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In: The Lancet Haematology, Elsevier BV, Vol. 9, No. 11 ( 2022-11), p. e810-e821

Type of Medium: Online Resource

ISSN: 2352-3026

URL: Article

DOI: 10.1016/S2352-3026(22)00263-0

Language: English

Publisher: Elsevier BV

Publication Date: 2022

detail.hit.zdb_id: 2802056-X

In: Leukemia, Springer Science and Business Media LLC, Vol. 35, No. 4 ( 2021-04), p. 1134-1144

Type of Medium: Online Resource

ISSN: 0887-6924 , 1476-5551

URL: Article

DOI: 10.1038/s41375-020-0948-0

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2021

detail.hit.zdb_id: 807030-1

detail.hit.zdb_id: 2008023-2

In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 463-463

Abstract: Background: In newly-diagnosed multiple myeloma (NDMM), lenalidomide/bortezomib/dexamethasone (RVd) is one of the most widely used combination regimens. Anti-CD38 monoclonal antibodies (CD38-moAb) increase efficacy when added to standard-of-care regimens. Here we present the first primary endpoint of the randomized, open-label, multicenter, phase III GMMG-HD7 trial, comparing RVd without (arm IA) or with the CD38-moAb isatuximab (Isa, arm IB) with regard to the rate of minimal residual disease (MRD) negativity after induction therapy in patients with transplant-eligible NDMM. Patients and Methods: Patients with transplant-eligible NDMM at 67 sites in Germany were equally randomized to receive three 42-day cycles of RVd (lenalidomide 25 mg/d p.o., d1-14 and d22-35; bortezomib 1.3 mg/m 2 s.c. d1, 4, 8, 11, 22, 25, 29, 32; dexamethasone 20 mg/d d1-2, 4-5, 8-9, 11-12, 15, 22-23, 25-26, 29-30, 32-33) in both arms. Isa was added to arm IB only (10 mg/kg i.v., cycle 1: d 1, 8, 15, 22, 29; cycles 2-3: d 1, 15, 29). Randomization for induction was stratified according to revised International Staging System (R-ISS). Primary endpoint of the trial was MRD negativity assessed by next-generation flow (NGF, cut off 1x10 -5) after induction. Secondary endpoints included rates of complete response (CR) after induction and safety. Data cut-off for the present analysis was April 2021. Results: Between 10/2018 and 09/2020, 662 patients were included in the trial. 660 patients were eligible for intention-to-treat analysis and 658 patients started induction (RVd: 329/328 and Isa-RVd: 331/330). Median age was 58 (range 26-70) years and baseline characteristics were well balanced between treatment arms. On induction, 35 (10.6%) and 18 (5.4%) patients discontinued treatment in the RVd vs. Isa-RVd arms (p=0.02). Among these, 8 (2.4%, RVd) vs. 7 (2.1%, Isa-RVd) patients discontinued induction due to adverse events (AE). 293 (89.1%) vs. 312 (94.3%) patients in the RVd vs. Isa-RVd arms continued further study treatment after induction. MRD negativity rates after induction were 35.6% vs. 50.1% (odds ratio [OR]=1.83, 95% confidence interval [95% CI] : 1.34-2.51, p & lt;0.001) for RVd vs. Isa-RVd, respectively. On multivariate analyses including treatment arm, R-ISS, performance status, renal impairment, age and sex, treatment with Isa-RVd (vs. RVd) remained the only significant predictor for increased MRD negativity after induction (OR=1.82, 95% CI: 1.33-2.49, p & lt;0.001). While the rates of CR after induction did not yet differ between the RVd vs. Isa-RVd arms (21.6% vs. 24.2%, p=0.46), the rate of very good partial response or better (≥VGPR) was significantly higher in the Isa-RVd arm (60.5% vs. 77.3%, p & lt;0.001). The rates of progressive disease were 4.0% (RVd) vs. 1.5% (Isa-RVd). At least one AE (grade ≥3) on induction occurred in 61.3% (RVd) and 63.6% (Isa-RVd) of patients (p=0.57). Most common AE (grade ≥3) by system organ class (SOC) for RVd vs. Isa-RVd were: "investigations": 23.5% vs. 23.9% (p=0.93), "blood and lymphatic system disorders": 16.8% vs. 25.8% (p=0.006), "infections and infestations": 10.4% vs. 13.0% (p=0.33) and "nervous system disorders": 10.1% vs. 8.5% (p=0.50). Rates of serious AE (SAE, any grade) on induction were similar between RVd and Isa-RVd (36.3% vs. 34.8%, p=0.75). Eight (RVd) and four (Isa-RVd) patients died during induction. Conclusions: The GMMG-HD7 trial met its primary endpoint. To the best of our knowledge this is the first phase III trial to demonstrate superiority of MRD negativity rates after induction by adding a CD38-moAb to RVd. There were no increased rates of SAE or early discontinuation in patients treated with Isa-RVd compared to RVd. The trial is ongoing, including analyses post autologous transplantation, which is followed by a second randomization to compare the efficacy of the addition of Isa to lenalidomide maintenance. Disclosures Goldschmidt: Takeda: Consultancy, Research Funding; Sanofi: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Adaptive Biotechnology: Consultancy; Incyte: Research Funding; GSK: Honoraria; Chugai: Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Celgene: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; BMS: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Janssen: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Johns Hopkins University: Other: Grant; Molecular Partners: Research Funding; MSD: Research Funding; Mundipharma: Research Funding; Dietmar-Hopp-Foundation: Other: Grant; Novartis: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding. Mai: Celgene / BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations and expenses, Research Funding; Glaxo Smith Kline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations and expenses, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations and expenses, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations and expenses, Research Funding. Fenk: Takeda: Honoraria; GSK: Honoraria; Amgen: Honoraria; Janssen: Honoraria; BMS/Celgene: Honoraria. Besemer: Takeda: Honoraria; Janssen: Honoraria; GSK: Honoraria. Dürig: Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Schroers: BMS/Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Takeda: Honoraria. Metzler: Takeda: Consultancy; BMS: Consultancy; GSK: Consultancy; Amgen: Consultancy; Janssen: Consultancy; AstraZeneca: Consultancy; Pfizer: Consultancy; Sanofi: Consultancy. Haenel: Takeda: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; GSK: Consultancy; Bayer Vital: Honoraria; Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy; Celgene: Consultancy, Honoraria. Mann: Cellgene: Consultancy. Asemissen: GSK: Honoraria; Pfizer: Honoraria; Celgene BMS: Honoraria. Heilmeier: Sanofi-Aventis Dtld. GmbH: Consultancy. Kriegsmann: Sanofi: Honoraria. Weinhold: Sanofi: Honoraria. Holderried: Amgen: Speakers Bureau; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Eurocept Pharmaceuticals: Other: Travel support; MSD: Speakers Bureau; Gilead Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Other: Travel support; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Other: Travel support; Therakos: Other: Travel support; Daiichi Sankyo: Other: travel support; Medac: Other: Travel support; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Trautmann-Grill: Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; GSK: Consultancy, Honoraria. Gezer: Amgen: Consultancy, Other: Invited Speaker; Takeda: Consultancy, Other: Invited Speaker; BMS: Consultancy, Other: Invited Speaker; Celgene: Consultancy, Other: Invited Speaker. Khandanpour: GSK: Honoraria; Takeda: Honoraria; Janssen: Honoraria; AstraZeneca: Honoraria, Research Funding; Pfizer: Honoraria; Sanofi: Honoraria, Research Funding; BMS/Celgene: Honoraria. Knauf: Amgen: Honoraria; Abbvie: Honoraria; Beigene: Consultancy, Honoraria; BMS: Honoraria; Celgene: Honoraria; Janssen: Consultancy, Honoraria; Sanofi: Honoraria; AstraZeneca: Consultancy, Honoraria. Munder: GSK: Consultancy; Amgen: Honoraria; Sanofi: Consultancy; Takeda: Consultancy, Honoraria; Abbvie: Consultancy; BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Incyte: Research Funding. Hoffmann: Sanofi-Aventis: Consultancy. Raab: Roche: Consultancy; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Salwender: GlaxoSmithKline: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Sanofi: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Chugai: Honoraria; Oncopeptides: Honoraria; Takeda: Honoraria; Amgen: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; AbbVie: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Janssen-Cilag: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Bristol-Myers Squibb/Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Pfizer: Honoraria. Weisel: Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy; Novartis: Honoraria; Pfizer: Honoraria. OffLabel Disclosure: Isatuximab prior to ASCT in NDMM

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-145097

Language: English

Publisher: American Society of Hematology

Publication Date: 2021

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Der Onkologe, Springer Science and Business Media LLC, Vol. 28, No. S1 ( 2022-02), p. 19-22

Type of Medium: Online Resource

ISSN: 0947-8965 , 1433-0415

URL: Article

DOI: 10.1007/s00761-022-01106-x

Language: German

Publisher: Springer Science and Business Media LLC

Publication Date: 2022

detail.hit.zdb_id: 1229978-9

detail.hit.zdb_id: 1462966-5

In: Annals of Surgery, Ovid Technologies (Wolters Kluwer Health), Vol. 256, No. 5 ( 2012-11), p. 828-836

Type of Medium: Online Resource

ISSN: 0003-4932

URL: Article

DOI: 10.1097/SLA.0b013e318272df97

Language: English

Publisher: Ovid Technologies (Wolters Kluwer Health)

Publication Date: 2012

detail.hit.zdb_id: 340-2

In: BMC Neurology, Springer Science and Business Media LLC, Vol. 8, No. 1 ( 2008-12)

Abstract: The treatment of Herpes-simplex-virus-encephalitis (HSVE) remains a major unsolved problem in Neurology. Current gold standard for therapy is acyclovir, a drug that inhibits viral replication. Despite antiviral treatment, mortality remains up to 15%, less than 20% of patients are able to go back to work, and the majority of patients suffer from severe disability. This is a discouraging, unsatisfactory situation for treating physicians, the disabled patients and their families, and constitutes an enormous burden to the public health services. The information obtained from experimental animal research and from recent retrospective clinical observations, indicates that a substantial benefit in outcome can be expected in patients with HSVE who are treated with adjuvant dexamethasone. But currently there is no available evidence to support the routine use of adjuvant corticosteroid treatment in HSVE. A randomized multicenter trial is the only useful instrument to address this question. Design GACHE is a multicenter, randomized, double-blind, placebo-controlled, parallel group clinical trial of treatment with acyclovir and adjuvant dexamethasone, as compared with acyclovir and placebo in adults with HSVE. The statistical design will be that of a 3-stage-group sequential trial with potential sample size adaptation in the last stage. Conclusion 372 patients with proven HSVE (positive HSV-DNA-PCR), aged 18 up to 85 years; with focal neurological signs no longer than 5 days prior to admission, and who give informed consent will be recruited from Departments of Neurology of academic medical centers in Germany, Austria and The Netherlands. Sample size will potentially be extended after the second interim analysis up to a maximum of 450 patients. Trial Registration Current Controlled Trials ISRCTN45122933

Type of Medium: Online Resource

ISSN: 1471-2377

URL: Article

DOI: 10.1186/1471-2377-8-40

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2008

detail.hit.zdb_id: 2041347-6

In: Medicine, Ovid Technologies (Wolters Kluwer Health), Vol. 100, No. 25 ( 2021-06-25), p. e26403-

Abstract: Sepsis and septic shock are the most severe forms of infection affecting predominantly elderly people, preterm and term neonates, and young infants. Even in high-income countries sepsis causes about 8% of admissions to pediatric intensive care units (PICUs). Early diagnosis, rapid anti-infective treatment, and prompt hemodynamic stabilization are crucial for patient survival. In this context, it is essential to identify the causative pathogen as soon as possible to optimize antimicrobial treatment. To date, culture-based diagnostic procedures (e.g., blood cultures) represent the standard of care. However, they have 2 major problems: on the one hand, in the case of very small sample volumes (and thus usually in children), they are not sufficiently sensitive. On the other hand, with a time-to-result of 2 to 5 days, blood cultures need a relatively long time for the anti-infective therapy to be calculated. To overcome these problems, culture-independent molecular diagnostic procedures such as unbiased sequence analysis of circulating cell-free DNA (cfDNA) from plasma samples of septic patients by next-generation sequencing (NGS) have been tested successfully in adult septic patients. However, these results still need to be transferred to the pediatric setting. Methods: The Next GeneSiPS-Trial is a prospective, observational, non-interventional, multicenter study used to assess the diagnostic performance of an NGS-based approach for the identification of causative pathogens in (preterm and term) neonates (d1–d28, n = 50), infants (d29 to 〈 1 yr, n = 50), and toddlers (1 yr to 〈 5 yr, n = 50) with suspected or proven severe sepsis or septic shock (according to the pediatric sepsis definition) by the use of the quantitative sepsis indicating quantifier (SIQ) score in comparison to standard of care (culture-based) microbiological diagnostics. Potential changes in anti-infective treatment regimens based on these NGS results will be estimated retrospectively by a panel of 3 independent clinical specialists. Discussion: Neonates, infants, and young children are significantly affected by sepsis. Fast and more sensitive diagnostic approaches are urgently needed. This prospective, observational, non-interventional, multicenter study seeks to evaluate an NGS-based approach in critically ill children suffering from sepsis. Trial registration: DRKS-ID: DRKS00015705 (registered October 24, 2018). https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML & TRIAL_ID=DRKS00015705

Type of Medium: Online Resource

ISSN: 0025-7974 , 1536-5964

URL: Article

DOI: 10.1097/MD.0000000000026403

Language: English

Publisher: Ovid Technologies (Wolters Kluwer Health)

Publication Date: 2021

detail.hit.zdb_id: 2049818-4

detail.hit.zdb_id: 80184-7

In: Trials, Springer Science and Business Media LLC, Vol. 10, No. 1 ( 2009-12)

Abstract: The development of suture hole bleeding at peripheral arterial bypass anastomoses using PTFE graft prostheses is a common problem in peripheral vascular surgery. Traditionally the problem is managed by compression with surgical swabs and reversal heparin or by using several haemostatic device (e.g. different forms of collagen, oxidized cellulose, gelatine sponge, ethylcyanoacrylate glue or fibrin) with various success. Preclinical data suggest that the haemostatic effect of collagen is stronger than that of oxidized cellulose, but no direct clinical comparison of their hemostatic performance has been published so far. Design This randomized, controlled, prospective trial evaluates the haemostatic effect of Lyostypt versus Surgicel in arterial bypass anastomosis. 28 patients undergoing an elective peripheral vascular reconstruction due to peripheral vascular disease will be included. Suture hole bleeding occurring at the arterial bypass anastomosis using a PTFE prostheses will be stopped by the application of Lyostypt and/or Surgicel. The proximal anastomoses will be randomized intraoperatively. The patients will be allocated into 4 different treatment groups. Group1 Lyostypt distal/Surgicel proximal; Group 2: Lyostypt proximal/Surgicel distal; Group 3: Surgicel distal and proximal; Group 4: Lyostypt distal and proximal. Primary endpoint of the study is time to haemostasis. Secondary endpoints are the number of intraoperatively used haemostatic devices, postoperative mortality within 30 days as well as the intraoperative efficacy rating of the two devices evaluated by the surgeon. As a safety secondary parameter, the local and general complication occurring till 30 ± 10 days postoperatively will also be analysed. After hospital discharge the investigator will examine the enrolled patients again at 30 days after surgery. Discussion The COBBANA trial aims to assess, whether the haemostatic effect of Lyostypt is superior to Surgicel in suture hole bleedings of arterial bypass anastomoses. Trial registration NCT00837954

Type of Medium: Online Resource

ISSN: 1745-6215

URL: Article

DOI: 10.1186/1745-6215-10-91

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2009

detail.hit.zdb_id: 2040523-6

In: International Journal of Stroke, SAGE Publications, Vol. 19, No. 1 ( 2024-01), p. 120-126

Abstract: Oxygen is essential for cellular energy metabolism. Neurons are particularly vulnerable to hypoxia. Increasing oxygen supply shortly after stroke onset could preserve the ischemic penumbra until revascularization occurs. Aims: PROOF investigates the use of normobaric oxygen (NBO) therapy within 6 h of symptom onset/notice for brain-protective bridging until endovascular revascularization of acute intracranial anterior-circulation occlusion. Methods and design: Randomized (1:1), standard treatment-controlled, open-label, blinded endpoint, multicenter adaptive phase IIb trial. Study outcomes: Primary outcome is ischemic core growth (mL) from baseline to 24 h (intention-to-treat analysis). Secondary efficacy outcomes include change in NIHSS from baseline to 24 h, mRS at 90 days, cognitive and emotional function, and quality of life. Safety outcomes include mortality, intracranial hemorrhage, and respiratory failure. Exploratory analyses of imaging and blood biomarkers will be conducted. Sample size: Using an adaptive design with interim analysis at 80 patients per arm, up to 456 participants (228 per arm) would be needed for 80% power (one-sided alpha 0.05) to detect a mean reduction of ischemic core growth by 6.68 mL, assuming 21.4 mL standard deviation. Discussion: By enrolling endovascular thrombectomy candidates in an early time window, the trial replicates insights from preclinical studies in which NBO showed beneficial effects, namely early initiation of near 100% inspired oxygen during short temporary ischemia. Primary outcome assessment at 24 h on follow-up imaging reduces variability due to withdrawal of care and early clinical confounders such as delayed extubation and aspiration pneumonia. Trial registrations: ClinicalTrials.gov: NCT03500939; EudraCT: 2017-001355-31.

Type of Medium: Online Resource

ISSN: 1747-4930 , 1747-4949

URL: Article

DOI: 10.1177/17474930231185275

Language: English

Publisher: SAGE Publications

Publication Date: 2024

detail.hit.zdb_id: 2303728-3

detail.hit.zdb_id: 2211666-7

In: Leukemia, Springer Science and Business Media LLC, Vol. 35, No. 3 ( 2021-03), p. 809-822

Abstract: Intensive upfront therapy in newly-diagnosed multiple myeloma (MM) including induction therapy (IT), high-dose melphalan (MEL200), and autologous blood stem cell transplantation (ASCT) followed by consolidation and/or maintenance is mostly restricted to patients up to 65 years of age. Prospective phase III trial data in the era of novel agents for patients up to 70 years of age are not available. The GMMG-MM5 trial included 601 patients between 18 and 70 years of age, divided in three groups for the present analysis: ≤60 years (S1, n  = 353), 61–65 years (S2, n  = 107) and 66–70 years (S3, n  = 141). Treatment consisted of a bortezomib-containing IT, MEL200/ASCT, consolidation, and maintenance with lenalidomide. Adherence to treatment was similar among patients of the three age groups. Overall toxicity during all treatment phases was increased in S2 and S3 compared to S1 (any adverse event/any serious adverse event: S1:81.7/41.8% vs. S2:90.7/56.5% vs. S3:87.2/68.1%, p  = 0.05/ 〈 0.001). With respect to progression-free survival (log-rank p  = 0.73), overall survival (log-rank p  = 0.54) as well as time-to-progression (Gray’s p  = 0.83) and non-relapse mortality (Gray’s p  = 0.25), no differences were found between the three age groups. Our results imply that an intensive upfront therapy with a bortezomib-containing IT, MEL200/ASCT, lenalidomide consolidation, and maintenance should be applied to transplant-eligible MM patients up to 70 years of age.

Type of Medium: Online Resource

ISSN: 0887-6924 , 1476-5551

URL: Article

DOI: 10.1038/s41375-020-0976-9

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2021

detail.hit.zdb_id: 807030-1

detail.hit.zdb_id: 2008023-2