Publications by authors named "Dominik Wolf"

230 Publications

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

Cancer Discov 2021 Oct 11. Epub 2021 Oct 11.

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

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

Management of Common Infections in German Primary Care: A Cross-Sectional Survey of Knowledge and Confidence among General Practitioners and Outpatient Pediatricians.

Antibiotics (Basel) 2021 Sep 20;10(9). Epub 2021 Sep 20.

Department of General Practice, University Hospital Würzburg, 97080 Würzburg, Germany.

Outpatient antibiotic use is closely related to antimicrobial resistance and in Germany, almost 70% of antibiotic prescriptions in human health are issued by primary care physicians (PCPs). The aim of this study was to explore PCPs, namely General Practitioners' (GPs) and outpatient pediatricians' (PDs) knowledge of guideline recommendations on rational antimicrobial treatment, the determinants of confidence in treatment decisions and the perceived need for training in this topic in a large sample of PCPs from southern Germany. Out of 3753 reachable PCPs, 1311 completed the survey (overall response rate = 34.9%). Knowledge of guideline recommendations and perceived confidence in making treatment decisions were high in both GPs and PDs. The two highest rated influencing factors on prescribing decisions were reported to be guideline recommendations and own clinical experiences, hence patients' demands and expectations were judged as not influencing treatment decisions. The majority of physicians declared to have attended at least one specific training course on antibiotic use, yet almost all the participating PCPs declared to need more training on this topic. More studies are needed to explore how consultation-related and context-specific factors could influence antibiotic prescriptions in general and pediatric primary care in Germany beyond knowledge. Moreover, efforts should be undertaken to explore the training needs of PCPs in Germany, as this would serve the development of evidence-based educational interventions targeted to the improvement of antibiotic prescribing decisions rather than being focused solely on knowledge of guidelines.
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http://dx.doi.org/10.3390/antibiotics10091131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8466449PMC
September 2021

NK Cells in Myeloproliferative Neoplasms (MPN).

Cancers (Basel) 2021 Aug 31;13(17). Epub 2021 Aug 31.

Internal Medicine V, Department of Haematology and Oncology, Medical University Innsbruck, Anichstr. 35, 6020 Innsbruck, Austria.

Myeloproliferative neoplasms (MPNs) comprise a heterogenous group of hematologic neoplasms which are divided into Philadelphia positive (Ph+), and Philadelphia negative (Ph-) or classical MPNs. A variety of immunological factors including inflammatory, as well as immunomodulatory processes, closely interact with the disease phenotypes in MPNs. NK cells are important innate immune effectors and substantially contribute to tumor control. Changes to the absolute and proportionate numbers of NK cell, as well as phenotypical and functional alterations are seen in MPNs. In addition to the disease itself, a variety of therapeutic options in MPNs may modify NK cell characteristics. Reports of suppressive effects of MPN treatment strategies on NK cell activity have led to intensive investigations into the respective compounds, to elucidate the possible negative effects of MPN therapy on control of the leukemic clones. We hereby review the available literature on NK cells in Ph+ and Ph- MPNs and summarize today's knowledge on disease-related alterations in this cell compartment with particular focus on known therapy-associated changes. Furthermore, we critically evaluate conflicting data with possible implications for future projects. We also aim to highlight the relevance of full NK cell functionality for disease control in MPNs and the importance of considering specific changes related to therapy in order to avoid suppressive effects on immune surveillance.
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http://dx.doi.org/10.3390/cancers13174400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8431564PMC
August 2021

Increased levels of NETosis in myeloproliferative neoplasms are not linked to thrombotic events.

Blood Adv 2021 Sep;5(18):3515-3527

Internal Medicine V, Hematology and Oncology, Medical University Innsbruck, Innsbruck, Austria; and.

Morbidity and mortality of Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) are mainly determined by thromboembolic complications. Thrombus formation is facilitated by a neutrophil-specific form of cell death linked to neutrophil extracellular trap (NET) formation (NETosis). Preclinical and clinical data suggested a potential link between NETosis and thrombosis in MPNs. In this study, we aimed to define the impact of NETosis on clinical end points in a large MPN cohort. NETosis was induced in vitro by ionomycin and quantified by enzyme-linked immunosorbent assay-based nucleosome release assays as well as fluorescent staining of free DNA in samples from 103 MPN patients and 28 healthy donors. NETosis rate was correlated with a broad set of clinical data, such as MPN subtype, mutational status, laboratory variables, history of thrombotic events, and treatment types. Triggered NETosis levels were clearly higher in MPN patients than in healthy donors. Positivity for JAK2 V617F or exon 12 as well as CALR mutations correlate with increased NET formation. However, neither JAK2 allelic burden nor history of thromboembolic complication nor the presence of other risk factors for thrombosis (eg, leukocytosis) were associated with the rate of NETosis. In addition, none of the analyzed laboratory parameters nor the type of treatment significantly impacted the rate of NETosis formation. The biology of MPNs has an impact on NET formation because genetic driver mutations favor induction of NETosis, but this does not seems to translate into important clinical end points such as thromboembolic complications. Therefore, NETosis may play a role in facilitating thrombosis, but it is not a sole causative determinant in MPN-associated thrombophilia.
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http://dx.doi.org/10.1182/bloodadvances.2020004061DOI Listing
September 2021

Ceftolozane/tazobactam versus meropenem in patients with ventilated hospital-acquired bacterial pneumonia: subset analysis of the ASPECT-NP randomized, controlled phase 3 trial.

Crit Care 2021 08 11;25(1):290. Epub 2021 Aug 11.

MRL, Merck & Co., Inc., Kenilworth, NJ, USA.

Background: Ceftolozane/tazobactam is approved for treatment of hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP) at double the dose approved for other infection sites. Among nosocomial pneumonia subtypes, ventilated HABP (vHABP) is associated with the lowest survival. In the ASPECT-NP randomized, controlled trial, participants with vHABP treated with ceftolozane/tazobactam had lower 28-day all-cause mortality (ACM) than those receiving meropenem. We conducted a series of post hoc analyses to explore the clinical significance of this finding.

Methods: ASPECT-NP was a multinational, phase 3, noninferiority trial comparing ceftolozane/tazobactam with meropenem for treating vHABP and VABP; study design, efficacy, and safety results have been reported previously. The primary endpoint was 28-day ACM. The key secondary endpoint was clinical response at test-of-cure. Participants with vHABP were a prospectively defined subgroup, but subgroup analyses were not powered for noninferiority testing. We compared baseline and treatment factors, efficacy, and safety between ceftolozane/tazobactam and meropenem in participants with vHABP. We also conducted a retrospective multivariable logistic regression analysis in this subgroup to determine the impact of treatment arm on mortality when adjusted for significant prognostic factors.

Results: Overall, 99 participants in the ceftolozane/tazobactam and 108 in the meropenem arm had vHABP. 28-day ACM was 24.2% and 37.0%, respectively, in the intention-to-treat population (95% confidence interval [CI] for difference: 0.2, 24.8) and 18.2% and 36.6%, respectively, in the microbiologic intention-to-treat population (95% CI 2.5, 32.5). Clinical cure rates in the intention-to-treat population were 50.5% and 44.4%, respectively (95% CI - 7.4, 19.3). Baseline clinical, baseline microbiologic, and treatment factors were comparable between treatment arms. Multivariable regression identified concomitant vasopressor use and baseline bacteremia as significantly impacting ACM in ASPECT-NP; adjusting for these two factors, the odds of dying by day 28 were 2.3-fold greater when participants received meropenem instead of ceftolozane/tazobactam.

Conclusions: There were no underlying differences between treatment arms expected to have biased the observed survival advantage with ceftolozane/tazobactam in the vHABP subgroup. After adjusting for clinically relevant factors found to impact ACM significantly in this trial, the mortality risk in participants with vHABP was over twice as high when treated with meropenem compared with ceftolozane/tazobactam.

Trial Registration: clinicaltrials.gov, NCT02070757. Registered 25 February, 2014, clinicaltrials.gov/ct2/show/NCT02070757.
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http://dx.doi.org/10.1186/s13054-021-03694-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8356211PMC
August 2021

The Biology of Classic Hairy Cell Leukemia.

Int J Mol Sci 2021 Jul 21;22(15). Epub 2021 Jul 21.

Department of Internal Medicine V, Hematology and Oncology, Medical University of Innsbruck, 6020 Innsbruck, Austria.

Classic hairy cell leukemia (HCL) is a rare mature B-cell malignancy associated with pancytopenia and infectious complications due to progressive infiltration of the bone marrow and spleen. Despite tremendous therapeutic advances achieved with the implementation of purine analogues such as cladribine into clinical practice, the culprit biologic alterations driving this fascinating hematologic disease have long stayed concealed. Nearly 10 years ago, BRAF V600E was finally identified as a key activating mutation detectable in almost all HCL patients and throughout the entire course of the disease. However, additional oncogenic biologic features seem mandatory to enable HCL transformation, an open issue still under active investigation. This review summarizes the current understanding of key pathogenic mechanisms implicated in HCL and discusses major hurdles to overcome in the context of other BRAF-mutated malignancies.
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http://dx.doi.org/10.3390/ijms22157780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8346068PMC
July 2021

ROCKing Chronic Graft-Versus-Host Disease.

J Clin Oncol 2021 Oct 4;39(29):3308. Epub 2021 Aug 4.

Annkristin Heine, MD, and Tobias A. W. Holderried, MD, Department of Oncology, Hematology, Immuneoncology and Rheumatology, University Hospital Bonn, Bonn, Germany and Dominik Wolf, MD, Department of Oncology, Hematology, Immuneoncology and Rheumatology, University Hospital Bonn, Bonn, Germany, Internal Medicine V, Hematology and Oncology, Medical University Innsbruck, Innsbruck, Austria, Laboratory of Tumorimmunology, Tyrolean Cancer Research Institute, Medical University Innsbruck, Innsbruck, Austria.

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http://dx.doi.org/10.1200/JCO.21.01081DOI Listing
October 2021

Deregulated glutamate to pro-collagen conversion is associated with adverse outcome in lung cancer and may be targeted by renin-angiotensin-aldosterone system (RAS) inhibition.

Lung Cancer 2021 09 16;159:84-95. Epub 2021 Jul 16.

Department of Internal Medicine V (Haematology & Oncology), Medical University of Innsbruck, Innsbruck, Austria. Electronic address:

Background: The tumor-microenvironment (TME) represents an attractive therapeutic target in NSCLC and plays an important role for efficacy of cancer therapeutics. We hypothesized that upregulation of collagen synthesis might be associated with adverse outcome in NSCLC. Literature evidence suggests that renin-angiotensin system inhibitors (RASi) decrease collagen deposition. Therefore, we aimed to explore the prognostic role of RASi intake and their influence on the TME in NSCLC.

Methods: Four publicly available datasets were used to evaluate the impact of key enzymes involved in collagen biosynthesis. To investigate the influence of RASi intake on the TME and prognosis we evaluated a cohort of metastatic NSCLC patients and performed histopathological characterization of the TME. A three-dimensional microtissue in vitro model was developed to define the impact of RASi on collagen synthesis.

Results: Expression of three genes of the collagen synthesis pathway, ALDH18A1, PLOD2 and P4HA1, was upregulated in NSCLC compared to normal lung tissue and linked to shortened overall survival in all investigated cohorts. Together, these genes formed a 'Collagen Signature' which represents an independent unfavourable prognostic factor in two NSCLC cohorts and was linked to alterations of the extracellular matrix deposition and cell cycle pathways. In the cohort of metastatic NSCLC, RASi intake was linked to improved overall response rate and survival. Exploratory in vitro experiments revealed that RASi led to a dose dependent reduction of collagen deposition and degradation of three-dimensional lung cancer cell spheroids.

Conclusion: We demonstrate that collagen synthesis is a key upregulated process in the NSCLC TME and its transcriptional readout, the three gene Collagen Signature is independently associated with poor outcome. Pharmacological targeting of this pathways e.g. by RASi bears potential of improving outcome in NSCLC.
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http://dx.doi.org/10.1016/j.lungcan.2021.06.020DOI Listing
September 2021

Comparison Between 5-Azacytidine Treatment and Allogeneic Stem-Cell Transplantation in Elderly Patients With Advanced MDS According to Donor Availability (VidazaAllo Study).

J Clin Oncol 2021 Oct 20;39(30):3318-3327. Epub 2021 Jul 20.

Medical Clinic and Policlinic 1, University Hospital "Carl Gustav Carus" Dresden, Dresden, Germany.

Purpose: In contrast to 5-azacytidine (5-aza), allogeneic stem-cell transplantation (HSCT) represents a curative treatment strategy for patients with myelodysplastic syndromes (MDS), but therapy-related mortality (TRM) limits its broader use in elderly patients with MDS. The present prospective multicenter study compared HSCT following 5-aza pretreatment with continuous 5-aza treatment in patients with higher-risk MDS age 55-70 years.

Methods: One hundred ninety patients with a median age of 63 years were enrolled. Patients received 4-6 cycles of 5-aza followed by HLA-compatible HSCT after reduced-intensity conditioning or by continuous 5-aza if no donor was identified.

Results: Twenty-eight patients did not fulfill inclusion criteria (n = 20), died (n = 2) withdrew informed consent (n = 5), or were excluded for an unknown reason (n = 1). 5-aza induction started in 162 patients, but only 108 (67%) were eligible for subsequent allocation to HSCT (n = 81) or continuation of 5-aza (n = 27) because of disease progression (n = 26), death (n = 12), or other reasons (n = 16). Seven percent died during 5-aza before treatment allocation. The cumulative incidence of TRM after HSCT at 1 year was 19%. The event-free survival and overall survival after 5-aza pretreatment and treatment allocation at 3 years were 34% (95% CI, 22 to 47) and 50% (95% CI, 39 to 61) after allograft and 0% and 32% (95% CI, 14 to 52) after continuous 5-aza treatment ( < .0001 and = .12), respectively. Fourteen patients progressing after continuous 5-aza received a salvage allograft from an alternative donor, and 43% were alive at last follow-up.

Conclusion: In older patients with MDS, reduced-intensity conditioning HSCT resulted in a significantly improved event-free survival in comparison with continuous 5-aza therapy. Bridging with 5-aza to HSCT before is associated with a considerable rate of dropouts because of progression, mortality, and adverse events.
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http://dx.doi.org/10.1200/JCO.20.02724DOI Listing
October 2021

Tumor rejection in mice depends on IL-9 and Th9 cells.

J Immunother Cancer 2021 07;9(7)

Oncology, Hematology, Immunoncology and Rheumatology, University Hospital Bonn, Bonn, Germany

Background: Casitas B lymphoma-b (Cbl-b) is a central negative regulator of cytotoxic T and natural killer (NK) cells and functions as an intracellular checkpoint in cancer. In particular, Th9 cells support mast cell activation, promote dendritic cell recruitment, enhance the cytolytic function of cytotoxic T lymphocytes and NK cells, and directly kill tumor cells, thereby contributing to tumor immunity. However, the role of Cbl-b in the differentiation and antitumor function of Th9 cells is not sufficiently resolved.

Methods: Using mice, we investigated the effect of knocking out on the differentiation process and function of different T helper cell subsets, focusing on regulatory T cell (Treg) and Th9 cells. We applied single-cell RNA (scRNA) sequencing of differentiated Th9 cells to understand how Cbl-b shapes the transcriptome and regulates the differentiation and function of Th9 cells. We transferred tumor-model antigen-specific Th9 cells into melanoma-bearing mice and assessed tumor control . In addition, we blocked interleukin (IL)-9 in melanoma cell-exposed mice to investigate the role of IL-9 in tumor immunity.

Results: Here, we provide experimental evidence that Cbl-b acts as a rheostat favoring Tregs at the expense of Th9 cell differentiation. Th9 cells exert superior antitumor activity leading to improved melanoma control . Accordingly, blocking IL-9 in melanoma cell-exposed mice reversed their tumor rejection phenotype. Furthermore, scRNA sequencing of in vitro differentiated Th9 cells from naïve T cells isolated from wildtype and animals revealed a transcriptomic basis for increased Th9 cell differentiation.

Conclusion: We established IL-9 and Th9 cells as key antitumor executers in animals. This knowledge may be helpful for the future improvement of adoptive T cell therapies in cancer.
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http://dx.doi.org/10.1136/jitc-2021-002889DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8287598PMC
July 2021

Pacritinib protects dendritic cells more efficiently than ruxolitinib.

Exp Hematol 2021 Aug 25;100:37-40. Epub 2021 Jun 25.

Department of Oncology, Hematology, Rheumatology and Immune-Oncology, University Hospital Bonn, Bonn, Germany; Department V (Hematology and Oncology), University Hospital Innsbruck, Innsbruck, Austria.

Targeting Janus kinase (JAK) has revolutionized the treatment of myeloproliferative neoplasms. The JAK inhibitor ruxolitinib has improved the outcome and quality of life of patients dramatically at the cost of increased risk of infections. As previously reported, ruxolitinib severely impairs the differentiation of peripheral blood mononuclear cells to monocyte-derived dendritic cells and inhibits the function of dendritic cells in vitro and in vivo, which expanded its use as an immunomodulatory compound. Pacritinib is a novel JAK inhibitor that will soon be approved for the treatment of myeloproliferative neoplasms, and early results are promising. We investigated the impact of the novel JAK inhibitor pacritinib on the function of monocyte-derived dendritic cells and compared it with that of ruxolitinib. In contrast to ruxolitinib, pacritinib exhibits only mild suppressive effects on dendritic cells. The upregulation of activation markers and CCR7 after TLR4 ligation is not or is only marginally affected by pacritinib. Pacritinib, at concentrations reflecting patients' plasma levels, reduces interleukin (IL)-12 secretion, whereas IL-6 and tumor necrosis factor α levels are unchanged at this concentration. In conclusion, the immunosuppressive effect of pacritinib on dendritic cells is significantly less pronounced than the effect of ruxolitinib. Therefore, our data may help to identify those patients with myelofibrosis who may benefit from pacritinib treatment.
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http://dx.doi.org/10.1016/j.exphem.2021.06.004DOI Listing
August 2021

Discontinuation versus continuation of renin-angiotensin-system inhibitors in COVID-19 (ACEI-COVID): a prospective, parallel group, randomised, controlled, open-label trial.

Lancet Respir Med 2021 08 11;9(8):863-872. Epub 2021 Jun 11.

Department of Internal Medicine I (Cardiology), University Hospital Aachen, Aachen, Germany.

Background: SARS-CoV-2 entry in human cells depends on angiotensin-converting enzyme 2, which can be upregulated by inhibitors of the renin-angiotensin system (RAS). We aimed to test our hypothesis that discontinuation of chronic treatment with ACE-inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) mitigates the course o\f recent-onset COVID-19.

Methods: ACEI-COVID was a parallel group, randomised, controlled, open-label trial done at 35 centres in Austria and Germany. Patients aged 18 years and older were enrolled if they presented with recent symptomatic SARS-CoV-2 infection and were chronically treated with ACEIs or ARBs. Patients were randomly assigned 1:1 to discontinuation or continuation of RAS inhibition for 30 days. Primary outcome was the maximum sequential organ failure assessment (SOFA) score within 30 days, where death was scored with the maximum achievable SOFA score. Secondary endpoints were area under the death-adjusted SOFA score (AUC), mean SOFA score, admission to the intensive care unit, mechanical ventilation, and death. Analyses were done on a modified intention-to-treat basis. This trial is registered with ClinicalTrials.gov, NCT04353596.

Findings: Between April 20, 2020, and Jan 20, 2021, 204 patients (median age 75 years [IQR 66-80], 37% females) were randomly assigned to discontinue (n=104) or continue (n=100) RAS inhibition. Within 30 days, eight (8%) of 104 died in the discontinuation group and 12 (12%) of 100 patients died in the continuation group (p=0·42). There was no significant difference in the primary endpoint between the discontinuation and continuation group (median [IQR] maximum SOFA score 0·00 (0·00-2·00) vs 1·00 (0·00-3·00); p=0·12). Discontinuation was associated with a significantly lower AUC (0·00 [0·00-9·25] vs 3·50 [0·00-23·50]; p=0·040), mean SOFA score (0·00 [0·00-0·31] vs 0·12 [0·00-0·78]; p=0·040), and 30-day SOFA score (0·00 [10-90th percentile, 0·00-1·20] vs 0·00 [0·00-24·00]; p=0·023). At 30 days, 11 (11%) in the discontinuation group and 23 (23%) in the continuation group had signs of organ dysfunction (SOFA score ≥1) or were dead (p=0·017). There were no significant differences for mechanical ventilation (10 (10%) vs 8 (8%), p=0·87) and admission to intensive care unit (20 [19%] vs 18 [18%], p=0·96) between the discontinuation and continuation group.

Interpretation: Discontinuation of RAS-inhibition in COVID-19 had no significant effect on the maximum severity of COVID-19 but may lead to a faster and better recovery. The decision to continue or discontinue should be made on an individual basis, considering the risk profile, the indication for RAS inhibition, and the availability of alternative therapies and outpatient monitoring options.

Funding: Austrian Science Fund and German Center for Cardiovascular Research.
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http://dx.doi.org/10.1016/S2213-2600(21)00214-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8195495PMC
August 2021

EnvIRONmental Aspects in Myelodysplastic Syndrome.

Int J Mol Sci 2021 May 14;22(10). Epub 2021 May 14.

Department of Internal Medicine V, Medical University of Innsbruck, Anichstraße 35, 6020 Innsbruck, Austria.

Systemic iron overload is multifactorial in patients suffering from myelodysplastic syndrome (MDS). Disease-immanent ineffective erythropoiesis together with chronic red blood cell transfusion represent the main underlying reasons. However, like the genetic heterogeneity of MDS, iron homeostasis is also diverse in different MDS subtypes and can no longer be generalized. While a certain amount of iron and reactive oxygen species (ROS) are indispensable for proper hematological output, both are harmful if present in excess. Consequently, iron overload has been increasingly recognized as an important player in MDS, which is worth paying attention to. This review focuses on iron- and ROS-mediated effects in the bone marrow niche, their implications for hematopoiesis and their yet unclear involvement in clonal evolution. Moreover, we provide recent insights into hepcidin regulation in MDS and its interaction between erythropoiesis and inflammation. Based on Tet methylcytosine dioxygenase 2 (), representing one of the most frequently mutated genes in MDS, leading to disturbances in both iron homeostasis and hematopoiesis, we highlight that different genetic alteration may have different implications and that a comprehensive workup is needed for a complete understanding and development of future therapies.
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http://dx.doi.org/10.3390/ijms22105202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8156755PMC
May 2021

Relapse Protection Following Early Cytomegalovirus Reactivation after Hematopoietic Stem Cell Transplantation Is Limited to HLA-C Killer Cell Immunoglobulin-Like Receptor Ligand Homozygous Recipients.

Transplant Cell Ther 2021 08 12;27(8):686.e1-686.e9. Epub 2021 May 12.

Department of Internal Medicine I: Hematology with Stem Cell Transplantation, Hemostaseology and Medical Oncology, Ordensklinikum Linz Elisabethinen, Linz, Austria; Medical Faculty, Johannes Kepler University, Linz, Austria.

Although the risk for nonrelapse mortality (NRM) associated with early cytomegalovirus (CMV) reactivation (CMVR) after allogeneic hematopoietic stem cell transplantation (HSCT) is well established, debate is ongoing on whether CMVR may reduce the risk of primary disease relapse. The aim of this study was to evaluate relapse protection following early CMV reactivation after HSCT in the context of the recipient HLA-C killer cell immunoglobulin-like receptor ligands (KIRLs). In this retrospective bicentric study, 406 matched related or unrelated donor transplantations for acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) were stratified by HLA-C KIRL group (homozygous versus heterozygous) and analyzed separately for the impact of early CMVR on the cumulative incidences of relapse, NRM, and acute and chronic graft-versus-host-disease (GVHD) using landmark and multistate analyses. By landmark analysis of patients alive and relapse-free at 45 days post-HSCT, HLA-C KIRL homozygous recipients (C1/1 or C2/2) had a lower risk of subsequent relapse if CMVR occurred before this landmark (subhazard ratio [sHR], 0.36; P = .002). In contrast, in HLA-C KIRL heterozygous (C1/2) recipients, early CMVR had no impact on subsequent relapse (sHR, 0.88; P = .63). NRM (sHR, 3.31; P < .001) and grade III-IV acute GVHD (sHR, 2.60; P = .04) were significantly increased after early CMVR in the homozygous cohort, but not in the heterozygous cohort (NRM: sHR, 1.23; P = .53; grade III-IV acute GVHD: sHR, 1.40; P = .50). Multivariable landmark analyses and a multistate model confirmed the limitation of the relapse-protective effect of early CMVR to the homozygous cohort. Chronic GVHD and overall survival were not influenced in neither cohort. An antileukemic effect of early CMVR after HSCT for AML/MDS was significant but strictly limited to recipients homozygous for HLA-C KIRL. However, particularly in this cohort, CMVR had an adverse impact on aGVHD and NRM.
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http://dx.doi.org/10.1016/j.jtct.2021.04.028DOI Listing
August 2021

The cancer patient's perspective of COVID-19-induced distress-A cross-sectional study and a longitudinal comparison of HRQOL assessed before and during the pandemic.

Cancer Med 2021 06 10;10(12):3928-3937. Epub 2021 May 10.

Department of Internal Medicine V, Hematology and Oncology, Comprehensive Cancer Center Innsbruck (CCCI), Medical University of Innsbruck, Innsbruck, Austria.

Background: To permit timely mitigation of adverse effects on overall clinical outcome, it is essential to understand how the pandemic influences distress and health-related quality of life (HRQOL) in cancer patients during the coronavirus disease 2019 (COVID-19) pandemic.

Methods: In this cross-sectional study, adult cancer patients, without COVID-19 symptoms, completed a 13-item questionnaire about the pandemic's impacts on distress and everyday-life; associations with age, sex, or impaired HRQOL were then assessed by binary logistic regressions. In a subsample of patients with HRQOL assessment available from both before and during the pandemic, we evaluated the pandemic's impact on longitudinal changes in HRQOL reported within 6 months before versus during the COVID-19 lockdown using McNemar's test, and thresholds for clinical importance.

Results: We consecutively enrolled 240 patients with solid (50%) or hematological (50%) cancers. Median age was 67 years, 46% were females. The majority ranked heeding their health (80%) and keeping their appointment schedule in hospital (78%) as important. Being younger than 60, or aged 60-70 was independently associated with limitations in everyday life (OR = 3.57, p < 0.001; and 2.05, p = 0.038); female individuals and those with restricted emotional functioning were more distressed by the COVID-19 situation (OR = 2.47, p = 0.040; and 3.17, p = 0.019); the latter group was also significantly more concerned about being a patient at risk (OR = 2.21, p = 0.029). Interestingly, in a subsample of patients (n = 47), longitudinal comparisons pre- versus during the pandemic revealed that HRQOL was not substantially affected by the pandemic.

Conclusion: Particularly younger and female cancer patients, and those with impaired emotional functioning are distressed by COVID-19. During the first COVID-19 lockdown, cancer patients remained predominantly resilient. This analysis highlights the need to mitigate distress situations in vulnerable patients and thereby enhance resilience during pandemics.
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http://dx.doi.org/10.1002/cam4.3950DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209623PMC
June 2021

Fecal microbiota transfer for refractory intestinal graft-versus-host disease - Experience from two German tertiary centers.

Eur J Haematol 2021 Aug 9;107(2):229-245. Epub 2021 Jun 9.

German Center for Infection Research (DZIF), Partner Site Bonn-Cologne, Germany.

Rationale: Steroid refractory graft-vs-host disease (sr-GvHD) represents a challenging complication after allogeneic hematopoietic cell transplantation (allo-HCT). Intestinal microbiota (IM) diversity and dysbiosis were identified as influencing factors for the development of acute GvHD. Fecal microbiota transfer (FMT) is hypothesized to restore IM dysbiosis, but there is limited knowledge about the significance of FMT in the treatment of sr-GvHD.

Objectives: We studied the effects of FMT on sr-GvHD in allo-HCT patients from two German tertiary clinical centers (n = 11 patients; period: March 2017 until July 2019). To assess safety and clinical efficacy, we analyzed clinical data pre- and post-FMT (day -14 to +30 relative to FMT). Moreover, IM were analyzed in donor samples and in a subset of patients pre- and post-FMT by 16S rRNA sequencing.

Results: Post-FMT, we observed no intervention-associated, systemic inflammatory responses and only minor side effects (5/11 patients: abdominal pain and transformation of peristalsis-each 3/11 and vomiting-1/11). Stool frequencies and volumes were significantly reduced [pre- vs post-FMT (d14): P < .05, respectively] as well as clear attenuation regarding both grading and staging of sr-GvHD was present upon FMT. Moreover, IM analyses revealed an increase of alpha diversity as well as a compositional shifts toward the donor post-FMT.

Conclusions: In our study, we observed positive effects on sr-GVHD after FMT without the occurrence of major adverse events. Although these findings are in line with published data on beneficial effects of FMT in sr-GvHD, further randomized clinical studies are urgently needed to better define the clinical validity including mode of action.
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http://dx.doi.org/10.1111/ejh.13642DOI Listing
August 2021

Case report: successful perioperative management of patients with haemophilia A using an extended half-life factor VIII (Efmoroctocog alfa) during neurosurgical procedures.

Ther Adv Hematol 2021 31;12:2040620721993686. Epub 2021 Mar 31.

Department of Internal Medicine V, Hematology & Oncology, Medical University of Innsbruck, Anichstrasse 35, Innsbruck, Tyrol 6020, Austria.

Patients with haemophilia A (HA) undergoing neurosurgical procedures have a high risk of haemorrhage with potential fatal outcome. Here, we present a successful perioperative haemostatic concept applying an extended half-life factor VIII (EHL FVIII), Efmoroctocog alfa, in two patients with HA undergoing neurosurgery for paramedian right-sided disc herniation (case 1) and astrocytoma (case 2). After adequate EHL FVIII treatment the surgical procedures were performed without any bleeding complications despite the high-risk interventions. Laboratory measurements confirmed stable FVIII levels throughout the hospital stay. We suggest close interdisciplinary collaboration between involved clinicians as mandatory prerequisite for an optimized perioperative management in patients with HA. The presented cases indicate, that the increased stability, safety and fewer injections provide a rationale to use EHL FVIII products in HA patients undergoing surgical interventions with a very high bleeding risk.
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http://dx.doi.org/10.1177/2040620721993686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020741PMC
March 2021

Death of unknown cause? Post-mortem diagnosis of fulminant course of an EBV-associated secondary hemophagocytic lymphohistiocytosis.

Memo 2021 Apr 1:1-5. Epub 2021 Apr 1.

Department of Hematology and Oncology, Internal Medicine V, Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria.

HLH is a life-threatening disease, which is characterized by a dysregulated immune response with uncontrolled T cell and macrophage activation. The often fulminant course of the disease needs a fast diagnostic work-up to initiate as soon as possible the appropriate therapy. We present herein the case of a 71-year-old patient with rapidly progressive hyperinflammatory syndrome, which post mortem resulted in the diagnosis of EBV-associated HLH. With this case report, we intend to highlight the relevance of the HScore in the diagnosis of HLH, to create a greater awareness for EBV as a trigger of HLH, and to demonstrate the importance of treating EBV-associated HLH as early as possible.
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http://dx.doi.org/10.1007/s12254-021-00701-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015738PMC
April 2021

Symmetric bilateral liposarcoma in an interventional cardiologist.

Lancet Oncol 2021 04;22(4):e173

Department of Hematology & Oncology, Medical University Innsbruck, Innsbruck, Austria.

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http://dx.doi.org/10.1016/S1470-2045(21)00119-4DOI Listing
April 2021

Rheumatologic diseases impact the risk of progression of MGUS to overt multiple myeloma.

Blood Adv 2021 03;5(6):1746-1754

Department of Internal Medicine V, Haematology and Medical Oncology, and.

Monoclonal gammopathy of undetermined significance (MGUS), a premalignant condition, is associated with various chronic inflammatory rheumatic diseases (RDs) and is frequently observed as an incidental finding during routine work-up. The association of MGUS and chronic RDs is well established, but the impact of RDs on the risk of transformation into overt multiple myeloma (MM) has not been evaluated so far. MGUS patients diagnosed between January 2000 and August 2016 were identified and screened for concomitant RDs. RDs were grouped into antibody (Ab)-mediated RDs and non-Ab-mediated RDs (polymyalgia rheumatica, large-vessel giant cell arteritis, spondyloarthritis, and gout). Progression to MM was defined as a categorical (yes/no) or continuous time-dependent (time to progression) variable. Of 2935 MGUS patients, 255 (9%) had a concomitant RD. MGUS patients diagnosed with non-Ab-mediated RDs had a doubled risk of progression compared with those without a concomitant RD (hazard ratio, 2.1; 95% CI, 1.1-3.9; P = .02). These data translate into a 5-year risk of progression of 4% in MGUS patients without rheumatologic comorbidity, 10% in those with concomitant non-Ab-mediated RDS, and 2% in those with Ab-mediated RDs. By using the complex risk stratification model that includes myeloma protein (M-protein) concentration, immunoglobulin type, and level of free light chain ratio as variables, patients with non-Ab-mediated RDs (n = 57) had the highest risk for progression (hazard ratio, 6.8; 95% CI, 1.5-30.7; P = .01) compared with patients with Ab-mediated RDs (n = 77). Chronic inflammatory diseases have an impact on the risk of MGUS progressing into overt MM, with a doubled risk of transformation observed in patients with non-Ab-mediated RDs. Future research can elucidate whether comorbidities such as RDs should be included in currently applied prognostic MGUS scores.
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http://dx.doi.org/10.1182/bloodadvances.2020003193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993106PMC
March 2021

Dorsolateral Prefrontal Functional Connectivity Predicts Working Memory Training Gains.

Front Aging Neurosci 2021 1;13:592261. Epub 2021 Mar 1.

Department of Psychosomatic Medicine and Psychotherapy, Rostock University Medical Center, Rostock, Germany.

Normal aging is associated with working memory decline. A decrease in working memory performance is associated with age-related changes in functional activation patterns in the dorsolateral prefrontal cortex (DLPFC). Cognitive training can improve cognitive performance in healthy older adults. We implemented a cognitive training study to assess determinants of generalization of training gains to untrained tasks, a key indicator for the effectiveness of cognitive training. We aimed to investigate the association of resting-state functional connectivity (FC) of DLPFC with working memory performance improvement and cognitive gains after the training. A sample of 60 healthy older adults (mean age: 68 years) underwent a 4-week neuropsychological training, entailing a working memory task. Baseline resting-state functional MRI (rs-fMRI) images were acquired in order to investigate the FC of DLPFC. To evaluate training effects, participants underwent a neuropsychological assessment before and after the training. A second follow-up assessment was applied 12 weeks after the training. We used cognitive scores of digit span backward and visual block span backward tasks representing working memory function. The training group was divided into subjects who had and who did not have training gains, which was defined as a higher improvement in working memory tasks than the control group ( = 19). A high FC of DLPFC of the right hemisphere was significantly associated with training gains and performance improvement in the visuospatial task. The maintenance of cognitive gains was restricted to the time period directly after the training. The training group showed performance improvement in the digit span backward task. Functional activation patterns of the DLPFC were associated with the degree of working memory training gains and visuospatial performance improvement. Although improvement through cognitive training and acquisition of training gains are possible in aging, they remain limited.
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http://dx.doi.org/10.3389/fnagi.2021.592261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956962PMC
March 2021

Helios-expressing CD8 T cells are decreased in patients with systemic lupus erythematosus.

Lupus 2021 05 9;30(6):1022-1024. Epub 2021 Mar 9.

Department of Hematology, Oncology, Immunoncology and Rheumatology, Internal Medicine III, University Hospital Bonn, Germany.

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http://dx.doi.org/10.1177/0961203321999723DOI Listing
May 2021

Structural Network Efficiency Predicts Resilience to Cognitive Decline in Elderly at Risk for Alzheimer's Disease.

Front Aging Neurosci 2021 22;13:637002. Epub 2021 Feb 22.

Department of Psychiatry and Psychotherapy, University Medical Center Mainz, Johannes Gutenberg University Mainz, Mainz, Germany.

: Functional imaging studies have demonstrated the recruitment of additional neural resources as a possible mechanism to compensate for age and Alzheimer's disease (AD)-related cerebral pathology, the efficacy of which is potentially modulated by underlying structural network connectivity. Additionally, structural network efficiency (SNE) is associated with intelligence across the lifespan, which is a known factor for resilience to cognitive decline. We hypothesized that SNE may be a surrogate of the physiological basis of resilience to cognitive decline in elderly persons without dementia and with age- and AD-related cerebral pathology.: We included 85 cognitively normal elderly subjects or mild cognitive impairment (MCI) patients submitted to baseline diffusion imaging, liquor specimens, amyloid-PET and longitudinal cognitive assessments. SNE was calculated from baseline MRI scans using fiber tractography and graph theory. Mixed linear effects models were estimated to investigate the association of higher resilience to cognitive decline with higher SNE and the modulation of this association by increased cerebral amyloid, liquor tau or WMHV. : For the majority of cognitive outcome measures, higher SNE was associated with higher resilience to cognitive decline (-values: 0.011-0.039). Additionally, subjects with higher SNE showed more resilience to cognitive decline at higher cerebral amyloid burden (-values: <0.001-0.036) and lower tau levels (-values: 0.002-0.015).: These results suggest that SNE to some extent may quantify the physiological basis of resilience to cognitive decline most effective at the earliest stages of AD, namely at increased amyloid burden and before increased tauopathy.
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http://dx.doi.org/10.3389/fnagi.2021.637002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937862PMC
February 2021

JAK2-V617F and interferon-α induce megakaryocyte-biased stem cells characterized by decreased long-term functionality.

Blood 2021 04;137(16):2139-2151

Department of Biomedicine, Experimental Hematology, University Hospital Basel-University of Basel, Basel, Switzerland.

We studied a subset of hematopoietic stem cells (HSCs) that are defined by elevated expression of CD41 (CD41hi) and showed bias for differentiation toward megakaryocytes (Mks). Mouse models of myeloproliferative neoplasms (MPNs) expressing JAK2-V617F (VF) displayed increased frequencies and percentages of the CD41hi vs CD41lo HSCs compared with wild-type controls. An increase in CD41hi HSCs that correlated with JAK2-V617F mutant allele burden was also found in bone marrow from patients with MPN. CD41hi HSCs produced a higher number of Mk-colonies of HSCs in single-cell cultures in vitro, but showed reduced long-term reconstitution potential compared with CD41lo HSCs in competitive transplantations in vivo. RNA expression profiling showed an upregulated cell cycle, Myc, and oxidative phosphorylation gene signatures in CD41hi HSCs, whereas CD41lo HSCs showed higher gene expression of interferon and the JAK/STAT and TNFα/NFκB signaling pathways. Higher cell cycle activity and elevated levels of reactive oxygen species were confirmed in CD41hi HSCs by flow cytometry. Expression of Epcr, a marker for quiescent HSCs inversely correlated with expression of CD41 in mice, but did not show such reciprocal expression pattern in patients with MPN. Treatment with interferon-α further increased the frequency and percentage of CD41hi HSCs and reduced the number of JAK2-V617F+ HSCs in mice and patients with MPN. The shift toward the CD41hi subset of HSCs by interferon-α provides a possible mechanism of how interferon-α preferentially targets the JAK2 mutant clone.
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http://dx.doi.org/10.1182/blood.2020005563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8103999PMC
April 2021

High indoleamine-2,3-dioxygenase 1 (IDO) activity is linked to primary resistance to immunotherapy in non-small cell lung cancer (NSCLC).

Transl Lung Cancer Res 2021 Jan;10(1):304-313

Department of Internal Medicine V (Hematology and Oncology), Comprehensive Cancer Center Innsbruck, Medical University of Innsbruck, Innsbruck, Austria.

Background: Metabolic profiling in non-small cell lung cancer (NSCLC) may identify key metabolic vulnerabilities and shows enormous discovery potential. Preclinical studies showed that metabolic rewiring in cancer plays an essential role in modulation of immunotherapy response. However, this situation is understudied in the clinical setting. Therefore, we aimed to evaluate the plasma metabolic profile of immune checkpoint inhibitor (CI) responding versus non-responding NSCLC patients. The aim of this project is to identify potential predictive biomarkers for CI response.

Methods: Plasma samples from CI treated NSCLC patients were analysed at baseline and at the first follow up scan by using a broad targeted metabolomics mass spectrometry panel, and were compared to healthy controls. For further validation of identified key alterations high-performance liquid chromatography (HPLC) for tryptophan (Trp) and kynurenine (Kyn) as indicator of IDO-activity was performed.

Results: Sixty-seven metabolites were significantly altered in NSCLC patients compared to healthy controls. The metabolic profile of patients with primary CI resistance showed an increase in indoleamine-2,3-dioxygenase (IDO) and a decrease in branched-chain amino acids (BCAA) compared to baseline concentrations. Deregulated IDO activity was validated by additional HPLC measurements, which revealed that baseline Trp levels were predictive for CI response. According to receiver operating characteristic (ROC)-analysis baseline Trp levels ≥49.3 µmol/L predicted disease control at the first follow up scan with a sensitivity of 89% and a specificity of 71%.

Conclusions: We showed that NSCLC patients are characterized by a distinct metabolic profile compared to healthy controls. Moreover, metabolic changes during CI therapy were observed. Of those IDO metabolism seemed to play an important role in primary CI resistance. Trp as a surrogate parameter of IDO activity is a promising biomarker in patients undergoing treatment with CIs and might be a future marker in trials investigating IDO inhibitors.
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http://dx.doi.org/10.21037/tlcr-20-380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867793PMC
January 2021

Atezolizumab for PD-L1-Selected Patients with NSCLC.

N Engl J Med 2021 02;384(6):584

Medical University of Innsbruck, Innsbruck, Austria

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http://dx.doi.org/10.1056/NEJMc2032432DOI Listing
February 2021

The Role of Anti-angiogenesis in the Treatment Landscape of Non-small Cell Lung Cancer - New Combinational Approaches and Strategies of Neovessel Inhibition.

Front Cell Dev Biol 2020 5;8:610903. Epub 2021 Jan 5.

Internal Medicine V, Department of Hematology and Oncology, Medical University Innsbruck, Innsbruck, Austria.

Tumor progression depends primarily on vascular supply, which is facilitated by angiogenic activity within the malignant tissue. Non-small cell lung cancer (NSCLC) is a highly vascularized tumor, and inhibition of angiogenesis was projected to be a promising therapeutic approach. Over a decade ago, the first anti-angiogenic agents were approved for advanced stage NSCLC patients, however, they only produced a marginal clinical benefit. Explanations why anti-angiogenic therapies only show modest effects include the highly adaptive tumor microenvironment (TME) as well as the less understood characteristics of the tumor vasculature. Today, advanced methods of in-depth characterization of the NSCLC TME by single cell RNA sequencing (scRNA-Seq) and preclinical observations enable a detailed characterization of individual cancer landscapes, allowing new aspects for a more individualized inhibition of angiogenesis to be identified. Furthermore, the tumor vasculature itself is composed of several cellular subtypes, which closely interact with other cellular components of the TME, and show distinct biological functions such as immune regulation, proliferation, and organization of the extracellular matrix. With these new insights, combinational approaches including chemotherapy, anti- angiogenic and immunotherapy can be developed to yield a more target-oriented anti-tumor treatment in NSCLC. Recently, anti-angiogenic agents were also shown to induce the formation of high endothelial venules (HEVs), which are essential for the formation of tertiary lymphoid structures, and key components in triggering anti-tumor immunity. In this review, we will summarize the current knowledge of tumor-angiogenesis and corresponding anti-angiogenic therapies, as well as new aspects concerning characterization of tumor-associated vessels and the resulting new strategies for anti-angiogenic therapies and vessel inhibition in NSCLC. We will further discuss why anti-angiogenic therapies form an interesting backbone strategy for combinational therapies and how anti-angiogenic approaches could be further developed in a more personalized tumor-oriented fashion with focus on NSCLC.
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http://dx.doi.org/10.3389/fcell.2020.610903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7813779PMC
January 2021

Disseminated focal F-fluoro-deoxyglucose uptake upon granulocyte colony-stimulating factor therapy mimicking malignant bone infiltration: case report of a patient with very severe aplastic anemia.

Ther Adv Hematol 2020 21;11:2040620720977613. Epub 2020 Dec 21.

Department of Internal Medicine V (Hematology and Oncology), Comprehensive Cancer Center Innsbruck, Medical University of Innsbruck, Anichstrasse 35, Innsbruck, Tirol 6020, Austria.

Combined F-fluoro-deoxyglucose ([18F]FDG) positron emission tomography and computed tomography ([18F]FDG-PET/CT) is increasingly used for the diagnostic and therapeutic management of hematologic and non-hematologic malignancies. Here, we describe a unique case of a patient presenting with very severe aplastic anemia and a mediastinal mass showing disseminated hypermetabolic lesions of the bones after receiving granulocyte colony-stimulating factor (G-CSF), highly suspicious for disseminated metastatic lesions. A 71-year-old patient presented with a 3 week history of dyspnea and fatigue. Blood tests showed severe pancytopenia and iliac crest bone marrow biopsy revealed an extensively hypoplastic bone marrow. Diagnostic work-up by histology, conventional cytogenetics and flow cytometry confirmed the diagnosis of very severe aplastic anemia. Besides blood transfusions, the patient was treated with G-CSF. Furthermore, computed tomography revealed a suspect mass in the anterior mediastinum, presenting with moderate glucose metabolism in the subsequent [18F]FDG-PET/CT scan. In addition, multiple disseminated and highly metabolic bone lesions of primarily the ribs were detected, suspicious of malignant bone infiltration. Since physiologic bone marrow activation by G-CSF-stimulation could not be ruled out, G-CSF therapy was interrupted to repeat the PET/CT scan 10 days later. On the second [18F]FDG-PET/CT the moderately hypermetabolic mediastinal mass persisted. However, the initially FDG-avid bone lesions almost completely resolved, rendering the diagnosis of G-CSF-induced bone marrow hypermetabolism very likely without the need for further invasive diagnostic procedures. The mediastinal mass was thereafter histologically verified as thymoma. Interpretation of [18F]FDG-PET/CT in patients with aplastic anemia may be complicated by the frequent therapeutic use of G-CSF. With G-CSF, islets of residual bone marrow activity can be visualized on [18F]FDG-PET/CT images that might be misinterpreted as malignant bone infiltration. Repeating PET/CT scan after G-CSF discontinuation can prevent unnecessary invasive diagnostic procedures in these patients.
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http://dx.doi.org/10.1177/2040620720977613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758561PMC
December 2020
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