Publications by authors named "Florian Posch"

82 Publications

Convalescent plasma therapy and mortality in COVID-19 patients admitted to the ICU: a prospective observational study.

Ann Intensive Care 2021 May 12;11(1):73. Epub 2021 May 12.

Intensive Care Unit, Department of Internal Medicine, Medical University of Graz, Graz, Austria.

Background: This study aimed to quantify the potential survival benefit of convalescent plasma therapy (CVP) in critically ill patients with acute respiratory failure related to coronavirus disease-2019 (COVID-19).

Methods: This is a single-center prospective observational cohort study in COVID-19 patients with acute respiratory failure. Immediately after intensive care unit (ICU) admission patients were allocated to CVP treatment following pre-specified criteria to rapidly identify those patients potentially susceptible for this treatment. A propensity score adjustment [inverse probability of treatment weighted (IPTW) analysis] was implemented to account rigorously for imbalances in prognostic variables between the treatment groups.

Results: We included 120 patients of whom 48 received CVP. Thirty percent were female with a median age of 66 years [25th-75th percentile 54-75]. Eighty-eight percent of patients presented with severe acute respiratory failure as displayed by a median paO/FiO ratio (Horowitz Index) of 92 [77-150]. All patients required any kind of ventilatory support with more than half of them (52%) receiving invasive ventilation. Thirty-day ICU overall survival (OS) was 69% in the CVP group and 54% in the non-CVP group (log-rank p = 0.049), respectively. After weighing the time-to-event data for the IPTW, the favorable association between CVP and OS became even stronger (log-rank p = 0.035). Moreover, an exploratory analysis showed an overall survival benefit of CVP therapy for patients with non-invasive ventilation (Hazard ratio 0.12 95% CI 0.03-0.57, p = 0.007) CONCLUSION: Administration of CVP in patients with acute respiratory failure related to COVID-19 is associated with improved ICU survival rates.
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http://dx.doi.org/10.1186/s13613-021-00867-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8114671PMC
May 2021

Gemcitabine/nab-Paclitaxel versus FOLFIRINOX for palliative first-line treatment of advanced pancreatic cancer: A propensity score analysis.

Eur J Cancer 2021 May 2;151:3-13. Epub 2021 May 2.

Division of Clinical Oncology, Department of Internal Medicine, Medical University of Graz, Graz, Austria. Electronic address:

Background: Gemcitabine/nab-paclitaxel (GN) and FOLFIRINOX are standard first-line treatment options for advanced pancreatic ductal adenocarcinoma (aPDAC), but currently no prospective randomised head-to-head comparison between these treatments has yet been performed.

Methods: We conducted a comparative propensity score (PS) analysis of overall (OS) and progression-free survival (PFS) in a tri-centre cohort of patients with aPDAC undergoing palliative first-line treatment with either GN or FOLFIRINOX.

Results: In unadjusted analysis, OS and PFS were highly similar between patients treated with GN (n = 297) and FOLFIRINOX (n = 158). In detail, median, 1- and 2-year OS estimates were 10.1 months, 42% and 18% in the GN group, as compared to 11.2 months, 45% and 12% in the FOLFIRINOX group, respectively (log-rank p = 0.783). Accordingly, median (4.6 versus 4.8 months), 6-month (40% versus 43%) and 1-year (9% versus 9%) PFS estimates did not significantly differ (log-rank p = 0.717). However, patients treated with FOLFIRINOX were significantly younger, had fewer comorbidities, and a better Eastern Cooperative Oncology Group performance status. These imbalances were accounted for by weighting the data with the PS. In PS analysis of survival outcomes, OS and PFS remained comparable between the two treatment groups. In detail, PS-weighted median, 1- and 2-year OS estimates were 10.1 months, 42% and 18% in the GN group, as compared to 10.1 months, 40% and 13% in the FOLFIRINOX group (PS-weighted log-rank p = 0.449). PS-weighted PFS estimates again did not differ (PS-weighted log-rank p = 0.329).

Conclusion: This real-world comparative effectiveness study indicates that FOLFIRINOX and GN have similar effectiveness in the palliative first-line treatment of aPDAC.
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http://dx.doi.org/10.1016/j.ejca.2021.03.040DOI Listing
May 2021

Relative risk of arterial and venous thromboembolism in persons with cancer vs. persons without cancer-a nationwide analysis.

Eur Heart J 2021 Mar 26. Epub 2021 Mar 26.

Clinical Division of Hematology and Hemostaseology, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, Vienna 1090, Austria.

Aims: An interrelation between cancer and thrombosis is known, but population-based studies on the risk of both arterial thromboembolism (ATE) and venous thromboembolism (VTE) have not been performed.

Methods And Results: International Classification of Disease 10th Revision (ICD-10) diagnosis codes of all publicly insured persons in Austria (0-90 years) were extracted from the Austrian Association of Social Security Providers dataset covering the years 2006-07 (n = 8 306 244). Patients with a history of cancer or active cancer were defined as having at least one ICD-10 'C' diagnosis code, and patients with ATE and/or VTE as having at least one of I21/I24 (myocardial infarction), I63/I64 (stroke), I74 (arterial embolism), and I26/I80/I82 (venous thromboembolism) diagnosis code. Among 158 675 people with cancer, 8559 (5.4%) had an ATE diagnosis code and 7244 (4.6%) a VTE diagnosis code. In contrast, among 8 147 569 people without cancer, 69 381 (0.9%) had an ATE diagnosis code and 29 307 (0.4%) a VTE diagnosis code. This corresponds to age-stratified random-effects relative risks (RR) of 6.88 [95% confidence interval (CI) 4.81-9.84] for ATE and 14.91 (95% CI 8.90-24.95) for VTE. ATE proportion was highest in patients with urinary tract malignancies (RR: 7.16 [6.74-7.61]) and lowest in patients with endocrine cancer (RR: 2.49 [2.00-3.10]). The corresponding VTE proportion was highest in cancer of the mesothelium/soft tissue (RR: 19.35 [17.44-21.47]) and lowest in oropharyngeal cancer (RR: 6.62 [5.61-7.81]).

Conclusion: The RR of both ATE and VTE are significantly higher in persons with cancer. Our population-level meta-data indicate a strong association between cancer, ATE and VTE, and support the concept of shared risk factors and pathobiology between these diseases.Relative risk of ATE and VTE in persons with a cancer diagnosis code versus persons without a cancer diagnosis code.
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http://dx.doi.org/10.1093/eurheartj/ehab171DOI Listing
March 2021

Influence of tumor-infiltrating immune cells on local control rate, distant metastasis, and survival in patients with soft tissue sarcoma.

Oncoimmunology 2021 Mar 11;10(1):1896658. Epub 2021 Mar 11.

Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria.

Soft tissue sarcomas (STS) are considered non-immunogenic, although distinct entities respond to anti-tumor agents targeting the tumor microenvironment. This study's aims were to investigate relationships between tumor-infiltrating immune cells and patient/tumor-related factors, and assess their prognostic value for local recurrence (LR), distant metastasis (DM), and overall survival (OS). One-hundred-eighty-eight STS-patients (87 females [46.3%]; median age: 62.5 years) were retrospectively analyzed. Tissue microarrays (in total 1266 cores) were stained with multiplex immunohistochemistry and analyzed with multispectral imaging. Seven cell types were differentiated depending on marker profiles (CD3+, CD3+ CD4+ helper, CD3+ CD8+ cytotoxic, CD3+ CD4+ CD45RO+ helper memory, CD3+ CD8+ CD45RO+ cytotoxic memory T-cells; CD20 + B-cells; CD68+ macrophages). Correlations between phenotype abundance and variables were analyzed. Uni- and multivariate Fine&Gray and Cox-regression models were constructed to investigate prognostic variables. Model calibration was assessed with C-index. IHC-findings were validated with TCGA-SARC gene expression data of genes specific for macrophages, T- and B-cells. B-cell percentage was lower in patients older than 62.5 years ( = .013), whilst macrophage percentage was higher ( = .002). High B-cell ( = .035) and macrophage levels ( = .003) were associated with increased LR-risk in the univariate analysis. In the multivariate setting, high macrophage levels ( = .014) were associated with increased LR-risk, irrespective of margins, age, gender or B-cells. Other immune cells were not associated with outcome events. High macrophage levels were a poor prognostic factor for LR, irrespective of margins, B-cells, gender and age. Thus, anti-tumor, macrophage-targeting agents may be applied more frequently in tumors with enhanced macrophage infiltration.
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http://dx.doi.org/10.1080/2162402X.2021.1896658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954425PMC
March 2021

Profiling of circulating tumor DNA and tumor tissue for treatment selection in patients with advanced and refractory carcinoma: a prospective, two-stage phase II Individualized Cancer Treatment trial.

Ther Adv Med Oncol 2021 27;13:1758835920987658. Epub 2021 Feb 27.

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

Background: Molecular profiling (MP) represents an opportunity to match patients to a targeted therapy and when tumor tissue is unavailable, circulating tumor deoxyribonucleic acid (ctDNA) can be harnessed as a non-invasive analyte for this purpose. We evaluated the success of a targeted therapy selected by profiling of ctDNA and tissue in patients with advanced and refractory carcinoma.

Patients And Methods: A blood draw as well as an optional tissue biopsy were obtained for MP. Whole-genome sequencing and a cancer hotspot panel were performed, and publicly available databases were used to match the molecular profile to targeted treatments. The primary endpoint was the progression-free survival (PFS) ratio (PFS on MP-guided therapy/PFS on the last evidence-based therapy), whereas the success of the targeted therapy was defined as a PFS ratio ⩾1.2. To test the impact of molecular profile-treatment matching strategies, we retrospectively analyzed selected cases the CureMatch PreciGENE™ decision support algorithm.

Results: Interim analysis of 24 patients yielded informative results from 20 patients (83%). A potential tumor-specific drug could be matched in 11 patients (46%) and eight (33%) received a matched treatment. Median PFS in the matched treatment group was 61.5 days [interquartile range (IQR) 49.8-71.0] compared with 81.5 days (IQR 68.5-117.8) for the last evidence-based treatment, resulting in a median PFS ratio of 0.7 (IQR 0.6-0.9). Hence, as no patient experienced a PFS ratio ⩾1.2, the study was terminated. Except for one case, the CureMatch analysis identified either a two-drug or three-drug combination option.

Conclusions: Our study employed a histotype-agnostic approach to harness molecular profiling data from both ctDNA and metastatic tumor tissue. The outcome results indicate that more innovative approaches to study design and matching algorithms are necessary to achieve improved patient outcomes. EudraCT: 2014-005341-44.
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http://dx.doi.org/10.1177/1758835920987658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923987PMC
February 2021

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

Support Care Cancer 2021 Feb 24. 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
February 2021

The AST/ALT Ratio Is an Independent Prognostic Marker for Disease-free Survival in Stage II and III Colorectal Carcinoma.

Anticancer Res 2021 Jan;41(1):429-436

Division of Oncology, Department of Internal Medicine, Graz, Austria.

Background/aim: The Aspartate aminotransaminase/Alanine aminotransaminase ratio (AST/ALT ratio) has been identified as a prognostic marker for several malignancies. In this study, we evaluated the prognostic value of the AST/ALT ratio in a large cohort of non-metastatic colorectal cancer patients (CRC).

Patients And Methods: A total of 536 patients with stage II and III CRC, as well as available AST/ALT ratio were included in this single-center retrospective analysis. Laboratory data were measured within two weeks before histological tumor diagnosis. Co-Primary endpoints for this analysis were disease-free survival (DFS) and overall survival (OS).

Results: In univariate cox regression DFS was significantly shorter in patients with an elevated AST/ALT ratio (HR=1.568, 95%CI=1.10-2.23, p=0.012). In multivariable analysis, the prognostic association between an elevated AST/ALT ratio and a poor survival prevailed statistically significant (HR=1.53, 95%C=1.05-2.22, p=0.026). No statistically significant association between the AST/ALT ratio and OS was observed (HR=1.4, 95% CI=0.89-2.22, p=0.14).

Conclusion: In this study, the serum AST/ALT ratio emerged as a valid prognostic marker for DFS in non-metastatic colorectal cancer patients at stage II and III.
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http://dx.doi.org/10.21873/anticanres.14792DOI Listing
January 2021

The use and diagnostic value of testing myositis-specific and myositis-associated autoantibodies by line immuno-assay: a retrospective study.

Ther Adv Musculoskelet Dis 2020 8;12:1759720X20975907. Epub 2020 Dec 8.

Department of Rheumatology & Immunology, Medical University of Graz, Auenbruggerplatz 15, Graz, Steiermark 8036, Austria.

Aims: Line immune-assays (LIA) for the detection of myositis-specific antibodies (MSA) are used widely for characterization of idiopathic inflammatory myopathies (IIM). Their current use and significance for the diagnosis of IIM remains unclear.

Methods: In this retrospective analysis, we retrieved clinical diagnoses of patients tested for MSA and myositis-associated antibodies (MAA) Jo-1, Mi-2α, Mi-2β, TIF1γ, SRP, MDA-5, NXP-2, SAE, PL-7, PL-12, EJ, OJ, PM-Scl100, PM-Scl75 and Ku. We calculated clinical specificity, clinical sensitivity, negative- and positive predictive values (PPV) as well as positive and negative likelihood ratios.

Results: In total, we analyzed 3167 samples. After exclusion of repeated measurements and patients with insufficient clinical information, data of 1118 patients were available for analysis. A total of 242 patients tested positive for at least one antibody, of which 45 patients had a diagnosis of IIM; 25 IIM patients were negative for all MSA/MAA. Clinical specificity of MSA/MAA for the diagnosis of IIM ranged between 94.2% and 99.9%. Clinical sensitivity and PPV across all antibodies tested ranged from 0.0% to 12.9% and 0.0% to 72.7%, respectively.

Conclusion: In clinical practice MSA/MAA are used widely for diagnostic work-up of IIM, resulting in a low pre-test probability. Clinicians should be aware that PPVs for most MSA/MAA are low.
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http://dx.doi.org/10.1177/1759720X20975907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727081PMC
December 2020

On-treatment measurements of circulating tumor DNA during FOLFOX therapy in patients with colorectal cancer.

NPJ Precis Oncol 2020 Nov 13;4(1):30. Epub 2020 Nov 13.

Institute of Human Genetics, Diagnostic and Research Center for Molecular BioMedicine, Medical University of Graz, Graz, Austria.

We addressed a significant unknown feature of circulating tumor DNA (ctDNA), i.e., how ctDNA levels change during chemotherapy, by serially monitoring ctDNA in patients with colorectal cancer during the 48-h application of FOLFOX. Surprisingly, we did not observe a spike in ctDNA as a sign of a responsive tumor, but instead ctDNA levels initially decreased and remained low in patients with stable disease or partial response. Our observations reveal further insights into cell destruction during chemotherapy with important implications for the management of patients.
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http://dx.doi.org/10.1038/s41698-020-00134-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666126PMC
November 2020

Longitudinal tumor fraction trajectories predict risk of progression in metastatic HR breast cancer patients undergoing CDK4/6 treatment.

Mol Oncol 2020 Dec 2. Epub 2020 Dec 2.

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

Despite improved clinical outcomes, intrinsic or acquired resistance to CDK4/6 inhibitor treatment has limited the success of this treatment in HR HER2 metastatic breast cancer patients. Biomarkers are urgently needed, and longitudinal biomarker measurements may harbor more dynamic predictive and prognostic information compared to single time point measurements. The aim of this study was to explore the longitudinal evolution of circulating tumor fractions within cell-free DNA assessed by an untargeted sequencing approach during CDK4/6 therapy and to quantify the potential association between longitudinal z-score measurements and clinical outcome by using joint models. Forty-nine HR HER2 metastatic breast cancer patients were enrolled, and z-score levels were measured at baseline and during 132 follow-up visits (median number of measurements per patient = 3, 25 -75 percentile: 3-5, range: 1-8). We observed higher baseline z-score levels (estimated difference 0.57, 95% CI: 0.147-0.983, P-value = 0.008) and a constant increase of z-score levels over follow-up time (overall P-value for difference in log z-score over time = 0.024) in patients who developed progressive disease. Importantly, the joint model revealed that elevated z-score trajectories were significantly associated with higher progression risk (HR of log z-score at any time of follow-up = 3.3, 95% CI, 1.44-7.55, P = 0.005). In contrast, single z-score measurement at CDK4/6 inhibitor treatment start did not predict risk of progression. In this prospective study, we demonstrate proof-of-concept that longitudinal z-score trajectories rather than single time point measurements may harbor important dynamic information on the development of disease progression in HR HER2 breast cancer patients undergoing CDK4/6 inhibitor treatment.
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http://dx.doi.org/10.1002/1878-0261.12870DOI Listing
December 2020

Arylesterase Activity of HDL Associated Paraoxonase as a Potential Prognostic Marker in Patients With Sepsis and Septic Shock-A Prospective Pilot Study.

Front Med (Lausanne) 2020 22;7:579677. Epub 2020 Oct 22.

Intensive Care Unit, Department of Internal Medicine, Medical University of Graz, Graz, Austria.

High-density lipoprotein (HDL) plays an essential role in the immune system and shows effective antioxidative properties. We investigated correlations of lipid parameters with the sequential organ failure assessment (SOFA) score and the prognostic association with mortality in sepsis patients admitted to intensive care unit (ICU). We prospectively recruited consecutive adult patients with sepsis and septic shock, according to sepsis-3 criteria as well as non-sepsis ICU controls. Fifty-three patients with sepsis (49% with septic shock) and 25 ICU controls without sepsis were enrolled. Dyslipidemia (HDL-C < 40 mg/l) was more common in sepsis compared to non-sepsis patients (85 vs. 52%, = 0.002). Septic patients compared to controls had reduced HDL-C (14 vs. 39 mg/l, < 0.0001), lower arylesterase activity of the antioxidative paraoxonase of HDL (AEA) (67 vs. 111 mM/min/ml serum, < 0.0001), and a non-significant trend toward reduced cholesterol efflux capacity (9 vs. 10%, = 0.091). We observed a strong association between higher AEA and lower risk of 28-day [per 10 mM/min/ml serum increase in AEA: odds ratio (OR) = 0.76; 95% CI, 0.61-0.94; = 0.01) and ICU mortality (per 10 mM/min/ml serum increase in AEA: OR = 0.71, 95% CI, 0.56-0.90, = 0.004) in the sepsis cohort in univariable logistic regression analysis. AEA was confirmed as an independent predictor of 28-day and ICU mortality in multivariable analyses. AEA discriminated well-regarding 28-day/ICU mortality in area under the receiver operating characteristic curve (AUROC) analyses. In survival analysis, 28-day mortality estimates were 40 and 69% with AEA ≥/< the 25th percentile of AEA's distribution, respectively (log-rank = 0.0035). Both compositional and functional HDL parameters are profoundly altered during sepsis. In particular, the functionality parameter AEA shows promising prognostic potential in sepsis patients.
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http://dx.doi.org/10.3389/fmed.2020.579677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642222PMC
October 2020

Serum levels of antibodies against oxidation-specific epitopes are decreased in patients with retinal vein occlusion.

Retina 2020 Oct 23. Epub 2020 Oct 23.

Department of Laboratory Medicine, Medical University of Vienna, Lazarettgasse 14, AKH BT 25.2, 1090 Vienna, Austria.

Purpose: Oxidative stress and inflammation have been implicated in the development of retinal vein occlusion (RVO). Oxidation-specific epitopes (OSEs) represent products of oxidative stress that can trigger vascular inflammation and thrombosis. Natural occurring antibodies have been shown to bind OSEs thereby inhibiting their inflammatory potential and promoting their removal.

Methods: This prospective cross-sectional study included 270 patients with RVO and 81 in-hospital control patients. We measured three types of serum levels of OSE-specific IgM and IgG antibodies (anti-copper-oxidized LDL (CuOx-LDL), anti-phosphocholine (PC), anti-malondialdehyde-modified LDL (MDA-LDL). History of arterial hypertension, hyperlipidemia, myocardial infarction, diabetes mellitus, stroke, smoking status and several laboratory parameters were determined to control for potential confounders.

Results: As compared to controls, patients with RVO had significantly lower levels of IgM and IgG antibodies against CuOx-LDL and PC, and significantly lower levels of IgG but not IgM antibodies against MDA-LDL. The association between RVO patients and lower levels of these antibodies prevailed upon multivariable adjustment.

Conclusions: These prospective data show that antibodies against OSE are lower in patients with RVO as compared to control patients and support the concept that oxidative stress and inflammation play key roles in the development and subsequent complications in RVO.
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http://dx.doi.org/10.1097/IAE.0000000000003001DOI Listing
October 2020

Heparins as cancer therapy: in theory, they should have worked.

Lancet Haematol 2020 10;7(10):e703-e704

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

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http://dx.doi.org/10.1016/S2352-3026(20)30276-3DOI Listing
October 2020

Microvascular density assessed by CD31 predicts clinical benefit upon bevacizumab treatment in metastatic colorectal cancer: results of the PassionATE study, a translational prospective Phase II study of capecitabine and irinotecan plus bevacizumab followed by capecitabine and oxaliplatin plus bevacizumab or the reverse sequence in patients in mCRC.

Ther Adv Med Oncol 2020 18;12:1758835920928635. Epub 2020 Aug 18.

Department of Medicine I, Division of Oncology, Comprehensive Cancer Center, Medical University Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.

Background: Targeted therapies offer novel opportunities to explore biomarkers based on their mode of action. Taking this into consideration, we evaluated six angiogenesis-related proteins as potential predictive biomarkers, which expression might predict the benefit of bevacizumab treatment in patients with metastatic colorectal cancer (mCRC).

Methods: This was a phase II multicenter, two-armed, randomized study, in which patients with mCRC were treated with XELIRI (capecitabine and irinotecan) plus bevacizumab followed by XELOX (capecitabine and oxaliplatin) plus bevacizumab (Arm A) or the reverse sequence (Arm B). Tissue expression level of six prespecified candidates [microvessel density assessed by CD31, PTEN, αV integrin, CD98hc, uPAR and NRP-1] was analyzed immunohistochemistry. The prognostic impact on survival was quantified using the Cox regression model. The predictive potential for benefit from Arm A Arm B treatment was investigated by fitting an interaction between the biomarkers and treatment assignment within a multivariable Cox model.

Results: In total, 74 out of 126 patients were included in the analysis. The expression of PTEN, αV integrin, uPAR and NRP-1 was not associated with progression-free survival (PFS) or overall survival (OS). For the first time, we identified that patients with tumors expressing CD98hc had a longer PFS than patients without CD98hc-expression ( = 0.032). More importantly, and in accordance with previous studies, low microvessel density was found to be associated with a reduced PFS [adjusted HR per doubling of CD31-expression ( = 0.53, 95% confidence interval: 0.30-0.95,  = 0.034)].

Conclusions: These results can contribute to the development of a personalized strategy for the treatment of mCRC with bevacizumab.
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http://dx.doi.org/10.1177/1758835920928635DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446555PMC
August 2020

Gemcitabine and Platinum-Based Agents for the Prediction of Cancer-Associated Venous Thromboembolism: Results from the Vienna Cancer and Thrombosis Study.

Cancers (Basel) 2020 Sep 3;12(9). Epub 2020 Sep 3.

Clinical Division of Haematology and Haemostaseology, Department of Medicine I, Comprehensive Cancer Center Vienna, Medical University of Vienna, 1090 Vienna, Austria.

Gemcitabine and platinum-based agents could increase the risk of venous thromboembolism (VTE) in patients with cancer. We evaluated the additive predictive utility of these agents towards cancer-associated VTE beyond a recently developed and externally validated clinical prediction model, which was based on tumor entity and continuous D-dimer levels. Analysis was performed in the derivation cohort of this model, obtained from the Vienna Cancer and Thrombosis Study (CATS), a prospective observational cohort study ( = 1409). Patients were followed for the occurrence of VTE for a maximum of two years. Competing-risk analysis was performed to obtain cumulative incidences and to conduct between-group comparisons of VTE risk. Cumulative two-year incidences of VTE were not elevated with gemcitabine treatment (10.2% vs. 7.5%, = 0.148), whereas they were higher for platinum-based therapy (11.6% vs. 5.9%, < 0.001). In a multivariable analysis, adjusting for tumor site category and D-dimer, gemcitabine was not associated with increased risk of VTE (subdistribution hazard ratio (SHR) 0.82, 95% confidence interval (CI) 0.53-1.28, = 0.390), whereas platinum-based therapy predicted for a numerically increased VTE risk (SHR 1.44, 95% CI 0.96-2.17, = 0.080). Similar results were obtained in a sensitivity analysis (updated cohort, = 1870). Our findings suggest limited additional value of chemotherapy for the prediction of cancer-associated VTE, beyond a validated clinical prediction model.
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http://dx.doi.org/10.3390/cancers12092493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564761PMC
September 2020

C-Reactive Protein (CRP) Levels in Immune Checkpoint Inhibitor Response and Progression in Advanced Non-Small Cell Lung Cancer: A Bi-Center Study.

Cancers (Basel) 2020 Aug 17;12(8). Epub 2020 Aug 17.

Division of Oncology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, A-8036 Graz, Austria.

Background: Biomarkers for predicting response to immune checkpoint inhibitors (ICI) are scarce and often lack external validation. This study provides a comprehensive investigation of pretreatment C-reactive protein (CRP) levels as well as its longitudinal trajectories as a marker of treatment response and disease outcome in patients with advanced non-small cell lung cancer (NSCLC) undergoing immunotherapy with anti PD-1 or anti PD-L1 agents.

Methods: We performed a retrospective bi-center study to assess the association between baseline CRP levels and anti PD-(L)1 treatment outcomes in the discovery cohort ( = 90), confirm these findings in an external validation cohort ( = 101) and explore the longitudinal evolution of CRP during anti PD-(L)1 treatment and the potential impact of dynamic CRP changes on treatment response and disease outcome in the discovery cohort. Joint models were implemented to evaluate the association of longitudinal CRP trajectories and progression risk. Primary treatment outcomes were progression-free survival (PFS) and overall survival (OS), while the objective response rate (ORR) was a secondary outcome, respectively.

Results: In the discovery cohort, elevated pretreatment CRP levels emerged as independent predictors of worse PFS (HR per doubling of baseline CRP = 1.37, 95% CI: 1.16-1.63, < 0.0001), worse OS (HR per doubling of baseline CRP = 1.42, 95% CI: 1.18-1.71, < 0.0001) and a lower ORR ((odds ratio (OR) of ORR per doubling of baseline CRP = 0.68, 95% CI: 0.51-0.92, = 0.013)). In the validation cohort, pretreatment CRP could be fully confirmed as a predictor of PFS and OS, but not ORR. Elevated trajectories of CRP during anti PD-(L)1 treatment (adjusted HR per 10 mg/L increase in CRP = 1.22, 95% CI: 1.15-1.30, < 0.0001), as well as a faster increases of CRP over time (HR per 10 mg/L/month faster increase in CRP levels = 13.26, 95% CI: 1.14-154.54, = 0.039) were strong predictors of an elevated progression risk, whereas an early decline of CRP was significantly associated with a reduction in PFS risk (HR = 0.91, 95% CI: 0.83-0.99, = 0.036), respectively.

Conclusion: These findings support the concept that CRP should be further explored by future prospective studies as a simple non-invasive biomarker for assessing treatment benefit during anti PD-(L)1 treatment in advanced NSCLC.
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http://dx.doi.org/10.3390/cancers12082319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464328PMC
August 2020

Diabetes mellitus is independently associated with adverse clinical outcome in soft tissue sarcoma patients.

Sci Rep 2020 07 24;10(1):12438. Epub 2020 Jul 24.

Division of Clinical Oncology, Department of Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria.

Diabetes mellitus (DM) and hyperglycemia are known predictors of adverse outcome in different tumor entities. The present study investigated the effect of DM and pre-surgery blood glucose levels on cancer specific survival (CSS), overall survival (OS), and disease-free survival (DFS) in non-metastatic soft tissue sarcoma (STS) patients. A total of 475 STS patients who underwent curative resection were included in this retrospective study. CSS, DFS, and OS were assessed using Kaplan-Meier curves. The association between pre-existing DM as well as mean pre-surgery blood glucose levels and all 3 survival endpoints was analyzed using Cox-hazard proportional (for OS and DFS) and competing risk regression models (for CSS). In unadjusted analysis, DM was significantly associated with adverse CSS (sub-hazard ratio [SHR]: 2.14, 95% confidence interval [CI] 1.18-3.90, p = 0.013) and OS (hazard ratio [HR]: 2.05, 95% CI 1.28-3.28) and remained significant after adjusting for established prognostic factors (CSS: adjusted SHR 2.33, 95% CI 1.21-4.49, p = 0.012; OS: adjusted HR 1.96, 95% CI 1.17-3.28, p = 0.010), respectively. There was no significant association of DM with DFS (p = 0.149). The mean pre-surgery glucose levels were not significantly associated with inferior outcome (CSS: p = 0.510, OS: p = 0.382 and DFS: p = 0.786). This study shows, that DM represents a negative prognostic factor for clinical outcome in STS patients after curative resection.
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http://dx.doi.org/10.1038/s41598-020-69237-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7382498PMC
July 2020

Estimation versus measurement of the glomerular filtration rate for kidney function assessment in patients with cancer undergoing cisplatin-based chemotherapy.

Sci Rep 2020 07 8;10(1):11219. Epub 2020 Jul 8.

Division of Oncology, Department of Internal Medicine, Comprehensive Cancer Center Graz, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria.

Glomerular filtration rate (GFR) assessment is indicated before every administration of cisplatin. The optimal modality for this purpose [GFR measurement by urinary Creatinine Clearance (uCrCl) versus GFR estimation (eGFR) by the CKD-EPI formula versus both] is unclear. We investigated whether eGFR only is safe in this setting. Paired uCrCl and eGFR determinations from 470 cisplatin cycles from 121 patients were analyzed [median age: 55 years; most frequent tumor site: genitourinary (45%); palliative treatment: n = 41 (34%)]. Primary endpoint was the proportion of cycles with uCrCl < 50 ml/min/1.73m and eGFR ≥ 50 ml/min/1.73m (i.e. a "false negative" result when only determining eGFR). The primary endpoint occurred in 8 of 470 cisplatin cycles (1.7%, 95%CI 0.5-2.9). In all 8 events, uCrCl was lower than eGFR (mean uCrCl vs. eGFR: 43 versus 112 ml/min/1.73m). The uCrCl was re-measured in all patients, and showed normal results in all but 1 patient. None of these events precluded the administration of cisplatin at the planned date, and no subsequent cases of acute nephrotoxicity occurred. Overall agreement between uCrCl and eGFR was low, with qualitative analysis suggesting frequent incompliance with 24-h urine collection. We conclude that an eGFR is sufficient for assessing kidney function in patients with cancer undergoing cisplatin therapy.
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http://dx.doi.org/10.1038/s41598-020-68010-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343883PMC
July 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

Systemic Inflammation and Activation of Haemostasis Predict Poor Prognosis and Response to Chemotherapy in Patients with Advanced Lung Cancer.

Cancers (Basel) 2020 Jun 18;12(6). Epub 2020 Jun 18.

Clinical Division of Haematology and Haemostaseology, Department of Medicine I, Comprehensive Cancer Center Vienna, Medical University of Vienna, 1190 Vienna, Austria.

Systemic inflammation and activation of haemostasis are common in patients with lung cancer. Both conditions support tumour growth and metastasis. Therefore, inflammatory and haemostatic biomarkers might be useful for prediction of survival and therapy response. Patients with unresectable/metastatic lung cancer initiating 1st-line chemotherapy ( = 277, 83% non-small cell lung cancer) were followed in a prospective observational cohort study. A comprehensive panel of haemostatic biomarkers (D-dimer, prothrombin fragment 1+2, soluble P-selectin, fibrinogen, coagulation factor VIII, peak thrombin generation), blood count parameters (haemoglobin, leucocytes, thrombocytes) and inflammatory markers (neutrophil-lymphocyte ratio, lymphocyte-monocyte ratio, platelet-lymphocyte ratio, C-reactive protein) were measured at baseline. We assessed the association of biomarkers with mortality, progression-free-survival (PFS) and disease-control-rate (DCR). A biomarker-based prognostic model was derived. Selected inflammatory and haemostatic biomarkers were strong and independent predictors of mortality and therapy response. The strongest predictors (D-dimer, LMR, CRP) were incorporated in a unified biomarker-based prognostic model (1-year overall-survival (OS) by risk-quartiles: 79%, 69%, 51%, 24%; 2-year-OS: 53%, 36%, 23%, 8%; log-rank < 0.001). The biomarker-based model further predicted shorter PFS and lower DCR. In conclusion, inflammatory and haemostatic biomarkers predict poor prognosis and treatment-response in patients with advanced lung cancer. A biomarker-based prognostic score efficiently predicts mortality and disease progression beyond clinical characteristics.
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http://dx.doi.org/10.3390/cancers12061619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352812PMC
June 2020

Direct oral anticoagulants compared to low-molecular-weight heparin for the treatment of cancer-associated thrombosis: Updated systematic review and meta-analysis of randomized controlled trials.

Res Pract Thromb Haemost 2020 May 21;4(4):550-561. Epub 2020 May 21.

Clinical Division of Haematology and Haemostaseology Department of Medicine I Comprehensive Cancer Center Vienna Medical University of Vienna Vienna Austria.

Background: Low-molecular-weight-heparins (LMWHs) have been established for the treatment of cancer-associated venous thromboembolism (VTE). Recently published randomized controlled trials (RCTs) have compared direct oral anticoagulants (DOACs) with LMWHs. The aim of this systematic review and meta-analysis was to evaluate efficacy and safety of DOACs versus LMWHs and update the evidence for treatment of VTE in cancer.

Methods: Biomedical databases were screened for RCTs evaluating DOACs for cancer-associated VTE. Primary efficacy and safety outcomes of this meta-analysis were recurrent VTE and major bleeding at 6 months. Secondary outcomes comprised clinically relevant nonmajor bleeding (CRNMB), major gastrointestinal (GI) and genitourinary bleeding, mortality, fatal bleeding/pulmonary embolism, and treatment discontinuation rate. We performed prespecified subgroup analyses. Pooled relative risk (RR) and 95% confidence intervals (CIs) were obtained by the Mantel-Haenszel method within a random-effect model.

Results: We screened 759 articles and included 4 RCTs (n = 2894). DOACs significantly reduced recurrent VTEs compared to LMWHs (5.2% vs 8.2%; RR, 0.62 [95% CI, 0.43-0.91]), but were associated with a nonsignificant increase in major bleedings (4.3% vs 3.3%; RR, 1.31 [95% CI, 0.83-2.08]) and a significant increase in CRNMB (10.4% vs 6.4%; RR, 1.65 [95% CI, 1.19-2.28]). Mortality risks were comparable between groups (RR, 0.99 [95% CI, 0.83-1.18]). Preterm treatment discontinuation was less common with DOACs (RR, 0.88 [95% CI, 0.81-0.96]). Major bleeding was more frequent in patients with GI cancer treated with DOACs (RR, 2.30 [95% CI, 1.08-4.88]).

Conclusion: In patients with cancer-associated VTE, DOACs are more effective in preventing recurrent VTE compared to LMWH. However, risk of bleeding is increased with DOACs, especially in patients with GI cancer.
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http://dx.doi.org/10.1002/rth2.12359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292654PMC
May 2020

The Dark Side of Arthroplasty: Competing Risk Analysis of Failed Hip and Knee Arthroplasty With Periprosthetic Joint Infection.

J Arthroplasty 2020 09 29;35(9):2601-2606.e1. Epub 2020 Apr 29.

Department of Orthopedics and Trauma, Medical University of Graz, Graz, Austria.

Background: Increasing total hip (THA) and knee (TKA) arthroplasties inevitably lead to accumulating failed arthroplasty (FA) with periprosthetic joint infections (PJI) and definite treatment recommendations are scarce. Our aims were to evaluate patient and infection site specific risk factors, and to identify case-dependent salvage procedure recommendations.

Methods: Retrospective analysis was conducted of salvage procedures for FA after PJI (amputation, Girdlestone resection arthroplasty [GRA], arthrodesis, or chronic fistulation [CF]) from 2008 to 2018. Univariable and multivariable modeling of revision and mortality rates, using cumulative incidence competing risk analysis, and Cox proportional hazards models were calculated.

Results: In total, 135 patients (THA 62%; TKA 38%) were diagnosed for FA after PJI, having undergone an average of 3 [1-4] revisions at a mean follow-up of 12.8 [7.8-20.9] years. Forty-four percent of THAs and 55% of TKAs had to be revised following FA, 44% deceased during follow-up, and 16% could be reconverted to an infection-free arthroplasty. GRA revealed significantly higher revision rates than CF (P = .015) for THA. Lower age (P = .003), higher number of revisions before FA (P = .007), more than one microorganism at infection site (P = .034), and GRA (P = .037, only THA) prevailed independent risk factors for revision. Patients' age remained an independent mortality risk factor (P = .001).

Conclusion: High-risk patients suffering from FA after THA with poor constitution profit from controlled constitution of CF, reducing the risk for revision surgeries and hospitalization. In case of FA after TKA, data did not allow definite treatment recommendations. We believe that education concerning amputation should be considered early after multiple TKA revisions.
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http://dx.doi.org/10.1016/j.arth.2020.04.078DOI Listing
September 2020

Association of programmed cell death ligand 1 and circulating lymphocytes with risk of venous thromboembolism in patients with glioma.

ESMO Open 2020 05;5(3):e000647

Division of Haematology and Haemostaseology, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria; I M Sechenov First Moscow State Medical University, Moscow, Russian Federation. Electronic address:

Introduction: The role of the adaptive immune system in the pathophysiology of cancer-associated venous thromboembolism (VTE) has not been investigated in detail. Programmed cell death ligand 1 (PD-L1) is an immune checkpoint molecule responsible for immune evasion in several cancer entities, as expression on tumour cells silences the T cell-mediated immune response. Given the interrelation between inflammation, haemostasis and cancer, we aimed to investigate the association of players of the adaptive immunity (eg, lymphocytes, tumour PD-L1) with risk of VTE in patients with glioma, one of the most prothrombotic cancer types.

Methods: In this prospective observational single-centre cohort study, patients with newly diagnosed glioma or regrowth after resection were included. Primary endpoint was objectively confirmed VTE. At study inclusion, a blood draw was performed. Tumour PD-L1 expression was assessed via immunohistochemistry.

Results: In total, 193 patients were included. PD-L1 expression in ≥1% of tumour cells was observed in 20/193 (10.4%) glioma. In multivariable cox-regression analysis, on adjustment for age, sex and WHO grade IV, systemic lymphocyte counts were significantly associated with risk of VTE (HR per 1 G/L increase (95% CI): 1.15 (1.03 to 1.29), p=0.013). In contrast, no significant difference in risk of VTE was found regarding the PD-L1 status: the cumulative 24 months probability of VTE was 17.0% in patients with no PD-L1 and 11.8% in those with PD-L1 expressing tumours (p=0.663).

Conclusion: In summary, PD-L1 expression was not associated with risk of VTE. Interestingly, peripheral lymphocytes, which are key players in adaptive immunity, were linked to an increased risk of glioma-associated VTE.
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http://dx.doi.org/10.1136/esmoopen-2019-000647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7239522PMC
May 2020

The AST/ALT (De Ritis) ratio predicts clinical outcome in patients with pancreatic cancer treated with first-line nab-paclitaxel and gemcitabine: analysis of an Austrian multicenter, noninterventional study.

Ther Adv Med Oncol 2020 10;12:1758835919900872. Epub 2020 Apr 10.

Division of Oncology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, Graz, 8036, Austria.

Background: The pretreatment De Ritis ratio [aspartate transaminase (AST)/alanine transaminase (ALT)] has been shown to be an adverse prognostic marker in various cancer entities. However, its relevance to advanced pancreatic ductal adenocarcinoma (PDAC) has not yet been studied. In the present study we investigated the AST/ALT ratio as a possible predictor of treatment response and disease outcome in patients with advanced PDAC treated with first-line gemcitabine/nab-paclitaxel.

Methods: A analysis of a prospective, multicenter, noninterventional study was performed. A total of 202 patients with advanced PDAC treated with first-line gemcitabine/nab-paclitaxel for whom the AST/ALT ratio was measured were included in this analysis.

Results: Median and 1-year progression-free survival estimates were 4.8 months and 5.1%, respectively in patients with an AST/ALT ratio above the 75th percentile of its distribution, and 6.0 months and 18.7%, respectively in patients with an AST/ALT ratio less than or equal to this cutoff, respectively (log-rank  = 0.004). In univariable Cox regression, a doubling of the AST/ALT ratio was associated with a 1.4-fold higher relative risk of progression or death [hazard ratio = 1.38, 95% confidence interval (CI): 1.06-1.80,  = 0.017]. The prognostic association was also found in multivariable analysis adjusting for Eastern Cooperative Oncology Group performance status and lung metastases (hazard ratio per AST/ALT ratio doubling = 1.32, 95% CI: 1.00-1.75,  = 0.047). In treatment response analysis, a doubling of the AST/ALT ratio was associated with a 0.5-fold lower odds of objective response (odds ratio = 0.54, 95% CI: 0.31-0.94,  = 0.020).

Conclusions: The pretreatment serum AST/ALT ratio predicts poor disease outcome and response rate in patients with advanced PDAC treated with gemcitabine/nab-paclitaxel and might represent a novel and inexpensive marker for individual risk assessment in the treatment of pancreatic cancer.
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http://dx.doi.org/10.1177/1758835919900872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7153180PMC
April 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

Dynamic assessment of venous thromboembolism risk in patients with cancer by longitudinal D-Dimer analysis: A prospective study.

J Thromb Haemost 2020 06 15;18(6):1348-1356. Epub 2020 Apr 15.

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

Background: Venous thromboembolism (VTE) is a frequent complication of cancer. Elevated D-dimer is associated with an increased risk of cancer-associated VTE. Whether changes in D-dimer over time harbor additional prognostic information that may be exploited clinically for dynamic prediction of VTE is unclear.

Objectives: To explore the potential role of longitudinal D-dimer trajectories for personalized prediction of cancer-associated VTE.

Patients/methods: A total of 167 patients with active malignancy were prospectively enrolled (gastrointestinal: n = 59 [35%], lung: n = 56 [34%], brain: n = 50 [30%], others: n = 2 [1%]; metastatic disease: n = 74 [44%]). D-dimer (median = 0.8 µg/mL [25th-75th percentile: 0.4-2.0]) was measured at baseline and during 602 monthly follow-up visits. Joint models of longitudinal and time-to-event data were implemented to quantify the association between D-dimer trajectories and prospective risk of VTE.

Results: VTE occurred in 20 patients (250-day VTE risk = 12.1%, 95% confidence interval [CI], 7.8-18.5). D-dimer increased by 34%/month (0.47 µg/mL/month, 95% CI, 0.22-0.72, P < .0001) in patients who developed VTE, but remained constant in patients who did not develop VTE (change/month = -0.06 µg/mL, 95% CI, -0.15 to 0.02, P = .121). In joint modeling, a doubling of the D-dimer trajectory was associated with a 2.8-fold increase in the risk of VTE (hazard ratio = 2.78, 95% CI, 1.69-4.58, P < .0001). This finding was independent of established VTE risk factors. Highly personalized, dynamic predictions of VTE conditional on individual patients' D-dimer trajectories could be obtained.

Conclusions: D-dimer increases before the onset of cancer-associated VTE, but remains constant over time in patients without VTE. This study represents proof-of-concept that longitudinal trajectories of D-Dimer may advance the personalized assessment of VTE risk in the oncologic setting.
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http://dx.doi.org/10.1111/jth.14774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317804PMC
June 2020

Haemostatic biomarkers for prognosis and prediction of therapy response in patients with metastatic colorectal cancer.

Thromb Res 2020 03 7;187:9-17. Epub 2020 Jan 7.

Clinical Division of Haematology and Haemostaseology, Department of Internal Medicine I, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria; I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia. Electronic address:

Background: Haemostatic activation and hypercoagulability are frequently observed in patients with metastatic colorectal cancer (mCRC), increase risk of venous thromboembolism (VTE) and have been implicated in tumour proliferation and progression. To date, the association of haemostatic biomarkers with oncologic outcomes including overall survival (OS), progression free survival (PFS) and disease control rate (DCR) is incompletely understood.

Methods: Within the framework of the Vienna Cancer and Thrombosis Study, a prospective observational cohort study, we conducted an exploratory analysis to investigate the association of six known biomarkers of haemostasis with oncologic outcomes in 99 patients with mCRC prior to chemotherapy initiation.

Results: Patients with high levels of factor VIII activity (FVIII), D-dimer, prothrombin fragment 1 + 2 (F1 + 2) and fibrinogen (defined as levels >75th percentile) had significantly shorter median OS than patients with lower levels. Elevation of four biomarkers was associated with mortality in multivariable analysis, adjusting for age, sex, number of metastatic sites and VTE (hazard ratio [95% CI] for death per doubling of levels: FVIII: 2.06 [1.28-3.30]; sP-selectin: 1.55 [1.07-2.24]; D-dimer: 1.40 [1.18-1.65]; F1 + 2: 1.64 [1.10-2.46]). Patients with elevated levels had numerically shorter median PFS across all markers and disease control rate (DCR) was significantly smaller in those with high levels of FVIII and F1 + 2 (adjusted odds ratio [95% CI] for DCR per doubling of levels: 0.23 [0.09-0.62] and 0.36 [0.16-0.82]) compared to patients with lower levels.

Conclusion: Specific elevated haemostatic biomarkers are associated with higher mortality and partially with worse response to chemotherapy in patients with mCRC.
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http://dx.doi.org/10.1016/j.thromres.2020.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212083PMC
March 2020

Prediction of Postoperative Clinical Outcomes in Resected Stage I Non-Small Cell Lung Cancer Focusing on the Preoperative Glasgow Prognostic Score.

Cancers (Basel) 2020 Jan 8;12(1). Epub 2020 Jan 8.

Division of Thoracic and Hyperbaric Surgery, Department of Surgery, Medical University of Graz, 8036 Graz, Austria.

The Glasgow Prognostic Score (GPS), which consists of albumin and C-reactive protein (CRP), may predict overall survival (OS) in cancer patients. The aim of this retrospective analysis was to evaluate the clinical impact of the preoperative GPS on patients with resected early stage non-small cell lung cancer (NSCLC). 300 patients with curatively resected stage I NSCLC were followed-up for OS, recurrence-free survival (RFS), cancer-specific survival (CSS), and death from other causes. 229 patients (76%) had a preoperative GPS of 0, and 71 (24%) a GPS ≥ 1. The three-year probabilities of RFS, OS, CSS, and death from other causes were 81%, 84%, 88%, and 96% in patients with GPS = 0, and 79%, 74%, 91%, and 82% in patients with a GPS ≥ 1, respectively. GPS ≥ 1 was significantly associated with a higher risk of death from other causes ( = 0.022), serving as an independent predictor of death from other causes ( = 0.034). Pathologically elevated CRP levels (CRP > 5 mg/L) were found in 91 patients (30%). The mean CRP level was 7.88 ± 15.80 mg/L (0.5-135.6 mg/L). Pre-treatment CRP level was significantly associated with coronary heart disease ( < 0.0001), histology ( = 0.013), tumor size ( = 0.018), tumor stage ( = 0.002), and vascular invasion ( = 0.017). The preoperative GPS predicts adverse survival outcomes in patients with resected stage I NSCLC.
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http://dx.doi.org/10.3390/cancers12010152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016624PMC
January 2020

Age as a Predictor of Treatment Outcome in Metastatic Testicular Germ Cell Tumors.

Anticancer Res 2019 Oct;39(10):5589-5596

Division of Clinical Oncology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.

Background/aim: To quantify the prognostic impact of age on relapse and mortality in patients with metastatic testicular germ cell tumors (TGCT).

Patients And Methods: Electronical medical records of 1,225 TGCT patients who were treated at a single academic center between 1994 and 2015 were reviewed.

Results: Higher age did not predict for worse progression-free survival (PFS) or for higher progression risk. The corresponding 5-year PFS estimates were 85% in patients younger than 40 years and 83% in the elderly population. Although not statistically significant, higher age was numerically associated with worse overall survival (OS) (univariate HR per five years increase in age=1.18, 95%CI=0.99-1.41). This was explained in regression analysis where age predicted for significantly higher risk of treatment-related death (p=0.022).

Conclusion: Elderly patients with metastatic TGCT can achieve high cure rates similar to younger patients if they tolerate risk-adapted chemotherapy.
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http://dx.doi.org/10.21873/anticanres.13753DOI Listing
October 2019

Ex vivo properties of plasma clot formation and lysis in patients with cancer at risk for venous thromboembolism, arterial thrombosis, and death.

Transl Res 2020 01 29;215:41-56. Epub 2019 Aug 29.

I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia. Electronic address:

A prothrombotic state is frequently observed in patients with cancer and contributes to the risks of venous thromboembolism (VTE), arterial thromboembolism (ATE), tumor progression, and death. Altered ex vivo properties of plasma clot formation and lysis have been observed in patients with cancer. The aim of this prospective study was to comprehensively characterize the relationship between plasma clot properties, inflammation, hypercoagulability, thrombotic complications, and mortality in patients with cancer using a tissue-factor-based turbidimetric assay of clot formation and lysis. Turbidity parameters were determined in 815 patients with newly-diagnosed or recurrent cancer and 97 healthy controls. Patients were followed-up for 2 years and rates of VTE (n = 72 events), ATE (n = 21 events), and death (n = 304 events) were assessed. Compared to controls, cancer patients' turbidity profiles showed an increased clot formation potential and higher resistance toward fibrinolysis. Elevated biomarkers of inflammation and hemostasis, such as C-reactive protein, FVIII, and thrombin generation explained substantial amounts of variation in turbidity parameters. In a prospective analysis, altered parameters of clot formation identified cancer patients at high risk of ATE (Hazard ratio [HR] per doubling of peak absorbance: 4.43, 95% CI: 1.50-13.07, P = 0.007) and death (HR per doubling of peak absorbance: 2.73, 2.00-3.72, P< 0.0001); these findings were independent of other prognostic covariates. Contrarily, turbidity parameters were not associated with risk of VTE (HR per doubling of peak absorbance: 1.15, 0.66-2.01, P = 0.62). We conclude that patients with cancer have altered ex vivo properties of clot formation which predict risks of ATE and mortality but not VTE.
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http://dx.doi.org/10.1016/j.trsl.2019.08.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332340PMC
January 2020