The equatorial visible/infrared Wide Angle Viewing System (WAVS) is one of the ITER key diagnostics for machine protection. It has to monitor the Plasma Facing Components (PFCs) by infrared ...thermography and visible imaging. Foreseen to be installed in 4 equatorial port plugs to maximize the coverage of divertor, first wall, heating antennas and upper strike zone, the WAVS is composed of 15 lines of sight and 15 optical systems transferring the light along several meters from the PFCs through the port plug and interspace up to the detectors located in the port cell. After a conceptual design phase led by ITER Organization, the design is being further developed through a Framework Partnership Agreement signed between the European Domestic Agency, Fusion for Energy, and a consortium gathering CEA, CIEMAT (with INTA as third party) and Bertin Technologies company. First the WAVS measurement specifications are presented. Secondly the description of the current design is given both for the in-vessel system and for the ex-vessel one. The on-going neutronic studies are depicted as well as the cameras and data acquisition system foreseen for the back-end of the diagnostic.
In this paper, we are dealing with remote participation in fusion experiments. The common problem of these different collaboration projects is the interactivity lack of the distant user. At the ...moment, remote participation in fusion experiments is still needed in the specification and analysis phases. In this context, tools which can identify the sub-systems involved and outside actors properly, and the dynamic views of the communications through use cases is very useful. We have experimented on Unified Modeling Language (UML) and found that it provides powerful diagrams for the conception of the future virtual control room.
T-follicular helper (TFH) markers are expressed in the microenvironnement of marginal zone B-cell lymphoma (MZL), and in lymphomas arising from TFH-cells, sometimes making the differential diagnosis ...difficult. In the skin, the "TFH-spectrum" is poorly defined, going from primary cutaneous lymphoproliferative disorder with small/medium CD4+ T-cells (SMLPD) to cutaneous localizations of systemic angioimmunoblastic T-cell lymphoma (cAITL), and may pass through intermediate forms (primary cutaneous T-follicular helper derived lymphoma, not otherwise specified (PCTFHL,NOS)). We retrospectively analyzed 20 MZL, 13 SMLPD, 5 PCTFHL, and 11 cAITL clinically, histologically, and molecularly, to define tools to differentiate them. Characteristics that might favor the diagnosis of MZL over SMLPD are: multiple skin nodules (p < 0.001), nodular architecture (p < 0.01), residual germinal centers with follicular dendritic cell network (p < 0.001), monotypic plasma cells (p < 0.001), and few staining with PD1 (p = 0.016) or CXCL13 (p = 0.03). PCTFHL and cAITL presented as multiple (p < 0.01) lesions, in older patients (p < 0.01), with systemic symptoms and/or biological alterations (p < 0.01). Immunophenotypic loss of T-cell markers (p < 0.001), BCL6 (p = 0.023) and/or CD10 staining (p = 0.08), and a higher proliferative index (≥ 30%, p = 0.039) favoured these diagnoses over SMLPD. Pathogenic variants were observed by genomic sequencing in 47% of MZL (TNFAIP3 (32%), EP300 (21%), NOTCH2 (16%), KMT2D (16%), CARD11 (10.5%)), 8% of SMLPD (TET2), 40% of PCTFHL (SOCS1 (20%), ARID1A (20%)) and 64% of cAITL (TET2 (63.6%), RHOA (36.4%), NOTCH1 (9%)). This study characterizes the various clinical and histological features between cutaneous lymphomas expressing TFH markers and highlights the value of the interest of screening for genomic mutations in difficult cases.
IMPORTANCE: The best surgical treatment modalities for subungual squamous cell carcinoma (SUSCC) without bone invasion need to be determined. The limited available data on Mohs micrographic surgery ...do not demonstrate its use as a standard procedure. A previous study in a limited series of patients has shown that wide surgical excision of the nail unit was associated with a low rate of recurrence. OBJECTIVES: To confirm the efficiency of wide surgical excision of the nail unit with full-thickness skin graft reconstruction on a series of patients with SUSCC with an extended follow-up and to evaluate short- and long-term postoperative morbidity and patient satisfaction. DESIGN, SETTING, AND PARTICIPANTS: A consecutive series of 55 patients with biopsy-proven SUSCC without bone invasion treated by wide surgical excision of the nail unit followed by full-thickness skin graft reconstruction from January 1, 2000, to August 31, 2012 were included. After a minimum follow-up of 5 years, the recurrences were collected from the referring physicians. Statistical analysis was conducted from January 1 to June 30, 2016. MAIN OUTCOMES AND MEASURES: Demographic data, pathologic characteristics of tumors, postoperative follow-up, and recurrences were collected from medical records. Patients’ satisfaction with surgery, quality of life, and delayed postoperative morbidity (functional outcome and sensory disorders) were assessed from a questionnaire mailed to patients and physicians. RESULTS: Among the 55 patients (23 women and 32 men; mean age, 64 years), the mean follow-up was 6.6 years (range, 5.0-11.2 years), with a minimum follow-up of 5 years. Fifty-two questionnaires (95%) were returned. Two recurrences were observed. Minor early postoperative complications, such as graft infection and delayed wound healing, were seen in 6 patients; 8 patients experienced severe pain. Late postoperative complications included hypersensitivity to mechanical shocks (39 of 51 patients 76%), mildly increased sensitivity to cold (38 of 51 patients 75%), loss of fine touch sensation (17 of 35 patients 49%), and epidermal inclusion cysts (9 of 51 patients 18%). Most patients were very satisfied with cosmetic and global outcomes of the surgery. CONCLUSIONS AND RELEVANCE: Total excision of the nail unit followed by a full-thickness skin graft is a safe and efficient treatment for SUSCC without bone involvement, with satisfying cosmetic and functional outcomes.
Together, puffbirds (Bucconidae) and jacamars (Galbulidae) form the suborder Galbulae, sister group of all other Piciformes. Hitherto, the Galbulae had no ascertained pre-Pleistocene fossil record, ...and all previous alleged candidates have been refuted, except possibly the Sylphornithidae. Here we describe a wing of a tiny fossil bird from the early Oligocene of the Luberon region (southern France), which we assign to the Galbulae, as a new genus and species. Several characters, especially of the ulna and wing phalanx 1 of digit II, exclude the Passeriformes and Zygodactylidae, and indicate a representative of the Piciformes. Among Piciformes, absence of papillae remigales caudales and several characters of the wing phalanx 1 of digit II make it possible to assign the fossil to the Galbulae, and exclude all other clades. The fossil Sylphornithidae, with the carpometacarpus of Sylphornis being available, show some similarity with the Luberon fossil. The combination of features of the wing elements leads to the placement of the new fossil as stem Galbulae, and tentatively within the family Sylphornithidae. As such, it fills a gap and permits to better assign the whole enigmatic tiny sylphornithids, otherwise essentially known from leg bones. This yields the first firm pre-Pleistocene fossil record for the Galbulae. Today, both the Bucconidae and Galbulidae live exclusively in tropical America. The presence of stem Galbulae in the Oligocene of Europe, and probably the late Eocene, is a new example of a present-day Neotropical clade that had stem representatives in the Paleogene of Europe. LAY SUMMARY A new fossil bird, named Jacamatia luberonensis, found in France and aged 30 myr, is the first pre-Pleistocene fossil for the whole suborder Galbulae (jacamars and puffbirds). The evolution of the total group Galbulae, now an exclusively tropical American clade, involved the Old World. Tentative placement of Jacamatia luberonensis in the fossil family Sylphornithidae helps to clarify the position of the latter enigmatic group of tiny, long-legged piciform birds.
BackgroundThe efficacy of immunotherapies in metastatic melanoma depends on a robust T cell infiltration. Oncogenic alterations of tumor cells have been associated to T cell exclusion. Identifying ...novel cancer cell-intrinsic non-genetic mechanisms of immune escape, the targeting of which would reinstate T cell recruitment, would allow to restore the response to anti-programmed cell death protein 1 (PD-1) antibody therapy. The epithelial-to-mesenchymal transition (EMT)-inducing transcription factor ZEB1 is a major regulator of melanoma cell plasticity, driving resistance to mitogen-activated protein kinase (MAPK) targeted therapies. We thus wondered whether ZEB1 signaling in melanoma cells may promote immune evasion and resistance to immunotherapy.MethodsWe evaluated the putative correlation between ZEB1 expression in melanoma cells and the composition of the immune infiltrate in a cohort of 60 human melanoma samples by combining transcriptomic (RNA-sequencing) and seven-color spatial multi-immunofluorescence analyses. Algorithm-based spatial reconstitution of tumors allowed the quantification of CD8+, CD4+ T cells number and their activation state (PD-1, Ki67). ZEB1 gain-of-function or loss-of-function approaches were then implemented in syngeneic melanoma mouse models, followed by monitoring of tumor growth, quantification of immune cell populations frequency and function by flow cytometry, cytokines secretion by multiplex analyses. Chromatin-immunoprecipitation was used to demonstrate the direct binding of this transcription factor on the promoters of cytokine-encoding genes. Finally, the sensitivity to anti-PD-1 antibody therapy upon ZEB1 gain-of-function or loss-of-function was evaluated.ResultsCombined spatial and transcriptomic analyses of the immune infiltrates in human melanoma samples demonstrated that ZEB1 expression in melanoma cells is associated with decreased CD8+ T cell infiltration, independently of β-catenin pathway activation. ZEB1 ectopic expression in melanoma cells impairs CD8+ T cell recruitment in syngeneic mouse models, resulting in tumor immune evasion and resistance to immune checkpoint blockade. Mechanistically, we demonstrate that ZEB1 directly represses the secretion of T cell-attracting chemokines, including CXCL10. Finally, Zeb1 knock-out, by promoting CD8+ T cell infiltration, synergizes with anti-PD-1 antibody therapy in promoting tumor regression.ConclusionsWe identify the ZEB1 transcription factor as a key determinant of melanoma immune escape, highlighting a previously unknown therapeutic target to increase efficacy of immunotherapy in melanoma.Trial registration numberNCT02828202.
Aggressive CD30-positive cutaneous T-cell lymphomas (CD30
+
CTCL) are associated with unfavorable prognosis. Anthracycline-based polychemotherapy (CHOP) and brentuximab-vedotin (BV) monotherapy are ...related to poor outcomes in case of extracutaneous involvement or rapidly-progressing disease. Our objective was to assess the effectiveness of BV + CHP in aggressive CD30
+
CTCL. We included 7 patients treated with BV + CHP from April 2015 to January 2022: 4 had mycosis fungoides with large-cell transformation, 2 had primary cutaneous anaplastic large-cell lymphoma, and 1 harbored a primary cutaneous aggressive epidermotropic CD8-positive T-cell lymphoma. After a median IQR follow-up of 17.2 13.2-21.0 months, 6/7 patients achieved an ORR lasting ≥4 months. The median IQR duration of response was 9.5 5.9-11.1 months and the median IQR progression free survival was 14.9 11.6-16.4 months. Four patients displayed progression with a median (range) time to next treatment of 15.8 (6.5-16.3) months. Two grade-3 adverse events were reported: febrile neutropenia and thromboembolic event. BV + CHP displayed substantial antitumor activity and favorable safety profile in 7 patients with aggressive CD30
+
CTCL.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Summary
Background
Primary cutaneous peripheral T‐cell lymphomas with a T‐follicular helper phenotype (pcTFH‐PTCL) are poorly characterized, and often compared to, but not corresponding with, mycosis ...fungoides (MF), Sézary syndrome, primary cutaneous CD4+ lymphoproliferative disorder, and skin manifestations of angioimmunoblastic T‐cell lymphomas (AITL).
Objectives
We describe the clinicopathological features of pcTFH‐PTCL in this original series of 23 patients, and also characterize these cases molecularly.
Methods
Clinical and histopathological data of the selected patients were reviewed. Patient biopsy samples were also analysed by targeted next‐generation sequencing.
Results
All patients (15 men, eight women; median age 66 years) presented with skin lesions, without systemic disease. Most were stage T3b, with nodular (n = 16), papular (n = 6) or plaque (atypical for MF, n = 1) lesions. Three (13%) developed systemic disease and died of lymphoma. Nine (39%) patients received more than one line of chemotherapy. Histologically, the lymphomas were CD4+ T‐cell proliferations, usually dense and located in the deep dermis (n = 14, 61%), with the expression of at least two TFH markers (CD10, CXCL13, PD1, ICOS, BCL6), including three markers in 16 cases (70%). They were associated with a variable proportion of B cells. Eight patients were diagnosed with an associated B‐cell lymphoproliferative disorder (LPD) on biopsy, including Epstein–Barr virus (EBV)‐positive diffuse large B‐cell lymphoma (n = 3), EBV+ LPD (n = 1) and monotypic plasma cell LPD (n = 4). Targeted sequencing showed four patients to have a mutated TET2–RHOAG17V association (as frequently seen in AITL) and another a TET2/DNMT3A/PLCG1/SETD2 mutational profile. The latter patient, one with a TET2–RHOA association, and one with no detected mutations, developed systemic disease and died. Five other patients showed isolated mutations in TET2 (n = 1), PLCG1 (n = 2), SETD2 (n = 1) or STAT5B (n = 1).
Conclusions
Patients with pcTFH‐PTCL have pathological and genetic features that overlap with those of systemic lymphoma of TFH derivation. Clinically, most remained confined to the skin, with only three patients showing systemic spread and death. Whether pcTFH‐PTCL should be integrated as a new subgroup of TFH lymphomas in future classifications is still a matter of debate.
What is already known about this topic?
There is a group of cutaneous lymphomas that express T‐follicular helper (TFH) markers that do not appear to correspond to existing World Health Organization diagnostic entities.
These include mycosis fungoides, Sézary syndrome, or primary cutaneous CD4+ small/medium‐sized T‐cell lymphoproliferative disorder or cutaneous extensions of systemic peripheral T‐cell lymphomas (PTCL) with TFH phenotype.
What does this study add?
This is the first large original series of patients with a diagnosis of primary cutaneous PTCL with a TFH phenotype (pcTFH‐PTCL) to be molecularly characterized.
pcTFH‐PTCL may be a standalone group of cutaneous lymphomas with clinicopathological and molecular characteristics that overlap with those of systemic TFH lymphomas, such as angioimmunoblastic T‐cell lymphoma, and does not belong to known diagnostic groups of cutaneous lymphoma.
This has an impact on the treatment and follow‐up of patients; the clinical behaviour needs to be better clarified in further studies to tailor patient management.
There is a group of cutaneous lymphomas that express TFH markers that do not appear to correspond to existing WHO diagnostic entities. This is the first large original series of patients with a diagnosis of primary cutaneous peripheral T‐cell lymphomas with a T‐follicular helper phenotype (pcTFH‐PTCL) to be molecularly characterised. pcTFH‐PTCL may be a standalone group of cutaneous lymphomas with clinicopathological and molecular characteristics that overlap with those of systemic TFH lymphomas, and does not belong to known diagnostic groups of cutaneous lymphoma.
Linked Comment: W. Kempf. Br J Dermatol 2022; 187:841–842.
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