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In: Journal of Human Genetics, Springer Science and Business Media LLC, Vol. 67, No. 12 ( 2022-12), p. 729-733

Type of Medium: Online Resource

ISSN: 1434-5161 , 1435-232X

URL: Article

DOI: 10.1038/s10038-022-01087-0

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2022

detail.hit.zdb_id: 1478797-0

SSG: 12

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 352-352

Abstract: Introduction Prognosis of elderly patients with newly diagnosed diffuse large B cell lymphoma (DLBCL) remains poor as compare to young patients. Co-morbidities and physiological organ function impairment often lead to non-manageable toxicities and limit optimal chemotherapy. A decreased dose of CHOP (doxorubicin 25mg/m2 on D1, cyclophosphamide 400mg/m2 on D1, vincristine 1 mg TD on D1, and prednisone 40mg/m2 D1 to D5) chemotherapy with a conventional dose of rituximab (R-miniCHOP) displays a good compromise between efficacy and safety in this population. Lenalidomide, an oral immunomodulatory drug, in combination with RCHOP (R2-CHOP) has an acceptable toxicity and a potential higher efficacy in the non-GCB subtype, more frequent in elderly patients. The SENIOR study evaluated the tolerance and efficacy of the R2-miniCHOP regimen in comparison to the standard R-miniCHOP in patients ≥80 years with newly diagnosed DLBCL. Methods SENIOR is a multicentric, phase III, open-label, randomized trial in patients aged of 80 years or more with non-previously treated CD20+ DLBCL, age-adjusted IPI= 0 to 3, and Ann Arbor stage II to IV. Eligible patients were randomized 1:1 to standard R-miniCHOP or R2-miniCHOP on a 21-days cycle for 6 cycles. Patients were stratified by CD10 expression and age (≤85 years old or & gt; 85 years old). The first cycle of rituximab was delivered by IV at the dose of 375mg/m2 on D1, then subcutaneoulsy at the dose of 1400mg TD on D1 of cycles 2-6. In the R2-miniCHOP arm, lenalidomide was administered at a dose of 10 mg TD on D1 to D14 every 3 weeks. Patients in the experimental arm had to receive deep venous thrombosis prophylaxis. This trial included a pre-phase treatment of prednisone (60 mg/m2 per os, days -7 to -1) and vincristine (1 mg TD IV, at D -7)). The primary end point was overall survival (OS). The statistical plan was based on the hypothesis of an increase of 15% of the 2y-OS (59 %- & gt; 74%) in favor of the experimental arm. Secondary endpoints were PFS (Progression-Free Survival), EFS (Event-Free Survival), duration of response, DFS (disease-free survival), response rate at the end of the treatment (registration number NCT02128061) Results From August 2014 to September 2017, 249 patients were randomized (127 in R-miniCHOP arm and 122 in R2-miniCHOP arm). Median age was 83y (range 80-96). Baseline characteristics were balanced between the two arms (Table 1). 48 (19%) patients discontinued treatment (27 in R-miniCHOP and 21 in R2-miniCHOP), 27% for concurrent illness and 25% for progressive disease. In the safety set population (n = 241), the 6 planned cycles were delivered in 80% and 86% of patients in both arms. The % of planned dose for each R-miniCHOP compound was similar in both arms. 75% of patients received ≥ 75% of the planned dose of lenalidomide. Twenty (17%) patients experienced a dose reduction, 17 (85%) due to adverse events (AE). After a median follow up of 25.1 months, in an intention to treat analysis , R2-miniCHOP did not improve OS (2y-OS 66% in R-miniCHOP and 65.7% in R2-miniCHOP arm, p=.98, Figure 1), and no significant difference was observed based on stratified analysis on age or CD10 expression status. There was no significant difference in PFS, EFS, and DFS. ORR was 73% in R-miniCHOP arm and 83% in R2-miniCHOP arm. Deaths occurred in 42 and 43 patients in R-miniCHOP and R2-miniCHOP arm respectively, mainly due to lymphoma (60%). Four deaths, 2 in each treatment arm, were related to treatment toxicity. Grade 3-4 AE occurred in 53% of cases in R-miniCHOP arm and in 81% in R2-miniCHOP arm, with neutropenia in 17.7% vs 32.5%, infections 8.1% vs 13.7%, and pulmonary embolism (n=1, 0.8% vs n=7, 6%). Second primary malignancies occurred in 8 patients in R-miniCHOP arm and in 11 patients in R2-minCHOP arm. Both MNA and IADL scales correlated significantly with OS and PFS. Conclusion SENIOR study is the first prospective phase III trial in ≥80 years old patients with newly diagnosed DLBCL. Addition of lenalidomide to R-miniCHOP does not significantly improve OS irrespective to CD10 status and results in more adverse events. Rituximab delivered subcutaneously was safe and well tolerated. The overall 2y-OS of 66% was similar or higher to those reported in previously published LYSA trials (2y-OS = 59%, Peyrade et al. Lancet Oncol 2011; 2y-OS = 64.7%, Lancet Hematol 2017). Tumour Molecular characterisation are currently ongoing to identify patients that could benefit of R2-miniCHOP. Table 1 Disclosures Oberic: Janssen: Honoraria; Roche: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Feugier:Roche,: Membership on an entity's Board of Directors or advisory committees, Other: Travel expense and grants; Gilead,: Membership on an entity's Board of Directors or advisory committees, Other: travel support and grants ; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: travel support and grants; Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: travel support and grants; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: travel support, grants. Thieblemont:Celgene: Honoraria; Cellectis: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Research Funding; Gilead: Honoraria; Novartis: Honoraria; Kyte: Honoraria; Janssen: Honoraria. Salles:Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Amgen: Honoraria, Other: Educational events; BMS: Honoraria; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis, Servier, AbbVie, Karyopharm, Kite, MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Epizyme: Consultancy, Honoraria. Tilly:roche: Membership on an entity's Board of Directors or advisory committees; servier: Honoraria; merck: Honoraria; Gilead: Honoraria; Janssen: Honoraria; BMS: Honoraria; Karyopharm: Consultancy; Astra-Zeneca: Consultancy; Roche: Consultancy; Celgene: Consultancy, Research Funding. Haioun:servier: Honoraria; amgen: Honoraria; janssen cilag: Consultancy; takeda: Consultancy; novartis: Honoraria; celgene: Honoraria; gilead: Consultancy; celgene: Consultancy; roche: Consultancy. Jardin:amgen: Honoraria; Servier: Honoraria; celgene: Honoraria; roche: Honoraria; janssen: Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-123612

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

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detail.hit.zdb_id: 80069-7

In: Human Molecular Genetics, Oxford University Press (OUP), Vol. 27, No. 2 ( 2018-01-15), p. 224-238

Type of Medium: Online Resource

ISSN: 0964-6906 , 1460-2083

URL: Article

DOI: 10.1093/hmg/ddx384

Language: English

Publisher: Oxford University Press (OUP)

Publication Date: 2018

detail.hit.zdb_id: 1474816-2

SSG: 12

In: Nature Genetics, Springer Science and Business Media LLC, Vol. 48, No. 11 ( 2016-11), p. 1349-1358

Type of Medium: Online Resource

ISSN: 1061-4036 , 1546-1718

URL: Article

DOI: 10.1038/ng.3676

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2016

detail.hit.zdb_id: 1494946-5

SSG: 12

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 2765-2765

Abstract: Introduction The outcome of very elderly patients with newly diagnosed diffuse large B cell lymphoma (DLBCL) remains poorer than that of younger patients, often because of co-morbidities and physiological organ function impairment. However, the biological specificities of DLBCL in very elderly patients are unknown. The LYSA conducted a multicentric, phase III, open-label, randomized trial in newly diagnosed DLBCL 〉 80y evaluating the efficacy of the combination of lenalidomide with R-miniCHOP (R2-miniCHOP) in comparison to the standard R-miniCHOP (SENIOR trial, NCT02128061). Based on targeted NGS sequencing and gene expression profile (GEP) analysis, the BIOSENIOR project aimed to provide a molecular characterisation of the cohort and detect clinically relevant biomarkers in according to treatment arm. Methods The SENIOR study enrolled patients aged of 80 years or more with non-previously treated CD20+ DLBCL, age-adjusted IPI= 0 to 3, and Ann Arbor stage II to IV. 249 patients were randomized (127 in R-miniCHOP arm and 122 in R2-miniCHOP arm). Median age was 83y (range 80-96. Patients with available tumor DNA /RNA from FFPE biopsies were included in the BIOSENIOR substudy. GEP was performed using Lymph2CX assay (Nanostring®) and a new RTMLPA assay (Bobée et al. J Mol Diagn 2017) able to quantify the expression of 137 relevant genes involved in B-cell biology, microenvironment or therapeutic response (cereblon). Genotyping (QiaSeq ®) was performed using a dedicated 36 genes panel. GEP features were compared to DLBCL patients 〈 60y enrolled in the LYSA GAINED trial (NCT01659099). Results Tumor DNA/RNA was available for 164/249 patients (66%). GEP was performed in 154 cases by RTMLPA and in 103 cases by Lymph2CX. The concordance to classify GCB/ABC was of 94% between the two technologies. DLBCL were mainly classified in the ABC subtype [77 = ABC (50%); 53 = GCB (34.4%); 17 unclassified (11%)]. Four cases (2.6%) were classified as EBV+ DLBCL and 1 as PMBL. 81 cases (52.5%) were considered as BCL2+, 23 (15%) as MYC+ and 16 (10.4%) as double-expressors (DE) by GEP. Comparison of GEP with younger patients highlighted distinct features and geriatric specificities (figure 1A). Genotypes were obtained in 159 patients. MYD88, PIM1, CREBBP, CD79B and TP53 were the five most frequently mutated genes (Figure 1B). Correlations between biomarkers and outcomes (OS and PFS) were performed in the overall population and according to treatment arms. The GCB/ABC subtyping, as determined by Lymph2CX (n = 97) was related to OS [HR = 0.38 (0.18 - 0.81) Log-rank: 0.009] and PFS in the overall population. This result was not confirmed in the extended cohort (n = 154) by RTMLPA. The MYC / BCL2 DE status assessed by GEP was a strong predictor of outcome (OS, HR = 2.89 (1.39 - 5.97) Log-rank: 0.003] in both arms. Importantly MYC/BCL2 DE was independent of the IPI score and albuminemia in multivariate analysis. In an exploratory analysis, cereblon (HR = 2.360; CI-95% 1.157-4.812, Log-rank: 0.015) and PD1 [HR = 0.33 (0.16 - 0.66) Log-rank: 0.001] expressions correlate exclusively with PFS in the R2-miniCHOP arm. MYD88 mutations (L265P and others variants) were associated with a worse outcome in the overall population (OS, HR= 2.05, CI-95% 1.190-3.554, Log-rank: 0.008; PFS, HR =1.731, CI-95% 1.059-2.830 Log-rank: 0.027). FOXO1 mutations were detected in 15 patients (9%). Its impact was only observed in the R-miniCHOP arm (OS, HR = 4.07 (1.52 - 10.87) Log-rank: 0.0024; PFS HR = 4.139 (1.59 - 10.79) Log-rank: 0.0016)] and was erased in the R2-miniCHOP arm. TP53 mutations, reported in 24% of cases were predictive of the PFS in the overall population [HR = 1.811 (1.09 - 3.01) Log-rank: 0.0199] (prognostic factors are summarized in Table 1). Conclusion BIOSENIOR is an ancillary study of the first prospective phase III trial in ³80 years old patients with newly diagnosed DLBCL. Some biomarkers, known to be predictive in younger patients, are relevant in this cohort, including MYC expression, BCL2/MYC DE, mutations of MYD88, TP53 or FOXO1. However, GEP characteristics of DLBCL occurring in this very old population are highly different of younger patients, suggesting distinct underlying oncogenic mechanisms. BIOSENIOR indicates that, beyond geriatric frailty, molecular features of DLBCL patients 〉 80y play also a crucial role that should be considered in the design of future trials. Markers that may predict R2-miniCHOP efficacy remain to be confirmed. Disclosures Thieblemont: Janssen: Honoraria; Celgene: Honoraria; Gilead: Honoraria; Novartis: Honoraria; Kyte: Honoraria; Roche: Honoraria, Research Funding; Cellectis: Membership on an entity's Board of Directors or advisory committees. Feugier:gilead: Honoraria, Research Funding, Speakers Bureau; roche: Honoraria, Research Funding, Speakers Bureau; janssen: Honoraria, Research Funding, Speakers Bureau; abbvie: Honoraria, Research Funding, Speakers Bureau. Salles:Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis, Servier, AbbVie, Karyopharm, Kite, MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Amgen: Honoraria, Other: Educational events; BMS: Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Epizyme: Consultancy, Honoraria. Tilly:Roche: Consultancy; Celgene: Consultancy, Research Funding; Astra-Zeneca: Consultancy; Karyopharm: Consultancy; BMS: Honoraria; Janssen: Honoraria; Gilead: Honoraria; merck: Honoraria; servier: Honoraria; roche: Membership on an entity's Board of Directors or advisory committees. Haioun:celgene: Honoraria; novartis: Honoraria; servier: Honoraria; amgen: Honoraria; janssen cilag: Consultancy; takeda: Consultancy; gilead: Consultancy; celgene: Consultancy; roche: Consultancy. Le Gouill:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Roche-Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support. Casasnovas:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Merck Sharp and Dohme: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Jardin:janssen: Honoraria; roche: Honoraria; amgen: Honoraria; celgene: Honoraria; Servier: Honoraria. OffLabel Disclosure: lenalidomide is evaluatd in combination with RminiHOP

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-124444

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 26, No. 13 ( 2020-07-01), p. 3145-3153

Abstract: The histone-methyl transferase EZH2, catalytic subunit of the PRC2 complex involved in transcriptional regulation, is mutated in approximately 25% of germinal center B-cell lymphomas. Aberrant proliferative dependency on EZH2 activity can be targeted by the orally available EZH2 inhibitor tazemetostat (EPZ-6438). We report the results of the phase Ib tazemetostat plus R-CHOP combination (NCT02889523), in patients 60 to 80 years of age with newly diagnosed diffuse large B-cell lymphoma. Patients and Methods: The primary objective of this dose-escalation study was to evaluate the safety of the combination and to determine the recommended phase II dose (RP2D) of tazemetostat. Results: A total of 17 patients were enrolled. During C1 and C2, two dose-limiting toxicities were observed: one grade 3 constipation at 400 mg and one grade 5 pulmonary infection at 800 mg. Grade 3 or more toxicities observed in more than 10% of the patients were constipation (24%), nausea (12%), and hypokalemia (12%). Grade 3 to 4 hematologic adverse events were recorded in 8 patients (47%): neutropenia (47%), leukopenia (29%), anemia (18%), and thrombocytopenia (12%). The tazemetostat RP2D was 800 mg. No organ-oriented toxicity increased with tazemetostat dosage escalation (severity and incidence). At 800 mg, AUC and Cmax of tazemetostat were similar compared with the single-agent study (E7438-G000-101). Conclusions: The RP2D of tazemetostat combined with R-CHOP is 800 mg twice a day. The association presents safety and PK comparable with R-CHOP alone. Preliminary efficacy data are encouraging and further investigations in phase II trial are warranted.

Type of Medium: Online Resource

ISSN: 1078-0432 , 1557-3265

URL: Article

DOI: 10.1158/1078-0432.CCR-19-3741

Language: English

Publisher: American Association for Cancer Research (AACR)

Publication Date: 2020

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detail.hit.zdb_id: 2036787-9

In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 114, No. 44 ( 2017-10-31)

Abstract: The family of WD40-repeat (WDR) proteins is one of the largest in eukaryotes, but little is known about their function in brain development. Among 26 WDR genes assessed, we found 7 displaying a major impact in neuronal morphology when inactivated in mice. Remarkably, all seven genes showed corpus callosum defects, including thicker ( Atg16l1 , Coro1c , Dmxl2 , and Herc1 ), thinner ( Kif21b and Wdr89 ), or absent corpus callosum ( Wdr47 ), revealing a common role for WDR genes in brain connectivity. We focused on the poorly studied WDR47 protein sharing structural homology with LIS1, which causes lissencephaly. In a dosage-dependent manner, mice lacking Wdr47 showed lethality, extensive fiber defects, microcephaly, thinner cortices, and sensory motor gating abnormalities. We showed that WDR47 shares functional characteristics with LIS1 and participates in key microtubule-mediated processes, including neural stem cell proliferation, radial migration, and growth cone dynamics. In absence of WDR47, the exhaustion of late cortical progenitors and the consequent decrease of neurogenesis together with the impaired survival of late-born neurons are likely yielding to the worsening of the microcephaly phenotype postnatally. Interestingly, the WDR47-specific C-terminal to LisH (CTLH) domain was associated with functions in autophagy described in mammals. Silencing WDR47 in hypothalamic GT1-7 neuronal cells and yeast models independently recapitulated these findings, showing conserved mechanisms. Finally, our data identified superior cervical ganglion-10 (SCG10) as an interacting partner of WDR47. Taken together, these results provide a starting point for studying the implications of WDR proteins in neuronal regulation of microtubules and autophagy.

Type of Medium: Online Resource

ISSN: 0027-8424 , 1091-6490

URL: Article

DOI: 10.1073/pnas.1713625114

Language: English

Publisher: Proceedings of the National Academy of Sciences

Publication Date: 2017

detail.hit.zdb_id: 209104-5

detail.hit.zdb_id: 1461794-8

SSG: 11

SSG: 12

In: The Journal of Experimental Medicine, Rockefeller University Press, Vol. 204, No. 2 ( 2007-02-19), p. 311-320

Abstract: Prostanoids, bioactive lipids derived from arachidonic acid (AA), are important for vascular homeostasis. Among them, prostaglandin E2 (PGE2) enhances aggregation of platelets submaximally stimulated in vitro. This results from activation of EP3, one of the four PGE2 receptors, which decreases the threshold at which agonists activate platelets to aggregate. Although PGE2 altered venous thrombosis induced by administration of AA, its role in pathophysiopathological conditions has remained speculative. We report that arterial walls subjected to inflammatory stimuli produce PGE2. In several models, we show that PGE2 produced by the arterial wall facilitates arterial thrombosis. Next, we detected PGE2 in mouse atherosclerotic plaques. We demonstrate that this plaque-produced PGE2 is not altered and is still able to activate EP3. In addition, we present evidence that PGE2 can leave the plaque and activate EP3 on blood platelets. Consistent with these findings, we observed that atherothrombosis induced in vivo by mechanical rupture of the plaque was drastically decreased when platelets lacked EP3. In conclusion, PGE2 facilitates the initiation of arterial thrombosis and, hence, contributes to atherothrombosis. Inhibition of the platelet EP3 receptor should improve prevention of atherothrombosis.

Type of Medium: Online Resource

ISSN: 1540-9538 , 0022-1007

URL: Article

DOI: 10.1084/jem.20061617

Language: English

Publisher: Rockefeller University Press

Publication Date: 2007

detail.hit.zdb_id: 1477240-1

In: Nature Communications, Springer Science and Business Media LLC, Vol. 10, No. 1 ( 2019-05-13)

Abstract: De novo heterozygous missense variants in the γ-tubulin gene TUBG1 have been linked to human malformations of cortical development associated with intellectual disability and epilepsy. Here, we investigated through in-utero electroporation and in-vivo studies, how four of these variants affect cortical development. We show that TUBG1 mutants affect neuronal positioning, disrupting the locomotion of new-born neurons but without affecting progenitors’ proliferation. We further demonstrate that pathogenic TUBG1 variants are linked to reduced microtubule dynamics but without major structural nor functional centrosome defects in subject-derived fibroblasts. Additionally, we developed a knock-in Tubg1 Y92C/+ mouse model and assessed consequences of the mutation. Although centrosomal positioning in bipolar neurons is correct, they fail to initiate locomotion. Furthermore, Tubg1 Y92C/+ animals show neuroanatomical and behavioral defects and increased epileptic cortical activity. We show that Tubg1 Y92C/+ mice partially mimic the human phenotype and therefore represent a relevant model for further investigations of the physiopathology of cortical malformations.

Type of Medium: Online Resource

ISSN: 2041-1723

URL: Article

DOI: 10.1038/s41467-019-10081-8

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2019

detail.hit.zdb_id: 2553671-0

In: Blood, American Society of Hematology, Vol. 126, No. 22 ( 2015-11-26), p. 2466-2474

Abstract: MYC-IG translocation partner gene is a negative predictor of survival in DLBCL patients.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2015-05-647602

Language: English

Publisher: American Society of Hematology

Publication Date: 2015

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7