Publications by authors named "Otto C Burghuber"

38 Publications

Low SARS-CoV-2 seroprevalence in the Austrian capital after an early governmental lockdown.

Sci Rep 2021 05 12;11(1):10158. Epub 2021 May 12.

Ludwig Boltzmann Institute for Lung Health, Vienna, Austria.

We analyzed SARS-CoV-2 seroprevalence in a large, well-described representative Viennese cohort after an early governmental lockdown with respect to the occurrence of symptoms and household transmission. Participants of the LEAD Study, a population-based cohort study from Vienna, Austria, were invited along with their household members (April 20th to May20th 2020). Sera were analyzed using anti-SARS-CoV-2 immunoassay including a neutralization test as a confirmatory assay. A total of 12,419 individuals participated (5984 LEAD participants; 6435 household members), 163 (1.31%; 59 LEAD cohort members) of whom were SARS-CoV-2 antibody positive. The estimated number of COVID-19 cases projected from our findings by age and sex for Vienna was 21,504 (1.13%). Cumulative number of positively tested cases in Vienna until May 20th 2020 was 3020, hence 7.1 times (95% confidence interval 5.5-9.1) lower than projected. Relative risk (RR) of seropositivity by age was highest for children aged 6-9 years [RR compared to age group 20-49: 1.21 (CI 0.37-4.01)], lowest for ≥ 65 years [RR 0.47 (CI 0.21-1.03)]. Half of the positive individuals developed no or mild symptoms. In a multivariate analysis, taste and smell disturbances were most strongly related to SARS-CoV-2 positivity. Infection probability within households with one confirmed SARS-CoV-2-specific antibody-positive person was 31%. Although seroprevalence was very low (1.13%) for a central European capital city, due to an early governmental lockdown, SARS-CoV-2 infections were more prevalent than officially reported polymerase chain reaction-positive cases. Of note, seroprevalence was highest in young children. Half of SARS-CoV-2 antibody-positive subjects had no or only mild symptoms. Taste and smell disturbances were most prominent, possibly guiding clinicians in diagnosing SARS-CoV-2 infection.
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http://dx.doi.org/10.1038/s41598-021-89711-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115109PMC
May 2021

Lung Cancer in Austria.

J Thorac Oncol 2021 05;16(5):725-733

Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Vienna, Austria.

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http://dx.doi.org/10.1016/j.jtho.2020.10.158DOI Listing
May 2021

Detection of EGFR Activating and Resistance Mutations by Droplet Digital PCR in Sputum of EGFR-Mutated NSCLC Patients.

Clin Med Insights Oncol 2021 17;15:1179554921993072. Epub 2021 Feb 17.

Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.

Background: Proof of the T790M resistance mutation is mandatory if patients with -mutated non-small cell lung cancer (NSCLC) progress under first- or second-generation tyrosine kinase inhibitor therapy. In addition to rebiopsy, analysis of plasma circulating tumor DNA is used to detect T790M resistance mutation. We studied whether sputum is another feasible specimen for detection of mutations.

Methods: Twenty-eight patients with advanced -mutated NSCLC were included during stable and/or progressive disease. The initial activating mutations (exon 19 deletions or L858R mutations) at stable disease and at progressive disease (together with T790M) were assessed in simultaneously collected plasma and sputum samples and detected by droplet digital polymerase chain reaction (ddPCR).

Results: Activating mutations were detected in 47% of the plasma samples and 41% of sputum samples during stable disease, and in 57% of plasma samples and 64% of sputum samples during progressive disease. T790M was detected in 44% of the plasma samples and 66% of the sputum samples at progressive disease. In ddPCR T790M-negative results for both specimens (plasma and sputum), negativity was confirmed by rebiopsy in 5 samples. Concordance rate of plasma and sputum for T790M was 0.86, with a positive percent agreement of 1.0 and a negative percent agreement of 0.80.

Conclusions: We demonstrated that mutation analysis with ddPCR is feasible in sputum samples. Combination of plasma and sputum analyses for detection of T790M in NSCLC patients with progressive disease increases the diagnostic yield compared with molecular plasma analysis alone.
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http://dx.doi.org/10.1177/1179554921993072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894584PMC
February 2021

Results of the Austrian National Lung Cancer Audit.

Clin Med Insights Oncol 2020 10;14:1179554920950548. Epub 2020 Sep 10.

Second Department of Respiratory and Critical Care Medicine and Ludwig Boltzmann Institute for COPD and Respiratory Epidemiology, Otto Wagner Hospital, Vienna, Austria.

Objectives: The Austrian Lung Cancer Audit (ALCA) is a pilot study to evaluate clinical and organizational factors related to lung cancer care across Austria.

Materials And Methods: The ALCA is a prospective, observational, noninterventional cohort study conducted in 17 departments in Austria between September 2013 and March 2015. Participating departments were selected based on an annual case load of >50 patients with lung cancer.

Results: The ALCA included 745 patients, representing 50.5% of all newly diagnosed cancer cases during that time period. In 75.8% of patients, diagnosis was based on histology, and in 24.2% on cytology; 83.1% had non-small-cell lung cancer, 16.9% small-cell lung cancer; and only 4.6% had to be classified as not otherwise specified cancers. The median time elapsed between first presentation at hospital and diagnosis was 8 days (interquartile range [IQR]: 4-15; range: 0-132); between diagnosis and start of treatment it was 15 days for chemotherapy (IQR: 9-27; range: 0-83), 21 days (IQR: 10-35; range: 0-69) for radiotherapy, and 24 days (IQR: 11-36; range: 0-138) for surgery, respectively. In 150 patients undergoing surgical treatment, only 3 (2.0%; n = 147, 3 missings) were seen with postoperative restaging indicating unjustified surgery. One-year follow-up data were available for 723 patients, indicating excellent 49.8% survival; however, a wide range of survival between departments (range: 37.8-66.7) was seen.

Conclusions: The ALCA conducted in high case load departments indicated management of lung cancer in accordance with international guidelines, and overall excellent 1-year survival.
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http://dx.doi.org/10.1177/1179554920950548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7488615PMC
September 2020

Side-by-Side Comparison of Three Fully Automated SARS-CoV-2 Antibody Assays with a Focus on Specificity.

Clin Chem 2020 11;66(11):1405-1413

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

Background: In the context of the COVID-19 pandemic, numerous new serological test systems for the detection of anti-SARS-CoV-2 antibodies rapidly have become available. However, the clinical performance of many of these is still insufficiently described. Therefore, we compared 3 commercial CE-marked, SARS-CoV-2 antibody assays side by side.

Methods: We included a total of 1154 specimens from pre-COVID-19 times and 65 samples from COVID-19 patients (≥14 days after symptom onset) to evaluate the test performance of SARS-CoV-2 serological assays by Abbott, Roche, and DiaSorin.

Results: All 3 assays presented with high specificities: 99.2% (98.6-99.7) for Abbott, 99.7% (99.2-100.0) for Roche, and 98.3% (97.3-98.9) for DiaSorin. In contrast to the manufacturers' specifications, sensitivities only ranged from 83.1% to 89.2%. Although the 3 methods were in good agreement (Cohen's Kappa 0.71-0.87), McNemar tests revealed significant differences between results obtained from Roche and DiaSorin. However, at low seroprevalences, the minor differences in specificity resulted in profound discrepancies of positive predictive values at 1% seroprevalence: 52.3% (36.2-67.9), 77.6% (52.8-91.5), and 32.6% (23.6-43.1) for Abbott, Roche, and DiaSorin, respectively.

Conclusion: We found diagnostically relevant differences in specificities for the anti-SARS-CoV-2 antibody assays by Abbott, Roche, and DiaSorin that have a significant impact on the positive predictive values of these tests.
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http://dx.doi.org/10.1093/clinchem/hvaa198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454460PMC
November 2020

Quality of Life and Limitations in Daily Life of Stable COPD Outpatients in a Real-World Setting in Austria - Results from the CLARA Project.

Int J Chron Obstruct Pulmon Dis 2020 12;15:1655-1663. Epub 2020 Jul 12.

Department of Pulmonology, Kepler University Hospital, Linz, Austria.

Background: COPD patients suffer from respiratory symptoms and limitations in daily life. We aimed to characterize the impact of disease on overall health, daily life, and perceived well-being in COPD outpatients.

Methods: We conducted a national, cross-sectional study among pulmonologists and general practitioners (GPs). The St. George's Respiratory Questionnaire for COPD patients (SGRQ-C) was used. Inclusion criteria were a physician's diagnosis of COPD and age ≥40 years. Subjects with a history of lung surgery, lung cancer or COPD exacerbation within the last four weeks were excluded.

Results: Sixty-seven pulmonologists and 6 GPs enrolled 1175 COPD patients. Two hundred forty-eight of those did not fulfill GOLD criteria for COPD (FEV/FVC <0.7) and 77 were excluded due to missing data. Finally, 850 patients (62.8% men; mean age 66.2 ± 0.3 (SE) years; mean FEV%pred. 51.5 ± 0.6 (SE)) were analyzed. Last year, 55.4% reported at least one exacerbation, and 12.7% were hospitalized for COPD exacerbation. Mean SGRQ-C total score was 43.1 ± 0.83 (SE) and mean component scores for symptoms, activity and impacts were 55.6, 55.4 and 30.5, respectively. Half of the patients (50.3%) reported not being able to do any sports and 78.7% stated that their respiratory symptoms did not allow them doing anything they would like to do. In patients with less severe COPD (FEVpred ≥50% and non-frequent exacerbations), global health status was overrated, ie, estimated as better by the physician than by the patient, while it was underrated in more severe COPD.

Conclusion: In Austria, the burden of disease in COPD outpatients tends to be underestimated in patients with milder airway obstruction and less exacerbations and overestimated in patients with more severe airway obstruction and frequent exacerbations. Our finding suggests that validated assessment of global health status might decrease these differences of perception.
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http://dx.doi.org/10.2147/COPD.S252033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367938PMC
June 2021

Effects of roflumilast on arterial stiffness in COPD (ELASTIC): A randomized trial.

Respirology 2021 02 28;26(2):153-160. Epub 2020 Jul 28.

Department of Respiratory and Critical Care Medicine and Ludwig Boltzmann Institute for COPD and Respiratory Epidemiology, Otto-Wagner-Hospital and Sigmund Freud University, Medical School, Vienna, Austria.

Background And Objective: Cardiovascular risk is substantially increased in patients with COPD and can be quantified via arterial stiffness. The PDE-IV inhibitor roflumilast revealed a potential reduction of COPD-related cardiovascular risk. We aimed to investigate the effects of roflumilast on arterial stiffness by quantification of pulse wave velocity (PWV) in stable COPD.

Methods: In this randomized placebo-controlled trial, 80 COPD patients received roflumilast or placebo for 24 weeks. The primary outcome was the change in cf-PWV. Secondary outcomes comprised markers of vascular function (e.g. Aix and RHI), systemic inflammation (e.g. IL-6 and TNF-α) and clinical characteristics of COPD (e.g. CAT and 6MWT).

Results: A total of 33 and 34 patients completed the roflumilast and placebo arm, respectively (age, median (IQR): 64.5 (61-69.5) vs 64.5 (56-72) years; FEV , median (IQR): 34.5 (25.5-48.6) vs 35.3 (27-46.8) % predicted; 6MWT, median (IQR): 428 (340-558) vs 456 (364-570) m). Change from baseline PWV did not show a significant difference between roflumilast and placebo (+5.0 (95% CI: -2.0 to +13.0) vs 0.0 (95% CI: -7.0 to +7.0)%, P = 0.268). Roflumilast did not improve markers of vascular function or systemic inflammation. We observed a significant improvement in change from baseline 6MWT with roflumilast versus placebo (+53.0 (95% CI: +19.1 to +86.9) vs -0.92 (95% CI: -35.1 to +33.3) m, P = 0.026).

Conclusion: Our study revealed no beneficial effects of roflumilast on arterial stiffness. Further studies are needed to test a potential improvement of exercise capacity with roflumilast in COPD.
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http://dx.doi.org/10.1111/resp.13914DOI Listing
February 2021

Reference charts for body composition parameters by dual-energy X-ray absorptiometry in European children and adolescents aged 6 to 18 years-Results from the Austrian LEAD (Lung, hEart, sociAl, boDy) cohort.

Pediatr Obes 2021 01 2;16(1):e12695. Epub 2020 Jul 2.

Ludwig Boltzmann Institute for COPD and Respiratory Epidemiology, Vienna, Austria.

Background: DXA is a widely used technique to assess body composition. Reference values based on a large general population cohort of European children and adolescents were missing. The aim of this study was to provide age- and sex-specific reference percentiles of body composition parameters for European children and adolescents and to compare them to the American NHANES cohort. Additionally, exponents accounting best for height biases were analysed.

Methods: DXA scans of 1573 participants, aged 6 to 18 years, recruited from 2011 to 2019 by the Austrian LEAD study, a representative population-based cohort, have been used to create reference charts using the LMS model.

Results: Reference charts displaying percentile curves and the corresponding reference values are provided. Fat mass parameters were higher in females, while lean mass parameters were higher in males. Compared to the NHANES cohort medians of FMI and LMI were always lower. For FMI, BMI, LMI and ALMI the best fitting exponent were 2.5, 3, 3 and 3.5 respectively CONCLUSIONS: The present study provides reference charts for children and adolescents aged 6 to 18 years, for body composition parameters assessed by DXA. The charts enable comparison to a European general-population cohort and indicate that reference populations should be chosen with caution.
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http://dx.doi.org/10.1111/ijpo.12695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757249PMC
January 2021

Reference values of body composition parameters and visceral adipose tissue (VAT) by DXA in adults aged 18-81 years-results from the LEAD cohort.

Eur J Clin Nutr 2020 08 2;74(8):1181-1191. Epub 2020 Mar 2.

Ludwig Boltzmann Institute for COPD and Respiratory Epidemiology, Vienna, Austria.

Background: Increasing attention has been drawn on the assessment of body composition phenotypes, since the distribution of soft tissue influences cardio-metabolic risk. Dual-energy X-ray absorptiometry (DXA) is a validated technique to assess body composition. European reference values from population-based cohorts are rare.

Aims: To provide age- and sex-related reference values of body composition parameters and visceral adipose tissue (VAT) mass, and for lean mass index (LMI) with regard to fat mass index (FMI) quantities and BMI categories.

Methods: GE-Lunar Prodigy DXA scans of 10.894 participants, aged 18-81 years, recruited from 2011 to 2019 by the Austrian LEAD study, a population-based cohort study, have been used to construct reference curves using the LMS method. Parameters assessed are FMI, LMI, appendicular LMI, fat mass ratios android/gynoid and trunk/limbs, and VAT.

Results: All lean mass and fat mass parameters indicating central fat accumulation were higher in men, whereas other fat mass indices were higher in women. LMI differed between each FMI subgroup (low vs. normal, low vs. high, normal vs. high), and BMI category in all ages and LMI increased with FMI and BMI classes. VAT mass was higher in men compared with women and increased across all age groups within both sexes.

Conclusion: The present study provides age- and sex-related reference values for European adults aged 18-81 years for body composition parameters and VAT mass for Lunar Prodigy DXA. In addition, this study reports LMI reference values with regard to fat mass quantities, showing a positive association with increasing FMI percentiles and BMI categories.
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http://dx.doi.org/10.1038/s41430-020-0596-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402993PMC
August 2020

Blood eosinophil count in the general population: typical values and potential confounders.

Eur Respir J 2020 05 14;55(5). Epub 2020 May 14.

Second Dept of Respiratory and Critical Care Medicine and Ludwig Boltzmann Institute for COPD and Respiratory Epidemiology, Otto Wagner Hospital, Vienna, Austria.

There is growing interest in blood eosinophil counts in the management of chronic respiratory conditions such as asthma and chronic obstructive pulmonary disease (COPD). Despite this, typical blood eosinophil levels in the general population, and the impact of potential confounders on these levels have not been clearly defined.We measured blood eosinophil counts in a random sample of 11 042 subjects recruited from the general population in Austria. We then: 1) identified factors associated with high blood eosinophil counts (>75th percentile); and 2) excluded subjects with these factors to estimate median blood eosinophil counts in a "healthy" sub-population (n=3641).We found that: 1) in the entire cohort, age ≤18 years (OR 2.41), asthma (OR 2.05), current smoking (OR 1.72), positive skin prick test (OR 1.64), COPD (OR 1.56), metabolic syndrome (OR 1.41), male sex (OR 1.36) and obesity (OR 1.16) were significantly (p<0.05) associated with high blood eosinophil counts (binary multivariable logistic regression analysis), and had an additive effect; and 2) after excluding these factors, in those older than 18 years, blood eosinophil counts were higher in males than in females (median 120 (5%-95% CI: 30-330) 100 (30-310) cells·µL, respectively) and did not change with age.Median blood eosinophil counts in adults are considerably lower than those currently regarded as normal, do not change with age beyond puberty, but are significantly influenced by a variety of factors which have an additive effect. These observations will contribute to the interpretation of blood eosinophil levels in clinical practice.
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http://dx.doi.org/10.1183/13993003.01874-2019DOI Listing
May 2020

Marked differences in prediabetes- and diabetes-associated comorbidities between men and women-Epidemiological results from a general population-based cohort aged 6-80 years-The LEAD (Lung, hEart, sociAl, boDy) study.

Eur J Clin Invest 2020 Mar 12;50(3):e13207. Epub 2020 Feb 12.

Department of Respiratory and Critical Care Medicine and Ludwig Boltzmann Institute for COPD and Respiratory Epidemiology, Otto Wagner Hospital, Vienna, Austria.

Background: Based on biological and behavioural diversity sex and gender may affect comorbidities associated with prediabetes and diabetes. Besides evaluating the prevalence of prediabetes and diabetes (using fasting plasma glucose and HbA1 levels), the primary aim of the study is to investigate sex and gender differences in the prevalence of comorbidities in subjects with prediabetes and diabetes and to identify possible risk factors associated with prediabetes and diabetes.

Design: This observational, population-based cohort study included 11.014 subjects aged 6-80 years. Examinations included blood samples, ankle-brachial index, ECG, dual-energy X-ray absorptiometry scan and an interviewer-administered questionnaire.

Results: Across all ages, prevalence of prediabetes was 20.2% (male 23.6%; female 17.1%), and 5.4% for diabetes (male 7.3%; female 3.7%). The prevalence of prediabetes ranged from 4.4% (6-<10 years) up to 40.4% (70+ years) in men and from 4.8% up to 42.3% in women. Comorbidity profile was markedly different between male and female, particularly in those with prediabetes: women more often suffered from arrhythmia, noncoronary artery disease, osteoporosis, increased systemic inflammatory biomarkers and depression, while men with prediabetes more often showed angina pectoris, myocardial infarction and media sclerosis.

Conclusions: The unexpected 4.6% prevalence of prediabetes in children aged 6-10 underscores the need for population-based studies across all ages and the onset of prevention of diabetes at a young age. Marked differences have been found in comorbidities as men with prediabetes and diabetes more often suffer from cardiovascular disease, while women more often show arrhythmia, noncoronary artery disease, increased systemic inflammatory biomarkers and depression.
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http://dx.doi.org/10.1111/eci.13207DOI Listing
March 2020

Treatment of ALK-rearranged non-small-cell lung cancer with brigatinib as second or later lines: real-world observations from a single institution.

Anticancer Drugs 2019 08;30(7):e0787

Department of Respiratory and Critical Care Medicine, Ludwig Boltzmann Institute of COPD and Respiratory Epidemiology.

The second-generation ALK tyrosine kinase inhibitor brigatinib has recently been approved in the European Union for use after crizotinib treatment in patients with EML4-ALK-rearranged lung cancer. In the current study, brigatinib was investigated as second-line or later-line treatment in 35 patients who had developed resistance to crizotinib, ceritinib, or alectinib. Most patients (68.6%) received brigatinib as second or third line (range: second to 12th line). In the total cohort, complete and partial responses were obtained for 9.1 and 75.8%, respectively. Overall median progression-free survival was 9.9 months, whereas the largest treatment cohort (brigatinib after crizotinib failure) showed a median progression-free survival of 8.4 months. Fifty-four percent of patients with baseline brain metastases responded to brigatinib treatment. Brigatinib was highly effective after crizotinib and ceritinib failure. Six patients had received alectinib as monotherapy, second-line, or third line before brigatinib; of these, four experienced partial responses and two progressed responses. Brigatinib treatment was well tolerated.
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http://dx.doi.org/10.1097/CAD.0000000000000787DOI Listing
August 2019

EGFR Mutations in Cell-free Plasma DNA from Patients with Advanced Lung Adenocarcinoma: Improved Detection by Droplet Digital PCR.

Target Oncol 2019 04;14(2):197-203

Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, 1090, Vienna, Austria.

Background: Analysis of cell-free DNA from blood could provide an alternative method for identifying genomic changes in the tumors of patients with advanced lung adenocarcinoma.

Objective: We compared the performance of droplet digital PCR (ddPCR) and Cobas EGFR Mutation Test v2 (Cobas) for detecting EGFR mutations in cell-free plasma DNA.

Patients And Methods: Plasma samples from patients with advanced EGFR-mutated lung adenocarcinoma were analyzed for EGFR T790M, exon 19 deletions, and L858R mutations by both ddPCR and Cobas.

Results: T790M testing was performed in 354 plasma samples collected from 129 patients. The concordance rate between ddPCR and Cobas for T790M, sensitivity, and specificity were 86, 100, and 85%, respectively. Exon 19 deletions were analyzed in 196 plasma samples obtained from 71 of the 129 patients using both platforms. The concordance rate between ddPCR and Cobas for exon 19 deletions, sensitivity, and specificity were 90, 92, and 89%, respectively. L858R mutations were studied in 124 plasma samples obtained from 44 of the 129 patients using both assays. The concordance rate between ddPCR and Cobas for L858R, sensitivity, and specificity were 90, 91, and 89%, respectively. In patients who progressed under treatment with an EGFR TKI (n = 50), the T790M positivity rate was 66% using ddPCR, but only 24% using Cobas.

Conclusions: We observed a high concordance between ddPCR and Cobas in detecting EGFR mutations in plasma samples of patients with advanced EGFR-mutated lung adenocarcinoma, but ddPCR was more sensitive than Cobas.
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http://dx.doi.org/10.1007/s11523-019-00623-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6453866PMC
April 2019

Liquid-Biopsy-Based Identification of EGFR T790M Mutation-Mediated Resistance to Afatinib Treatment in Patients with Advanced EGFR Mutation-Positive NSCLC, and Subsequent Response to Osimertinib.

Target Oncol 2019 02;14(1):75-83

Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, 1090, Vienna, Austria.

Background: Acquired epidermal growth factor receptor (EGFR) T790M mutation is the primary resistance mechanism to first-generation EGFR tyrosine kinase inhibitors (TKIs) used in advanced, EGFR mutation-positive non-small-cell lung cancer (NSCLC). Available data, predominantly in Asian patients, suggest that this mutation is also the major cause of resistance to the irreversible ErbB family blocker, afatinib. For EGFR T790M-positive patients who progress on EGFR TKI therapy, osimertinib is an effective treatment option. However, data on osimertinib use after afatinib are, to date, scarce.

Objective: To identify the prevalence of EGFR T790M mutations in predominantly Caucasian patients with stage IV EGFR mutation-positive NSCLC who progressed on afatinib, and to investigate the subsequent response to osimertinib.

Patients And Methods: In this single-center, retrospective analysis, EGFR T790M mutation status after afatinib failure was assessed using liquid biopsy and tissue rebiopsy. EGFR T790M-positive patients subsequently received osimertinib.

Results: Sixty-seven patients received afatinib in the first-, second-, or third-line (80.6%, 14.9%, and 4.5%, respectively). After afatinib failure, the T790M mutation was identified in 49 patients (73.1%). Liquid biopsy and tissue rebiopsy were concordant in 79.4% of cases. All patients with T790M-positive tumors received osimertinib (73.5% after first-line afatinib); 37 (75.5%) of these had an objective response (complete response: 22.4%; partial response: 53.1%). Response rate was independent of T790M copy number.

Conclusion: EGFR T790M mutation is a major mechanism of acquired resistance to afatinib. Osimertinib confers high response rates after afatinib failure in EGFR T790M-positive patients and its use in sequence potentially allows extended chemotherapy-free treatment.
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http://dx.doi.org/10.1007/s11523-018-0612-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6403194PMC
February 2019

Cell-Free Plasma DNA-Guided Treatment With Osimertinib in Patients With Advanced EGFR-Mutated NSCLC.

J Thorac Oncol 2018 06 2;13(6):821-830. Epub 2018 Mar 2.

Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical Center of Vienna, Vienna, Austria. Electronic address:

Introduction: Osimertinib is standard treatment for patients with advanced EGFR T790M-mutated non-small-cell lung cancer who have been pre-treated with EGFR-tyrosine kinase inhibitors (TKIs). We studied whether cell-free plasma DNA for T790M detection can be used to select patients for osimertinib treatment in the clinical routine.

Methods: From April 2015 to November 2016, we included 119 patients with advanced EGFR-mutated non-small-cell lung cancer who had progressed under treatment with an EGFR-TKI. The T790M mutation status was assessed in cell-free plasma DNA by droplet digital polymerase chain reaction in all patients and by tissue analyses in selected patients.

Results: T790M mutations were detected in 85 (93%) patients by analyses of cell-free plasma DNA and in 6 (7%) plasma-negative patients by tumor re-biopsy. Eighty-nine of 91 T790M-positive patients received osimertinib. Median progression-free survival (PFS) was 10.1 months (95% confidence interval [CI]: 8.1-12.1). Median survival was not reached and the 1-year survival was 64%. The response rate was 70% in T790M-positive patients (n = 91) in the intention-to-treat population. PFS trended to be shorter in patients with high T790M copy number (≥10 copies/mL) compared to those with low T790M copy number (<10 copies/mL) (hazard ratio for PFS = 1.72, 95% CI: 0.92-3.2, p = 0.09). A comparable trend was observed for overall survival (hazard ratio for overall survival = 2.16, 95% CI: 0.89-5.25, p = 0.09). No difference in response rate was observed based on T790M copy numbers.

Conclusion: Plasma genotyping using digital polymerase chain reaction is clinically useful for the selection of patients who had progressed during first-line EGFR-TKI therapy for treatment with osimertinib.
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http://dx.doi.org/10.1016/j.jtho.2018.02.014DOI Listing
June 2018

Symptomatic pseudo-progression followed by significant treatment response in two lung cancer patients treated with immunotherapy.

Lung Cancer 2017 11 31;113:4-6. Epub 2017 Aug 31.

Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Währingergürtel 18-22, 1090 Vienna, Austria. Electronic address:

In the setting of pseudo-progression in a cancer patient who receives immunotherapeutic treatment, discontinuation of therapy is recommended if the patient is symptomatic. Here, we present two patients with advanced adenocarcinoma of the lung who developed massive tumor growth after initiation of treatment with the anti-PD-1 antibody pembrolizumab. Even though clinical deterioration occurred in the form of severe dyspnea and weight loss, pembrolizumab therapy was continued, as the speed of tumor growth suggested pseudo-progression and the tumors showed marked PD-L1 expression. This approach was successful, and both patients experienced impressive treatment responses within a few weeks.
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http://dx.doi.org/10.1016/j.lungcan.2017.08.020DOI Listing
November 2017

Complete remissions in afatinib-treated non-small-cell lung cancer patients with symptomatic brain metastases.

Anticancer Drugs 2016 10;27(9):914-5

Respiratory Oncology Unit, Department of Respiratory and Critical Care Medicine, Otto-Wagner-Spital, Vienna, Austria.

In patients with non-small-cell lung cancer, the presence of brain metastases requires specific treatment due to the unfavourable overall impact of these lesions. Treatment with the tyrosine kinase inhibitor afatinib was shown to induce complete and long-lasting remissions in the five patients described here. All of them had multiple brain lesions and presented with symptoms. Study evidence suggests beneficial effects of afatinib in this respect, underlining these clinical observations. Afatinib might be incorporated into current treatment algorithms, allowing for the omission of radiotherapy, provided that larger phase III trials confirm the potential of epidermal growth factor receptor tyrosine kinase inhibitors in this respect.
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http://dx.doi.org/10.1097/CAD.0000000000000410DOI Listing
October 2016

Soluble receptor of advanced glycation end-products and endothelial dysfunction in COPD.

Respir Med 2014 Jun 2;108(6):891-7. Epub 2014 Apr 2.

Department of Respiratory and Critical Care Medicine, Ludwig Boltzmann Institute for COPD, Otto Wagner Hospital, Sanatoriumstrasse 2, 1140 Vienna, Austria.

Background: Chronic obstructive pulmonary disease (COPD) is accompanied by an increased cardiovascular risk which is aggravated by the incidence of acute exacerbations (AE). Endothelial function, as well as the soluble receptor for advanced glycation end-products (sRAGE), both markers of cardiovascular risk, has been shown to be decreased in stable COPD.

Objectives: We aimed to investigate a possible link between sRAGE and endothelial function in AE of COPD. We hypothesize that circulating levels of sRAGE and endothelial function are impaired during AE and improve after clinical recovery, respectively.

Methods: We enrolled patients admitted to hospital due to an AE of COPD without overt cardiovascular comorbidities. Study related procedures comprised spirometry, measurement of plasma sRAGE levels and the quantification of endothelial function by means of the flow-mediated dilation technique (FMD). All measurements were scheduled during hospitalization and after confirmed clinical stability.

Results: We recruited 29 patients (27% female) with moderate to severe COPD. Median sRAGE concentration was 525 pg/mL (371-770, 1st-3rd quartile) and mean FMD 6.7 ± 3.6% at AE. There was a significant increase of sRAGE levels to 876 pg/mL (633-1371, 1st-3rd quartile, p < 0.001) and a simultaneous improvement in FMD (10.0 ± 3.4%, p < 0.001) after clinical recovery. There was a significant positive association between sRAGE and FMD (regression coefficient = 2.43; p = 0.01) in our study sample.

Conclusion: Our results indicate a substantial decrease in sRAGE levels and endothelial function during AE, with evidence of improvements after clinical recovery. sRAGE may contribute to cardiovascular risk in COPD.
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http://dx.doi.org/10.1016/j.rmed.2014.03.013DOI Listing
June 2014

Target lobe volume reduction and COPD outcome measures after endobronchial valve therapy.

Eur Respir J 2014 Feb 11;43(2):387-96. Epub 2013 Jul 11.

Ludwig-Boltzmann-Institute for COPD and Respiratory Epidemiology, Otto-Wagner-Hospital, Vienna, Austria.

Endobronchial valve (EBV) therapy may be associated with improvements in chronic obstructive pulmonary disease-related outcomes and may therefore be linked to improvements in the body mass index, airflow obstruction, dyspnoea, exercise capacity (BODE) index. Data from 416 patients with advanced emphysema and hyperinflation across Europe and USA, who were randomised to EBV (n=284) or conservative therapy (n=132) were analysed. Quantitative image analysis was used to compare the volume of the targeted lobe at baseline and at 6 months to determine target lobe volume reduction (TLVR). 44% of patients receiving EBV therapy (versus 24.7% of controls) had clinically significant improvements in the BODE index (p<0.001). BODE index was significantly reduced by mean ± sd 1.4 ± 1.8, 0.2 ± 1.3 and 0.1 ± 1.3 points in patients with TLVR >50%, 20%-50% and <20%, respectively (intergroup differences p<0.001), but increased by 0.3 ± 1.2 points in controls. Changes in BODE were predicted by baseline BODE and correlated significantly with lobar exclusion and lung volumes at 6 months. A greater proportion of patients in the treatment group than in the control group achieved a clinically meaningful improvement in BODE index; however, the likelihood of benefit was less than half in both groups. Patients in whom TLVR was obtained had greater improvements in clinical outcomes.
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http://dx.doi.org/10.1183/09031936.00133012DOI Listing
February 2014

Endoscopic one-way valve implantation in patients with prolonged air leak and the use of digital air leak monitoring.

Ann Thorac Surg 2013 Apr 21;95(4):1243-9. Epub 2013 Feb 21.

Department of Respiratory and Critical Care Medicine, Ludwig-Boltzmann-Institute for COPD and Respiratory Epidemiology, Otto Wagner Hospital, Vienna, Austria.

Background: Prolonged alveolar-pleural air leaks are associated with increased morbidity and mortality. Endoscopic valve therapy has been recently introduced as a potential less invasive treatment option. We aimed at quantifying the effects of valve therapy on air leak flow and clinical outcomes in patients with prolonged air leaks.

Methods: We report on a series of 16 patients with high comorbidity and evidence of continuous air leak flow in whom chest tubes remained in place for at least 7 days. After identification of the source of the air leak by use of the balloon occlusion technique, endobronchial one-way valves were implanted. Digital chest tube monitoring was used to assess air leak flow before, during, and after valve implantation until chest tube removal.

Results: The source of the air leak was endoscopically identified in 13 patients (81%). After valve implantation, air leak flow decreased significantly from 871±551 mL/min to 61±72 mL/min immediately after the intervention (p<0.001). The mean duration of chest tube drainage was 18±8 days before and 9±6 days after the intervention (p<0.01). Ten patients were considered responders, and 3 patients were nonresponders. Responders demonstrated consistent air leak flow levels below 100 mL/min until chest tube removal. Long-term follow-up was available for 9 patients. No adverse events related to the valve implants were reported at follow-up. Seven patients underwent valve removal without any further complications.

Conclusions: Endoscopic implantation of one-way valves leads to a significant reduction in air leakage flow and may thus be a valuable treatment option in patients with prolonged air leakage.
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http://dx.doi.org/10.1016/j.athoracsur.2012.12.036DOI Listing
April 2013

Active tuberculosis is characterized by an antigen specific and strictly localized expansion of effector T cells at the site of infection.

Eur J Immunol 2012 Nov 20;42(11):2844-50. Epub 2012 Sep 20.

Department of Internal Medicine I, Division of Infectious Diseases and Tropical Medicine, Medical University of Vienna, Vienna, Austria.

Mycobacterium tuberculosis (MTB)-specific cytokine responses in the peripheral blood and at the site of infection may differ significantly within the same individual, but the under-lying T-cell subset changes are largely unknown. Here, we measured effector and memory T-cell markers on CD4⁺ T cells (CD45RO, cysteine chemokine receptor (CCR)7, and CD27) in peripheral blood and at the site of active tuberculosis (TB). Additionally, T cells were stimulated overnight with purified protein derivative (PPD) and early secretory antigenic target (ESAT)-6 to determine which T-cell subset produces MTB-specific interferon (IFN)-γ. A striking decrease in CCR7 and CD27 expression on T cells was noted at the site of active TB. Likewise, IFN-γ expressing, ESAT-6 specific CD4⁺CD45RO⁺CD27⁻ T cells were dramatically increased at the site of infection but were not detectable in peripheral blood. An antigen-specific expansion of differentiated T cells at the site of active TB infection was poorly reflected in peripheral blood. Insight in these changes in MTB-specific effector T cells in different compartments of the body could lead to new approaches for immune-based diagnosis and interventions.
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http://dx.doi.org/10.1002/eji.201242678DOI Listing
November 2012

Peripheral T cell cytokine responses for diagnosis of active tuberculosis.

PLoS One 2012 16;7(4):e35290. Epub 2012 Apr 16.

Department of Internal Medicine I, Division of Infectious Diseases and Tropical Medicine, Medical University of Vienna, Vienna, Austria.

Background: A test for diagnosis of active Tuberculosis (TB) from peripheral blood could tremendously improve clinical management of patients.

Methods: Of 178 prospectively enrolled patients with possible TB, 60 patients were diagnosed with pulmonary and 27 patients with extrapulmonary TB. The frequencies of Mycobacterium tuberculosis (MTB) specific CD4(+) T cells and CD8(+) T cells producing cytokines were assessed using overnight stimulation with purified protein derivate (PPD) or early secretory antigenic target (ESAT)-6, respectively.

Results: Among patients with active TB, an increased type 1 cytokine profile consisting of mainly CD4(+) T cell derived interferon (IFN)-γ was detectable. Despite contributing to the cytokine profile as a whole, the independent diagnostic performance of one cytokine producing T cells as well as polyfunctional T cells was poor. IFN-γ/Interleukin(IL)-2 cytokine ratios discriminated best between active TB and other diseases.

Conclusion: T cells producing one cytokine and polyfunctional T cells have a limited role in diagnosis of active TB. The significant shift from a "memory type" to an "effector type" cytokine profile may be useful for further development of a rapid immune-diagnostic tool for active TB.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0035290PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3327656PMC
August 2012

Clinical highlights from the 2011 ERS Congress in Amsterdam.

Eur Respir J 2012 Jun 9;39(6):1501-10. Epub 2012 Mar 9.

Program Development Centre of CIRO+, Centre of Expertise for Chronic Organ Failure, Horn, France.

This article reports on selected papers pertinent to the most important clinical problems in the field of respiratory medicine. Expert authors from the Clinical Assembly of the European Respiratory Society (ERS) have selected updated reports related to presentations given at the 2011 ERS Annual Congress, which was held in Amsterdam (the Netherlands) and attended by more than 20,000 participants. The hot topics and selected abstracts from the scientific groups of the Clinical Assembly are discussed here in the context of recent literature.
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http://dx.doi.org/10.1183/09031936.00217111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3365251PMC
June 2012

The European Respiratory Society spirometry tent: a unique form of screening for airway obstruction.

Eur Respir J 2012 Jun 20;39(6):1458-67. Epub 2012 Jan 20.

Pulmonary Environmental Epidemiology Unit, CNR Institute of Clinical Physiology, Pisa, Italy.

In order to raise public awareness of the importance of early detection of airway obstruction and to enable many people who had not been tested previously to have their lung function measured, the European Lung Foundation and the European Respiratory Society (ERS) organised a spirometry testing tent during the annual ERS Congresses in 2004-2009. Spirometry was performed during the ERS Congresses in volunteers; all participants answered a simple, brief questionnaire on their descriptive characteristics, smoking and asthma. Portable spirometers were freely provided by the manufacturer. Nurses and doctors from pulmonary departments of local hospitals/universities gave their service for free. Lower limit of normal (LLN) and Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria for diagnosing and grading airway obstruction were used. Of 12,448 participants in six congress cities, 10,395 (83.5%) performed acceptable spirometry (mean age 51.0 ± 18.4 yrs; 25.5% smokers; 5.5% asthmatic). Airway obstruction was present in 12.4% of investigated subjects according to LLN criteria and 20.3% according to GOLD criteria. Through multinomial logistic regression analysis, age, smoking habits and asthma were significant risk factors for airway obstruction. Relative risk ratio and 95% confidence interval for LLN stage I, for example, was 2.9 (2.0-4.1) for the youngest age (≤ 19 yrs), 1.9 (1.2-3.0) for the oldest age (≥ 80 yrs), 2.4 (2.0-2.9) for current smokers and 2.8 (2.2-3.6) for reported asthma diagnosis. In addition to being a useful advocacy tool, the spirometry tent represents an unusual occasion for early detection of airway obstruction in large numbers of city residents with an important public health perspective.
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http://dx.doi.org/10.1183/09031936.00111910DOI Listing
June 2012

Nordic walking improves daily physical activities in COPD: a randomised controlled trial.

Respir Res 2010 Aug 22;11:112. Epub 2010 Aug 22.

Department of Respiratory and Critical Care Medicine and Ludwig Boltzmann Institute for COPD and Respiratory Epidemiology, Otto Wagner Hospital, Sanatoriumstreet 2, 1140 Vienna, Austria.

Background: In patients with COPD progressive dyspnoea leads to a sedentary lifestyle. To date, no studies exist investigating the effects of Nordic Walking in patients with COPD. Therefore, the aim was to determine the feasibility of Nordic Walking in COPD patients at different disease stages. Furthermore we aimed to determine the short- and long-term effects of Nordic Walking on COPD patients' daily physical activity pattern as well as on patients exercise capacity.

Methods: Sixty COPD patients were randomised to either Nordic Walking or to a control group. Patients of the Nordic Walking group (n = 30; age: 62 +/- 9 years; FEV1: 48 +/- 19% predicted) underwent a three-month outdoor Nordic Walking exercise program consisting of one hour walking at 75% of their initial maximum heart rate three times per week, whereas controls had no exercise intervention. Primary endpoint: daily physical activities (measured by a validated tri-axial accelerometer); secondary endpoint: functional exercise capacity (measured by the six-minute walking distance; 6MWD). Assessment time points in both groups: baseline, after three, six and nine months.

Results: After three month training period, in the Nordic Walking group time spent walking and standing as well as intensity of walking increased (Delta walking time: +14.9 +/- 1.9 min/day; Delta standing time: +129 +/- 26 min/day; Delta movement intensity: +0.40 +/- 0.14 m/s2) while time spent sitting decreased (Delta sitting time: -128 +/- 15 min/day) compared to baseline (all: p < 0.01) as well as compared to controls (all: p < 0.01). Furthermore, 6MWD significantly increased compared to baseline (Delta 6MWD: +79 +/- 28 meters) as well as compared to controls (both: p < 0.01). These significant improvements were sustained six and nine months after baseline. In contrast, controls showed unchanged daily physical activities and 6MWD compared to baseline for all time points.

Conclusions: Nordic Walking is a feasible, simple and effective physical training modality in COPD. In addition, Nordic Walking has proven to positively impact the daily physical activity pattern of COPD patients under short- and long-term observation.
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http://dx.doi.org/10.1186/1465-9921-11-112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2933683PMC
August 2010

[The effect of one year outpatient pulmonary rehabilitation on patients with COPD].

Wien Klin Wochenschr 2009 ;121(5-6):189-95

Department of Respiratory and Critical Care Medicine, Ludwig Boltzmann Institute for Chronic Obstructive Pulmonary Disease, Otto Wagner Hospital, Wien, Austria.

Background: The aim of our study was to determine the effect of one year of pulmonary rehabilitation (PR) on functional parameters and exacerbation rates in patients with chronic obstructive pulmonary disease (COPD).

Methods: A total of 100 patients were enrolled in a multidisciplinary PR program. PR included endurance, resistance and respiratory muscle training. We performed spiroergometry, a modified Bruce Test and measurements of upper and lower limb contractility as well as inspiratory muscle strength before, six and 12 months after beginning rehabilitation. Additionally, we assessed the quality of life and the number of exacerbations and exacerbation days one year before and after starting rehabilitation.

Results: 100 patients (42 female/58 male) with COPD (COPD IV-N=36, COPD III-N=42, COPD II-N=22), a mean age of 60.5+/-9.6 years, BMI 25.8+/-6.0 attended a rehabilitation training program over a time period of one year. Spiroergometry (VO2max from 1.1 to 1.3 l/min, P<0.05), modified Bruce Test (from 13+/-7 Min to 18+/-9 Min; P<0.001), upper limb (from 39.9+/-3 to 52.9+/-8 kg; P<0.001) and lower limb strength increased significantly (from 85.3+/-45 to 131.5+/-57 kg; P<0.001). The maximal inspiratory pressure rose from 81.1 mbar to 108.8 mbar (p<0.001). There was no improvement in FEV1 or FEV1/FVC but Saint Georges Respiratory Questionnaire (total score) improved from 37.2+/-3.6 to 26.5+/-2.8; P<0.001. The same was true for exacerbation rates (they dropped from 2.8 to 0.8; P=0.006) and the number of hospitalization days (from 27.3 to 3.3, P<0.001).

Conclusions: One year of outpatient pulmonary rehabilitation is an effective intervention leading to a significant improvement in exercise tolerance and quality of life in patients with COPD also reducing COPD exacerbation rates and hospitalizations.
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http://dx.doi.org/10.1007/s00508-008-1066-6DOI Listing
June 2009

Comparison of daily physical activity between COPD patients from Central Europe and South America.

Respir Med 2009 Mar 9;103(3):421-6. Epub 2008 Nov 9.

Departamento de Fisioterapia, Universidade Estadual de Londrina, Brazil.

Background: In healthy elderly and adults, lower physical activity level in daily life has been associated with lower socio-economic level and non-Caucasian race. The objective of this study was to determine if this is also applicable in chronic obstructive pulmonary disease (COPD) by comparing physical activity levels in daily life in stable patients from two countries (Austria and Brazil) with different socio-economic and ethnic characteristics.

Methods: Physical activity in daily life was objectively assessed in 40 Austrian and 40 Brazilian COPD patients. Groups were matched for age, gender, body mass index, disease severity, smoking history, presence of concomitant heart disease, lung function, dyspnea and functional exercise capacity. In addition, climatic conditions were similar during the period of data collection in the two groups.

Results: In comparison to Brazilian patients, Austrian patients had a significantly lower walking time (p=0.04), higher sitting time (p=0.02) and lower movement intensity (p=0.0001). The proportion of patients who did not reach an average of 30min of walking per day was 48% in the Austrian group and 23% in the Brazilian group.

Conclusions: Austrian patients with COPD showed a significantly lower daily physical activity level in comparison to matched Brazilian patients. Socio-economic and ethnic factors appear to influence stable COPD patients differently than described in previous studies including healthy subjects.
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http://dx.doi.org/10.1016/j.rmed.2008.09.019DOI Listing
March 2009
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