Acute graft-versus-host disease (aGVHD) is a serious complication after stem cell transplantation and is associated with high non-relapse mortality. If steroid treatment as first-line therapeutic ...approach fails, treatment options are limited. In retrospective studies, ruxolitinib, a selective Janus kinase 1/2 inhibitor as well as extracorporeal photopheresis (ECP) could show high efficacy in treatment of steroid refractory acute and chronic GVHD. Here, we report single-center experience of combining JAK-inhibitor treatment with ECP in 18 patients with severe steroid refractory aGVHD of lower GI-tract. The treatment was well tolerated and no severe cytopenia (grade IV) occurred, in three patients grade III cytopenia could be observed. Response was complete or partial in 44% and 11%, respectively, resulting in an estimated 2 year overall survival of 56%. Steroids were tapered rapidly with a median time of 2 days for halving of dosage avoiding additional steroid-associated side effects. Under treatment with ruxolitinib and ECP, an increased level of regulatory T cells could be observed elucidating direct effects of this treatment on immune response.
The majority of publications regarding SARS-CoV-2 infections in adult patients with acute leukemia (AL) refer to hematological patients in general and are not focused on acute myeloid leukemia (AML) ...or acute lymphoblastic leukemia (ALL). We herein report a review of the current literature on adult AL patients infected with SARS-CoV-2. Overall, SARS-CoV-2-associated mortality ranges from 20–52% in patients with adult AL. AML patients have a particularly high COVID-19-related mortality. Of note, most of the available data relate to the pre-vaccination era and to variants before Omicron. The impact of COVID-19 infections on AL treatment is rarely reported. Based on the few studies available, treatment delay does not appear to be associated with an increased risk of relapse, whereas therapy discontinuation was associated with worse outcomes in AML patients. Therefore, the current recommendations suggest delaying systemic AL treatment in SARS-CoV-2-positive patients until SARS-CoV-2 negativity, if immediate AL treatment is not required. It is recommended to offer vaccination to all AL patients; the reported antibody responses are around 80–96%. Seronegative patients should additionally receive prophylactic administration of anti-SARS-CoV-2 monoclonal antibodies. Patients with AL infected with SARS-CoV-2 should be treated early with antiviral therapy to prevent disease progression and enable the rapid elimination of the virus.
Modern cancer therapies increased the survival rates of acute myeloid leukemia (AML) patients tremendously. However, the complexity of the disease and the identification of new targets require the ...adaptation of treatment protocols to reduce side effects and increase benefit for the patients. One key regulator of leukemogenesis and chemotherapy resistance in AML is the Hedgehog (HH) signaling pathway. It is deregulated in numerous cancer entities and inhibition of its downstream transcription factors GLI translates into anti-leukemic effects. One major regulator of GLI is BRD4, a BET family member with epigenetic functions. We investigated the effect of ZEN-3365, a novel BRD4 inhibitor, on AML cells in regard to the HH pathway. We show that ZEN-3365 alone or in combination with GANT-61 reduced GLI promoter activity, cell proliferation and colony formation in AML cell lines and primary cells. Our findings strongly support the evaluation of the BRD4 inhibitor ZEN-3365 as a new therapeutic option in AML.
Hepatitis E virus is increasingly being reported to cause chronic infection in immunocompromised patients. However, less is known about patients with an underlying hematologic disease. In particular, ...the impact of hepatitis E infection on oncological therapy has been poorly described. In this retrospective single-center study, we analyzed 35 hematologic patients with hepatitis E, including 20 patients under active oncological treatment and 15 patients who were in the posttreatment follow-up or under active surveillance. The primary aim was to describe the clinical courses with particular focus on any hepatitis E-related therapy modifications of cancer-directed therapy. In the majority (60%) of patients who were under active oncological treatment, hepatitis E-related therapy modifications were made, and 25% of deaths were due to progression of the hematologic disease. In patients receiving concomitant oncological treatment, no hepatitis Erelated deaths occurred. In contrast, two patients in the follow-up group died from hepatitis E-associated acute-onchronic liver failure. Chronic hepatitis E was observed in 34% of all cases and 43% received ribavirin therapy; of those, 27% achieved a sustained virological response. CD20-directed therapy was the only independent risk factor for developing chronic hepatitis E. We conclude that CD20-directed treatment at any time point is a risk factor for developing chronic hepatitis E. Nevertheless, since mortality from the progression of hematologic disease was higher than hepatitis E-related mortality, we suggest careful case-by-case decisions on modifications of cancer treatment. Patients in the posttreatment follow-up phase may also suffer from severe courses and hepatitis E chronicity occurs as frequently as in patients undergoing active therapy.
The prognosis of elderly AML patients is still poor due to chemotherapy resistance. The Hedgehog (HH) pathway is important for leukemic transformation because of aberrant activation of GLI ...transcription factors. MBZ is a well-tolerated anthelmintic that exhibits strong antitumor effects. Herein, we show that MBZ induced strong, dose-dependent anti-leukemic effects on AML cells, including the sensitization of AML cells to chemotherapy with cytarabine. MBZ strongly reduced intracellular protein levels of GLI1/GLI2 transcription factors. Consequently, MBZ reduced the GLI promoter activity as observed in luciferase-based reporter assays in AML cell lines. Further analysis revealed that MBZ mediates its anti-leukemic effects by promoting the proteasomal degradation of GLI transcription factors via inhibition of HSP70/90 chaperone activity. Extensive molecular dynamics simulations were performed on the MBZ-HSP90 complex, showing a stable binding interaction at the ATP binding site. Importantly, two patients with refractory AML were treated with MBZ in an off-label setting and MBZ effectively reduced the GLI signaling activity in a modified plasma inhibitory assay, resulting in a decrease in peripheral blood blast counts in one patient. Our data prove that MBZ is an effective GLI inhibitor that should be evaluated in combination to conventional chemotherapy in the clinical setting.
Abstract
Pediatric high-grade gliomas of the subclass MYCN (HGG-MYCN) are highly aggressive tumors frequently carrying
MYCN
amplifications,
TP53
mutations, or both alterations. Due to their rarity, ...such tumors have only recently been identified as a distinct entity, and biological as well as clinical characteristics have not been addressed specifically. To gain insights into tumorigenesis and molecular profiles of these tumors, and to ultimately suggest alternative treatment options, we generated a genetically engineered mouse model by breeding
hGFAP-cre::Trp53
Fl/Fl
::lsl-MYCN
mice. All mice developed aggressive forebrain tumors early in their lifetime that mimic human HGG-MYCN regarding histology, DNA methylation, and gene expression. Single-cell RNA sequencing revealed a high intratumoral heterogeneity with neuronal and oligodendroglial lineage signatures. High-throughput drug screening using both mouse and human tumor cells finally indicated high efficacy of Doxorubicin, Irinotecan, and Etoposide as possible therapy options that children with HGG-MYCN might benefit from.
The zinc-finger transcription factor GLI2 is frequently amplified in childhood medulloblastoma of the Sonic-hedgehog type (SHH-MB), with or without amplification of NMYC or deletion of TP53. Despite ...the aggressive tumor behavior, tumorigenesis is not well understood, and adequate mouse models are lacking. Therefore, we generated mice with a GLI2 overexpression under control of the hGFAP-promoter. These mice died within 150 days. The majority only survived until postnatal day 40. They displayed severe cerebellar hypoplasia, cortical malformations, but no brain tumors, except for one out of 23 animals with an undifferentiated hindbrain lesion. Additional loss of p53 did not result in cerebellar tumors, but partially rescued the cerebellar phenotype induced by GLI2 overexpression. Similarly, the combination of GLI2 and NMYC was neither sufficient for the development of SHH-MB. We therefore assume that the development of childhood SHH-MB in mice is either occurring in cellular origins outside the hGFAP-positive lineage or needs additional genetic drivers.
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•Childhood SHH-medulloblastoma shows amplification of Gli2 and/or NMYC or deletion of TP53•Mice with Gli2 overexpression show cerebellar malformations or rare brain tumors•Further p53Fl/Fl loss or NMYCFl/Fl expression affects cerebellar development and survival•Additional alterations did not lead to MB
Biological sciences; Molecular biology; Cancer
Despite therapeutic advances in the prevention and treatment of febrile neutropenia, acute leukemia (AL) patients still have considerable febrile neutropenia-related mortality. However, the ...diagnostic yield of flexible bronchoscopy (FB) and bronchoalveolar lavage (BAL) in acute leukemia patients is unclear. In this retrospective single-center study, we analyzed 88 BAL samples of patients with acute leukemia and pulmonary infiltrates in spite of treatment with broad-spectrum anti-infective agents. The aim was to investigate the impact of FB with BAL on detecting causative organisms, which would result in a change in treatment regimens. The median age was 59 years, and 86% had acute myeloid leukemia. In 47%, pathogens were detectable in BAL fluid (pathogen bacteria, viruses, and fungi in 2, 15, and 18%, respectively), with
detected most frequently. BAL-guided anti-infective therapy changes were performed in 15%. The detection of herpes simplex and influenza viruses were the main reasons for treatment changes. Despite broad-spectrum anti-infective treatment, in approximately half of all patients, pathogens could still be isolated in BAL samples. However, consecutive changes in anti-infective treatment were considerably less frequent, with most changes performed in patients with
and
detection. The need for FB with BAL in patients with AL receiving broad-spectrum empiric anti-infective treatment should therefore be weighed carefully.
Hematologic patients requiring abdominal emergency surgery are considered to be a high-risk population based on disease- and treatment-related immunosuppression. However, the optimal surgical therapy ...and perioperative management of patients with abdominal emergency surgery in patients with coexisting hematological malignancies remain unclear.
We here report a single-center retrospective analysis aimed to investigate the impact of abdominal emergency surgery due to clinically suspected gastrointestinal perforation (group A), intestinal obstruction (group B), or acute cholecystitis (group C) on mortality and morbidity of patients with coexisting hematological malignancies. All patients included in this retrospective single-center study were identified by screening for the ICD 10 diagnostic codes for gastrointestinal perforation, intestinal obstruction, and ischemia and acute cholecystitis. In addition, a keyword search was performed in the database of all pathology reports in the given time frame.
A total of 56 patients were included in this study. Gastrointestinal perforation and intestinal obstruction occurred in 26 and 13 patients, respectively. Of those, 21 patients received a primary gastrointestinal anastomosis, and anastomotic leakage (AL) occurred in 33.3% and resulted in an AL-related 30-day mortality rate of 80%. The only factor associated with higher rates of AL was sepsis before surgery. In patients with suspected acute cholecystitis, postoperative bleeding events requiring abdominal packing occurred in three patients and lead to overall perioperative morbidity of 17.6% and surgery-related 30-day mortality of 5.9%.
In patients with known or suspected hematologic malignancies who require emergency abdominal surgery due to gastrointestinal perforation or intestinal obstruction, a temporary or permanent stoma might be preferred to a primary intestinal anastomosis.
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