Publications by authors named "Michael von Bergwelt-Baildon"

180 Publications

Severe Candida glabrata pancolitis and fatal Aspergillus fumigatus pulmonary infection in the setting of bone marrow aplasia after CD19-directed CAR T-cell therapy - a case report.

BMC Infect Dis 2021 Jan 28;21(1):121. Epub 2021 Jan 28.

Department of Hematology and Oncology, University Hospital, LMU Munich, Munich, Germany.

Background: Prolonged myelosuppression following CD19-directed CAR T-cell transfusion represents an important, yet underreported, adverse event. The resulting neutropenia and multifactorial immunosuppression can facilitate severe infectious complications.

Case Presentation: We describe the clinical course of a 59-year-old patient with relapsed/refractory DLBCL who received Axicabtagene-Ciloleucel (Axi-cel). The patient developed ASTCT grade I CRS and grade IV ICANS, necessitating admission to the neurological ICU and prolonged application of high-dose corticosteroids and other immunosuppressive agents. Importantly, neutropenia was profound (ANC < 100/μl), G-CSF-refractory, and prolonged, lasting more than 50 days. The patient developed severe septic shock 3 weeks after CAR transfusion while receiving anti-fungal prophylaxis with micafungin. His clinical status stabilized with broad anti-infective treatment and intensive supportive measures. An autologous stem cell backup was employed on day 46 to support hematopoietic recovery. Although the counts of the patient eventually started to recover, he developed an invasive pulmonary aspergillosis, which ultimately lead to respiratory failure and death. Postmortem examination revealed signs of Candida glabrata pancolitis.

Conclusions: This case highlights the increased risk for fatal infectious complications in patients who present with profound and prolonged cytopenia after CAR T-cell therapy. We describe a rare case of C. glabrata pancolitis associated with multifactorial immunosuppression. Although our patient succumbed to a fatal fungal infection, autologous stem cell boost was able to spur hematopoiesis and may represent an important therapeutic strategy for DLBCL patients with CAR T-cell associated bone marrow aplasia who have underwent prior stem cell harvest.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12879-020-05755-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841988PMC
January 2021

Clinical and pharmacoeconomic evaluation of antifungal prophylaxis with continuous micafungin in patients undergoing allogeneic stem cell transplantation: A six-year cohort analysis.

Mycoses 2020 Dec 22. Epub 2020 Dec 22.

Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University Hospital of Cologne, Cologne, Germany.

Background: Patients undergoing allogeneic stem cell transplantation (aSCT) are at high risk to develop an invasive fungal disease (IFD). Optimisation of antifungal prophylaxis strategies may improve patient outcomes and reduce treatment costs.

Objectives: To analyse the clinical and economical impact of using continuous micafungin as antifungal prophylaxis.

Patients/methods: We performed a single-centre evaluation comparing patients who received either oral posaconazole with micafungin as intravenous bridging as required (POS-MIC) to patients who received only micafungin (MIC) as antifungal prophylaxis after aSCT. Epidemiological, clinical and direct treatment cost data extracted from the Cologne Cohort of Neutropenic Patients (CoCoNut) were analysed.

Results: Three hundred and thirteen patients (97 and 216 patients in the POS-MIC and MIC groups, respectively) were included into the analysis. In the POS-MIC and MIC groups, median overall length of stay was 42 days (IQR: 35-52 days) vs 40 days (IQR: 35-49 days; p = .296), resulting in median overall costs of €42,964 (IQR: €35,040-€56,348) vs €43,291 (IQR: €37,281 vs €51,848; p = .993), respectively. Probable/proven IFD in the POS-MIC and MIC groups occurred in 5 patients (5%) vs 3 patients (1%; p = .051), respectively. The Kaplan-Meier analysis showed improved outcome of patients in the MIC group at day 100 (p = .037) and day 365 (p < .001) following aSCT.

Conclusions: Our study results demonstrate improved outcomes in the MIC group compared with the POS-MIC group, which can in part be explained by a tendency towards less probable/proven IFD. Higher drug acquisition costs of micafungin did not translate into higher overall costs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/myc.13232DOI Listing
December 2020

Vascular neutrophilic inflammation and immunothrombosis distinguish severe COVID-19 from influenza pneumonia.

J Thromb Haemost 2021 02 20;19(2):574-581. Epub 2020 Dec 20.

Medizinische Klinik und Poliklinik I, University Hospital, LMU Munich, Munich, Germany.

Objective: Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can lead to severe pneumonia, but also thrombotic complications and non-pulmonary organ failure. Recent studies suggest intravascular neutrophil activation and subsequent immune cell-triggered immunothrombosis as a central pathomechanism linking the heterogenous clinical picture of coronavirus disease 2019 (COVID-19). We sought to study whether immunothrombosis is a pathognomonic factor in COVID-19 or a general feature of (viral) pneumonia, as well as to better understand its upstream regulation.

Approach And Results: By comparing histopathological specimens of SARS-CoV-2 with influenza-affected lungs, we show that vascular neutrophil recruitment, NETosis, and subsequent immunothrombosis are typical features of severe COVID-19, but less prominent in influenza pneumonia. Activated neutrophils were typically found in physical association with monocytes. To explore this further, we combined clinical data of COVID-19 cases with comprehensive immune cell phenotyping and bronchoalveolar lavage fluid scRNA-seq data. We show that a HLADR CD9 monocyte population expands in severe COVID-19, which releases neutrophil chemokines in the lungs, and might in turn explain neutrophil expansion and pulmonary recruitment in the late stages of severe COVID-19.

Conclusions: Our data underline an innate immune cell axis causing vascular inflammation and immunothrombosis in severe SARS-CoV-2 infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jth.15179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7753335PMC
February 2021

PET/CT imaging for tumour response assessment to immunotherapy: current status and future directions.

Eur Radiol Exp 2020 11 17;4(1):63. Epub 2020 Nov 17.

Department of Radiology, University Hospital, LMU Munich, Marchioninistr. 15, 81377, Munich, Germany.

Recent immunotherapeutic approaches have evolved as powerful treatment options with high anti-tumour responses involving the patient's own immune system. Passive immunotherapy applies agents that enhance existing anti-tumour responses, such as antibodies against immune checkpoints. Active immunotherapy uses agents that direct the immune system to attack tumour cells by targeting tumour antigens. Active cellular-based therapies are on the rise, most notably chimeric antigen receptor T cell therapy, which redirects patient-derived T cells against tumour antigens. Approved treatments are available for a variety of solid malignancies including melanoma, lung cancer and haematologic diseases. These novel immune-related therapeutic approaches can be accompanied by new patterns of response and progression and immune-related side-effects that challenge established imaging-based response assessment criteria, such as Response Evaluation Criteria in Solid tumours (RECIST) 1.1. Hence, new criteria have been developed. Beyond morphological information of computed tomography (CT) and magnetic resonance imaging, positron emission tomography (PET) emerges as a comprehensive imaging modality by assessing (patho-)physiological processes such as glucose metabolism, which enables more comprehensive response assessment in oncological patients. We review the current concepts of response assessment to immunotherapy with particular emphasis on hybrid imaging with F-FDG-PET/CT and aims at describing future trends of immunotherapy and additional aspects of molecular imaging within the field of immunotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s41747-020-00190-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669926PMC
November 2020

Tumor and microenvironment response but no cytotoxic T-cell activation in classic Hodgkin lymphoma treated with anti-PD1.

Blood 2020 Dec;136(25):2851-2863

Hematopathology Section and Lymph Node Registry, Department of Pathology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.

Classic Hodgkin lymphoma (cHL) is the cancer type most susceptible to antibodies targeting programmed cell death protein 1 (PD1) and is characterized by scarce Hodgkin and Reed-Sternberg cells (HRSCs), perpetuating a unique tumor microenvironment (TME). Although anti-PD1 effects appear to be largely mediated by cytotoxic CD8+ T cells in solid tumors, HRSCs frequently lack major histocompatibility complex expression, and the mechanism of anti-PD1 efficacy in cHL is unclear. Rapid clinical responses and high interim complete response rates to anti-PD1 based first-line treatment were recently reported for patients with early-stage unfavorable cHL treated in the German Hodgkin Study Group phase 2 NIVAHL trial. To investigate the mechanisms underlying this very early response to anti-PD1 treatment, we analyzed paired biopsies and blood samples obtained from NIVAHL patients before and during the first days of nivolumab first-line cHL therapy. Mirroring the rapid clinical response, HRSCs had disappeared from the tissue within days after the first nivolumab application. The TME already shows a reduction in type 1 regulatory T cells and PD-L1+ tumor-associated macrophages at this early time point of treatment. Interestingly, a cytotoxic immune response and a clonal T-cell expansion were not observed in the tumors or peripheral blood. These early changes in the TME were distinct from alterations found in a separate set of cHL biopsies at relapse during anti-PD1 therapy. We identify a unique very early histologic response pattern to anti-PD1 therapy in cHL that is suggestive of withdrawal of prosurvival factors, rather than induction of an adaptive antitumor immune response, as the main mechanism of action.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2020008553DOI Listing
December 2020

Evidence-based management of COVID-19 in cancer patients: Guideline by the Infectious Diseases Working Party (AGIHO) of the German Society for Haematology and Medical Oncology (DGHO).

Eur J Cancer 2020 11 21;140:86-104. Epub 2020 Sep 21.

Department of Haematology and Medical Oncology, Clinic for Internal Medicine II, University Hospital Jena, Jena, Germany; Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute, Jena, Germany.

Since its first detection in China in late 2019 the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the associated infectious disease COVID-19 continue to have a major impact on global healthcare and clinical practice. Cancer patients, in particular those with haematological malignancies, seem to be at an increased risk for a severe course of infection. Deliberations to avoid or defer potentially immunosuppressive therapies in these patients need to be balanced against the overarching goal of providing optimal antineoplastic treatment. This poses a unique challenge to treating physicians. This guideline provides evidence-based recommendations regarding prevention, diagnostics and treatment of SARS-CoV-2 infection and COVID-19 as well as strategies towards safe antineoplastic care during the COVID-19 pandemic. It was prepared by the Infectious Diseases Working Party (AGIHO) of the German Society for Haematology and Medical Oncology (DGHO) by critically reviewing the currently available data on SARS-CoV-2 and COVID-19 in cancer patients applying evidence-based medicine criteria.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejca.2020.09.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7505554PMC
November 2020

[Psychosocial support during the COVID-19 pandemic: interdisciplinary concept of care at a university hospital].

Nervenarzt 2020 Oct 6. Epub 2020 Oct 6.

Klinik für Psychiatrie und Psychotherapie, LMU Klinikum, Nußbaumstraße 7, 80336, München, Deutschland.

Background: Since the beginning of the outbreak, the COVID-19 pandemic has caused an increased demand for psychosocial support for patients, their family members, and healthcare workers. Concurrently, possibilities to provide this support have been hindered. Quarantine, social isolation, and SARS-CoV‑2 infections represent new and severe stressors that have to be addressed with innovative psychosocial care.

Objective And Method: This article describes the COVID-19 psychosocial first aid concept at the University Hospital Munich (LMU Klinikum) developed by an interdisciplinary team of psychiatric, psychological, spiritual care, psycho-oncological, and palliative care specialists.

Results: A new psychosocial first aid model has been implemented for COVID-19 inpatients, family members, and hospital staff consisting of five elements.

Conclusion: The concept integrates innovative and sustainable ideas, e.g. telemedicine-based approaches and highlights the importance of multidisciplinary collaboration to cope with challenges in the healthcare system.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00115-020-01014-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538057PMC
October 2020

Microwave ablation enhances tumor-specific immune response in patients with hepatocellular carcinoma.

Cancer Immunol Immunother 2020 Oct 2. Epub 2020 Oct 2.

Center for Molecular Medicine Cologne, University of Cologne, Köln, Germany.

Thermal ablative therapies are standard treatments for localized hepatocellular carcinoma (HCC). In addition to local tumor destruction, ablation leads to abscopal effects in distant lesions most likely mediated by an anti-tumor immune response. Although microwave ablation (MWA) is increasingly substituting other ablative techniques, its systemic immunostimulatory effects are poorly studied. We analyzed tumor-specific immune responses in peripheral blood of HCC patients after thermal ablation with regard to T cell responses and disease outcome. While comprehensive flow cytometric analyses in sequential samples of a prospective patient cohort (n = 23) demonstrated only moderate effects of MWA on circulating immune cell subsets, fluorospot analyses of specific T cell responses against seven tumor-associated antigens (TTAs) revealed de-novo or enhanced tumor-specific immune responses in 30% of patients. This anti-tumor immune response was related to tumor control as Interferon-y and Interleukin-5 T cell responses against TAAs were more frequent in patients with a long-time remission (> 1 year) after MWA (7/16) compared to patients suffering from an early relapse (0/13 patients) and presence of tumor-specific T cell response (IFN-y and/or IL-5) was associated to longer progression-free survival (27.5 vs. 10.0 months). Digital image analysis of immunohistochemically stained archival HCC samples (n = 18) of patients receiving combined MWA and resection revealed a superior disease-free survival of patients with high T cell abundance at the time of thermal ablation (37.4 vs. 13.1 months). Our data demonstrates remarkable immune-related effects of MWA in HCC patients and provides additional evidence for a combination of local ablation and immunotherapy in this challenging disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00262-020-02734-1DOI Listing
October 2020

First results of the "Lean European Open Survey on SARS-CoV-2-Infected Patients (LEOSS)".

Infection 2021 Feb 1;49(1):63-73. Epub 2020 Oct 1.

Department I for Internal Medicine, University Hospital of Cologne, University of Cologne, Cologne, Germany.

Purpose: Knowledge regarding patients' clinical condition at severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) detection is sparse. Data in the international, multicenter Lean European Open Survey on SARS-CoV-2-Infected Patients (LEOSS) cohort study may enhance the understanding of COVID-19.

Methods: Sociodemographic and clinical characteristics of SARS-CoV-2-infected patients, enrolled in the LEOSS cohort study between March 16, 2020, and May 14, 2020, were analyzed. Associations between baseline characteristics and clinical stages at diagnosis (uncomplicated vs. complicated) were assessed using logistic regression models.

Results: We included 2155 patients, 59.7% (1,287/2,155) were male; the most common age category was 66-85 years (39.6%; 500/2,155). The primary COVID-19 diagnosis was made in 35.0% (755/2,155) during complicated clinical stages. A significant univariate association between age; sex; body mass index; smoking; diabetes; cardiovascular, pulmonary, neurological, and kidney diseases; ACE inhibitor therapy; statin intake and an increased risk for complicated clinical stages of COVID-19 at diagnosis was found. Multivariable analysis revealed that advanced age [46-65 years: adjusted odds ratio (aOR): 1.73, 95% CI 1.25-2.42, p = 0.001; 66-85 years: aOR 1.93, 95% CI 1.36-2.74, p < 0.001; > 85 years: aOR 2.38, 95% CI 1.49-3.81, p < 0.001 vs. individuals aged 26-45 years], male sex (aOR 1.23, 95% CI 1.01-1.50, p = 0.040), cardiovascular disease (aOR 1.37, 95% CI 1.09-1.72, p = 0.007), and diabetes (aOR 1.33, 95% CI 1.04-1.69, p = 0.023) were associated with complicated stages of COVID-19 at diagnosis.

Conclusion: The LEOSS cohort identified age, cardiovascular disease, diabetes and male sex as risk factors for complicated disease stages at SARS-CoV-2 diagnosis, thus confirming previous data. Further data regarding outcomes of the natural course of COVID-19 and the influence of treatment are required.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s15010-020-01499-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527665PMC
February 2021

Non-canonical effector functions of the T-memory-like T-PLL cell are shaped by cooperative TCL1A and TCR signaling.

Blood 2020 Sep 21. Epub 2020 Sep 21.

University of Cologne (UoC), Cologne, Germany.

T-cell prolymphocytic leukemia (T-PLL) is a poor-prognostic neoplasm. Differentiation stage and immune-effector functions of the underlying tumor cell are insufficiently characterized. Constitutive activation of the T-cell-leukemia-1A (TCL1A) oncogene distinguishes the (pre)leukemic cell from regular post-thymic T-cells. We assessed here activation-response patterns of the T-PLL lymphocyte and interrogated the modulatory impact by TCL1A. Immunophenotypic and gene expression profiles revealed a unique spectrum of memory-type differentiation of T-PLL with predominant central-memory stages and frequent non-canonical patterns. Virtually all T-PLL expressed a T-cell receptor (TCR) and/or CD28-coreceptor without overrepresentation of specific TCR-clonotypes. The highly activated leukemic cells also revealed losses of negative-regulatory TCR-coreceptors (e.g. CTLA4). TCR-stimulation of T-PLL cells evoked higher-than-normal cell-cycle transition and profiles of cytokine release that resembled those of normal memory T-cells. More activated phenotypes and higher TCL1A correlated with inferior clinical outcomes. TCL1A was linked to T-PLL's marked resistance to activation- and FAS-induced cell death. Enforced TCL1A enhanced phosho-activation of TCR-kinases, second-messenger generation, and JAK/STAT or NFAT transcriptional responses. This reduced the input thresholds for IL-2 secretion in a sensitizer-like fashion. Mice of TCL1A-initiated protracted T-PLL development resembled such features. When equipped with epitope-defined TCRs or CARs, these Lckpr-hTCL1Atg T-cells gained a leukemogenic growth advantage in scenarios of receptor stimulation. Overall, we propose a model of T-PLL pathogenesis in which TCL1A enhances TCR-signals and drives accumulation of death-resistant memory-type cells that utilize amplified low-level stimulatory input and whose loss of negative coregulators additionally maintains their activated state. Treatment rationales are provided by combined interception in TCR- and survival signaling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2019003348DOI Listing
September 2020

Addition of Radiotherapy to Immunotherapy: Effects on Outcome of Different Subgroups Using a Propensity Score Matching.

Cancers (Basel) 2020 Aug 27;12(9). Epub 2020 Aug 27.

Department of Radiation Oncology and Cyberknife Center, University Hospital of Cologne, Kerpener Str. 62, 50937 Cologne, Germany.

Immune checkpoint inhibition (ICI) has been established as successful modality in cancer treatment. Combination concepts are used to optimize treatment outcome, but may also induce higher toxicity rates than monotherapy. Several rationales support the combination of radiotherapy (RT) with ICI as radioimmunotherapy (RIT), but it is still unknown in which clinical situation RIT would be most beneficial. Therefore, we have conducted a retrospective matched-pair analysis of 201 patients with advanced-stage cancers and formed two groups treated with programmed cell death protein 1 (PD-1) inhibitors only (PD1i) or in combination with local RT (RIT) at our center between 2013 and 2017. We collected baseline characteristics, programmed death ligand 1 (PD-L1) status, mutational status, PD-1 inhibitor and RT treatment details, and side effects according to the Common Terminology Criteria for Adverse Events (CTCAE) v.5.0. Patients received pembrolizumab ( = 93) or nivolumab ( = 108), 153 with additional RT. For overall survival (OS) and progression-free survival (PFS), there was no significant difference between both groups. After propensity score matching (PSM), we analyzed 96 patients, 67 with additional and 29 without RT. We matched for different covariates that could have a possible influence on the treatment outcome. The RIT group displayed a trend towards a longer OS until the PD1i group reached a survival plateau. PD-L1-positive patients, smokers, patients with a BMI ≤ 25, and patients without malignant melanoma showed a longer OS when treated with RIT. Our data show that some subgroups may benefit more from RIT than others. Suitable biomarkers as well as the optimal timing and dosage must be established in order to achieve the best effect on cancer treatment outcome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12092429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563550PMC
August 2020

Bacterial lipopolysaccharide as negative predictor of gemcitabine efficacy in advanced pancreatic cancer - translational results from the AIO-PK0104 Phase 3 study.

Br J Cancer 2020 Oct 24;123(9):1370-1376. Epub 2020 Aug 24.

Institute of Pathology, Faculty of Medicine, Ludwig-Maximilians-University, Munich, Germany.

Background: Gram-negative bacteria mediated gemcitabine resistance in pre-clinical models. We determined if intratumoural lipopolysaccharide (LPS) detection by immunohistochemistry is associated with outcome in advanced pancreatic ductal adenocarcinoma (PDAC) treated with gemcitabine and non-gemcitabine containing 1st-line chemotherapy.

Methods: We examined LPS on tumour tissue from 130 patients treated within the randomised AIO-PK0104 trial and a validation cohort (n = 113) and analysed the association of LPS detection to patient outcome according to treatment subgroups.

Results: In 24% of samples from the AIO-PK0104 study LPS was detected; in LPS-positive patients median OS was 4.4 months, compared to 7.3 months with LPS negative tumours (HR 1.732, p = 0.010). A difference in OS was detected in 1st-line gemcitabine-treated patients (n = 71; HR 2.377, p = 0.002), but not in the non-gemcitabine treatment subgroup (n = 59; HR 1.275, p = 0.478). Within the validation cohort, the LPS positivity rate was 23%, and LPS detection was correlated with impaired OS in the gemcitabine subgroup (n = 94; HR 1.993, p = 0.008) whereas no difference in OS was observed in the non-gemcitabine subgroup (n = 19; HR 2.596, p = 0.219).

Conclusions: The detection of intratumoural LPS as surrogate marker for gram-negative bacterial colonisation may serve as a negative predictor for gemcitabine efficacy in advanced PDAC.

Clinical Trial Registry: The Clinical trial registry identifier is NCT00440167.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41416-020-01029-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591915PMC
October 2020

Immunothrombotic Dysregulation in COVID-19 Pneumonia Is Associated With Respiratory Failure and Coagulopathy.

Circulation 2020 09 28;142(12):1176-1189. Epub 2020 Jul 28.

Medizinische Klinik und Poliklinik I (L.N., A.L., S.B., R.K., T.W., C.S., S.K., S.M., K.P., K.S.), University Hospital Ludwig-Maximilian University Munich, Germany.

Background: Severe acute respiratory syndrome corona virus 2 infection causes severe pneumonia (coronavirus disease 2019 [COVID-19]), but the mechanisms of subsequent respiratory failure and complicating renal and myocardial involvement are poorly understood. In addition, a systemic prothrombotic phenotype has been reported in patients with COVID-19.

Methods: A total of 62 subjects were included in our study (n=38 patients with reverse transcriptase polymerase chain reaction-confirmed COVID-19 and n=24 non-COVID-19 controls). We performed histopathologic assessment of autopsy cases, surface marker-based phenotyping of neutrophils and platelets, and functional assays for platelet, neutrophil functions, and coagulation tests, as well.

Results: We provide evidence that organ involvement and prothrombotic features in COVID-19 are linked by immunothrombosis. We show that, in COVID-19, inflammatory microvascular thrombi are present in the lung, kidney, and heart, containing neutrophil extracellular traps associated with platelets and fibrin. Patients with COVID-19 also present with neutrophil-platelet aggregates and a distinct neutrophil and platelet activation pattern in blood, which changes with disease severity. Whereas cases of intermediate severity show an exhausted platelet and hyporeactive neutrophil phenotype, patients severely affected with COVID-19 are characterized by excessive platelet and neutrophil activation in comparison with healthy controls and non-COVID-19 pneumonia. Dysregulated immunothrombosis in severe acute respiratory syndrome corona virus 2 pneumonia is linked to both acute respiratory distress syndrome and systemic hypercoagulability.

Conclusions: Taken together, our data point to immunothrombotic dysregulation as a key marker of disease severity in COVID-19. Further work is necessary to determine the role of immunothrombosis in COVID-19.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCULATIONAHA.120.048488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497892PMC
September 2020

[Correction: Onko-Nexus: A Bavarian "Caretaker Project" to Overcome the Interface Outpatient/Hospitalized Division - Three-Year Results].

Gesundheitswesen 2020 Aug 3. Epub 2020 Aug 3.

Medizinische Klinik und Poliklinik III, Ludwig-Maximilians-Universität München, München.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/a-1228-1722DOI Listing
August 2020

[COVID-19: The Intensive Care Point-of-View].

Dtsch Med Wochenschr 2020 Jul 30;145(15):1057-1062. Epub 2020 Jul 30.

Approx. 93 % of COVID-19 infections are mild, and not all severely ill patients are transferred to the intensive care unit. But the Corona crisis implies high demands on intensive care medicine. Many treatment modalities of COVID patients are "best practice", but some aspects remain unclear at present. This article deals with diagnostics, monitoring and therapy with COVID-19 patients in intensive care units and with a suitable hygiene concepts.A hygiene concept is obligatory and must ensure - in addition to general measures - the training of employees and the hygienic discharge of material. Ideally, a cohort isolation is implemented.Monitoring of patients with COVID-19 is not different from other intensive care patients and should be adapted to the clinical situation of the individual patient. In laboratory analysis the typical abnormality of COVID-19 patients should be taken into account. In case of increasing inflammatory parameters, fungal infections should be tested.Due to the formation of aerosols, disconnection of the respiratory system must be avoided in invasive ventilation. If a disconnection from the respirator is necessary, the tube should be disconnected. After extubation, an intermittent NIV treatment for atelectase prophylaxis can be performed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/a-1164-4100DOI Listing
July 2020

[COVID-19 from the Perspective of Haematology and Haemostaseology].

Dtsch Med Wochenschr 2020 Jul 30;145(15):1044-1050. Epub 2020 Jul 30.

Infection with SARS-COV-2 leads to a number of pathologies in the hematopoetic system that have significant impact on clinical symptoms and mortality. There are 3 stages of infection: (1) early upper respiratory tract infection with fever and lymphopenia (2) pulmonary phase and (3) hyperinflammatory phase with the clinical signs of organ failure such as ARDS/shock. Hyperinflammation, which is triggered by activation of T cells and monocytes/macrophages, is essential for organ pathologies. Interferon IFN-ɣ, tumor necrosis factor (TNF)-α, IL-10 and interleukin-6 (IL-6) play important roles as mediators of inflammation. In analogy to the cytokine release syndrome (CRS) after CAR-T cell therapy, the therapeutic activity of the IL-6 receptor antibody tocilizumab is investigated in clinical studies.The coagulation system is activated during the inflammatory phase of COVID infection, most likely on the pathophysiological basis of immune thrombosis. Clinically, there is a significantly increased incidence of venous (especially pulmonary artery embolism), but also arterial thromboembolism (TE). In laboratory chemistry, the D-dimer, fibrinogen but also vWF and FVIII are significantly increased. Guidelines for the prophylaxis and therapy of COVID-associated coagulopathy have been developed. Analogous to other viral infections, there are approaches to passive immunization using convalescent plasma. Its administration has shown promising activity in first uncontrolled case series and is currently being examined in clinical studies worldwide for its therapeutic activity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/a-1164-4191DOI Listing
July 2020

[COVID-19: Where are we now?]

Dtsch Med Wochenschr 2020 07 30;145(15):1019. Epub 2020 Jul 30.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/a-1164-4293DOI Listing
July 2020

[Multiple Myeloma: better prognosis thanks timely and effective treatment].

Dtsch Med Wochenschr 2020 06 17;145(12):799. Epub 2020 Jun 17.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/a-0952-9620DOI Listing
June 2020

Characterization of a Novel FLT3 BiTE Molecule for the Treatment of Acute Myeloid Leukemia.

Mol Cancer Ther 2020 09 9;19(9):1875-1888. Epub 2020 Jun 9.

Amgen Research, Amgen Inc., South San Francisco, California.

Despite advances in the treatment of acute myeloid leukemia (AML), novel therapies are needed to induce deeper and more durable clinical response. Bispecific T-cell Engager (BiTE) molecules, which redirect patient T cells to lyse tumor cells, are a clinically validated modality for hematologic malignancies. Due to broad AML expression and limited normal tissue expression, fms-related tyrosine kinase 3 (FLT3) is proposed to be an optimal BiTE molecule target. Expression profiling of FLT3 was performed in primary AML patient samples and normal hematopoietic cells and nonhematopoietic tissues. Two novel FLT3 BiTE molecules, one with a half-life extending (HLE) Fc moiety and one without, were assessed for T-cell-dependent cellular cytotoxicity (TDCC) of FLT3-positive cell lines , and FLT3 protein was detected on the surface of most primary AML bulk and leukemic stem cells but only a fraction of normal hematopoietic stem and progenitor cells. FLT3 protein detected in nonhematopoietic cells was cytoplasmic. FLT3 BiTE molecules induced TDCC of FLT3-positive cells , reduced tumor growth and increased survival in AML mouse models Both molecules exhibited reproducible pharmacokinetic and pharmacodynamic profiles in cynomolgus monkeys , including elimination of FLT3-positive cells in blood and bone marrow. In cultures of primary AML samples, patient T cells induced TDCC of FLT3-positive target cells. Combination with PD-1 blockade increased BiTE activity. These data support the clinical development of an FLT3 targeting BiTE molecule for the treatment of AML.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-19-1093DOI Listing
September 2020

Elevated levels of IL-6 and CRP predict the need for mechanical ventilation in COVID-19.

J Allergy Clin Immunol 2020 Jul 18;146(1):128-136.e4. Epub 2020 May 18.

Emergency Department, University Hospital, LMU Munich, Munich, Germany; Department of Medicine I, University Hospital, LMU Munich, Munich, Germany; German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany.

Background: Coronavirus disease 2019 (COVID-19) can manifest as a viral-induced hyperinflammation with multiorgan involvement. Such patients often experience rapid deterioration and need for mechanical ventilation. Currently, no prospectively validated biomarker of impending respiratory failure is available.

Objective: We aimed to identify and prospectively validate biomarkers that allow the identification of patients in need of impending mechanical ventilation.

Methods: Patients with COVID-19 who were hospitalized from February 29 to April 9, 2020, were analyzed for baseline clinical and laboratory findings at admission and during the disease. Data from 89 evaluable patients were available for the purpose of analysis comprising an initial evaluation cohort (n = 40) followed by a temporally separated validation cohort (n = 49).

Results: We identified markers of inflammation, lactate dehydrogenase, and creatinine as the variables most predictive of respiratory failure in the evaluation cohort. Maximal IL-6 level before intubation showed the strongest association with the need for mechanical ventilation, followed by maximal CRP level. The respective AUC values for IL-6 and CRP levels in the evaluation cohort were 0.97 and 0.86, and they were similar in the validation cohort (0.90 and 0.83, respectively). The calculated optimal cutoff values during the course of disease from the evaluation cohort (IL-6 level > 80 pg/mL and CRP level > 97 mg/L) both correctly classified 80% of patients in the validation cohort regarding their risk of respiratory failure.

Conclusion: The maximal level of IL-6, followed by CRP level, was highly predictive of the need for mechanical ventilation. This suggests the possibility of using IL-6 or CRP level to guide escalation of treatment in patients with COVID-19-related hyperinflammatory syndrome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaci.2020.05.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7233239PMC
July 2020

Cathepsin S Alterations Induce a Tumor-Promoting Immune Microenvironment in Follicular Lymphoma.

Cell Rep 2020 05 23;31(5):107522. Epub 2020 Apr 23.

Department of Medicine III, Laboratory for Experimental Leukemia and Lymphoma Research (ELLF), Hospital of the Ludwig-Maximilians-University (LMU), Munich, Bavaria 81377, Germany; German Cancer Consortium (DKTK), Munich, Bavaria 81377, Germany; German Cancer Research Center (DKFZ), Heidelberg, Baden-Wuerttemberg 69120, Germany. Electronic address:

Tumor cells orchestrate their microenvironment. Here, we provide biochemical, structural, functional, and clinical evidence that Cathepsin S (CTSS) alterations induce a tumor-promoting immune microenvironment in follicular lymphoma (FL). We found CTSS mutations at Y132 in 6% of FL (19/305). Another 13% (37/286) had CTSS amplification, which was associated with higher CTSS expression. CTSS Y132 mutations lead to accelerated autocatalytic conversion from an enzymatically inactive profrom to active CTSS and increased substrate cleavage, including CD74, which regulates major histocompatibility complex class II (MHC class II)-restricted antigen presentation. Lymphoma cells with hyperactive CTSS more efficiently activated antigen-specific CD4 T cells in vitro. Tumors with hyperactive CTSS showed increased CD4 T cell infiltration and proinflammatory cytokine perturbation in a mouse model and in human FLs. In mice, this CTSS-induced immune microenvironment promoted tumor growth. Clinically, patients with CTSS-hyperactive FL had better treatment outcomes with standard immunochemotherapies, indicating that these immunosuppressive regimens target both the lymphoma cells and the tumor-promoting immune microenvironment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2020.107522DOI Listing
May 2020

Cathepsin D Expression and Gemcitabine Resistance in Pancreatic Cancer.

JNCI Cancer Spectr 2020 Feb 16;4(1):pkz060. Epub 2019 Aug 16.

Department of Medicine II (UMM, EG, QL, FL, GB, JM), Department of Medicine III (SK, MvBB, VH, SB), Department of Radiation Oncology (CB), University Hospital, LMU-Munich, Munich, Germany; Department of Medicine A, University Medicine Greifswald, Greifswald, Germany (UMM, EL, GB, FUW, MS, MML, JM); National Institute for Health Research Liverpool Pancreas Biomedical Research Centre, University of Liverpool, UK (EC, WG, CH, PG, JPN); Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany (SO, TKi); Leibniz Institute for Prevention Research and Epidemiology - BIPS, Bremen, Germany (MM); Department of General, Visceral, and Tumor Surgery, University Hospital Cologne, Cologne, Germany (YZ, CJB); Department of Community Medicine, University Medicine Greifswald, Greifswald, Germany (TKo); Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany (JW, JGD); Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany (JPN, MWB); German Cancer Consortium, German Cancer Research Center, Heidelberg, Germany (TKi, VH, SB).

Background: Cathepsin-D (CatD), owing to its dual role as a proteolytic enzyme and as a ligand, has been implicated in cancer progression. The role of CatD in pancreatic ductal adenocarcinoma is unknown.

Methods: CatD expression quantified by immunohistochemistry of tumor-tissue microarrays of 403 resected pancreatic cancer patients from the ESPAC-Tplus trial, a translational study within the ESPAC (European Study Group for Pancreatic Cancer) trials, was dichotomously distributed to low and high H scores (cut off 22.35) for survival and multivariable analysis. The validation cohort (n = 69) was recruited based on the hazard ratio of CatD from ESPAC-Tplus. 5-fluorouracil-, and gemcitabine-resistant pancreatic cancer cell lines were employed for mechanistic experiments. All statistical tests were two-sided.

Results: Median overall survival was 23.75 months and median overall survival for patients with high CatD expression was 21.09 (95% confidence interval [CI] = 17.31 to 24.80) months vs 27.20 (95% CI = 23.75 to 31.90) months for low CatD expression (χ = 4.00;  = .04). Multivariable analysis revealed CatD expression as a predictive marker in gemcitabine-treated (z stat = 2.33;  = .02) but not in 5-fluorouracil-treated (z stat = 0.21;  = .82) patients. An independent validation cohort confirmed CatD as a negative predictive marker for survival (χ = 6.80;  = .009) and as an independent predictive marker in gemcitabine-treated patients with a hazard ratio of 3.38 (95% CI = 1.36 to 8.38, = .008). Overexpression of CatD was associated with a concomitant suppression of the acid sphingomyelinase, and silencing of CatD resulted in upregulation of acid sphingomyelinase with rescue of gemcitabine resistance.

Conclusions: Adjuvant gemcitabine is less effective in pancreatic ductal adenocarcinoma with high CatD expression, and thus CatD could serve as a marker for biomarker-driven therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jncics/pkz060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050148PMC
February 2020

[Onko-Nexus: A Bavarian "Caretaker Project" to Overcome the Interface Outpatient/Hospitalized Division - Three-Year Results].

Gesundheitswesen 2020 Apr 7. Epub 2020 Apr 7.

Medizinische Klinik und Poliklinik III, Ludwig-Maximilians-Universität München, München.

The Onko-Nexus ("Caretaker-Project"), sponsored by the Bavarian Ministry for Health and Nursing, is dedicated to improving the outpatient/hospitalized care interface issue for patients with highly complex malignant diseases requiring inpatient care in a university hospital. A total of 26 patients were recruited during the 3-year period of the project. The patients were managed and supported by 2 "Caretakers" (physician assistants), one from the outpatient unit and one working in the wards. Additionally, the university hospital provided a special consultation hour in an oncological private practice close to patient's home. After completion of the project, 9 patients and the 2 "Caretakers" were interviewed via guided qualitative interviews. The main benefits for the patients were intensive support, avoiding long journeys and the close contact between hospital and private practice. The project had a clear positive effect on the patients' quality of life.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/a-1128-038DOI Listing
April 2020

Ten things the hematologist wants you to know about CAR-T cells.

Intensive Care Med 2020 06 30;46(6):1243-1245. Epub 2020 Mar 30.

Working Party on Intensive Care Medicine in Hematologic and Oncologic Patients (iCHOP) of the German Society of Hematology and Medical Oncology (DGHO), Berlin, Germany.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00134-020-06002-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292811PMC
June 2020

Sixth Immunotherapy of Cancer conference (ITOC): advances and perspectives-a meeting report.

J Immunother Cancer 2020 02;8(1)

Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Klinikum der Ludwig-Maximilians-Universitat Munchen, Munich, Germany

Immunotherapy has moved to the forefront of cancer treatment, illustrated by the accelerating pace of novel therapy approvals. In this complex environment, scientists rely on cutting edge conferences to stay informed. The Immunotherapy of Cancer (ITOC) conference was established jointly with the Society of the Immunotherapy of Cancer to bring the European researchers together. In its sixth edition, the ITOC conference has recently been held in Vienna, Austria.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jitc-2019-000268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057436PMC
February 2020

Corrigendum: Abscopal Effects in Radio-Immunotherapy-Response Analysis of Metastatic Cancer Patients With Progressive Disease Under Anti-PD-1 Immune Checkpoint Inhibition.

Front Pharmacol 2019;10:1615. Epub 2020 Jan 31.

Faculty of Medicine and University Hospital Cologne, Department of Radiation Oncology and Cyberknife Center, University of Cologne, Cologne, Germany.

[This corrects the article DOI: 10.3389/fphar.2019.00511.].
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphar.2019.01615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7006368PMC
January 2020

Correction to: Expert statement on the ICU management of patients with thrombotic thrombocytopenic purpura.

Intensive Care Med 2020 Mar;46(3):570-571

Division of Pulmonary and Critical Care, Penn State University College of Medicine, Hershey, PA, USA.

The original version of this article unfortunately contained a mistake. The penultimate row of Table 4 shows INR > 1.5 which is incorrect. The correct figure is INR < 1.5. The authors apologize for the mistake. The correct table is given below.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00134-019-05904-7DOI Listing
March 2020

Systemic antitumor effect by regional hyperthermia combined with low-dose chemotherapy and immunologic correlates in an adolescent patient with rhabdomyosarcoma - a case report.

Int J Hyperthermia 2020 ;37(1):55-65

Immunoanalytics Research Group - Tissue Control of Immunocytes & Core Facility, Helmholtz Center, Munich, Germany.

An abscopal effect is a clinical observation whereby a local treatment is associated with regression of metastatic cancer at a site distant from the primary location of treatment. Here, we describe the clinical systemic effect induced by regional hyperthermia combined with low-dose chemotherapy and provide immunologic correlates. A 15-year-old patient had been diagnosed with alveolar rhabdomyosarcoma (ARMS). All previous treatment options failed in the patient including haploidentical stem cell transplantation and donor lymphocyte infusion. The patient presented with local and metastatic disease, and upon admission, underwent regional hyperthermia combined with low-dose chemotherapy. Immediately following therapy severe skin reactions were observed. Skin biopsies revealed an intraepithelial lymphocytic infiltration dominated by CD3/CD8 T cells with a regular network of dendritic cells. Clinical images compared before and during sequential treatment cycles showed complete metabolic response of the local tumor for more than 10 months of therapy. In addition, metastases completely regressed although they were not direct targets of regional hyperthermia. The systemic effect was associated with enhanced frequency of NK cells and T cells expressing the lectin-like natural-killer group 2 D activating receptor (NKG2D), an increase of the CD56 subset of NK cells, as well as an increase of effector/memory and effector CD8 and CD4 T cells in the blood while the percentage of CD25FOXP3 regulatory T cells declined. Regional hyperthermia combined with low-dose chemotherapy had the potential to create a systemic effect which was associated with activation of NK cells and T cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/02656736.2019.1709666DOI Listing
October 2020