Prognostic value of ascites in patients with liver cirrhosis undergoing cardiac surgery.

INTRODUCTION: Mild or moderate liver cirrhosis increases the risk of complications after cardiac surgery. Ascites is the most common complication associated with liver cirrhosis. However, the prognostic value of ascites on postoperative morbidity and mortality after cardiac surgery remains uninvestigated. METHODS: A retrospective study included 69 patients with preoperatively diagnosed liver cirrhosis who underwent cardiac surgery between January 2009 and January 2018 at the Department of Cardiothoracic Surgery, University Hospital of Cologne, Germany. The patients were divided into ascites and non-ascites groups based on preoperatively diagnosed ascites. Thirty-day mortality, postoperative complications, length of stay, and blood transfusions were analyzed postoperatively. RESULTS: Out of the total of 69 patients, 14 (21%) had preoperatively diagnosed ascites. Ascites group had more postoperative complications such as blood transfusions (packed red blood cells: 78.6% vs. 40.0%, p = 0.010; fresh frozen plasma: 57.1% vs. 29.1%, p = 0.049), acute kidney injury (78.6% vs. 45.5%, p = 0.027), longer ICU stay (8 vs. 3 days, p = 0.044) with prolonged mechanical ventilation (57.1% vs. 23.6%, p = 0.015) and tracheotomy (28.6% vs. 3.6%, p = 0.003). The 30-day mortality rate was significantly higher in the ascites group than in the non-ascites group (35.7% vs. 5.5%, p = 0.002). CONCLUSION: Ascites should be implemented in preoperative risk score assessments in cirrhotic patients undergoing cardiac surgery. Preoperative treatment of ascites could reduce the negative impact of ascites on postoperative complications after cardiac surgery. However, this needs to be thoroughly investigated in prospective randomized clinical trials.

Impact of the COVID-19 pandemic on training conditions and education in oncologic disciplines: a survey-based analysis.

PURPOSE: The COVID-19 pandemic has led to changes in global health care. Medical societies had to update guidelines and enhance new services such as video consultations. Cancer treatment had to be modified. The aim of this study is to ensure optimal care for cancer patients with the help of high-quality training even in times of crisis. We therefore conducted a nationwide survey of physicians in training in oncological disciplines during the pandemic to assess the impact on their education. METHODS: The survey was sent to tumour centres, hospitals, specialist societies, and working and junior research groups and distributed via newsletters and homepages. Interim results and a call for participation were published as a poster (DEGRO) [26] and in the German Cancer Society (DKG) journal FORUM [42]. The survey contained 53 questions on conditions of education and training and on clinical and scientific work. Statistics were carried out with LimeSurvey and SPSS (IBM Corp., Armonk, NY, USA). RESULTS: Between February and November 2022, 450 participants answered the survey, with radio-oncologists being the largest group (28%). Most colleagues (63%) had access to digital training methods. Virtual sessions were rated as a good alternative, especially as multidisciplinary meetings (54%) as well as in-house and external training programs (48%, 47%). The time spent by training supervisors on education was rated as less than before the pandemic by 57%. Half of all participants perceived communication (54%), motivation (44%) and atmosphere (50%) in the team as bad. The participants felt strongly burdened by extra work (55%) and by a changed team atmosphere (49%). One third felt a change in the quality of training during the pandemic and rated it as negative (35%). According to 37% of the participants, this had little influence on their own quality of work. Additional subgroup analyses revealed significant differences in gender, specialty and education level. CONCLUSION: In order to improve oncology training in times of crisis, access to digital training options and meetings should be ensured. Participants wish for regular team meetings in person to enable good team spirit, compensation for overtime work and sufficient time for training supervisors for discussion and feedback.

Tripartite antigen-agnostic combination immunotherapy cures established poorly immunogenic tumors.

BACKGROUND: Single-agent immunotherapy has shown remarkable efficacy in selected cancer entities and individual patients. However, most patients fail to respond. This is likely due to diverse immunosuppressive mechanisms acting in a concerted way to suppress the host anti-tumor immune response. Combination immunotherapy approaches that are effective in such poorly immunogenic tumors mostly rely on precise knowledge of antigenic determinants on tumor cells. Creating an antigen-agnostic combination immunotherapy that is effective in poorly immunogenic tumors for which an antigenic determinant is not known is a major challenge. METHODS: We use multiple cell line and poorly immunogenic syngeneic, autochthonous, and autologous mouse models to evaluate the efficacy of a novel combination immunotherapy named tripartite immunotherapy (TRI-IT). To elucidate TRI-ITs mechanism of action we use immune cell depletions and comprehensive tumor and immune infiltrate characterization by flow cytometry, RNA sequencing and diverse functional assays. RESULTS: We show that combined adoptive cellular therapy (ACT) with lymphokine-activated killer cells, cytokine-induced killer cells, Vγ9Vδ2-T-cells (γδ-T-cells) and T-cells enriched for tumor recognition (CTLs) display synergistic antitumor effects, which are further enhanced by cotreatment with anti-PD1 antibodies. Most strikingly, the full TRI-IT protocol, a combination of this ACT with anti-PD1 antibodies, local immunotherapy of agonists against toll-like receptor 3, 7 and 9 and pre-ACT lymphodepletion, eradicates and induces durable anti-tumor immunity in a variety of poorly immunogenic syngeneic, autochthonous, as well as autologous humanized patient-derived models. Mechanistically, we show that TRI-IT coactivates adaptive cellular and humoral, as well as innate antitumor immune responses to mediate its antitumor effect without inducing off-target toxicity. CONCLUSIONS: Overall, TRI-IT is a novel, highly effective, antigen-agnostic, non-toxic combination immunotherapy. In this study, comprehensive insights into its preclinical efficacy, even in poorly immunogenic tumors, and mode of action are given, so that translation into clinical trials is the next step.

Independent risk factors for myasthenic crisis and disease exacerbation in a retrospective cohort of myasthenia gravis patients.

BACKGROUND: Myasthenic crisis (MC) and disease exacerbation in myasthenia gravis (MG) are associated with significant lethality and continue to impose a high disease burden on affected patients. Therefore, we sought to determine potential predictors for MC and exacerbation as well as to identify factors affecting outcome. METHODS: We examined a retrospective, observational cohort study of patients diagnosed with MG between 2000 and 2021 with a mean follow-up of 62.6 months after diagnosis from eight tertiary hospitals in Germany. A multivariate Cox regression model with follow-up duration as the time variable was used to determine independent risk factors for MC and disease exacerbation. RESULTS: 815 patients diagnosed with MG according to national guidelines were included. Disease severity at diagnosis (quantitative MG score or Myasthenia Gravis Foundation of America class), the presence of thymoma and anti-muscle specific tyrosine kinase-antibodies were independent predictors of MC or disease exacerbation. Patients with minimal manifestation status 12 months after diagnosis had a lower risk of MC and disease exacerbation than those without. The timespan between diagnosis and the start of immunosuppressive therapy did not affect risk. Patients with a worse outcome of MC were older, had higher MGFA class before MC and at admission, and had lower vital capacity before and at admission. The number of comorbidities, requirement for intubation, prolonged mechanical ventilation, and MC triggered by infection were associated with worse outcome. No differences between outcomes were observed comparing treatments with IVIG (intravenous immunoglobulin) vs. plasma exchange vs. IVIG together with plasma exchange. CONCLUSIONS: MC and disease exacerbations inflict a substantial burden of disease on MG patients. Disease severity at diagnosis and antibody status predicted the occurrence of MC and disease exacerbation. Intensified monitoring with emphasis on the prevention of infectious complications could be of value to prevent uncontrolled disease in MG patients.

Eculizumab versus rituximab in generalised myasthenia gravis.

OBJECTIVE: Myasthenia gravis (MG) is the most common autoimmune disorder affecting the neuromuscular junction. However, evidence shaping treatment decisions, particularly for treatment-refractory cases, is sparse. Both rituximab and eculizumab may be considered as therapeutic options for refractory MG after insufficient symptom control by standard immunosuppressive therapies. METHODS: In this retrospective observational study, we included 57 rituximab-treated and 20 eculizumab-treated patients with MG to compare the efficacy of treatment agents in generalised, therapy-refractory anti-acetylcholine receptor antibody (anti-AChR-ab)-mediated MG with an observation period of 24 months. Change in the quantitative myasthenia gravis (QMG) score was defined as the primary outcome parameter. Differences between groups were determined in an optimal full propensity score matching model. RESULTS: Both groups were comparable in terms of clinical and demographic characteristics. Eculizumab was associated with a better outcome compared with rituximab, as measured by the change of the QMG score at 12 and 24 months of treatment. Minimal manifestation of disease was more frequently achieved in eculizumab-treated patients than rituximab-treated patients at 12 and 24 months after baseline. However, the risk of myasthenic crisis (MC) was not ameliorated in either group. INTERPRETATION: This retrospective, observational study provides the first real-world evidence supporting the use of eculizumab for the treatment of refractory, anti-AChR-ab positive MG. Nonetheless, the risk of MC remained high and prompts the need for intensified monitoring and further research effort aimed at this vulnerable patient cohort.

Linear Endobronchial Ultrasound in the Era of Personalized Lung Cancer Diagnostics-A Technical Review.

Major advances in molecular profiling for available targeted treatments and immunotherapy for lung cancer have significantly increased the complexity of tissue-based diagnostics. Endobronchial ultrasound-guided transbronchial needle aspirations (EBUS-TBNA) are commonly performed for diagnostic biopsies and lymph node staging. EBUS-TBNA has increasingly become one of the main sources of tumor cells for molecular analyses. As a result, there is a growing need for high quality EBUS-TBNA samples with adequate cellularity. This has increased the technical demands of the procedure and has created additional challenges, many of which are not addressed in the current EBUS guidelines. This review provides an overview of current evidence on the technical aspects of EBUS-TBNA in light of comprehensive sample processing for personalized lung cancer management. These include sonographic lymph node characterization, optimal needle choice, suction biopsy technique, and the role of rapid on-site evaluation. Attention to these technical details will be important to maximize the throughput of EBUS-TBNA biopsies for molecular testing.

Detection of circulating tumor DNA by digital droplet PCR in resectable lung cancer as a predictive tool for recurrence.

Lung cancer is the leading cause of cancer-related mortality worldwide due to difficulties in early detection and high postsurgical recurrence rate. Current European Guidelines recommend follow-up via computerized tomography (CT) scans on regular basis within the first 2 years after radical surgical resection. Despite these efforts, recurrence rates remain high with 30-70 %. Therefore, it is imperative to develop predictive markers for metastases and postsurgical recurrence using minimally invasive methods. This prospective study aims at defining the feasibility of detecting circulating tumor DNA (ctDNA) in presurgical plasma samples of patients with lung cancer by digital droplet PCR. Resected tumor tissue and simultaneous blood samples were collected from 24 patients with lung cancer in stage I-IIIA (12 stage I, 8 stage II, 4 stage III). Genomic DNA from the tumor tissue samples were analyzed for hotspot mutations using a 17 gene panel next-generation sequencing (NGS) assay. CtDNA from corresponding plasma samples were analyzed using digital droplet PCR (ddPCR). Additionally, DNA sequencing results were correlated with patients' outcome. At least one somatic mutation was detected by NGS (96 %) in 23 of the tested tissue samples. DdPCR detected mutations in circulating cell-free DNA (ccfDNA) of nine patients' samples (9/23, 39 %). Postsurgical outcome analysis was performed for those patients who had received complete tumor resection (n = 21). Four of them suffered from an early relapse within the first two years after surgery, including two with detectable somatic mutations in ccfDNA during primary staging. Taken together, we showed that the 17 gene panel assay revealed in 23 of 24 patients at least one somatic mutation in the primary tumor by NGS. Tumor-specific mutation was detectable in 39 % from the blood of early stage lung cancer patients by ddPCR.

Circulating tumor DNA as an emerging liquid biopsy biomarker for early diagnosis and therapeutic monitoring in hepatocellular carcinoma.

As one of the most common malignant tumors worldwide, hepatocellular carcinoma (HCC) is known for its poor prognosis due to diagnosis only in advanced stages. Nearly 50% of the patients with the first diagnosis of HCC die within a year. Currently, the advancements in the integration of omics information have begun to transform the clinical management of cancer patients. Molecular profiling for HCC patients is in general obtained from resected tumor materials or biopsies. However, the resected tumor tissue is limited and can only be obtained through surgery, so that dynamic monitoring of patients cannot be performed. Compared to invasive procedures, circulating tumor DNA (ctDNA) has been proposed as an alternative source to perform molecular profiling of tumor DNA in cancer patients. The detection of abnormal forms of circulating cell-free DNA (cfDNA) that originate from cancer cells (ctDNA) provides a novel tool for cancer detection and disease monitoring. This may also be an opportunity to optimize the early diagnosis of HCC. In this review, we summarized the updated methods, materials, storage of sampling, detection techniques for ctDNA and the comparison of the applications among different biomarkers in HCC patients. In particular, we analyzed ctDNA studies dealing with copy number variations, gene integrity, mutations (RAS, TERT, CTNNB1, TP53 and so on), DNA methylation alterations (DBX2, THY1, TGR5 and so on) for the potential utility of ctDNA in the diagnosis and management of HCC. The biological functions and correlated signaling pathways of ctDNA associated genes (including MAPK/RAS pathway, p53 signaling pathway and Wnt-ß catenin pathway) are also discussed and highlighted. Thus, exploration of ctDNA/cfDNA as potential biomarkers may provide a great opportunity in future liquid biopsy applications for HCC.

Identification of targeted therapy options for gastric adenocarcinoma by comprehensive analysis of genomic data.

BACKGROUND: So far only trastuzumab, pembrolizumab and ramucirumab have been approved by the FDA for targeted therapy in gastric cancer (GC). Here we report on potential targeted therapy options for gastric adenocarcinoma based on a novel analysis of "The Cancer Genome Atlas (TCGA)" database. METHODS: One hundred two FDA-approved targeted cancer drugs were compiled and molecular targets defined. Drugs were considered as potentially effective if targeted genes showed (1) an increase in copy number, (2) gain of function with oncogene activation, (3) specific alterations responsive to approved drugs. Additionally, genetic changes that confer drug resistance and/or sensitivity were evaluated. RESULTS: Fifty percentage of patients with GC may be treatable with non-GC but FDA-approved targeted cancer therapies. The major drug identified in our in silico study for GC is copanlisib, a PI3K inhibitor. In the TCGA patient database, our genetically based drug response prediction identified more patients with alterations sensitive to copanlisib compared to the already-GC-approved drug trastuzumab (20%, 78 out of 393 patients, vs. trastuzumab: 13%, 52 of 393 patients), which is mainly due to the high incidence of PIK3CA gain of function mutations within mutation hot spots. CONCLUSION: Our results demonstrate that various currently FDA-approved drugs might be candidates for targeted therapy of GC. For clinical trials, cancer patients should be selected based on the genomic profile of their tumor.

Higher incidence of perivalvular abscess determines perioperative clinical outcome in patients undergoing surgery for prosthetic valve endocarditis.

BACKGROUND: Cardiac surgery for prosthetic valve endocarditis (PVE) is associated with substantial mortality. We aimed to analyze 30-day and 1-year outcome in patients undergoing surgery for PVE and sought to identify preoperative risk factors for mortality with special regard to perivalvular infection. METHODS: We retrospectively analyzed data of 418 patients undergoing valve surgery for infective endocarditis between January 2009 and July 2018. After 1:1 propensity matching 158 patients (79 PVE/79 NVE) were analyzed with regard to postoperative 30-day and 1-year outcomes. Univariate and multivariable analyses were performed to identify potential risk factors for mortality. RESULTS: 315 patients (75.4%) underwent surgery for NVE and 103 (24.6%) for PVE. After propensity matching groups were comparable with regard to preoperative characteristics, clinical presentation and microbiological findings, except a higher incidence of perivalvular infection in patients with PVE (51.9%) compared to NVE (26.6%) (p = 0.001), longer cardiopulmonary bypass (166 [76-130] vs. 97 [71-125] min; p < 0.001) and crossclamp time (95 [71-125] vs. 68 [55-85] min; p < 0.001). Matched patients with PVE showed a 4-fold increased 30-day mortality (20.3%) in comparison with NVE patients (5.1%) (p = 0.004) and 2-fold increased 1-year mortality (PVE 29.1% vs. NVE 13.9%; p = 0.020). Multivariable analysis revealed perivalvular abscess, sepsis, preoperative AKI and PVE as independent risk factors for mortality. Patients with perivalvular abscess had a significantly higher 30-day mortality (17.7%) compared to patients without perivalvular abscess (8.0%) (p = 0.003) and a higher rate of perioperative complications (need for postoperative pacemaker implantation, postoperative cerebrovascular events, postoperative AKI). However, perivalvular abscess did not influence 1-year mortality (20.9% vs. 22.3%; p = 0.806), or long-term complications such as readmission rate or relapse of IE. CONCLUSIONS: Patients undergoing surgery for PVE had a significantly higher 30-day and 1-year mortality compared to NVE. After propensity-matching 30-day mortality was still 4-fold increased in PVE compared to NVE. Patients with perivalvular abscess showed a significantly higher 30-day mortality and perioperative complications, whereas perivalvular abscess seems to have no relevant impact on 1-year mortality, the rate of readmission or relapse of IE.

Characteristics and outcomes of patients with right-sided endocarditis undergoing cardiac surgery.

BACKGROUND: There has been an increasing incidence of right-sided infective endocarditis (RSIE) due to the global rise of intravenous drug use (IVDU) and an increasing number of implantable cardiac electronic devices and central venous catheters. Our aim was to investigate differences in the clinical presentation, microbiological findings and prognosis of patients undergoing surgery for RSIE compared to left-sided infective endocarditis (LSIE). METHODS: Relevant clinical data of all 432 consecutive patients undergoing valve surgery for infective endocarditis (IE) at our institution between January 2009 and December 2018 were retrospectively analyzed. Acquired data included patients' demographic and preoperative comorbidities, manifestation of IE according to the recently modified Duke Criteria, perioperative data and relevant clinical outcomes. RESULTS: A total of 403 patients (93.3%) underwent surgery for LSIE and twenty-nine patients (6.7%) for RSIE. Eleven patients with RSIE (37.9%) showed a concomitant left-sided infection. Compared to LSIE, RSIE patients were significantly younger [47.5 (40.4-69.3) vs. 65.1 (53.7-74.6); P=0.008] and presented with less comorbidities such as hypertension (41.4% vs. 65.3%; P=0.010) and coronary artery disease (6.9% vs. 29.0%; P=0.010). Rates of IVDU (34.5% vs. 4.5%; P<0.001), human immunodeficiency virus (HIV) (10.3% vs. 1.7%; P=0.023) and hepatitis C virus (HCV) infection (24.1% vs. 5.2%; P=0.001) were greater in RSIE. The proportion of Staphylococcus aureus IE was significantly higher in RSIE compared to LSIE (37.9% vs. 21.1%; P=0.035). 30-day mortality was 6.9% after surgery for RSIE compared to 14.6% after operation for LSIE (P=0.372). CONCLUSIONS: Patients undergoing surgery for RSIE compared to LSIE presented with a higher rate of pulmonary septic emboli, more Staphylococcus aureus infections and larger vegetations. Larger multicenter prospective trials are needed to provide more reliable data on the clinical profile of these patients, in order to determine optimal surgical management.

Severity of Presentation, Not Sex, Increases Risk of Surgery for Infective Endocarditis.

BACKGROUND: Cardiac surgery for infective endocarditis (IE) is associated with substantial short- and long-term mortality, and female sex seems to be associated with even worse outcomes. The aim of our study was to analyze the impact of sex on 30-day and long-term mortality and to identify sex-related risk factors in IE patients requiring cardiac surgery. METHODS: Relevant clinical data of all consecutive 305 patients undergoing cardiac surgery for IE between 2009 and 2016 were extracted from our institutional database and retrospectively analyzed. Infective endocarditis was defined according to the recent modified Duke criteria and surgery indicated in compliance with current European Society of Cardiology guidelines. Sex-related postoperative outcomes including 30-day and 1-year mortality were recorded. Univariate and multivariable analysis was performed to identify potential sex-dependent risk factors. RESULTS: In all, 229 male patients (75.1%) and 76 female patients (24.9%) underwent surgery for IE. Female patients showed significantly more mitral valve infection (52.6% versus 33.6%, p = 0.003), and Staphylococcus aureus as causative microorganisms was diagnosed in 44.7% of female patients compared with 24.5% of male patients (p = 0.001). Female sex was associated with a higher 30-day mortality (18.4% versus 8.3%, p = 0.014) and 1-year mortality (46.1% versus 27.1%, p = 0.002). Multivariable analysis revealed not female sex, but European System for Cardiac Operative Risk Evaluation II score, reexploration for bleeding, and postoperative acute kidney injury as independent risk factors for 30-day mortality and preoperative dialysis for 1-year mortality, respectively. CONCLUSIONS: In this study, female sex was associated with more severe manifestations of IE and significantly higher 30-day and 1-year mortality. After multivariable analysis, not female sex, but the underlying comorbidities seem to determine clinical outcomes.

Somatic alterations in circulating cell-free DNA of oesophageal carcinoma patients during primary staging are indicative for post-surgical tumour recurrence.

Oesophageal cancer (OC) has high mortality. This study aims at determining the feasibility of liquid biopsies for genomic profiling in early stage OC, comparing two different technologies for mutational analysis in circulating cell -free DNA (ccfDNA) and evaluating the clinical impact of these somatic alterations during primary staging. In 25 patients with locally advanced OC, endoscopic tumour biopsies and simultaneous blood samples were taken during primary staging. Genomic DNA from biopsies and ccfDNA were analysed for mutations using a 12 gene panel next-generation sequencing (NGS) assay as well as digital droplet PCR (ddPCR). Genetic data was correlated with patients' outcome. In 21 of the tested biopsies (84%) at least one somatic mutation was detected by NGS. Mutations detected by NGS were detectable by ddPCR with similar allele frequencies. In three out of the 21 patients with proven mutations, the same mutations were also detectable in ccfDNA using NGS (14%). In contrast, ddPCR detected mutations in ccfDNA of five additional patients (8/21, 38%). Post-surgical outcome analysis was performed for those patients who had received complete tumour resection (n = 16). Five of them suffered from an early relapse within the first year after surgery, including four with detectable somatic mutations in ccfDNA during primary staging. Taken together, we showed a higher sensitivity for ddPCR compared to NGS in detecting mutated ccfDNA in OC. Detection of somatically altered ccfDNA during primary staging seems to be indicative for post-surgical tumour recurrence.

Effect of preoperative low serum albumin on postoperative complications and early mortality in patients undergoing transcatheter aortic valve replacement.

BACKGROUND: Patients undergoing transcatheter aortic valve replacement (TAVR) are mostly elderly patients with substantial comorbidities. Established risk scores are not validated for TAVR and collectives with elderly patients making periprocedural risk stratification difficult. Serum albumin is known to be an indicator for malnutrition and frailty and is simple to measure, independent of physician's bias. Using serum albumin as a preoperative marker for postoperative complications might help estimating morbidity and mortality of these patients. METHODS: A total of 457 patients with severe symptomatic aortic stenosis undergoing TAVR at our institution in a period from January 2014 to December 2015 were included in this retrospective study. Baseline characteristics as well as preoperative laboratory parameters were registered. Postoperative morbidity and 30-day mortality were analyzed as primary end points. Enrolled patients with preoperative low serum albumin (<3.5 g/dL) were compared with those revealing normal serum albumin (≥3.5 g/dL). RESULTS: Among 457 patients, 51 (11%) presented pre-procedural low serum albumin and 406 (89%) had normal serum albumin. Patients' mean age was 81±6 years and 50% of them were male. Postoperative complications such as requirement of blood transfusions (63% versus 33%, P<0.001), infection (53% versus 24%, P<0.001), acute kidney injury (41% versus 19%, P=0.001) and 30-day mortality (10% versus 3%, P=0.045) showed significant differences between preoperative low and normal albumin groups. CONCLUSIONS: Preoperative low serum albumin might be an indicator for higher morbidity and mortality in patients undergoing TAVR.

Spatiotemporally restricted arenavirus replication induces immune surveillance and type I interferon-dependent tumour regression.

Immune-mediated effector molecules can limit cancer growth, but lack of sustained immune activation in the tumour microenvironment restricts antitumour immunity. New therapeutic approaches that induce a strong and prolonged immune activation would represent a major immunotherapeutic advance. Here we show that the arenaviruses lymphocytic choriomeningitis virus (LCMV) and the clinically used Junin virus vaccine (Candid#1) preferentially replicate in tumour cells in a variety of murine and human cancer models. Viral replication leads to prolonged local immune activation, rapid regression of localized and metastatic cancers, and long-term disease control. Mechanistically, LCMV induces antitumour immunity, which depends on the recruitment of interferon-producing Ly6C+ monocytes and additionally enhances tumour-specific CD8+ T cells. In comparison with other clinically evaluated oncolytic viruses and to PD-1 blockade, LCMV treatment shows promising antitumoural benefits. In conclusion, therapeutically administered arenavirus replicates in cancer cells and induces tumour regression by enhancing local immune responses.

CD169+ macrophages regulate PD-L1 expression via type I interferon and thereby prevent severe immunopathology after LCMV infection.

Upon infection with persistence-prone virus, type I interferon (IFN-I) mediates antiviral activity and also upregulates the expression of programmed death ligand 1 (PD-L1), and this upregulation can lead to CD8+ T-cell exhaustion. How these very diverse functions are regulated remains unknown. This study, using the lymphocytic choriomeningitis virus, showed that a subset of CD169+ macrophages in murine spleen and lymph nodes produced high amounts of IFN-I upon infection. Absence of CD169+ macrophages led to insufficient production of IFN-I, lower antiviral activity and persistence of virus. Lack of CD169+ macrophages also limited the IFN-I-dependent expression of PD-L1. Enhanced viral replication in the absence of PD-L1 led to persistence of virus and prevented CD8+ T-cell exhaustion. As a consequence, mice exhibited severe immunopathology and died quickly after infection. Therefore, CD169+ macrophages are important contributors to the IFN-I response and thereby influence antiviral activity, CD8+ T-cell exhaustion and immunopathology.

IL-10 Induces T Cell Exhaustion During Transplantation of Virus Infected Hearts.

BACKGROUND/AIMS: Unexpected transmissions of viral pathogens during solid organ transplantation (SOT) can result in severe, life-threatening diseases in transplant recipients. Immune activation contributes to disease onset. However mechanisms balancing the immune response against transmitted viral infection through organ transplantation remain unknown. Methods & RESULTS: Here we found, using lymphocytic choriomeningitis virus (LCMV), that transplantation of LCMV infected hearts led to exhaustion of virus specific CD8+ T cells, viral persistence in organs and survival of graft and recipient. Genetic depletion of Interleukin-10 (IL-10) resulted in strong immune activation, graft dysfunction and death of mice, suggesting that IL-10 was a major regulator of CD8+ T cell exhaustion during SOT. In the presence of memory CD8+ T cells, virus could be controlled. However sufficient antiviral immune response resulted in acute rejection of transplanted heart. CONCLUSION: We found that virus transmitted via SOT could not be controlled by naïve mice recipients due to IL-10 mediated CD8+ T cell exhaustion which thereby prevented immunopathology and graft failure whereas memory mice recipients were able to control the virus and induced graft failure.

High Frequencies of Anti-Host Reactive CD8+ T Cells Ignore Non-Hematopoietic Antigen after Bone Marrow Transplantation in a Murine Model.

BACKGROUND: Graft versus host disease (GvHD) occurs in 20% of cases with patients having an MHC I matched bone marrow transplantation (BMT). Mechanisms causing this disease remain to be studied. METHODS: Here we used a CD8+ T cell transgenic mouse line (P14/CD45.1+) and transgenic DEE mice bearing ubiquitously the glycoprotein 33-41 (GP33) antigen derived from the major lymphocytic choriomeningitis virus (LCMV) epitope to study mechanisms of tolerance in anti-host reactive CD8+ T cells after BMT. RESULTS: We found that anti-host reactive CD8+ T cells (P14 T cells) were not negatively selected in the thymus and that they were present in wild type (WT) recipient mice as well as in DEE recipient mice. Anti-host reactive CD8+ T cells ignored the GP33 antigen expressed ubiquitously by host cells but they could be activated ex vivo via LCMV-infection. Lipopolysaccharides (LPS) induced transient cell damage in DEE mice bearing anti-host reactive CD8+ T cells after BMT, suggesting that induction of host inflammatory response could break antigen ignorance. Introducing the GP33 antigen into BM cells led to deletion of anti-host reactive CD8+ T cells. CONCLUSION: We found that after BMT anti-host reactive CD8+ T cells ignored host antigen in recipients and that they were only deleted when host antigen was present in hematopoietic cells. Moreover, LPS-induced immune activation contributed to induction of alloreactivity of anti-host reactive CD8+ T cells after BMT.

Virus-specific antibodies allow viral replication in the marginal zone, thereby promoting CD8(+) T-cell priming and viral control.

Clinically used human vaccination aims to induce specific antibodies that can guarantee long-term protection against a pathogen. The reasons that other immune components often fail to induce protective immunity are still debated. Recently we found that enforced viral replication in secondary lymphoid organs is essential for immune activation. In this study we used the lymphocytic choriomeningitis virus (LCMV) to determine whether enforced virus replication occurs in the presence of virus-specific antibodies or virus-specific CD8(+) T cells. We found that after systemic recall infection with LCMV-WE the presence of virus-specific antibodies allowed intracellular replication of virus in the marginal zone of spleen. In contrast, specific antibodies limited viral replication in liver, lung, and kidney. Upon recall infection with the persistent virus strain LCMV-Docile, viral replication in spleen was essential for the priming of CD8(+) T cells and for viral control. In contrast to specific antibodies, memory CD8(+) T cells inhibited viral replication in marginal zone but failed to protect mice from persistent viral infection. We conclude that virus-specific antibodies limit viral infection in peripheral organs but still allow replication of LCMV in the marginal zone, a mechanism that allows immune boosting during recall infection and thereby guarantees control of persistent virus.