Search

•IDCH differs from LCH in its clinical, molecular, and immunohistochemical features.•IDCH is often associated with other hematopoietic neoplasms, and such cases are associated with an inferior prognosis.

Les enjeux de cette étude sont de familiariser les jeunes accueillis en Institut médico-éducatif (IME) et Centre d’éducation motrice (CEM) avec la consommation de légumineuses variées et de stimuler le plaisir de la consommation des repas végétariens pris en collectivité. Un des leviers favorisant la consommation de ces repas est de limiter les effets de la néophobie, en proposant des préparations adaptées et en formant les chefs à ce propos. Les textures doivent donc être homogènes, les innovations amenées progressivement. Les assaisonnements déjà familiers doivent aussi être privilégiés. Et une attention particulière au « moelleux » est nécessaire pour faciliter la palatabilité des aliments. De plus, les intitulés des plats ont une fonction rassurante. Ils doivent être clairs et précis sur les ingrédients inclus dans le plat, sans termes génériques (végétal/végétarien), ni termes privatifs (sans viande). Ils doivent aussi correspondre à l’image sensorielle associée au plat. Enfin, le positionnement des professionnels joue également un rôle primordial dans l’accompagnement de ce public pendant le repas. Ils ont besoin d’être formés à ce qu’est un plat végétarien et comment le servir, ainsi qu’aux comportements alimentaires des jeunes en situation de handicap.

Kidney transplant survival is shortened by chronic rejection and side effects of standard immunosuppressive drugs. Cell-based immunotherapy with tolerogenic dendritic cells has long been recognized as a promising approach to reduce general immunosuppression. Published trials report the safety and the absence of therapy-related adverse reactions in patients treated with tolerogenic dendritic cells suffering from several inflammatory diseases. Here, we present the first phase I clinical trial results using human autologous tolerogenic dendritic cells (ATDC) in kidney transplantation. Eight patients received ATDC the day before transplantation in conjunction with standard steroids, mycophenolate mofetil and tacrolimus immunosuppression with an option to taper mycophenolate mofetil. ATDC preparations were manufactured in a Good Manufacturing Practice–compliant facility and fulfilled cell count, viability, purity and identity criteria for release. A control group of nine patients received the same standard immunosuppression, except basiliximab induction replaced ATDC therapy and mycophenolate tapering was not allowed. During the three-year follow-up, no deaths occurred and there was 100% graft survival. No significant increase of adverse events was associated with ATDC infusion. Episodes of rejection were observed in two patients from the ATDC group and one patient from the control group. However, all rejections were successfully treated by glucocorticoids. Mycophenolate was successfully reduced/stopped in five patients from the ATDC group, allowing tacrolimus monotherapy for two of them. Regarding immune monitoring, reduced CD8 T cell activation markers and increased Foxp3 expression were observed in the ATDC group. Thus, our results demonstrate ATDC administration safety in kidney-transplant recipients.

Giant cell tumors (GCTs) with high mobility group AT-Hook 2 (HMGA2)::nuclear receptor corepressor 2 (NCOR2) fusion are rare mesenchymal tumors of controversial nosology, which have been anecdotally reported to respond to CSFR1 inhibitors. Here, we performed a comprehensive study of 6 GCTs with HMGA2::NCOR2fusion and explored their relationship with other giant cell-rich neoplasms. Tumors occurred in 4 females and 2 males ranging in age from 17 to 32 years old (median 24). Three lesions originated in subcutaneous soft tissue and 3 in bone. Tumor size ranged from 20 to 33 mm (median 27 mm). The lesions had a nodular/multinodular architecture and were composed of sheets of mononuclear “histiocytoid” cells with uniform nuclei intermingled with multinucleated giant cells. Mitotic activity was low and nuclear atypia and metaplastic bone were absent. Variable findings included necrosis, cystic degeneration, lymphocytic infiltrate (sometimes forming nodules), and xanthogranulomatous inflammation. On immunohistochemistry, all cases focally expressed pan-keratin and were negative with SATB2 and H3.3G34W. Whole RNA-sequencing was performed in all cases of GCT with HMGA2::NCOR2fusion and a subset of giant cell-rich tumors (tenosynovial-GCT, n = 19 and “wild-type” GCT of soft tissue, n = 9). Hierarchical clustering of RNA-sequencing data showed that GCT with HMGA2::NCOR2fusion formed a single cluster, independent of the other 2 entities. Methylome profiling showed similar results, but the distinction from “wild-type” GCT of soft tissue was less flagrant. Gene expression analysis showed similar levels of expression of the CSF1/CSFR1 axis between GCT with HMGA2::NCOR2fusion and tenosynovial-GCT, supporting their potential sensitivity to CSFR1 inhibitors. Clinical follow-up was available for 5 patients (range: 10 to 64 mo; median 32 mo). Three patients (60%) experienced local recurrences, whereas none had distant metastases or died of disease. Overall, our study confirms and expands previous knowledge on GCT with HMGA2::NCOR2fusion and supports its inclusion as an independent entity.

Le syndrome de neurotoxicité associée au traitement par cellules CAR-T (ICANS) est la deuxième complication spécifique la plus fréquente après réinjection de cellules CAR-T. Le délai médian d’apparition des symptômes neurologiques est de cinq jours, le plus souvent après la survenue d’un syndrome de relargage cytokinique. La durée des symptômes est courte d’environ cinq jours si la prise en charge thérapeutique est adaptée et précoce. La symptomatologie clinique est hétérogène allant de symptômes peu graves rapidement réversibles (troubles de l’attention, de l’écriture…) à des formes plus graves avec convulsions voire état comateux. L’évaluation de la sévérité de l’ICANS se base actuellement sur le score ASTCT. Les examens complémentaires utiles en contexte d’ICANS sont simplifiés et adaptés à la clinique du patient. La prise en charge thérapeutique doit être précoce, adaptée au niveau de sévérité de l’ICANS et repose sur de la corticothérapie. Une collaboration avec les services de réanimation et de neurologie est nécessaire. Le but de cet atelier est d’apporter une aide pratique à la prise en charge de cette complication neurologique.

Depuis leur mise sur le marché dans le traitement des hémopathies B en rechute ou réfractaires, les CAR-T cellsvoient leur utilisation augmenter de manière constante. Leurs toxicités spécifiques, notamment le syndrome de relargage cytokinique (CRS) et le syndrome d’activation macrophagique (SAM), sont de mieux en mieux connues et la place de leurs traitements se précise. Cette mise à jour des recommandations de la SFGM-TC précise l’utilisation de critères consensuels de définition et de gradation, ainsi qu’un guide de prise en charge symptomatique et spécifique en fonction de la sévérité de ces complications. En association au traitement symptomatique et à l’antibiothérapie probabiliste, les immunomodulateurs tels que le tocilizumab et les corticostéroïdes sont la pierre angulaire du traitement du CRS. Une collaboration étroite avec la réanimation est une condition indispensable à la bonne prise en charge des malades. Le rare mais redouté syndrome d’activation macrophagique post-CRS doit être suspecté en cas de CRS résistant aux corticostéroïdes/tocilizumab, notamment lorsqu’il est associé à un ou plusieurs marqueurs d’hémophagocytose tels qu’une hépato-splénomégalie, une hyperferritinémie>10 000ng/mL, une hypofibrinogénémie. Le traitement sera basé sur des fortes doses d’anakinra en intraveineuse et corticostéroïdes. L’utilisation de la chimiothérapie tel que l’étoposide doit être réservée aux stades avancés et réfractaire du CRS/MAS.

According to expert guidelines, lymph node surgical excision is the standard of care for lymphoma diagnosis. However, core needle biopsy (CNB) has become widely accepted as part of the lymphoma diagnostic workup over the past decades. The aim of this study was to present the largest multicenter inventory of lymph nodes sampled either by CNB or surgical excision in patients with suspected lymphoma and to compare their diagnostic performance in routine pathologic practice. We reviewed 32 285 cases registered in the French Lymphopath network, which provides a systematic expert review of all lymphoma diagnoses in France, and evaluated the percentage of CNB and surgical excision cases accurately diagnosed according to the World Health Organization classification. Although CNB provided a definitive diagnosis in 92.3% and seemed to be a reliable method of investigation for most patients with suspected lymphoma, it remained less conclusive than surgical excision, which provided a definitive diagnosis in 98.1%. Discordance rates between referral and expert diagnoses were higher on CNB (23.1%) than on surgical excision (21.2%; P = .004), and referral pathologists provided more cases with unclassified lymphoma or equivocal lesion through CNB. In such cases, expert review improved the diagnostic workup by classifying ∼90% of cases, with higher efficacy on surgical excision (93.3%) than CNB (81.4%; P < 10−6). Moreover, diagnostic concordance for reactive lesions was higher on surgical excision than CNB (P = .009). Overall, although CNB accurately diagnoses lymphoma in most instances, it increases the risk of erroneous or nondefinitive conclusions. This large-scale survey also emphasizes the need for systematic expert review in cases of lymphoma suspicion, especially in those sampled by using CNB.

•CNB accurately diagnoses lymphoma in most instances but increases the risk of erroneous or nondefinitive conclusions.•Systematic expert review highly contributes to a precise lymphoma diagnosis, especially in cases sampled by CNB.

The pathogenic role of terminally differentiated effector memory (TEMRA) CD8+T cells has been implicated in kidney transplant failure. The authors showed that humoral rejection of kidney allografts is associated with an accumulation of cytolytic TEMRA CD8+T cells in blood and in kidney graft biopsies. They demonstrated that TEMRA CD8+T cells from kidney transplant recipients exhibit enhanced migratory properties compared with effector memory CD8+T cells and that the chemokine CXCL12 not only promotes migration of TEMRA CD8+T cells toward nonlymphoid organs but also triggers a purinergic P2X4 receptor–dependent proinflammatory response. They also found that agents aimed at potential TEMRA CD8+T cell–specific targets inhibited the migration of TEMRA CD8+T cells from kidney transplant recipients, suggesting a possible strategy in treating kidney transplant failure.

To study prevalence of targeted therapy (TT)-related adverse events requiring ICU admission in solid tumor patients.

Chronic hypomagnesemia is commonly due to diarrhea, alcoholism, and drugs; more rarely, genetic defects in the effectors of renal magnesium reabsorption are responsible. The authors report on an adult patient with acquired severe hypomagnesemia, hypocalcemia, and tubulointerstitial nephropathy, with rapidly progressing kidney injury. In in vivoand in vitrostudies, they found evidence of a causal link between the patient?s condition and autoantibodies against claudin-16, a transmembrane paracellular protein involved in renal magnesium absorption. The patient was subsequently diagnosed with a renal carcinoma that expressed a high level of claudin-16 mRNA. Pathogenic claudin-16 autoantibodies represent a novel autoimmune cause of specific renal tubular transport disturbances and tubulointerstitial nephropathy. Screening for autoantibodies targeting claudin-16 and potentially other renal magnesium transporters or channels may be warranted in patients with acquired unexplained hypomagnesemia.

In view of the high mortality rate of immunocompromised patients with ARDS, it is important to identify targets for improvement.

The transplantation field requires the identification of specific risk factors associated with the level of immunosuppression. Here, our aim was to analyze the association between the number of circulating lymphocytes, monitored routinely by complete blood cell counts during outpatient visits, and patient and graft survival. In total, 2,999 kidney or combined kidney-pancreas recipients transplanted between 2000 and 2016, from two University hospitals, were enrolled. We investigated the etiological relationship between time-dependent lymphocyte count beyond one year after transplantation and patient and graft survival, viral infection and cancer risk using time-dependent multivariate Cox models. Model 1 considered kidney function at one year and model 2 as time-dependent variable. At the time of inclusion (one year after transplantation), 584 patients (19.4%) had deep lymphopenia (under 750 /mm3) and 1,072 (35.7%) had a normal count (over 1,500 /mm3). A patient with deep lymphopenia at a given follow-up time had significantly higher risks of graft failure, death and viral infection than comparable patients with a normal lymphocyte count at the same time point. Thus, after the first year of transplantation, the occurrence of deep lymphopenia within a patient’s follow-up is a risk factor for long-term graft failure, death and viral infection.

Chimeric antigen receptor (CAR) T-cell therapy can induce side-effects such as cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome (ICANS), which often require intensive care unit admission. The aim of this study was to describe management of critically ill CAR T-cell recipients in intensive care.

•Hospital mortality was 54%, mainly related to multi-organ failure.•Organ supports needed were predictors of hospital mortality.•Defibrotide prophylaxis effect need additional investigation.

LyMA trial has demonstrated the benefit of rituximab maintenance after autologous stem cell transplantation (ASCT) in previously untreated mantle-cell lymphoma patients (MCL). Induction consisted of four courses of R-DHAP (rituximab, dexamethasone, high-dose cytarabine, and platinum derivative). The platinum derivative (PD) choice was free: R-DHA-cisplatin, R-DHA-carboplatin, or R-DHA-oxaliplatin. We investigated the prognostic impact of each PD. PFS and OS calculated from inclusion and investigated in an intention-to-treat (ITT) (= 298) and per-protocol analyses (PP) (n= 227). R-DHACis, R-DHACa, or R-DHAOx were used at first cycle in 184, 76, and 38 patients, respectively. Overall, 71 patients (59 in the R-DHACis) required a change in PD, mainly because of PD toxicity. In ITT-analysis, PFS in the R-DHACis and R-DHACa groups were similar (4-year PFS of 65%), while R-DHAOx had a better PFS (4-year PFS of 65% versus 86.5%, respectively, HR = 0.44, p= 0.02). The 4-year OS was 92% for R-DHAOx versus 75.9% for R-DHACis/DHACa (HR = 0.37, p= 0.03). Similar results were yielded in the PP analysis. Low MIPI and R-DHAOx were independent favorable prognostic markers for both PFS (HR = 0.44, p= 0.035) and OS (HR = 0.36, p= 0.045). In vitro and in silico analyses confirmed that oxaliplatin has an anti-MCL cytotoxic effect that differs from that of other PD. R-DHAOx before ASCT provides better outcome in transplantation eligible young MCL patients.

Obinutuzumab monotherapy has shown promising efficacy in mantle cell lymphoma. We aimed to investigate the activity of obinutuzumab plus DHAP (dexamethasone, high-dose cytarabine, and cisplatin), measured by minimal residual disease quantitative (q)PCR status in the bone marrow after four cycles.

Rhabdomyosarcomas with TFCP2fusions represent an emerging subtype of tumors, initially discovered by RNA-sequencing. We report herein the clinicopathological, transcriptional, and genomic features of a series of 14 cases. Cases were retrospectively and prospectively recruited and studied by immunohistochemistry (MYF4, MYOD1, S100, AE1/E3, ALK), fluorescence in situ hybridization with TFCP2break-apart probe (n= 10/14), array-comparative genomic hybridization (Agilent), whole RNA-sequencing (Truseq Exome, Illumina), or anchored multiplex PCR-based targeted next-generation sequencing (Archer® FusionPlex® Sarcoma kit). Patient’s age ranged between 11 and 86 years, including 5 pediatric cases. Tumors were located in the bone (n= 12/14) and soft tissue (n= 2/14). Most bone tumors invaded surrounding soft tissue. Craniofacial bones were over-represented (n= 8/12). Median survival was 8 months and five patients are currently alive with a median follow-up of 20 months. Most tumors displayed a mixed spindle cell and epithelioid pattern with frequent vesicular nuclei. All tumors expressed keratins and showed a rhabdomyogenic phenotype (defined as expression of MYF4 and/or MYOD1). ALK was overexpressed in all but three cases without underlying ALKfusion on break-apart FISH (n= 5) nor next-generation sequencing (n= 14). ALKupregulation was frequently associated with an internal deletion at genomic level. TFCP2was fused in 5′ either to EWSR1(n= 6) or FUS(n= 8). EWSR1was involved in both soft tissue cases. FISH with TFCP2break-apart probe was positive in all tested cases (n= 8), including one case with unbalanced signal. On array-CGH, all tested tumors displayed complex genetic profiles with genomic indexes ranging from 13 to 107.55 and recurrent CDKN2Adeletions. FET-TFCP2rhabdomyosarcomas clustered together and distinctly from other rhabdomyosarcomas subgroups. Altogether, our data confirm and expand the spectrum of the new family of FET-TFCP2rhabdomyosarcomas, which are associated with a predilection for the craniofacial bones, an aggressive course, and recurrent pathological features. Their association with ALK overexpression might represent a therapeutic vulnerability.

Rhabdomyosarcomas with TFCP2fusions represent an emerging subtype of tumors, initially discovered by RNA-sequencing. We report herein the clinicopathological, transcriptional, and genomic features of a series of 14 cases. Cases were retrospectively and prospectively recruited and studied by immunohistochemistry (MYF4, MYOD1, S100, AE1/E3, ALK), fluorescence in situ hybridization with TFCP2break-apart probe (n= 10/14), array-comparative genomic hybridization (Agilent), whole RNA-sequencing (Truseq Exome, Illumina), or anchored multiplex PCR-based targeted next-generation sequencing (Archer® FusionPlex® Sarcoma kit). Patient's age ranged between 11 and 86 years, including 5 pediatric cases. Tumors were located in the bone (n= 12/14) and soft tissue (n= 2/14). Most bone tumors invaded surrounding soft tissue. Craniofacial bones were over-represented (n= 8/12). Median survival was 8 months and five patients are currently alive with a median follow-up of 20 months. Most tumors displayed a mixed spindle cell and epithelioid pattern with frequent vesicular nuclei. All tumors expressed keratins and showed a rhabdomyogenic phenotype (defined as expression of MYF4 and/or MYOD1). ALK was overexpressed in all but three cases without underlying ALKfusion on break-apart FISH (n= 5) nor next-generation sequencing (n= 14). ALKupregulation was frequently associated with an internal deletion at genomic level. TFCP2was fused in 5′ either to EWSR1(n= 6) or FUS(n= 8). EWSR1was involved in both soft tissue cases. FISH with TFCP2break-apart probe was positive in all tested cases (n= 8), including one case with unbalanced signal. On array-CGH, all tested tumors displayed complex genetic profiles with genomic indexes ranging from 13 to 107.55 and recurrent CDKN2Adeletions. FET-TFCP2rhabdomyosarcomas clustered together and distinctly from other rhabdomyosarcomas subgroups. Altogether, our data confirm and expand the spectrum of the new family of FET-TFCP2rhabdomyosarcomas, which are associated with a predilection for the craniofacial bones, an aggressive course, and recurrent pathological features. Their association with ALK overexpression might represent a therapeutic vulnerability.

The oncogenic events involved in breast implant–associated anaplastic large cell lymphoma (BI-ALCL) remain elusive. To clarify this point, we have characterized the genomic landscape of 34 BI-ALCLs (15 tumor and 19 in situ subtypes) collected from 54 BI-ALCL patients diagnosed through the French Lymphopathnetwork. Whole-exome sequencing (n = 22, with paired tumor/germline DNA) and/or targeted deep sequencing (n = 24) showed recurrent mutations of epigenetic modifiers in 74% of cases, involving notably KMT2C(26%), KMT2D(9%), CHD2(15%), and CREBBP(15%). KMT2Dand KMT2Cmutations correlated with a loss of H3K4 mono- and trimethylation by immunohistochemistry. Twenty cases (59%) showed mutations in ≥1 member of the JAK/STATpathway, including STAT3(38%), JAK1(18%), and STAT5B(3%), and in negative regulators, including SOCS3(6%), SOCS1(3%), and PTPN1(3%). These mutations were more frequent in tumor-type samples than in situ samples (P =.038). All BI-ALCLs expressed pSTAT3, regardless of the mutational status of genes in the JAK/STATpathway. Mutations in the EOMESgene (12%) involved in lymphocyte development, PI3K-AKT/mTOR(6%), and loss-of-function mutations in TP53(12%) were also identified. Copy-number aberration (CNA) analysis identified recurrent alterations, including gains on chromosomes 2, 9p, 12p, and 21 and losses on 4q, 8p, 15, 16, and 20. Regions of CNA encompassed genes involved in the JAK/STATpathway and epigenetic regulators. Our results show that the BI-ALCL genomic landscape is characterized by not only JAK/STATactivating mutations but also loss-of-function alterations of epigenetic modifiers.

The oncogenic events involved in breast implant–associated anaplastic large cell lymphoma (BI-ALCL) remain elusive. To clarify this point, we have characterized the genomic landscape of 34 BI-ALCLs (15 tumor and 19 in situ subtypes) collected from 54 BI-ALCL patients diagnosed through the French Lymphopath network. Whole-exome sequencing (n = 22, with paired tumor/germline DNA) and/or targeted deep sequencing (n = 24) showed recurrent mutations of epigenetic modifiers in 74% of cases, involving notably KMT2C (26%), KMT2D (9%), CHD2 (15%), and CREBBP (15%). KMT2D and KMT2C mutations correlated with a loss of H3K4 mono- and trimethylation by immunohistochemistry. Twenty cases (59%) showed mutations in ≥1 member of the JAK/STAT pathway, including STAT3 (38%), JAK1 (18%), and STAT5B (3%), and in negative regulators, including SOCS3 (6%), SOCS1 (3%), and PTPN1 (3%). These mutations were more frequent in tumor-type samples than in situ samples (P = .038). All BI-ALCLs expressed pSTAT3, regardless of the mutational status of genes in the JAK/STAT pathway. Mutations in the EOMES gene (12%) involved in lymphocyte development, PI3K-AKT/mTOR (6%), and loss-of-function mutations in TP53 (12%) were also identified. Copy-number aberration (CNA) analysis identified recurrent alterations, including gains on chromosomes 2, 9p, 12p, and 21 and losses on 4q, 8p, 15, 16, and 20. Regions of CNA encompassed genes involved in the JAK/STAT pathway and epigenetic regulators. Our results show that the BI-ALCL genomic landscape is characterized by not only JAK/STAT activating mutations but also loss-of-function alterations of epigenetic modifiers.

L’encéphalopathie liée à l’utilisation des lymphocytes dotés de récepteur à l’antigène chimérique (CAR-T) (CAR-T cell-related encephalopathy syndrome, CRES) traduit la neurotoxicité potentielle de cette approche thérapeutique et doit être envisagée devant la survenue de tout symptôme neurologique après l’infusion des cellules CAR-T. Il s’agit du second effet indésirable le plus fréquent sous cette thérapie et son incidence varie entre 12 et 55 % selon les études. Le délai médian de survenue des premiers symptômes neurologiques est de quatre jours suivant l’infusion de cellules CAR-T. La durée des symptômes du CRES est comprise généralement entre deux et quatre jours mais des CRES tardifs peuvent survenir. La surveillance fait appel notamment au suivi clinique, à l’imagerie par résonance magnétique et à l’électroencéphalographie. La prise en charge, en dehors des mesures symptomatiques, consiste, en premier lieu, en une corticothérapie, les thérapies ciblant IL-6 étant plutôt réservées aux formes sévères. Le but de cet atelier est d’apporter une aide pratique à la prise en charge de cette complication.

Host‐microbiota interactions can modulate the immune system both at local and systemic levels, with potential consequences for organ transplantation outcomes. In this study, we hypothesized that differences in the urinary microbiome following kidney transplantation would be associated with posttransplantation status: stable, minimally immunosuppressed, or tolerant. One hundred thirteen urine samples from stable (n = 51), minimally immunosuppressed (n = 19), and spontaneously tolerant (n = 16) patients, paired with age‐matched controls (n = 27) were profiled and compared to each other at a taxonomic level with special interest in the immunosuppressive regimen. All comparisons and correlations were adjusted on sex and time posttransplantation. Our results highlighted a unique and specific urinary microbiota associated with spontaneous tolerance characterized by a high diversity and a clear Proteobacteriaprofile. Finally, we report that this profile is (1) impacted by gender, (2) inversely correlated with immunosuppressive drugs (calcineurin inhibitors and mammalian target of rapamycin inhibitors), and (3) stable in time. Comparing taxonomic relative abundance and diversity of urinary microbiota between healthy volunteers and tolerant, stable, and minimally immunosuppressed kidney transplanted recipients, this study identifies and associates a specific Proteobacteriaprofile in the urine of kidney transplanted recipients with spontaneous tolerance.

Le syndrome de relargage des cytokines (CRS) a été décrit avec l’utilisation de différentes thérapeutiques et surtout des immunothérapies adoptives telles que les cellules CAR-T (CAR-T). Le CRS est la complication la plus fréquente après CAR-T. L’incidence varie de 30 à 100 %. Les cas sévères concernent 10 à 30 % des patients. L’événement déclenchant est l’activation des CAR-T, après rencontre avec leur cible. Ceci entraîne la libération de cytokines effectrices, telles que IFNγ, TNFα et IL2, activant à leur tour le système monocyte/macrophage, entraînant la production de cytokines pro-inflammatoires, (incluant IL6, IFN-y, IL10, MCP1) associée à une élévation importante de la CRP et de la ferritine. Le CRS apparaît généralement entre 1 et 14 jours après l’injection et peut durer de 1 à 10 jours. De rares cas mortels ont été rapportés. Le premier symptôme est souvent une fièvre parfois très élevée nécessitant de renforcer la surveillance. Dans les formes modérées, on trouve fatigue, céphalées, rash, arthralgies et myalgies. Un syndrome d’encéphalopathie lié aux CAR-T (CRES) peut être associé. En cas d’aggravation, un choc vasoplégique associant fuite capillaire et détresse respiratoire peut se rencontrer. Une surveillance clinique rapprochée est indispensable dès l’injection pour détecter rapidement les premiers symptômes. Le traitement des formes sévères, outre une prise en charge symptomatique fait intervenir des anticorps monoclonaux ciblant le récepteur à l’IL6 ou l’IL6, et parfois les stéroïdes. Une coopération étroite avec les services de réanimation est indispensable, 20 à 50 % des patients nécessitant un transfert en unité de soins intensifs.

Intensive Care Units (ICU) acquired Pneumonia (ICU-AP) is one of the most frequent nosocomial infections in critically ill patients. Our aim was to determine the effects of having an ICU-AP in immunosuppressed patients with acute hypoxemic respiratory failure.

The microenvironment strongly influences mantle cell lymphoma (MCL) survival, proliferation, and chemoresistance. However, little is known regarding the molecular characterization of lymphoma niches. Here, we focused on the interplay between MCL cells and the associated monocytes/macrophages. Using circulating MCL cells (n= 58), we showed that, through the secretion of CSF1 and, to a lesser extent, IL-10, MCL polarized monocytes into specific CD163+M2-like macrophages (MϕMCL). In turn, MϕMCL favored lymphoma survival and proliferation ex vivo. We next demonstrated that BTK inhibition abrogated CSF1 and IL-10 production in MCL cells, leading to the inhibition of macrophage polarization and consequently resulting in the suppression of microenvironment-dependent MCL expansion. In vivo, we showed that CSF1 and IL-10 plasma concentrations were higher in MCL patients than in healthy donors, and that monocytes from MCL patients overexpressed CD163. Further analyses of serial samples from ibrutinib-treated patients (n= 8) highlighted a rapid decrease of CSF1, IL-10, and CD163 in responsive patients. Finally, we showed that targeting the CSF1R abrogated MϕMCL-dependent MCL survival, irrespective of their sensitivity to ibrutinib. These data reinforced the role of the microenvironment in lymphoma and suggested that macrophages are a potential target for developing novel therapeutic strategies in MCL.

In presence of calcium ions, β-lactoglobulin (BLG) unfolds and subsequently aggregates after heating. This process has important pharmaceutical and agroalimentary applications. Nowadays, the molecular mechanism of unfolding and BLG aggregation, and the role of calcium in the mechanism, is poorly understood. Actually, in most studies, data have been acquired at room temperature, after heating and after aggregation, which makes it difficult to establish a clear causal–temporal relation between calcium binding, heat, and aggregation. Thus, the goal of the present study is to get accurate, nanoscale data about the molecular events leading to BLG unfolding and calcium-dependent aggregation. The molecular transformation of BLG during heating has been investigated, using the NMR pulse field gradient technique, operating in a high field (900 MHz). Thanks to this technique, the molecular conformation of newly formed unfolded BLG molecules can be distinguished in a large pool of native ones. The present work shows that BLG at neutral pH at 65 °C displays fast, cooperative-like unfolding, in which no long-lived intermediary state (as a molten globule one) is detected, before aggregation. These data also indicate that calcium ions bind unfolded BLG in specific sites which might be a necessary feature to form the aggregate. Finally, these data also provide an NMR-based methodology to monitor the rate of protein unfolding using NMR.

During storage, a series of changes occur for dairy powders, such as protein lactosylation and the formation of Maillard reaction products (MRPs), leading to powder browning and an increase of insoluble matter. The kinetics of protein lactosylation and MRP formation are influenced by the lactose content of the dairy powder. However, the influence of lactose in the formation of insoluble matter and its role in the underlying mechanisms is still a subject of speculation. In this study, we aim to investigate the role of lactose in the formation of insoluble matter in a more comprehensive way than the existing literature. For that, two casein powders with radically different lactose contents, standard micellar casein (MC) powder (MC1) and a lactose-free (less than 10 ppm) MC powder (MC2), were prepared and stored under controlled conditions for different periods of time. Powder browning index measurements and solubility tests on reconstituted powders were performed to study the evolution of the functional properties of MC powders during aging. Proteomic approaches [one-dimensional electrophoresis and liquid chromatography–mass spectrometry (LC–MS)] and innovative label-free quantification methods were used to track and quantify the chemical modifications occurring during the storage of the powders. Reducing the amount of lactose limited the browning of MC powders but had no effect on the loss of solubility of proteins after storage, suggesting that the action of lactose, leading to the production of MRC, does not promotes the formation of insoluble matter. Electrophoresis analysis did not reveal any links between the formation of covalent bonds between caseins and loss in solubility, regardless of the lactose content. However, LC–MS analyses have shown that different levels of chemical modifications occur during the MC powder storage, depending upon the presence of lactose. An increase of protein lactosylation and acetylation was observed for the powder with a higher lactose content, while an increase of protein deamidation and dephosphorylation was observed for that containing lower lactose. The decrease of pH in the presence of lactose as a result of Maillard reaction (MR) may explain the difference in the chemical modifications of the two powders. In view of the present results, it is clear that lactose is not a key factor promoting insolubility and for the formation of cross-links between caseins during storage. This suggests that lactosylation is not the core reaction giving rise to loss in solubility.

Les cellules T – autologues ou allogéniques – génétiquement manipulées pour exprimer un récepteur antigénique chimérique (« CAR T-cells ») et reconnaître un antigène exprimé par la population de cellules tumorales, tel que CD19, représentent une nouvelle classe de médicaments appartenant à la catégorie des médicaments de thérapies innovantes tels que définis par le règlement européen 2007-1394, et plus précisément à la sous-catégorie des médicaments de thérapie génique. Bien qu’il s’agisse de thérapies cellulaires, les circuits de production et de délivrance seront différents de ceux des greffons hématopoïétiques pour prendre en compte leur statut de médicament. Les résultats cliniques aujourd’hui disponibles proviennent d’essais cliniques conduits essentiellement aux États-Unis d’Amérique et en Chine. Ils font apparaître une efficacité clinique remarquable dans des pathologies hématologiques avancées, assortie toutefois d’effets secondaires sévères chez une proportion importante de patients. Ces évènements indésirables doivent être anticipés et pris en charge dans le cadre d’une coordination parfaite entre l’unité clinique de thérapie cellulaire accueillant le patient en première intention, et l’unité de soins intensifs ou de réanimation médicale correspondante. Le présent atelier a pour but d’identifier les prérequis permettant aux hôpitaux français de s’organiser efficacement pour répondre aux sollicitations de promoteurs industriels d’essais cliniques visant à évaluer des « CAR T-cells ».

Acute respiratory failure occurs in up to 50% of patients treated for hematologic malignancies and is associated with a high case fatality rate. Because of residual organ dysfunction and time spent receiving respiratory care, underlying disease control is affected. Early admission to an intensive care unit for acute respiratory failure has proven benefit because it is the best place for rapid implementation of noninvasive diagnostic and therapeutic strategies. This article reviews the clinical approach and diagnostic strategies for acute respiratory failure in patients with hematologic malignancies.

Les histiocytoses sont des maladies rares et de nature très hétérogène n’ayant en commun que l’histologie avec une accumulation d’histiocytes. Elles peuvent être d’origine héréditaire ou sporadique et liées notamment à l’accumulation de matériel endo- ou exogène dans les macrophages ou à l’activation des macrophages. Des découvertes récentes ont permis de démontrer la nature tumorale de certaines histiocytoses jusqu’à présent considérées comme idiopathiques ou inflammatoires, telles que les histiocytoses à cellules de Langerhans ou les maladies d’Erdheim-Chester. Cette revue aborde la classification générale des histiocytoses, puis précise les critères diagnostiques et les altérations moléculaires des histiocytoses idiopathiques et tumorales.

Radioimmunotherapy represents a potential option as consolidation after chemoimmunotherapy in patients with diffuse large B-cell lymphoma who are not candidates for transplantation. We aimed to assess activity and toxicity of fractionated radioimmunotherapy using anti-CD22 90Y-epratuzumab tetraxetan as consolidation after front-line induction chemoimmunotherapy in untreated elderly patients with diffuse large B-cell lymphoma.

Mantle cell lymphoma (MCL) accumulates in lymphoid organs, but disseminates early on in extranodal tissues. Although proliferation remains located in lymphoid organs only, suggesting a major role of the tumor ecosystem, few studies have assessed MCL microenvironment. We therefore cocultured primary circulating MCL cells from 21 patients several weeks ex vivo with stromal or lymphoid-like (CD40L) cells to determine which interactions could support their proliferation. We showed that coculture with lymphoid-like cells, but not stromal cells, induced cell-cycle progression, which was amplified by MCL-specific cytokines (insulin-like growth factor-1, B-cell activating factor, interleukin-6, interleukin-10). Of interest, we showed that our model recapitulated the MCL in situ molecular signatures (ie, proliferation, NF-κB, and survival signatures). We further demonstrated that proliferating MCL harbored an imbalance in Bcl-2 family expression, leading to a consequent loss of mitochondrial priming. Of interest, this loss of priming was overcome by the type II anti-CD20 antibody obinutuzumab, which counteracted Bcl-xL induction through NF-κB inhibition. Finally, we showed that the mitochondrial priming directly correlated with the sensitivity toward venetoclax and alkylating drugs. By identifying the microenvironment as the major support for proliferation and drug resistance in MCL, our results highlight a selective approach to target the lymphoma niche.

Mantle cell lymphoma (MCL) accumulates in lymphoid organs, but disseminates early on in extranodal tissues. Although proliferation remains located in lymphoid organs only, suggesting a major role of the tumor ecosystem, few studies have assessed MCL microenvironment. We therefore cocultured primary circulating MCL cells from 21 patients several weeks ex vivo with stromal or lymphoid-like (CD40L) cells to determine which interactions could support their proliferation. We showed that coculture with lymphoid-like cells, but not stromal cells, induced cell-cycle progression, which was amplified by MCL-specific cytokines (insulin-like growth factor-1, B-cell activating factor, interleukin-6, interleukin-10). Of interest, we showed that our model recapitulated the MCL in situ molecular signatures (ie, proliferation, NF-κB, and survival signatures). We further demonstrated that proliferating MCL harbored an imbalance in Bcl-2 family expression, leading to a consequent loss of mitochondrial priming. Of interest, this loss of priming was overcome by the type II anti-CD20 antibody obinutuzumab, which counteracted Bcl-xLinduction through NF-κB inhibition. Finally, we showed that the mitochondrial priming directly correlated with the sensitivity toward venetoclax and alkylating drugs. By identifying the microenvironment as the major support for proliferation and drug resistance in MCL, our results highlight a selective approach to target the lymphoma niche.

In immunocompromised patients with acute respiratory failure (ARF), the clinical significance of respiratory virus detection in the nasopharynx remains uncertain.

Le transfert d’un patient allogreffé de cellules-souches hématopoïétiques en réanimation est toujours une situation délicate, tant sur le plan médical que sur le plan psychologique, à la fois pour le patient, sa famille mais aussi l’équipe soignante. Malgré les progrès diagnostique et thérapeutique en hématologie et en réanimation de ces dernières années, le pronostic de ces patients, reste très sombre. La mortalité en réanimation atteint environ 50 %. Les 6esateliers d’harmonisation des pratiques de la SFGM-TC ont réuni des médecins hématologues et réanimateurs afin d’améliorer les conditions et modalités pratiques de transfert en réanimation des patients allogreffés. Dans ce cadre, nous proposons un modèle de dossier de transfert du patient contenant les informations essentielles à leur prise en charge.

Degenerative disc disease (DDD) primarily affects the central part of the intervertebral disc namely the nucleus pulposus (NP). DDD explains about 40% of low back pain and is characterized by massive cellular alterations that ultimately result in the disappearance of resident NP cells. Thus, repopulating the NP with regenerative cells is a promising therapeutic approach and remains a great challenge. The objectives of this study were to evaluate the potential of growth factor‐driven protocols to commit human adipose stromal cells (hASCs) toward NP‐like cell phenotype and the involvement of Smad proteins in this differentiation process. Here, we demonstrate that the transforming growth factor‐β1 and the growth differentiation factor 5 synergistically drive the nucleopulpogenic differentiation process. The commitment of the hASCs was robust and highly specific as attested by the expression of NP‐related genes characteristic of young healthy human NP cells. In addition, the engineered NP‐like cells secreted an abundant aggrecan and type II collagen rich extracellular matrix comparable with that of native NP. Furthermore, we demonstrate that these in vitro engineered cells survived, maintained their specialized phenotype and secretory activity after in vivo transplantation in nude mice subcutis. Finally, we provide evidence suggesting that the Smad 2/3 pathway mainly governed the acquisition of the NP cell molecular identity while the Smad1/5/8 pathway controlled the NP cell morphology. This study offers valuable insights for the development of biologically‐inspired treatments for DDD by generating adapted and exhaustively characterized autologous regenerative cells. StemCells2016;34:653–667