Publications by authors named "Rolf Mesters"

104 Publications

Allogeneic hematopoietic stem cell transplantation for therapy-related myeloid neoplasms following treatment of a lymphoid malignancy.

Leuk Lymphoma 2021 Mar 29:1-10. Epub 2021 Mar 29.

Department of Medicine A, Hematology and Oncology, University Hospital Muenster, Muenster, Germany.

Advances in lymphoma treatment lead to increasing numbers of long-term survivors. Thus, secondary therapy-related myeloid neoplasms (t-MN) gain clinical relevance. We analyzed 38 t-MN patients receiving an allogeneic stem cell transplantation (SCT) after successful cytotoxic treatment of Hodgkin lymphoma ( = 9), non-Hodgkin lymphoma ( = 24), and multiple myeloma ( = 5), who had developed t-AML ( = 20) or t-MDS ( = 18). Overall survival (OS) and relapse-free survival at 3 years after allogeneic SCT were 43% and 39%. The cumulative incidences of relapse and non-relapse mortality (NRM) at 3 years were 19% and 42%. More than one therapy line for the lymphoid malignancy resulted in a significantly higher NRM rate and inferior 3-year-OS. Our data indicate that allogeneic SCT for patients with t-MN after treatment of a lymphoid malignancy leads to OS rates comparable to patients transplanted for MN. Multiple lines of lymphoma therapy increase NRM and lead to inferior survival after allogeneic SCT.
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http://dx.doi.org/10.1080/10428194.2021.1894645DOI Listing
March 2021

Role of prothrombin 19911 A>G polymorphism, blood group and male gender in patients with venous thromboembolism: Results of a German cohort study.

J Thromb Thrombolysis 2021 Feb;51(2):494-501

UKSH, Institute of Clinical Chemistry, Hemostasis Unit, Arnold-Heller-Str. 3 Building 17, Kiel, 24105, Germany.

The role of the A>G polymorphism at position 19911 in the prothrombin gene (factor [F] 2 at rs3136516) as a risk factor for venous thromboembolism [VTE] is still unclear. To evaluate the presence of the F2 polymorphism in VTE patients compared to healthy blood donors and to adjust the results for common inherited thrombophilias [IT], age at onset and blood group [BG], and to calculate the risk of VTE recurrence. We investigated 1012 Caucasian patients with a diagnosis of VTE for the presence of the F2 rs3136516 polymorphism and compared these with 902 healthy blood donors. Odds ratios [OR] together with their 95% confidence intervals were calculated adjusted for F5 at rs6025, F2 at rs1799963, blood group, age and gender. In addition, we evaluated the risk of recurrent VTE during patient follow-up calculating hazard ratios [HR] together with their 95% CI. Compared with the AA wildtype, the F2 GG and AG genotypes (rs3136516) were associated with VTE (OR 1.48 and 1.45). The OR in F5 carriers compared to controls was 5.68 and 2.38 in patients with F2 (rs1799963). BG "non-O" was significantly more often diagnosed in patients compared to BG "O" (OR 2.74). VTE recurrence more often occurred in males (HR 2.3) and in carriers with combined thrombophilia (HR 2.11). Noteworthy, the rs3136516 polymorphism alone was not associated significantly with recurrence. In Caucasian patients with VTE the F2 GG/GA genotypes (rs3136516) were moderate risk factors for VTE. Recurrence was associated with male gender and combined thrombophilia.
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http://dx.doi.org/10.1007/s11239-020-02169-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886710PMC
February 2021

Clinically relevant interaction of rivaroxaban and valproic acid - A case report.

Seizure 2020 08 1;80:46-47. Epub 2020 Jun 1.

University Hospital Münster, Department of Neurology with Institute of Translational Neurology, Albert-Schweitzer-Campus 1, Gebäude A1, 48149 Münster, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.seizure.2020.05.024DOI Listing
August 2020

First-In-Class CD13-Targeted Tissue Factor tTF-NGR in Patients with Recurrent or Refractory Malignant Tumors: Results of a Phase I Dose-Escalation Study.

Cancers (Basel) 2020 Jun 7;12(6). Epub 2020 Jun 7.

Department of Medicine A, Hematology, Oncology, University Hospital Muenster, D-48149 Muenster, Germany.

Background: Aminopeptidase N (CD13) is present on tumor vasculature cells and some tumor cells. Truncated tissue factor (tTF) with a C-terminal NGR-peptide (tTF-NGR) binds to CD13 and causes tumor vascular thrombosis with infarction.

Methods: We treated 17 patients with advanced cancer beyond standard therapies in a phase I study with tTF-NGR (1-h infusion, central venous access, 5 consecutive days, and rest periods of 2 weeks). The study allowed intraindividual dose escalations between cycles and established Maximum Tolerated Dose (MTD) and Dose-Limiting Toxicity (DLT) by verification cohorts.

Results: MTD was 3 mg/m tTF-NGR/day × 5, q day 22. DLT was an isolated and reversible elevation of high sensitivity (hs) Troponin T hs without clinical sequelae. Three thromboembolic events (grade 2), tTF-NGR-related besides other relevant risk factors, were reversible upon anticoagulation. Imaging by contrast-enhanced ultrasound (CEUS) and dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) showed major tumor-specific reduction of blood flow in all measurable lesions as proof of principle for the mode of action of tTF-NGR. There were no responses as defined by Response Evaluation Criteria in Solid Tumors (RECIST), although some lesions showed intratumoral hemorrhage and necrosis after tTF-NGR application. Pharmacokinetic analysis showed a t of 8 to 9 h without accumulation in daily administrations.

Conclusion: tTF-NGR is safely applicable with this regimen. Imaging showed selective reduction of tumor blood flow and intratumoral hemorrhage and necrosis.
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http://dx.doi.org/10.3390/cancers12061488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352358PMC
June 2020

Long-term survival and polyclonal immunoglobulin reconstitution after allogeneic stem cell transplantation in multiple myeloma.

Ann Hematol 2020 Aug 22;99(8):1907-1915. Epub 2020 May 22.

Department of Medicine A, University Hospital Münster, Münster, Germany.

Despite significant progress made in the treatment of patients with multiple myeloma (MM) in the last decade, for patients with early relapse or rapidly progressing high-risk disease, allogeneic hematopoietic stem cell transplantation (SCT) might be an option leading to long-term survival. Here, we retrospectively analyzed the outcomes of 90 MM patients who received allogeneic SCT in our center between 1999 and 2017. We specifically assessed the association of impaired humoral immune reconstitution, referred to as immunoparesis, and post-transplant survival. Sixty-four patients received allogeneic SCT in relapse following 2-7 lines of therapy; 26 patients received upfront tandem autologous-allogeneic SCT. With a median follow-up of 76 months, OS and PFS were 52.6% (95% CI 42.9-64.3) and 36.4% (95% CI 27.6-47.9) at 2 years and 38.6% (95% CI 29.2-51.1) and 25.3% (95% CI 17.5-36.4) at 5 years, respectively. Receiving more than two therapy lines prior to transplantation was an independent risk factor for OS (HR 3.68, 95% CI 2.02-6.70) and PFS (HR 3.69, 95% CI 2.09-6.50). In a landmark analysis at day 200, prolonged immunoparesis was associated with reduced OS (HR 3.22, 95% CI 1.14-9.11). Allogeneic stem cell transplantation offers an additional treatment element that may lead to long-term remission in selected patients with poor prognosis, probably exploiting graft-versus-myeloma effects. Immunoparesis could potentially serve as an indicator for impaired survival following allogeneic transplantation, an observation to be further studied prospectively.
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http://dx.doi.org/10.1007/s00277-020-04068-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7340674PMC
August 2020

Radiation synergizes with antitumor activity of CD13-targeted tissue factor in a HT1080 xenograft model of human soft tissue sarcoma.

PLoS One 2020 21;15(2):e0229271. Epub 2020 Feb 21.

Department of Medicine A, Hematology, Oncology, University Hospital Muenster, Muenster, Germany.

Background: Truncated tissue factor (tTF) retargeted by NGR-peptides to aminopeptidase N (CD13) in tumor vasculature is effective in experimental tumor therapy. tTF-NGR induces tumor growth inhibition in a variety of human tumor xenografts of different histology. To improve on the therapeutic efficacy we have combined tTF-NGR with radiotherapy.

Methods: Serum-stimulated human umbilical vein endothelial cells (HUVEC) and human HT1080 sarcoma cells were irradiated in vitro, and upregulated early-apoptotic phosphatidylserine (PS) on the cell surface was measured by standard flow cytometry. Increase of cellular procoagulant function in relation to irradiation and PS cell surface concentration was measured in a tTF-NGR-dependent Factor X activation assay. In vivo experiments with CD-1 athymic mice bearing human HT1080 sarcoma xenotransplants were performed to test the systemic therapeutic effects of tTF-NGR on tumor growth alone or in combination with regional tumor ionizing radiotherapy.

Results: As shown by flow cytometry with HUVEC and HT1080 sarcoma cells in vitro, irradiation with 4 and 6 Gy in the process of apoptosis induced upregulation of PS presence on the outer surface of both cell types. Proapoptotic HUVEC and HT1080 cells both showed significantly higher procoagulant efficacy on the basis of equimolar concentrations of tTF-NGR as measured by FX activation. This effect can be reverted by masking of PS with Annexin V. HT1080 human sarcoma xenografted tumors showed shrinkage induced by combined regional radiotherapy and systemic tTF-NGR as compared to growth inhibition achieved by either of the treatment modalities alone.

Conclusions: Irradiation renders tumor and tumor vascular cells procoagulant by PS upregulation on their outer surface and radiotherapy can significantly improve the therapeutic antitumor efficacy of tTF-NGR in the xenograft model used. This synergistic effect will influence design of future clinical combination studies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0229271PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7034830PMC
May 2020

Baseline and interim PET-based outcome prediction in peripheral T-cell lymphoma: A subgroup analysis of the PETAL trial.

Hematol Oncol 2020 Aug 18;38(3):244-256. Epub 2020 Feb 18.

Klinik für Hämatologie, Universitätsklinikum Essen, Essen, Germany.

The prospective randomized Positron Emission Tomography (PET)-Guided Therapy of Aggressive Non-Hodgkin Lymphomas (PETAL) trial was designed to test the ability of interim PET (iPET) to direct therapy. As reported previously, outcome remained unaffected by iPET-based treatment changes. In this subgroup analysis, we studied the prognostic value of baseline total metabolic tumor volume (TMTV) and iPET response in 76 patients with T-cell lymphoma. TMTV was measured using the 41% maximum standardized uptake value (SUV ) and SUV thresholding methods. Interim PET was performed after two treatment cycles and evaluated using the ΔSUV approach and the Deauville scale. Because of significant differences in outcome, patients with anaplastic lymphoma kinase (ALK)-positive lymphoma were analyzed separately from patients with ALK-negative lymphoma. In the latter, TMTV was statistically significantly correlated with progression-free survival, with thresholds best dichotomizing the population, of 232 cm using SUV and 460 cm using SUV . For iPET response, the respective thresholds were 46.9% SUV reduction and Deauville score 1-4 vs 5. The proportion of poor prognosis patients was 46% and 29% for TMTV by SUV and SUV , and 29% and 25% for iPET response by ΔSUV and Deauville, respectively. At diagnosis, the hazard ratio (95% confidence interval) for poor prognosis vs good prognosis patients according to TMTV was 2.291 (1.135-4.624) for SUV and 3.206 (1.524-6.743) for SUV . At iPET, it was 3.910 (1.891-8.087) for ΔSUV and 4.371 (2.079-9.187) for Deauville. On multivariable analysis, only TMTV and iPET response independently predicted survival. Patients with high baseline TMTV and poor iPET response (22% of the population) invariably progressed or died within the first year (hazard ratio, 9.031 [3.651-22.336]). Due to small numbers and events, PET did not predict survival in ALK-positive lymphoma. Baseline TMTV and iPET response are promising tools to select patients with ALK-negative T-cell lymphoma for early allogeneic transplantation or innovative therapies.
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http://dx.doi.org/10.1002/hon.2697DOI Listing
August 2020

The neuropeptide receptor calcitonin receptor-like (CALCRL) is a potential therapeutic target in acute myeloid leukemia.

Leukemia 2019 12 10;33(12):2830-2841. Epub 2019 Jun 10.

Department of Medicine A, University Hospital Münster, Münster, Germany.

Calcitonin receptor-like (CALCRL) is a G-protein-coupled neuropeptide receptor involved in the regulation of blood pressure, angiogenesis, cell proliferation, and apoptosis, and is currently emerging as a novel target for the treatment of migraine. This study characterizes the role of CALCRL in acute myeloid leukemia (AML). We analyzed CALCRL expression in collectively more than 1500 well-characterized AML patients from five international cohorts (AMLCG, HOVON, TCGA, Leucegene, and UKM) and evaluated associations with survival. In the AMLCG analytic cohort, increasing transcript levels of CALCRL were associated with decreasing complete remission rates (71.5%, 53.7%, 49.6% for low, intermediate, high CALCRL expression), 5-year overall (43.1%, 26.2%, 7.1%), and event-free survival (29.9%, 15.8%, 4.7%) (all P < 0.001). CALCRL levels remained associated with all endpoints on multivariable regression analyses. The prognostic impact was confirmed in all validation sets. Genes highly expressed in CALCRL AML were significantly enriched in leukemic stem cell signatures and CALCRL levels were positively linked to the engraftment capacity of primary patient samples in immunocompromised mice. CRISPR-Cas9-mediated knockout of CALCRL significantly impaired colony formation in human myeloid leukemia cell lines. Overall, our study demonstrates that CALCRL predicts outcome beyond existing risk factors and is a potential therapeutic target in AML.
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http://dx.doi.org/10.1038/s41375-019-0505-xDOI Listing
December 2019

Gadofosveset-enhanced MRI as simple surrogate parameter for real-time evaluation of the initial tumour vessel infarction by retargeted tissue factor tTF-NGR.

Oncol Lett 2019 Jan 29;17(1):270-280. Epub 2018 Oct 29.

Department of Radiology, St. Franziskus-Hospital Münster, D-48145 Münster, Germany.

Truncated tissue factor (tTF)-NGR consists of the extracellular domain of the human TF and the binding motif NGR. tTF-NGR activates blood coagulation within the tumour vasculature following binding to CD13, and is overexpressed in the endothelial cells of tumour vessels, resulting in tumour vessel infarction and subsequent retardation/regression of tumour growth. The aim of the present study was to investigate gadofosveset-based real-time dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in evaluating the initial therapeutic effects of the anti-vascular tTF-NGR approach. DCE-MRI (3.0 T) was performed in human U87-glioblastoma tumour-bearing nude mice. During a dynamic T1w GE-sequence, a gadolinium-based blood pool contrast agent (gadofosveset) was injected via a tail vein catheter. Following the maximum contrast intensity inside the tumour being obtained, tTF-NGR was injected (controls received NaCl) and the contrast behaviour of the tumour was monitored by ROI analysis. The slope difference of signal intensities between controls and the tTF-NGR group was investigated, as well as the differences between the average area under the curve (AUC) of the two groups. The association between intensity, group (control vs. tTF-NGR group) and time was analysed by fitting a linear mixed model. Following the injection of tTF-NGR, the signal intensity inside the tumours exhibited a statistically significantly stronger average slope decrease compared with the signal intensity of the tumours in the NaCl group. Furthermore, the initial average AUC values of mice treated with tTF-NGR were 5.7% lower than the average AUC of the control animals (P<0.05). Gadofosveset-enhanced MRI enables the visualization of the initial tumour response to anti-vascular treatment in real-time. Considering the clinical application of tTF-NGR, this method may provide a simple alternative parameter for monitoring the tumour response to vascular disrupting agents and certain vascular targeting agents in humans.
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http://dx.doi.org/10.3892/ol.2018.9638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6313167PMC
January 2019

Six versus eight doses of rituximab in patients with aggressive B cell lymphoma receiving six cycles of CHOP: results from the "Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin Lymphomas" (PETAL) trial.

Ann Hematol 2019 Apr 4;98(4):897-907. Epub 2019 Jan 4.

Klinik für Hämatologie, Universitätsklinikum Essen, Essen, Germany.

Standard first-line treatment of aggressive B cell lymphoma comprises six or eight cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus eight doses of rituximab (R). Whether adding two doses of rituximab to six cycles of R-CHOP is of therapeutic benefit has not been systematically investigated. The Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin Lymphomas (PETAL) trial investigated the ability of [F]-fluorodesoxyglucose PET scanning to guide treatment in aggressive non-Hodgkin lymphomas. Patients with B cell lymphomas and a negative interim scan received six cycles of R-CHOP with or without two extra doses of rituximab. For reasons related to trial design, only about a third underwent randomization between the two options. Combining randomized and non-randomized patients enabled subgroup analyses for diffuse large B cell lymphoma (DLBCL; n = 544), primary mediastinal B cell lymphoma (PMBCL; n = 37), and follicular lymphoma (FL) grade 3 (n = 35). With a median follow-up of 52 months, increasing the number of rituximab administrations failed to improve outcome. A non-significant trend for improved event-free survival was seen in DLBCL high-risk patients, as defined by the International Prognostic Index, while inferior survival was observed in female patients below the age of 60 years. Long-term outcome in PMBCL was excellent. Differences between FL grade 3a and FL grade 3b were not apparent. The results were confirmed in a Cox proportional hazard regression model and a propensity score matching analysis. In conclusion, adding two doses of rituximab to six cycles of R-CHOP did not improve outcome in patients with aggressive B cell lymphomas and a fast metabolic treatment response.
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http://dx.doi.org/10.1007/s00277-018-3578-0DOI Listing
April 2019

Aminopeptidase N (CD13): Expression, Prognostic Impact, and Use as Therapeutic Target for Tissue Factor Induced Tumor Vascular Infarction in Soft Tissue Sarcoma.

Transl Oncol 2018 Dec 17;11(6):1271-1282. Epub 2018 Aug 17.

Department of Medicine A, Hematology, Oncology, University Hospital Muenster, Muenster, Germany.

Aminopeptidase N (CD13) is expressed on tumor vasculature and tumor cells. It represents a candidate for targeted therapy, e.g., by truncated tissue factor (tTF)-NGR, binding to CD13, and causing tumor vascular thrombosis. We analyzed CD13 expression by immunohistochemistry in 97 patients with STS who were treated by wide resection and uniform chemo-radio-chemotherapy. Using a semiquantitative score with four intensity levels, CD13 was expressed by tumor vasculature, or tumor cells, or both (composite value, intensity scores 1-3) in 93.9% of the STS. In 49.5% tumor cells, in 48.5% vascular/perivascular cells, and in 58.8%, composite value showed strong intensity score 3 staining. Leiomyosarcoma and synovial sarcoma showed low expression; fibrosarcoma and undifferentiated pleomorphic sarcoma showed high expression. We found a significant prognostic impact of CD13, as high expression in tumor cells or vascular/perivascular cells correlated with better relapse-free survival and overall survival. CD13 retained prognostic significance in multivariable analyses. Systemic tTF-NGR resulted in significant growth reduction of CD13-positive human HT1080 sarcoma cell line xenografts. Our results recommend further investigation of tTF-NGR in STS patients. CD13 might be a suitable predictive biomarker for patient selection.
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http://dx.doi.org/10.1016/j.tranon.2018.08.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6113655PMC
December 2018

Adjuvant chemotherapy-Radiotherapy-Chemotherapy sandwich protocol in resectable soft tissue sarcoma: An updated single-center analysis of 104 cases.

PLoS One 2018 22;13(5):e0197315. Epub 2018 May 22.

University Hospital Muenster, Department of Medicine A, Muenster, Germany.

Adjuvant therapy of local soft tissue sarcomas (STS) after wide surgical excision still is a topic under controversial scientific debate. In this single center report we have offered an adjuvant "sandwich" therapy protocol consisting of 4 cycles of doxorubicin (75 mg/m2 i.v. over 1 h on day 1) followed by ifosfamide (5 g/m2 i.v. over 24 h starting on day 1) and local radiotherapy scheduled between chemotherapy cycles 2 and 3 to 104 consecutive patients after wide surgical excision (R0) of histologically proven high-grade STS. After a mean follow-up of 39 months (range 5-194 months) relapse free survival (RFS) at 2 and 5 years was 68.1% (95% CI, 58.5-77.7%) and 61.2% (95% CI, 50.4-71.6%). When analyzing the 82 STS cases of the extremities only 2- and 5-year RFS was 74.0% (95% CI, 64.0-84.0%) and 65.3% (95% CI, 53.7-76.9%). By intent-to-treat analysis, the overall survival (OS) at 2 years was 87.3% (95% CI, 80.5-94.1%) and 75.6% (95% CI, 65.2-86.0%) at 5 years, while OS for STS of the extremities only cohort was 90.5% (95% CI, 83.7-97.3%) and 79.0% (95% CI, 68.4-89.6%), respectively. Tolerability of the treatment was good. This analysis demonstrates the feasibility of adjuvant chemoradiotherapy and reflects the results of the long lasting intensive multidisciplinary team approach at our "high-volume" sarcoma center. The long-term survival in our patients is among the highest reported and the low local and distant recurrence rate in high-risk STS is at least comparable to the published data.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0197315PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5963910PMC
December 2018

Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin Lymphomas (PETAL): A Multicenter, Randomized Phase III Trial.

J Clin Oncol 2018 07 11;36(20):2024-2034. Epub 2018 May 11.

Ulrich Dührsen, Stefan Müller, Jan Dürig, Johannes Matschke, Christine Schmitz, Thorsten Pöppel, Andreas Bockisch, and Andreas Hüttmann, Universitätsklinikum Essen; Claudia Ose, Marcus Brinkmann, Karl-Heinz Jöckel, André Scherag, and Jan Rekowski, Universität Duisburg-Essen, Essen; Bernd Hertenstein and Henrike Thomssen, Klinikum Bremen Mitte; Christiane Franzius, Zentrum für moderne Diagnostik, Bremen; Jörg Kotzerke and Frank Kroschinsky, Universitätsklinikum Carl Gustav Carus; Gabriele Prange-Krex, Onkologische Gemeinschaftspraxis, Dresden; Rolf Mesters, Wolfgang E. Berdel, and Matthias Weckesser, Universitätsklinikum Münster, Münster; Dorothea Kofahl-Krause, Frank M. Bengel, and Lilli Geworski, Medizinische Hochschule Hannover, Hannover; Paul La Rosée, Martin Freesmeyer, and André Scherag, Universitätsklinikum Jena, Jena; Andreas Hertel and Heinz-Gert Höffkes, Klinikum Fulda, Fulda; Dirk Behringer, Augusta-Kranken-Anstalt, Bochum; Stefan Wilop and Thomas Krohn, Universitätsklinikum Aachen, Aachen; Jens Holzinger and Martin Griesshammer, Johannes Wesling Klinikum, Minden; Aristoteles Giagounidis, Helios St Johannes Klinik, Duisburg; Aruna Raghavachar, Helios Universitätsklinikum, Wuppertal; Georg Maschmeyer and Ingo Brink, Klinikum Ernst von Bergmann, Potsdam; Helga Bernhard, Klinikum Darmstadt, Darmstadt; Uwe Haberkorn, Universitätsklinikum Heidelberg, Heidelberg; Tobias Gaska, Brüderkrankenhaus St Josef, Paderborn; Lars Kurch, Universitätsklinikum Leipzig, Leipzig; Wolfram Klapper, Universitätsklinikum Schleswig-Holstein, Kiel; Dieter Hoelzer, Onkologikum, Frankfurt/Main, Germany; and Daniëlle M.E. van Assema, Vrije Universiteit Medical Center, Amsterdam, the Netherlands.

Purpose Interim positron emission tomography (PET) using the tracer, [F]fluorodeoxyglucose, may predict outcomes in patients with aggressive non-Hodgkin lymphomas. We assessed whether PET can guide therapy in patients who are treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Patients and Methods Newly diagnosed patients received two cycles of CHOP-plus rituximab (R-CHOP) in CD20-positive lymphomas-followed by a PET scan that was evaluated using the ΔSUV method. PET-positive patients were randomly assigned to receive six additional cycles of R-CHOP or six blocks of an intensive Burkitt's lymphoma protocol. PET-negative patients with CD20-positive lymphomas were randomly assigned or allocated to receive four additional cycles of R-CHOP or the same treatment with two additional doses rituximab. The primary end point was event-free survival time as assessed by log-rank test. Results Interim PET was positive in 108 (12.5%) and negative in 754 (87.5%) of 862 patients treated, with statistically significant differences in event-free survival and overall survival. Among PET-positive patients, 52 were randomly assigned to R-CHOP and 56 to the Burkitt protocol, with 2-year event-free survival rates of 42.0% (95% CI, 28.2% to 55.2%) and 31.6% (95% CI, 19.3% to 44.6%), respectively (hazard ratio, 1.501 [95% CI, 0.896 to 2.514]; P = .1229). The Burkitt protocol produced significantly more toxicity. Of 754 PET-negative patients, 255 underwent random assignment (129 to R-CHOP and 126 to R-CHOP with additional rituximab). Event-free survival rates were 76.4% (95% CI, 68.0% to 82.8%) and 73.5% (95% CI, 64.8% to 80.4%), respectively (hazard ratio, 1.048 [95% CI, 0.684 to 1.606]; P = .8305). Outcome prediction by PET was independent of the International Prognostic Index. Results in diffuse large B-cell lymphoma were similar to those in the total group. Conclusion Interim PET predicted survival in patients with aggressive lymphomas treated with R-CHOP. PET-based treatment intensification did not improve outcome.
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http://dx.doi.org/10.1200/JCO.2017.76.8093DOI Listing
July 2018

Autologous Stem Cell Transplantation in Multiple Myeloma in the Era of Novel Drug Induction: A Retrospective Single-Center Analysis.

Acta Haematol 2017 12;137(3):163-172. Epub 2017 Apr 12.

Department of Oncology, Hematology, and Bone Marrow Transplantation with Section of Pneumology, Hubertus Wald University Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Within this retrospective single-center study, we analyzed the survival of 320 multiple myeloma (MM) patients receiving melphalan high-dose chemotherapy (HDCT) and either single (n = 286) or tandem (n = 34) autologous stem cell transplantation (ASCT) from 1996 to 2012. Additionally, the impact of novel induction regimens was assessed. Median follow-up was 67 months, median overall survival (OS) 62 months, median progression-free survival (PFS) 33 months (95% CI 27-39), and treatment-related death (TRD) 3%. Multivariate analysis revealed age ≥60 years (p = 0.03) and stage 3 according to the International Staging System (p = 0.006) as adverse risk factors regarding PFS. Median OS was significantly better in newly diagnosed MM patients receiving induction therapy with novel agents, e.g., bortezomib, thalidomide, or lenalidomide, compared with a traditional regimen (69 vs. 58 months; p = 0.01). More patients achieved at least a very good partial remission in the period from 2005 to 2012 than from 1996 to 2004 (65 vs. 30%; p < 0.001), with a longer median OS in the later period (71 vs. 52 months, p = 0.027). In conclusion, our analysis confirms HDCT-ASCT as an effective therapeutic strategy in an unselected large myeloma patient cohort with a low TRD rate and improved prognosis due to novel induction strategies.
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http://dx.doi.org/10.1159/000463534DOI Listing
July 2017

Rare genetic variants in SMAP1, B3GAT2, and RIMS1 contribute to pediatric venous thromboembolism.

Blood 2017 02 23;129(6):783-790. Epub 2016 Dec 23.

Genetic Epidemiology, Institute for Human Genetics, Westfälische Wilhelms University, Muenster, Germany.

Recent genome-wide association studies (GWAS) have confirmed known risk mutations for venous thromboembolism (VTE) and identified a number of novel susceptibility loci in adults. Here we present a GWAS in 212 nuclear families with pediatric VTE followed by targeted next-generation sequencing (NGS) to identify causative mutations contributing to the association. Three single nucleotide polymorphisms (SNPs) exceeded the threshold for genome-wide significance as determined by permutation testing using 100 000 bootstrap permutations ( < 10). These SNPs reside in a region on chromosome 6q13 comprising the genes small ARF GAP1 (), an ARF6 guanosine triphosphatase-activating protein that functions in clathrin-dependent endocytosis, and β-1,3-glucoronyltransferase 2 (), a member of the human natural killer 1 carbohydrate pathway. Rs1304029 and rs2748331 are associated with pediatric VTE with unpermuted/permuted values of = 1.42 × 10/2.0 × 10 and = 6.11 × 10/1.8 × 10, respectively. Rs2748331 was replicated ( = .00719) in an independent study sample coming from our GWAS on pediatric thromboembolic stroke (combined = 7.88 × 10). Subsequent targeted NGS in 24 discordant sibling pairs identified 17 nonsynonymous coding variants, of which 1 located in and 3 in , a member of the RIM family of active zone proteins, are predicted as damaging by Protein Variation Effect Analyzer and/or sorting intolerant from tolerant scores. Three SNPs curtly missed statistical significance in the transmission-disequilibrium test in the full cohort (rs112439957: = .08326, ; rs767118962: = .08326, ; and rs41265501: = .05778, ). In conjunction, our data provide compelling evidence for , , and as novel susceptibility loci for pediatric VTE and warrant future functional studies to unravel the underlying molecular mechanisms leading to VTE.
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http://dx.doi.org/10.1182/blood-2016-07-728840DOI Listing
February 2017

Impact of high risk thrombophilia status on recurrence among children and adults with VTE: An observational multicenter cohort study.

Blood Cells Mol Dis 2016 11 5;62:24-31. Epub 2016 Nov 5.

Institute of Clinical Chemistry, Univ. Hospital Kiel, Germany; Institute of Clinical Chemistry, Univ. Hospital Lübeck, Germany; Department of Pediatric Hematology/Oncology, Univ. Children Hospital Münster, Germany. Electronic address:

Background: Antithrombin [AT]-, protein C [PC]- or protein S [PS]-deficiency [D] constitutes a major risk factor for venous thromboembolism [VTE]. Primary study objective was to evaluate if the clinical presentation at first VTE onset differs between children and adults and to compare the individual recurrence risk among patients with respect to age at onset and their thrombophilia status ATD, PCD or PSD.

Methods/patients/results: In 137 of 688 consecutively enrolled pediatric and adult VTE patients we calculated the absolute risk of VTE recurrence and event-free-survival adjusted for thrombophilia and positive family VTE history. At first VTE children manifested i) with a lower rate of pulmonary embolism, ii) a higher rate of cerebral vascular events or multiple VTEs, and iii) showed a higher proportion of unprovoked VTE compared to adolescents and adults. Adult patients reported more often a positive VTE history compared to younger study participants. The adjusted odds of recurrence in adults was 2.05 compared to children.

Conclusion: At disease manifestation children and adults differ with respect to i) thrombotic locations, ii) percentage of unprovoked versus provoked VTE, and iii) different rates of positive VTE family histories. Furthermore, adults showed a two-fold increase risk of VTE recurrence compared to children.
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http://dx.doi.org/10.1016/j.bcmd.2016.10.024DOI Listing
November 2016

Prothrombin and factor X are elevated in multiple sclerosis patients.

Ann Neurol 2016 12 14;80(6):946-951. Epub 2016 Nov 14.

Department of Neurology, University of Münster, Münster.

Animal models have implicated an integral role for coagulation factors in neuroinflammatory diseases such as multiple sclerosis (MS) beyond their role in hemostasis. However, their relevance in humans requires further elucidation. This study aimed to determine whether levels of coagulation factors differ between patients with neuroimmunological disorders and respective controls. Individuals suffering from relapsing-remitting and secondary progressive MS had significantly higher prothrombin and factor X levels than healthy donors, whereas levels were unchanged in primary progressive MS and neuromyelitis optica patients. Our study demonstrates that coagulation factors may be key mediators in neuroinflammation and may therefore provide future targets for therapeutic strategies. Ann Neurol 2016;80:946-951.
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http://dx.doi.org/10.1002/ana.24807DOI Listing
December 2016

Combinatorial effects of doxorubicin and retargeted tissue factor by intratumoral entrapment of doxorubicin and proapoptotic increase of tumor vascular infarction.

Oncotarget 2016 Dec;7(50):82458-82472

Department of Medicine A (Hematology, Hemostaseology, Oncology and Pneumology), University Hospital of Muenster, Muenster, Germany.

Truncated tissue factor (tTF), retargeted to tumor vasculature by GNGRAHA peptide (tTF-NGR), and doxorubicin have therapeutic activity against a variety of tumors. We report on combination experiments of both drugs using different schedules. We have tested fluorescence- and HPLC-based intratumoral pharmacokinetics of doxorubicin, flow cytometry for cellular phosphatidylserine (PS) expression, and tumor xenograft studies for showing in vivo apoptosis, proliferation decrease, and tumor shrinkage upon combination therapy with doxorubicin and induced tumor vascular infarction. tTF-NGR given before doxorubicin inhibits the uptake of the drug into human fibrosarcoma xenografts in vivo. Reverse sequence does not influence the uptake of doxorubicin into tumor, but significantly inhibits the late wash-out phase, thus entrapping doxorubicin in tumor tissue by vascular occlusion. Incubation of endothelial and tumor cells with doxorubicin in vitro increases PS concentrations in the outer layer of the cell membrane as a sign of early apoptosis. Cells expressing increased PS concentrations show comparatively higher procoagulatory efficacy on the basis of equimolar tTF-NGR present in the Factor X assay. Experiments using human M21 melanoma and HT1080 fibrosarcoma xenografts in athymic nude mice indeed show a combinatorial tumor growth inhibition applying doxorubicin and tTF-NGR in sequence over single drug treatment. Combination of cytotoxic drugs such as doxorubicin with tTF-NGR-induced tumor vessel infarction can improve pharmacodynamics of the drugs by new mechanisms, entrapping a cytotoxic molecule inside tumor tissue and reciprocally improving procoagulatory activity of tTF-NGR in the tumor vasculature via apoptosis induction in tumor endothelial and tumor cells.
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http://dx.doi.org/10.18632/oncotarget.12559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5347705PMC
December 2016

Impact of gender on safety and efficacy of Rivaroxaban in adolescents & young adults with venous thromboembolism.

Thromb Res 2016 Dec 13;148:145-151. Epub 2016 Sep 13.

Institute of Clinical Chemistry, Univ. Hospital Schleswig-Holstein, Campus Kiel, Germany; Institute of Clinical Chemistry, Univ. Hospital Schleswig-Holstein, Campus Lübeck, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.thromres.2016.09.007DOI Listing
December 2016

Ciprofloxacin versus colistin prophylaxis during neutropenia in acute myeloid leukemia: two parallel patient cohorts treated in a single center.

Haematologica 2016 10 28;101(10):1208-1215. Epub 2016 Jul 28.

Department of Medicine A, Hematology and Oncology, University Hospital of Muenster, Germany Cluster of Excellence EXC 1003, Cells in Motion, Germany.

Patients undergoing intensive chemotherapy for acute myeloid leukemia are at high risk for bacterial infections during therapy-related neutropenia. However, the use of specific antibiotic regimens for prophylaxis in afebrile neutropenic acute myeloid leukemia patients is controversial. We report a retrospective evaluation of 172 acute myeloid leukemia patients who received 322 courses of myelosuppressive chemotherapy and had an expected duration of neutropenia of more than seven days. The patients were allocated to antibiotic prophylaxis groups and treated with colistin or ciprofloxacin through 2 different hematologic services at our hospital, as available. The infection rate was reduced from 88.6% to 74.2% through antibiotic prophylaxis (vs without prophylaxis; P=0.04). A comparison of both antibiotic drugs revealed a trend towards fewer infections associated with ciprofloxacin prophylaxis (69.2% vs 79.5% in the colistin group; P=0.07), as determined by univariate analysis. This result was confirmed through multivariate analysis (OR: 0.475, 95%CI: 0.236-0.958; P=0.041). The prophylactic agents did not differ with regard to the microbiological findings (P=0.6, not significant). Of note, the use of ciprofloxacin was significantly associated with an increased rate of infections with pathogens that are resistant to the antibiotic used for prophylaxis (79.5% vs 9.5% in the colistin group; P<0.0001). The risk factors for higher infection rates were the presence of a central venous catheter (P<0.0001), mucositis grade III/IV (P=0.0039), and induction/relapse courses (vs consolidation; P<0.0001). In conclusion, ciprofloxacin prophylaxis appears to be of particular benefit during induction and relapse chemotherapy for acute myeloid leukemia. To prevent and control drug resistance, it may be safely replaced by colistin during consolidation cycles of acute myeloid leukemia therapy.
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http://dx.doi.org/10.3324/haematol.2016.147934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5046650PMC
October 2016

Impact of high-risk thrombophilia status on recurrence among children with a first non-central-venous-catheter-associated VTE: an observational multicentre cohort study.

Br J Haematol 2016 Oct 22;175(1):133-40. Epub 2016 Jun 22.

Institute of Clinical Chemistry, University Hospital Kiel, Kiel, Germany.

Deficiency of antithrombin (AT), protein C (PC) or protein S (PS) constitutes a major risk factor for venous thromboembolism (VTE). Individuals at high risk for recurrence who benefit from screening need to be identified. The primary study objective was to determine the individual recurrence risk among children with a first non-central-venous-catheter-associated VTE with respect to their thrombophilia status and to evaluate if the clinical presentation at first VTE onset differs between children with AT, PC or PS deficiency versus no thrombophilia. We calculated the absolute risk of VTE recurrence and event-free-survival adjusted for thrombophilia, age, sex and positive family VTE history in 161 consecutively enrolled paediatric VTE patients. The presence of a deficiency relative to no thrombophilia was evaluated as a potential predictor of recurrence. Predictors for recurrence were AT deficiency (hazard ratio/95% CI: 6·5/2·46-17·2) and female gender (2·6/1·1-6·35). The annual recurrence rates (95% CIs) were 5·4% (2·6-10) in AT-deficient children, 1·3% (0·3-3·8) in patients with PC deficiency, 0·7% (0·08-2·4) in the PS-deficient cohort and 0·9% (0·4-1·8) in patients with no thrombophilia. Positive family VTE history or combined thrombophilias did not predict recurrence. Given the overall annual incidence rate of recurrence of 1·5% we suggest screening for AT deficiency in children with VTE.
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http://dx.doi.org/10.1111/bjh.14192DOI Listing
October 2016

NG2 proteoglycan as a pericyte target for anticancer therapy by tumor vessel infarction with retargeted tissue factor.

Oncotarget 2016 Feb;7(6):6774-89

Department of Medicine A, Hematology, Oncology and Pneumology, University of Muenster, Albert-Schweitzer-Campus 1, D-48129 Muenster, Germany.

tTF-TAA and tTF-LTL are fusion proteins consisting of the extracellular domain of tissue factor (TF) and the peptides TAASGVRSMH and LTLRWVGLMS, respectively. These peptides represent ligands of NG2, a surface proteoglycan expressed on angiogenic pericytes and some tumor cells. Here we have expressed the model compound tTF-NGR, tTF-TAA, and tTF-LTL with different lengths in the TF domain in E. coli and used these fusion proteins for functional studies in anticancer therapy. We aimed to retarget TF to tumor vessels leading to tumor vessel infarction with two barriers of selectivity, a) the leaky endothelial lining in tumor vessels with the target NG2 being expressed on pericytes on the abluminal side of the endothelial cell barrier and b) the preferential expression of NG2 on angiogenic vessels such as in tumors. Chromatography-purified tTF-TAA showed identical Factor X (FX)-activating procoagulatory activity as the model compound tTF-NGR with Km values of approx. 0.15 nM in Michaelis-Menten kinetics. The procoagulatory activity of tTF-LTL varied with the chosen length of the TF part of the fusion protein. Flow cytometry revealed specific binding of tTF-TAA to NG2-expressing pericytes and tumor cells with low affinity and dissociation KD in the high nM range. In vivo and ex vivo fluorescence imaging of tumor xenograft-carrying animals and of the explanted tumors showed reduction of tumor blood flow upon tTF-TAA application. Therapeutic experiments showed a reproducible antitumor activity of tTF-TAA against NG2-expressing A549-tumor xenografts, however, with a rather small therapeutic window (active/toxic dose in mg/kg body weight).
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http://dx.doi.org/10.18632/oncotarget.6725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4872748PMC
February 2016

Tumor Growth Inhibition via Occlusion of Tumor Vasculature Induced by N-Terminally PEGylated Retargeted Tissue Factor tTF-NGR.

Mol Pharm 2015 Oct 31;12(10):3749-58. Epub 2015 Aug 31.

Department of Medicine A, Hematology, Oncology and Pneumology, ‡Integrated Functional Genomics (IZKF Muenster), and §Central Institute for Animal Experimentation, University of Muenster , Albert-Schweitzer-Campus 1, D-48129 Muenster, Germany.

tTF-NGR retargets the extracellular domain of tissue factor via a C-terminal peptide GNGRAHA, a ligand of the surface protein aminopeptidase N (CD13) and upon deamidation of integrin αvβ3, to tumor vasculature. tTF-NGR induces tumor vascular infarction with consecutive antitumor activity against xenografts and selectively inhibits tumor blood flow in cancer patients. Since random PEGylation resulted in favorable pharmacodynamics of tTF-NGR, we performed site-directed PEGylation of PEG units to the N-terminus of tTF-NGR to further improve the antitumor profile of the molecule. Mono-PEGylation to the N-terminus did not change the procoagulatory activity of the tTF-NGR molecule as measured by Factor X activation. Experiments to characterize pharmacokinetics in mice showed a more than 1 log step higher mean area under the curve of PEG20k-tTF-NGR over tTF-NGR. Acute (24 h) tolerability upon intravenous application for the mono-PEGylated versus non-PEGylated tTF-NGR compounds was comparable. PEG20k-tTF-NGR showed clear antitumor efficacy in vivo against human tumor xenografts when systemically applied. However, site-directed mono-PEGylation to the N-terminus does not unequivocally improve the therapeutic profile of tTF-NGR.
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http://dx.doi.org/10.1021/acs.molpharmaceut.5b00508DOI Listing
October 2015

Assessment of Hemostasis after Plasma Exchange Using Rotational Thrombelastometry (ROTEM).

PLoS One 2015 29;10(6):e0130402. Epub 2015 Jun 29.

Department of Medicine D, Division of General Internal Medicine, Nephrology and Rheumatology, University Hospital of Münster, Albert-Schweitzer-Campus 1, Münster, 48149, Germany.

Background: Therapeutic plasma exchange (TPE)-based protocols immediately before cadaveric donor kidney transplantation have been extensively used in highly sensitized recipients. Plasma is generally preferred over human albumin as replacement fluid to avoid depletion of coagulation factors and perioperative bleeding. The aim of this study was to estimate bleeding risk after TPE replaced with albumin using rotational thromboelastography (ROTEM).

Methodology: Ten patients without overt coagulation abnormalities underwent TPE. Standard laboratory coagulation tests (thromboplastin time, activated partial thromboplastin time (aPTT), international normalized ratio (INR), thrombin clotting time, fibrinogen levels and antithrombin activity) were compared with thrombelastometry analysis (EXTEM and INTEM tests) before and after TPE.

Principal Findings: TPE significantly reduced fibrinogen levels (482 ± 182 vs. 223 ± 122 mg/dL), antithrombin activity (103 ± 11 vs. 54 ± 11 %), and prolonged aPTT (28 ± 3 vs. 45 ± 8 s), thromboplastin time (108 ± 11 vs. 68 ± 11 %), INR (0.95 ± 0.06 vs. 1.25 ± 0.16), and thrombin clotting time (18 ± 2 vs. 20 ± 3 s). INTEM and EXTEM analyses revealed significantly prolonged clot-formation time and reduced maximum clot firmness.

Conclusions/significance: TPE replaced with albumin induces significant changes in global hemostasis parameters thus potentially increasing bleeding risk. Therefore, pretransplant TPE should be considered carefully in indicated patients before kidney transplantation. The role of the ROTEM point-of-care test to estimate the risk of bleeding in renal transplantation needs to be evaluated in further studies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0130402PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4488284PMC
March 2016

Low-Energy Ultrasound Treatment Improves Regional Tumor Vessel Infarction by Retargeted Tissue Factor.

J Ultrasound Med 2015 Jul;34(7):1227-36

Department of Medicine A, Hematology, Oncology, and Pneumology (C.B., R.R., H.H., C.S., C.M.-T., R.M.M., W.E.B., C.S.), Department of Cardiovascular Medicine, Division of Cardiology (J.S.), and Cluster of Excellence EXC 1003, Cells in Motion (W.E.B.), University of Muenster, Muenster, Germany; Institute of Medical Engineering, Ruhr University, Bochum, Germany (S.D., G.S.); and Nijmegen Center for Mitochondrial Disorders, Radboud University Medical Center, Nijmegen, the Netherlands (M.M.).

Objectives: To enhance the regional antitumor activity of the vascular-targeting agent truncated tissue factor (tTF)-NGR by combining the therapy with low-energy ultrasound (US) treatment.

Methods: For the in vitro US exposure of human umbilical vein endothelial cells (HUVECs), cells were put in the focus of a US transducer. For analysis of the US-induced phosphatidylserine (PS) surface concentration on HUVECs, flow cytometry was used. To demonstrate the differences in the procoagulatory efficacy of TF-derivative tTF-NGR on binding to HUVECs with a low versus high surface concentration of PS, we performed factor X activation assays. For low-energy US pretreatment, HT1080 fibrosarcoma xenotransplant-bearing nude mice were treated by tumor-regional US-mediated stimulation (ie, destruction) of microbubbles. The therapy cohorts received the tumor vessel-infarcting tTF-NGR protein with or without US pretreatment (5 minutes after US stimulation via intraperitoneal injection on 3 consecutive days).

Results: Combination therapy experiments with xenotransplant-bearing nude mice significantly increased the antitumor activity of tTF-NGR by regional low-energy US destruction of vascular microbubbles in tumor vessels shortly before application of tTF-NGR (P < .05). Mechanistic studies proved the upregulation of anionic PS on the outer leaflet of the lipid bilayer of endothelial cell membranes by low-energy US and a consecutive higher potential of these preapoptotic endothelial cells to activate coagulation via tTF-NGR and coagulation factor X as being a basis for this synergistic activity.

Conclusions: Combining retargeted tTF to tumor vessels with proapoptotic stimuli for the tumor vascular endothelium increases the antitumor effects of tumor vascular infarction. Ultrasound treatment may thus be useful in this respect for regional tumor therapy.
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http://dx.doi.org/10.7863/ultra.34.7.1227DOI Listing
July 2015

Implantation of left ventricular assist devices under extracorporeal life support in patients with heparin-induced thrombocytopenia.

J Artif Organs 2015 Dec 5;18(4):291-9. Epub 2015 Jun 5.

Department of Cardiothoracic Surgery, Division of Cardiac Surgery, University Hospital of the Westfaelische Wilhelms-University Muenster, Albert-Schweitzer-Campus 1, 48159, Muenster, Germany.

Heparin-induced thrombocytopenia (HIT) is a rare but life-threatening side effect of heparin therapy. It is a demanding therapeutic challenge in patients undergoing left ventricular assist device (LVAD) implantation. We present our experience with LVAD implantation under extracorporeal life support (ECLS) in patients suffering from HIT. Seven patients (mean age 54.0 ± 16.7 years, 1 female, 6 male patients) suffering from acute heart failure were stabilized with ECLS. Under heparin therapy, they all showed a sudden decrease of mean platelet count (maximum 212.6 ± 41.5 tsd/μl; minimum 30.7 ± 13.1 tsd/μl). Due to the clinical suspicion of HIT anticoagulation was switched from heparin to argatroban (aPTT 70-80 s.). No improvement of cardiac function could be detected under ECLS, so LVAD implantation was indicated. We performed LVAD implantation under ECLS. During LVAD implantation under argatroban (aPTT of 50-60 s.) one patient developed massive intraventricular thrombus formations, so the device had to be removed. In 6 cases, we could successfully perform LVAD implantation under argatroban with a higher aPTT of 70-80 s and modified operative strategy. Four patients needed postoperative re-exploration because of bleeding complications. Perioperative management of LVAD patients under argatroban anticoagulation is very difficult. We were able to minimize the perioperative risk for thrombosis with a target aPTT of 70-80 s. To keep the phase of stasis within the device as short as possible we anastomosed the VAD outflow graft to the ascending aorta first before connecting the device to the apex. However, postoperative bleeding complications are frequent.
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http://dx.doi.org/10.1007/s10047-015-0846-9DOI Listing
December 2015

The syndrome of hemophagocytic lymphohistiocytosis in primary immunodeficiencies: implications for differential diagnosis and pathogenesis.

Haematologica 2015 Jul 28;100(7):978-88. Epub 2015 May 28.

Center of Chronic Immunodeficiency, University Medical Center Freiburg, Germany Center for Pediatrics and Adolescent Medicine, University Medical Center Freiburg, Germany

Hemophagocytic lymphohistiocytosis is a hyperinflammatory syndrome defined by clinical and laboratory criteria. Current criteria were created to identify patients with familial hemophagocytic lmyphohistiocytosis in immediate need of immunosuppressive therapy. However, these criteria also identify patients with infection-associated hemophagocytic inflammatory states lacking genetic defects typically predisposing to hemophagocytic lymphohistiocytosis. These patients include those with primary immunodeficiencies, in whom the pathogenesis of the inflammatory syndrome may be distinctive and aggressive immunosuppression is contraindicated. To better characterize hemophagocytic inflammation associated with immunodeficiencies, we combined an international survey with a literature search and identified 63 patients with primary immunodeficiencies other than cytotoxicity defects or X-linked lymphoproliferative disorders, presenting with conditions fulfilling current criteria for hemophagocytic lymphohistiocytosis. Twelve patients had severe combined immunodeficiency with <100/μL T cells, 18 had partial T-cell deficiencies; episodes of hemophagocytic lymphohistiocytosis were mostly associated with viral infections. Twenty-two patients had chronic granulomatous disease with hemophagocytic episodes mainly associated with bacterial infections. Compared to patients with cytotoxicity defects, patients with T-cell deficiencies had lower levels of soluble CD25 and higher ferritin concentrations. Other criteria for hemophagocytoc lymphohistiocytosis were not discriminative. Thus: (i) a hemophagocytic inflammatory syndrome fulfilling criteria for hemophagocytic lymphohistiocytosis can be the initial manifestation of primary immunodeficiencies; (ii) this syndrome can develop despite severe deficiency of T and NK cells, implying that the pathophysiology is distinct and not appropriately described as "lympho"-histiocytosis in these patients; and (iii) current criteria for hemophagocytoc lymphohistiocytosis are insufficient to differentiate hemophagocytic inflammatory syndromes with different pathogeneses. This is important because of implications for therapy, in particular for protocols targeting T cells.
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http://dx.doi.org/10.3324/haematol.2014.121608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4486233PMC
July 2015

Potentiating the activity of rituximab against mantle cell lymphoma in mice by targeting interleukin-2 to the neovasculature.

Leuk Res 2015 Jul 17;39(7):739-48. Epub 2015 Apr 17.

Department of Medicine A, University Hospital Muenster, Muenster, Germany. Electronic address:

There is increasing interest in the site-directed pharmacodelivery of therapeutic payloads to the tumor site using antibodies as transport vehicles. Here, we investigated the efficacy of L19-IL2, an antibody-cytokine fusion protein that specifically delivers IL-2 to the tumor site by homing to the extra-domain B of fibronectin (EDB-Fn) expressed on tumor-associated blood vessels, against mantle cell lymphoma (MCL) in mice. L19-IL2 was shown to selectively localize at lymphoma lesions in vivo and to mediate significant lymphoma growth retardation, which was potentiated by co-administration of the anti-CD20 antibody rituximab. When co-injected with rituximab, L19-IL2 induced complete remissions of localized MCL xenografts in 6/8 mice (75%), whereas the combination of rituximab and equivalent doses of non-targeted IL-2 only slightly delayed tumor growth. In disseminated MCL, combination therapy with L19-IL2 and rituximab exhibited a significant survival benefit over treatment with IL-2 and rituximab and completely eradicated the disease in 2/7 cases (28.6%). Mechanistically, histological analyses of post-therapeutic lymphoma tissues revealed a strong intratumoral accumulation of macrophages and natural killer cells after a single dose of the immunocytokine, whereas L19-IL2 had no significant impact on microvessel density or on tissue penetration of co-injected rituximab. Collectively, these results provide the scientific rationale for the clinical evaluation of L19-IL2 in combination with anti-CD20 immunotherapy in patients with MCL.
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http://dx.doi.org/10.1016/j.leukres.2015.04.005DOI Listing
July 2015

Targeting interleukin-2 to the bone marrow stroma for therapy of acute myeloid leukemia relapsing after allogeneic hematopoietic stem cell transplantation.

Cancer Immunol Res 2015 May 11;3(5):547-56. Epub 2015 Feb 11.

Department of Medicine A, Hematology and Oncology, University Hospital Muenster, Muenster, Germany.

The antibody-based delivery of IL2 to extracellular targets expressed in the easily accessible tumor-associated vasculature has shown potent antileukemic activity in xenograft and immunocompetent murine models of acute myelogenous leukemia (AML), especially in combination with cytarabine. Here, we report our experience with 4 patients with relapsed AML after allogeneic hematopoietic stem cell transplantation (allo-HSCT), who were treated with the immunocytokine F16-IL2, in combination with low-dose cytarabine. One patient with disseminated extramedullary AML lesions achieved a complete metabolic response identified by PET/CT, which lasted 3 months. Two of 3 patients with bone marrow relapse achieved a blast reduction with transient molecular negativity. One of the 2 patients enjoyed a short complete remission before AML relapse occurred 2 months after the first infusion of F16-IL2. In line with a site-directed delivery of the cytokine, F16-IL2 led to an extensive infiltration of immune effector cells in the bone marrow. Grade 2 fevers were the only nonhematologic side effects in 2 patients. Grade 3 cytokine-release syndrome developed in the other 2 patients but was manageable in both cases with glucocorticoids. The concept of specifically targeting IL2 to the leukemia-associated stroma deserves further evaluation in clinical trials, especially in patients who relapse after allo-HSCT.
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http://dx.doi.org/10.1158/2326-6066.CIR-14-0179DOI Listing
May 2015

Thromboembolic events in Fabry disease and the impact of factor V Leiden.

Neurology 2015 Mar 6;84(10):1009-16. Epub 2015 Feb 6.

From Internal Medicine D, Department of Nephrology, Hypertension and Rheumatology (M.L., M.S., E.B.), Department of Neurology (T.D.), Institute of Sports Medicine, Molecular Genetics of Cardiovascular Disease (B.S., S.-M.B.), Internal Medicine A, Department of Hematology and Oncology (R.M.), Institute of Epidemiology and Social Medicine (H.-W.H.), University Hospital Muenster; and Department of Pediatric and Adolescent Medicine (N.K., M.B.), Villa Metabolica, University Medical Center of the Johannes Gutenberg University, University of Mainz, Germany.

Objectives: Although several reports suggest an increased thromboembolic event rate, especially regarding strokes and TIAs at early age in patients with Fabry disease (FD), the risk for patients with FD to experience these events, the clinical relevance of additional risk factors including the concurrence of factor V Leiden (FVL), and the benefit of enzyme replacement therapy (ERT) regarding these events remain unclear.

Methods: Three hundred four consecutively recruited patients with FD were evaluated for their lifetime occurrence of thromboembolic events such as stroke, TIA, deep vein thrombosis, and pulmonary embolism. The thromboembolic risk was determined in patients with FD and concurrent FVL, and the impact of ERT was assessed.

Results: The 304 patients with FD had a median age of 41 years and 53 (17.4%) had experienced at least one thromboembolic event during their lifetime. Among 226 patients with FD screened for FVL, 16 gene carriers were identified (7.1%). The occurrence of thromboembolic events in patients with FD and concurrent FVL was significantly increased compared to those without FVL (hazard ratio = 5.45, 95% confidence interval 2.29-12.99; p < 0.001). Patients with FD receiving ERT had a significantly decreased risk of thromboembolic events compared to those without ERT (hazard ratio = 0.362, 95% confidence interval 0.132-0.992; p = 0.0422).

Conclusion: This observational study confirms that patients with FD have a high risk of clinically relevant thromboembolic events, which could be aggravated by a concurrence of FVL. ERT might be of benefit in preventing vascular events in patients with FD. The latter observation needs confirmation, however, by randomized and controlled clinical trials.
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http://dx.doi.org/10.1212/WNL.0000000000001333DOI Listing
March 2015