Publications by authors named "Mathias Schneeweiss"

10 Publications

  • Page 1 of 1

A kinase profile-adapted drug combination elicits synergistic cooperative effects on leukemic cells carrying BCR-ABL1 in Ph+ CML.

Leuk Res 2019 03 28;78:36-44. Epub 2018 Dec 28.

Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Austria; Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Austria. Electronic address:

In chronic myeloid leukemia (CML), resistance against second-generation tyrosine kinase inhibitors (TKI) remains a serious clinical challenge, especially in the context of multi-resistant BCR-ABL1 mutants, such as T315I. Treatment with ponatinib may suppress most of these mutants, including T315I, but is also associated with a high risk of clinically relevant side effects. We screened for alternative treatment options employing available tyrosine kinase inhibitors (TKI) in combination. Dasatinib and bosutinib are two second-generation TKI that bind to different, albeit partially overlapping, spectra of kinase targets in CML cells. This observation prompted us to explore anti-leukemic effects of the combination dasatinib + bosutinib in highly resistant primary CML cells, various CML cell lines (K562, K562R, KU812, KCL22) and Ba/F3 cells harboring various BCR-ABL1 mutant-forms. We found that bosutinib synergizes with dasatinib in inducing growth inhibition and apoptosis in all CML cell lines and in Ba/F3 cells exhibiting BCR-ABL1. Clear synergistic effects were also observed in primary CML cells in all patients tested (n = 20), including drug-resistant cells carrying BCR-ABL1. Moreover, the drug combination produced cooperative or even synergistic apoptosis-inducing effects on CD34/CD38 CML stem cells. Finally, we found that the drug combination is a potent approach to block the activity of major additional CML targets, including LYN, KIT and PDGFRα. Together, bosutinib and dasatinib synergize in producing anti-leukemic effects in drug-resistant CML cells. Whether such cooperative TKI effects also occur in vivo in patients with drug-resistant CML, remains to be determined in forthcoming studies.
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http://dx.doi.org/10.1016/j.leukres.2018.12.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6834439PMC
March 2019

Energy-Dense versus Routine Enteral Nutrition in the Critically Ill.

N Engl J Med 2019 01;380(5):498

Medical University of Vienna, Vienna, Austria

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http://dx.doi.org/10.1056/NEJMc1816396DOI Listing
January 2019

Correction: Different enteral nutrition formulas have no effect on glucose homeostasis but on diet-induced thermogenesis in critically ill medical patients: a randomized controlled trial.

Eur J Clin Nutr 2019 01;73(1):158

Medical University of Vienna, Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Intensive Care Unit, Waehringer Guertel 18-20, 1090, Vienna, Austria.

After publication, the author noticed that Table 2 was incorrectly formatted for the final PDF despite being correct in earlier proofs. The table was correct in the HTML version of the article. The EJCN apologizes for the inadvertent error in the formatting of Table 2. The corrected version is uploaded and should be read in conjunction with the original paper. Any inconvenience to the author and readership is regretted.
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http://dx.doi.org/10.1038/s41430-018-0269-9DOI Listing
January 2019

Different enteral nutrition formulas have no effect on glucose homeostasis but on diet-induced thermogenesis in critically ill medical patients: a randomized controlled trial.

Eur J Clin Nutr 2018 04 19;72(4):496-503. Epub 2018 Feb 19.

Medical University of Vienna, Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Intensive Care Unit, Waehringer Guertel 18-20, 1090, Vienna, Austria.

Background/objectives: Hyperglycemia is common in critically ill patients and associated with increased mortality. It has been suggested that different nutrition formulas may beneficially influence glucose levels in surgical intensive care patients. In this prospective randomized clinical cohort study we investigated glucose homeostasis in response to different enteral nutrition formulas in medical critically ill patients.

Subjects/methods: 60 medical critically ill patients were randomized to receive continuous fat-based (group A, n = 30) or glucose-based enteral nutrition (group B, n = 30) for seven days. Indirect calorimetry was performed to determine energy demand at baseline and on days 3 and 7. Glucose levels and area under the curve (AUC), insulin demand, glucose variability, and calorie and substrate intake per 24 h were assessed for 7 days.

Results: Over the course of 7 days patients had similar average daily glucose (p = 0.655), glucose AUC (A: 758 (641-829) mg/dl/day vs B: 780 (733-845) mg/dl/day, p = 0.283), similar overall insulin demand (A: 153.5 (45.3-281.5) IE vs B: 167.9 (82.3-283.8) IE, p = 0.525), and received similar amounts of enteral nutrition per 24 h. Resting energy expenditure was similar at baseline (A: 1556 (1227-1808) kcal/day vs B: 1563 (1306-1789) kcal/day, p = 0.882) but energy expenditure increased substantially over time in group A (p < 0.0001), but not in group B (p = 0.097).

Conclusion: Fat-based and glucose-based EN influence glucose homeostasis and insulin demand similarly, yet diet-induced thermogenesis was substantially higher in critically ill patients receiving fat-based enteral nutrition.
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http://dx.doi.org/10.1038/s41430-018-0111-4DOI Listing
April 2018

The KIT and PDGFRA switch-control inhibitor DCC-2618 blocks growth and survival of multiple neoplastic cell types in advanced mastocytosis.

Haematologica 2018 05 8;103(5):799-809. Epub 2018 Feb 8.

Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Austria

Systemic mastocytosis is a complex disease defined by abnormal growth and accumulation of neoplastic mast cells in various organs. Most patients exhibit a D816V-mutated variant of , which confers resistance against imatinib. Clinical problems in systemic mastocytosis arise from mediator-related symptoms and/or organ destruction caused by malignant expansion of neoplastic mast cells and/or other myeloid cells in various organ systems. DCC-2618 is a spectrum-selective pan KIT and PDGFRA inhibitor which blocks KIT D816V and multiple other kinase targets relevant to systemic mastocytosis. We found that DCC-2618 inhibits the proliferation and survival of various human mast cell lines (HMC-1, ROSA, MCPV-1) as well as primary neoplastic mast cells obtained from patients with advanced systemic mastocytosis (IC <1 μM). Moreover, DCC-2618 decreased growth and survival of primary neoplastic eosinophils obtained from patients with systemic mastocytosis or eosinophilic leukemia, leukemic monocytes obtained from patients with chronic myelomonocytic leukemia with or without concomitant systemic mastocytosis, and blast cells obtained from patients with acute myeloid leukemia. Furthermore, DCC-2618 was found to suppress the proliferation of endothelial cells, suggesting additional drug effects on systemic mastocytosis-related angiogenesis. Finally, DCC-2618 was found to downregulate IgE-mediated histamine release from basophils and tryptase release from mast cells. Together, DCC-2618 inhibits growth, survival and activation of multiple cell types relevant to advanced systemic mastocytosis. Whether DCC-2618 is effective in patients with advanced systemic mastocytosis is currently under investigation in clinical trials.
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http://dx.doi.org/10.3324/haematol.2017.179895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5927976PMC
May 2018

Combined targeting of STAT3 and STAT5: a novel approach to overcome drug resistance in chronic myeloid leukemia.

Haematologica 2017 09 8;102(9):1519-1529. Epub 2017 Jun 8.

Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Austria.

In chronic myeloid leukemia, resistance against BCR-ABL1 tyrosine kinase inhibitors can develop because of mutations, activation of additional pro-oncogenic pathways, and stem cell resistance. Drug combinations covering a broad range of targets may overcome resistance. CDDO-Me (bardoxolone methyl) is a drug that inhibits the survival of leukemic cells by targeting different pro-survival molecules, including STAT3. We found that CDDO-Me inhibits proliferation and survival of tyrosine kinase inhibitor-resistant cell lines and primary leukemic cells, including cells harboring or T315I compound mutations. Furthermore, CDDO-Me was found to block growth and survival of CD34/CD38 leukemic stem cells (LSC). Moreover, CDDO-Me was found to produce synergistic growth-inhibitory effects when combined with BCR-ABL1 tyrosine kinase inhibitors. These drug-combinations were found to block multiple signaling cascades and molecules, including STAT3 and STAT5. Furthermore, combined targeting of STAT3 and STAT5 by shRNA and STAT5-targeting drugs also resulted in synergistic growth-inhibition, pointing to a new efficient concept of combinatorial STAT3 and STAT5 inhibition. However, CDDO-Me was also found to increase the expression of heme-oxygenase-1, a heat-shock-protein that triggers drug resistance and cell survival. We therefore combined CDDO-Me with the heme-oxygenase-1 inhibitor SMA-ZnPP, which also resulted in synergistic growth-inhibitory effects. Moreover, SMA-ZnPP was found to sensitize cells against the combination 'CDDO-Me+ tyrosine kinase inhibitor'. Together, combined targeting of STAT3, STAT5, and heme-oxygenase-1 overcomes resistance in cells, including stem cells and highly resistant sub-clones expressing BCR-ABL1 or T315I-compound mutations. Whether such drug-combinations are effective in tyrosine kinase inhibitor-resistant patients with chronic myeloid leukemia remains to be elucidated.
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http://dx.doi.org/10.3324/haematol.2016.163436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5685220PMC
September 2017

TKI rotation-induced persistent deep molecular response in multi-resistant blast crisis of Ph+ CML.

Oncotarget 2017 Apr;8(14):23061-23072

Department of Laboratory Medicine, Medical University of Vienna, Austria.

In chronic myeloid leukemia (CML) resistance against one or more BCR-ABL1 tyrosine kinase inhibitors (TKI) remains a clinical challenge. Preclinical data suggest that TKI combinations may overcome resistance. We report on a heavily pre-treated 78 year-old female patient with CML who developed multi-resistant blast crisis with bone marrow fibrosis and a Ph- clone. Treatment with ponatinib resulted in blast cell clearance, decrease in fibrosis, and disappearance of BCR-ABL1, but also in severe thrombocytopenia with bleedings requiring platelet transfusions. We therefore switched from ponatinib to bosutinib. During bosutinib, platelet counts recovered. However, after 6 months, BCR-ABL1 mRNA levels increased to > 1%. Therefore, we ´switched back´ to ponatinib, and this was again followed by disappearance of BCR-ABL1 and a decrease in platelets. During the next 2 years, we applied ponatinib and bosutinib in continuous rotation-cycles and added hydroxyurea in order to suppress all sub-clones and to balance between efficacy and potential side effects following the principle of personalized medicine. With this approach the patient remained in complete molecular response and reached normal blood counts and a normal quality of life without vascular or other side effects. In conclusion, TKI rotation is a novel potent approach to suppress multiple resistant sub-clones and to balance between clinical efficacy and side effects in patients with advanced CML. Clinical trials are now warranted to show that TKI-rotation is in general safe and effective in these patients.
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http://dx.doi.org/10.18632/oncotarget.15481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5410285PMC
April 2017

Advanced age impacts surgical characteristics and postoperative course in patients with Crohn's disease.

Int J Surg 2016 Sep 13;33 Pt A:182-6. Epub 2016 Aug 13.

Medical University of Vienna, Department of Surgery, Austria.

Purpose: Due to a lack of data, the present study was designed to assess the impact of advanced age on surgical characteristics and short-term outcome of patients operated on for symptomatic Crohn's disease.

Methods: We enrolled 454 consecutive Crohn's disease patients, who underwent intestinal resection at an academic tertiary referral center between 1997 and 2012. Patients were divided into 3 groups according to their age (group I: <30 years, group II: 30-50 years, group III: >50 years) and analyzed retrospectively.

Results: Altogether, 152 (33.5%) patients were included in group I, 234 (51.5%) in group II and 68 (15.0%) in group III. Abscess formation and penetrating disease were significantly more common in younger patients (p = 0.0014 and p = 0.0182). The number of intestinal resections was higher in older patients (p < 0.0001), whereas the laparoscopic approach was more frequently observed in younger adults (p = 0.0006). Group II (n = 58 (24.8%)) and group III (n = 15 (22.1%)) showed significantly more complications compared to group I (n = 20 (13.2%)) (p = 0.0346). Notably, major complications and anastomotic leaks were significantly higher in older patients (p = 0.0004).

Conclusion: Crohn's disease patients of advanced age show different surgical characteristics compared to younger patients and are at an increased risk of developing postoperative complications.
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http://dx.doi.org/10.1016/j.ijsu.2016.08.012DOI Listing
September 2016

Identification of the Ki-1 antigen (CD30) as a novel therapeutic target in systemic mastocytosis.

Blood 2015 Dec 20;126(26):2832-41. Epub 2015 Oct 20.

Department of Internal Medicine I, Division of Hematology and Hemostaseology and Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria;

The Ki-1 antigen (CD30) is an established therapeutic target in patients with Hodgkin lymphoma and anaplastic large-cell lymphoma. We have recently shown that CD30 is expressed abundantly in the cytoplasm of neoplastic mast cells (MCs) in patients with advanced systemic mastocytosis (SM). In the current study, we asked whether CD30 is expressed on the surface of neoplastic MCs in advanced SM, and whether this surface structure may serve as therapeutic target in SM. As assessed by flow cytometry, CD30 was found to be expressed on the surface of neoplastic MCs in 3 of 25 patients (12%) with indolent SM, 4 of 7 patients (57%) with aggressive SM, and 4 of 7 patients (57%) with MC leukemia. The immature RAS-transformed human MC line MCPV-1.1 also expressed cell surface CD30, whereas the KIT-transformed MC line HMC-1.2 expressed no detectable CD30. The CD30-targeting antibody-conjugate brentuximab-vedotin inhibited proliferation in neoplastic MCs, with lower IC50 values obtained in CD30(+) MCPV-1.1 cells (10 µg/mL) compared with CD30(-) HMC-1.2 cells (>50 µg/mL). In addition, brentuximab-vedotin suppressed the engraftment of MCPV-1.1 cells in NSG mice. Moreover, brentuximab-vedotin produced apoptosis in all CD30(+) MC lines tested as well as in primary neoplastic MCs in patients with CD30(+) SM, but did not induce apoptosis in neoplastic MCs in patients with CD30(-) SM. Furthermore, brentuximab-vedotin was found to downregulate anti-IgE-induced histamine release in CD30(+) MCs. Finally, brentuximab-vedotin and the KIT D816V-targeting drug PKC412 produced synergistic growth-inhibitory effects in MCPV-1.1 cells. Together, CD30 is a promising new drug target for patients with CD30(+) advanced SM.
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http://dx.doi.org/10.1182/blood-2015-03-637728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4692143PMC
December 2015

Transformed mycosis fungoides: bridging to allogeneic stem cell transplantation with brentuximab vedotin.

Leuk Lymphoma 2016 19;57(1):206-8. Epub 2015 Jun 19.

a Department of Internal Medicine I , Division of Hematology and Hemostaseology, Medical University of Vienna , Vienna , Austria.

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http://dx.doi.org/10.3109/10428194.2015.1044748DOI Listing
October 2016