Pla2g5 contributes to viral-like-induced lung inflammation through macrophage proliferation and LA/Ffar1 lung cell recruitment.

Macrophages expressing group V phospholipase A2 (Pla2g5) release the free fatty acid (FFA) linoleic acid (LA), potentiating lung type 2 inflammation. Although Pla2g5 and LA increase in viral infections, their role remains obscure. We generated Pla2g5flox/flox mice, deleted Pla2g5 by using the Cx3cr1cre transgene, and activated bone marrow-derived macrophages (BM-Macs) with poly:IC, a synthetic double-stranded RNA that triggers a viral-like immune response, known Pla2g5-dependent stimuli (IL-4, LPS + IFNγ, IL-33 + IL-4 + GM-CSF) and poly:IC + LA followed by lipidomic and transcriptomic analysis. Poly:IC-activated Pla2g5flox/flox;Cx3cr1cre/+ BM-Macs had downregulation of major bioactive lipids and critical enzymes producing those bioactive lipids. In addition, AKT phosphorylation was lower in poly:IC-stimulated Pla2g5flox/flox;Cx3cr1cre/+ BM-Macs, which was not restored by adding LA to poly:IC-stimulated BM-Macs. Consistently, Pla2g5flox/flox;Cx3cr1cre/+ mice had diminished poly:IC-induced lung inflammation, including inflammatory macrophage proliferation, while challenging Pla2g5flox/flox;Cx3cr1cre/+ mice with poly:IC + LA partially restored lung inflammation and inflammatory macrophage proliferation. Finally, mice lacking FFA receptor-1 (Ffar1)-null mice had reduced poly:IC-induced lung cell recruitment and tissue macrophage proliferation, not corrected by LA. Thus, Pla2g5 contributes to poly:IC-induced lung inflammation by regulating inflammatory macrophage proliferation and LA/Ffar1-mediated lung cell recruitment and tissue macrophage proliferation.

Prophylactic recombinant thrombomodulin treatment prevents hepatic sinusoidal obstruction syndrome in high-risk pediatric patients that undergo hematopoietic stem cell transplants.

Hepatic SOS is a potentially life-threatening complication of conditioning for allogeneic HSCT. rTM is a new drug for treating DIC. We report our experience of the use of rTM as a prophylaxis against SOS in high-risk pediatric patients that underwent HSCT. We evaluated the cases of 19 pediatric hematology and oncology patients who underwent HSCT at our institution between 2007 and 2016. The patients who received HSCT after 2012 (n = 8) were treated with rTM as a prophylaxis against SOS together with UDCA and LMWH, whereas the others (n = 11) were only treated with UDCA and LMWH. Although SOS occurred by post-HSCT day 35 in 3 (27%) patients in the control group, SOS was not seen in the rTM group. Two of the former three patients suffered severe SOS, and one died of the condition. The mean peak level of PAI-1 (a marker of endothelial damage) was significantly lower in the rTM group. rTM appears to be a safe prophylaxis for SOS. The present findings suggest that prophylactic rTM after HSCT might help to prevent SOS.

[Initial presentation of lymphoblastic crisis in a pediatric chronic myelogenous leukemia patient].

A 9-year-old girl was referred to our hospital because of facial palsy. Both physical and blood examination revealed hepatosplenomegaly and leukocytosis, respectively. A bone marrow examination demonstrated marked hypercellularity involving myeloblasts and lymphoblasts. Based on these results, we suspected mixed phenotype acute leukemia. However, her leukemic blasts expressed B-cell antigens, and a chromosomal analysis of her bone marrow cells revealed the following karyotype: 46, XX, t (9;22) (q34;q11.2). All her neutrophils were positive for the breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 fusion protein. Based on these findings, she was diagnosed with a lymphoblastic crisis of chronic myelogenous leukemia (CML). Combined chemotherapy, involving imatinib, resulted in complete molecular remission. She received cord blood transplant (CBT) during the first complete remission; she is alive and has not suffered a relapse since two years after the CBT. The sudden onset of a blastic crisis in pediatric CML is rare, and it may be difficult to distinguish such cases from de novo Ph-positive leukemia. For diagnostic purposes, it is essential to consider a patient's clinical course and blood test results.

Invasive Pulmonary Aspergillosis Successfully Treated with Granulocyte Transfusions Followed by Hematopoietic Stem Cell Transplantation in a Patient with Severe Childhood Aplastic Anemia.

Granulocyte transfusions (GTX) have been used in patients with neutropenia or neutropenia associated with invasive fungal infection. An 11-year-old girl with severe aplastic anemia (SAA) received immunosuppressive therapy (IST) with rabbit antithymocyte globulin, cyclosporine, and granulocyte colony-stimulating factor. However, IST was not effective and her condition became complicated with life-threatening invasive pulmonary aspergillosis. Owing to the necessity for early neutrophil recovery to resolve the infection, GTX were performed, followed by bone marrow transplantation (BMT) from her mother with human leukocyte antigen-B locus mismatch. Her dyspnea improved and she eventually became afebrile after the initiation of GTX. Despite engraftment failure following BMT, successful engraftment was achieved by salvage therapy with peripheral blood stem cell transplantation. Chest computed tomography scan obtained 4 months after BMT revealed marked improvement in pneumonia. The current case illustrates that GTX may be useful in controlling invasive fungal infections before hematopoietic stem cell transplantation in patients with SAA.

Summer Hospitalization and Bronchial Asthma Make Treatment of Respiratory Syncytial Virus Infection Difficult: A Retrospective Study in Japan.

In recent years, epidemics of respiratory syncytial virus (RSV) have been seen in the summer in Japan. Patients hospitalized in the summer used a high-flow oxygen administration device more frequently than patients hospitalized in the winter. This study was a retrospective study to examine the variables associated with duration of oxygen therapy and severe cases. Subjects were pediatric patients diagnosed with RSV infection and hospitalized for treatment during the 5 years from April 2014 to March 2019. Data from 292 patients were analyzed. Duration of oxygen therapy was significantly associated with bronchial asthma (partial regression coefficient: 0.897, P = .004). Hospitalization in summer was significantly associated with severe condition (adjusted odds ratio: 4.07, 95% confidence interval: 1.16-14.27). The present study showed that bronchial asthma is a risk factor for prolonged oxygen therapy and infection in summer is a risk factor for progression to severe condition in cases of RSV infection.

Successful combination chemotherapy involving clofarabine, cyclophosphamide, and etoposide for pediatric relapsed acute myeloid leukemia: A case report.

Limited salvage chemotherapies are available for relapsed/refractory acute myeloid leukemia. Herein, we described successful reinduction chemotherapy, involving a combination of clofarabine, cyclophosphamide, and etoposide, in a 12-year-old male with relapsed acute myeloid leukemia prior to allogeneic bone marrow transplantation from his father. Although treatment with a combination of fludarabine, cytarabine, granulocyte colony-stimulating factor, idarubicin, and gemtuzumab ozogamicin had no positive effects, the aforementioned clofarabine-based chemotherapy induced complete remission and allowed the transplantation to go ahead. The abovementioned regimen may be useful for induction chemotherapy prior to hematopoietic stem cell transplantation for refractory/relapsed acute myeloid leukemia.

Anticoagulation treatment and prophylactic edoxaban for cerebral sinus venous thrombosis in an adolescent with acute lymphoblastic leukemia.

Pediatric acute lymphoblastic leukemia regimens include large L-asparaginase dosages and steroids, which are associated with an increased risk of venous thromboemboli in adolescents and young adults. Herein, we report the case of an 18-year-old male with acute lymphoblastic leukemia, who was treated with the pediatric regimen, in which edoxaban was employed as a prophylaxis against cerebral sinus venous thrombosis. The event happened on day 20 of induction therapy, when brain magnetic resonance imaging demonstrated a cerebral sinus venous thrombosis in the superior sagittal sinus. Anticoagulation therapy was initiated, and the patient's symptoms disappeared 3 days later. The induction therapy was restarted after an interruption of 16 days, and the consolidation therapies, which included L-asparaginase and steroids, were completed. Edoxaban was administered as a prophylaxis during the consolidation therapy. There were no further adverse events. Edoxaban could be an effective prophylaxis for coagulation complications in adolescents and young adults with acute lymphoblastic leukemia.

Lipid Profile of Activated Macrophages and Contribution of Group V Phospholipase A2.

Macrophages activated by Interleukin (IL)-4 (M2) or LPS+ Interferon (IFN)γ (M1) perform specific functions respectively in type 2 inflammation and killing of pathogens. Group V phospholipase A2 (Pla2g5) is required for the development and functions of IL-4-activated macrophages and phagocytosis of pathogens. Pla2g5-generated bioactive lipids, including lysophospholipids (LysoPLs), fatty acids (FAs), and eicosanoids, have a role in many diseases. However, little is known about their production by differentially activated macrophages. We performed an unbiased mass-spectrometry analysis of phospholipids (PLs), LysoPLs, FAs, and eicosanoids produced by Wild Type (WT) and Pla2g5-null IL-4-activated bone marrow-derived macrophages (IL-4)BM-Macs (M2) and (LPS+IFNγ)BM-Macs (M1). Phosphatidylcholine (PC) was preferentially metabolized in (LPS+IFNγ)BM-Macs and Phosphatidylethanolamine (PE) in (IL-4)BM-Macs, with Pla2g5 contributing mostly to metabolization of selected PE molecules. While Pla2g5 produced palmitic acid (PA) in (LPS+IFNγ)BM-Macs, the absence of Pla2g5 increased myristic acid (MA) in (IL-4)BM-Macs. Among eicosanoids, Prostaglandin E2 (PGE2) and prostaglandin D2 (PGD2) were significantly reduced in (IL-4)BM-Macs and (LPS+IFNγ)BM-Macs lacking Pla2g5. Instead, the IL-4-induced increase in 20-carboxy arachidonic acid (20CooH AA) was dependent on Pla2g5, as was the production of 12-hydroxy-heptadecatrienoic acid (12-HHTrE) in (LPS+IFNγ)BM-Macs. Thus, Pla2g5 contributes to PE metabolization, PGE2 and PGD2 production independently of the type of activation, while in (IL-4)BM-Macs, Pla2g5 regulates selective lipid pathways and likely novel functions.

Successful Treatment of Pediatric Refractory/Relapsed AML with KIR-Ligand-Mismatched Cord Blood Transplant after FLAG-IDA Reinduction Therapy with or without the GO Regimen.

Prognosis in pediatric patients with refractory/relapsed acute myeloid leukemia (AML) is grim, and there is no standard treatment for such patients. Combined treatment with intensive chemotherapy and gemtuzumab ozogamicin (GO), a monoclonal anti-CD33 antibody conjugated with calicheamicin, is useful as reinduction therapy in refractory/relapsed AML. Here, we describe three cases of pediatric refractory/relapsed AML that were successfully managed with FLAG-IDA (fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin), with or without GO, as reinduction therapy before a KIR-ligand-mismatched cord blood transplant. This strategy relies on the fact that killer cell immunoglobulin-like receptors (KIR) on cord blood natural killer (NK) cells recognize human leukocyte antigen (HLA) class I alleles, and that donor KIR-ligand incompatibility may be associated with lower incidence of relapse and improved survival in AML, as cells that lack these inhibitory HLA ligands can activate NK cells. All three patients are currently alive and have been disease-free for 24-65 months, although one patient developed severe sinusoidal obstructive syndrome (SOS). Thus, our strategy can result in excellent outcomes in pediatric patients with refractory/relapsed AML.

Gastric antral vascular ectasia in a pediatric patient with neuroblastoma who underwent tandem stem cell transplantation.

Gastric antral vascular ectasia (GAVE) is an angiodysplastic disorder, which causes severe and prolonged gastric bleeding. Although GAVE has been described in adult patients treated with hematopoietic stem cell transplantation (HSCT), a few cases involving pediatric patients have also been reported. A 5-year-old boy with neuroblastoma (NB) developed severe hematemesis after undergoing tandem HSCT, i.e. autologous peripheral blood stem cell transplantation (auto-PBSCT), followed by allogeneic cord blood transplantation (allo-CBT). The patient suffered oral feeding difficulties because of the effects of chemotherapy and an unbalanced diet. Intravenous Busulfan (ivBU) was used as a conditioning regimen for the auto-PBSCT. The diagnosis of GAVE was made based on endoscopy of the upper gastrointestinal tract on day 31 after the allo-CBT. Argon plasma coagulation (APC) was performed twice, and the complete resolution of GAVE was confirmed by an endoscopic re-evaluation, conducted on day 87. GAVE in this case might have been associated with ivBU treatment. Atrophy of the gastric mucosa due to loss of appetite might also have contributed to GAVE. NB was treated using high-doses of alkylating agents, such as BU. Such treatment can cause significant mucositis of the oral cavity as well as vascular lesions and is associated with GAVE. Therefore, GAVE should be considered when gastrointestinal bleeding occurs in NB patients treated with HSCT. APC might be effective against HSCT-GAVE.