Kooperativer Bibliotheksverbund

In: Neuro-Oncology, Oxford University Press (OUP), Vol. 21, No. Supplement_6 ( 2019-11-11), p. vi25-vi26

Abstract: The CeTeG/NOA-09 trial recently showed a survival benefit for combination chemotherapy with CCNU/TMZ in glioblastoma patients with a methylated MGMT promoter as determined by quantitative Methylation-Specific PCR (qMSP). Identifying patient subgroups with a pronounced benefit from this novel treatment is crucial. Here, we report on the prognostic and predictive value of MGMT promoter methylation ratio determined by qMSP and investigate the concordance of pyrosequencing (PSQ) and qMSP for patients in this trial. METHODS qMSP and PSQ were used for MGMT promoter methylation analysis. The mITT population of the CeTeG/NOA-09 trial was used for multivariate analysis including the parameters MGMT promoter methylation ratio, RPA class and study center. RESULTS Patients of the mITT population of the CeTeG/NOA-09 trial (n=129) with MGMT promoter methylation ratio greater than 4 (qMSP) showed a superior overall survival compared to patients with borderline methylation ratio of 2–4 (p=0.0251). In the latter patients, treatment with CCNU/TMZ did not show a survival benefit (p=0.924). Multivariate analysis with treatment arm, RPA class and study center as covariates did not confirm a prognostic or predictive value of MGMT promoter methylation ratio (qMSP) for patients of the mITT population (n=129, HR=0.88; 95% CI: 0.72 – 1.08) or patients with a ratio greater than 4 (n=117, HR =0.86; 95% CI: 0.69 – 1.07). In a subset of 49 trial patients, qMSP and PSQ showed not only a high qualitative (45/49; 91.8%), but also a high quantitative concordance rate (Spearman correlation, r=0.83, p 〈 0.0001). CONCLUSION Glioblastoma patients with borderline MGMT promoter methylation (qMSP ratio 2–4) do not seem to benefit from combination treatment with CCNU/TMZ. Thus, we propose a qMSP cut-off of 4 as a novel decision tool for clinicians. qMSP and PSQ show a high concordance rate indicating that a decision for combination therapy can also be based on PSQ results.

Type of Medium: Online Resource

ISSN: 1522-8517 , 1523-5866

URL: Article

DOI: 10.1093/neuonc/noz175.095

Language: English

Publisher: Oxford University Press (OUP)

Publication Date: 2019

detail.hit.zdb_id: 2094060-9

In: International Journal of Cancer, Wiley, Vol. 148, No. 7 ( 2021-04), p. 1695-1707

Abstract: What's new? In patients with IDH‐wildtype glioblastoma, methylation of the MGMT promoter allows for improved survival after chemotherapy, due to reduced ability to repair DNA damage. Here, the authors set out to evaluate the use of different tests for promoter methylation, with an eye toward their usefulness at allocation of chemotherapy, and on their prognostic applicability. They show that three different methods of testing methylation—quantitative methylation‐specific PCR, pyrosequencing, and DNA methylation arrays—agree more than 90% of the time. Patients with lower MGMT promoter methylation had shorter survival times, but still benefited from CCNU/TMZ therapy.

Type of Medium: Online Resource

ISSN: 0020-7136 , 1097-0215

URL: Issue

URL: Article

DOI: 10.1002/ijc.v148.7

DOI: 10.1002/ijc.33363

Language: English

Publisher: Wiley

Publication Date: 2021

detail.hit.zdb_id: 218257-9

detail.hit.zdb_id: 1474822-8

In: American Heart Journal, Elsevier BV, Vol. 265 ( 2023-11), p. 66-76

Type of Medium: Online Resource

ISSN: 0002-8703

URL: Article

DOI: 10.1016/j.ahj.2023.06.016

Language: English

Publisher: Elsevier BV

Publication Date: 2023

detail.hit.zdb_id: 2003210-9

In: The Lancet, Elsevier BV, Vol. 396, No. 10262 ( 2020-11), p. 1574-1584

Type of Medium: Online Resource

ISSN: 0140-6736

URL: Article

DOI: 10.1016/S0140-6736(20)32163-2

Language: English

Publisher: Elsevier BV

Publication Date: 2020

detail.hit.zdb_id: 2067452-1

detail.hit.zdb_id: 3306-6

detail.hit.zdb_id: 1476593-7

SSG: 5,21

In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 136, No. 10 ( 2017-09-05), p. 907-916

Abstract: Patients with minor acute ischemic stroke or transient ischemic attack are at high risk for subsequent stroke, and more potent antiplatelet therapy in the acute setting is needed. However, the potential benefit of more intense antiplatelet therapy must be assessed in relation to the risk for major bleeding. The SOCRATES trial (Acute Stroke or Transient Ischemic Attack Treated With Aspirin or Ticagrelor and Patient Outcomes) was the first trial with ticagrelor in patients with acute ischemic stroke or transient ischemic attack in which the efficacy and safety of ticagrelor were compared with those of aspirin. The main safety objective was assessment of PLATO (Platelet Inhibition and Patient Outcomes)–defined major bleeds on treatment, with special focus on intracranial hemorrhage (ICrH). Methods: An independent adjudication committee blinded to study treatment classified bleeds according to the PLATO, TIMI (Thrombolysis in Myocardial Infarction), and GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) definitions. The definitions of ICrH and major bleeding excluded cerebral microbleeds and asymptomatic hemorrhagic transformations of cerebral infarctions so that the definitions better discriminated important events in the acute stroke population. Results: A total of 13 130 of 13 199 randomized patients received at least 1 dose of study drug and were included in the safety analysis set. PLATO major bleeds occurred in 31 patients (0.5%) on ticagrelor and 38 patients (0.6%) on aspirin (hazard ratio, 0.83; 95% confidence interval, 0.52–1.34). The most common locations of major bleeds were intracranial and gastrointestinal. ICrH was reported in 12 patients (0.2%) on ticagrelor and 18 patients (0.3%) on aspirin. Thirteen of all 30 ICrHs (4 on ticagrelor and 9 on aspirin) were hemorrhagic strokes, and 4 (2 in each group) were symptomatic hemorrhagic transformations of brain infarctions. The ICrHs were spontaneous in 6 and 13, traumatic in 3 and 3, and procedural in 3 and 2 patients on ticagrelor and aspirin, respectively. In total, 9 fatal bleeds occurred on ticagrelor and 4 on aspirin. The composite of ICrH or fatal bleeding included 15 patients on ticagrelor and 18 on aspirin. Independently of bleeding classification, PLATO, TIMI, or GUSTO, the relative difference between treatments for major/severe bleeds was similar. Nonmajor bleeds were more common on ticagrelor. Conclusions: Antiplatelet therapy with ticagrelor in patients with acute ischemic stroke or transient ischemic attack showed a bleeding profile similar to that of aspirin for major bleeds. There were few ICrHs. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01994720.

Type of Medium: Online Resource

ISSN: 0009-7322 , 1524-4539

URL: Article

DOI: 10.1161/CIRCULATIONAHA.117.028566

Language: English

Publisher: Ovid Technologies (Wolters Kluwer Health)

Publication Date: 2017

detail.hit.zdb_id: 1466401-X

In: Open Forum Infectious Diseases, Oxford University Press (OUP), Vol. 6, No. Supplement_2 ( 2019-10-23), p. S776-S776

Abstract: In recent years, survival of patients with invasive aspergillosis (IA) has improved mainly due to availability of extended spectrum triazoles. These advances are jeopardized by the emergence of azole resistance in Aspergillus fumigatus, the most common causative pathogen of IA. Despite several studies suggesting high probability of azole treatment failure in patients with azole-resistant isolates, the clinical implications of azole-resistant IA compared with azole-susceptible IA remain unclear. Methods In patients with hematological malignancies, cases of proven or probable IA (EORTC/MSG 2008) caused by A. fumigatus are registered. Retrospective data are documented, comprising demographics, diagnosis, treatment, response and outcome. Participating sites provided susceptibility results or isolates. Provided isolates were analyzed in a central laboratory. Results Since January 2018, 51 sites in 15 countries worldwide enrolled 154 cases diagnosed with IA between 2010 and 2019, of which 23 (14.9%) had azole-resistant IA. Of 44 cases, the respective clinical fungal isolate was analyzed in the central laboratory. A mixed fungal infection was reported for 34 patients (22.1%), 1 (2.9%) in the azole-resistant group; most were related to non-fumigatus Aspergillus species (n = 12, 35.3%) and non-Aspergillus molds (n = 10, 29.4). Most patients were male (n = 98, 63.6%); 19 (82.6%) in the azole-resistant group, 79 (60.3%) in the azole-susceptible group. Age was documented in categories instead of the exact age. Median age group was 50–69 years in both groups (ranging from 7–11 to 70–89 years for azole-resistant cases, 1–12 months to 70–89 years for azole-susceptible cases). Underlying disease and survival are shown in the table. Conclusion A worldwide network of investigators contributes to the CLARITY registry study. Completion of recruitment and subsequent data analysis are planned for 2019. Further sites may be added if azole-resistant cases are encountered. Disclosures All authors: No reported disclosures.

Type of Medium: Online Resource

ISSN: 2328-8957

URL: Article

DOI: 10.1093/ofid/ofz360.1946

Language: English

Publisher: Oxford University Press (OUP)

Publication Date: 2019

detail.hit.zdb_id: 2757767-3

In: Open Forum Infectious Diseases, Oxford University Press (OUP), Vol. 7, No. Supplement_1 ( 2020-12-31), p. S795-S796

Abstract: Advances in the survival of patients with invasive aspergillosis (IA) are jeopardized by the emergence of azole resistance in Aspergillus fumigatus, which has been associated with high probability of azole treatment failure. The clinical implications of azole-resistant IA compared to azole-susceptible IA remain unclear. Thus, we seek to describe the epidemiology and to determine the efficacy of antifungal therapy in patients with documented azole-resistant IA compared to azole-susceptible IA in patients with hematological malignancy. Methods For proven and probable IA (EORTC/MSG 2019) caused by A. fumigatus in patients with hematological malignancies retrospective data were documented, comprising demographics, diagnosis, treatment, response, and outcome. Sites provided susceptibility results or respective isolates for analysis in a central laboratory. Results Sites in 16 countries worldwide enrolled 187 cases diagnosed with IA between 2010 and 2019; 31 (16.6%) were resistant to at least one of the clinical azoles. Fungal isolates were available from 42 cases. A mixed fungal infection was reported for 32 patients (17.1%), most were related to non-fumigatus Aspergillus and non-Aspergillus molds (n=22, 69%). Most patients were male (66.8%) and overall the majority of patients were in the age groups between 50 and 89 years (71%). Amphotericin B was used for treatment in 24 (77%) patients with azole-resistant IA, compared to 76 (49%) in the azole-susceptible group (lipid-based formulation in 98%); only five (16%) patients with azole-resistant IA were treated with an azole alone vs. 57 (36%) of those with azole-susceptible IA. Overall, all-cause mortality rate was higher for patients with azole-resistant compared to azole-susceptible IA (74.2% vs. 53.8%, log rank P=0.004), the 8 patients with an azole-resistant IA treated in the intensive care unit died within 1 month (Figure 1). Details on underlying disease and survival are given in Table 1. Table 1. Underlying hematological malignancy and clinical outcome of patients with azole-resistant and azole-susceptible invasive aspergillosis Figure 1. Intensive care unit 1-year survival probability for patients with azole-resistant and azole-susceptible invasive aspergillosis Conclusion Azole-resistance in IA is associated with worse outcome, especially in critically ill patients. Susceptibility testing should be considered in patients with a suspected azole-resistant IA to support treatment decisions. Disclosures Danila Seidel, PhD, Basilea (Other Financial or Material Support, travel grant) Oliver Cornely, Prof., Actelion (Grant/Research Support)Actelion (Other Financial or Material Support, Personal fees)Al Jazeera Pharmaceuticals (Consultant)Allecra Therapeutics (Other Financial or Material Support, Personal fees)Amplyx (Other Financial or Material Support, Personal fees)Amplyx (Grant/Research Support)Astellas (Grant/Research Support)Astellas (Other Financial or Material Support, Personal fees)Basilea (Other Financial or Material Support, Personal fees)Basilea (Grant/Research Support)Biosys UK Limited (Other Financial or Material Support, Personal fees)Cidara (Other Financial or Material Support, Personal fees)Cidara (Grant/Research Support)Da Volterra (Grant/Research Support)Da Volterra (Other Financial or Material Support, Personal fees)Entasis (Other Financial or Material Support, Personal fees)F2G (Other Financial or Material Support)F2G (Grant/Research Support)Gilead (Grant/Research Support)Gilead (Other Financial or Material Support, Personal fees)Grupo Biotoscana (Other Financial or Material Support, Personal fees)Janssen Pharmaceuticals (Grant/Research Support)Matinas (Other Financial or Material Support, Personal fees)Medicines Company (Grant/Research Support)MedPace (Grant/Research Support)MedPace (Other Financial or Material Support, Personal fees)Melinta Therapeutics (Grant/Research Support)Menarini Ricerche (Other Financial or Material Support, Personal fees)Merck/MSD (Other Financial or Material Support, Personal fees)Merck/MSD (Grant/Research Support)Mylan Pharmaceuticals (Consultant)Nabriva Therapeutics (Other Financial or Material Support, Personal fees)Octapharma (Other Financial or Material Support, Personal fees)Paratek Pharmaceuticals (Other Financial or Material Support, Personal fees)Pfizer (Other Financial or Material Support, Personal fees)Pfizer (Grant/Research Support)PSI (Other Financial or Material Support, Personal fees)Rempex (Other Financial or Material Support, Personal fees)Roche Diagnostics (Other Financial or Material Support, Personal fees)Scynexis (Other Financial or Material Support, Personal fees)Scynexis (Grant/Research Support)Seres Therapeutics (Other Financial or Material Support, Personal fees)Tetraphase (Other Financial or Material Support, Personal fees) Philipp Koehler, MD, Akademie für Infektionsmedizin e.V., (Other Financial or Material Support, Personal fees)Astellas Pharma GmbH (Other Financial or Material Support, Personal fees)Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany (Other Financial or Material Support, Other)Gilead Sciences GmbH (Other Financial or Material Support, Personal fees)GPR Academy Ruesselsheim (Speaker’s Bureau)Miltenyi Biotec GmbH (Other Financial or Material Support, Non-financial support)MSD Sharp & Dohme GmbH (Other Financial or Material Support, Personal fees)Noxxon N.V. (Speaker’s Bureau)University Hospital, LMU Munich (Other Financial or Material Support, Personal fees) Katrien Lagrou, n/a, FUJIFILM WAKO (Speaker’s Bureau)Gilead (Consultant, Speaker’s Bureau)MSD (Consultant, Speaker’s Bureau, Other Financial or Material Support, travel grant)Pfizer (Speaker’s Bureau, travel grant)SMB Laboratoires Brussels (Consultant) Zdenek Racil, n/a, Astellas (Grant/Research Support, Speaker’s Bureau, travel grant) Blandine Rammaert, n/a, Gilead (Speaker’s Bureau, Other Financial or Material Support, travel grant)Merck/MSD (Speaker’s Bureau)Pfizer (Other Financial or Material Support, travel grant) Nikolay Klimko, n/a, Astellas (Speaker’s Bureau)Gilead (Speaker’s Bureau)Merck/MSD (Speaker’s Bureau)Pfizer (Speaker’s Bureau) Sung-Yeon Cho, MD, Gilead (Grant/Research Support, Speaker’s Bureau)Merck Sharp & Dohme (Grant/Research Support, Speaker’s Bureau)Pfizer (Grant/Research Support, Speaker’s Bureau)

Type of Medium: Online Resource

ISSN: 2328-8957

URL: Article

DOI: 10.1093/ofid/ofaa439.1778

Language: English

Publisher: Oxford University Press (OUP)

Publication Date: 2020

detail.hit.zdb_id: 2757767-3

In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 51, No. 1 ( 2020-01), p. 209-215

Abstract: Relative signal intensity of acute ischemic stroke lesions in fluid-attenuated inversion recovery (fluid-attenuated inversion recovery relative signal intensity [FLAIR-rSI]) magnetic resonance imaging is associated with time elapsed since stroke onset with higher intensities signifying longer time intervals. In the randomized controlled WAKE-UP trial (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke Trial), intravenous alteplase was effective in patients with unknown onset stroke selected by visual assessment of diffusion weighted imaging fluid-attenuated inversion recovery mismatch, that is, in those with no marked fluid-attenuated inversion recovery hyperintensity in the region of the acute diffusion weighted imaging lesion. In this post hoc analysis, we investigated whether quantitatively measured FLAIR-rSI modifies treatment effect of intravenous alteplase. Methods— FLAIR-rSI of stroke lesions was measured relative to signal intensity in a mirrored region in the contralesional hemisphere. The relationship between FLAIR-rSI and treatment effect on functional outcome assessed by the modified Rankin Scale (mRS) after 90 days was analyzed by binary logistic regression using different end points, that is, favorable outcome defined as mRS score of 0 to 1, independent outcome defined as mRS score of 0 to 2, ordinal analysis of mRS scores (shift analysis). All models were adjusted for National Institutes of Health Stroke Scale at symptom onset and stroke lesion volume. Results— FLAIR-rSI was successfully quantified in stroke lesions in 433 patients (86% of 503 patients included in WAKE-UP). Mean FLAIR-rSI was 1.06 (SD, 0.09). Interaction of FLAIR-rSI and treatment effect was not significant for mRS score of 0 to 1 ( P =0.169) and shift analysis ( P =0.086) but reached significance for mRS score of 0 to 2 ( P =0.004). We observed a smooth continuing trend of decreasing treatment effects in relation to clinical end points with increasing FLAIR-rSI. Conclusions— In patients in whom no marked parenchymal fluid-attenuated inversion recovery hyperintensity was detected by visual judgement in the WAKE-UP trial, higher FLAIR-rSI of diffusion weighted imaging lesions was associated with decreased treatment effects of intravenous thrombolysis. This parallels the known association of treatment effect and elapsing time of stroke onset.

Type of Medium: Online Resource

ISSN: 0039-2499 , 1524-4628

URL: Article

DOI: 10.1161/STROKEAHA.119.027390

Language: English

Publisher: Ovid Technologies (Wolters Kluwer Health)

Publication Date: 2020

detail.hit.zdb_id: 1467823-8

In: Rheumatology, Oxford University Press (OUP), Vol. 59, No. 8 ( 2020-08-01), p. 2016-2023

Abstract: In patients with SSc, peripheral vasculopathy can promote critical ischaemia and gangrene. The aim of this study was to investigate the prevalence, incidence and risk factors for gangrene in the EUSTAR cohort. Methods We included patients from the EUSTAR database fulfilling the ACR 1980 or the ACR/EULAR 2013 classification criteria for SSc, with at least one visit recording data on gangrene. Centres were asked for supplementary data on traditional cardiovascular risk factors. We analysed the cross-sectional relationship between gangrene and its potential risk factors by univariable and multivariable logistic regression. Longitudinal data were analysed by Cox proportional hazards regression. Results 1757 patients were analysed (age 55.9 [14.5] years, disease duration 7.9 [10.3]  years, male sex 16.7%, 24.6% diffuse cutaneous subset [dcSSc]). At inclusion, 8.9% of patients had current or previous digital gangrene, 16.1% had current digital ulcers (DUs) and 42.7% had ever had DUs (current or previous). Older age, DUs ever and dcSSc were statistically significant risk factors for gangrene in the cross-sectional multivariable model. During a median follow-up of 13.1 months, 16/771 (0.9%) patients developed gangrene. All 16 patients who developed gangrene had previously had DUs and gangrene. Further risk factors for incident gangrene were the dcSSc subset and longer disease duration. Conclusion In unselected SSc patients, gangrene occurs in about 9% of SSc patients. DUs ever and, to a lesser extent, the dcSSc subset are strongly and independently associated with gangrene, while traditional cardiovascular risk factors could not be identified as risk factors.

Type of Medium: Online Resource

ISSN: 1462-0324 , 1462-0332

URL: Article

DOI: 10.1093/rheumatology/kez558

Language: English

Publisher: Oxford University Press (OUP)

Publication Date: 2020

detail.hit.zdb_id: 1474143-X

In: Journal of Neuro-Oncology, Springer Science and Business Media LLC, Vol. 164, No. 2 ( 2023-09), p. 353-366

Abstract: Multimodal therapies have significantly improved prognosis in glioma. However, in particular radiotherapy may induce long-term neurotoxicity compromising patients’ neurocognition and quality of life. The present prospective multicenter study aimed to evaluate associations of multimodal treatment with neurocognition with a particular focus on hippocampal irradiation. Methods Seventy-one glioma patients (WHO grade 1–4) were serially evaluated with neurocognitive testing and quality of life questionnaires. Prior to (baseline) and following further treatment (median 7.1 years [range 4.6–11.0] after baseline) a standardized computerized neurocognitive test battery (NeuroCog FX) was applied to gauge psychomotor speed and inhibition, verbal short-term memory, working memory, verbal and non-verbal memory as well as verbal fluency. Mean ipsilateral hippocampal radiation dose was determined in a subgroup of 27 patients who received radiotherapy according to radiotherapy plans to evaluate its association with neurocognition. Results Between baseline and follow-up mean performance in none of the cognitive domains significantly declined in any treatment modality (radiotherapy, chemotherapy, combined radio-chemotherapy, watchful-waiting), except for selective attention in patients receiving chemotherapy alone. Apart from one subtest (inhibition), mean ipsilateral hippocampal radiation dose  〉  50 Gy (Dmean) as compared to  〈  10 Gy showed no associations with long-term cognitive functioning. However, patients with Dmean  〈  10 Gy showed stable or improved performance in all cognitive domains, while patients with  〉  50 Gy numerically deteriorated in 4/8 domains. Conclusions Multimodal glioma therapy seems to affect neurocognition less than generally assumed. Even patients with unilateral hippocampal irradiation with  〉  50 Gy showed no profound cognitive decline in this series.

Type of Medium: Online Resource

ISSN: 0167-594X , 1573-7373

URL: Article

DOI: 10.1007/s11060-023-04419-y

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2023

detail.hit.zdb_id: 2007293-4