Publications by authors named "Peter Neumeister"

76 Publications

Functional Precision Medicine Provides Clinical Benefit in Advanced Aggressive Hematological Cancers and Identifies Exceptional Responders.

Cancer Discov 2021 Oct 11. Epub 2021 Oct 11.

Platform Austria for Chemical Biology, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences.

Personalized medicine aims to match the right drug with the right patient by utilizing specific features of the individual patients' tumor. However, current strategies of personalized therapy matching only provide treatment opportunities for less than 10% of cancer patients. A promising method may be drug profiling of patient biopsies with single-cell resolution to directly quantify drug effects. We prospectively tested an image-based single-cell functional precision medicine (scFPM) approach to guide treatments in 143 patients with advanced aggressive hematologic cancers. Fifty-six patients (39%) were treated according to scFPM results. At a median follow-up of 23.9 months, 30 patients (54%) demonstrated a clinical benefit of more than 1.3-fold enhanced progression-free survival (PFS) compared to their previous therapy. Twelve patients (40% of responders) experienced exceptional responses lasting three times longer than expected for their respective disease. We conclude, that therapy matching by scFPM is clinically feasible, and effective in advanced aggressive hematologic cancers.
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http://dx.doi.org/10.1158/2159-8290.CD-21-0538DOI Listing
October 2021

The Agony of Choice-Where to Place the Wave of BCMA-Targeted Therapies in the Multiple Myeloma Treatment Puzzle in 2022 and Beyond.

Cancers (Basel) 2021 Sep 19;13(18). Epub 2021 Sep 19.

Division of Hematology and Hemostaseology, Department of Internal Medicine I, Medical University of Vienna, 1090 Vienna, Austria.

Since the introduction of first-generation proteasome inhibitors and immunomodulatory agents, the multiple myeloma (MM) treatment landscape has undergone a remarkable development. Most recently, immunotherapeutic strategies targeting the B cell maturation antigen (BCMA) entered the clinical stage providing access to highly anticipated novel treatment strategies. At present, numerous different approaches investigate BCMA as an effective multi-modal target. Currently, BCMA-directed antibody-drug conjugates, bispecific and trispecific antibodies, autologous and allogeneic CAR-T cell as well as CAR-NK cell constructs are either approved or in different stages of clinical and preclinical development for the treatment of MM. This armamentarium of treatment choices raises several challenges for clinical decision making, particularly in the absence of head-to-head comparisons. In this review, we provide a comprehensive overview of BCMA-targeting therapeutics, deliver latest updates on clinical trial data, and focus on potential patient selection criteria for different BCMA-targeting immunotherapeutic strategies.
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http://dx.doi.org/10.3390/cancers13184701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8471156PMC
September 2021

Tafasitamab combined with idelalisib or venetoclax in patients with CLL previously treated with a BTK inhibitor.

Leuk Lymphoma 2021 Aug 20:1-12. Epub 2021 Aug 20.

Division of Hematology, Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.

Patients with relapsed/refractory chronic lymphocytic leukemia (R/R CLL) whose treatment failed with a Bruton's tyrosine kinase inhibitor have poor outcomes. We investigated tafasitamab plus idelalisib (cohort A) or venetoclax (cohort B) in this patient population in a phase II study (NCT02639910). In total, 24 patients were enrolled (cohort A:  = 11, median time on study, 7.4 months; cohort B:  = 13, median time on study, 15.6 months). The most common treatment-emergent adverse event (TEAE) in cohort A was anemia (63.6%) and in cohort B was infusion-related reaction (53.8%). The most common severe TEAE was neutropenia (cohort A: 45.5%; cohort B: 46.2%). The best overall response rate was 90.9% (cohort A) and 76.9% (cohort B). Undetectable minimal residual disease in peripheral blood was achieved in 2/8 patients (cohort A) and 6/7 patients (cohort B). Overall, these results suggest that anti-CD19 antibody-based combinations may be important in the treatment of patients with CLL.
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http://dx.doi.org/10.1080/10428194.2021.1964020DOI Listing
August 2021

Chronic lymphocytic leukaemia-what is new and notable in 2021, with a special focus on COVID-19.

Memo 2021 Aug 11:1-4. Epub 2021 Aug 11.

Division of Haematology, Department of Internal Medicine, Medical University Graz, Auenbruggerplatz 38, 8036 Graz, Austria.

In the last few years, treatment of patients exhibiting chronic lymphocytic leukaemia has changed extensively due to advances in the development of targeted therapies. The role of immunochemotherapy has been for the most part replace and the guidelines have been modified accordingly. Herein, we give an overview on updated onkopedia guidelines, studded with updates of the landmark studies of the latest American Society of Hematology (ASH) meeting. In addition, since still crucial, recommendations concerning coronavirus disease 2019 (COVID-19) in chronic lymphocytic leukaemia patients will be covered.
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http://dx.doi.org/10.1007/s12254-021-00735-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8356209PMC
August 2021

Rituximab as a Treatment Option after Autologous Hematopoietic Stem Cell Transplantation in a Patient with Systemic Sclerosis.

J Pers Med 2021 Jun 25;11(7). Epub 2021 Jun 25.

Division of Rheumatology and Immunology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria.

Systemic sclerosis (SSc) is an intractable autoimmune disease characterized by vasculopathy and organ fibrosis. Autologous hematopoietic stem cell transplantation (AHSCT) should be considered for the treatment of selected patients with rapid progressive SSc at high risk of organ failure. It, however, remains elusive whether immunosuppressive therapies such as rituximab (RTX) are still necessary for such patients after AHSCT, especially in those with bad outcomes. In the present report, a 43-year-old man with diffuse cutaneous SSc received AHSCT. Despite AHSCT, SSc further progressed with progressive symptomatic heart failure with newly developed concomitant mitral and tricuspid valve insufficiency, thus the patient started on RTX 8 months after AHSCT. Shortly after initiation of RTX, clinical symptoms and organ functions ameliorated subsequently. Heart valve regurgitations were reversible after initiation of RTX treatment. Currently, the patient remains in a stable condition with significant improvement of clinical symptoms and organ functions. Reporting about therapies after AHSCT in SSc is a very important issue, as randomized controlled trials are lacking, and therefore this report adds to evidence that RTX can be considered as a treatment option in patients with SSc that do not respond to AHSCT.
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http://dx.doi.org/10.3390/jpm11070600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8305780PMC
June 2021

Vinorelbine as substitute for vincristine in patients with diffuse large B cell lymphoma and vincristine-induced neuropathy.

Support Care Cancer 2021 Sep 24;29(9):5197-5207. Epub 2021 Feb 24.

Division of Hematology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.

Background: A combination of rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is the standard first-line therapy for diffuse large B cell lymphoma (DLBCL), the most common aggressive lymphoma in adults. One of the major adverse effects of this regimen is vincristine-induced polyneuropathy which leads to discontinuation of vincristine in up to 30% of DLBCL-patients. Dose reduction of vincristine might worsen treatment outcomes of DLBCL but identification of treatment alternatives for patients exhibiting peripheral neuropathy during R-CHOP is an unmet need in hematology.

Methods: In this retrospective cohort study, comprising 987 patients with de novo DLBCL, we delineated the role of vinorelbine as a substitute for vincristine in R-CHOP by measuring improvements in neuropathy and outcome variables.

Results: Five-year overall survival (OS) and progression-free survival (PFS) were 72.6% and 63.1% in patients who received regular doses of vincristine, as compared to 60.6% and 51.7% in patients who received reduced doses of vincristine (p = 0.022 and p = 0.003, respectively). Of 199 patients who switched to vinorelbine, the majority experienced an improvement of neuropathy Furthermore, vinorelbine-switched patients showed favorable oncologic outcomes.

Conclusion: Replacement of vincristine by vinorelbine due to neuropathy is effective and safe, and results in a significant improvement in neuropathy as compared to treatment with R-CHOP.
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http://dx.doi.org/10.1007/s00520-021-06059-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8295169PMC
September 2021

Pyrocatalytic oxidation - strong size-dependent poling effect on catalytic activity of pyroelectric BaTiO nano- and microparticles.

Phys Chem Chem Phys 2020 Oct;22(41):23464-23473

Institute of Technical Chemistry and Environmental Chemistry, Friedrich Schiller University Jena, Philosophenweg 7a, 07743 Jena, Germany. and Center for Energy and Environmental Chemistry (CEEC Jena), Friedrich Schiller University Jena, Philosophenweg 7a, 07743 Jena, Germany.

Pyrocatalysis is an emerging advanced oxidation process for wastewater remediation with the potential for thermal energy harvesting and utilization. Although several studies explored the potential of new pyrocatalyst materials to degrade harmful organic water pollutants, the role of important material properties and electric poling procedures on the pyrocatalytic activity is still unclear. In this work, we investigate the interdependence between particle size, electric poling and pyrocatalytic activity of BaTiO3 powders with nominal particle sizes of 100, 200 and 500 nm by using the dichlorofluorescein redox assay. Depending on the particle size, the influence of surface area or phase composition on the pyrocatalytic activity predominates. Moreover, we demonstrate that poling of pyrocatalysts leads to a strong size-dependent increase of pyrocatalytic activity. This poling effect increases with particle size up to +247% and can be explained with size-dependent changes in phase composition and domain structure. Combining all results, the progression of the pyrocatalytic activity as a function of particle size was derived and a future strategy for maximizing the catalytic performance of pyrocatalysts was developed. This study greatly improves the understanding about the role of important material properties and electric poling on pyrocatalytic activity, thus enabling an effective catalyst design. With the help of highly active catalysts, the pyrocatalytic process can take the next step in its development into a new and energy-efficient advanced oxidation process for water remediation.
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http://dx.doi.org/10.1039/d0cp03158eDOI Listing
October 2020

The Role of Immunohistochemical Overexpression of p53 as Adverse Prognostic Factor in Primary Testicular Diffuse Large B Cell Lymphoma.

Pathol Oncol Res 2020 Oct 29;26(4):2831-2833. Epub 2020 Jun 29.

Division of Hematology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 38D, A-8036, Graz, Austria.

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http://dx.doi.org/10.1007/s12253-020-00864-6DOI Listing
October 2020

Immunohistochemistry for c-myc and bcl-2 overexpression improves risk stratification in primary central nervous system lymphoma.

Hematol Oncol 2020 Aug 7;38(3):277-283. Epub 2020 Mar 7.

Division of Hematology, Department of Internal Medicine, Medical University of Graz (MUG), Austria.

Overexpression of bcl-2 and c-myc are defining features of double-expressor-lymphoma (DEL) but may also occur separately in patients with primary central nervous system lymphoma (PCNSL). Despite all progress in optimizing treatment regimen, there is lack of sufficient risk stratification models. Here, we first describe the relationship between DEL biology, the National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI), treatment response, disease progression, and mortality in PCNSL. In this study, we determined c-myc and bcl-2 status immunohistochemically in samples of 48 patients with newly diagnosed PCNSL and followed these patients for a median interval of 6.2 years. Twelve, 18, and 17 patients harbored none, one, or both DEL features. Corresponding overall response rates after first-line therapy were strongly associated with DEL biology (100%, 42%, and 44% in patients with 0, 1, or 2 DEL features). Patients with one or both DEL features had a 5-fold and 13-fold higher 5-year risk of progression and/or death than patients without DEL features. These associations prevailed after adjusting for the NCCN-IPI. DEL improved the discriminatory capability of the NCCN-IPI (P = .0001). Furthermore, we could show that addition of DEL biology to the NCCN-IPI significantly improved the score's discriminatory potential both toward progression-free survival (increase in Harell's c = 0.15, P = .005) and overall survival (increase in Harell's c = 0.11, P = .029). In conclusion, DEL biology is a strong and simple-to-use predictor of adverse outcome in PCNSL. Addition of DEL to the NCCN-IPI improves its prognostic potential. Disease progression from PCNSL harboring both DEL features is invariably fatal. This defines a novel PCNSL patient subset with a great unmet need for improved therapy.
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http://dx.doi.org/10.1002/hon.2727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496545PMC
August 2020

Evaluation of host-based molecular markers for the early detection of human sepsis.

J Biotechnol 2020 Feb 1;310:80-88. Epub 2020 Feb 1.

Institute of Computational Biotechnology, Graz University of Technology, Petersgasse 14/V, 8010, Graz, Styria, Austria; CNA Diagnostics GmbH, Parkring 18, 8074, Grambach, Styria, Austria; BioTechMed Graz, Mozartgasse 12/II, 8010, Graz, Styria, Austria. Electronic address:

We have identified 24 molecular markers, based on circulating nucleic acids (CNA) originating from the human genome, which in combination can be used in a quantitative real-time PCR (qPCR) assay to identify the presence of human sepsis, starting two to three days before the first clinical signs develop and including patients who meet the SEPSIS-3 criteria. The accuracy was more than 87 % inside of the same patient cohort for which the markers were developed and up to 81 % in blind studies of patient cohorts which were not included in the marker development. As our markers are host-based, they can be used to capture bacterial as well as fungal sepsis, unlike the current PCR-based tests, which require species-specific primer sets for each organism causing human sepsis. Our assay directly uses an aliquot of cell-free blood as the substrate for the PCR reaction, thus allowing to obtain the diagnostic results in three to four hours after the collection of the blood samples.
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http://dx.doi.org/10.1016/j.jbiotec.2020.01.013DOI Listing
February 2020

The -Axis Is of Prognostic Relevance in DLBCL and Its Antagonists Exert Pro-Apoptotic Effects In Vitro.

Int J Mol Sci 2019 Sep 24;20(19). Epub 2019 Sep 24.

Division of Hematology, Medical University Graz; Auenbruggerplatz 38, 8036 Graz, Austria.

In tumor cells of more than 20 different cancer types, the -axis is involved in multiple key processes including proliferation, survival, migration, invasion, and metastasis. Since data on this axis in diffuse large B cell lymphoma (DLBCL) are inconsistent and limited, we comprehensively studied the -axis in our DLBCL cohort as well as the effects of CXCR4 antagonists on lymphoma cell lines in vitro. In DLBCL, we observed a 140-fold higher expression compared to non-neoplastic controls, which was associated with poor clinical outcome. In corresponding bone marrow biopsies, we observed a correlation of expression and lymphoma infiltration rate as well as a reduction of expression in remission of bone marrow involvement after treatment. Additionally, we investigated the effects of three CXCR4 antagonists in vitro. Therefore, we used AMD3100 (Plerixafor), AMD070 (Mavorixafor), and WKI, the niacin derivative of AMD070, which we synthesized. WK1 demonstrated stronger pro-apoptotic effects than AMD070 in vitro and induced expression of pro-apoptotic genes of the BCL2-family in CXCR4-positive lymphoma cell lines. Finally, WK1 treatment resulted in the reduced expression of JNK-, ERK1/2- and NF-κB/BCR-target genes. These data indicate that the -axis impacts the pathogenesis of DLBCL and represents a potential therapeutic target in aggressive lymphomas.
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http://dx.doi.org/10.3390/ijms20194740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6801866PMC
September 2019

Using Interleukin 6 and 8 in Blood and Bronchoalveolar Lavage Fluid to Predict Survival in Hematological Malignancy Patients With Suspected Pulmonary Mold Infection.

Front Immunol 2019 2;10:1798. Epub 2019 Aug 2.

Division of Infectious Diseases, Department of Medicine, University of California, San Diego, San Diego, CA, United States.

Molds and other pathogens induce elevated levels of several cytokines, including interleukin (IL)-6 and IL-8. The objective of this study was to investigate the prognostic value of IL-6 and IL-8 as well as fungal biomarkers in blood and bronchoalveolar lavage fluid (BAL) for overall survival in patients with underlying hematological malignancies and suspected mold infection. This cohort study included 106 prospectively enrolled adult cases undergoing bronchoscopy. Blood samples were collected within 24 h of BAL sampling and, in a subset of 62 patients, serial blood samples were collected up until 4 days after bronchoscopy. IL-6, IL-8, and other cytokines as well as galactomannan (GM) and β-D-glucan (BDG) were assayed in blood and BAL fluid and associations with overall mortality were assessed at the end of the study using receiver operating characteristic (ROC) curve analysis. Both blood IL-8 (AUC 0.731) and blood IL-6 (AUC 0.699) as well as BAL IL-6 (AUC 0.763) and BAL IL-8 (AUC 0.700) levels at the time of bronchoscopy were predictors of 30-day all-cause mortality. Increasing blood IL-6 levels between bronchoscopy and day four after bronchoscopy were significantly associated with higher 90-day mortality, with similar findings for increasing IL-8 levels. In ROC analysis the difference of blood IL-8 levels between 4 days after bronchoscopy and the day of bronchoscopy had an AUC of 0.829 (95%CI 0.71-0.95; < 0.001) for predicting 90-day mortality. Elevated levels of IL-6 and IL-8 in blood or BAL fluid at the time of bronchoscopy, and rising levels in blood 4 days following bronchoscopy were predictive of mortality in these patients with underlying hematological malignancy who underwent bronchoscopy for suspected mold infection.
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http://dx.doi.org/10.3389/fimmu.2019.01798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6687868PMC
October 2020

Development of 40-MHz Ultrasonic Transducers via Soft Mold Process.

IEEE Trans Ultrason Ferroelectr Freq Control 2019 09 17;66(9):1497-1503. Epub 2019 Jun 17.

This paper reports on the fabrication of 1-3 piezocomposites for ultrasonic transducers with operating frequencies up to 40 MHz based on recent developments of the soft mold technique. Compared to the established dice-and-fill technique, the soft mold process allows for the manufacturing of 1-3 piezocomposites with higher variability of pillar design and distribution as well as smaller structural size. Consequently, spurious modes generated by the lateral composite layout can be pushed to higher frequencies, which allows for increased operating frequency. Different designs of circular piezoceramic pillars in hexagonal arrangement with decreasing diameters and spacings have been developed and characterized in order to shift spurious modes to frequencies approximately twice the desired working frequency. The influence of the lateral composite layout on resonance modes is investigated by analyzing the produced transducers with respect to their electrical impedance spectra. Experimental results are explained in detail and compared to modeled data. Results show that by downsizing pillar diameter from 30 to [Formula: see text] and pitch from 40 to [Formula: see text], the first spurious mode could be shifted from ~42 to ~78 MHz. Thereby, the soft mold process proves to be suitable for the fabrication of 40-MHz ultrasonic transducers based on 1-3 piezocomposites.
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http://dx.doi.org/10.1109/TUFFC.2019.2923554DOI Listing
September 2019

Epidemiology and Treatment of Patients with Haemophilia in Austria-Update from the Austrian Haemophilia Registry.

Hamostaseologie 2019 Aug 12;39(3):284-293. Epub 2018 Nov 12.

Clinical Division of Haematology and Haemostaseology, Department of Medicine I, Medical University of Vienna, Vienna, Austria.

The Austrian Haemophilia Registry collects epidemiological data on patients with haemophilia, on treatment modalities and potential side effects. The Registry covers more than 85% of the assumed total number of haemophilia patients in Austria. This report summarizes data on 753 patients: 84.3% (635) have haemophilia A and 15.7% (118) have haemophilia B. Patients' median age is 34 years (range: 1-93 years). Of the total cohort, 39.0% (294) patients have severe haemophilia, 11.3% (85) moderate haemophilia, and 49.4% (372) mild haemophilia. Of the patients with severe haemophilia, 38.4% (113) have been infected with hepatitis C virus (HCV) and 12.6% (37) are human immunodeficiency virus (HIV) positive. Overall, 10.6% (67) of patients with haemophilia A and 1.7% (2) of those with haemophilia B have had an inhibitor in their history. Among patients with severe haemophilia, 68.4% (201) receive prophylaxis and 28.6% (84) receive on-demand therapy. There are 65.0% (191) patients with severe haemophilia who are treated with recombinant products. In conclusion, most patients with severe haemophilia receive prophylactic treatment. HCV and HIV infections are still important issues in the Austrian haemophilia population.
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http://dx.doi.org/10.1055/s-0038-1675354DOI Listing
August 2019

Cytoplasmic location of NR4A1 in aggressive lymphomas is associated with a favourable cancer specific survival.

Sci Rep 2018 09 28;8(1):14528. Epub 2018 Sep 28.

Division of Hematology, Department of Internal Medicine, Medical University Graz, Graz, Austria.

The nuclear orphan receptor NR4A1 functions as tumour suppressor in aggressive lymphomas by pro-apoptotic genomic and non-genomic effects. Here, we immunohistochemically studied the clinico-pathological relevance of NR4A1 protein expression patterns in a cohort of 60 diffuse large B cell lymphoma (DLBCL) patients and non-neoplastic lymph nodes. We observed a significant association between high cytoplasmic NR4A1 and favourable cancer-specific survival and the germinal centre B cell-like subtype, respectively. Moreover, the percentage of lymphoma cells exhibiting cytoplasmic NR4A1 significantly correlated to those showing cleaved caspase 3. Complementary, functional profiling using gene set enrichment of Reactome pathways based on publicly available microarray data was applied to determine pathways potentially implicated in cytoplasmic localization of NR4A1 and validated by means of semi quantitative real-time PCR. The pathway analysis revealed changes in the ERK1/2 pathway, and this was corroborated by the finding that high cytoplasmic NR4A1 was associated with higher expression of ERK1/2 targets in our cohort. These data indicate that high cytoplasmic NR4A1 is associated with a favourable lymphoma-specific survival and highlights the importance of NR4A1 expression patterns as potential prognostic marker for risk assessment in aggressive lymphomas.
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http://dx.doi.org/10.1038/s41598-018-32972-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6162226PMC
September 2018

Diagnosis of invasive aspergillosis in hematological malignancy patients: Performance of cytokines, Asp LFD, and Aspergillus PCR in same day blood and bronchoalveolar lavage samples.

J Infect 2018 09 1;77(3):235-241. Epub 2018 Jul 1.

Division of Pulmonology, Medical University of Graz, Graz, Austria; Section of Infectious Diseases and Tropical Medicine, Department of Medicine, Medical University of Graz, 8036 Graz, Austria; CBmed - Center for Biomarker Research in Medicine, Graz, Austria; Division of Infectious Diseases, Department of Medicine, University of California San Diego, San Diego, CA 92103, USA. Electronic address:

Background: Aspergillus spp. induce elevated levels of several cytokines. It remains unknown whether these cytokines hold value for clinical routine and enhance diagnostic performances of established and novel biomarkers/tests for invasive aspergillosis (IA).

Methods: This cohort study included 106 prospectively enrolled (2014-2017) adult cases with underlying hematological malignancies and suspected pulmonary infection undergoing bronchoscopy. Serum samples were collected within 24 hours of bronchoalveolar lavage fluid (BALF) sampling. Both, serum and BALF samples were used to evaluate diagnostic performances of the Aspergillus-specific lateral-flow device test (LFD), Aspergillus PCR, β-D-glucan, and cytokines that have shown significant associations with IA before.

Results: Among 106 cases, 11 had probable IA, and 32 possible IA; 80% received mold-active antifungals at the time of sampling. Diagnostic tests and biomarkers showed better performance in BALF versus blood, with the exception of serum interleukin (IL)-8 which was the most reliable blood biomarker. Combinations of serum IL-8 with either BALF LFD (sensitivity 100%, specificity 94%) or BALF PCR (sensitivity 91%, specificity 97%) showed promise for differentiating probable IA from no IA.

Conclusions: High serum IL-8 levels were highly specific, and when combined with either the BALF Aspergillus-specific LFD, or BALF Aspergillus PCR also highly sensitive for diagnosis of IA.
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http://dx.doi.org/10.1016/j.jinf.2018.05.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6097945PMC
September 2018

Real-world challenges and unmet needs in the diagnosis and treatment of suspected invasive pulmonary aspergillosis in patients with haematological diseases: An illustrative case study.

Mycoses 2018 Mar 22;61(3):201-205. Epub 2017 Nov 22.

Section of Infectious Diseases and Tropical Medicine, Department of Internal Medicine, Medical University Graz, Graz, Austria.

Recent years have seen important advances in the diagnosis of invasive pulmonary aspergillosis (IPA), complemented by the introduction of new therapies. Despite this, IPA remains a major cause of infection-related mortality in patients with haematological diseases. There are two main reasons for this. First, diagnosis of IPA remains a challenge, since risk factors and the clinical, radiological and mycological presentations vary not only by fungal disease stage, but also by patient group (eg neutropenic vs non-neutropenic patients). Diagnosis is particularly challenging in patients receiving mould-active prophylactic or empirical treatment, which reduces the sensitivity of all diagnostic tests for IPA. Second, treatment of IPA is complex due to unpredictable pharmacokinetic profiles of antifungal agents, small therapeutic window in terms of exposure and adverse events, and multiple drug-drug interactions through the CYP450 system. Here we report a case of a 23-year-old male with severe aplastic anaemia and subpleural nodules. Diagnostic tests for IPA obtained during ongoing mould-active empirical treatment were negative. Intravenous voriconazole was stopped after visual disturbances and hallucinations. The patient then had an anaphylactic reaction to liposomal amphotericin B and was switched to intravenous posaconazole, which had to be discontinued due to a significant increase in transaminase levels. He was treated with oral isavuconazole with reduced dosage, triggered by increasing transaminases under the standard dosage. Even under reduced dosage, blood concentrations of isavuconazole were high and treatment was successful. The case illustrates real-world challenges and unmet needs in the diagnosis and treatment of IPA in patients with haematological diseases.
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http://dx.doi.org/10.1111/myc.12727DOI Listing
March 2018

Levels of interleukin (IL)-6 and IL-8 are elevated in serum and bronchoalveolar lavage fluid of haematological patients with invasive pulmonary aspergillosis.

Mycoses 2017 Dec 6;60(12):818-825. Epub 2017 Sep 6.

Division of Pulmonology, Medical University of Graz, Graz, Austria.

Aspergillus spp. have been shown to induce T-helper cell (Th) 1 and Th17 subsets resulting in elevated levels of several cytokines. The objective of this study was to analyse a bundle of cytokines in serum and bronchoalveolar lavage fluid (BALF) in patients with and without invasive pulmonary aspergillosis (IPA). This nested case-control analysis included 10 patients with probable/proven IPA and 20 matched controls without evidence of IPA, out of a pool of prospectively enrolled (2014-2017) adult cases with underlying haematological malignancies and suspected pulmonary infection. Serum samples were collected within 24 hours of BALF sampling. All samples were stored at -70°C for retrospective determination of cytokines. IL-6 and IL-8 were significantly associated with IPA in both serum (P = .011 and P = .028) and BALF (P = .006 and P = .012, respectively), and a trend was observed for serum IL-10 (P = .059). In multivariate conditional logistic regression analysis, IL-10 remained a significant predictor of IPA in serum and IL-8 among BALF cytokines. In conclusion, levels of IL-6 and IL-8 were significantly associated with probable/proven IPA, and a similar trend was observed for serum IL-10. Future cohort studies should determine the diagnostic potential of these cytokines for IPA, and evaluate combinations with other IPA biomarkers/diagnostic tests.
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http://dx.doi.org/10.1111/myc.12679DOI Listing
December 2017

Early Hyperglycemia after Initiation of Glucocorticoid Therapy Predicts Adverse Outcome in Patients with Acute Graft-versus-Host Disease.

Biol Blood Marrow Transplant 2017 Jul 8;23(7):1186-1192. Epub 2017 Mar 8.

Division of Hematology, Department of Internal Medicine, Medical University of Graz, Graz, Austria; Center for Biomarker Research in Medicine, CBMed, Graz, Austria. Electronic address:

Because of first-line treatment with high-dose glucocorticoids (GC), steroid-induced hyperglycemia develops frequently in patients with acute graft-versus-host disease (aGVHD), potentially affecting their outcome. We performed a retrospective analysis on 104 patients who received systemic GC for aGVHD and investigated the consequences of aberrant glucose metabolism. In particular, we focused on glucose parameters early after initiation of GC. With a median of 50 (range, 4 to 513) blood glucose measurements during GC treatment, increasing mean, median, and maximum glucose levels and the need for insulin treatment were associated with decreased overall survival (OS) in simple and multiple survival analysis. Early hyperglycemia, as defined by mean blood glucose levels >125 mg/dL during the first 3 days of GC therapy, was also found to be highly associated with adverse outcome (hazard ratio [HR], 2.5 for death; 95% confidence interval [CI], 1.3 to 4.8, and HR of 3.5 for death due to nonrelapse mortality, 95% CI, 1.7 to 7.5, in a competing risk analysis). A score based on early hyperglycemia and nonresponse to GC within 7 days allowed the identification of 3 risk groups: patients with both risk factors had an inferior OS at 5 years of 4.1% compared with 75.4% in patients with none. Patients with 1 risk factor had a 5-year OS rate of 32.0% (P = .0002 for trend). Early hyperglycemia after GC initiation is a prominent risk factor for adverse outcome in patients with aGVHD. A score based solely on early hyperglycemia and lack of response to GC can predict survival in these patients.
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http://dx.doi.org/10.1016/j.bbmt.2017.03.010DOI Listing
July 2017

NR4A3 Suppresses Lymphomagenesis through Induction of Proapoptotic Genes.

Cancer Res 2017 05 1;77(9):2375-2386. Epub 2017 Mar 1.

Division of Hematology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.

Nuclear orphan receptor NR4A1 exerts an essential tumor suppressor function in aggressive lymphomas. In this study, we investigated the hypothesized contribution of the related NR4A family member NR4A3 to lymphomagenesis. In aggressive lymphoma patients, low expression of NR4A3 was associated with poor survival. Ectopic expression or pharmacological activation of NR4A3 in lymphoma cell lines led to a significantly higher proportion of apoptotic cells. In a mouse NSG xenograft model of lymphoma (stably transduced SuDHL4 cells), NR4A3 expression abrogated tumor growth, compared with vector control and uninduced cells that formed massive tumors. Transcript analysis of four different aggressive lymphoma cell lines overexpressing either NR4A3 or NR4A1 revealed that apoptosis was driven similarly by induction of BAK, Puma, BIK, BIM, BID, and Trail. Overall, our results showed that NR4A3 possesses robust tumor suppressor functions of similar impact to NR4A1 in aggressive lymphomas. .
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http://dx.doi.org/10.1158/0008-5472.CAN-16-2320DOI Listing
May 2017

NCCN-IPI score-independent prognostic potential of pretreatment uric acid levels for clinical outcome of diffuse large B-cell lymphoma patients.

Br J Cancer 2016 Nov 20;115(10):1264-1272. Epub 2016 Oct 20.

Division of Oncology, Department of Internal Medicine, Medical University of Graz (MUG), Graz 8036, Austria.

Background: Blood-based parameters are gaining increasing interest as potential prognostic biomarkers in patients with diffuse large B-cell lymphoma (DLBCL). The aim of this study was to comprehensively evaluate the prognostic significance of pretreatment plasma uric acid levels in patients with newly diagnosed DLBCL.

Methods: The clinical course of 539 DLBCL patients, diagnosed and treated between 2004 and 2013 at two Austrian high-volume centres with rituximab-based immunochemotherapy was evaluated retrospectively. The prognostic influence of uric acid on overall survival (OS) and progression-free survival (PFS) were studied including multi-state modelling, and analysis of conditional survival.

Results: Five-year OS and PFS were 50.4% (95% CI: 39.2-60.6) and 44.0% (33.4-54.0) in patients with uric acid levels above the 75th percentile of the uric acid distribution (Q3, cut-off: 6.8 mg dl), and 66.2% (60.4-71.5) and 59.6% (53.7-65.0%) in patients with lower levels (log-rank P=0.002 and P=0.0045, respectively). In univariable time-to-event analysis, elevated uric acid levels were associated with a worse PFS (hazard ratio (HR) per 1 log increase in uric acid 1.47, 95% CI: 1.10-1.97, P=0.009) and a worse OS (HR=1.60, 95% CI: 1.16-2.19, P=0.004). These associations prevailed upon multivariable adjustment for the NCCN-IPI score. Uric acid levels significantly improved the predictive performance of the R-IPI and NCCN-IPI scores, and in multi-state analysis, it emerged as a highly significant predictor of an increased risk of death without developing recurrence (transition-HR=4.47, 95% CI: 2.17-9.23, P<0.0001).

Conclusions: We demonstrate that elevated uric acid levels predict poor long-term outcomes in DLBCL patients beyond the NCCN-IPI risk index.
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http://dx.doi.org/10.1038/bjc.2016.325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5104895PMC
November 2016

Galactomannan testing and Aspergillus PCR in same-day bronchoalveolar lavage and blood samples for diagnosis of invasive aspergillosis.

Med Mycol 2017 Jul;55(5):528-534

Mannheim University Hospital, Mannheim, Germany.

In recent years galactomannan antigen testing (GM) and also Aspergillus PCR have become increasingly important for diagnosis of invasive aspergillosis (IA). Whether or not these tests need to be performed with bronchoalveolar lavage fluid (BALF; i.e., primary site of infection), or testing of blood samples is sufficient, remains, however, a matter of debate. We evaluated the diagnostic performance of GM ELISA, and Aspergillus PCR by using BALF samples and blood samples obtained at the same day from a total of 53 immunocompromised patients (16 with probable/proven IA and 37 with no evidence of IA according to the revised EORTC/MSG criteria; 38 patients with hematological malignancies were prospectively enrolled at the Medical University of Graz, Austria, 15 patients with mixed underlying diseases at the Mannheim University Hospital). Patients with possible IA were excluded from this analysis. A total of 34/53 (64%) of all patients and 12/16 (75%) of patients with probable/proven IA received mold-active antifungal prophylaxis/therapy at the time of the BALF procedure. Sensitivities of GM and Aspergillus PCR were 38% and 44% in BALF, and 31% and 0% in blood, respectively. Best sensitivity (75%) for detecting proven/probable IA was achieved when BALF Aspergillus PCR, BALF GM (>1.0 ODI), BALF-culture and serum-GM (>0.5 ODI) were combined (specificity 95%). In conclusion, sensitivities of the evaluated diagnostic tests-when interpreted on their own-were low in BALF and even lower in blood, sensitivities increased markedly when diagnostic tests were combined.
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http://dx.doi.org/10.1093/mmy/myw102DOI Listing
July 2017

Independent Prognostic Value of Serum Markers in Diffuse Large B-Cell Lymphoma in the Era of the NCCN-IPI.

J Natl Compr Canc Netw 2015 Dec;13(12):1501-8

From the Department of Internal Medicine III, Cancer Research Institute, Paracelsus Medical University Salzburg, Salzburg, Austria; Division of Hematology, Medical University of Graz, Graz, Austria; Institute of Pathology, Paracelsus Medical University Salzburg, Salzburg, Austria; and Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Duarte, Texas.

Background: Several serum parameters have been evaluated for adding prognostic value to clinical scoring systems in diffuse large B-cell lymphoma (DLBCL), but none of the reports used multivariate testing of more than one parameter at a time. The goal of this study was to validate widely available serum parameters for their independent prognostic impact in the era of the National Comprehensive Cancer Network-International Prognostic Index (NCCN-IPI) score to determine which were the most useful.

Patients And Methods: This retrospective bicenter analysis includes 515 unselected patients with DLBCL who were treated with rituximab and anthracycline-based chemoimmunotherapy between 2004 and January 2014.

Results: Anemia, high C-reactive protein, and high bilirubin levels had an independent prognostic value for survival in multivariate analyses in addition to the NCCN-IPI, whereas neutrophil-to-lymphocyte ratio, high gamma-glutamyl transferase levels, and platelets-to-lymphocyte ratio did not.

Conclusions: In our cohort, we describe the most promising markers to improve the NCCN-IPI. Anemia and high C-reactive protein levels retain their power in multivariate testing even in the era of the NCCN-IPI. The negative role of high bilirubin levels may be associated as a marker of liver function. Further studies are warranted to incorporate these markers into prognostic models and define their role opposite novel molecular markers.
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http://dx.doi.org/10.6004/jnccn.2015.0178DOI Listing
December 2015

The clinical significance of fibrinogen plasma levels in patients with diffuse large B cell lymphoma.

J Clin Pathol 2016 Apr 7;69(4):326-30. Epub 2015 Dec 7.

Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Background: Fibrinogen plays a crucial role in the pathophysiology of tumour cell growth, invasion and metastasis. The aim of this study was to evaluate the prognostic significance of pretreatment plasma fibrinogen levels in patients with diffuse large B cell lymphoma (DLBCL) METHODS: Data from 372 patients with DLBCL, diagnosed and treated between 2004 and 2013 at two Austrian centres, were evaluated retrospectively. The prognostic influences of plasma fibrinogen levels and other factors, including age, tumour stage and the National Comprehensive Cancer Network-International Prognostic Index, on 5-year overall survival (OS) and 5-year disease-free survival (DFS) were studied using Kaplan-Meier curves as well as univariate and multivariate Cox regression models.

Results: Kaplan-Meier analysis revealed that a high fibrinogen plasma level is associated with decreased 5-year OS and 5-year DFS in patients with DLBCL (p<0.001, log-rank test). Furthermore, in multivariate analysis, elevated serum fibrinogen was found to be an independent marker of poor clinical outcome: 5-year OS (HR=1.69, 95% CI 1.06 to 2.72, p=0.029) and 5-year DFS (HR=1.68, 95% CI 1.08 to 2.61, p=0.021).

Conclusions: In the current study, we demonstrate that high plasma fibrinogen levels at diagnosis predict poor outcome in patients with DLBCL.

Trial Registration Number: 25-434 ex 12713 and 415-EP/73/127-2012.
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http://dx.doi.org/10.1136/jclinpath-2015-203356DOI Listing
April 2016
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