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Despite routine use of DNA-hypomethylating agents (HMAs) in AML/MDS therapy, their mechanisms of action are not yet unraveled. Pleiotropic effects of HMAs include global methylome and transcriptome changes. We asked whether in blasts and T-cells from AML patients HMA-induced in vivo demethylation and remethylation occur randomly or non-randomly, and whether gene demethylation is associated with gene induction. Peripheral blood AML blasts from patients receiving decitabine (20 mg/m2 day 1–5) were serially isolated for methylome analyses (days 0, 8 and 15, n = 28) and methylome-plus-transcriptome analyses (days 0 and 8, n = 23), respectively. T-cells were isolated for methylome analyses (days 0 and 8; n = 16). We noted massive, non-random demethylation at day 8, which was variable between patients. In contrast, T-cells disclosed a thousand-fold lesser, random demethylation, indicating selectivity of the demethylation for the malignant blasts. The integrative analysis of DNA demethylation and transcript induction revealed 87 genes displaying a significant inverse correlation, e.g. the tumor suppressor gene IFI27, whose derepression was validated in two AML cell lines. These results support HMA-induced, non-random early in vivo demethylation events in AML blasts associated with gene induction. Larger patient cohorts are needed to determine whether a demethylation signature may be predictive for response to this treatment.

Background Alveolar echinococcosis (AE) is an endemic parasitic zoonosis in Germany. In most cases, the liver is the primary organ affected. Case presentation A 59-year old female patient presented with increasing exertional dyspnea and unintentional weight loss. A computed tomography (CT) scan showed a left-sided chylous pleural effusion and multiple intrahepatic masses with infiltration of the diaphragm and the pleura. The findings were initially misinterpreted as hepatocellular carcinoma (HCC) with infiltrating growth. Liver biopsy of one of the masses showed no evidence of malignancy, but an amorphous necrosis of unclear origin. HCC was further ruled out by magnetic resonance imaging (MRI). However, MRI findings were highly suspicious for hepatothoracic dissemination and complications due to AE. Typical histologic findings in a repeated and more specific examination of the liver tissue and a positive serology for echinococcosis confirmed the diagnosis of AE. As the hepatic and pulmonary manifestations were considered inoperable in a curative matter, an anti-parasitic treatment with albendazole was initiated. A video-assisted thoracoscopic surgery (VATS) with removal of the chylous effusion as well as a talc pleurodesis was performed to relieve the patient from dyspnea. Two months later, the patient was asymptomatic and a positron emission tomography (PET)-CT-scan with [18 F] fluoro-2-deoxy-d-glucose (FDG) showed a remarkable diminution of the hepatic manifestation. Conclusions This case demonstrates a rare presentation of alveolar echinococcosis with a focus on pulmonary symptoms, emphasizing the importance of evaluation for pulmonary involvement in patients with AE and respiratory symptoms.

Wilms’ tumor 1 (WT1) protein is highly immunogenic and overexpressed in acute myeloid leukemia (AML), consequently ranked as a promising target for novel immunotherapeutic strategies. Here we report our experience of a phase I/II clinical trial (NCT01051063) of a vaccination strategy based on WT1 recombinant protein (WT1-A10) together with vaccine adjuvant AS01B in five elderly AML patients (median age 69 years, range 63–75) receiving a total of 62 vaccinations (median 18, range 3–20) after standard chemotherapy. Clinical benefit was observed in three patients: one patient achieved measurable residual disease clearance during WT1 vaccination therapy, another patient maintained long-term molecular remission over 59 months after the first vaccination cycle. Interestingly, in one case, we observed a complete clonal switch at AML relapse with loss of WT1 expression, proposing suppression of the original AML clone by WT1-based vaccination therapy. Detected humoral and cellular CD4+ T cell immune responses point to efficient immune stimulation post-vaccination, complementing hints for induced conventional T cell infiltration into the bone marrow and a shift from senescent/exhausted to a more activated T cell profile. Overall, the vaccinations with WT1 recombinant protein had an acceptable safety profile and were thus well tolerated.To conclude, our data provide evidence of potential clinical efficacy of WT1 protein-based vaccination therapy in AML patients, warranting further investigations.

Vaccination is considered one of the most important achievements of modern medicine and has saved millions of lives. As a result, the age-old fear of severe or fatal infectious diseases has largely been forgotten in society; however, the pandemic triggered by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) shows how quickly this fear can return. Also, many people have reservations about medical measures, especially if they are directed against vague dangers. Paradoxically, the success of vaccinations jeopardizes the acceptance. To counteract this development, this article provides information on basic vaccination principles, legal frameworks and components of vaccines. It explains the most important categories, goals, core elements of vaccination programs and the most important recommendations of the Standing Committee on Vaccination at the Robert Koch Institute (STIKO). It explains the current state of knowledge with respect to required resources, assessment of vaccine reactions, complication management and possible vaccine damage.

Treatment of myelodysplastic syndromes includes the administration of the hypomethylating agent decitabine. An early platelet response in decitabine-treated myelodysplastic syndrome patients is a predictor of overall survival. The effect of decitabine on megakaryocytes and the bone marrow, however, is understudied. We show that an early platelet increment was not detectable in healthy mice during decitabine treatment. Analyses of bone marrow sections revealed vessels with dilated lumina, decreased cellularity, but increased number of red blood cells and the presence of (pro)platelet-like particles. Taken together, decitabine treatment of healthy mice does not induce an early platelet increment, but affects the bone marrow.

ZusammenfassungDie Formale Begriffsanalyse vermag aus den Daten zu Gegenständen und deren Merkmalen eine Datenstruktur zu ermitteln. Es wird ein weitgehend automatisierbares Verfahren vorgestellt, das ausgehend von Elementarsätzen in Form von RDF-Tripeln in einem iterativen Bottom-up-Prozess mittels Semantischer Netze und der Formalen Begriffsanalyse zu einem Ontologieschema führt. Neben der Taxonomie der Klassen wird hierbei auch eine Taxonomie der Relationstypen erstellt. Die durch die Formale Begriffsanalyse automatisch erstellten Merkmalimplikationen können für die Qualitätssicherung herangezogen werden. Führt diese zu Korrekturen und Erweiterungen der Elementarsätze, wird der Prozess wiederholt. Das resultierende Ontologieschema wird in ein Entity-Relationship-Diagramm überführt, das die Grundlage für ein konzeptionelles Datenbankschema liefert. Zur Demonstration des Verfahrens wird exemplarisch eine Ontologie eines Wissensgebiets erstellt.Alle Überlegungen zur Erstellung des Ontologieschemas lassen sich prinzipiell auch bei der Erstellung und Ausarbeitung beliebiger semantischer Datenschemata anwenden. Somit bietet diese Bottom-up-Methode die Chance, die Generierung des Datenbankschemas algorithmisch durch Beispielsammlungen zu unterstützen. Da jeder Schritt im Verfahren nachvollziehbar und somit von der Person des Modellierers unabhängig ist, liefert das Verfahren einen Beitrag zur Automatisierung der Modellierung, insbesondere von Ontologien.

Myelodysplastic syndrome (MDS) with isolated deletion of chromosome 5q (MDS del5q) is a distinct subtype of MDS with quite favorable prognosis and excellent response to treatment with lenalidomide. Still, a relevant percentage of patients do not respond to lenalidomide and even experience progression to acute myeloid leukemia (AML). In this study, we aimed to investigate whether global DNA methylation patterns could predict response to lenalidomide. Genome-wide DNA methylation analysis using Illumina 450k methylation arrays was performed on n=51 patients with MDS del5q who were uniformly treated with lenalidomide in a prospective multicenter trial of the German MDS study group. To study potential direct effects of lenalidomide on DNA methylation, 17 paired samples pre- and post-treatment were analyzed. Our results revealed no relevant effect of lenalidomide on methylation status. Furthermore, methylation patterns prior to therapy could not predict lenalidomide response. However, methylation clustering identified a group of patients with a trend towards inferior overall survival. These patients showed hypermethylation of several interesting target genes, including genes of relevant signaling pathways, potentially indicating the evaluation of novel therapeutic targets. Supplementary Information The online version contains supplementary material available at 10.1007/s00277-021-04492-1.

Purpose Infectious complications are as high as 30% in elective colorectal surgery. In recent years, several studies have discussed the topic of preoperative bowel decontamination prior to colorectal surgery in order to reduce postoperative infectious complications and have found significant effects of oral antibiotic administration with a large variety of drugs used. No study has evaluated the combination of oral paromomycin and metronidazole in this context. Methods We performed a prospective single-center study with a matched-pair retrospective cohort to evaluate postoperative infectious complications (superficial site infections, organ space abscess, anastomotic leakage) in elective colorectal surgery. Patients A total of 120 patients were available for study inclusion; 101 gave informed consent and were included. A total of 92 patients were matched and subsequently analyzed. We could show a reduction in overall infectious complications in the intervention group (15.2% vs 30.8%, p = 0.018; odds ratio 0.333, 95% CI 0.142–0.784) as well as a reduction in superficial surgical site infections (8.7 vs 19.6%, p = 0.041, OR 0.333, 95% CI 0.121–0.917). The frequency of the other infectious complications such as intraabdominal abscesses and anastomotic leakage showed a tendency towards decreased frequencies in the intervention group (OR 0.714, 95% CI 0.235–2.169 and OR 0.571; 95% CI 0.167–1.952, respectively). Finally, the oral antibiotic administration led to an almost significantly reduced length of stay (12.24 days vs 15.25 days; p = 0.057). Conclusions Oral paromomycin and metronidazole with intravenous ertapenem effectively reduce infectious complications in elective colorectal surgery. Trial registration The study was registered at Clinicaltrials.gov (NCT03759886) December 17, 2018

Die chronischen myelomonozytaren Leukamien (CMML) sind klonale Stammzellerkrankungen mit persistierendem Nachweis einer Monozytose im peripheren Blut. Die Festlegung der Klassifikation CMML‑0, CMML‑I und CMML-II erfolgt in Abhangigkeit vom medullaren und peripheren Blastengehalt. Je nach Leukozytenwert (

Myelodysplastic syndromes (MDS) are a heterogeneous group of diseases, with a variable probability of transformation into acute leukemia, which is, in the vast majority of cases, of myeloid lineage. Nevertheless, rare cases of acute lymphoblastic leukemia in patients with previously diagnosed MDS have been reported. We describe a series of 3 cases of MDS/CMML marked with evolution to acute lymphoblastic leukemia (ALL) and provide a comprehensive review of the 49 cases documented in the literature so far. These sporadic events have only been published as single-case reports or small series to date. Such atypical cases emphasize the possibility of major phenotypic switches arising at the leukemic stem cell (LSC) and/or early progenitor levels, as a consequence of epigenetic and genomic events driving these changes in the bone marrow niche.

Mucken sind Ubertrager einer Vielzahl humanpathogener Erreger. Stechmucken ubertragen neben Viren aus der Gruppe der Flavi-, Alpha- und Bunyaviren auch Protozoen, parasitische Fadenwurmer (Filarien) sowie seltener Bakterien. Viele der durch Stechmucken ubertragenen Viruserkrankungen verlaufen oligo- oder asymptomatisch. Teilweise sind aber auch ernste Erkrankungsformen moglich. Kausale Therapieansatze sind fur die meisten Viruserkrankungen - im Gegensatz zu Malaria, Leishmaniose und Filariose - nicht verfugbar. In den meisten Fallen konnen schon einfache Prophylaxemasnahmen (Expositionsprophylaxe, Impfungen z.B. gegen Gelbfieber und Japanische Enzephalitis), bei der Malaria auch eine adaquate Chemoprophylaxe, das Erkrankungsrisiko erheblich senken.

Es wird der Fall einer 48-jahrigen Reiseruckkehrerin aus Bangladesch mit uber Monate persistierender Polyarthralgie und -arthritis infolge einer Chikungunya-Virus-Infektion dargestellt. Die Infektion manifestiert sich meist mit hohem Fieber und muskuloskeletalen Beschwerden, welche Monate bis Jahre persistieren konnen. Die Therapie der chronisch entzundlichen Form orientiert sich an den Empfehlungen fur andere chronisch entzundliche Gelenkerkrankungen. Infolge der zunehmenden Verbreitung des Virus und seiner Vektoren sowie der ungebrochenen Reiseaktivitat ist auch in Europa gehauft mit importierten Fallen bzw. einer Etablierung des Erregers zu rechnen.

Aufgrund der ungebrochenen Reisefreudigkeit spielen reisespezifische Erkrankungen in Deutschland weiterhin eine grose Rolle. Oft ist die Leber dabei primar oder sekundar betroffen. Als Ausloser kommen so gut wie alle Erregerklassen und viele toxische Substanzen infrage: Die Hepatitis A gehort zu den wichtigsten vermeidbaren viralen Hepatitiden. Andere Hepatitisviren (HBV/HDV, HCV, HEV) und Erreger viraler und bakterieller Begleithepatitiden (Zytomegalievirus [CMV], Epstein-Barr-Virus [EBV], humanes Immundefizienzvirus [HIV], Flaviviren, Rickettsien, Brucellen, Treponemen, Leptospiren etc.) konnen ebenfalls relevant sein. Insbesondere Leberabszesse durch Entamoeba histolytica und hypervirulente Klebsiellen mussen schnell erkannt werden. Auch parasitare Wurmer konnen unter bestimmten Expositionsbedingungen etliche hepatobiliare Erkrankungen (Helminthosen) verursachen. Dazu gehoren z. B. Leber- und Parchenegel sowie bestimmte Faden- und Bandwurmer. Bei unklaren (Leber‑)Symptomen und passender Reiseanamnese sollten Malaria und die viszerale Form der Leishmaniose bedacht werden. Auch Leberintoxikationen durch Pflanzen‑, Pilz- und Umweltgifte sowie Drogen sind in der Reisemedizin bekannt. Aufgrund potenziell schwerwiegender Komplikationen sollten reisespezifische Lebererkrankungen rechtzeitig erkannt bzw. im Sinne der Primarprophylaxe durch professionelle Reiseberatung verhindert werden.

Angesichts der zunehmenden antimikrobiellen Resistenzentwicklung ist Antibiotic Stewardship (ABS) eine wichtige Masnahme gegen die Ausbreitung resistenter Erreger und die Entstehung von Multiresistenz. Fur Deutschland und Osterreich steht eine 2018 aktualisierte umfangreiche S3-Leitlinie zur Verfugung. Die Steuerung des Antibiotika‑/Antiinfektivaeinsatzes im Krankenhausbereich sollen ABS-Teams begleiten. ABS beinhaltet auf Krankenhausebene die fortlaufende Analyse lokaler Antibiotikaverbrauchs- und Resistenzdaten. Daraus sollen Empfehlungen fur lokal angepasste Therapieschemata abgeleitet werden. In regelmasigen Visiten diskutieren Mitglieder des ABS-Teams am Krankenbett Indikation, Dosierung, Applikationsweg und Dauer einer antimikrobiellen Therapie. Herausfordernd ist der „sparsame“ Umgang mit Antibiotika, ohne den Patienten zu gefahrden. Digitalisierung und kunstliche Intelligenz bieten neue Moglichkeiten fur ABS. Wichtig ist auch die Adaptierung stationarer Konzepte an die ambulante Versorgung.

Antibiotic stewardship (ABS) is an important measure to counteract the spread of resistant pathogens and multidrug resistance. The most important ABS tools include the implementation of local guidelines, the development of a house-related list of anti-infective agents, regular ABS visits and practice-oriented internal training events. Effective strategies for therapy optimization include indication testing and therapy evaluation, dose optimization as well as determining an appropriate duration of therapy. Oralization of anti-infectives (sequence therapy) should be supported by consistent clinical criteria in in-house guidelines. The incidence of Clostridioides difficile infections (CDI) can be more than halved by restricting the so-called "4C antibiotics". Point-of-care tests help to minimize the use of antibiotics in the outpatient setting. Vaccination reduces the need for antibiotic therapy.

Zu den haufigsten Gesundheitsstorungen auf Fernreisen gehort die akute Reisediarrho, die je nach geographischer Region mit einer Pravalenz von >50 % auftreten kann. Dieses uberwiegend bakteriell (v. a. durch enteropathogene Escherichia coli, Campylobacter spp., Shigella, Salmonella) bzw. manchmal viral (durch Noro- oder Rotaviren) oder seltener parasitar (durch Giardien/Lamblien, Entamoben) verursachte Krankheitsbild verlauft in den meisten Fallen unkompliziert und selbstlimitierend. Eine persistierende Diarrho ist jedoch der haufigste Grund fur eine arztliche Vorstellung nach Fernreisen in der Praxis. Fur bestimmte Personengruppen, wie Immunsupprimierte oder Schwangere, ist auch eine scheinbar banale Reisediarrho immer abklarungsbedurftig. Dann ist eine gezielte Stuhldiagnostik gerechtfertigt, ebenso bei Fieber und blutigem Stuhl. Die Therapie ist meistens symptomatisch (Flussigkeits- und Elektrolytersatz); selten sind Antibiotika indiziert. Im Rahmen einer qualifizierten Reiseberatung sollten Praventionsmasnahmen (Destinationswahl, Hygieneverhalten, Impfungen) im Vorfeld besprochen werden.

Zecken sind Ubertrager einer Vielzahl humanpathogener Krankheitserreger mit einer grosen Bandbreite klinischer Symptome. Das Verbreitungsgebiet der einzelnen Erreger ist vom Vorkommen der Vektoren und Wirte abhangig. Aufgrund verschiedener Faktoren ist es in den letzten Jahren zum Teil zu einer Ausdehnung der Endemiegebiete gekommen. Am weitesten verbreitet sind Zecken-ubertragene Rickettsiosen, welche v.a. in der Reisemedizin eine Rolle spielen. Die haufigsten Zecken-ubertragbaren Erkrankungen in Deutschland und Europa sind Lyme-Borreliose und Fruhsommer-Meningoenzephalitis (FSME). Meist verlaufen die Infektionen mild oder sind — im Falle bakterieller Infektionen — gut behandelbar. Die wichtigsten praventiven Masnahmen bei Aufenthalten in einem Risikogebiet sind der Schutz vor Zeckenstichen und im Falle der FSME die sehr gut wirksame Impfung.

An amendment to this paper has been published and can be accessed via the original article.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is potentially curative for acute myeloid leukemia (AML). The inherent graft-versus-leukemia activity (GvL) may be optimized by donor lymphocyte infusions (DLI). Here we present our single-center experience of DLI use patterns and effectiveness, based on 342 consecutive adult patients receiving a first allo-HSCT for AML between 2009 and 2017. The median age at transplantation was 57 years (range 19–79), and the pre-transplant status was active disease in 58% and complete remission (CR) in 42% of cases. In a combined landmark analysis, patients in CR on day +30 and alive on day +100 were included. In this cohort (n=292), 93 patients received cryopreserved aliquots of peripheral blood-derived grafts for DLI (32%) and median survival was 55.7 months (2-year/5-year probability: 62%/49%). Median survival for patients receiving a first dose of DLI “preemptively,” in the absence of relapse and guided by risk marker monitoring (preDLI; n=42), or only after hematological relapse (relDLI; n=51) was 40.9 months (2-year/5-year: 64%/43%) vs 10.4 months (2-year/5-year: 26%/10%), respectively. Survival was inferior when preDLI was initiated at a time of genetic risk marker detection vs mixed chimerism or clinical risk only. Time to first-dose preDLI vs time to first-dose relDLI was similar, suggesting that early warning and intrinsically lower dynamics of AML recurrence may contribute to effectiveness of preDLI-modified GvL activity. Future refinements of the preemptive DLI concept will benefit from collaborative efforts to diagnose measurable residual disease more reliably across the heterogeneous genomic spectrum of AML.