGLL3 rearrangements fused in 5' either to CHD7 or CHD9 (n=6/7) and had simple diploid genetic profiles with few copy number alterations. Compared with a control group composed of 28 tumors associated with varied neural phenotypes, all VGLL3-fused tumors clustered together by transcriptomic analysis. In contrast, 1 case of hybrid schwannoma/perineurioma tumor harbored a CDH9-ZFHX3 fusion, a prominent perineurial component identified by immunohistochemistry and clustered with perineuriomas. No recurrent genetic alteration was seen in the 3 hybrid schwannoma/neurofibromas. To summarize, this study confirms and expands the recent findings on hybrid schwannoma/perineurioma, highlighting the predominance of VGLL3 fusions in these tumors.

Molecular profiling of advanced soft-tissue sarcomas: the MULTISARC randomized trial.

BACKGROUND: Soft-tissue sarcomas (STS) represent a heterogeneous group of rare tumors including more than 70 different histological subtypes. High throughput molecular analysis (next generation sequencing exome [NGS]) is a unique opportunity to identify driver mutations that can change the usual one-size-fits-all treatment paradigm to a patient-driven therapeutic strategy. The primary objective of the MULTISARC trial is to assess whether NGS can be conducted for a large proportion of metastatic STS participants within a reasonable time, and, secondarily to determine whether a NGS-guided therapeutic strategy improves participant's outcome. METHODS: This is a randomized, multicentre, phase II/III trial inspired by the design of umbrella and biomarker-driven trials. The setting plans up to 17 investigational centres across France and the recruitment of 960 participants. Participants aged at least 18 years, with unresectable locally advanced and/or metastatic STS confirmed by the French sarcoma pathological reference network, are randomized according to 1:1 allocation ratio between the experimental arm "NGS" and the standard "No NGS". NGS will be considered feasible if (i) NGS results are available and interpretable, and (ii) a report of exome sequencing including a clinical recommendation from a multidisciplinary tumor board is provided to investigators within 7 weeks from reception of the samples on the biopathological platform. A feasibility rate of more than 70% is expected (null hypothesis: 70% versus alternative hypothesis: 80%). In terms of care, participants randomized in "No NGS" arm and who fail treatment will be able to switch to the NGS arm at the request of the investigator. DISCUSSION: The MULTISARC trial is a prospective study designed to provide high-level evidence to support the implementation of NGS in routine clinical practice for advanced STS participants, on a large scale. TRIAL REGISTRATION: clinicaltrial.gov NCT03784014 .

Superficial CD34-positive fibroblastic tumor and PRDM10-rearranged soft tissue tumor are overlapping entities: a comprehensive study of 20 cases.

AIMS: Superficial CD34-positive fibroblastic tumor (SCD34FT) and PRDM10-rearranged soft tissue tumor (PRDM10-STT) are rare mesenchymal tumors. These lesions have clinicopathological similarities, but their relationship remains controversial. This study aimed to characterise a series of cases of SCD34FT and PRDM10-STT. METHODS AND RESULTS: Ten lesions each of SCD34FT and PRDM10-STT were studied using immunohistochemistry, array-comparative genomic hybridisation (aCGH), RNA sequencing and exome sequencing. Tumors mainly occurred in young adults, were generally small (< 5 cm) and arose predominantly in the superficial soft tissues of the lower extremities. Follow-up data were available in 15 cases (SCD34FT, n = 7, median 16 months; PRDM10-STT, n = 8, median 14 months), local recurrences occurred in four cases (SCD34FT, two of 10; PRDM10-STT, two of 10), while no distant spread was documented. Morphologically, tumors were relatively well-circumscribed and composed of sheets and fascicles of spindle and pleomorphic cells showing low mitotic activity (< 1/mm²) without necrosis. Other findings included: granular cell change, lipoblast-like cells, ectatic blood vessels with fibrinous material, myxoid stromal changes, metaplastic bone and increased mitotic activity (> 1/mm²). All tumors diffusely expressed CD34, while pan-keratin and desmin were commonly seen focally. SynCAM3 was diffusely expressed in 12 cases (SCD34FT, n = 5; PRDM10-STT, n = 7), independently of fusion status. aCGH profiles were 'flat' (PRDM10-STT, n = 4; SCD34FT, n = 2) and exome sequencing showed no recurrent pathogenic mutations (PRDM10-STT, n = 2; SCD34FT, n = 4). Overall, the only morphological features seen exclusively in PRDM10-STT were myxoid stromal changes (three of 10) and metaplastic bone (two of 10). CONCLUSION: We expand the current knowledge on PRDM10-STT and SCD34FT and provide additional evidence for considering them as overlapping entities.

High throughput profiling of undifferentiated pleomorphic sarcomas identifies two main subgroups with distinct immune profile, clinical outcome and sensitivity to targeted therapies.

BACKGROUND: Undifferentiated pleomorphic sarcoma (UPS) is the most frequent, aggressive and less-characterized sarcoma subtype. This study aims to assess UPS molecular characteristics and identify specific therapeutic targets. METHODS: High-throughput technologies encompassing immunohistochemistry, RNA-sequencing, whole exome-sequencing, mass spectrometry, as well as radiomics were used to characterize three independent cohorts of 110, 25 and 41 UPS selected after histological review performed by an expert pathologist. Correlations were made with clinical outcome. Cell lines and xenografts were derived from human samples for functional experiments. FINDINGS: CD8 positive cell density was independently associated with metastatic behavior and prognosis. RNA-sequencing identified two main groups: the group A, enriched in genes involved in development and stemness, including FGFR2, and the group B, strongly enriched in genes involved in immunity. Immune infiltrate patterns on tumor samples were highly predictive of gene expression classification, leading to call the group B 'immune-high' and the group A 'immune-low'. This molecular classification and its prognostic impact were confirmed on an independent cohort of UPS from TCGA. Copy numbers alterations were significantly more frequent in immune-low UPS. Proteomic analysis identified two main proteomic groups that highly correlated with the two main transcriptomic groups. A set of nine radiomic features from conventional MRI sequences provided the basis for a radiomics signature that could select immune-high UPS on their pre-therapeutic imaging. Finally, in vitro and in vivo anti-tumor activity of FGFR inhibitor JNJ-42756493 was selectively shown in cell lines and patient-derived xenograft models derived from immune-low UPS. INTERPRETATION: Two main disease entities of UPS, with distinct immune phenotypes, prognosis, molecular features and MRI textures, as well as differential sensitivity to specific anticancer agents were identified. Immune-high UPS may be the best candidates for immune checkpoint inhibitors, whereas this study provides rational for assessing FGFR inhibition in immune-low UPS. FUNDING: This work was partly founded by a grant from La Ligue.

Feasibility of high-throughput sequencing in clinical routine cancer care: lessons from the cancer pilot project of the France Genomic Medicine 2025 plan.

BACKGROUND: Whole exome sequencing and RNA sequencing (WES/RNASeq) should now be implemented in the clinical practice in order to increase access to optimal care for cancer patients. Providing results to Tumour Boards in a relevant time frame-that is, compatible with the clinical pathway-is crucial. Assessing the feasibility of this implementation in the French care system is the primary objective of the Multipli study, as one of the four pilot projects of the national France Genomic Medicine 2025 (FGM 2025) plan. The Multipli study encompasses two innovative trials which will be driven in around 2400 patients suffering from a soft-tissue sarcoma (Multisarc) or a metastatic colorectal carcinoma (Acompli). METHODS: Prior to launching the FGM 2025 cancer pilot study itself, the performance of the Multipli genomic workflow has been evaluated through each step, from the samples collection to the Molecular Tumour Board (MTB) report. Two Multipli-assigned INCa-labelled molecular genetics centres, the CEA-CNRGH sequencing platform and the Institut Bergonié's Bioinformatics Platform were involved in a multicentric study. The duration of each step of the genomic workflow was monitored and bottlenecks were identified. RESULTS: Thirty barriers which could affect the quality of the samples, sequencing results and the duration of each step of the genomic pathway were identified and mastered. The global turnaround time from the sample reception to the MTB report was of 44 calendar days. CONCLUSION: Our results demonstrate the feasibility of tumour genomic analysis by WES/RNASeq within a time frame compatible with the current cancer patient care. Lessons learnt from the Multipli WES/RNASeq Platforms Workflow Study will constitute guidelines for the forthcoming Multipli study and more broadly for the future clinical routine practice in the first two France Genomic Medicine 2025 platforms.

Recurrent novel THBS1-ADGRF5 gene fusion in a new tumor subtype "Acral FibroChondroMyxoid Tumors".

Acral soft tissue tumors are common neoplasms, a subset of which pose a diagnostic challenge. We report 10 cases of a previously unrecognized acral benign soft tissue tumor. These tumors arose on the fingers and toes and involved bone in half of cases. Histologically, the tumors were lobulated and displayed an abundant stroma made of variable fibrous, chondroid and myxoid material reminiscent of cartilaginous or myoepithelial differentiation. Tumor cells harbored small round to reniform nuclei with clear chromatin and inconspicuous nucleoli along with scant eosinophilic cytoplasm. The cells were mostly arranged haphazardly in the stroma but also in small clusters. No mitotic activity was detected. No specific feature was identified in recurrent cases. By immunohistochemistry, the cells consistently stained for CD34 (10/10), ERG (9/10), and SOX9 (7/10). Whole RNA sequencing identified a previously undescribed recurrent in frame THBS1-ADGRF5 gene fusion in all cases. The transcript was confirmed by RT-PCR and was not found in the control group of mimickers including soft tissue chondromas. We propose the name of Acral FibroChondroMyxoid Tumors for this new entity.

Activity and Safety of Palbociclib in Patients with Advanced Gastrointestinal Stromal Tumors Refractory to Imatinib and Sunitinib: A Biomarker-driven Phase II Study.

PURPOSE: CDKN2A loss is frequent in gastrointestinal stromal tumors (GISTs) and associated with aggressive outcome. Palbociclib is a CDK4 inhibitor with preclinical antitumor efficacy in tumors with P16/CDKN2A loss. PATIENTS AND METHODS: This is a multicenter single-arm phase II clinical trial assessing safety and efficacy of palbociclib in patients with advanced GIST bearing CDKN2A gene loss. Adults with unresectable locally advanced or metastatic, refractory to at least imatinib and sunitinib, measurable and documented progressive disease (PD) as per RECIST 1.1, and CDKN2A deletion centrally assessed were eligible. Patients received palbociclib 125 mg orally daily on a 21 days on/7 days off dosing schedule, until PD or unacceptable toxicity. The primary endpoint was 4-month non-PD rate according to RECIST 1.1. RESULTS: As of May 2017, 71 patients had been included in the study, and 29 patients (40.3%) met the molecular eligibility requirement. Twenty-five patients (86.2%) had grade 1-2 adverse events (AEs) and 12 patients (41.4%) grade 3-4 AEs possibly related to the drug. The planned interim statistical analysis performed after central histologic and radiological review showed that 19 (86.4%) out of the first 22 evaluable patients had PD at 4 months. CDKN2A status had no impact either on overall survival or outcome on previous standard lines of treatment. Translational analysis suggested upregulation of CCNE1 or downregulation of CDKN1A/P21 or LRRC3B as potential mechanisms of resistance. CONCLUSIONS: Palbociclib has no significant clinical activity as a single agent in P16/CDKN2A -deleted GIST refractory to imatinib and sunitinib.

About Universality and Thermodynamics of Turbulence.

This paper investigates the universality of the Eulerian velocity structure functions using velocity fields obtained from the stereoscopic particle image velocimetry (SPIV) technique in experiments and direct numerical simulations (DNS) of the Navier-Stokes equations. It shows that the numerical and experimental velocity structure functions up to order 9 follow a log-universality (Castaing et al. Phys. D Nonlinear Phenom. 1993); this leads to a collapse on a universal curve, when units including a logarithmic dependence on the Reynolds number are used. This paper then investigates the meaning and consequences of such log-universality, and shows that it is connected with the properties of a "multifractal free energy", based on an analogy between multifractal and thermodynamics. It shows that in such a framework, the existence of a fluctuating dissipation scale is associated with a phase transition describing the relaminarisation of rough velocity fields with different Hölder exponents. Such a phase transition has been already observed using the Lagrangian velocity structure functions, but was so far believed to be out of reach for the Eulerian data.