High Efficacy and Safety of Asciminib in a Chronic Myeloid Leukemia Patient with Chronic Kidney Disease Following Renal Transplantation.

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm driven by the BCR::ABL1 tyrosine kinase. Tyrosine kinase inhibitors (TKIs) have been established as standard therapies for CML. However, some CML patients experience TKI intolerance. Asciminib was approved for CML patients either intolerant or refractory to TKI therapy. We herein report a 63-year-old CML patient who underwent renal transplantation and exhibited TKI intolerance. He was switched to asciminib, which achieved a deep molecular response without exacerbation of the renal function. Our experience revealed that asciminib is effective and safe for CML patients complicated with chronic kidney disease.

Impaired Repopulating Ability of Uhrf2-/- Hematopoietic Progenitor Cells in Mice.

UHRF proteins catalyze the ubiquitination of target proteins and are involved in regulating gene expression. Some studies reported a reduced expression of UHRF2 in acute leukemia cells, but the role of UHRF2 in hematopoiesis remains unknown. Here, we generated Uhrf2-/- mice to clarify the role of UHRF2 deletion in hematopoiesis. Compared to Uhrf2+/+ mice, Uhrf2-/- mice showed no differences in complete blood counts, as well as bone marrow (BM) findings and spleen weights. Proportions of cells in progenitor fractions in BM were comparable between Uhrf2+/+ mice and Uhrf2-/- mice. However, in competitive repopulation assays with BM transplants (BMT), the proportions of Uhrf2-/- cells were decreased relative to Uhrf2+/+ cells in all lineages. After the second BMT, Uhrf2-/- neutrophils were few, while 20-30% of Uhrf2-/- T cells and B cells were still detected. RNA sequencing showed downregulation of some genes associated with stem-cell function in Uhrf2-/- hematopoietic stem/progenitor cells (HSPCs). Interestingly, trimethylated histone H3 lysine 9 was increased in Uhrf2-/- HSPCs in a cleavage under targets and tagmentation assay. While UHRF2 deletion did not cause hematologic malignancy or confer a growth advantage of HSPCs, our results suggest that UHRF2 may play a role in the regulation of hematopoiesis.

Successful management of unstable angina in a ravulizumab-treated patient with paroxysmal nocturnal hemoglobinuria.

Ravulizumab is an anti-C5 antibody approved for treating paroxysmal nocturnal hemoglobinuria (PNH). In August 2019, a 77-year-old Japanese man with PNH, who had been on ravulizumab treatment for 2 years, was hospitalized for chest discomfort and malaise. Electrocardiography identified a right bundle block, and elevated serum troponin I and d-dimer suggested ischemic heart disease. Cardiac catheterization revealed severe stenosis in the left anterior descending coronary artery, and intracoronary stenting relieved his chest discomfort. The final diagnosis was unstable angina unrelated to ravulizumab, and the patient's ravulizumab treatment was uninterrupted with no significant complications of PNH. This case report highlights the importance of continuing complement inhibition therapy during acute coronary events.

The suppressive effects of Mer inhibition on inflammatory responses in the pathogenesis of LPS-induced ALI/ARDS.

The pathogenesis of sepsis-induced acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) has not yet been fully elucidated. Growth arrest-specific 6 (Gas6) has marked effects on hemostasis and reduces inflammation through its interaction with receptor tyrosine kinases of the TAM family: Tyro3, Axl, and Mer. Here, we found that plasma concentrations of Gas6 and soluble Mer were greater in patients with severe sepsis or septic ALI/ARDS compared with those in normal healthy donors. To determine whether the Gas6-Mer axis was critical in the pathogenesis of ALI/ARDS, we investigated the effects of intravenous administration of the selective Mer inhibitor UNC2250 on lipopolysaccharide (LPS)-induced ALI in mouse models subjected to inhalation of LPS. UNC2250 markedly inhibited the infiltration into the lungs of neutrophils and monocytes with increased amounts of Gas6 and Mer proteins, severe lung damage, and increased amounts of reactive oxygen species (ROS) in LPS-induced ALI in mice. In human pulmonary aortic endothelial cells, LPS induced decreases in the amounts of endothelial nitric oxide synthase, thrombomodulin, and vascular endothelial-cadherin, which was blocked by treatment with UNC2250. UNC2250 also inhibited the LPS-dependent increases in cell proliferation and enhanced apoptosis in HL-60 cells, a human neutrophil-like cell line, and RAW264.7 cells, a mouse monocyte/macrophage cell line. These data provide insights into the potential multiple beneficial effects of the Mer inhibitor UNC2250 as a therapeutic reagent to treat inflammatory responses in ALI/ARDS.

A Case of Acquired von Willebrand Syndrome Complicated by Acute Myelomonocytic Leukemia.

We here report a 21-year-old male who presented with acute myelomonocytic leukemia (AMML) associated with acquired von Willebrand syndrome (AVWS). To our knowledge, this is the first case of AVWS caused by AMML. In our case, following remission-induction chemotherapy combined with idarubicin and cytarabine, the patient showed remarkable improvement of bleeding symptoms due to AVWS. Moreover, after an allogeneic stem cell transplantation from a sibling donor, both AMML and AVWS maintain complete remission.

[Acute HIV infection pathologically mimicking T-cell lymphoma].

A 49-year-old man was hospitalized with infectious mononucleosis-like symptoms, hepatosplenomegaly, and circulating abnormal lymphocytes. Hepatosplenic T-cell lymphoma was suspected, and bone marrow aspiration and liver biopsy were performed. The pathological diagnosis was T-cell lymphoma. When explaining malignant lymphoma to the patient, he disclosed his Men Who Have Sex with Men (MSM) status. HIV RNA test showed a markedly high viral load, and TCR gene rearrangement was negative. In view of these results, the patient was diagnosed with acute HIV infection. The previous lack of information concerning his MSM status led to a misdiagnosis, highlighting the relevance of this case to raise awareness of the importance of previously interviewing the patient.

[Airway obstruction due to localized tracheal lesion of extranodal NK/T-cell lymphoma, nasal type].

A 76-year-old man presented with a tracheal tumor associated with severe respiratory obstruction. A tracheotomy was performed due to respiratory failure. F-fluorodeoxyglucose (FDG) -positron emission tomography/computed tomography revealed an abnormal accumulation of FDG (maximum standardized uptake value: 16) in the trachea. A histopathological examination of the tracheal biopsy revealed extranodal NK/T-cell lymphoma, nasal type (ENKL). He was treated with concurrent radiotherapy (50 Gy) for the tracheal tumor and three courses of two-thirds dose ofdexamethasone, etoposide, ifosfamide, and carboplatin. Although the tumor responded remarkably well to this therapy, the patient died of an ENKL recurrence in the lungs and liver 11 months post therapy.

Lenalidomide as a Beneficial Treatment Option for Renal Impairment Caused by Light Chain Deposition Disease.

Light chain deposition disease (LCDD) is a rare systemic disorder caused by the deposition of light chain immunoglobulins, which often results in renal impairment associated with either nephrotic syndrome or asymptomatic proteinuria. B-cell neoplasms, such as multiple myeloma and lymphoproliferative disorders, are well-known underlying diseases in LCDD. Some chemotherapy regimens have been reported, but both evidence-based treatment and management for LCDD have yet to be established. We herein report three cases of LCDD treated with lenalidomide-based therapy, resulting in hematologic responses accompanied by a significant reduction in proteinuria and improvement in the renal function. We recommend lenalidomide-based therapy for renal impairment caused by LCDD.

The Amelioration of Myelofibrosis with Thrombocytopenia by a JAK1/2 Inhibitor, Ruxolitinib, in a Post-polycythemia Vera Myelofibrosis Patient with a JAK2 Exon 12 Mutation.

Less than 5% of patients with polycythemia vera (PV) show JAK2 exon 12 mutations. Although PV patients with JAK2 exon 12 mutations are known to develop post-PV myelofibrosis (MF) as well as PV with JAK2V617F, the role of JAK inhibitors in post-PV MF patients with JAK2 exon 12 mutations remains unknown. We describe how treatment with a JAK1/2 inhibitor, ruxolitinib, led to the rapid amelioration of marrow fibrosis, erythrocytosis and thrombocytopenia in a 77-year-old man with post-PV MF who carried a JAK2 exon 12 mutation (JAK2H538QK539L). This case suggests that ruxolitinib is a treatment option for post-PV MF in patients with thrombocytopenia or JAK2 exon 12 mutations.

Steroid-resistant autoimmune myelofibrosis in a patient with autoimmune hepatitis and Evans syndrome complicated with increased expression of TGF-ß in the bone marrow: a case report.

We here report a 47-year-old female with autoimmune myelofibrosis (AIMF) associated with liver damage caused by autoimmune hepatitis and Evans syndrome. Bone marrow biopsy revealed hypocellular marrow with grade 2 reticulin fibrosis and increased levels of B lymphocytes (CD20+), T lymphocytes (CD3+, CD8+), and plasma cells (CD138+). Immunohistochemical analysis revealed increased expression of transforming growth factor-ß (TGF-ß) in infiltrating lymphocytes and macrophages in the bone marrow. She was initially treated with oral prednisolone (PSL) for 2 months, which had a limited effect. However, after treatment with rituximab, the patient's pancytopenia showed improvement, allowing us to rapidly reduce the PSL dosage. The present case suggests the possibility that increased expression of TGF-ß in infiltrating lymphocytes and macrophages of bone marrow may contribute to the pathogenesis of AIMF. Prednisolone combined with rituximab may thus be an effective option for steroid-refractory cases.

Hmga2 collaborates with JAK2V617F in the development of myeloproliferative neoplasms.

High-mobility group AT-hook 2 (HMGA2) is crucial for the self-renewal of fetal hematopoietic stem cells (HSCs) but is downregulated in adult HSCs via repression by MIRlet-7 and the polycomb-recessive complex 2 (PRC2) including EZH2. The HMGA2 messenger RNA (mRNA) level is often elevated in patients with myelofibrosis that exhibits an advanced myeloproliferative neoplasm (MPN) subtype, and deletion of Ezh2 promotes the progression of severe myelofibrosis in JAK2V617F mice with upregulation of several oncogenes such as Hmga2. However, the direct role of HMGA2 in the pathogenesis of MPNs remains unknown. To clarify the impact of HMGA2 on MPNs carrying the driver mutation, we generated ΔHmga2/JAK2V617F mice overexpressing Hmga2 due to deletion of the 3' untranslated region. Compared with JAK2V617F mice, ΔHmga2/JAK2V617F mice exhibited more severe leukocytosis, anemia and splenomegaly, and shortened survival, whereas severity of myelofibrosis was comparable. ΔHmga2/JAK2V617F cells showed a greater repopulating ability that reproduced the severe MPN compared with JAK2V617F cells in serial bone marrow transplants, indicating that Hmga2 promotes MPN progression at the HSC level. Hmga2 also enhanced apoptosis of JAK2V617F erythroblasts that may worsen anemia. Relative to JAK2V617F hematopoietic stem and progenitor cells (HSPCs), over 30% of genes upregulated in ΔHmga2/JAK2V617F HSPCs overlapped with those derepressed by Ezh2 loss in JAK2V617F/Ezh2Δ/Δ HSPCs, suggesting that Hmga2 may facilitate upregulation of Ezh2 targets. Correspondingly, deletion of Hmga2 ameliorated anemia and splenomegaly in JAK2V617F/Ezh2Δ/wild-type mice, and MIRlet-7 suppression and PRC2 mutations correlated with the elevated HMGA2 mRNA levels in patients with MPNs, especially myelofibrosis. These findings suggest the crucial role of HMGA2 in MPN progression.

Favorable outcome of Epstein-Barr virus-associated B-cell lymphoproliferative disorder complicated by immunoglobulin G4-related disease treated with rituximab-based therapy: a case report.

BACKGROUND: After acute infection of Epstein-Barr virus, Epstein-Barr virus-infected B cells survive but usually do not show clonal proliferation. However, Epstein-Barr virus-infected B cells occasionally acquire a proliferative capacity that provokes clonal lymphoproliferative disorders. We herein present a case with Epstein-Barr virus-infected CD30+ B cell and immunoglobulin G4+ plasmacytoid cell proliferation in the lymph nodes, suggesting a pathological and clinical interaction between Epstein-Barr virus-associated B-cell lymphoproliferative disorders and immunoglobulin G4-related disease. Immunoglobulin G4-related disease has been recognized as a benign disease with proliferation of IgG4-related disease+ plasmacytoid cells. Several studies have recently reported the coexistence of immunoglobulin G4-related disease+ plasmacytoid cells with Epstein-Barr virus-infected B cells in lymph nodes in some immunoglobulin G4-related disease cases. However, the pathogenic role of the clonal proliferation of Epstein-Barr virus-infected B cells in immunoglobulin G4-related disease, as well as the treatments for patients with both Epstein-Barr virus-infected B cells and immunoglobulin G4-related disease, have never been discussed. CASE PRESENTATION: A 50-year-old Japanese man was referred to us for persistent fatigue and lymphadenopathy. His blood examination showed elevated IgG4, and detected high levels of Epstein-Barr virus DNA. A lymph node biopsy revealed IgG4+ plasmacytoid cells and infiltration of large lymphoid cells, which were positive for CD20, CD30, Epstein-Barr virus-related late membrane protein 1, and Epstein-Barr virus-encoded RNA, and were negative for IgG4. Based on the diagnosis of both Epstein-Barr virus-associated B-cell lymphoproliferative disorder and IgG4-related disease, the patient received eight cycles of rituximab combined with cyclophosphamide and prednisolone, which resulted in the complete disappearance of lymphadenopathy. Moreover, his serum IgG4 level was significantly reduced, and plasma Epstein-Barr virus DNA became undetectable. Although prednisolone was transiently administered in each cycle of immunochemotherapy, the therapeutic effect has persisted for Epstein-Barr virus-associated B-cell lymphoproliferative disorder and IgG4-related disease as of 1 year after finishing treatment. CONCLUSIONS: In the present case, clinical presentation and pathological findings revealed that Epstein-Barr virus-associated B-cell lymphoproliferative disorder coexisted with IgG4-related disease. Although several studies have described the relationship between Epstein-Barr virus-infected B cells and IgG4-related disease, this is the first report of a patient whose plasma Epstein-Barr virus DNA level, which correlated with the disease statuses of both diseases, was monitored. Moreover, rituximab-based immunochemotherapy was highly effective for both diseases. Our findings are suggestive for establishing a novel treatment strategy for IgG4-related disorders associated with chronic Epstein-Barr virus infection.

Gene expression and localization of two types of AQP5 in Xenopus tropicalis under hydration and dehydration.

Two types of aquaporin 5 (AQP5) genes (aqp-xt5a and aqp-xt5b) were identified in the genome of Xenopus tropicalis by synteny comparison and molecular phylogenetic analysis. When the frogs were in water, AQP-xt5a mRNA was expressed in the skin and urinary bladder. The expression of AQP-xt5a mRNA was significantly increased in dehydrated frogs. AQP-xt5b mRNA was also detected in the skin and increased in response to dehydration. Additionally, AQP-xt5b mRNA began to be slightly expressed in the lung and stomach after dehydration. For the pelvic skin of hydrated frogs, immunofluorescence staining localized AQP-xt5a and AQP-xt5b to the cytoplasm of secretory cells of the granular glands and the apical plasma membrane of secretory cells of the small granular glands, respectively. After dehydration, the locations of both AQPs in their respective glands did not change, but AQP-xt5a was visualized in the cytoplasm of secretory cells of the small granular glands. For the urinary bladder, AQP-xt5a was observed in the apical plasma membrane and cytoplasm of a number of granular cells under normal hydration. After dehydration, AQP-xt5a was found in the apical membrane and cytoplasm of most granular cells. Injection of vasotocin into hydrated frogs did not induce these changes in the localization of AQP-xt5a in the small granular glands and urinary bladder, however. The results suggest that AQP-xt5a might be involved in water reabsorption from the urinary bladder during dehydration, whereas AQP-xt5b might play a role in water secretion from the small granular gland.

[Establishment of a cut-off value for the diagnosis of acute myocardial infarction using a new CK-MB activity measurement reagent containing anti-MtCK antibody].

CK-MB is an important marker for the diagnosis of acute myocardial infarction (AMI). Since mitochondrial CK (MtCK) is universally present in the blood of healthy individuals, it is known to positively affect the measurement of CK-MB using the immunoinhibition method, causing false-positive results. We performed basic evaluation of ACCURAS AUTO CK-MB MtO, a new reagent containing anti-MtCK antibody that inhibits MtCK activity, and attempted to calculate a cut-off CK-MB level to diagnose AMI. The measurement was performed in samples submitted to the Clinical Laboratory of our center for the measurement of CK-MB. This method was confirmed to have satisfactory basic attributes concerning the reproducibility, linearity, lower detection limit, and effects of interfering substances. When 2886 samples were examined using this and conventional methods, the results of the two methods were correlated in some but not in others. In the samples that showed no correlation, MtCK was demonstrated by isozyme analysis using electrophoresis. The AUC calculated from the ROC curve in AMI patients was 0.912 with this method and 0.861 with the conventional method. The sensitivity and specificity of the new method were higher than those of the conventional method. The cut-off value determined by ROC analysis was 7.7 U/l using the new method and 13.6 U/l using the conventional method, causing an increase in false-positive results compared with the cut off value of 25 U/l widely used for the conventional method to date. However, the cut-off value for the new method that yielded a specificity comparable to 99.1%, which is the specificity of the conventional method using a cut-off value of 25 U/l, was 12 U/l. With a cut-off value of 12 U/l, the sensitivity was improved compared with that employing the conventional method, and both the sensitivity and specificity became comparable to those of the CK-MB mass method. This method is very useful for the accurate measurement of CK-MB activity.

[A case of recurrent small cell lung cancer with symptoms improved by nogitecan hydrochloride].

A 68-year-old woman with recurrent advanced small cell lung cancer (SCLC), previously treated with 7 courses of carboplatin + etoposide, 4 courses of cisplatin + irinotecan and radiotherapy (primary site and whole brain irradiation), received 3 courses of a single nogitecan hydrochloride i.v. bolus with 4 consecutive days of administration, for a total dose of 7.5 mg. MR-imaging revealed a response in the brain metastasis, and tumor markers (NSE and ProGRP) were improved after the first course. Headache, her main complaint, was also alleviated. These observations suggest that nogitecan hydrochloride alone might be useful for treatment of recurrent SCLC in cases of poor performance status (PS), especially when the patient requires remission of symptoms.

Effect of vinorelbine monotherapy in taxane-treated patients with advanced non-small-cell lung cancer.

Taxane-based chemotherapy now plays an important role in the first-line treatment on patients with advanced non-small-cell lung cancer (NSCLC). Recent attention has been focused on the treatment of patients with NSCLC who failed to respond to taxane-based chemotherapy. In the present article, we report the effect of single-agent vinorelbine (VNR) in 10 patients with NSCLC previously treated with taxanes. An antitumor effect was observed in five patients, resulting in a response rate of 50.0% (5/10). The absence of vinca alkaloid pretreatment was an important factor in the clinical response in these patients. Further study is warranted to investigate the clinical efficacy of VNR monotherapy in taxane-resistant NSCLC patients.