Explore the vast range of titles available.

Autologous T cells transduced with CD19-directed chimeric antigen receptors have recently been approved by several regulatory agencies for the treatment of relapsed and refractory leukemia and lymphoma, after demonstrating remarkable remission rate in advanced patients. The most common adverse events reported are cytokine-release syndrome (CRS), neurotoxicity, and hematologic toxicity. Here, we focus on early and late cytopenia occurring after CD19 CAR-T cells in 38 patients treated with CD19 CAR-T cells. Neutropenia, thrombocytopenia, and anemia occur frequently (94, 80, and 51%, respectively) after CAR-T cell infusion, and are associated with a biphasic nature, as in 93% of patients hematologic toxicity occurs after 21 days from cell infusion. Late hematologic toxicity was more common in patients with high grade CRS and in patients treated after a recent stem cell transplantation. Interestingly, since these events occur late after the lymphodepleting chemotherapy and after resolution of CRS, we found perturbations in SDF-1 levels to correlate with events of late neutropenia, likely associated with B-cell recovery.

The primary treatment for fatal pediatric‐type diffuse high‐grade glioma (PED‐DHGG) which harbor the H3K27M or H3G34R/V mutation is radiation, but it provides only short‐term relief. Inhibitors of phosphorylated eIF2α (PeIF2α) phosphatase—namely raphin‐1 and salubrinal—decrease survival of PED‐DHGG cell lines and sensitize them to radiation. However, although both drugs increase PeIF2α, they have different effects on common targets and different targets altogether. Here, we aimed to identify PeIF2α‐phosphatase‐dependent and PeIF2α‐phosphatase‐independent molecular targets. Raphin‐1 but not salubrinal, decreased the level of BiP and CReP and increased that of DR5, in an ISRIB‐independent manner. Raphin‐1 induced similar changes in MEFS51A cells and in irradiated PED‐DHGG, suggesting a PeIF2α‐independent contribution to raphin‐1's radiosensitizing effect. Importantly, while the expression of [S51D] eIF2α decreased the survival of PED‐DHGG and both raphin‐1 and salubrinal decreased the survival of MEFWT cells, only raphin‐1 decreased the survival of mutant MEFS51A cells. Our results suggest that the sensitivity of PED‐DHGG to raphin‐1 is mediated by both PeIF2α‐dependent and PeIF2α‐independent processes. Elucidating these processes could reveal targets for the development of drugs to overcome radiotherapy resistance of PED‐DHGG. Raphin‐1 reduces the survival of PED‐DHGG cells and enhances their radiation sensitivity through both PeIF2α‐dependent and PeIF2α‐independent mechanisms. Raphin‐1 sustains elevated levels of PeIF2α, contributing to its PeIF2α‐dependent effects. Additionally, raphin‐1 interacts with CReP to mediate a separate radiosensitizing pathway that operates independently of PeIF2α. This mechanism involves: Downregulation of BiP, upregulation of DR5 and activation of caspase‐8.

Neural stem cells are currently being investigated as potential therapies for neurodegenerative diseases, stroke, and trauma. However, concerns have been raised over the safety of this experimental therapeutic approach, including, for example, whether there is the potential for tumors to develop from transplanted stem cells. A boy with ataxia telangiectasia (AT) was treated with intracerebellar and intrathecal injection of human fetal neural stem cells. Four years after the first treatment he was diagnosed with a multifocal brain tumor. The biopsied tumor was diagnosed as a glioneuronal neoplasm. We compared the tumor cells and the patient's peripheral blood cells by fluorescent in situ hybridization using X and Y chromosome probes, by PCR for the amelogenin gene X- and Y-specific alleles, by MassArray for the ATM patient specific mutation and for several SNPs, by PCR for polymorphic microsatellites, and by human leukocyte antigen (HLA) typing. Molecular and cytogenetic studies showed that the tumor was of nonhost origin suggesting it was derived from the transplanted neural stem cells. Microsatellite and HLA analysis demonstrated that the tumor is derived from at least two donors. This is the first report of a human brain tumor complicating neural stem cell therapy. The findings here suggest that neuronal stem/progenitor cells may be involved in gliomagenesis and provide the first example of a donor-derived brain tumor. Further work is urgently needed to assess the safety of these therapies.

BackgroundCOVID-19, the novel coronavirus has caused a global pandemic affecting millions of people around the world. Although children, including children with cancer, have been found to be affected less commonly and less severely than adults, indirect effects of the pandemic on the diagnosis and treatment of children with cancer have been less described.MethodsA survey was performed in the four largest tertiary pediatric hematology-oncology medical centers in Israel. Clinical and laboratory data were collected from the medical files of patients diagnosed or treated with cancer during April–October 2020.ResultsSeventeen patients are described, who had a significant delay in diagnosis or treatment of cancer. These represent approximately 10% of all pediatric cancer diagnosed during the study period in these centers. A main cause of delay was fear of exposure to COVID-19 (fears felt by the patient, parent, physician, or decision-makers at the institution; or the implementation of national guidelines). Delays also resulted from co-infection with COVID-19 and the attribution of the oncologic symptoms to the infection. In addition, treatment was delayed of patients already diagnosed with cancer, due to COVID-19 infection detected in the patient, a family member, or a bone marrow donor.ConclusionFear from the COVID-19 pandemic may result in delayed diagnosis and treatment of children with cancer, which may carry a risk to dismal prognosis. It is crucial that pediatricians and patients alike remember that other diseases still prevail and must be thought of and treated in a timely fashion.

Background Pericytic tumors are a group of soft tissue neoplasms characterized by a hemangiopericytoma (HPC)-like pattern. The underlying genetic lesion of pericytic neoplasms is still obscure; however, recent advances in molecular pathology have enabled a mechanistic understanding and accurate diagnosis of these tumors. Nevertheless, a subset of unclassified pericytic tumors continues to present substantial diagnostic challenges, potentially impacting clinical decision-making and therapeutic strategies. Methods Using Ion AmpliSeq Comprehensive Cancer Panel (Thermo Fisher Scientific, Inc.) assay, we searched for HPC-like-associated mutations in a newborn female with a congenital large sublingual unclassified pericytic tumor that recurred after resection and was refractory to chemotherapy treatment. Further analysis of a series of other tumors with distinctive pericytic features was performed via Sanger sequencing and the results were validated via the auto genomics INFINITI ® and Biocartis Assays. Results A BRAF V600D mutation was identified in the tumor tissue of the newborn patient. Treatment with the BRAF inhibitor (BRAFi) dabrafenib resulted in a dramatic response and regression of the tumor. Sequencing of 15 additional HPCs revealed the presence of a BRAF V600E mutation in 6 samples. Conclusions Our findings suggest that BRAFi may be a useful therapy for unclassified pericytic tumors. Genetic testing for BRAFV600 mutations and other actionable oncogenic variants should be part of the evaluation for pericytic neoplasms, especially with the currently available targeted drug therapies.

Seven children in five families were found to have homozygous mutations in a gene associated with vacuolar protein sorting, VPS45, which regulates endosomal membrane trafficking. Five of the seven children have died of overwhelming infection. Rare hematopoietic disorders often reveal basic mechanisms of immune processes. One component of this system, the neutrophil, plays a particularly prominent role in the defense against bacterial and fungal infections. 1 Functional defects in neutrophils can involve impaired granule content (e.g., neutrophil-specific granule deficiency), secretion of inflammatory proteins, impaired cell adherence (e.g., leukocyte adhesion deficiency), cell migration (e.g., as a result of CXCR4 mutations), chemotaxis, endocytosis, and oxygen-dependent killing (e.g., chronic granulomatous disease). 2 Other disorders related to neutrophils are manifested as severe neutropenia, which may result from impaired differentiation, as in mutations in the gene encoding the transcription-repressor protein growth factor . . .

MicroRNAs (miRNAs) are short non-coding regulatory RNAs that control gene expression and play an important role in cancer development and progression. However, little is known about the role of miRNAs in chronic myeloid leukemia (CML). Our objective is to decipher a miRNA expression signature associated with CML and to determine potential target genes and signaling pathways affected by these signature miRNAs. Using miRNA microarrays and miRNA real-time PCR we characterized the miRNAs expression profile of CML cell lines and patients in reference to non-CML cell lines and healthy blood. Of all miRNAs tested, miR-31, miR-155, and miR-564 were down-regulated in CML cells. Down-regulation of these miRNAs was dependent on BCR-ABL activity. We next analyzed predicted targets and affected pathways of the deregulated miRNAs. As expected, in K562 cells, the expression of several of these targets was inverted to that of the miRNA putatively regulating them. Reassuringly, the analysis identified CML as the main disease associated with these miRNAs. MAPK, ErbB, mammalian target of rapamycin (mTOR) and vascular endothelial growth factor (VEGF) were the main molecular pathways related with these expression patterns. Utilizing Venn diagrams we found appreciable overlap between the CML-related miRNAs and the signaling pathways-related miRNAs. The miRNAs identified in this study might offer a pivotal role in CML. Nevertheless, while these data point to a central disease, the precise molecular pathway/s targeted by these miRNAs is variable implying a high level of complexity of miRNA target selection and regulation. These deregulated miRNAs highlight new candidate gene targets allowing for a better understanding of the molecular mechanism underlying the development of CML, and propose possible new avenues for therapeutic treatment.

The clinical yield and benefit of performing bone marrow cultures for various clinical indications has been challenged and their clinical necessity remains debatable. We sought to assess the clinical yield and benefit of performing routine bone marrow cultures and determine whether various clinical, laboratory, and imaging parameters were predictive of a diagnostic bone marrow culture. This was a single center retrospective analysis of all patients who underwent a bone marrow study comprising bone marrow cultures from January 1, 2012, through March 1, 2018. Baseline clinical data were extracted from the institution's electronic medical records system. The analyzed cohort consisted of 139 patients with a median age of 46 years (range 4 months to 85 years). The most common indication for a bone marrow study was workup of a fever of unknown origin (105 patients, 76%) while investigation for infection in immunocompromised patients accounted for 22 cases (16%) and suspected tuberculosis was the reason for acquisition of bone marrow cultures in 6 patients (4%). Only 3 patients had positive bone marrow cultures, yielding in 2 patients a diagnosis of Mycobacterium avium and in one patient a microbiologically unclassifiable fungal infection. A univariate analysis revealed that mean age, hemoglobin level, platelet count, c-reactive protein levels, gender, indication for bone marrow study, yield of blood cultures, and contribution of imaging studies and bone marrow pathology results were not significantly different between patients with diagnostic and non-diagnostic bone marrow cultures. Mean white blood cell count was found to be significantly lower in patients with diagnostic bone marrow cultures (2.4 × 10 3 /µL versus 8.7 × 10 3 /µL; P  = 0.038). We conclude that for most patients, performance of bone marrow cultures holds limited clinical value.

Glioblastomas (GBM), the most common and aggressive type of malignant glioma, are characterized by increased invasion into the surrounding brain tissues. Despite intensive therapeutic strategies, the median survival of GBM patients has remained dismal over the last decades. In this study we examined the expression of miR-145 in glial tumors and its function in glioma cells. Using TCGA analysis and real-time PCR we found that the expression of miR-145/143 cluster was downregulated in astrocytic tumors compared to normal brain specimens and in glioma cells and glioma stem cells (GSCs) compared to normal astrocytes and neural stem cells. Moreover, the low expression of both miR-145 and miR-143 in GBM was correlated with poor patient prognosis. Transfection of glioma cells with miR-145 mimic or transduction with a lentivirus vector expressing pre-miR 145 significantly decreased the migration and invasion of glioma cells. We identified connective tissue growth factor (CTGF) as a novel target of miR-145 in glioma cells; transfection of the cells with this miRNA decreased the expression of CTGF as determined by Western blot analysis and the expression of its 3'-UTR fused to luciferase. Overexpression of a CTGF plasmid lacking the 3'-UTR and administration of recombinant CTGF protein abrogated the inhibitory effect of miR-145 on glioma cell migration. Similarly, we found that silencing of CTGF decreased the migration of glioma cells. CTGF silencing also decreased the expression of SPARC, phospho-FAK and FAK and overexpression of SPARC abrogated the inhibitory effect of CTGF silencing on cell migration. These results demonstrate that miR-145 is downregulated in glial tumors and its low expression in GBM predicts poor patient prognosis. In addition miR-145 regulates glioma cell migration by targeting CTGF which downregulates SPARC expression. Therefore, miR-145 is an attractive therapeutic target for anti-invasive treatment of astrocytic tumors.

We report the results of national retrospective study of 45 children with hemophagocytic lymphohistiocytosis (HLH) who underwent allogeneic hematopoietic stem-cell transplantation (HSCT) in Israel between the years 2000–2018. Donors were either HLA-matched (n = 26), partially mismatched (n = 7), haploidentical (n = 8), or cord-blood (n = 4). Myeloablative conditioning (MAC) was used in 20 procedures, and reduced-intensity conditioning (RIC) in 25. Forty-two patients engrafted, two had primary graft failure (one successfully retransplanted), one died prior to engraftment, and two developed secondary graft failure. Of the eight patients who had mixed donor chimerism at day 30 (5–95%), five achieved stable mixed or full donor chimerism. The 5-year probabilities of overall survival and event-free survival (EFS) were 86% and 82%, respectively. Five-year EFS was lower for patients receiving RIC compared to MAC (72% vs. 100%, p = 0.018) and following alternative-donor transplant (68% vs. 92% for HLA-matched donors, p = 0.034), mostly due to increased transplant-related mortality (TRM). Thus, both HLA-matched and alternative donor transplant procedures may benefit form a myeloablative conditioning regimen.