Publications by authors named "Armin Gerger"

148 Publications

Benefit of second-line therapy for advanced esophageal squamous cell carcinoma: a tri-center propensity score analysis.

Ther Adv Med Oncol 2021 30;13:17588359211039930. Epub 2021 Sep 30.

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

Background: The level of evidence for palliative second-line therapy in advanced esophageal squamous cell carcinoma (aESCC) is limited. This is the first study that reports efficacy data comparing second-line therapy + active symptom control (ASC) ASC alone in aESCC.

Methods: We conducted a tri-center retrospective cohort study ( = 166) including patients with aESCC who had experienced disease progression on palliative first-line therapy. A propensity score model using inverse probability of treatment weighting (IPTW) was implemented for comparative efficacy analysis of overall survival (OS) in patients with second-line + ASC ( = 92, 55%) ASC alone ( = 74, 45%).

Results: The most frequent second-line regimens used were docetaxel (36%) and paclitaxel (18%). In unadjusted primary endpoint analysis, second-line + ASC was associated with significantly longer OS compared with ASC alone [hazard ratio (HR) = 0.49, 95% confidence interval (CI): 0.35-0.69,  < 0.0001]. However, patients in the second-line + ASC group were characterized by more favorable baseline features including a better Eastern Cooperative Oncology Group (ECOG) performance status, a longer first-line treatment duration and lower C-reactive protein levels. After rigorous adjusting for baseline confounders by re-weighting the data with the IPTW the favorable association between second-line and longer OS weakened but prevailed. The median OS was 6.1 months in the second-line + ASC group and 3.2 months in the ASC group, respectively (IPTW-adjusted HR = 0.40, 95% CI: 0.24-0.69,  = 0.001). Importantly, the benefit of second-line was consistent across several clinical subgroups, including patients with ECOG performance status ⩾1 and age ⩾65 years. The most common grade 3 or 4 adverse events associated with palliative second-line therapy were hematological toxicities.

Conclusion: This real-world study supports the concept that systemic second-line therapy prolongs survival in patients with aESCC.
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http://dx.doi.org/10.1177/17588359211039930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8488508PMC
September 2021

MiR-200c-3p Modulates Cisplatin Resistance in Biliary Tract Cancer by ZEB1-Independent Mechanisms.

Cancers (Basel) 2021 Aug 8;13(16). Epub 2021 Aug 8.

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

Biliary tract cancer is a major global health issue in cancer-related mortality. Therapeutic options are limited, and cisplatin-based treatment schedules represent the mainstay of first-line therapeutic strategies. Although the gain of survival by the addition of cisplatin to gemcitabine is moderate, acquired cisplatin resistance frequently leads to treatment failures with mechanisms that are still poorly understood. Epithelial-mesenchymal transition (EMT) is a dynamic process that changes the shape, function, and gene expression pattern of biliary tract cancer cells. In this study, we explored the influence of the EMT-regulating miR-200c-3p on cisplatin sensitivity in biliary tract cancer cells. Using gain of function experiments, we demonstrated that miR-200c-3p regulates epithelial cell markers through the downregulation of the transcription factor ZEB1. MiR-200c-3p upregulation led to a decreased sensitivity against cisplatin, as observed in transient overexpression models as well as in cell lines stably overexpressing miR-200c-3p. The underlying mechanism seems to be independent of miR-200c-3p's influence on expression, as ZEB1 knockdown resulted in the opposite effect on cisplatin resistance, which was abolished when ZEB1 knockdown and miR-200c-3p overexpression occurred in parallel. Using a gene panel of 40 genes that were previously associated with cisplatin resistance, two (Dual Specificity Phosphatase 16 () and Stratifin ()) were identified as significantly (>2 fold, -value < 0.05) up-regulated in miR-200c-3p overexpressing cells. In conclusion, miR-200c-3p might be an important contributor to cisplatin resistance in biliary tract cancer, independently of its interaction with ZEB1.
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http://dx.doi.org/10.3390/cancers13163996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8392278PMC
August 2021

Molecular profiling of soft-tissue sarcomas with FoundationOne Heme identifies potential targets for sarcoma therapy: a single-centre experience.

Ther Adv Med Oncol 2021 25;13:17588359211029125. Epub 2021 Jul 25.

Division of Clinical Oncology, Medical University of Graz, Graz, Austria.

Background: Molecular diagnosis has become an established tool in the characterisation of adult soft-tissue sarcomas (STS). FoundationOne Heme analyses somatic gene alterations in sarcomas DNA and RNA-hotspot sequencing of tumour-associated genes.

Methods: We evaluated FoundationOne Heme testing in 81 localised STS including 35 translocation-associated and 46 complex-karyotyped cases from a single institution.

Results: Although FoundationOne Heme achieved broad patient coverage and identified at least five genetic alterations in each sample, the sensitivity for fusion detection was rather low, at 42.4%. Nevertheless, potential targets for STS treatment were detected using the FoundationOne Heme assay: complex-karyotyped sarcomas frequently displayed copy-number alterations of common tumour-suppressor genes, particularly deletions in , , , and . A subset of myxofibrosarcomas (MFS) was amplified for ( = 3) and ( = 1). was mutated in 7/15 cases of myxoid liposarcoma (MLS; 46.7%). Epigenetic regulators (e.g. and ) were frequently mutated.

Conclusions: In summary, FoundationOne Heme detected a broad range of genetic alterations and potential therapeutic targets in STS (e.g. in a subset of MFS, or in MLS). The assay's sensitivity for fusion detection was low in our sample and needs to be re-evaluated in a larger cohort.
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http://dx.doi.org/10.1177/17588359211029125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8317253PMC
July 2021

Patterns of Thromboembolism in Patients with Advanced Pancreatic Cancer Undergoing First-Line Chemotherapy with FOLFIRINOX or Gemcitabine/nab-Paclitaxel.

Thromb Haemost 2021 Jul 12. Epub 2021 Jul 12.

IIIrd Medical Department of Hematology, Medical Oncology, Hemostaseology, Rheumatology and Infectious Disease, Salzburg Cancer Research Institute, Paracelsus Medical University, Salzburg, Austria.

Introduction:  Recent advances in prophylactic anticoagulation and antineoplastic treatment for advanced pancreatic cancer (aPC) warrant an updated reassessment of thromboembolic risk in this population. This multicenter retrospective cohort study aims to comprehensively characterize incidence, risk factors, and outcomes of venous (VTE) and arterial thromboembolism (ATE) in homogenously treated patients with aPC.

Methods:  Four hundred and fifty-five patients with aPC undergoing palliative first-line chemotherapy (Gemcitabine/nab-Paclitaxel (GN) or FOLIRINOX) were included. Primary outcomes were objectively confirmed VTE and/or ATE.

Results:  Over a median follow-up of 26 months, 86 VTE (cumulative incidence: 20.0%; 95% confidence interval [CI]: 16.3-24.0) and 11 ATE events (cumulative incidence: 2.8%; 95% CI: 1.5-4.9) were observed. VTE diagnosis was associated with increased mortality (transition hazard ratio [THR]: 1.59 [95% CI: 1.21-2.09]) and increased risk of cancer progression (THR: 1.47 [95% CI: 1.08-2.01]), while the impact of ATE on mortality was numerically but not statistically significant (THR: 1.85 [95% CI: 0.87-3.94]). The strongest predictor of increased VTE risk was history of cancer-associated VTE (subdistribution hazard ratio [SHR]: 3.29 [95% CI: 2.09-5.18]), while the Khorana score (SHR: 0.78 [0.57-1.06]) failed to predict VTE risk. A history of cerebrovascular disease was associated with markedly increased ATE risk (SHR: 22.05 [95% CI: 6.83-71.22],  < 0.001), especially ischemic stroke. Risk of VTE/ATE did not significantly differ according to type of first-line chemotherapy.

Conclusion:  Patients with aPC undergoing palliative first-line chemotherapy with FOLFIRINOX or GN face a high risk for VTE/ATE and its diagnosis is linked to worse clinical outcomes. VTE-risk prediction models have limited ability to sub-stratify thrombotic events in this high-risk scenario.
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http://dx.doi.org/10.1055/a-1548-4847DOI Listing
July 2021

Immune Aging and Immunotherapy in Cancer.

Int J Mol Sci 2021 Jun 29;22(13). Epub 2021 Jun 29.

Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, 8036 Graz, Austria.

Immune functions decline as we age, while the incidence of cancer rises. The advent of immune checkpoint blockade (ICB) has not only revolutionized cancer therapy, but also spawned great interest in identifying predictive biomarkers, since only one third of patients show treatment response. The aging process extensively affects the adaptive immune system and thus T cells, which are the main target of ICB. In this review, we address age-related changes regarding the adaptive immune system with a focus on T cells and their implication on carcinogenesis and ICB. Differences between senescence, exhaustion, and anergy are defined and current knowledge, treatment strategies, and studies exploring T cell aging as a biomarker for ICB are discussed. Finally, novel approaches to improve immunotherapies and to identify biomarkers of response to ICB are presented and their potential is assessed in a comparative analysis.
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http://dx.doi.org/10.3390/ijms22137016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8269421PMC
June 2021

T-regulatory cells predict clinical outcome in soft tissue sarcoma patients: a clinico-pathological study.

Br J Cancer 2021 Aug 14;125(5):717-724. Epub 2021 Jun 14.

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

Background: Soft tissue sarcomas (STS) are generally considered non-immunogenic, although specific subtypes respond to immunotherapy. Antitumour response within the tumour microenvironment relies on a balance between inhibitory and activating signals for tumour-infiltrating lymphocytes (TILs). This study analysed TILs and immune checkpoint molecules in STS, and assessed their prognostic impact regarding local recurrence (LR), distant metastasis (DM), and overall survival (OS).

Methods: One-hundred and ninety-two surgically treated STS patients (median age: 63.5 years; 103 males [53.6%]) were retrospectively included. Tissue microarrays were constructed, immunohistochemistry for PD-1, PD-L1, FOXP3, CD3, CD4, and CD8 performed, and staining assessed with multispectral imaging. TIL phenotype abundance and immune checkpoint markers were correlated with clinical and outcome parameters (LR, DM, and OS).

Results: Significant differences between histology and all immune checkpoint markers except for FOXP3+ and CD3-PD-L1+ cell subpopulations were found. Higher levels of PD-L1, PD-1, and any TIL phenotype were found in myxofibrosarcoma as compared to leiomyosarcoma (all p < 0.05). The presence of regulatory T cells (Tregs) was associated with increased LR risk (p = 0.006), irrespective of margins. Other TILs or immune checkpoint markers had no significant impact on outcome parameters.

Conclusions: TIL and immune checkpoint marker levels are most abundant in myxofibrosarcoma. High Treg levels are independently associated with increased LR risk, irrespective of margins.
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http://dx.doi.org/10.1038/s41416-021-01456-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8405702PMC
August 2021

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

Eur J Cancer 2021 Jul 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
July 2021

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

Oncoimmunology 2021 03 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

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

Comparison of nab-paclitaxel plus gemcitabine in elderly versus younger patients with metastatic pancreatic cancer: Analysis of a multicentre, prospective, non-interventional study.

Eur J Cancer 2021 01 6;143:101-112. Epub 2020 Dec 6.

Klinikum Klagenfurt Am Wörthersee, Internal Medicine and Oncology, Feschnigstraße 11, 9020, Klagenfurt, Austria. Electronic address:

Background: Pancreatic cancer (PC) ranks among the deadliest malignancies worldwide. In the MPACT study, first-line nab-paclitaxel plus gemcitabine (nab-P/G) demonstrated activity (median overall survival [OS], 8.7 months) and tolerability in patients with metastatic PC (mPC). However, the clinical evidence of nab-P/G in the elderly (>70 years), who account for the majority of patients with mPC, is limited. This is the first prospective, multicentre, non-interventional study evaluating the tolerability and effectiveness of nab-P/G in younger (≤70 years) versus elderly (>70 years) patients with mPC in the daily clinical routine.

Methods: Eligible patients with mPC were treated with nab-P/G and observed until disease progression or unacceptable toxicity. The primary objectives were safety and tolerability of nab-P/G, and the secondary objectives were efficacy and real-life dosing.

Results: A total of 317 patients with mPC (median age, 70 years) were recruited, of which 299, aged ≤70 (n = 162) and >70 (n = 137) years, were eligible for analysis. Baseline characteristics and the safety profile were comparable between the groups. However, fatigue (22.8% versus 13.0%) and decreased appetite (8.8% versus 1.2%) were more frequent in elderly patients. Younger versus elderly patients equally benefited in terms of objective response rate (36% versus 48%), median progression-free survival (5.6 versus 5.5 months; hazard ratio [HR] = 1.03; p = 0.81) and OS (10.6 versus 10.2 months; HR = 0.89; p = 0.4). In addition, the median treatment duration (5 versus 4 cycles), relative dose intensity (70% versus 74%) or reasons for treatment discontinuation were similar. Most patients (56.2% versus 47.4%) benefited from a second-line therapy.

Conclusion: This prospective real-world analysis confirms the feasibility and tolerability of nab-P/G treatment and reveals OS data similar for younger patients and elderly patients aged >70 years. CLINICALTRIALS.

Gov Registration: NCT02555813.

Austrian Nis Registry: NIS005071.
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http://dx.doi.org/10.1016/j.ejca.2020.11.003DOI Listing
January 2021

Comparison of three commercial decision support platforms for matching of next-generation sequencing results with therapies in patients with cancer.

ESMO Open 2020 09;5(5):e000872

Institute of Human Genetics, Diagnostic and Research Center for Molecular BioMedicine, Medical University of Graz, Graz, Austria; BioTechMed-Graz, Graz, Austria. Electronic address:

Objective: Precision oncology depends on translating molecular data into therapy recommendations. However, with the growing complexity of next-generation sequencing-based tests, clinical interpretation of somatic genomic mutations has evolved into a formidable task. Here, we compared the performance of three commercial clinical decision support tools, that is, NAVIFY Mutation Profiler (NAVIFY; Roche), QIAGEN Clinical Insight (QCI) Interpret (QIAGEN) and CureMatch Bionov (CureMatch).

Methods: In order to obtain the current status of the respective tumour genome, we analysed cell-free DNA from patients with metastatic breast, colorectal or non-small cell lung cancer. We evaluated somatic copy number alterations and in parallel applied a 77-gene panel (AVENIO ctDNA Expanded Panel). We then assessed the concordance of tier classification approaches between NAVIFY and QCI and compared the strategies to determine actionability among all three platforms. Finally, we quantified the alignment of treatment suggestions across all decision tools.

Results: Each platform varied in its mode of variant classification and strategy for identifying druggable targets and clinical trials, which resulted in major discrepancies. Even the frequency of concordant actionable events for tier I-A or tier I-B classifications was only 4.3%, 9.5% and 28.4% when comparing NAVIFY with QCI, NAVIFY with CureMatch and CureMatch with QCI, respectively, and the obtained treatment recommendations differed drastically.

Conclusions: Treatment decisions based on molecular markers appear at present to be arbitrary and dependent on the chosen strategy. As a consequence, tumours with identical molecular profiles would be differently treated, which challenges the promising concepts of genome-informed medicine.
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http://dx.doi.org/10.1136/esmoopen-2020-000872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7513637PMC
September 2020

A higher ctDNA fraction decreases survival in regorafenib-treated metastatic colorectal cancer patients. Results from the regorafenib's liquid biopsy translational biomarker phase II pilot study.

Int J Cancer 2021 03 16;148(6):1452-1461. Epub 2020 Oct 16.

Department of Medicine I, Division of Oncology, Medical University of Vienna, Vienna, Austria.

The predictive effect of circulating tumor DNA (ctDNA) in colorectal cancer (CRC) treatment is still highly discussed. The primary objective of our study was to investigate a possible prognostic/predictive value of ctDNA under regorafenib treatment. This prospective multicenter translational biomarker phase II pilot study enrolled 30 metastatic CRC patients (67% men, 33% women) treated with regorafenib. ctDNA was assessed in plasma before treatment start and at defined time points during administration. Measurement of tumor fraction as well as mutation and copy number analysis of CRC driver genes were performed by next-generation sequencing approaches. Multivariate analyses for survival and treatment efficacy were adjusted to age, gender and Eastern Cooperative Oncology Group. Disease control rate was 30%. Median tumor fraction at baseline was 18.5% (0-49.9). Mutations in CRC driver genes or genes involved in angiogenesis were identified in 25 patients (83.3%). KRAS mutations were detected in 13 of 14 KRAS-positive tumors; in three patients without KRAS mutation in the respective tumors, acquired mutations as a consequence of prior anti-EGFR treatment were detected. In a subset of patients, novel occurring mutations or focal amplifications were detected. A tumor fraction of 5% and higher at baseline was significantly associated with a decreased OS (P = .022; hazard ratio 3.110 (95% confidence interval: 1.2-8.2). ctDNA is detectable in a high proportion of mCRC patients. Higher ctDNA levels are associated with survival among regorafenib treatment. Moreover, our data highlight the benefit of a combined evaluation of mutations and somatic copy number alterations in advanced cancer patients.
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http://dx.doi.org/10.1002/ijc.33303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894541PMC
March 2021

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

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 Lipase/Amylase Ratio (LAR) in Peripheral Blood Might Represent a Novel Prognostic Marker in Patients with Surgically Resectable Pancreatic Cancer.

Cancers (Basel) 2020 Jul 5;12(7). Epub 2020 Jul 5.

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

Pancreatic enzymes might play a pivotal role in the pathophysiology and prognosis of pancreatic cancer. The aim of this study is to investigate the lipase/amylase ratio (LAR), representing a marker previously used in the differentiation of pancreatitis, as a potential prognostic marker in pancreatic cancer. Data from 157 surgically treated patients with ductal pancreatic adenocarcinoma and 351 patients with metastatic disease were evaluated retrospectively. Cancer-specific survival (CSS) was considered the endpoint of the study. After applying Kaplan-Meier curve analysis, uni- and multivariate Cox regression models were calculated to evaluate the prognostic relevance of LAR. An elevated LAR at diagnosis of localized pancreatic cancer was significantly associated with higher CA19-9 levels ( < 0.05). In univariate analysis, we observed an increased LAR as a significant factor for lower CSS in localized pancreatic cancer patients (HR = 1.63; 95% CI = 1.12-2.36; = 0.01), but not in metastatic patients (HR = 1.12; 95% CI = 0.87-1.43; = 0.363). In multivariate analysis, including age, gender, tumor stage, Karnofsky Performance Status, tumor grade, administration of chemotherapy and the LAR, an increased LAR was confirmed to represent an independent prognostic factor regarding CSS (HR = 1.81; 95% CI = 1.17-2.77; = 0.007) in localized pancreatic cancer patients. In conclusion, our study identified the LAR as an independent prognostic factor in surgically treated pancreatic cancer patients.
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http://dx.doi.org/10.3390/cancers12071798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408133PMC
July 2020

External validation of the prognostic relevance of the advanced lung cancer inflammation index (ALI) in pancreatic cancer patients.

Cancer Med 2020 08 14;9(15):5473-5479. Epub 2020 Jun 14.

Division of Clinical Oncology, Department of Medicine, Comprehensive Cancer Center Graz, Medical University of Graz, Graz, Austria.

Background: The advanced lung cancer inflammation index (ALI) was first introduced for prognosis prediction in lung cancer patients and since then evaluated in several other malignancies. However, in pancreatic cancer (PC) the ALI and its prognostic utility were only investigated in a comparably small and specific cohort of locally advanced PC patients treated with chemoradiotherapy.

Methods: In our single-center cohort study, we included 429 patients with histologically verified PC who were treated between 2003 and 2015 at our academic institution. The ALI was defined as body mass index (BMI; kg/m ) × serum albumin levels (g/dL)/neutrophil-lymphocyte ratio (NLR) and we defined the optimal cutoff for biomarker dichotomization by ROC-analysis. Kaplan-Meier method as well as uni- and multivariate Cox regression Hazard proportional models were implemented to assess the prognostic potential of ALI in PC patients. We considered cancer-specific survival (CSS) as the primary endpoint of the study.

Results: The ALI showed a significant negative correlation with CA19-9 levels and C-reactive protein levels whereas we found an association with localized tumor stage and better performance status (P < .05 for all mentioned variables). As opposed to patients with a high ALI, decreased ALI was significantly associated with shorter CSS (HR = 0.606, 95% CI: 0.471-0.779, P = .001). Multivariate analysis demonstrated tumor grade, tumor stage, chemotherapy, C-reactive protein levels, and CA19-9 levels to independently predict for CSS (all P < .05). In contrast the ALI failed to independently predict for CSS in the performed multivariate models (HR = 0.878, 95% CI: 0.643-1.198, P = .411).

Conclusion: In this large cohort of PC patients, the ALI did not complement existing clinicopathological factors for outcome determination.
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http://dx.doi.org/10.1002/cam4.3233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402815PMC
August 2020

Decreased Activity of Circulating Butyrylcholinesterase in Blood Is an Independent Prognostic Marker in Pancreatic Cancer Patients.

Cancers (Basel) 2020 May 4;12(5). Epub 2020 May 4.

Division of Clinical Oncology, Department of Medicine, Comprehensive Cancer Center Graz, Medical University of Graz, 8010 Graz, Austria.

The activity of butyrylcholinesterase (BChE) in blood reflects liver function and has recently been associated with systemic inflammatory response and tumor cachexia. As these conditions have been previously linked with pancreatic cancer (PC), the purpose of the present study was to evaluate the prognostic impact of plasma BChE in PC. Data from 574 consecutive PC patients, treated between 2004 and 2018 at a single academic center, was evaluated. The primary endpoint was cancer-specific survival (CSS), analyzed by Kaplan-Meier curve, and both univariate and multivariate Cox proportional models. BChE activity negatively correlated with other liver parameters (bilirubin, gamma-glutamyl transferase (GGT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and C-reactive protein (CRP)), and positively correlated with albumin levels, respectively ( < 0.01). In univariate analysis, a low plasma BChE activity was a factor of poor CSS (hazard ratio: 1.4, 95% confidence interval: 1.129-1.754, = 0.002). In multivariate analysis, tumor stage, tumor grade, administration of chemotherapy, bilirubin levels and a low BChE activity (hazard ratio: 1.42, 95% confidence interval: 1.10-1.82; = 0.006) were identified as independent prognostic factors. : Decreased activity of BChE in blood plasma predicts shorter survival time in PC patients. Therefore, BChE might be helpful in additional stratification of patients into different prognostic risk groups.
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http://dx.doi.org/10.3390/cancers12051154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281496PMC
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

Publisher Correction: Inference of transcription factor binding from cell-free DNA enables tumor subtype prediction and early detection.

Nat Commun 2020 04 20;11(1):1965. Epub 2020 Apr 20.

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

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41467-020-15799-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7170910PMC
April 2020

Cell-free DNA analysis reveals POLR1D-mediated resistance to bevacizumab in colorectal cancer.

Genome Med 2020 02 22;12(1):20. Epub 2020 Feb 22.

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

Background: Bevacizumab, a monoclonal antibody against soluble VEGFA, is an approved and commonly administered anti-angiogenic drug in patients with metastasized colorectal cancer (mCRC). The survival benefit of anti-VEGF therapy in mCRC patients is limited to a few months, and acquired resistance mechanisms are largely unknown. Here, we employed whole-genome sequencing of plasma DNA to evaluate the tumor genome of patients undergoing treatment with bevacizumab to determine novel aberrations associated with resistance.

Methods: Using longitudinal plasma analyses, we studied the evolution of tumor genomes in a mCRC cohort (n = 150) and conducted analyses of CRC cases from The Cancer Genome Atlas (TCGA) database (n = 619) to identify associations between genomic aberrations and clinical features. We employed whole-genome sequencing to identify the most frequently occurring focal somatic copy number alterations (SCNAs). Using the TCGA data as a comparative and supporting dataset, we defined the minimally amplified overlapping region and studied the mechanistic consequences of copy number gain of the involved genes in this segment. In addition, we established an in vitro cell model and conducted downstream gene expression and cell viability assays to confirm our findings from the patient dataset.

Results: We observed a recurrent focal amplification (8.7% of cases) on chromosome 13q12.2. Analysis of CRC cases from the TCGA database suggested that this amplicon is associated with more advanced stages. We confirmed that this 13q12.2 amplicon frequently emerges later during the clinical course of disease. After defining the minimally amplified region, we observed that the amplification and expression of one gene, POLR1D, impacted cell proliferation and resulted in upregulation of VEGFA, an important regulator of angiogenesis which has been implicated in the resistance to bevacizumab treatment. In fact, in several patients, we observed the emergence of this 13q12.2 amplicon under bevacizumab treatment, which was invariably associated with therapy resistance.

Conclusions: Non-invasive analyses of cell-free DNA from patients undergoing treatment with bevacizumab enabled the tracking of evolving tumor genomes and helped identify a recurrent focal SCNA of clinical relevance. Here, we describe a novel resistance mechanism against a widely applied treatment in patients with mCRC which will impact the clinical management of patients.
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http://dx.doi.org/10.1186/s13073-020-0719-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7036260PMC
February 2020

Individualizing Follow-Up Strategies in High-Grade Soft Tissue Sarcoma with Flexible Parametric Competing Risk Regression Models.

Cancers (Basel) 2019 Dec 21;12(1). Epub 2019 Dec 21.

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

Currently, patients with extremity soft tissue sarcoma (eSTS) who have undergone curative resection are followed up by a heuristic approach, not covering individual patient risks. The aim of this study was to develop two flexible parametric competing risk regression models (FPCRRMs) for local recurrence (LR) and distant metastasis (DM), aiming at providing guidance on how to individually follow-up patients. Three thousand sixteen patients (1931 test, 1085 validation cohort) with high-grade eSTS were included in this retrospective, multicenter study. Histology (9 categories), grading (time-varying covariate), gender, age, tumor size, margins, (neo)adjuvant radiotherapy (RTX), and neoadjuvant chemotherapy (CTX) were used in the FPCRRMs and performance tested with Harrell-C-index. Median follow-up was 50 months (interquartile range: 23.3-95 months). Two hundred forty-two (12.5%) and 603 (31.2%) of test cohort patients developed LR and DM. Factors significantly associated with LR were gender, size, histology, neo- and adjuvant RTX, and margins. Parameters associated with DM were margins, grading, gender, size, histology, and neoadjuvant RTX. C-statistics was computed for internal (C-index for LR: 0.705, for DM: 0.723) and external cohort (C-index for LR: 0.683, for DM: 0.772). Depending on clinical, pathological, and patient-related parameters, LR- and DM-risks vary. With the present model, implemented in the updated Personalised Sarcoma Care (PERSARC)-app, more individualized prediction of LR/DM-risks is made possible.
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http://dx.doi.org/10.3390/cancers12010047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017264PMC
December 2019

Inference of transcription factor binding from cell-free DNA enables tumor subtype prediction and early detection.

Nat Commun 2019 10 11;10(1):4666. Epub 2019 Oct 11.

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

Deregulation of transcription factors (TFs) is an important driver of tumorigenesis, but non-invasive assays for assessing transcription factor activity are lacking. Here we develop and validate a minimally invasive method for assessing TF activity based on cell-free DNA sequencing and nucleosome footprint analysis. We analyze whole genome sequencing data for >1,000 cell-free DNA samples from cancer patients and healthy controls using a bioinformatics pipeline developed by us that infers accessibility of TF binding sites from cell-free DNA fragmentation patterns. We observe patient-specific as well as tumor-specific patterns, including accurate prediction of tumor subtypes in prostate cancer, with important clinical implications for the management of patients. Furthermore, we show that cell-free DNA TF profiling is capable of detection of early-stage colorectal carcinomas. Our approach for mapping tumor-specific transcription factor binding in vivo based on blood samples makes a key part of the noncoding genome amenable to clinical analysis.
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http://dx.doi.org/10.1038/s41467-019-12714-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6789008PMC
October 2019

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

Treatment Algorithm for Patients With Gastric Adenocarcinoma: An Austrian Consensus on Systemic Therapy.

Anticancer Res 2019 Sep;39(9):4589-4596

Third Medical Department with Haematology, Medical Oncology, Haemostaseology, Infectious Diseases and Rheumatology, Oncology Centre, Paracelsus Medical University Salzburg, Salzburg, Austria.

Despite recent advances in the treatment of gastric cancer, mortality related to this disease is still substantial. Surgery and chemotherapy represent the cornerstones of patient management. Targeted treatments that include anti-angiogenic agents and the advent of immunotherapies can contribute to improved patient prognosis. Herein, we present an Austrian consensus on the systemic treatment of patients with gastric adenocarcinoma and lower gastroesophageal junction, including those with human epidermal growth factor receptor 2 (HER2)-positive disease. The consensus considers the curative setting, as well as first-line to late-line systemic treatment options in the palliative setting. For HER2-positive disease, first-line and second-line therapies are discussed, as well as HER2 testing. Potential future therapies are also listed, with a focus on anti-angiogenic treatments and checkpoint inhibition, that might provide a further step forward in the management of patients with gastric cancer.
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http://dx.doi.org/10.21873/anticanres.13638DOI Listing
September 2019

Benefit of second-line systemic chemotherapy for advanced biliary tract cancer: A propensity score analysis.

Sci Rep 2019 04 3;9(1):5548. Epub 2019 Apr 3.

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

Whether 2-line-chemotherapy (2LCTX) + best-supportive-care (BSC) benefits patients with advanced biliary tract cancer (aBTC) more than BSC alone is unclear. We therefore conducted a propensity-score-based comparative effectiveness analysis of overall survival (OS) outcomes in 80 patients with metastatic, recurrent, or inoperable aBTC, of whom 38 (48%) were treated with BSC + 2LCTX and 42 (52%) with BSC alone. After a median follow-up of 14.8 months and 49 deaths, the crude 6-, 12-, and 18-month Kaplan-Meier OS estimates were 77%, 53% and 23% in the BSC + 2LCTX group, and 29%, 21%, and 14% in patients in the BSC group (p = 0.0003; Hazard ratio (HR) = 0.36, 95%CI:0.20-0.64, p = 0.001). An inverse-probability-of-treatment-weighted (IPTW) analysis was conducted to rigorously account for the higher prevalence of favorable prognostic variables in the 2LCTX + BSC group. After IPTW-weighting, the favorable association between 2LCTX and OS prevailed (adjusted HR = 0.40, 95%CI: 0.17-0.95, p = 0.037). IPTW-weighted 6-, 12-, and 18-month OS estimates were 77%, 58% and 33% in the BSC + 2LCTX group, and 39%, 28% and 22% in the BSC group (p = 0.037). Moreover, the benefit of 2LCTX was consistent across several clinically-relevant subgroups. Within the limitations of an observational study, these findings support the concept that 2LCTX + BSC is associated with an OS benefit over BSC alone in aBTC.
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http://dx.doi.org/10.1038/s41598-019-42069-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6447553PMC
April 2019

Genetic Analysis Using a Gene Panel in 87 Caucasian Patients With Colorectal Cancer: Own Results and Review of Literature.

Anticancer Res 2019 Feb;39(2):847-852

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

Background/aim: Colorectal cancer (CRC) is the third most common cancer worldwide. The prognosis between left- and right-sided CRC differs, partly due to baseline differences as vascular supply. The purpose of the present study was to investigate whether there are genetic differences between left- and right-sided CRC.

Patients And Methods: Eighty-seven patients with CRC (mean age: 61 years) were retrospectively included in the study. Blood samples were used for genetic analysis, by applying the sequencing research panel Ion AmpliSeq Colon and Lung Cancer Research Panel V2. Statistical analyses included Chi-square tests, Kaplan-Meier survival curves, and univariate/multivariate Cox-regression analyses.

Results: By testing the sequence of 22 genes included in the panel, a significant difference was detected between left- and right-sided CRC regarding the expression of BRAF and DDR2 genes, with mutations occurring more often in the right-sided CRC. In the multivariate setting, left-sided CRC only turned out as a significant positive prognostic parameter regarding progression-free survival, irrespective of the type of chemotherapy or BRAF and NRAS mutations.

Conclusion: Tumour location was the only parameter proven to be an independent prognostic factor for CRC in the present study.
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http://dx.doi.org/10.21873/anticanres.13184DOI Listing
February 2019

MiR-371a-3p Serum Levels Are Increased in Recurrence of Testicular Germ Cell Tumor Patients.

Int J Mol Sci 2018 Oct 12;19(10). Epub 2018 Oct 12.

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

Metastatic testicular germ cell tumors (TGCTs) are a potentially curable disease by administration of risk-adapted cytotoxic chemotherapy. Nevertheless, a disease-relapse after curative chemotherapy needs more intensive salvage chemotherapy and significantly worsens the prognosis of TGCT patients. Circulating tumor markers (β-subunit of human chorionic gonadotropin (β-HCG), alpha-Fetoprotein (AFP), and Lactate Dehydrogenase (LDH)) are frequently used for monitoring disease recurrence in TGCT patients, though they lack diagnostic sensitivity and specificity. Increasing evidence suggests that serum levels of stem cell-associated microRNAs (miR-371a-3p and miR-302/367 cluster) are outperforming the traditional tumor markers in terms of sensitivity to detect newly diagnosed TGCT patients. The aim of this study was to investigate whether these miRNAs are also informative in detection of disease recurrence in TGCT patients after curative first line therapy. For this purpose, we measured the serum levels of miR-371a-3p and miR-367 in 52 samples of ten TGCT patients at different time points during disease relapse and during salvage chemotherapy. In our study, miR-371a-3p levels in serum samples with proven disease recurrence were 13.65 fold higher than levels from the same patients without evidence of disease ( = 0.014). In contrast, miR-367 levels were not different in these patient groups ( = 0.985). In conclusion, miR-371a-3p is a sensitive and potentially novel biomarker for detecting disease relapse in TGCT patients. This promising biomarker should be investigated in further large prospective trials.
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http://dx.doi.org/10.3390/ijms19103130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6213366PMC
October 2018
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